Vitamin E

WILMINGTON, Del.--(BUSINESS WIRE)--AstraZeneca advances its ambition to eliminate cancer as a cause of death with new data across its diverse, industry-leading portfolio and pipeline at the American Society of Clinical Oncology (ASCO) Annual Meeting, May 30 to June 3, 2025. More than 80 abstracts will feature 20 approved and potential new medicines from the Company including two plenary presentations, one special late-breaking oral abstract session and 19 additional oral presentations. Highlights include: SERENA-6 Phase III trial of camizestrant in combination with widely approved cyclin-dependent kinase (CDK) 4/6 inhibitors in the 1st-line treatment of patients with hormone receptor (HR)-positive, HER2-negative advanced breast cancer whose tumors have an emergent ESR1 mutation (Plenary #LBA4). Camizestrant is an investigational, next-generation oral selective estrogen receptor degrader (SERD) and complete ER antagonist. This is the first positive Phase III trial for a next-generation oral SERD in this 1st-line setting and the first positive Phase III trial for camizestrant. MATTERHORN Phase III trial of perioperative IMFINZI ® (durvalumab) plus FLOT chemotherapy in patients with resectable, early-stage and locally advanced gastric and gastroesophageal junction (GEJ) cancers (Plenary #LBA5). DESTINY-Breast09 Phase III trial of ENHERTU ® (fam-trastuzumab deruxtecan-nxki) in combination with pertuzumab in the 1st-line treatment of patients with HER2-positive metastatic breast cancer (Oral Abstract #LBA1008). DESTINY-Gastric04 Phase III trial of ENHERTU in patients with 2nd-line HER2-positive unresectable and/or metastatic gastric and GEJ cancers (#LBA4002). NeoADAURA Phase III trial of neoadjuvant TAGRISSO ® (osimertinib) with or without chemotherapy in resectable, early-stage EGFR -mutated non-small cell lung cancer (NSCLC) (Oral Abstract #8001). TROPION-Lung02: Computational pathology biomarker analyses of the TROPION-Lung02 Phase Ib trial of DATROWAY ® (datopotamab deruxtecan-dlnk) plus pembrolizumab with or without platinum chemotherapy as 1st-line treatment for patients with advanced NSCLC without actionable genomic alterations (Oral Abstract #8501). KOMET Phase III trial of KOSELUGO ® (selumetinib) in adults with neurofibromatosis type 1 and symptomatic, inoperable plexiform neurofibromas (Rapid Oral Abstract #3014). Susan Galbraith, Executive Vice President, Oncology Haematology R&D, AstraZeneca, said: “Two key breast cancer presentations at ASCO will highlight the progress we are making with our innovative medicines and pipeline to change the treatment landscape. For camizestrant, SERENA-6 is the first pivotal Phase III trial to use circulating tumor DNA to inform a treatment switch, pioneering this technology in the first-line setting to delay disease progression in HR-positive, HER2-negative advanced breast cancer. In addition, DESTINY-Breast09 for ENHERTU in combination with pertuzumab is the first trial in more than a decade to demonstrate superiority over first-line standard of care across a broad HER2-positive metastatic patient population.” Dave Fredrickson, Executive Vice President, Oncology Haematology Business Unit, AstraZeneca, said: “The MATTERHORN data for perioperative IMFINZI in gastric and gastroesophageal junction cancers are a further example of our successful strategy to move immunotherapy into early stages of cancer where cure is the treatment goal. This is the seventh consecutive year AstraZeneca medicines will be featured in an ASCO plenary session, an extraordinary milestone which underscores the strength of our industry-leading oncology portfolio and pipeline across many types of cancer.” AstraZeneca is collaborating with Daiichi Sankyo Company Limited to develop and commercialize ENHERTU and DATROWAY, with Merck & Co., Inc., known as MSD outside the US and Canada, to develop and commercialize KOSELUGO, and with HUTCHMED to develop and commercialize savolitinib. Key AstraZeneca presentations during ASCO 20251 Lead Author Abstract Title Presentation details (CDT) Antibody drug conjugates Shitara, K Trastuzumab deruxtecan (T-DXd) vs ramucirumab (RAM) + paclitaxel (PTX) in second-line treatment of patients (pts) with human epidermal growth factor receptor 2-positive (HER2+) unresectable/metastatic gastric cancer (GC) or gastroesophageal junction adenocarcinoma (GEJA): Primary analysis of the randomized, phase 3 DESTINY-Gastric04 study. Abstract #LBA4002 Oral Abstract Session May 31, 2025 3:24pm Tolaney, SM Trastuzumab deruxtecan (T-DXd) + pertuzumab (P) vs taxane + trastuzumab + pertuzumab (THP) for first-line (1L) treatment of patients (pts) with human epidermal growth factor receptor 2–positive (HER2+) advanced/metastatic breast cancer (a/mBC): Interim results from DESTINY-Breast09. Abstract #LBA1008 Oral Abstract Session June 2, 2025 7:30am Dent, R Exploratory biomarker analysis of trastuzumab deruxtecan (T-DXd) vs physician's choice of chemotherapy (TPC) in HER2-low/-ultralow, hormone receptor-positive (HR+) metastatic breast cancer (mBC) in DESTINY-Breast06 (DB-06). Abstract #1013 Oral Abstract Session May 31, 2025 3:23pm Levy, BP TROPION-Lung02: Datopotamab deruxtecan (Dato-DXd) plus pembrolizumab (pembro) with or without platinum chemotherapy (Pt-CT) as first-line (1L) therapy for advanced non-small cell lung cancer (aNSCLC). Abstract #8501 Oral Abstract Session June 1, 2025 8:12am Waqar, SN First-line (1L) datopotamab deruxtecan (Dato-DXd) + rilvegostomig in advanced or metastatic non-small cell lung cancer (a/mNSCLC): Results from TROPION-Lung04 (cohort 5). Abstract #8521 Poster Session May 31, 2025 1:30pm Tumor drivers and resistance Turner, NC Camizestrant + CDK4/6 inhibitor (CDK4/6i) for the treatment of emergent ESR1 mutations during first-line (1L) endocrine-based therapy (ET) and ahead of disease progression in patients (pts) with HR+/HER2– advanced breast cancer (ABC): Phase 3, double-blind ctDNA-guided SERENA-6 trial. Abstract #LBA4 Plenary Session June 1, 2025 2:41pm Lu, S Savolitinib (Savo) combined with osimertinib (osi) versus chemotherapy (chemo) in EGFR-mutant (EGFRm) and MET-amplification (METamp) advanced NSCLC after disease progression (PD) on EGFR tyrosine kinase inhibitor (TKI): Results from a randomized phase 3 SACHI study. Abstract #LBA8505 Oral Abstract Session June 1, 2025 9:48am Levy, BP Efficacy and CNS results from a randomized subset of the phase 2 SAVANNAH study comparing savolitinib (savo) + osimertinib (osi) combination with savo + placebo (PBO). Abstract #8513 Rapid Oral Abstract Session June 2, 2025 8:06am Chaft JE Neoadjuvant (neoadj) osimertinib (osi) ± chemotherapy (CT) vs CT alone in resectable (R) epidermal growth factor receptor-mutated (EGFRm) NSCLC: NeoADAURA. Abstract #8001 Oral Abstract Session June 2, 2025 3:12pm Immuno-oncology & bispecifics Janjigian, YY Event-free survival in MATTERHORN: a randomized, phase 3 study of durvalumab plus 5-fluorouracil, leucovorin, oxaliplatin, and docetaxel chemotherapy (FLOT) in resectable gastric/gastroesophageal junction cancer (GC/GEJC). Abstract #LBA5 Plenary Session June 1, 2025 3:13pm Powles, T Circulating tumor DNA (ctDNA) in patients with muscle-invasive bladder cancer (MIBC) who received perioperative durvalumab (D) in NIAGARA Abstract #4503 Oral Abstract Session June 1, 2025 10:45am Reck, M Associations of post-surgical MRD status with neoadjuvant ctDNA dynamics, genomic mutations, and clinical outcomes in patients with resectable NSCLC (R-NSCLC) from the phase 3 AEGEAN trial. Abstract #8009 Rapid Oral Abstract Session June 1, 2025 4:30pm Barbie, DA Clinical and molecular characteristics of early progressors (EPs) and long-term progression-free survivors (LTPs) from the phase 3 ADRIATIC trial of consolidation durvalumab (D) vs placebo (P) after concurrent chemoradiotherapy (cCRT) in limited-stage small-cell lung cancer (LS-SCLC). Abstract #8014 Rapid Oral Abstract Session June 1, 2025 5:12pm Mayadev, J Ultrasensitive detection and tracking of circulating tumor DNA (ctDNA) and association with relapse and survival in locally advanced cervical cancer (LACC): Phase 3 CALLA trial analyses. Abstract #5502 Oral Abstract Session June 2, 2025 8:48am Westin, SN Durvalumab plus carboplatin/paclitaxel followed by durvalumab with or without olaparib as first-line treatment for endometrial cancer: Longitudinal changes in circulating tumor DNA. Abstract #5512 Rapid Oral Abstract Session June 3, 2025 8:30am Erinjeri, JP Outcomes by baseline tumor burden using the 6-and-12 score in EMERALD-1: a phase 3 study of durvalumab (D) ± bevacizumab (B) with transarterial chemoembolization (TACE) in embolization-eligible unresectable hepatocellular carcinoma (uHCC). Abstract #4083 Poster Session May 31, 2025 9:00am Cascone, T Neoadjuvant durvalumab (D) + chemotherapy (CT) + novel anticancer agents and adjuvant D ± novel agents in resectable non-small-cell lung cancer (NSCLC): Updated outcomes from NeoCOAST-2. Abstract #8046 Poster Session May 31, 2025 1:30pm Zhou, J First-line rilvegostomig (rilve) plus chemotherapy (CTx) in advanced biliary tract cancer (BTC): Primary analysis of GEMINI-Hepatobiliary substudy 2 Cohort A. Abstract #4080 Poster Session May 31, 2025 9:00am Xu, R ARTEMIDE-Gastric01: a phase 3 randomized study of rilvegostomig with fluoropyrimidine and trastuzumab deruxtecan (T-DXd) as first-line (1L) treatment for locally advanced or metastatic HER2-positive gastric or gastroesophageal junction cancer (GC/GEJC). Abstract #TPS4204 Poster Session May 31, 2025 9:00am Mathias, C ARTEMIDE-Lung03: a phase 3, randomized, double-blind, multicenter, global study of rilvegostomig or pembrolizumab in combination with platinum-based chemotherapy as first-line treatment for patients with metastatic non-squamous non-small-cell lung cancer whose tumors express PD-L1. Abstract #TPS8653 Poster Session May 31, 2025 1:30pm Cell therapy Yoo, C RHEA-1: First-in-human (FIH) study of AZD9793, a first-in-class CD8-guided T cell-engager (TCE) for glypican-3-positive (GPC3+) advanced or metastatic hepatocellular carcinoma (HCC). Abstract #TPS4215 Poster Session May 31, 2025 9:00am Kim, TM Safety and Efficacy of AZD0486, a CD19xCD3 T-cell Engager, in Relapsed or Refractory Diffuse Large B-cell Lymphoma. Abstract #7046 Poster Session June 1, 2025 9:00am Shadman, M TITANium: An open-label, global multicenter Phase 1/2 study of AZD5492, a first-in-class subcutaneous CD8-guided tri-specific T-cell engager (TCE), in patients (pts) with relapsed or refractory (r/r) B-cell malignancies. Abstract #TPS7091 Poster Session June 1, 2025 9:00am Le Gouill, S SOUNDTRACK-E: A Phase 1/2 Open-label Multicenter Study to Evaluate the Safety and Efficacy of AZD0486 Monotherapy or Combination Therapy in Patients With Mature B-cell Malignancies. Abstract #TPS7083 Poster Session June 1, 2025 9:00am Rare disease medicines Chen, AP Efficacy and safety of selumetinib in adults with neurofibromatosis type 1 (NF1) and symptomatic, inoperable plexiform neurofibroma (PN): Primary analysis of KOMET (NCT04924608), a Phase 3, international, randomized, placebo-controlled study. Abstract #3014 Rapid Oral Abstract Session June 2, 2025 8:00am 1 More than 80 abstracts at ASCO 2025 will feature AstraZeneca medicines and pipeline molecules. IMPORTANT SAFETY INFORMATION FOR IMFINZI® (durvalumab) There are no contraindications for IMFINZI® (durvalumab) or IMJUDO® (tremelimumab-actl). Severe and Fatal Immune-Mediated Adverse Reactions Important immune-mediated adverse reactions listed under Warnings and Precautions may not include all possible severe and fatal immune-mediated reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. Immune-mediated adverse reactions can occur at any time after starting treatment or after discontinuation. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate clinical chemistries including liver enzymes, creatinine, adrenocorticotropic hormone (ACTH) level, and thyroid function at baseline and before each dose. