This study encompasses multicenter open-label, phase II trials.
Patients will be dispatched into 2 cohorts:
* Cohort A: Patients naïve from systemic treatment will be randomized according to two treatment modalities: atezolizumab + tiragolumab (arm A1) versus atezolizumab monotherapy (arm A2).
43 patients are to be included in each arm.
* Cohort B: Patients with previous exposure to ICI will be treated with the combination of atezolizumab and tiragolumab.
29 patients are to be included in this cohort.

开始日期2025-07-01

申办/合作机构

Institut Gustave Roussy EURL

[+1]

NCT06603818

/ Not yet recruiting临床2期IIT

A Phase II Study of Immunotherapies (Tiragolumab and Atezolizumab) in Combination With Stereotactic Body Radiation Radiotherapy in Microsatellite Stable (MSS) Metastatic Colorectal Cancer (mCRC)

Background:
Metastatic colorectal cancer (mCRC) is cancer that has spread beyond the colon and rectum. Most people with mCRC die within 5 years. New immune-based treatments are making progress with some types of colon cancer. But these treatments do little for people with a type of cancer that is microsatellite stable (MSS). MSS is a specific cancer biomarker. Better treatments are needed.
Objective:
To test 2 drugs (tiragolumab and atezolizumab) combined with radiation therapy in people with MSS mCRC.
Eligibility:
People aged 18 years and older with MSS mCRC.
Design:
Participants will be screened. They will have a physical exam with blood tests. They will have imaging scans and a test of their heart function. They will provide a tissue sample from their tumor; if one is not already available, a new sample will be taken. Their ability to perform normal tasks will be assessed.
Tiragolumab and atezolizumab are both administered through a tube attached to a needle inserted into a vein. Participants will receive both drugs on day 1 of 3-week treatment cycles. Each study visit should last about 8 hours.
Participants will receive radiation therapy on days 1, 3, and 5 of cycle 1 only.
Blood samples and rectal swabs will be collected on day 1 of every cycle.
Imaging scans will be repeated every 9 weeks. Additional tumor samples may be taken during treatment.
Treatment will continue for up to 2 years.
Participants will have a follow-up visit 1 month after treatment ends. Follow-up visits will continue every 3 months for 1 more year.

开始日期2025-06-29

申办/合作机构

National Cancer Institute

NCT06328036

/ Withdrawn临床2期IIT

Phase 2 and Biomarker Trial of Anti-TIGIT and Anti-PDL1 in Patients With Recurrent Glioblastoma

This phase II trial compares the safety, side effects and effectiveness of atezolizumab with tiragolumab to atezolizumab alone in treating patients with glioblastoma that has come back after a period of improvement (recurrent). Glioblastoma is the most common primary brain cancer in adults and despite aggressive treatment, it is nearly always fatal. Currently, there are limited effective treatment options in patients that have recurrence. Immunotherapy has been shown to be effective in other types of cancer and may be an appealing potential treatment option for recurrent glioblastoma. Immunotherapy with monoclonal antibodies, such as atezolizumab and tiragolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Study doctors also want to learn if a tumor infiltrating T lymphocyte (TIL) response is helpful to determine the benefit of the combination of study drugs compared to the usual approach. TILs are a type of immune cell that has moved from the blood into a tumor. TILs can recognize and kill tumor cells. Giving atezolizumab with tiragolumab may be safe, tolerable and/or effective compared to atezolizumab alone in treating patients with recurrent glioblastoma.

开始日期2025-04-30

申办/合作机构

National Cancer Institute

100 项与替瑞利尤单抗相关的临床结果

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100 项与替瑞利尤单抗相关的转化医学

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100 项与替瑞利尤单抗相关的专利（医药）

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项与替瑞利尤单抗相关的文献（医药）

2025-05-01·CLINICAL PHARMACOLOGY & THERAPEUTICS

Model‐Informed Selection of the Recommended Phase 2 Dosage for Anti‐TIGIT Immunotherapy Leveraging co‐Expressed PD‐1 Inhibitor Target Engagement

Article

作者: Hu, Ping ; Venkatakrishnan, Karthik ; Gao, Wei ; Kareva, Irina ; Victor, Anja ; Kitzing, Thomas ; Richter, Emilia ; Pierre, Vadryn ; Zutshi, Anup

Refining dose projections requires a deep understanding of drug‐target relationships at the site of action, which is often challenging to achieve. Here we present a case study of how one can refine dose projections for a TIGIT‐targeted immunotherapy by leveraging information from the well‐studied PD‐1 pathway since the co‐expression of PD‐1 and TIGIT on immune cells provides a unique opportunity to extrapolate data from one target to inform the dosing strategy for the other. We develop a fit‐for‐purpose mathematical model that captures the experimentally observed relationship between the concentration of a mouse PD‐1 antagonist in the plasma and PD‐1 target engagement within the tumor microenvironment (TME). We then assess the applicability of this PD‐1 model to elucidate the relationship between drug concentration and target engagement for tiragolumab, an anti‐TIGIT antibody, across various doses. This analysis aims to refine our understanding of the dose–response relationship for targeting TIGIT, a critical step in optimizing therapeutic efficacy, without conducting additional experiments. The approach is then extended to project efficacious doses for M6223, another anti‐TIGIT antibody, using the established PD‐1 model, by leveraging the M6223 clinical PK and PD data, as well as virtual population analysis. This work provides a case study of a possible framework for refining dose projections via quantitative estimation of drug‐target relationship at the site of action by leveraging established drug‐target relationships. Through extrapolating information from a well‐characterized pathway, we offer a method to inform dose optimization strategies with limited data using model‐informed drug development.

