Taking on Big Pharma rivals, biotech startup unveils first-in-human data on ROS1 drug

2022-10-28

Nuvalent set out to show that by leveraging structure-based drug design and a bit of chemistry whiz out of its Harvard founder’s lab, it can hit well-known cancer targets in ways that no others can. On Friday, it offered the first proof in humans. The biotech’s shares soared 62.45% to $35.74 on data from an early trial showing that almost half of the 21 heavily pretreated ROS1-positive non-small cell lung cancer ROS1-positive non-small cell lung cancer patients that got its lead drug, NVL-520, saw a partial response — a rate of 48%. While early, Nuvalent, founded by Matt Shair, believes that the positive data in this tough setting could pave the way for a speedy regulatory journey. These are patients who have exhausted all other options, CEO Jim Porter told Endpoints News from Barcelona, where the data are being presented at a symposium . They would have taken the two therapies approved for their specific mutation — Pfizer’s Xalkori and Roche’s Rozlytrek. In many cases, they’ve taken experimental drugs like Pfizer’s lorlatinib (which is approved for a different type of lung cancer as Lorbrena) and repotrectinib from Turning Point Therapeutics, now acquired by Bristol Myers Squibb. And there’s a good chance they’ve taken chemotherapy, he added — even multiple courses. “In a typical Phase I, that kind of patient population is very hard to treat,” he said. “The disease has become heterogeneous at that point. We’re still seeing really encouraging activity in this heavily pretreated patient population, which really got us pretty excited about the drug and its potential.” The Phase I trial Nuvalent conducted has enrolled 35 patients so far, and out of 21 patients who were evaluable at the data cutoff date, 10 showed a partial response. It’s not just about the topline number either, Porter said. From talking to physicians, Nuvalent concluded that off-target effects for prior ROS1 inhibitors have often led to interruptions, discontinuations or dose reductions — all of which can limit the drug’s impact. “We had heard loud and clear from physicians, if you could solve for that, you can keep patients on therapy,” Porter said, and hopefully advance to earlier lines of treatment down the line. The biotech observed no dose-limiting toxicities, treatment-related serious adverse events, treatment-emergent dizziness, or adverse events leading to treatment reductions or discontinuations. Looking at the specific attributes that they had in mind when designing NVL-520, Nuvalent said the drug appears to overcome the limitations of previous generation drugs as it hoped. The overall response rate was 78% among the nine patients with ROS1 G2032R mutations; 73% among the 11 with a history of CNS metastases; 53% among the most heavily pretreated patients who received two or more prior ROS1 TKIs or one or more prior lines of chemotherapy; and 50% among the 18 who got lorlatinib or repotrectinib. When asked about regulatory plans, Porter said Nuvalent will need to finalize a Phase II dose and talk to the FDA about it, but it intends to enroll both patients who are previously treated with ROS1 drugs and those who are kinase inhibitor-naive. He also noted that both Xalkori and Rozlytrek were approved on single-arm Phase II studies. “What’s interesting is the FDA had communicated in the second approval that this is a relatively rare patient population. They’re not necessarily advocating for randomized studies,” he said, suggesting that the Phase II data could serve as the basis for registration. But to get there, he also acknowledges Nuvalent will need to follow patients for much longer and collect more data over time. So far, patients have only been treated for anywhere from one to more than eight months, with a median of 3.6 months. “That’s going to be very important for any decision that a regulator would make on any drug — it’s not just can you drive responses, but are they durable?” Porter said.

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