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate. Withhold or permanently discontinue IMFINZI and IMJUDO depending on severity. See USPI Dosing and Administration for specific details. In general, if IMFINZI and IMJUDO requires interruption or discontinuation, administer systemic corticosteroid therapy (1 mg to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy. Immune-Mediated Pneumonitis IMFINZI and IMJUDO can cause immune-mediated pneumonitis, which may be fatal. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation. In patients who did not receive recent prior radiation, the incidence of immune-mediated pneumonitis was 2.4% (34/1414), including fatal (<0.1%), and Grade 3-4 (0.4%) adverse reactions. In patients who received recent prior radiation, the incidence of pneumonitis (including radiation pneumonitis) in patients with unresectable Stage III NSCLC following definitive chemoradiation within 42 days prior to initiation of IMFINZI in PACIFIC was 18.3% (87/475) in patients receiving IMFINZI and 12.8% (30/234) in patients receiving placebo. Of the patients who received IMFINZI (475), 1.1% were fatal and 2.7% were Grade 3 adverse reactions. The incidence of pneumonitis (including radiation pneumonitis) in patients with LS-SCLC following chemoradiation within 42 days prior to initiation of IMFINZI in ADRIATIC was 14% (37/262) in patients receiving IMFINZI and 6% (16/265) in patients receiving placebo. Of the patients who received IMFINZI (262), 0.4% had a fatal adverse reaction and 2.7% had Grade 3 adverse reactions. The frequency and severity of immune-mediated pneumonitis in patients who did not receive definitive chemoradiation prior to IMFINZI were similar in patients who received IMFINZI as a single agent or with ES-SCLC or BTC when given in combination with chemotherapy. Immune‑mediated pneumonitis occurred in 1.3% (5/388) of patients receiving IMFINZI and IMJUDO, including fatal (0.3%) and Grade 3 (0.2%) adverse reactions. Immune-mediated pneumonitis occurred in 3.5% (21/596) of patients receiving IMFINZI in combination with IMJUDO and platinum-based chemotherapy, including fatal (0.5%), and Grade 3 (1%) adverse reactions. Immune-Mediated Colitis IMFINZI with IMJUDO and platinum-based chemotherapy can cause immune-mediated colitis, which may be fatal. IMFINZI and IMJUDO can cause immune-mediated colitis that is frequently associated with diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 2% (37/1889) of patients receiving IMFINZI, including Grade 4 (<0.1%) and Grade 3 (0.4%) adverse reactions. Immune‑mediated colitis or diarrhea occurred in 6% (23/388) of patients receiving IMFINZI and IMJUDO, including Grade 3 (3.6%) adverse reactions. Intestinal perforation has been observed in other studies of IMFINZI and IMJUDO. Immune-mediated colitis occurred in 6.5% (39/596) of patients receiving IMFINZI in combination with IMJUDO and platinum-based chemotherapy including fatal (0.2%) and Grade 3 (2.5%) adverse reactions. Intestinal perforation and large intestine perforation were reported in 0.1% of patients. Immune-Mediated Hepatitis IMFINZI and IMJUDO can cause immune-mediated hepatitis, which may be fatal. Immune-mediated hepatitis occurred in 2.8% (52/1889) of patients receiving IMFINZI, including fatal (0.2%), Grade 4 (0.3%) and Grade 3 (1.4%) adverse reactions. Immune‑mediated hepatitis occurred in 7.5% (29/388) of patients receiving IMFINZI and IMJUDO, including fatal (0.8%), Grade 4 (0.3%) and Grade 3 (4.1%) adverse reactions. Immune-mediated hepatitis occurred in 3.9% (23/596) of patients receiving IMFINZI in combination with IMJUDO and platinum-based chemotherapy, including fatal (0.3%), Grade 4 (0.5%), and Grade 3 (2%) adverse reactions. Immune-Mediated Endocrinopathies Adrenal Insufficiency : IMFINZI and IMJUDO can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. IMFINZI as a Single Agent Immune-mediated adrenal insufficiency occurred in 0.5% (9/1889) of patients receiving IMFINZI, including Grade 3 (<0.1%) adverse reactions. IMFINZI with IMJUDO Immune-mediated adrenal insufficiency occurred in 1.5% (6/388) of patients receiving IMFINZI and IMJUDO, including Grade 3 (0.3%) adverse reactions. IMFINZI with IMJUDO and Platinum-Based Chemotherapy Immune-mediated adrenal insufficiency occurred in 2.2% (13/596) of patients receiving IMFINZI in combination with IMJUDO and platinum-based chemotherapy, including Grade 3 (0.8%) adverse reactions. Hypophysitis : IMFINZI and IMJUDO can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field cuts. Hypophysitis can cause hypopituitarism. Initiate symptomatic treatment including hormone replacement as clinically indicated. IMFINZI as a Single Agent Grade 3 hypophysitis/hypopituitarism occurred in <0.1% (1/1889) of patients who received IMFINZI. IMFINZI with IMJUDO Immune-mediated hypophysitis/hypopituitarism occurred in 1% (4/388) of patients receiving IMFINZI and IMJUDO. IMFINZI with IMJUDO and Platinum-Based Chemotherapy Immune-mediated hypophysitis occurred in 1.3% (8/596) of patients receiving IMFINZI in combination with IMJUDO and platinum-based chemotherapy, including Grade 3 (0.5%) adverse reactions. Thyroid Disorders (Thyroiditis, Hyperthyroidism, and Hypothyroidism) : IMFINZI and IMJUDO can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement therapy for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. IMFINZI as a Single Agent Immune-mediated thyroiditis occurred in 0.5% (9/1889) of patients receiving IMFINZI, including Grade 3 (<0.1%) adverse reactions. Immune-mediated hyperthyroidism occurred in 2.1% (39/1889) of patients receiving IMFINZI. Immune-mediated hypothyroidism occurred in 8.3% (156/1889) of patients receiving IMFINZI, including Grade 3 (<0.1%) adverse reactions. IMFINZI with IMJUDO Immune-mediated thyroiditis occurred in 1.5% (6/388) of patients receiving IMFINZI and IMJUDO. Immune-mediated hyperthyroidism occurred in 4.6% (18/388) of patients receiving IMFINZI and IMJUDO, including Grade 3 (0.3%) adverse reactions. Immune-mediated hypothyroidism occurred in 11% (42/388) of patients receiving IMFINZI and IMJUDO. IMFINZI with IMJUDO and Platinum-Based Chemotherapy Immune-mediated thyroiditis occurred in 1.2% (7/596) of patients receiving IMFINZI in combination with IMJUDO and platinum-based chemotherapy. Immune-mediated hyperthyroidism occurred in 5% (30/596) of patients receiving IMFINZI in combination with IMJUDO and platinum-based chemotherapy, including Grade 3 (0.2%) adverse reactions. Immune-mediated hypothyroidism occurred in 8.6% (51/596) of patients receiving IMFINZI in combination with IMJUDO and platinum-based chemotherapy, including Grade 3 (0.5%) adverse reactions. IMFINZI with Carboplatin and Paclitaxel Immune-mediated hypothyroidism occurred in 14% (34/235) of patients receiving IMFINZI in combination with carboplatin and paclitaxel. Type 1 Diabetes Mellitus, which can present with diabetic ketoacidosis : Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. IMFINZI as a Single Agent Grade 3 immune-mediated Type 1 diabetes mellitus occurred in <0.1% (1/1889) of patients receiving IMFINZI. IMFINZI with IMJUDO Two patients (0.5%, 2/388) had events of hyperglycemia requiring insulin therapy that had not resolved at last follow-up. IMFINZI with IMJUDO and Platinum-Based Chemotherapy Immune-mediated Type 1 diabetes mellitus occurred in 0.5% (3/596) of patients receiving IMFINZI in combination with IMJUDO and platinum-based chemotherapy including Grade 3 (0.3%) adverse reactions. Immune-Mediated Nephritis with Renal Dysfunction IMFINZI and IMJUDO can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.5% (10/1889) of patients receiving IMFINZI, including Grade 3 (<0.1%) adverse reactions. Immune-mediated nephritis occurred in 1% (4/388) of patients receiving IMFINZI and IMJUDO, including Grade 3 (0.5%) adverse reactions. Immune-mediated nephritis occurred in 0.7% (4/596) of patients receiving IMFINZI in combination with IMJUDO and platinum-based chemotherapy, including Grade 3 (0.2%) adverse reactions. Immune-Mediated Dermatology Reactions IMFINZI and IMJUDO can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson Syndrome (SJS), drug rash with eosinophilia and systemic symptoms (DRESS), and toxic epidermal necrolysis (TEN), has occurred with PD-1/L-1 and CTLA-4 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes. Immune-mediated rash or dermatitis occurred in 1.8% (34/1889) of patients receiving IMFINZI, including Grade 3 (0.4%) adverse reactions. Immune-mediated rash or dermatitis occurred in 4.9% (19/388) of patients receiving IMFINZI and IMJUDO, including Grade 4 (0.3%) and Grade 3 (1.5%) adverse reactions. Immune-mediated rash or dermatitis occurred in 7.2% (43/596) of patients receiving IMFINZI in combination with IMJUDO and platinum-based chemotherapy, including Grade 3 (0.3%) adverse reactions. Immune-Mediated Pancreatitis IMFINZI in combination with IMJUDO can cause immune-mediated pancreatitis. Immune-mediated pancreatitis occurred in 2.3% (9/388) of patients receiving IMFINZI and IMJUDO, including Grade 4 (0.3%) and Grade 3 (1.5%) adverse reactions. Other Immune-Mediated Adverse Reactions The following clinically significant, immune-mediated adverse reactions occurred at an incidence of less than 1% each in patients who received IMFINZI and IMJUDO or were reported with the use of other immune-checkpoint inhibitors. Cardiac/vascular : Myocarditis, pericarditis, vasculitis. Nervous system : Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy. Ocular : Uveitis, iritis, and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment to include blindness can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss. Gastrointestinal : Pancreatitis including increases in serum amylase and lipase levels, gastritis, duodenitis. Musculoskeletal and connective tissue disorders : Myositis/polymyositis, rhabdomyolysis and associated sequelae including renal failure, arthritis, polymyalgia rheumatic. Endocrine : Hypoparathyroidism. Other (hematologic/immune) : Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenia, solid organ transplant rejection, other transplant (including corneal graft) rejection. Infusion-Related Reactions IMFINZI and IMJUDO can cause severe or life-threatening infusion-related reactions. Monitor for signs and symptoms of infusion-related reactions. Interrupt, slow the rate of, or permanently discontinue IMFINZI and IMJUDO based on the severity. See USPI Dosing and Administration for specific details. For Grade 1 or 2 infusion-related reactions, consider using pre-medications with subsequent doses. Infusion-related reactions occurred in 2.2% (42/1889) of patients receiving IMFINZI, including Grade 3 (0.3%) adverse reactions. Infusion-related reactions occurred in 2.6% (10/388) of patients receiving IMFINZI and IMJUDO. Infusion-related reactions occurred in 2.9% (17/596) of patients receiving IMFINZI in combination with IMJUDO and platinum-based chemotherapy, including Grade 3 (0.3%) adverse reactions. Complications of Allogeneic HSCT after IMFINZI Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1/L-1 blocking antibody. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between PD-1/L-1 blockade and allogeneic HSCT. Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1/L-1 blocking antibody prior to or after an allogeneic HSCT. Embryo-Fetal Toxicity Based on their mechanism of action and data from animal studies, IMFINZI and IMJUDO can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. In females of reproductive potential, verify pregnancy status prior to initiating IMFINZI and IMJUDO and advise them to use effective contraception during treatment with IMFINZI and IMJUDO and for 3 months after the last dose of IMFINZI and IMJUDO. Lactation There is no information regarding the presence of IMFINZI and IMJUDO in human milk; however, because of the potential for serious adverse reactions in breastfed infants from IMFINZI and IMJUDO, advise women not to breastfeed during treatment and for 3 months after the last dose. Adverse Reactions Unresectable Stage III NSCLC In patients with Stage III NSCLC in the PACIFIC study receiving IMFINZI (n=475), the most common adverse reactions (≥20%) were cough (40%), fatigue (34%), pneumonitis or radiation pneumonitis (34%), upper respiratory tract infections (26%), dyspnea (25%), and rash (23%). The most common Grade 3 or 4 adverse reactions (≥3%) were pneumonia (7%) and pneumonitis/radiation pneumonitis (3.4%). In patients with Stage III NSCLC in the PACIFIC study receiving IMFINZI (n=475), discontinuation due to adverse reactions occurred in 15% of patients in the IMFINZI arm. Serious adverse reactions occurred in 29% of patients receiving IMFINZI. The most frequent serious adverse reactions (≥2%) were pneumonitis or radiation pneumonitis (7%) and pneumonia (6%). Fatal pneumonitis or radiation pneumonitis and fatal pneumonia occurred in <2% of patients and were similar across arms. Resectable NSCLC In patients with resectable NSCLC in the AEGEAN study, the most common adverse reactions (occurring in ≥20% of patients) were anemia, nausea, constipation, fatigue, musculoskeletal pain, and rash. In patients with resectable NSCLC in the neoadjuvant phase of the AEGEAN study receiving IMFINZI in combination with platinum-containing chemotherapy (n=401), permanent discontinuation of IMFINZI due to an adverse reaction occurred in 6.7% of patients. Serious adverse reactions occurred in 21% of patients. The most frequent (≥1%) serious adverse reactions were pneumonia (2.7%), anemia (1.5%), myelosuppression (1.5%), vomiting (1.2%), neutropenia (1%), and acute kidney injury (1%). Fatal adverse reactions occurred in 2% of patients, including death due to COVID-19 pneumonia (0.5%), sepsis (0.5%), myocarditis (0.2%), decreased appetite (0.2%), hemoptysis (0.2%), and death not otherwise specified (0.2%). Of the 401 IMFINZI treated patients who received neoadjuvant treatment and 398 placebo-treated patients who received neoadjuvant treatment, 1.7% (n=7) and 1% (n=4), respectively, did not receive surgery due to adverse reactions. In patients with resectable NSCLC in the adjuvant phase of the AEGEAN study receiving IMFINZI as a single agent (n=265), permanent discontinuation of IMFINZI due to an adverse reaction occurred in 8% of patients. Serious adverse reactions occurred in 13% of patients. The most frequent serious adverse reactions reported in >1% of patients were pneumonia (1.9%), pneumonitis (1.1%), and COVID-19 (1.1%). Four fatal adverse reactions occurred during the adjuvant phase of the study, including COVID-19 pneumonia, pneumonia aspiration, interstitial lung disease and aortic aneurysm. Metastatic NSCLC In patients with mNSCLC in the POSEIDON study receiving IMFINZI and IMJUDO plus platinum-based chemotherapy (n=330), the most common adverse reactions (occurring in ≥20% of patients) were nausea (42%), fatigue (36%), musculoskeletal pain (29%), decreased appetite (28%), rash (27%), and diarrhea (22%). In patients with mNSCLC in the POSEIDON study receiving IMFINZI in combination with IMJUDO and platinum-based chemotherapy (n=330), permanent discontinuation of IMFINZI or IMJUDO due to an adverse reaction occurred in 17% of patients. Serious adverse reactions occurred in 44% of patients, with the most frequent serious adverse reactions reported in at least 2% of patients being pneumonia (11%), anemia (5%), diarrhea (2.4%), thrombocytopenia (2.4%), pyrexia (2.4%), and febrile neutropenia (2.1%). Fatal adverse reactions occurred in a total of 4.2% of patients. Limited-stage Small Cell Lung Cancer In patients with limited-stage SCLC in the ADRIATIC study receiving IMFINZI (n=262), the most common adverse reactions occurring in ≥20% of patients receiving IMFINZI were pneumonitis or radiation pneumonitis (38%), and fatigue (21%). The most common Grade 3 or 4 adverse reactions (≥3%) were pneumonitis or radiation pneumonitis and pneumonia. In patients with limited-stage SCLC in the ADRIATIC study receiving IMFINZI (n=262), IMFINZI was permanently discontinued due to adverse reactions in 16% of the patients receiving IMFINZI. Serious adverse reactions occurred in 30% of patients receiving IMFINZI. The most frequent serious adverse reactions reported in ≥1% of patients receiving IMFINZI were pneumonitis or radiation pneumonitis (12%), and pneumonia (5%). Fatal adverse reactions occurred in 2.7% of patients who received IMFINZI including pneumonia (1.5%), cardiac failure, encephalopathy and pneumonitis (0.4% each). Extensive-stage Small Cell Lung Cancer In patients with extensive-stage SCLC in the CASPIAN study receiving IMFINZI plus chemotherapy (n=265), the most common adverse reactions (≥20%) were nausea (34%), fatigue/asthenia (32%), and alopecia (31%). The most common Grade 3 or 4 adverse reaction (≥3%) was fatigue/asthenia (3.4%). In patients with extensive-stage SCLC in the CASPIAN study receiving IMFINZI plus chemotherapy (n=265), IMFINZI was discontinued due to adverse reactions in 7% of the patients receiving IMFINZI plus chemotherapy. Serious adverse reactions occurred in 31% of patients receiving IMFINZI plus chemotherapy. The most frequent serious adverse reactions reported in at least 1% of patients were febrile neutropenia (4.5%), pneumonia (2.3%), anemia (1.9%), pancytopenia (1.5%), pneumonitis (1.1%), and COPD (1.1%). Fatal adverse reactions occurred in 4.9% of patients receiving IMFINZI plus chemotherapy. Locally Advanced or Metastatic Biliary Tract Cancers In patients with locally advanced or metastatic BTC in the TOPAZ-1 study receiving IMFINZI (n=338), the most common adverse reactions (occurring in ≥20% of patients) were fatigue (42%), nausea (40%), constipation (32%), decreased appetite (26%), abdominal pain (24%), rash (23%), and pyrexia (20%). In patients with locally advanced or metastatic BTC in the TOPAZ-1 study receiving IMFINZI (n=338), discontinuation due to adverse reactions occurred in 6% of the patients receiving IMFINZI plus chemotherapy. Serious adverse reactions occurred in 47% of patients receiving IMFINZI plus chemotherapy. The most frequent serious adverse reactions reported in at least 2% of patients were cholangitis (7%), pyrexia (3.8%), anemia (3.6%), sepsis (3.3%) and acute kidney injury (2.4%). Fatal adverse reactions occurred in 3.6% of patients receiving IMFINZI plus chemotherapy. These include ischemic or hemorrhagic stroke (4 patients), sepsis (2 patients), and upper gastrointestinal hemorrhage (2 patients). Unresectable Hepatocellular Carcinoma In patients with unresectable HCC in the HIMALAYA study receiving IMFINZI and IMJUDO (n=388), the most common adverse reactions (occurring in ≥20% of patients) were rash (32%), diarrhea (27%), fatigue (26%), pruritus (23%), musculoskeletal pain (22%), and abdominal pain (20%). In patients with unresectable HCC in the HIMALAYA study receiving IMFINZI and IMJUDO (n=388), serious adverse reactions occurred in 41% of patients. Serious adverse reactions in >1% of patients included hemorrhage (6%), diarrhea (4%), sepsis (2.1%), pneumonia (2.1%), rash (1.5%), vomiting (1.3%), acute kidney injury (1.3%), and anemia (1.3%). Fatal adverse reactions occurred in 8% of patients who received IMFINZI and IMJUDO, including death (1%), hemorrhage intracranial (0.5%), cardiac arrest (0.5%), pneumonitis (0.5%), hepatic failure (0.5%), and immune-mediated hepatitis (0.5%). Permanent discontinuation of treatment regimen due to an adverse reaction occurred in 14% of patients. Primary advanced or Recurrent dMMR Endometrial Cancer In patients with advanced or recurrent dMMR endometrial cancer in the DUO-E study receiving IMFINZI in combination with carboplatin and paclitaxel followed by IMFINZI as a single-agent (n=44), the most common adverse reactions, including laboratory abnormalities (occurring in >20% of patients) were peripheral neuropathy (61%), musculoskeletal pain (59%), nausea (59%), alopecia (52%), fatigue (41%), abdominal pain (39%), constipation (39%), rash (39%), decreased magnesium (36%), increased ALT (32%), increased AST (30%), diarrhea (27%), vomiting (27%), cough (27%), decreased potassium (25%), dyspnea (25%), headache (23%), increased alkaline phosphatase (20%), and decreased appetite (18%). The most common Grade 3 or 4 adverse reactions (≥3%) were constipation (4.5%) and fatigue (4.5%). In patients with advanced or recurrent dMMR endometrial cancer in the DUO-E study receiving IMFINZI in combination with carboplatin and paclitaxel followed by IMFINZI as a single-agent (n=44), permanent discontinuation of IMFINZI due to adverse reactions occurred in 11% of patients. Serious adverse reactions occurred in 30% of patients who received IMFINZI with carboplatin and paclitaxel; the most common serious adverse reactions (≥4%) were constipation (4.5%) and rash (4.5%). Muscle-Invasive Bladder Cancer (MIBC) In patients with muscle-invasive bladder cancer (MIBC), the most common adverse reactions, including laboratory abnormalities, in the overall study (occurring in ≥20% of patients) were decreased hemoglobin, decreased neutrophils, increased blood creatinine, decreased sodium, nausea, increased ALT, decreased calcium, decreased platelets, fatigue, increased potassium, decreased lymphocytes, increased AST, constipation, decreased magnesium, decreased appetite, increased alkaline phosphate, rash, pyrexia, diarrhea, vomiting and abdominal pain. In patients with MIBC in the neoadjuvant phase of the NIAGARA study receiving IMFINZI in combination with gemcitabine and cisplatin (n=530), permanent discontinuation of IMFINZI due to an adverse reaction occurred in 9% of patients. Serious adverse reactions occurred in 24% of patients; the most frequent (≥1%) serious adverse reactions were pulmonary embolism (1.9%), febrile neutropenia (1.5%), acute kidney injury (1.3%), thrombocytopenia (1.3%), urinary tract infection (1.3%), and pneumonia (1.3%). Fatal adverse reactions occurred in 1.1% of patients including sepsis, myocardial infarction, and pulmonary embolism (0.2% each). One fatal adverse reaction of pneumonia was reported in 1 (0.2%) patient in the post-surgery phase before adjuvant treatment started. Of the 530 patients in the IMFINZI treatment arm and 526 patients in the chemotherapy treatment arm who received neoadjuvant treatment, 1 (0.2%) patient in each treatment arm did not receive surgery due to adverse reactions. The adverse reaction that led to cancellation of surgery in the IMFINZI treatment arm was interstitial lung disease. In patients with MIBC in the adjuvant phase of the NIAGARA study receiving IMFINZI as a single agent (n=383), permanent discontinuation of adjuvant IMFINZI due to an adverse reaction occurred in 5% of patients. Serious adverse reactions occurred in 26% of patients. The most frequent serious adverse reactions (occurring in ≥1% of patients) were urinary tract infection (7%), acute kidney injury (3.7%), hydronephrosis (2.1%), pyelonephritis (2.1%), urosepsis (1.8%) and sepsis (1.6%). Fatal adverse reactions occurred in 1.8% of patients, including COVID-19, severe acute respiratory syndrome, cardiopulmonary failure, gastrointestinal hemorrhage, and chronic hepatic failure (0.3% each). The safety and effectiveness of IMFINZI and IMJUDO have not been established in pediatric patients. Indications: IMFINZI, as a single agent, is indicated for the treatment of adult patients with unresectable Stage III non-small cell lung cancer (NSCLC) whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy (cCRT). IMFINZI in combination with platinum-containing chemotherapy as neoadjuvant treatment, followed by IMFINZI continued as a single agent as adjuvant treatment after surgery, is indicated for the treatment of adult patients with resectable (tumors ≥4 cm and/or node positive) NSCLC and no known epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements. IMFINZI, in combination with IMJUDO and platinum-based chemotherapy, is indicated for the treatment of adult patients with metastatic NSCLC with no sensitizing EGFR mutations or ALK genomic tumor aberrations. IMFINZI, as a single agent, is indicated for the treatment of adult patients with limited-stage small cell lung cancer (LS-SCLC) whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy (cCRT). IMFINZI, in combination with etoposide and either carboplatin or cisplatin, is indicated for the first-line treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC). IMFINZI, in combination with gemcitabine and cisplatin, is indicated for the treatment of adult patients with locally advanced or metastatic biliary tract cancer (BTC). IMFINZI in combination with IMJUDO is indicated for the treatment of adult patients with unresectable hepatocellular carcinoma (uHCC). IMFINZI in combination with carboplatin and paclitaxel followed by IMFINZI as a single agent is indicated for the treatment of adult patients with primary advanced or recurrent endometrial cancer that is mismatch repair deficient (dMMR) as determined by an FDA-approved test. IMFINZI in combination with gemcitabine and cisplatin as neoadjuvant treatment, followed by single-agent IMFINZI as adjuvant treatment following radical cystectomy, is indicated for the treatment of adult patients with muscle-invasive bladder cancer (MIBC). Please refer to the Important Safety Information included above and the full Prescribing Information for IMFINZI and IMJUDO for important dosage modification and management information specific to adverse reactions. INDICATIONS AND IMPORTANT SAFETY INFORMATION FOR ENHERTU® (fam-trastuzumab deruxtecan-nxki) Indications ENHERTU is a HER2-directed antibody and topoisomerase inhibitor conjugate indicated for the treatment of adult patients with: Unresectable or metastatic HER2-positive (IHC 3+ or ISH positive) breast cancer who have received a prior anti-HER2-based regimen either: – In the metastatic setting, or – In the neoadjuvant or adjuvant setting and have developed disease recurrence during or within six months of completing therapy Unresectable or metastatic: – Hormone receptor (HR)-positive, HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2-ultralow (IHC 0 with membrane staining) breast cancer, as determined by an FDA-approved test, that has progressed on one or more endocrine therapies in the metastatic setting – HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer, as determined by an FDA-approved test, who have received a prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy Unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have activating HER2 (ERBB2) mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy This indication is approved under accelerated approval based on objective response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. Locally advanced or metastatic HER2-positive (IHC 3+ or IHC 2+/ISH positive) gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen Unresectable or metastatic HER2-positive (IHC 3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options This indication is approved under accelerated approval based on objective response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. Important Safety Information WARNING: INTERSTITIAL LUNG DISEASE and EMBRYO-FETAL TOXICITY Contraindications None. Warnings and Precautions Interstitial Lung Disease / Pneumonitis Severe, life-threatening, or fatal interstitial lung disease (ILD), including pneumonitis, can occur in patients treated with ENHERTU. A higher incidence of Grade 1 and 2 ILD/pneumonitis has been observed in patients with moderate renal impairment. Advise patients to immediately report cough, dyspnea, fever, and/or any new or worsening respiratory symptoms. Monitor patients for signs and symptoms of ILD. Promptly investigate evidence of ILD. Evaluate patients with suspected ILD by radiographic imaging. Consider consultation with a pulmonologist. For asymptomatic ILD/pneumonitis (Grade 1), interrupt ENHERTU until resolved to Grade 0, then if resolved in ≤28 days from date of onset, maintain dose. If resolved in >28 days from date of onset, reduce dose 1 level. Consider corticosteroid treatment as soon as ILD/pneumonitis is suspected (e.g., ≥0.5 mg/kg/day prednisolone or equivalent). For symptomatic ILD/pneumonitis (Grade 2 or greater), permanently discontinue ENHERTU. Promptly initiate systemic corticosteroid treatment as soon as ILD/pneumonitis is suspected (e.g., ≥1 mg/kg/day prednisolone or equivalent) and continue for at least 14 days followed by gradual taper for at least 4 weeks. HER2-Positive, HER2-Low, and HER2-Ultralow Metastatic Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC 3+) (5.4 mg/kg) In patients with metastatic breast cancer, HER2-mutant NSCLC, and other solid tumors treated with ENHERTU 5.4 mg/kg, ILD occurred in 12% of patients. Median time to first onset was 5.5 months (range: 0.9 to 31.5). Fatal outcomes due to ILD and/or pneumonitis occurred in 0.9% of patients treated with ENHERTU. HER2-Positive Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg) In patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, ILD occurred in 10% of patients. Median time to first onset was 2.8 months (range: 1.2 to 21). Neutropenia Severe neutropenia, including febrile neutropenia, can occur in patients treated with ENHERTU. Monitor complete blood counts prior to initiation of ENHERTU and prior to each dose, and as clinically indicated. For Grade 3 neutropenia (Absolute Neutrophil Count [ANC] <1.0 to 0.5 x 109/L), interrupt ENHERTU until resolved to Grade 2 or less, then maintain dose. For Grade 4 neutropenia (ANC <0.5 x 109/L), interrupt ENHERTU until resolved to Grade 2 or less, then reduce dose by 1 level. For febrile neutropenia (ANC <1.0 x 109/L and temperature >38.3º C or a sustained temperature of ≥38º C for more than 1 hour), interrupt ENHERTU until resolved, then reduce dose by 1 level. HER2-Positive, HER2-Low, and HER2-Ultralow Metastatic Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC 3+) (5.4 mg/kg) In patients with metastatic breast cancer, HER2-mutant NSCLC, and other solid tumors treated with ENHERTU 5.4 mg/kg, a decrease in neutrophil count was reported in 65% of patients. Nineteen percent had Grade 3 or 4 decreased neutrophil count. Median time to first onset of decreased neutrophil count was 22 days (range: 2 to 939). Febrile neutropenia was reported in 1.2% of patients. HER2-Positive Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg) In patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, a decrease in neutrophil count was reported in 72% of patients. Fifty-one percent had Grade 3 or 4 decreased neutrophil count. Median time to first onset of decreased neutrophil count was 16 days (range: 4 to 187). Febrile neutropenia was reported in 4.8% of patients. Left Ventricular Dysfunction Patients treated with ENHERTU may be at increased risk of developing left ventricular dysfunction. Left ventricular ejection fraction (LVEF) decrease has been observed with anti-HER2 therapies, including ENHERTU. Assess LVEF prior to initiation of ENHERTU and at regular intervals during treatment as clinically indicated. Manage LVEF decrease through treatment interruption. When LVEF is >45% and absolute decrease from baseline is 10-20%, continue treatment with ENHERTU. When LVEF is 40-45% and absolute decrease from baseline is <10%, continue treatment with ENHERTU and repeat LVEF assessment within 3 weeks. When LVEF is 40-45% and absolute decrease from baseline is 10-20%, interrupt ENHERTU and repeat LVEF assessment within 3 weeks. If LVEF has not recovered to within 10% from baseline, permanently discontinue ENHERTU. If LVEF recovers to within 10% from baseline, resume treatment with ENHERTU at the same dose. When LVEF is <40% or absolute decrease from baseline is >20%, interrupt ENHERTU and repeat LVEF assessment within 3 weeks. If LVEF of <40% or absolute decrease from baseline of >20% is confirmed, permanently discontinue ENHERTU. Permanently discontinue ENHERTU in patients with symptomatic congestive heart failure. Treatment with ENHERTU has not been studied in patients with a history of clinically significant cardiac disease or LVEF <50% prior to initiation of treatment. HER2-Positive, HER2-Low, and HER2-Ultralow Metastatic Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC 3+) (5.4 mg/kg) In patients with metastatic breast cancer, HER2-mutant NSCLC, and other solid tumors treated with ENHERTU 5.4 mg/kg, LVEF decrease was reported in 4.6% of patients, of which 0.6% were Grade 3 or 4. HER2-Positive Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg) In patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, no clinical adverse events of heart failure were reported; however, on echocardiography, 8% were found to have asymptomatic Grade 2 decrease in LVEF. Embryo-Fetal Toxicity ENHERTU can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risks to a fetus. Verify the pregnancy status of females of reproductive potential prior to the initiation of ENHERTU. Advise females of reproductive potential to use effective contraception during treatment and for 7 months after the last dose of ENHERTU. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ENHERTU and for 4 months after the last dose of ENHERTU. Additional Dose Modifications Thrombocytopenia For Grade 3 thrombocytopenia (platelets <50 to 25 x 109/L) interrupt ENHERTU until resolved to Grade 1 or less, then maintain dose. For Grade 4 thrombocytopenia (platelets <25 x 109/L) interrupt ENHERTU until resolved to Grade 1 or less, then reduce dose by 1 level. Adverse Reactions HER2-Positive, HER2-Low, and HER2-Ultralow Metastatic Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC 3+) (5.4 mg/kg) The pooled safety population reflects exposure to ENHERTU 5.4 mg/kg intravenously every 3 weeks in 2233 patients in Study DS8201-A-J101 (NCT02564900), DESTINY-Breast01, DESTINY-Breast02, DESTINY-Breast03, DESTINY-Breast04, DESTINY-Breast06, DESTINY-Lung01, DESTINY-Lung02, DESTINY-CRC02, and DESTINY-PanTumor02. Among these patients, 67% were exposed for >6 months and 38% were exposed for >1 year. In this pooled safety population, the most common (≥20%) adverse reactions, including laboratory abnormalities, were decreased white blood cell count (73%), nausea (72%), decreased hemoglobin (67%), decreased neutrophil count (65%), decreased lymphocyte count (60%), fatigue (55%), decreased platelet count (48%), increased aspartate aminotransferase (46%), increased alanine aminotransferase (44%), increased blood alkaline phosphatase (39%), vomiting (38%), alopecia (37%), constipation (32%), decreased blood potassium (32%), decreased appetite (31%), diarrhea (30%), and musculoskeletal pain (24%). HER2-Positive Metastatic Breast Cancer DESTINY-Breast03 The safety of ENHERTU was evaluated in 257 patients with unresectable or metastatic HER2-positive breast cancer who received at least 1 dose of ENHERTU 5.4 mg/kg intravenously once every 3 weeks in DESTINY-Breast03. The median duration of treatment was 14 months (range: 0.7 to 30) for patients who received ENHERTU. Serious adverse reactions occurred in 19% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were vomiting, ILD, pneumonia, pyrexia, and urinary tract infection. Fatalities due to adverse reactions occurred in 0.8% of patients including COVID-19 and sudden death (1 patient each). ENHERTU was permanently discontinued in 14% of patients, of which ILD/pneumonitis accounted for 8%. Dose interruptions due to adverse reactions occurred in 44% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, leukopenia, anemia, thrombocytopenia, pneumonia, nausea, fatigue, and ILD/pneumonitis. Dose reductions occurred in 21% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were nausea, neutropenia, and fatigue. The most common (≥20%) adverse reactions, including laboratory abnormalities, were nausea (76%), decreased white blood cell count (74%), decreased neutrophil count (70%), increased aspartate aminotransferase (67%), decreased hemoglobin (64%), decreased lymphocyte count (55%), increased alanine aminotransferase (53%), decreased platelet count (52%), fatigue (49%), vomiting (49%), increased blood alkaline phosphatase (49%), alopecia (37%), decreased blood potassium (35%), constipation (34%), musculoskeletal pain (31%), diarrhea (29%), decreased appetite (29%), headache (22%), respiratory infection (22%), abdominal pain (21%), increased blood bilirubin (20%), and stomatitis (20%). HER2-Low and HER2-Ultralow Metastatic Breast Cancer DESTINY-Breast06 The safety of ENHERTU