2025-03-01·BMJ Open

NeoTRACK trial: Neoadjuvant TiRagolumab, Atezolizumab and Chemotherapy – dissection of IO- efficacy in NSCLC by longitudinal tracKing – protocol of a non-randomised, open-label, single-arm, phase II study

Article

作者: Kirchner, Marietta ; Doerr, Fabian ; Cvetkovic, Jelena ; Christopoulos, Petros ; Bölükbas, Servet ; Thomas, Michael ; Wiesweg, Marcel ; Stenzinger, Albrecht ; Eichhorn, Martin E ; Winter, Hauke ; Hegedüs, Balazs ; Schnorbach, Johannes ; Klotz, Laura V ; Schneider, Marc ; Allgaeuer, Michael ; Schramm, Alexander ; Eichhorn, Florian ; Bozorgmehr, Farastuk ; Schuler, Martin ; Griffo, Raffaella ; Roesch, Romina M

Background:

Immunotherapies targeting the programmed death receptor-1/programmed death ligand-1(PD-1/PD-L1) checkpoint have a major impact on the treatment of both resectable and advanced non-small cell lung cancer (NSCLC). Additional blockade of the T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domain (TIGIT)-receptor may synergistically foster the immune-related response. Several trials are currently investigating the combination of neoadjuvant platinum-based chemotherapy and dual checkpoint inhibition prior to curative surgery. The investigator-initiated NeoTRACK trial (EU CT number: 2022-501322-38-00; ClinicalTrials.gov identifier:NCT05825625; IKF056) aims to evaluate the feasibility and safety of perioperative anti-PD-L1 (by atezolizumab) and anti-TIGIT (by tiragolumab) treatment in combination with chemotherapy in patients with early stage NSCLC.

Methods and analysis:

NeoTRACK is an open-label, single-arm, prospective, bicentric phase II trial. Patients with NSCLC in clinical stages II, IIIA and IIIB (only T3N2) will receive two cycles of standard platinum-based chemotherapy in combination with the anti-TIGIT antibody tiragolumab and the anti-PD-L1 antibody atezolizumab, followed by curative surgery. After surgery, patients without pathological complete response (pCR) will receive another two cycles of chemotherapy in combination with tiragolumab and atezolizumab, followed by tiragolumab/atezolizumab maintenance for up to 1 year (maximum 16 cycles). Patients with pCR will only receive dual immunotherapy. All patients will be followed-up for 30 months after the last study treatment. The clinical study will be aligned with a translational research programme to investigate treatment-naïve tumour tissues, surgical specimens and longitudinally collected blood samples. 35 patients are planned for enrolment. Patient recruitment started in August 2023, and treatment of the last patient is estimated to start 2.5 years thereafter.

Discussion:

The NeoTRACK trial aims to assess the feasibility and efficacy of combining tiragolumab and atezolizumab as both neoadjuvant and adjuvant therapies in patients with resectable NSCLC. The concept of treatment personalisation based on postoperative pCR is of great clinical interest.

Ethics and dissemination:

The trial obtained ethical and regulatory approval in Germany through the Clinical Trials Information System (CTIS, ID: 2022-501322-38-00) and the Paul Ehrlich Institute (PEI, competent authority for approval of clinical trials using medicinal products for human use in Germany, process number: PB00148) on 30 March 2023. A data safety and monitoring board will meet regularly to review ongoing treatment in terms of safety.Study results will be published in peer-reviewed journals, presented at conferences and in the public registry of CTIS, following trial completion.

Trial registration number:

NCT05825625.

2025-02-01·LANCET ONCOLOGY

Tiragolumab in combination with atezolizumab and bevacizumab in patients with unresectable, locally advanced or metastatic hepatocellular carcinoma (MORPHEUS-Liver): a randomised, open-label, phase 1b–2, study

Article

作者: Yu, Nancy ; Wang, Yulei ; Hack, Stephen P ; Ryoo, Baek-Yeol ; Mahrus, Sami ; Burgoyne, Adam M ; Secrest, Matthew H ; Li, Daneng ; Yin, Anqi ; Edubilli, Tirupathi Rao ; Gane, Ed ; Finn, Richard S ; Badhrinarayanan, Shreya ; Shemesh, Colby S ; Cotter, Christopher ; Cha, Edward ; Hsu, Chih-Hung

BACKGROUND:

PD-L1 and VEGF blockade with atezolizumab plus bevacizumab has been shown to improve survival in unresectable hepatocellular carcinoma. TIGIT is an immune checkpoint regulator implicated in many cancers, including unresectable hepatocellular carcinoma. Here, we evaluate the clinical activity and safety of the addition of tiragolumab, an anti-TIGIT monoclonal antibody, to atezolizumab plus bevacizumab.

METHODS:

This randomised, open-label, phase 1b-2 umbrella study was conducted at 26 centres across China, France, Israel, New Zealand, South Korea, Taiwan, and the USA. Eligible patients were adults aged 18 years old or older with previously untreated locally advanced unresectable hepatocellular carcinoma, an Eastern Cooperative Oncology Group performance status of 0-1, Child-Pugh class A disease, and a life expectancy of at least 3 months. Eligible patients were randomly assigned (2:1) using permuted block randomisation to receive either tiragolumab 600 mg plus atezolizumab 1200 mg plus bevacizumab 15 mg/kg or atezolizumab 1200 mg plus bevacizumab 15 mg/kg, administered via intravenous infusion every 3 weeks on day 1 of each 21-day cycle. Patients received treatment until unacceptable toxic effects or loss of clinical benefit, whichever occurred first. The primary endpoint was objective response rate. Analysis of clinical activity was done in the efficacy-evaluable population (all patients who received at least one dose of each drug for their assigned treatment regimen) and safety was assessed in all patients who received any study treatment. The trial is registered with ClinicalTrials.gov, NCT04524871, and is ongoing.

FINDINGS:

Between Aug 20, 2020, and Feb 10, 2022, we assessed 154 patients for eligibility and 59 eligible patients were randomly assigned to receive tiragolumab plus atezolizumab plus bevacizumab (n=41) or atezolizumab plus bevacizumab (n=18); one patient in the tiragolumab plus atezolizumab plus bevacizumab group experienced an adverse event before receiving any treatment and withdrew from the study. Median age was 65·0 years (IQR 61·0-73·0). 46 (79%) of 58 patients were male and 12 (21%) were female. Most patients were Asian (23 [40%]) or White (21 [36%]). At the time of clinical cutoff (Aug 21, 2023), median follow-up was 20·6 months (IQR 10·6-28·0) in the tiragolumab plus atezolizumab plus bevacizumab group and 14·0 months (4·2-18·5) in the atezolizumab plus bevacizumab group. The confirmed objective response rate was 43% (95% CI 27-59, n=17) in the tiragolumab plus atezolizumab plus bevacizumab group and 11% (1-35, n=2) in the atezolizumab plus bevacizumab group. All patients in both groups experienced an adverse event. The incidence of pruritis (20 [50%] of 40 patients vs three [17%] of 18 patients), arthralgia (13 [33%] vs two [11%]), and diarrhoea (12 [30%] vs one [6%]) was notably higher in the tiragolumab plus atezolizumab plus bevacizumab group than in the atezolizumab plus bevacizumab group, although these were mainly grade 1-2. The most common grade 3-4 adverse events were hypertension (six [15%] of 40 patients in the tiragolumab plus atezolizumab plus bevacizumab group vs two [11%] of 18 patients in the atezolizumab plus bevacizumab group), aspartate aminotransferase increased (three [8%] of 40 patients vs one [6%] of 18 patients), and proteinuria (two [5%] of 40 patients vs two [11%] of 18 patients). Serious adverse events occurred in 21 (53%) of 40 patients in the tiragolumab plus atezolizumab plus bevacizumab group and in ten (56%) of 18 patients in the atezolizumab plus bevacizumab group. Treatment-related deaths occurred in one patient in the tiragolumab plus atezolizumab plus bevacizumab group (due to cholestasis) and two patients in the atezolizumab plus bevacizumab group (due to oesophageal varices haemorrhage and upper gastrointestinal haemorrhage). The addition of tiragolumab to atezolizumab plus bevacizumab did not appear to result in a substantial worsening of treatment-related or immune-mediated adverse events, and no new safety signals were identified.

INTERPRETATION:

This signal-seeking study suggests that the addition of tiragolumab to atezolizumab and bevacizumab might be more clinically active than atezolizumab plus bevacizumab alone in unresectable hepatocellular carcinoma. Based on these data, further study of combination tiragolumab plus atezolizumab plus bevacizumab is warranted.

FUNDING:

F Hoffmann-La Roche and Genentech.

312

项与替瑞利尤单抗相关的新闻（医药）

2025-06-13

·FierceBiotech

The trouble with TIGITs: How \'overenthusiasm\' led to Big Pharma\'s risky $6B gamble

“People went for Fc-competent [TIGITs] because it worked best in mice,” said Leerink Partners analyst Daina Graybosch, Ph.D. “They couldn\'t help themselves.\"\n Once hailed as the future of immuno-oncology, it’s been a tough few months for any remaining fans of anti-TIGIT antibodies.In April, BeOne Medicines, formerly known as BeiGene, announced it was scrapping ociperlimab over a disappointing phase 3 outlook two years after Novartis handed back the asset. Specifically, the study’s independent data monitoring committee deemed the trial unlikely to show that a combination of ociperlimab and BeOne’s own PD-1 inhibitor Tevimbra would beat Keytruda in patients with PD-L1-high non-small cell lung cancer (NSCLC).The following month brought more tough times for TIGITs, as GSK halted development of its own candidate belrestotug after deciding the iTeos Therapeutics-partnered drug in combination with anti-PD-1 inhibitor Jemperli wouldn’t score a phase 2 win in a similar NSCLC population.Even executives at Roche, whose tiragolumab appeared to buck the trend with a caveated phase 3 win in esophageal cancer in 2024, reaffirmed to Fierce Biotech earlier this year that “we stopped all of the tiragolumab trials that we could stop, and those that couldn\'t be stopped are just running out.”With Big Pharma having pumped $6 billion into this modality, what went so wrong for TIGITs?Daina Graybosch, Ph.D., a senior research analyst at Leerink Partners who covers immuno-oncology, traces the problems back to the exuberant reaction to Roche’s impressive phase 2 tiragolumab data that read out across 2020 and 2021. The Cityscape trial demonstrated that the TIGIT drug in combination with Roche’s own PD-L1 blocker Tecentriq shrank tumors in 31% of patients with metastatic lung cancer—twice as many patients as Tecentriq alone.