was evaluated in 434 patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2-ultralow (IHC 0 with membrane staining) breast cancer who received ENHERTU 5.4 mg/kg intravenously once every 3 weeks in DESTINY-Breast06. The median duration of treatment was 11 months (range: 0.4 to 39.6) for patients who received ENHERTU. Serious adverse reactions occurred in 20% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were ILD/pneumonitis, COVID-19, febrile neutropenia, and hypokalemia. Fatalities due to adverse reactions occurred in 2.8% of patients including ILD (0.7%); sepsis (0.5%); and COVID-19 pneumonia, bacterial meningoencephalitis, neutropenic sepsis, peritonitis, cerebrovascular accident, general physical health deterioration (0.2% each). ENHERTU was permanently discontinued in 14% of patients. The most frequent adverse reaction (>2%) associated with permanent discontinuation was ILD/pneumonitis. Dose interruptions due to adverse reactions occurred in 48% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were COVID-19, decreased neutrophil count, anemia, pyrexia, pneumonia, decreased white blood cell count, and ILD. Dose reductions occurred in 25% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were nausea, fatigue, decreased platelet count, and decreased neutrophil count. The most common (≥20%) adverse reactions, including laboratory abnormalities, were decreased white blood cell count (86%), decreased neutrophil count (75%), nausea (70%), decreased hemoglobin (69%), decreased lymphocyte count (66%), fatigue (53%), decreased platelet count (48%), alopecia (48%), increased alanine aminotransferase (44%), increased blood alkaline phosphatase (43%), increased aspartate aminotransferase (41%), decreased blood potassium (35%), diarrhea (34%), vomiting (34%), constipation (32%), decreased appetite (26%), COVID-19 (26%), and musculoskeletal pain (24%). DESTINY-Breast04 The safety of ENHERTU was evaluated in 371 patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer who received ENHERTU 5.4 mg/kg intravenously once every 3 weeks in DESTINY-Breast04. The median duration of treatment was 8 months (range: 0.2 to 33) for patients who received ENHERTU. Serious adverse reactions occurred in 28% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were ILD/pneumonitis, pneumonia, dyspnea, musculoskeletal pain, sepsis, anemia, febrile neutropenia, hypercalcemia, nausea, pyrexia, and vomiting. Fatalities due to adverse reactions occurred in 4% of patients including ILD/pneumonitis (3 patients); sepsis (2 patients); and ischemic colitis, disseminated intravascular coagulation, dyspnea, febrile neutropenia, general physical health deterioration, pleural effusion, and respiratory failure (1 patient each). ENHERTU was permanently discontinued in 16% of patients, of which ILD/pneumonitis accounted for 8%. Dose interruptions due to adverse reactions occurred in 39% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, fatigue, anemia, leukopenia, COVID-19, ILD/pneumonitis, increased transaminases, and hyperbilirubinemia. Dose reductions occurred in 23% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were fatigue, nausea, thrombocytopenia, and neutropenia. The most common (≥20%) adverse reactions, including laboratory abnormalities, were nausea (76%), decreased white blood cell count (70%), decreased hemoglobin (64%), decreased neutrophil count (64%), decreased lymphocyte count (55%), fatigue (54%), decreased platelet count (44%), alopecia (40%), vomiting (40%), increased aspartate aminotransferase (38%), increased alanine aminotransferase (36%), constipation (34%), increased blood alkaline phosphatase (34%), decreased appetite (32%), musculoskeletal pain (32%), diarrhea (27%), and decreased blood potassium (25%). HER2-Mutant Unresectable or Metastatic NSCLC (5.4 mg/kg) DESTINY-Lung02 evaluated 2 dose levels (5.4 mg/kg [n=101] and 6.4 mg/kg [n=50]); however, only the results for the recommended dose of 5.4 mg/kg intravenously every 3 weeks are described below due to increased toxicity observed with the higher dose in patients with NSCLC, including ILD/pneumonitis. The safety of ENHERTU was evaluated in 101 patients with HER2-mutant unresectable or metastatic NSCLC who received ENHERTU 5.4 mg/kg intravenously once every 3 weeks until disease progression or unacceptable toxicity in DESTINY‑Lung02. Nineteen percent of patients were exposed for >6 months. Serious adverse reactions occurred in 30% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were ILD/pneumonitis, thrombocytopenia, dyspnea, nausea, pleural effusion, and increased troponin I. Fatality occurred in 1 patient with suspected ILD/pneumonitis (1%). ENHERTU was permanently discontinued in 8% of patients. Adverse reactions which resulted in permanent discontinuation of ENHERTU were ILD/pneumonitis, diarrhea, decreased blood potassium, hypomagnesemia, myocarditis, and vomiting. Dose interruptions of ENHERTU due to adverse reactions occurred in 23% of patients. Adverse reactions which required dose interruption (>2%) included neutropenia and ILD/pneumonitis. Dose reductions due to an adverse reaction occurred in 11% of patients. The most common (≥20%) adverse reactions, including laboratory abnormalities, were nausea (61%), decreased white blood cell count (60%), decreased hemoglobin (58%), decreased neutrophil count (52%), decreased lymphocyte count (43%), decreased platelet count (40%), decreased albumin (39%), increased aspartate aminotransferase (35%), increased alanine aminotransferase (34%), fatigue (32%), constipation (31%), decreased appetite (30%), vomiting (26%), increased alkaline phosphatase (22%), and alopecia (21%). HER2-Positive Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg) The safety of ENHERTU was evaluated in 187 patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma in DESTINY-Gastric01. Patients intravenously received at least 1 dose of either ENHERTU (N=125) 6.4 mg/kg every 3 weeks or either irinotecan (N=55) 150 mg/m2 biweekly or paclitaxel (N=7) 80 mg/m2 weekly for 3 weeks. The median duration of treatment was 4.6 months (range: 0.7 to 22.3) for patients who received ENHERTU. Serious adverse reactions occurred in 44% of patients receiving ENHERTU 6.4 mg/kg. Serious adverse reactions in >2% of patients who received ENHERTU were decreased appetite, ILD, anemia, dehydration, pneumonia, cholestatic jaundice, pyrexia, and tumor hemorrhage. Fatalities due to adverse reactions occurred in 2.4% of patients: disseminated intravascular coagulation, large intestine perforation, and pneumonia occurred in 1 patient each (0.8%). ENHERTU was permanently discontinued in 15% of patients, of which ILD accounted for 6%. Dose interruptions due to adverse reactions occurred in 62% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, anemia, decreased appetite, leukopenia, fatigue, thrombocytopenia, ILD, pneumonia, lymphopenia, upper respiratory tract infection, diarrhea, and decreased blood potassium. Dose reductions occurred in 32% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were neutropenia, decreased appetite, fatigue, nausea, and febrile neutropenia. The most common (≥20%) adverse reactions, including laboratory abnormalities, were decreased hemoglobin (75%), decreased white blood cell count (74%), decreased neutrophil count (72%), decreased lymphocyte count (70%), decreased platelet count (68%), nausea (63%), decreased appetite (60%), increased aspartate aminotransferase (58%), fatigue (55%), increased blood alkaline phosphatase (54%), increased alanine aminotransferase (47%), diarrhea (32%), decreased blood potassium (30%), vomiting (26%), constipation (24%), increased blood bilirubin (24%), pyrexia (24%), and alopecia (22%). HER2-Positive (IHC 3+) Unresectable or Metastatic Solid Tumors The safety of ENHERTU was evaluated in 347 adult patients with unresectable or metastatic HER2-positive (IHC 3+) solid tumors who received ENHERTU 5.4 mg/kg intravenously once every 3 weeks in DESTINY-Breast01, DESTINY-PanTumor02, DESTINY-Lung01, and DESTINY-CRC02. The median duration of treatment was 8.3 months (range 0.7 to 30.2). Serious adverse reactions occurred in 34% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were sepsis, pneumonia, vomiting, urinary tract infection, abdominal pain, nausea, pneumonitis, pleural effusion, hemorrhage, COVID-19, fatigue, acute kidney injury, anemia, cellulitis, and dyspnea. Fatalities due to adverse reactions occurred in 6.3% of patients including ILD/pneumonitis (2.3%), cardiac arrest (0.6%), COVID-19 (0.6%), and sepsis (0.6%). The following events occurred in 1 patient each (0.3%): acute kidney injury, cerebrovascular accident, general physical health deterioration, pneumonia, and hemorrhagic shock. ENHERTU was permanently discontinued in 15% of patients, of which ILD/pneumonitis accounted for 10%. Dose interruptions due to adverse reactions occurred in 48% of patients. The most frequent adverse reactions (>2%) associated with dose interruption were decreased neutrophil count, anemia, COVID-19, fatigue, decreased white blood cell count, and ILD/pneumonitis. Dose reductions occurred in 27% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were fatigue, nausea, decreased neutrophil count, ILD/pneumonitis, and diarrhea. The most common (≥20%) adverse reactions, including laboratory abnormalities, were decreased white blood cell count (75%), nausea (69%), decreased hemoglobin (67%), decreased neutrophil count (66%), fatigue (59%), decreased lymphocyte count (58%), decreased platelet count (51%), increased aspartate aminotransferase (45%), increased alanine aminotransferase (44%), increased blood alkaline phosphatase (36%), vomiting (35%), decreased appetite (34%), alopecia (34%), diarrhea (31%), decreased blood potassium (29%), constipation (28%), decreased sodium (22%), stomatitis (20%), and upper respiratory tract infection (20%). Use in Specific Populations Pregnancy: ENHERTU can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risks to a fetus. There are clinical considerations if ENHERTU is used in pregnant women, or if a patient becomes pregnant within 7 months after the last dose of ENHERTU. Lactation: There are no data regarding the presence of ENHERTU in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with ENHERTU and for 7 months after the last dose. Females and Males of Reproductive Potential: Pregnancy testing : Verify pregnancy status of females of reproductive potential prior to initiation of ENHERTU. Contraception : Females : ENHERTU can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with ENHERTU and for 7 months after the last dose. Males : Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ENHERTU and for 4 months after the last dose. Infertility : ENHERTU may impair male reproductive function and fertility. Pediatric Use: Safety and effectiveness of ENHERTU have not been established in pediatric patients. Geriatric Use: Of the 1741 patients with HER2-positive, HER2-low, or HER2-ultralow breast cancer treated with ENHERTU 5.4 mg/kg, 24% were ≥65 years and 4.9% were ≥75 years. No overall differences in efficacy within clinical studies were observed between patients ≥65 years of age compared to younger patients. There was a higher incidence of Grade 3-4 adverse reactions observed in patients aged ≥65 years (61%) as compared to younger patients (52%). Of the 101 patients with HER2-mutant unresectable or metastatic NSCLC treated with ENHERTU 5.4 mg/kg, 40% were ≥65 years and 8% were ≥75 years. No overall differences in efficacy or safety were observed between patients ≥65 years of age compared to younger patients. Of the 125 patients with HER2-positive locally advanced or metastatic gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg in DESTINY-Gastric01, 56% were ≥65 years and 14% were ≥75 years. No overall differences in efficacy or safety were observed between patients ≥65 years of age compared to younger patients. Of the 192 patients with HER2-positive (IHC 3+) unresectable or metastatic solid tumors treated with ENHERTU 5.4 mg/kg in DESTINY-PanTumor02, DESTINY-Lung01, or DESTINY-CRC02, 39% were ≥65 