“That\'s probably the biggest point where the field went wrong, in that they looked at this massive benefit in the small phase 2, and everybody ran after it in a parallel and broad way,” Graybosch told Fierce in an interview.“We had randomized phase 2 data from Roche, from Arcus-Gilead, from iTeos-GSK, and they all consistently showed benefit in response rate and in [progression-free survival],” she added.“I think the challenge ultimately was: How much benefit is there really? Is it enough benefit to be clinically meaningful? And are we developing the drugs in the right way, in the right format, to optimize and bring that benefit to patients?”The industry’s “overenthusiasm” for the potential of TIGITs led to a “simplistic approach” to how other companies planned to develop their own candidates, according to Graybosch.If pharmas had anticipated a “more realistic demonstration of benefit,” as seen in the failed Skyscraper-01 phase 3 study in NSCLC, “I think everybody would have developed [TIGITs] differently,” she suggested.Companies swimming in the TIGIT space have broadly fallen into two camps. Roche’s tiragolumab, along with Merck & Co.’s vibostolimab, GSK and iTeos’ EOS-448, and BeOne’s ociperlimab, are all Fc-enabled. These antibodies retain a fully functional Fc region, meaning they can bind to Fc receptors found on the cell surface and contribute to the protective antitumor functions of the immune system.The theory behind Fc-enabled anti-TIGIT antibodies is that they have enhanced tumor-killing effects. However, the risk is that they could possibly also eliminate certain regulatory T cells and therefore lead to unwanted immune responses.In fact, side effects did cast a shadow over some of the Fc-enabled TIGIT trials, with Merck halting a phase 3 trial of vibostolimab due to a higher than expected rate of discontinuations blamed on “immune-mediated adverse experiences.”“Toxicity that may lead patients to discontinue I think ended up being a contributing factor across the Fc-enabled TIGITs that are all now dead,” Graybosch said.The last TIGITs still standing—Arcus Biosciences and Gilead’s domvanalimab, as well as AstraZeneca’s TIGIT/PD-1 bispecific antibody rilvegostomig—have mutated out the Fc function. This should mean they are less toxic for patients.“People went for Fc-competent because it worked best in mice,” Graybosch explained. “They couldn\'t help themselves, even though they knew there was some risk of depleting T effector cells that are actually what you need to fight your tumor.” Focusing on \'modest benefit\'So, what would a more measured approach to the TIGIT gold rush have meant in practice?“I think you ultimately do what Astra is doing,” said Graybosch, referring to AstraZeneca’s ongoing phase 3 trials of its bispecific rilvegostomig in a range of phase 3 studies for NSCLC or stomach cancer, including in combination with its Daiichi Sankyo-partnered antibody-drug conjugates Enhertu or Datroway.“Astra is recognizing the modest benefit,” she explained. “Their bispecific is very safe because it\'s Fc silent. And in some ways, Astra can\'t lose because [rilvegostomig] doesn\'t need to work that much for a lot of their trials to be successful.”AstraZeneca’s Puja Sapra, Ph.D., senior vice president for biologics engineering and oncology target discovery, was also upbeat about rilvegostomig’s prospects when she spoke to Fierce back in April. She pointed to the fact that engineering the bispecific to reduce Fc effector functionality should reduce unwanted side effects, while blocking both PD-1 and TIGIT at the same time “should hopefully help us increase the response rate and durability.”“At least in preclinical studies, we see that a bispecific molecule has better responses than a combination of both agents alone,” Sapra said at the time. “The molecule is doing very well in the clinic so far, so we continue to believe in this molecule.”Gilead is also staying loyal to its TIGIT candidate, which is being evaluated in phase 3 trials for first-line NSCLC as well as for locally advanced unresectable or metastatic gastric, gastroesophageal junction and esophageal adenocarcinoma.The pharma’s chief medical officer Dietmar Berger, M.D., Ph.D., told Fierce earlier this month that the Arcus-partnered domvanalimab still has a chance, pointing to its Fc-silent character.“We believe there is differentiation but, of course, we need to see how those studies read out,” Berger said. “Any additional activities around that will be based on what we see in those studies.”With AstraZeneca and Gilead still holding a candle for their Fc-silent candidates, Leerink’s Graybosch doesn’t think “it\'s fair to completely write off TIGIT.”“But if you ask 99% of average investors, generalists or specialists and [key opinion leaders], I think they’ll tell you it\'s dead,” she added.Angus Liu contributed to this reporting.