years and 9% were ≥75 years. No overall differences in efficacy or safety were observed between patients ≥65 years of age compared to younger patients. Renal Impairment: A higher incidence of Grade 1 and 2 ILD/pneumonitis has been observed in patients with moderate renal impairment. Monitor patients with moderate renal impairment more frequently. The recommended dosage of ENHERTU has not been established for patients with severe renal impairment (CLcr <30 mL/min). Hepatic Impairment: In patients with moderate hepatic impairment, due to potentially increased exposure, closely monitor for increased toxicities related to the topoisomerase inhibitor, DXd. The recommended dosage of ENHERTU has not been established for patients with severe hepatic impairment (total bilirubin >3 times ULN and any AST). To report SUSPECTED ADVERSE REACTIONS, contact Daiichi Sankyo, Inc. at 1-877-437-7763 or FDA at 1-800-FDA-1088 or fda.gov/medwatch. Please see full Prescribing Information, including Boxed WARNINGS, and Medication Guide. IMPORTANT SAFETY INFORMATION FOR TAGRISSO® (osimertinib) There are no contraindications for TAGRISSO TAGRISSO can cause severe and fatal interstitial lung disease (ILD)/pneumonitis. ILD/pneumonitis occurred in 4% of the 1813 patients treated with TAGRISSO monotherapy who had not received recent definitive chemoradiation therapy; 0.4% of cases were fatal ILD/Pneumonitis with TAGRISSO in combination with Pemetrexed and Platinum-based Chemotherapy: ILD/Pneumonitis Following Definitive Platinum-based Chemoradiation Therapy (CRT): In the LAURA study, following definitive platinum-based CRT, ILD/pneumonitis including radiation pneumonitis, occurred in 80 of the 143 patients (56%) who received TAGRISSO monotherapy and 28 of the 73 patients (38%) who received placebo. There was one fatal case (0.7%), 3.5% Grade 3, 34% Grade 2, and 18% Grade 1 adverse reactions of ILD/pneumonitis in TAGRISSO-treated patients. For TAGRISSO-treated patients, ILD/pneumonitis led to permanent discontinuation of TAGRISSO in 7% of patients and dosage interruptions of TAGRISSO in 35% of patients. Among the 46 patients who were rechallenged with TAGRISSO, 11% had recurrence of ILD/pneumonitis. In the 80 TAGRISSO-treated patients, ILD/pneumonitis resolved in 40%, resolved with sequelae in 1.3%, were resolving in 16%, did not resolve in 41%, and resulted in death in 1.3% For patients receiving TAGRISSO who have not received recent definitive platinum-based CRT, withhold TAGRISSO and promptly investigate for ILD in patients who present with worsening of respiratory symptoms which may be indicative of ILD (e.g., dyspnea, cough, and fever). Permanently discontinue TAGRISSO if ILD/pneumonitis is confirmed. For patients who have received recent definitive platinum- based CRT with Grade 1 ILD/pneumonitis, continue TAGRISSO or interrupt and restart, as appropriate. Permanently discontinue TAGRISSO in patients diagnosed with Grade ≥2 ILD/pneumonitis TAGRISSO can cause heart rate-corrected QT (QTc) interval prolongation. Of the 1813 TAGRISSO monotherapy-treated patients in clinical trials, 1.1% were found to have a QTc >500 msec, and 4.3% of patients had an increase from baseline QTc >60 msec. Of the 276 patients treated with TAGRISSO in combination with pemetrexed and platinum-based chemotherapy in the FLAURA2 study, 1.8% were found to have a QTc >500 msec, and 10.5% of patients had an increase from baseline QTc >60 msec. No QTc-related arrhythmias were reported. Clinical trials of TAGRISSO did not enroll patients with baseline QTc of >470 msec. Conduct periodic monitoring with ECGs and electrolytes in patients with congenital long QTc syndrome, congestive heart failure, electrolyte abnormalities, or those who are taking medications known to prolong the QTc interval. Permanently discontinue TAGRISSO in patients who develop QTc interval prolongation with signs/symptoms of life-threatening arrhythmia TAGRISSO can cause cardiomyopathy, including cardiac failure, chronic cardiac failure, congestive heart failure, pulmonary edema or decreased ejection fraction. Cardiomyopathy occurred in 3.8% of the 1813 TAGRISSO-treated patients; 0.1% of cardiomyopathy cases were fatal. In the FLAURA2 study, cardiomyopathy occurred in 9% of the 276 patients who received TAGRISSO in combination with pemetrexed and platinum-based chemotherapy; 1.1% of cardiomyopathy cases were fatal. A decline in left ventricular ejection fraction (LVEF) ≥10% from baseline and to <50% LVEF occurred in 4.2% of 1557 patients who had baseline and at least one follow-up LVEF assessment. In the ADAURA study, 1.5% (5/325) of TAGRISSO-treated patients experienced LVEF decreases ≥10% from baseline and a drop to <50%. In the LAURA study, following platinum-based CRT, 3% (4/135) of TAGRISSO-treated patients and no placebo-treated patients experienced LVEF decreases ≥10% and a drop to <50%. In the FLAURA2 study, 8% (21/262) of patients treated with TAGRISSO in combination with pemetrexed and platinum- based chemotherapy, who had baseline and at least one follow-up LVEF assessment, experienced LVEF decreases ≥10% and a drop to <50%. For patients receiving TAGRISSO monotherapy, conduct cardiac monitoring in patients with cardiac risk factors, including assessment of LVEF at baseline and during treatment. For patients receiving TAGRISSO in combination with pemetrexed and platinum-based chemotherapy, conduct cardiac monitoring in all patients, including assessment of LVEF at baseline and during treatment. Assess LVEF in patients who develop relevant cardiac signs or symptoms during treatment. For symptomatic congestive heart failure, permanently discontinue TAGRISSO Keratitis was reported in 0.6% of 1813 patients treated with TAGRISSO monotherapy in clinical trials. Promptly refer patients with signs and symptoms suggestive of keratitis (such as eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain and/or red eye) to an ophthalmologist Postmarketing cases consistent with erythema multiforme major (EMM), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in patients receiving TAGRISSO. Withhold TAGRISSO if EMM, SJS, or TEN is suspected and permanently discontinue if confirmed Postmarketing cases of cutaneous vasculitis including leukocytoclastic vasculitis, urticarial vasculitis, and IgA vasculitis have been reported in patients receiving TAGRISSO. Withhold TAGRISSO if cutaneous vasculitis is suspected, evaluate for systemic involvement, and consider dermatology consultation. If no other etiology can be identified, consider permanent discontinuation of TAGRISSO based on severity Aplastic anemia has been reported in TAGRISSO-treated patients in clinical trials (0.06% of 1813) and postmarketing. Some cases had a fatal outcome. Inform patients of the signs and symptoms of aplastic anemia including but not limited to, new or persistent fevers, bruising, bleeding, and pallor. If aplastic anemia is suspected, withhold TAGRISSO and obtain a hematology consultation. If aplastic anemia is confirmed, permanently discontinue TAGRISSO. Perform complete blood count with differential before starting TAGRISSO, periodically throughout treatment, and more frequently if indicated Verify pregnancy status of females of reproductive potential prior to initiating TAGRISSO. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TAGRISSO and for 6 weeks after the last dose. Advise males with female partners of reproductive potential to use effective contraception for 4 months after the last dose Because of the potential for serious adverse reactions in breastfed infants from TAGRISSO, women should not breastfeed during treatment with TAGRISSO and for 2 weeks after the last dose Most common (≥20%) adverse reactions, including laboratory abnormalities, were: INDICATIONS TAGRISSO is indicated as adjuvant therapy after tumor resection in adult patients with non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test TAGRISSO is indicated for the treatment of adult patients with locally advanced, unresectable (stage III) NSCLC whose disease has not progressed during or following concurrent or sequential platinum-based chemoradiation therapy and whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test TAGRISSO is indicated for the first-line treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test TAGRISSO is indicated in combination with pemetrexed and platinum-based chemotherapy, for the first-line treatment of adult patients with locally advanced or metastatic NSCLC whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test TAGRISSO is indicated for the treatment of adult patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive NSCLC, as detected by an FDA-approved test, whose disease has progressed on or after EGFR tyrosine kinase inhibitor (TKI) therapy Please see complete Prescribing Information, including Patient Information for TAGRISSO. INDICATION AND IMPORTANT SAFETY INFORMATION FOR DATROWAY® (datopotamab deruxtecan-dlnk) Indication DATROWAY® is a Trop-2-directed antibody and topoisomerase inhibitor conjugate indicated for the treatment of adult patients with unresectable or metastatic, hormone receptor (HR)-positive, HER2-negative (IHC 0, IHC 1+, or IHC 2+/ISH−) breast cancer who have received prior endocrine-based therapy and chemotherapy for unresectable or metastatic disease. Contraindications None. Warnings and Precautions Interstitial Lung Disease/Pneumonitis DATROWAY can cause severe, life-threatening, or fatal interstitial lung disease (ILD) or pneumonitis. In TROPION-Breast01, ILD/pneumonitis occurred in 4.2% of patients treated with DATROWAY, including 0.5% of patients with Grade 3-4 ILD/pneumonitis, and 0.3% with fatal ILD/pneumonitis. Six patients (1.7%) permanently discontinued DATROWAY due to ILD/pneumonitis. The median time to onset of ILD/pneumonitis was 3.5 months (range: 1.2 months to 10.8 months). Patients were excluded from TROPION-Breast01 for a history of ILD/pneumonitis requiring treatment with steroids or for ongoing ILD/pneumonitis. Monitor patients for new or worsening respiratory symptoms indicative of ILD/pneumonitis (eg, dyspnea, cough, fever) during treatment with DATROWAY. For asymptomatic (Grade 1) ILD/pneumonitis, consider corticosteroid treatment (eg, ≥0.5 mg/kg/day prednisolone or equivalent). For symptomatic ILD/pneumonitis (Grade 2 or greater), promptly initiate systemic corticosteroid treatment (eg, ≥1 mg/kg/day prednisolone or equivalent) and continue for at least 14 days followed by gradual taper for at least 4 weeks. Withhold DATROWAY in patients with suspected ILD/pneumonitis and permanently discontinue DATROWAY if Grade ≥2 ILD/pneumonitis is confirmed. Ocular Adverse Reactions DATROWAY can cause ocular adverse reactions including dry eye, keratitis, blepharitis, meibomian gland dysfunction, increased lacrimation, conjunctivitis, and blurred vision. In TROPION-Breast01, ocular adverse reactions occurred in 51% of patients treated with DATROWAY. Seven patients (1.9%) experienced Grade 3 ocular adverse reactions, including dry eye, keratitis, and blurred vision. The most common (≥5%) ocular adverse reactions were dry eye (27%), keratitis (24%), blepharitis and increased lacrimation (8% each), and meibomian gland dysfunction (7%). Patients with clinically significant corneal disease were excluded from TROPION-Breast01. The median time to onset for ocular adverse reactions was 2.1 months (range: 0.03 months to 23.2 months). Of the patients who experienced ocular adverse reactions, 45% had complete resolution; 9% had partial improvement (defined as a decrease in severity by one or more grades from the worst grade at last follow up). Ocular adverse reactions led to permanent discontinuation of DATROWAY in 0.8% of patients. Advise patients to use preservative-free lubricant eye drops several times daily for prophylaxis. Advise patients to avoid use of contact lenses unless directed by an eye care professional. Refer patients to an eye care professional for an ophthalmic exam including visual acuity testing, slit lamp examination (with fluorescein staining), intraocular pressure, and fundoscopy at treatment