$The trouble with TIGITs: How \'overenthusiasm\' led to Big Pharma\'s risky $6B gamble$

临床3期临床结果临床2期

2025-06-09

·FierceBiotech

\'We are in a good spot\': Gilead\'s new chief medical officer is committed to pipeline diversification

“We have a pipeline that can deliver at this point, but we will absolutely further optimize it,” Gilead Sciences\' Dietmar Berger, M.D., Ph.D., told Fierce.\n Dietmar Berger, M.D., Ph.D., joined Gilead Sciences as chief medical officer at the start of this year after the company’s oncology department suffered some prominent setbacks. The run of bad luck included two back-to-back phase 3 flops of Trodelvy in non-small cell lung cancer and bladder cancer as well as the demise of the anti-CD47 drug magrolimab from a $4.9 billion acquisition.But Berger, who boasts a deep background in cancer drug development, still believes the virology giant made the right move to branch out into oncology and immunology.“I am a strong believer that diversification for Gilead is the right decision,” Berger told Fierce in an interview on the sidelines of the 2025 American Society of Clinical Oncology (ASCO) annual meeting.“I also think that oncology and immunology are the right areas for Gilead, because of the emerging science … and because we can apply a lot of the strength that Gilead has—for example in chemistry, in protein design and deep understanding of biology—very strongly to oncology and immunology.”As a new head of development joining a biopharma company, it’s natural to think about ways to improve the portfolio, he said. “We have a pipeline that can deliver at this point, but we will absolutely further optimize it,” Berger added.The CMO said he’s trying to build a “balanced” and “partially derisked portfolio” by combining direct cytotoxic mechanisms with immuno-oncology. Again, diversification is key here. At ASCO, Gilead’s cell therapy unit Kite Pharma reported some early positive data for its anti-CD19/CD20 bicistronic CAR-T therapy in advanced B-cell lymphoma. Another bivalent CAR-T candidate partnered with the University of Pennsylvania targeting EGFR and interleukin-13 receptor alpha 2 recorded notable tumor shrinkage in eight (62%) of 13 patients with recurrent glioblastoma, a notoriously aggressive and hard-to-treat brain cancer.Trodelvy also had a positive story to tell at this year’s ASCO, courtesy of two positive phase 3 readouts in first-line triple-negative breast cancer (TNBC). In a potentially practice-changing data set, Trodelvy and Merck & Co.’s Keytruda significantly reduced the risk of progression or death by 35% versus Keytruda and chemotherapy in first-line PD-L1-positive TNBC.In immuno-oncology, Berger highlighted GS-1811, an anti-CCR8 antibody Gilead obtained from Jounce Therapeutics. The drug, designed to remove immunosuppressive tumor-infiltrating T regulatory cells, is still in early-stage development.All told, Gilead has 58 projects across virology, oncology and immunology in its portfolio, the largest and most diverse pipeline in the biopharma\'s history. Challenges in ADC and immuno-oncologyFor Trodelvy, new TROP2 competition has arrived in the form of AstraZeneca and Daiichi Sankyo’s Datroway and Merck and Kelun-Biotech’s sac-TMT.In Trodelvy’s home base of second-line TNBC, the Gilead drug is the only one that has demonstrated an overall survival benefit. Parallel data that could help experts compare these drugs side by side in a cross-trial fashion have not yet read out, Berger explained.Besides first-line TNBC, Trodelvy is also being tested in earlier-line HR-positive, HER2-negative breast cancer, which could represent a bigger patient population than TNBC. Following the Evoke-01 flop, the Evoke-03 study for Trodelvy and Keytruda in first-line PD-L1-high NSCLC remains ongoing.Since Gilead’s $21 billion acquisition of Immunomedics in 2020, the company still has only one antibody-drug conjugate asset, whereas other players in the space such as AstraZeneca and Pfizer have developed multiple products.The Immunomedics deal was a strategic acquisition designed to give Gilead an anchor in its diversification into solid tumors, and the company then built R&D capabilities around that, Berger noted.“That bit of a time lag is largely based on: How do you build an oncology organization?” Berger said.New oncology molecules are now coming out of Gilead’s internal research capabilities, and the company will also “focus strongly” on external opportunities, he said. Berger wouldn’t name specific ADC projects outside of Gilead that he’s interested in. Toward the end of 2024, before Berger officially moved across from Sanofi, Gilead penned a deal with Tubulis to develop a topoisomerase I inhibitor-based ADC.“There’s usually the question, do you combine different mechanisms, or do you double down on a specific pathway,” Berger said of target selection for ADCs.Choosing the linker is dependent on whether a bystander effect—in which the cytotoxic payload from the ADC kills cells surrounding the target cell—is desired, and the toxin needs to be carefully evaluated because these payloads hit different tumor types differently, Berger noted.Meanwhile, things don’t look too promising for Gilead’s late-stage immuno-oncology program, the Arcus Biosciences-partnered domvanalimab. The drug is one of the few remaining anti-TIGIT antibodies still in development after companies such as Merck, Bristol Myers Squibb, GSK and BeOne (formerly BeiGene) walked away from the field. Roche’s Genentech, where Berger used to lead oncology clinical development, has all but abandoned tiragolumab after several disappointing studies, and the pharma is now only waiting for two fully enrolled phase 3 trials to read out.Berger argued that domvanalimab may still stand a chance. The TIGIT molecules that have failed so far are mostly Fc-competent antibodies, whereas domvanalimab is Fc-silent.Fc-enabled anti-TIGIT antibodies theoretically have enhanced tumor-killing effects because they can bind to FcγRs and activate immune cells. But they could possibly also eliminate certain regulatory T cells and therefore lead to unwanted immune responses. Before nixing its TIGIT candidate vibostolimab, Merck had noted a higher rate of immune-related adverse events in at least two failed phase 3 trials. Only data will tell whether Fc-competence is the key. Gilead and Arcus are running two phase 3 trials that combine domvanalimab with Arcus’ PD-1 drug zimberelimab and chemotherapy in first-line NSCLC and gastric, gastroesophageal junction and esophageal adenocarcinoma.Gilead has a stated goal to have 30% of its revenue from oncology products by 2030. Berger acknowledged that the huge clinical success—and potential imminent approval—of twice-yearly lenacapavir for HIV prevention could make achieving that goal harder but said the company remains committed to a target of 30% of revenue from outside virology.“It does place a stronger focus on oncology,” Berger said. “But don’t get me wrong, I think we are in a good spot now.”

$\'We are in a good spot\': Gilead\'s new chief medical officer is committed to pipeline diversification$

临床3期免疫疗法临床结果ASCO会议并购

2025-06-07

·同写意

巨头药企，砸了上千亿

同写意年度巨献！！7月25-26日，邀您相聚金鸡湖畔，与5000人一起为中国医药创新“同写意”！随着生物医药并购、BD持续高涨，跨国巨头作为“收割者”的形象似乎越发牢固。虽然Biotech贡献了更多原始创新已成为定论，但这不意味着MNC就在新药开发方面乏善可陈。Evaluate Pharma最新报告显示，2024年全球制药行业的研发支出增长1.5%，其中，来自MNC的资金占据大半。考虑到2023年整体研发预算飙升了11.5%，以行业自身的标准来看，2024年的1.5%属于一个相对温和的增幅。尽管如此，去年用于新药开发的资金规模仍然令人震惊：全球药企在研发方面投入了近2880亿美元。众所周知，从Lipitor、Humira再到今天的“药王”Keytruda，无论多么成功的“重磅炸弹”，都有其专利时限。如果药企不持续投入研发资金，产品组合得不到更新，那么“专利悬崖”带来的压力就将是实打实的“刀刀见血”——营收减少、股价下滑乃至需要裁员重组。直接买资产固然是条快捷通道，然而归根结底，这仍需要有人来完成“从0到1”的工作。因此，Evaluate Pharma预计，到2030年，该行业的研发开支将继续增加，达到3400亿美元左右。不确定之处在于，制药行业的研发支出模式可能面临越来越不稳定的外部环境。例如，美国特朗普政府正在推动的“最惠国定价”政策会导致药企在美国市场的收入骤减，进而影响可用的研发资金。分析师认为，制药公司可能更加注重对管线的排序，优先考虑盈利能力更强、竞争优势更大的研发项目。换言之，把握这些“金主”的动向，某种程度就是在捕捉未来的创新机会。下文将就2024年制药行业研发支出排名前五的MNC进行梳理。TONACEA01默沙东 2024年研发支出：179亿美元同比变化：-41%对于默沙东而言，2023年是一个耗资不菲的交易大年。这家巨头先是与Proxygen达成一项最高25.5亿美元的分子胶开发合作协议，随后宣布斥资108亿美元收购免疫药物开发商Prometheus Biosciences、以30亿美元收购新锐眼科公司EyeBio，下半年又以40亿美元的预付款、总计220亿美元的对价获得第一三共旗下三种ADC的授权许可。由于2023年的研发资金特别庞大，2024年默沙东的研发支出同比减少41%，更像是对预算的合理调整。事实上，它仍以179.4亿美元的巨额投资领先于其MNC，相当于其总收入的28%。不惜成本的砸钱，很直接的因素是“现金牛”Keytruda即将迎来专利到期，默沙东不得不大开发力度，以弥补这款“药王”留下的约300亿美元营收缺口。根据默沙东披露的信息，一些值得密切的研发管线，包括约20种潜在的“重磅炸弹”，未来有望给其带来超过500亿美元的回报。其中，包括ifinatamab deruxtecan，这款ADC靶向一种在多种癌症中过表达的跨膜蛋白B7-H3。默沙东正在进行一项III期临床（IDeate-Esophageal01研究），测试该药在晚期或转移性食管鳞状细胞癌中的疗效。Ifinatamab deruxtecan也有望用于治疗已接受过大量治疗的晚期小细胞肺癌，目前该适应症正处于后期开发阶段。默沙东还在探索从Prometheus获得的tulisokibart（MK-7240）在多种炎症性疾病中的疗效。II期临床试验数据显示，与安慰剂相比，使用这款TL1A抗体治疗的溃疡性结肠炎患者中，获得临床缓解的比例更高。目前，tulisokibart正处于治疗溃疡性结肠炎和克罗恩病的III期临床。2月，默沙东首席执行官Robert Davis透露，由于EyeBio的加入，公司眼科业务将迎来巨大机遇。此次收购的核心资产是一款三特异性抗体restoret，现阶段正在评估治疗糖尿病性黄斑水肿（DME）和新生血管性年龄相关性黄斑变性（AMD）的效果。2024年9月，默沙东启动了restoret治疗DME的IIb/III期临床试验，这项名为BRUNELLO的研究最快将在2027年底完成。TONACEA02强生 2024年研发支出：172亿美元同比变化：14.2%早在2023年财报电话会上，强生首席执行官Joaquin Duato就告诉投资者，2024年开始，强生将重新关注其三大优先治疗领域——肿瘤学、免疫学和神经科学，而该公司去年的研发支出在很大程度上反映了这一点。例如，2024年1月，强生斥资20亿美元收购ADC明星公司Ambrx，从而扩大自己在这种癌症治疗热门资产上的布局。对于免疫业务，强生去年还推进了两项巨额投资：以8.5亿美元收购Proteologix及其抗炎皮肤病学资产，并向Numab Therapeutics支付12.5亿美元来收购其用于治疗特应性皮炎的双抗。2024年，强生的研发支出总计超过172亿美元，占其总收入的19%以上。业内人士分析，这些交易不仅帮助强生扩充其早期和中期研发管线，去年该公司也积极推进其后期研发资产的开发。在免疫领域，强生2024年8月递交了申请nipocalimab单抗用于治疗重症肌无力的上市许可申请，并今年4月获得批准，商品名为Imaavy。值得注意的是，神经科学是强生2024年研发计划的薄弱环节。2024年10月，强生削减了其早期、中期神经研究管线，将正在研究的人类食欲素-2受体阻滞剂seltorexant搁置一旁。此前，这家MNC一直在探索seltorexant用于治疗AD患者的躁动和攻击行为。此外，强生还取消了一款用于治疗双相抑郁症的II期离子通道阻滞剂，以及一款用于治疗帕金森病的I期药物。但这种处境似乎正在逆转。1月，强生以146亿美元收购Intra-Cellular Therapies，获得斩获多个适应症的商业化产品Caplyta。强生预计，该药峰值年销售额将达到50亿美元。除了Intra-Cellular的产品组合，当前强生在CNS领域还布局了其他管线，包括esketamine新适应症的拓展，以及开发重度抑郁症药物aticaprant（已处于III期临床），未来销售额峰值预计最高达50亿美元。TONACEA03罗氏研发支出：130亿瑞士法郎（158亿美元）同比变化：1%2024年财报中，罗氏领导层承认，公司面临销售额停滞不前的挑战，主要原因是其COVID产品需求暴跌以及当时的经济困难。该公司将交易列为重振增长的战略之一。不过，与默沙东、强生大幅调整预算不同，罗氏2024年的研发支出同比基本持平。