initiation, annually while on treatment, at end of treatment, and as clinically indicated. Promptly refer patients to an eye care professional for any new or worsening ocular adverse reactions. Monitor patients for ocular adverse reactions during treatment with DATROWAY, and if diagnosis is confirmed, dose delay, dose reduce, or permanently discontinue DATROWAY based on severity. Stomatitis DATROWAY can cause stomatitis, including mouth ulcers and oral mucositis. In the TROPION-Breast01 study, stomatitis occurred in 59% of patients treated with DATROWAY, including 7% of patients with Grade 3-4 events. Median time to first onset was 0.7 months (range: 0.03 months to 8.8 months). Stomatitis led to interruption of DATROWAY in 1.9%, dosage reductions in 13%, and permanent discontinuation in 0.3% of patients. In patients who received DATROWAY, 38% used a mouthwash containing corticosteroid for management or prophylaxis of stomatitis/oral mucositis at any time during the treatment. Advise patients to use a steroid-containing mouthwash for prophylaxis and treatment of stomatitis. Instruct the patient to hold ice chips or ice water in the mouth throughout the infusion of DATROWAY. Monitor patients for signs and symptoms of stomatitis. If stomatitis occurs, increase the frequency of mouthwash and administer other topical treatments as clinically indicated. Based on the severity of the adverse reaction, withhold, dose reduce, or permanently discontinue DATROWAY. Embryo-Fetal Toxicity Based on its mechanism of action, DATROWAY can cause embryo-fetal harm when administered to a pregnant woman because the topoisomerase inhibitor component of DATROWAY, DXd, is genotoxic and affects actively dividing cells. Advise patients of the potential risk to a fetus. Advise female patients of reproductive potential to use effective contraception during treatment with DATROWAY and for 7 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with DATROWAY and for 4 months after the last dose. Adverse Reactions The safety of DATROWAY was evaluated in 360 patients with unresectable or metastatic HR-positive, HER2-negative (IHC 0, IHC 1+ or IHC 2+/ISH−) breast cancer who received at least one dose of DATROWAY 6 mg/kg in TROPION-Breast01. DATROWAY was administered by intravenous infusion once every three weeks. The median duration of treatment was 6.7 months (range: 0.7 months to 16.1 months) for patients who received DATROWAY. Serious adverse reactions occurred in 15% of patients who received DATROWAY. Serious adverse reactions in >0.5% of patients who received DATROWAY were urinary tract infection (1.9%), COVID-19 infection (1.7%), ILD/pneumonitis (1.1%), acute kidney injury, pulmonary embolism, vomiting, diarrhea, hemiparesis, and anemia (0.6% each). Fatal adverse reactions occurred in 0.3% of patients who received DATROWAY and were due to ILD/pneumonitis. Permanent discontinuation of DATROWAY due to an adverse reaction occurred in 3.1% of patients. Adverse reactions which resulted in permanent discontinuation of DATROWAY in >0.5% of patients included ILD/pneumonitis (1.7%) and fatigue (0.6%). Dosage interruptions of DATROWAY due to an adverse reaction occurred in 22% of patients. Adverse reactions which required dosage interruption in >1% of patients included COVID-19 (3.3%), infusion-related reaction (1.4%), ILD/pneumonitis (1.9%), stomatitis (1.9%), fatigue (1.7%), keratitis (1.4%), acute kidney injury (1.1%), and pneumonia (1.1%). Dose reductions of DATROWAY due to an adverse reaction occurred in 23% of patients. Adverse reactions which required dose reduction in >1% of patients included stomatitis (13%), fatigue (3.1%), nausea (2.5%), and weight decrease (1.9%). The most common (≥20%) adverse reactions, including laboratory abnormalities, were stomatitis (59%), nausea (56%), fatigue (44%), decreased leukocytes (41%), decreased calcium (39%), alopecia (38%), decreased lymphocytes (36%), decreased hemoglobin (35%), constipation (34%), decreased neutrophils (30%), dry eye (27%), vomiting (24%), increased ALT (24%), keratitis (24%), increased AST (23%), and increased alkaline phosphatase (23%). Clinically relevant adverse reactions occurring in <10% of patients who received DATROWAY included infusion-related reactions (including bronchospasm), ILD/pneumonitis, headache, pruritus, dry skin, dry mouth, conjunctivitis, blepharitis, meibomian gland dysfunction, blurred vision, increased lacrimation, photophobia, visual impairment, skin hyperpigmentation, and madarosis. Use in Specific Populations Pregnancy: Based on its mechanism of action, DATROWAY can cause embryo-fetal harm when administered to a pregnant woman because the topoisomerase inhibitor component of DATROWAY, DXd, is genotoxic and affects actively dividing cells. There are no available data on the use of DATROWAY in pregnant women to inform a drug-associated risk. Advise patients of the potential risks to a fetus. Lactation: There are no data regarding the presence of datopotamab deruxtecan-dlnk or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with DATROWAY and for 1 month after the last dose. Females and Males of Reproductive Potential: Pregnancy Testing: Verify pregnancy status of females of reproductive potential prior to initiation of DATROWAY. Contraception: Females: Advise females of reproductive potential to use effective contraception during treatment with DATROWAY and for 7 months after the last dose. Males: Because of the potential for genotoxicity, advise male patients with female partners of reproductive potential to use effective contraception during treatment with DATROWAY and for 4 months after the last dose. Infertility: Based on findings in animal toxicity studies, DATROWAY may impair male and female reproductive function and fertility. The effects on reproductive organs in animals were irreversible. Pediatric Use: Safety and effectiveness of DATROWAY have not been established in pediatric patients. Geriatric Use: Of the 365 patients in TROPION-Breast01 treated with DATROWAY 6 mg/kg, 25% were ≥65 years of age and 5% were ≥75 years of age. Grade ≥3 and serious adverse reactions were more common in patients ≥65 years (42% and 25%, respectively) compared to patients <65 years (33% and 15%, respectively). In TROPION-Breast01, no other meaningful differences in safety or efficacy were observed between patients ≥65 years of age versus younger patients. Renal Impairment: A higher incidence of ILD/pneumonitis has been observed in patients with mild and moderate renal impairment (creatinine clearance [CLcr] 30 to <90 mL/min). Monitor patients with renal impairment for increased adverse reactions, including respiratory reactions. No dosage adjustment is recommended in patients with mild to moderate renal impairment. The effect of severe renal impairment (CLcr <30 mL/min) on the pharmacokinetics of datopotamab deruxtecan-dlnk or DXd is unknown. Hepatic Impairment: No dosage adjustment is recommended in patients with mild hepatic impairment (total bilirubin ≤ULN and any AST >ULN or total bilirubin >1 to 1.5 times ULN and any AST). Limited data are available in patients with moderate hepatic impairment (total bilirubin >1.5 to 3 times ULN and any AST). Monitor patients with moderate hepatic impairment for increased adverse reactions. The recommended dosage of DATROWAY has not been established for patients with severe hepatic impairment (total bilirubin >3 times ULN and any AST). To report SUSPECTED ADVERSE REACTIONS, contact Daiichi Sankyo, Inc. at 1-877-437-7763 or FDA at 1-800-FDA-1088 or fda.gov/medwatch. Please see accompanying full Prescribing Information, including Warnings and Precautions, and Medication Guide. IMPORTANT SAFETY INFORMATION FOR KOSELUGO® (selumetinib) What are the possible side effects of Koselugo? Koselugo may cause serious side effects, including: Heart problems. Koselugo can lower the amount of blood pumped by your heart, which is common and can also be severe. Your healthcare provider will do tests before and during treatment to check how well your heart is working. Tell your healthcare provider right away if you get any of the following signs or symptoms: persistent coughing or wheezing, shortness of breath, swelling of your ankles and feet, tiredness, increased heart rate. Eye problems. Koselugo can cause eye problems that can lead to blindness. Your healthcare provider will check your vision before and during treatment. Tell your healthcare provider right away if you get any of the following signs or symptoms: blurred vision, loss of vision, dark spots in your vision (floaters), other changes to your vision. Severe diarrhea. Diarrhea is common with Koselugo and can also be severe. Tell your healthcare provider right away the first time that you get diarrhea during treatment. Your healthcare provider may give you medicine to help control your diarrhea and may tell you to drink more fluids. Skin rash. Skin rashes are common with Koselugo and can also be severe. Tell your healthcare provider if you get any of the following signs or symptoms: rash that covers a large area of your body, peeling skin, blisters. Muscle problems (rhabdomyolysis). Muscle problems are common with Koselugo and can also be severe. Treatment with Koselugo may increase the level of a muscle enzyme in your blood called creatine phosphokinase (CPK) and may be a sign of muscle damage. Your healthcare provider should do a blood test to check your muscle enzyme levels of CPK before you start taking Koselugo and during treatment. Tell your healthcare provider right away if you get any of the following signs or symptoms: muscle aches or pain; muscle spasms and weakness; dark, reddish urine. Before taking Koselugo, tell your healthcare provider about all your medical conditions, including if you: have heart problems. have eye problems. have liver problems. are pregnant or plan to become pregnant. Koselugo can harm your unborn baby. Your healthcare provider should verify if you/your partner are pregnant before beginning treatment. Ensure you/your partner use effective birth control (contraception) during treatment and for 1 week after your last dose if there is possibility pregnancy could occur. Tell your healthcare provider right away if you/your partner think you may be pregnant. are breastfeeding or plan to breastfeed. It is not known if Koselugo passes into your breast milk. Do not breastfeed during treatment and for 1 week after your last dose. Talk to your healthcare provider about the best way to feed your baby during this time. Tell your healthcare provider about all the medicines you take, including prescription, over-the-counter medicines, vitamins, or herbal supplements. Especially tell your healthcare provider if you are taking aspirin, blood thinners, or other medicines to treat blood clots. Koselugo contains vitamin E, which may increase risk of bleeding. What should I avoid while taking Koselugo? Do not drink grapefruit juice, eat grapefruit, or take supplements with grapefruit or St. John’s Wort during treatment. Most common side effects include: vomiting, stomach-area pain, nausea, dry skin, muscle and bone pain, feeling of tiredness or lacking energy, fever, sores in your mouth, headache, redness around the fingernails, itching. These are not all the possible side effects of Koselugo. Call your healthcare provider for medical advice about side effects. Your healthcare provider may change your dose, temporarily stop, or permanently ask you to stop taking Koselugo if you have any of these side effects. You may report side effects to AstraZeneca at 1-800-236-9933 or at https://us-aereporting.astrazeneca.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Indication What is Koselugo? Koselugo is a prescription medicine that is used to treat children 2 years of age and older with neurofibromatosis type 1 (NF1) who have plexiform neurofibromas that cannot be completely removed by surgery. It is not known if Koselugo is safe and effective in children under 2 years of age. Please see Patient Information in the full Prescribing Information for Koselugo (selumetinib). Notes AstraZeneca in oncology AstraZeneca is leading a revolution in oncology with the ambition to provide cures for cancer in every form, following the science to understand cancer and all its complexities to discover, develop and deliver life-changing medicines to patients. The Company’s focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyze changes in the practice of medicine and transform the patient experience. AstraZeneca has the vision to redefine cancer care and, one day, eliminate cancer as a cause of death. AstraZeneca AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialization of prescription medicines in Oncology, Rare Diseases and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca's innovative medicines are sold in more than 125 countries and used by millions of patients worldwide. Please visit www.astrazeneca-us.com and follow the Company on social media @AstraZeneca. US-101588 Last Updated 5/25