这家瑞士巨头去年在研发和业务发展方面投入了略高于130亿瑞士法郎（约合158亿美元）的资金，较2023年增长1%。在癌症领域研发工作上，2024年也给罗氏带来巨大挑战。例如，2024年7月，TIGIT抗体tiragolumab在用于治疗非小细胞肺癌的II/III期临床试验SKYSCRAPER-06中，未能显著改善患者的无进展生存期，迫使罗氏终止了该试验。同年11月，tiragolumab针对非小细胞肺癌的SKYSCRAPER-01研究数据披露，疗效再次令人失望。或许因为肿瘤药物的开发风险，2024年4月，罗氏就砍掉了三条早期管线，包括曾达成超13亿美元合作、一度被认为是新一代合成致死疗法的camonsertinib。2024年8月，罗氏关闭了其子公司基因泰克的癌症免疫学部门，当时一位发言人称，此次重组的原因是“免疫肿瘤学科学的转变”。与肿瘤治疗赛道不同，过去一年罗氏在肥胖症产品组合布局上可谓收获颇丰，而这得益于其2023年12月以27亿美元现金、4亿美元里程碑付款收购Carmot Therapeutics所获得的资产。2024年5月，罗氏宣布，Carmot开发的GLP-1/GIP受体双重激动剂CT-388在24周内能够使体重降低18.8%。同年7月，罗氏又发布另一项源自Carmot的候选药物数据。根据I期临床结果，口服GLP-1受体激动剂CT-996在使用四周后可使体重减轻6.1%。罗氏去年最引人瞩目的交易，是2024年11月以10亿美元预付款收购Poseida Therapeutics。二者长期保持合作——2022年8月，罗氏就与Poseida达成一项60亿美元的战略合作——罗氏表示，收购加强了双方在CAR-T疗法领域的协同。Poseida手握一系列通用型CAR-T，主要针对多发性骨髓瘤、B细胞淋巴瘤以及其他血液肿瘤。2025年还剩下一半多的时间，罗氏的研发预算将如何变化尚不明朗。不过，这家MNC不太可能在短期内大举花钱。2月份发布的最新年报中，罗氏首席执行官Thomas Schinecker称，公司今年将在交易方面保持“谨慎”，只专注于对公司财务状况有利的资产。TONACEA04阿斯利康 2024年研发支出：136亿美元同比变化：25%阿斯利康首席执行官Pascal Soriot在2024年2月的电话会上表示，公司从2024年开始“投资新技术和新产品”。同年3月，阿斯利康兑现承诺，签署了两项高价收购协议，以扩充其后期研发管线。第一笔交易是与Amolyt Pharma达成的，阿斯利康以8亿美元的预付款收购后者。几天后，阿斯利康又斥资20亿美元收购Fusion Pharmaceuticals。Amolyt核心产品之一是甲状旁腺功能减退症候选药物eneboparatide，该药最近在III期临床中取得了成功，另外，阿斯利康还获得其他正在开发的罕见疾药物。而作为核药明星公司，Fusion为阿斯利康提供了一系列放射性药物研发管线，包括基于锕-225开发的FPI-2265，拟用于治疗转移性去势抵抗性前列腺癌。2024年，阿斯利康也向其早研端投入重金，扩大了其产品组合。例如去年5月，阿斯利康与和铂医药子公司诺纳生物达成总计超6亿美元的协议，引进临床前阶段肿瘤靶向治疗单抗项目。同月，阿斯利康开始进军肥胖领域，斥资8000万美元参与初创公司SixPeaks的A轮融资，后者计划开发可以减肥增肌的ActRIIA/B抗体药物。当然，作为一家肿瘤药物巨头，阿斯利康备受关注的资产除了开创HER2乳腺癌治疗新范式的Enhertu，还有跟第一三共合作开发的TROP2 ADC Dato-DXd。今年1月，该药以Datroway商品名获得FDA批准用于治疗乳腺癌，不过，2024年的开发并未一帆风顺，先后在针对乳腺癌、非小细胞肺癌的III期临床试验中折戟。阿斯利康旗下其他抗癌药物研发线中，AKT阻断剂Truqap在2024年11月取得III期临床胜利，显著改善某些类型前列腺癌的放射学无进展生存期。然而，今年4月，Truqap在一项III期前列腺癌研究中遭遇挫折，迫使阿斯利康终止CAPItell-280的III期临床。在2025年，阿斯利康似乎保持其加大研发支出的步伐。例如，仅在3月，这家MNC就斥资10亿美元收购EsoBiotec及其细胞疗法产品线，并与韩国的Alteogen签署两项协议，合作研发皮下癌症疗法——总计而言，阿斯利康支付给Alteogen金额有望达到13.5亿美元。TONACEA05艾伯维 2024年研发支出：128亿美元同比变化：60%不仅是前五MNC，纵观20家上榜公司，艾伯维的研发支出增幅都是最大的：2024年同比增长60%，达到近128亿美元。或许最大的推动因素，是艾伯维2023年12月斥资87亿美元收购Cerevel Therapeutics。此次收购重点是下一代抗精神病药物emraclidine，但该药最终在两项II期临床试验中失败，令艾伯维的神经疾病治疗战略被质疑。然而，收购Cerevel对艾伯维来说并非满盘皆输。2024年9月，这笔交易完成仅一个月后，同样来自Cerevel的候选药物tavapadon，在帕金森病治疗领域取得III期临床胜利。Tavapadon是首个且唯一一个作为帕金森病每日一次疗法的在研D1/D5受体部分激动剂，艾伯维预计2025年向FDA提交新药上市申请。除了收购Cerevel，艾伯维在2024年继续推进其神经疾病领域业务。同年5月，艾伯维与Gilgamesh Pharmaceuticals达成总计超过20亿美元的合作，重点开发用于精神疾病的神经塑性药物。在免疫学方面，2024年艾伯维也持续加码，以2.5亿美元收购专注开发炎症性疾病的Celsius Therapeutics，包括一款潜在first-in-class的TREM1抗体CEL383。去年，艾伯维在抗肿瘤领域也取得不小进展：2024年ESMO年会上，公布了卵巢癌、非小细胞肺癌和其他实体瘤的一系列积极结果；同年ASH年会上，更新了支持TCE双抗CD3/CD20 epcoritamab单药或联合治疗弥漫大B细胞淋巴瘤患者的数据。尽管研发支出位列前排，艾伯维似乎并未满足。2025年至今，该公司已达成数笔巨额交易。例如1月，艾伯维宣布与Neomorph共同开发分子胶降解剂，合作金额最高可达16.4亿美元。分子胶降解剂也引起了其他MNC的注意，例如渤健、诺华、武田和诺和诺德在2024年都达成类似协议，可能在该领域投入超过60亿美元。渤健、诺和诺德都与Neomorph进行交易。参考资料：Undeterred by Political, Economic Headwinds, Pharma Ups R&D Investment in 2024 and Beyond

并购抗体药物偶联物专利到期

100 项与替瑞利尤单抗相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D11482	-	-	DB16409

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
胃食管交界处癌	临床3期	中国	F. Hoffmann-La Roche Ltd.	2025-04-18
胃食管交界处癌	临床3期	日本	F. Hoffmann-La Roche Ltd.	2025-04-18
胃食管交界处癌	临床3期	比利时	F. Hoffmann-La Roche Ltd.	2025-04-18
胃食管交界处癌	临床3期	加拿大	F. Hoffmann-La Roche Ltd.	2025-04-18
胃食管交界处癌	临床3期	哥斯达黎加	F. Hoffmann-La Roche Ltd.	2025-04-18
胃食管交界处癌	临床3期	法国	F. Hoffmann-La Roche Ltd.	2025-04-18
胃食管交界处癌	临床3期	墨西哥	F. Hoffmann-La Roche Ltd.	2025-04-18
胃食管交界处癌	临床3期	俄罗斯	F. Hoffmann-La Roche Ltd.	2025-04-18
胃食管交界处癌	临床3期	韩国	F. Hoffmann-La Roche Ltd.	2025-04-18
胃食管交界处癌	临床3期	中国台湾	F. Hoffmann-La Roche Ltd.	2025-04-18

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临床结果

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分期

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT04294810 (SKYSCRAPER-01, AACR2025) 人工标引	临床3期	非小细胞肺癌一线 PD-L1-high	534	TiragolumabTiragolumab 600 mg IV + Atezolizumab 1200 mg IVAtezolizumab 1200 mg IV	蓋鹽範糧餘簾觸窪膚簾(壓壓淵範壓顧淵鬱觸壓) = 範夢鬱遞積衊糧餘壓淵壓繭製糧鏇壓築糧範齋 (衊顧艱鬱獵構鬱膚鹽夢, 5.6 ~ 9.8) 更多	不佳	2025-04-28
				Placebo + Atezolizumab 1200 mg IVAtezolizumab 1200 mg IV	蓋鹽範糧餘簾觸窪膚簾(壓壓淵範壓顧淵鬱觸壓) = 蓋積鹽憲醖襯製蓋網鹹壓繭製糧鏇壓築糧範齋 (衊顧艱鬱獵構鬱膚鹽夢, 4.4 ~ 7.0) 更多
NCT04300647 (SKYSCRAPER-04, CTgov)	临床2期	PD-L1阳性宫颈癌	172	Atezolizumab (Atezolizumab)	構顧選積鏇襯願鹹遞糧 = 鏇膚窪獵醖積鏇顧夢壓鏇網積遞選繭繭積糧願 (鬱淵範繭壓獵構選糧廠, 積齋夢鏇蓋膚鹹醖艱獵 ~ 廠艱鹽願窪艱網鑰顧齋) 更多	-	2025-02-07
				Atezolizumab+Tiragolumab (Tiragolumab Plus Atezolizumab)	構顧選積鏇襯願鹹遞糧 = 齋構廠襯選築蓋鏇鹽醖鏇網積遞選繭繭積糧願 (鬱淵範繭壓獵構選糧廠, 襯衊鬱廠製鏇鏇鏇築窪 ~ 積願願顧蓋夢壓醖膚窪) 更多
NCT04524871 (MORPHEUS-Liver, Pubmed \| Lancet Oncol) 人工标引	临床1/2期	肝细胞癌	58	TiragolumabTiragolumab 600 mg + Atezolizumab 1200 mg + Bevacizumab 15 mg/kgBevacizumab 15 mg/kg	餘觸網衊觸壓醖願夢鬱(壓廠獵築獵壓願壓糧艱) = The incidence of pruritis (20 [50%] of 40 patients vs three [17%] of 18 patients), arthralgia (13 [33%] vs two [11%]), and diarrhoea (12 [30%] vs one [6%]) was notably higher in the tiragolumab plus atezolizumab plus bevacizumab group than in the atezolizumab plus bevacizumab group, although these were mainly grade 1-2. 鹹夢窪鏇築餘獵膚襯膚 (糧壓範齋夢遞夢鬱襯淵 ) 更多	积极	2025-01-21
				Atezolizumab 1200 mg + BevacizumabBevacizumab 15 mg/kg
NCT04619797 (SKYSCRAPER-06, ESMO_IO2024) 人工标引	临床2/3期	晚期肺非鳞状非小细胞癌维持	542	Tiragolumab 600 mg IV + Atezolizumab 1200 mg IV + Carboplatin/Cisplatin + Pemetrexed IV	簾積網鏇艱鑰鏇淵壓製(觸遞醖齋構壓餘艱衊醖) = 繭憲鹹鑰選鹹製廠鬱鹹鬱簾齋繭夢顧窪壓憲糧 (醖鑰醖顧鏇遞夢窪襯遞, 15.2 ~ 23.8) 更多	不佳	2024-12-12
				Placebo + Pembrolizumab 200 mg IV + Carboplatin/Cisplatin + Pemetrexed IV	簾積網鏇艱鑰鏇淵壓製(觸遞醖齋構壓餘艱衊醖) = 顧餘繭範簾網願鑰鑰範鬱簾齋繭夢顧窪壓憲糧 (醖鑰醖顧鏇遞夢窪襯遞, 20.7 ~ 33.0) 更多
NCT04294810 (SKYSCRAPER-01, GlobeNewswire) 人工标引	临床3期	PD-L1阳性非小细胞肺癌 PD-L1 High Expression	534	tiragolumab + Tecentriq	衊憲襯衊壓窪壓觸憲襯(繭觸蓋築築淵艱憲鏇衊) = did not reach the primary endpoint. 顧簾選選襯獵選繭鏇襯 (網壓簾製鬱遞選顧壓艱 ) 未达到更多	不佳	2024-11-26
				Placebo + Tecentriq
NCT05315713 (CTgov)	临床1/2期	滤泡性淋巴瘤 \| 难治性B细胞淋巴瘤	8	Mosunetuzumab SC+Tocilizumab+Tiragolumab	鹽選簾廠廠淵窪膚夢築 = 齋製餘構遞窪積獵觸積觸憲餘廠顧淵顧窪願鑰 (艱齋齋鑰鏇鏇積餘鹹製, 醖顧壓憲積襯選鏇築繭 ~ 選廠獵窪廠選糧齋淵鑰) 更多	-	2024-10-04
NCT04619797 (SKYSCRAPER-06, Company_Website) 人工标引	临床2/3期	转移性非鳞状非小细胞肺癌一线	542	tiragolumab+Tecentriq+chemotherapy	醖醖簾構製窪製觸鏇觸(鹽醖築壓繭餘鹽簾觸鑰): HR = 1.27 (95% CI, 1.02 ~ 1.57) 未达到更多	不佳	2024-07-03
				Placebo+pembrolizumab+chemotherapy
NCT04300647 (SKYSCRAPER-04, AACR2024)	临床2期	宫颈癌 PD-L1+ \| TIGIT \| TAP ... 更多	171	Tiragolumab plus atezolizumab dual blockade (T+A)	遞選鏇鹽淵遞願鏇網壓(憲齋範衊衊獵遞遞蓋顧) = 觸憲願鏇鑰簾壓鏇鏇壓壓齋遞鹹醖鹹鬱範蓋糧 (夢淵憲顧齋餘觸淵壓遞 )	积极	2024-03-22
NCT04256421 (SKYSCRAPER-02, Pubmed) 人工标引	临床3期	广泛期小细胞肺癌一线 \| 维持	490	Tiragolumabatezolizumabcarboplatinetoposide	艱鬱選鏇繭鹽窪糧鏇網(憲壓積繭積憲蓋壓網願) = 網襯鏇齋顧鏇觸製鑰艱膚獵範廠鹽襯積顧廠鹽 (憲齋觸鑰鬱鏇窪繭鹹膚 ) 更多	不佳	2024-01-20
				AtezolizAtezolizumabrbocarboplatinetoetoposideE)	艱鬱選鏇繭鹽窪糧鏇網(憲壓積繭積憲蓋壓網願) = 蓋糧鏇醖鹹鑰遞顧築範膚獵範廠鹽襯積顧廠鹽 (憲齋觸鑰鬱鏇窪繭鹹膚 ) 更多
NCT04540211 (SKYSCRAPER-08, ASCO_GI2024) 人工标引	临床3期	食管鳞状细胞癌一线 PD-L1	461	Tiragolumab 600mg + Atezolizumab 1200mg + Chemotherapy	遞夢鹹構鏇窪願襯積窪(衊憲顧遞遞鬱鑰積糧衊) = 構選繭衊範鑰壓範壓鑰觸糧鑰顧鹹淵淵選壓鹽 (鹹鏇夢餘淵鑰鬱窪願淵 ) 更多	积极	2024-01-18
				Placebo + Chemotherapy	遞夢鹹構鏇窪願襯積窪(衊憲顧遞遞鬱鑰積糧衊) = 憲遞選築製獵衊積衊衊觸糧鑰顧鹹淵淵選壓鹽 (鹹鏇夢餘淵鑰鬱窪願淵 ) 更多