摘要：可用基因组数据的快速扩展继续对生物医学科学和医学产生巨大影响。实现基因发现的临床潜力需要开发能够特异性调节疾病相关基因表达的治疗方法。基于RNA的药物，包括短干扰RNA和反义寡核苷酸，是这类新型生物制剂特别有前途的例子。二十多年来，研究人员一直在努力克服在治疗环境中利用此类RNA的主要挑战，包括细胞内递送、稳定性和免疫反应激活。随着第一批RNA药物获得FDA批准并进一步进入临床试验的最后阶段，这项研究终于开始结出硕果。此外，最近出现的CRISPR（一种RNA引导的基因编辑技术）以及体外转录信使RNA递送的新进展，引发了RNA治疗学领域的重大扩张。在这篇综述中讨论了基于RNA的疗法临床转化的挑战，重点是递送技术的最新进展，并概述了基于RNA的药物在调节基因/蛋白质表达和基因组编辑中的应用，这些应用目前正在实验室和临床中研究。【NO.1】RNA的递送材料和化学修饰1.递送材料      广义上讲，RNA递送可以由病毒和非病毒载体介导。对于病毒RNA递送，人们对改造腺相关病毒来携带核酸货物非常感兴趣——然而，本节将主要关注非病毒材料的开发（表1）。在非病毒RNA递送载体中，纳米颗粒可能是研究最多的。RNA的纳米颗粒包封在物理上保护核酸不被降解，并且根据特定的化学性质，可以帮助细胞摄取和内体逃逸。鉴于聚合物具有高度的化学柔韧性，聚合物是纳米颗粒递送的常用材料。通常，阳离子聚合物用于将带负电荷的RNA静电冷凝成纳米颗粒（图1a）。这些带正电的基团通常由在生理pH值（pKa~7.4）下质子化的胺组成，被认为会导致离子不平衡，从而导致内体破裂，尽管这种所谓的“质子海绵”假说尚未在各种材料中得到严格证明。无论聚合物帮助RNA递送的确切机制如何，市售的含胺聚合物是最早用于核酸递送的非病毒材料之一。聚-L-赖氨酸、聚酰胺胺和聚乙烯亚胺等合成聚合物，以及壳聚糖等天然聚合物都已应用于RNA递送，并取得了不同程度的成功。此外，一些研究人员已经合成了专门用于核酸递送的聚合物。特别是聚（β-氨基酯），由于其易于合成和生物降解性而在DNA递送中得到了广泛的应用，但也已被证明能够影响短干扰RNA（siRNA）和mRNA的递送。表1临床相关RNA递送平台比较备注：ASO 反义寡核苷酸、siRNA 短干扰 RNA图1：RNA的常见递送方式。a描绘了包含RNA和阳离子聚合物的聚合物纳米颗粒的示意图。b示意图描述了含有RNA、阳离子/可电离脂质和纳米颗粒制剂中常用的其他疏水部分（如胆固醇）的脂质纳米颗粒。c目前正在临床试验中的N-乙酰半乳糖胺（GalNAc）和RNA之间的三级偶联物的化学结构。d用于递送核酸的碱基、糖和接头修饰示例（修饰的化学成分以蓝色突出显示）)      脂质和脂质样材料是第二大类基于纳米颗粒的RNA递送载体。与聚合物一样，阳离子脂质通常用于静电结合核酸。然而，许多实验室已经开始使用可电离脂质，这些脂质仅在酸性pH值下带正电荷。与在生理pH值下保持阳离子的颗粒相比，这种可电离行为被认为可以通过帮助内体逃逸和降低毒性来提高疗效。脂质还能够自组装成有序的纳米颗粒结构，称为脂质体（图1b），由与RNA的静电相互作用和疏水相互作用共同驱动。除了可电离/阳离子脂质外，还通过添加其他疏水部分（如胆固醇和PEG-脂质）来优化脂质纳米颗粒（LNP）的配方，可增强纳米颗粒的稳定性，并可以显着提高RNA递送的功效。然而，与聚合物类似，研究发现可电离脂质结构是影响纳米颗粒功效的主要因素。因此，一个实验室率先使用半自动高通量合成方法创建用于RNA递送的化学多样化脂质和脂质样材料文库，从而产生能够在体内全身递送后将多种RNA类型递送到肝脏和肺高效纳米颗粒。     作为纳米颗粒的替代方案，一种概念上更直接且化学上定义明确的递送方式是将生物活性配体直接与RNA偶联，使其能够进入目标细胞。也许这种技术在临床上最先进的例子是N-乙酰半乳糖胺（GalNAc；Fig.1C）靶向肝细胞上的唾液酸糖蛋白受体，靶向siRNA与许多静脉给药的纳米颗粒不同，GalNAc偶联物通常皮下给药，并且已显示出快速进入体循环并靶向肝脏的能力。过去已经探索了其他偶联物，如胆固醇、维生素E、抗体和细胞穿透肽，尽管除了专门的三天线GalNAc-siRNA偶联物外，没有其他偶联物获得任何临床关注（表2），这表明需要在偶联物的设计上做更多的工作，以高效递送核酸。表2目前涉及RNA递送的临床试验备注：ASO 反义寡核苷酸、mRNA 信使 RNA、siRNA 短干扰 RNA、ND 未披露2.RNA修饰     对RNA本身进行化学修饰对RNA本身进行化学修饰同样重要，这会赋予RNA降解抗性，并使免疫系统无法识别它们。偶联物递送系统（在注射后立即使RNA暴露）和纳米颗粒递送系统（必须在某个时候将RNA暴露给细胞内免疫受体）都是如此。RNA可以通过对核糖（特别重要的是2′位置）、磷酸盐键和单个碱基的化学改变来修饰（图.1d）。通过纳米颗粒递送的RNA（稍后讨论）通常也被修饰，以避免被内体表达的模式识别受体识别[。除了少数例外，修饰的RNA是临床试验的金标准（表2）。RNA可以被修饰并仍然保持其效力的程度在很大程度上取决于核酸的性质及其作用机制。例如，依赖于相对强大的RNA诱导沉默复合物（RISC）的siRNA等短RNA，通常可以被严重修饰。相比之下，必须由核糖体有效翻译的大mRNA对修饰更敏感，并利用天然存在的RNA修饰，如假尿嘧啶和5-甲基胞苷取代。事实上，最近的研究表明，在某些情况下，mRNA的碱基修饰实际上会降低效力，而siRNA中的化学修饰几乎无处不在地应用于体内使用【NO.2】基于RNA的基因/蛋白质调控的应用1.蛋白质下调—siRNA、ASO和microRNA     简单来说，疾病相关蛋白可以通过以下两种方式之一改变：上调或下调。在Fire及其同事发现siRNA后，使用RNA选择性下调蛋白质经历了范式转变。短干扰RNA的长度通常为21-23个碱基对，可以通过RISC选择性地结合和降解互补的mRNA（图2）。经过近二十年的研究，基于siRNA的疗法代表了临床上最先进的RNA药物平台之一。特别是Alnylam Pharmaceuticals，有几种siRNA药物正在进行临床试验。他们最先进的药物，也是最先进的siRNA疗法之一patisiran，是一种含有针对突变转甲状腺素蛋白的siRNA的LNP，用于治疗转甲状腺素蛋白淀粉样变性。Patisiran目前处于III期临床试验中在II期试验中显示出显著的剂量依赖性敲低，不良事件最小，其他公司也投资了基于脂质复合物的siRNA药物的使用（表2）。然而，Alnylam和其他人越来越多地报道了GalNAc偶联物技术的重大进展（表2）。尽管Alnylam最近决定停止开发revusiran，这是一种GalNAc-siRNA偶联药物，也可以治疗转甲状腺素蛋白淀粉样变性但该公司还有几种GalNAc偶联物正在其管道中，这些偶联物利用了一种更新的“增强稳定化学”，可以解决导致Revusiran从临床试验中删除的问题].令人惊讶的是，目前的一些临床试验使用裸露的、尽管是化学修饰的siRNA。几乎所有这些裸siRNA都是局部递送的（表2），与全身递送相关的RNA降解和全身免疫激活的风险相比，降低了RNA降解和全身免疫激活的风险。裸siRNA的一个有趣用途是Silenseed的siG12DLODER，它将靶向KRAS癌蛋白的siRNA封装在可植入和可降解的聚合物基质中，用于治疗胰腺癌。然而，人们担心，在某些情况下，这种治疗的积极作用可能是通过诱导非特异性和免疫机制介导的，例如siRNA与toll样受体的结合。图2：使用RNA调节基因和蛋白质表达。一旦递送到细胞中，RNA大分子可以利用不同的细胞内机制来控制基因和蛋白质表达。（I）反义寡核苷酸（ASO）与靶mRNA杂交可通过诱导RNaseH核酸内切酶活性导致基因表达的特异性抑制，从而裂解mRNA-ASO异源双链体。（II）短干扰RNA（siRNA）被RNA诱导的沉默复合物（RISC）识别，该复合物在siRNA的反义链的引导下特异性结合和切割靶标mRNA。（III）体外转录的mRNA利用宿主细胞的蛋白质合成机制将编码的遗传信息翻译成蛋白质。核糖体亚基与帽和poly（A）结合蛋白一起被募集到mRNA中，形成翻译起始复合物。（IV）在CRISPR-Cas9系统中，单向导RNA（sgRNA）与编码Cas9DNA核酸内切酶的mRNA共同递送允许双链DNA的位点特异性切割，导致靶基因及其产物的敲除。CRISPR，成簇的规则间隔短回文重复序列。     尽管siRNA在临床试验中占有重要地位，但它并不是唯一，甚至不是第一个在临床阶段研究蛋白质敲低的RNA药物。临床试验中最早广泛使用的RNA药物是反义寡核苷酸（ASO）。与siRNA一样，ASO旨在通过与靶mRNA的Watson-Crick碱基配对来阻断蛋白质翻译，并且可以对其进行修饰以提高稳定性。然而，ASO通过多种机制抑制蛋白质的产生，例如空间阻断核糖体附着或引发RNase-H激活。它们还可以促进外显子跳跃（一种省略有缺陷外显子的RNA剪接形式），从而可以删除蛋白质内的错误序列，在某些情况下，甚至会导致蛋白质上调，这可用于治疗某些基因受到抑制的疾病。ASO的另一个用途是它们能够在不使用转染试剂的情况下进入细胞，尽管这种摄取并不总是导致治疗作用。四种ASO已获得临床批准，所有这些ASO都经过化学修饰，无需递送载体即可使用，是迄今为止唯一获得FDA批准的用于蛋白质调节的RNA药物。最近的一种是Spinraza（nusinersen），鞘内注射用于治疗脊髓性肌萎缩症。它与静脉输注的ASO药物Exondys51（eteplirsen）一起治疗杜氏肌营养不良症，玻璃体内注射的ASO用于治疗眼巨细胞病毒的Vitravene（fomivirsen），以及皮下注射的Kynamro（mipomersen），以编码载脂蛋白B的mRNA为靶点，用于治疗高胆固醇血症。临床试验中仍有几种ASO，其中大多数是在没有载体的情况下交付的（表2）。特别令人感兴趣的是IonisPharmaceuticals利用类似于Alnylam开发的GalNAc-ASO偶联物来递送siRNA的研究。此类批准和临床研究的乐观情绪也促使研究人员继续研究ASO治疗肌萎缩侧索硬化症（ALS）和脊髓小脑性共济失调等疾病。      一种新兴的、尽管临床上不太先进的基于RNA的蛋白质敲低平台是microRNA（miRNA）。内源性microRNA是非编码RNA，是多种细胞通路的关键调节因子，在疾病中经常下调。因此，以治疗方式递送的外源性microRNA或microRNA模拟物可用于同时敲低多种蛋白质，这在癌症等疾病中特别有用，因为这些疾病很少具有单一疾病相关靶点。还值得注意的是，一种罕见的microRNA亚群被认为可以增强蛋白质的产生，并且使用ASO靶向基因抑制的microRNA也可用于增加蛋白质的产生。目前大多数涉及microRNA的临床试验都是筛选以研究microRNA与某些疾病的关系，尽管有几项正在进行的利用microRNA递送的动物研究。例如，使用LNP治疗结直肠癌小鼠模型，以及使用聚合物纳米颗粒将microRNA输送到心脏以治疗纤维化。第一个进入临床试验的microRNA模拟疗法是MRX-34，这是一种来自MirnaTherapeutics的脂质体封装的microRNA模拟物，旨在治疗多种癌症。然而，在报告了几起免疫相关严重不良事件后，该公司于2017年初终止了这项研究。不良事件具有免疫学特征这一事实进一步凸显了RNA修饰对临床应用的重要性，因为这种修饰仍然是逃避RNA药物免疫检测的最重要手段之一。然而，由于miRNA诱导的基因调控的复杂性，特别是miRNA模拟物的化学修饰可能具有挑战性。2.蛋白过表达—mRNA     疾病相关蛋白的表达可以通过质粒DNA（pDNA）或信使RNA（mRNA）的细胞内递送来实现。应用DNA或mRNA作为蛋白质中间体，可在宿主细胞和组织内表达几乎任何所需的蛋白质。这种方法可以解决基于蛋白质的药物面临的配方和递送挑战，尤其是那些针对细胞内靶点的药物。特别是，与pDNA相比，基于mRNA的疗法具有多项优势，包括快速和瞬时蛋白质生产、无插入诱变风险以及凭借mRNA细胞质活性实现更高的非病毒递送功效（图2）。自1990年代首次临床前研究以来，mRNA技术已经取得了长足的发展，现在有可能彻底改变疫苗接种、蛋白质替代疗法和遗传病的治疗，因此在科学界和生物技术行业中获得了相当大的兴趣。     在最大化mRNA的翻译和稳定性、防止其免疫刺激活性和体内递送技术的发展方面取得重大进展，促进了mRNA疗法的递送，其中一些将在下面讨论。5'帽和3'poly（A）尾是成熟真核mRNA有效翻译和延长半衰期的主要贡献者。将ARCA（抗反向帽类似物）和120-150bp的poly（A）尾等帽类似物掺入体外转录（IVT）mRNA中，显著提高了编码蛋白质的表达和mRNA稳定性。新型帽类似物，如1,2-二硫代二磷酸修饰的帽，对RNA脱帽复合物具有抵抗力，可以进一步提高RNA翻译的效率。用同义的频繁出现的密码子替换mRNA蛋白编码序列中的稀有密码子，即所谓的密码子优化，也有助于提高蛋白质合成的功效，并限制稀有密码子对mRNA的不稳定，从而防止转录本的加速降解。同样，设计3'和5'非翻译区（UTR），其中包含负责募集RNA结合蛋白（RBP）和miRNA的序列，可以提高蛋白质产物的水平。有趣的是，UTR可以被有意修饰以编码调节元件（例如，K转基因基序和miRNA结合位点），从而提供了一种以细胞特异性方式控制RNA表达的方法。前面讨论的一些RNA碱基修饰，如N1-甲基假尿苷，不仅有助于掩盖mRNA免疫刺激活性，而且还被证明可以通过增强翻译起始来增加mRNA翻译。除了观察到的对蛋白质翻译的影响外，碱基修饰和密码子优化还会影响mRNA的二级结构，进而影响其翻译。了解mRNA折叠结构的重要性和预测能力可能有助于mRNA疗法的工程设计——然而，目前可用预测工具的准确性有限。尽管针对其他类型的RNA药物研究了大量载体，但mRNA分子明显大于前面讨论的siRNA（~14kDa）和ASO（4-10kDa），这给mRNA治疗的递送带来了额外的挑战。将大的带电mRNA容纳到纳米颗粒中及其有效的细胞内释放已被证明需要对现有配方进行微调，并开发具有更高效力的新一代生物材料。      目前正在探索的mRNA治疗应用包括针对癌症和传染病的疫苗接种、蛋白质替代疗法和基因编辑。表2中提供了正在进行的涉及mRNA的临床试验的完整列表。mRNA疫苗正处于临床开发的最高级阶段，紧随竞争性DNA和基于蛋白质的技术的脚步。合成mRNA疫苗可以同时递送多种抗原，与其他系统相比，生产更快、更容易且成本低，从而能够更快速地应对新出现的病原体。此外，裸mRNA产生的免疫反应可能有利于疫苗接种。目前正在临床试验中使用离体mRNA转染的树突状细胞（DC）对传染病进行免疫，并已证明具有良好的安全性和诱导抗原特异性T细胞反应的能力。      另一种RNA疫苗接种方法是使用自扩增mRNA复制子，这些复制子已被开发用于延长抗原表达的持续时间和幅度以及增强免疫反应。在最近的一项研究中，将复制子疫苗配制成由反复支化的树状大分子（树状）分子组成的纳米颗粒，已经产生了针对广谱致命病原体的保护性免疫，包括寨卡病毒、埃博拉病毒和流感病毒。传统的修饰mRNA也被探索用于疫苗接种。最近有报道，编码寨卡病毒前膜糖蛋白和包膜糖蛋白的脂质纳米颗粒包膜mRNA在皮内给药后可在小鼠和非人灵长类动物中引发针对病毒的强大且持久的中和抗体反应。此外，在全身施用mRNA-LNPs后，编码广泛中和抗体的修饰mRNA在肝脏中的表达保护了人源化小鼠免受HIV-1攻击。在癌症免疫疗法成功的推动下，癌症mRNA疫苗经历了加速开发和临床转化。临床试验中测试的大多数方法采用过继转移转染编码肿瘤特异性抗原（tumor-specificantigen，TSA）的mRNA，以及用表达嵌合抗原受体（chimericantigenreceptor，CAR）或TSA的mRNA对T细胞进行免疫调节。此外，目前正在临床上研究直接皮内和全身施用编码肿瘤特异性抗原的LNP配制的mRNA以诱导T细胞免疫反应。      相比之下，大多数基于mRNA的蛋白质替代疗法仍处于临床前开发阶段，涉及补充缺陷或异常蛋白质以及通过表达外源性蛋白质来调节细胞行为。RNA-蛋白质疗法的体内疗效已得到证实，可用于多种疾病。由于将RNA递送到肝组织的成熟且有效的方法，大多数研究优先靶向肝脏。在血友病B小鼠中，单次静脉注射载有hFIXmRNA的LNP后，达到治疗相关的人FIX（hFIX）蛋白量，并维持生理活性4-9天。同样，用编码促红细胞生成素（Epo）的mRNA配制的LNP已被证明可在大型动物（包括猪和非人灵长类动物）中引发全身生理反应。mRNA的治疗作用也已在其他组织中得到证实。表面活性剂蛋白B（SP-B）mRNA的肺递送可保护小鼠免受呼吸衰竭，而心肌注射编码人血管内皮生长因子A（VEGF-A）的RNAiMAX配制的mRNA可改善小鼠心肌梗死后的心脏再生。基于这一概念，阿斯利康与Moderna合作，从2017年1月开始启动了VEGFmRNA本地递送的I期临床试验。临床前研究表明，基于mRNA的蛋白质疗法对分泌蛋白靶标和细胞内蛋白靶标均具有转化潜力。然而，慢性病的治疗可能会带来更高的毒性风险，这与维持蛋白质治疗水平所需的重复mRNA-LNP给药有关。使用mRNA递送基因编辑工具可以解决这一挑战。3.基因编辑      上面讨论的基于RNA的技术构成了瞬时抑制或过表达基因表达的强大手段。相比之下，治疗性基因编辑需要通过在细胞基因组中引入位点特异性修饰来替换或改变基因表达，包括纠正有害突变或引入保护性突变。虽然目前大多数基因编辑工作都集中在治疗由单个基因的有害变化引起的单基因疾病上，但基因编辑和递送工具的扩展使得复杂多基因疾病的治疗，如心血管疾病和抗病毒疗法，以及编辑表观基因组更加可行。RNA引导的DNA核酸内切酶的发现，如与CRISPR（成簇的规则间隔短回文重复序列）相关的Cas9，这些元件构成了原核适应性免疫系统，为科学家们提供了一个易于使用和高效的平台来改变基因组信息。所谓的CRISPR-Cas系统依赖于单个向导RNA（sgRNA）和相应的DNA靶位点之间的Watson-Crick碱基配对，后跟一个独特的前间隔区相邻基序（PAM），这是一个结合Cas9和切割靶序列所需的3-5个核苷酸的DNA序列，以便将双链断裂（DSB）引入DNA分子。DSB可由细胞使用非同源末端连接（NHEJ）和同源定向修复（HDR）进行修复。NHEJ导致随机插入和缺失（“插入缺失”），导致永久性基因敲除，而HDR发生在存在与DSB位点两侧区域同源的DNA模板的情况下，导致修复模板中编码的所需变化掺入基因组。DSB的组合也可用于通过使用不同的sgRNA来编辑多个基因座。      迄今为止，使用最广泛和表征最明确的基因编辑技术是CRISPR-Cas9系统，其效应结构域源自化脓性链球菌（SpCas9）。最近，在杜氏肌营养不良症（mdx）、遗传性I型酪氨酸血症（fah）和致死性代谢性肝病（OCT）的动物模型中，将spCas9直接递送到患病细胞中，用于纠正基因突变，并通过敲除PCSK9来降低具有人源化肝脏的嵌合小鼠的血液胆固醇。使用spCas9进行离体编辑已应用于人类造血干细胞，以纠正由编码β-珠蛋白的基因突变引起的镰状细胞贫血，以及耗尽CCR5表达的T细胞以触发抗HIV保护或耗尽PD-1以促进抗癌治疗。尽管取得了积极的结果，但这些研究揭示了CRISPR-Cas9系统与临床翻译相关的局限性，包括（1）DNA靶向特异性不完善导致脱靶效应，（2）使用HDR进行基因组编辑的效率低，以及（3）使用病毒和非病毒方法难以递送CRISPR-Cas9成分。       通过将优化设计和向导RNA的合成相结合，可以提高CRISPR-Cas9的DNA靶向特异性。特别是，短于20个核苷酸且包含5'错配的sgRNA显示出较少的脱靶效应，而化学合成的在5'和3'末端带有碱基修饰的sgRNA显示出更高的靶向功效。此外，根据spCas9-gRNA复合物与DNA之间的相互作用，将特异性突变引入spCas9中，从而改造了改进的spCas9类型，例如高保真spCas9-HF1或增强特异性的eSpCas9。最近发现了新的RNA引导的核酸酶，如来自酸氨基球菌属的Cpf1（AsCpf1），具有编辑哺乳动物细胞基因组的能力。Cpf1核酸酶mRNA（~1.3kb）明显小于Cas9，具有不同的PAM要求和比spCas9更高的DNA特异性，这使得它对临床使用具有吸引力。也可以通过在有利于瞬时表达而不是持久表达的条件下减少spCas9的细胞存在来限制脱靶效应，这可以通过优化递送方法来实现。      通过HDR获得更好的基因组编辑效率对于解决需要高水平治疗产品的遗传疾病是必要的，特别是当编辑后的细胞在适应性方面没有表现出积极的变化，并且随着时间的推移而超过患病的细胞时。通过设计一种不对称的单链DNA模板，该模板与非靶DNA链退火，可以显著提高HDR校正的效率，这是第一个从Cas9-DNA复合物中释放的DNA链。此外，许多研究报道了将CRISPR-Cas9与NHEJ的小分子抑制剂（如DNA连接酶IV或DNA依赖性蛋白激酶抑制剂）联合使用具有更好的HDR疗效。或者，可以通过参与同源重组的关键蛋白质激动剂（如Rad51）来增强HDR。最近，已经开发了其他使用CRISPR-Cas9进行基因编辑的方法，称为同源非依赖性靶向整合（HITI），它利用NHEJ修复机制进行基因敲入。HITI供体模板旨在确保仅在以正确方向插入时才能确保稳健的基因整合，否则目标DNA会经历Cas9的额外切割。与HDR依赖性编辑相比，该方法已证明转基因插入的体外功效更高，但到目前为止，当在体内进行时，它仅达到敲入效率的3-10%。     由于基本成分的数量，基于CRISPR的药物的细胞内递送是治疗性基因组编辑面临的最重大挑战之一。CRISPR-Cas9组分可以DNA、RNA、RNA-蛋白复合物（RNP）或这些大分子的组合形式递送。这些大分子无法自发地进入细胞，依赖于使用递送载体（如病毒载体、纳米颗粒）或物理和机械递送方法（如核转染、细胞挤压或脂质），这些方法利用电场、机械力或阳离子脂质暂时破坏细胞膜。后者主要适用于治疗性的离体基因编辑，而病毒载体和纳米颗粒主要用于体内基因治疗。      已经使用慢病毒、腺病毒和腺相关病毒（AAV）探索了CRISPR-Cas9的病毒递送。AAV最广泛地用于基因治疗临床试验，因为它们能够转导不同的细胞类型和组织，并且基因组整合的风险低，免疫原性低。然而，AAV的包装容量有限（~4.5kb）使得无法将CRISPR-spCas9的所有组分（包括sgRNA和供体DNA模板）容纳到单个AAV中。值得注意的是，在小鼠中观察到宿主对AAV-CRISPR-Cas9的免疫反应，Cas9免疫原性引起，并可能因其长时间的表达而加剧。      与病毒系统互补，正在开发大量包含各种生物相容性材料的纳米颗粒，用于递送CRISPR-Cas9。与它们在蛋白质调节中的应用一样，用于基因编辑的纳米颗粒已经显示出对核酸货物的高负载能力，能够通过主动靶向和配方来改变有效载荷的生物分布和药代动力学，以及制造简单，对其物理化学参数（如大小/形状和有效载荷释放的动力学）的高度控制。由于mRNA表达的瞬时性质，基于纳米颗粒的CRISPR-Cas成分mRNA递送在治疗上具有吸引力，没有基因组整合和mRNA细胞质活性的风险，与pDNA相比，减轻了克服核屏障的需要（图2）。迄今为止，纳米颗粒介导的spCas9mRNA递送已与编码sgRNA和修复模板的AAV联合使用，以诱导成年动物遗传性酪氨酸血症中Fah基因的修复。单次施用后，肝细胞的校正效率为>6%，远高于先前报道的相同疾病的流体动力学注射pDNA（0.4%）。同样，编码锌指核酸酶的mRNA复合成壳聚糖包被的纳米颗粒，与表达AAV6的供体模板联合使用，导致SP-B缺陷小鼠编码表面活性剂蛋白B的基因得到纠正，并延长了它们的生存期。有趣的是，mRNA纳米颗粒与病毒的组合优于单独的AAV，在肺细胞中达到~9%的HDR率。最近，一项研究描述了两性离子氨基脂质的合成和开发，该脂质由磺基甜菜碱头部基团和具有疏水尾部的多胺接头组成，用于配制能够在体内同时递送Cas9mRNA和sgLoxP的纳米颗粒，以诱导LSL-TdTomato小鼠肝脏、肾脏和肺中氟化tdTomato的表达。这项研究表明，纳米颗粒-RNA平台有可能将CRISPR-Cas9的多个组分容纳到单个载体中，并且可能扩展到还包括供体模板。脂质和多肽纳米颗粒也被用于递送Cas9和sgRNA的RNA-蛋白质复合物，这是确保Cas9瞬时细胞存在的另一种有前途的策略，可以显著降低脱靶效应。然而，体内RNP递送的治疗潜力尚未得到证明。【NO.3】结论      经过二十多年的发展，RNA疗法已成为临床现实。用于合成siRNA、ASO和mRNA的设计和化学试剂已经发展到能够实现足够稳定性和免疫逃逸，同时允许维持疗效和特异性的程度。由于在高通量筛选技术的帮助下发现了有效且具有生物相容性的材料，递送技术也取得了长足的进步。尽管最近在撤回Alnylams的siRNA-GalNac偶联物和Curevac的首个mRNA疫苗方面遇到了挫折，但基于核酸的疗法仍在继续取得进展，FDA批准了四种ASO，并且更多具有改进化学修饰的RNA候选药物进入人体试验的晚期阶段（表2)。此外，围绕CRISPR-Cas基因组编辑及其对生物医学科学的变革性影响的巨大兴奋推动了基于RNA的递送方法的发展，以促进CRISPR-Cas技术的临床转化。宾夕法尼亚大学在美国进行的第一项人体试验将使用CRISPR-Cas9离体敲除从癌症患者身上分离的T细胞中编码PD1和T细胞受体α/β的基因，用于癌症治疗。领先的CRISPR生物技术公司，如CRISPR Therapeutics、Editas Medicine和Intellia Therapeutics，在其产品组合中都有处于临床前开发阶段的项目，并且可能很快就会遵循临床路线。这些公司主要关注影响肝脏、肺和造血功能的疾病，同时利用AAV、LNP和RNP开发离体和体内递送方法。这凸显了安全性和递送仍然是基于RNA的药物的主要挑战，尤其是RNA-蛋白质和CRISPR-Cas疗法，并将塑造即将到来的临床试验的范围。毫无疑问，RNA疗法领域目前正在经历重大扩张，将RNA药物用于个性化医疗和免疫疗法以及解决遗传、感染和慢性疾病的潜力将确保RNA疗法在未来几年的持续发展。识别微信二维码，添加抗体圈小编，符合条件者即可加入抗体圈微信群！请注明：姓名+研究方向！本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。