IMM-2510

BARCELONA — Last week, Summit and Akeso set the industry abuzz after their bispecific antibody beat Merck’s Keytruda in a Phase 3 lung cancer trial. Now, BioNTech is touting mid-stage data for its own lung cancer asset with a similar mechanism. The German drugmaker on Saturday presented data for the PD-L1xVEGF bispecific that it licensed from Biotheus at Europe’s biggest cancer conference in Barcelona. BioNTech said BNT327 achieved a 57.8% confirmed objective response rate in a single-arm Phase 2 trial of 64 patients with EGFR-mutant non-small cell lung cancer (NSCLC) in China who were first given standard treatment. In 13 patients with high PD-L1 expression, the confirmed ORR stood higher, at 92.3%. For BioNTech, it’s good news on two fronts. The company’s $BNTX share price gained about 37% in the week after Summit announced the full data for its PD-1/VEGF bispecific ivonescimab. And the data from the Biotheus-sponsored trial presented at ESMO warrant further study of BNT327, the drugmaker said, although details about what’s next have yet to be confirmed. Both readouts are fueling newly high expectations for this approach, which wasn’t widely hyped prior to Summit’s readout. Bigger drugmakers are still observing from the sidelines, while a smaller biotech company is touting its own development plans amid rocketing interest in its stock. According to TD Cowen analysts on Monday, BNT327 showed “solid efficacy on par” with Summit’s PD-1xVEGF bispecific, ivonescimab, and fewer anti-VEGF-related toxicities compared with bevacizumab, an anti-VEGF antibody. After BioNTech’s presentation, Adrianus Johannes de Langen, a pulmonary medicine doctor at Amsterdam University Medical Center who was not involved with the study, told delegates that the ORR is “impressive” but said it remains to be seen how those results could translate to key survival outcomes. He also said it’s unclear which patients could benefit from adding a PD-L1xVEGF bispecific antibody to chemo in the second line given a recent first-line approval for lung cancer. The FDA last month approved Johnson & Johnson’s EGFRxMET bispecific Rybrevant combined with EGFR tyrosine kinase inhibitor Lazcluze for certain patients with first-line EGFR-mutated NSCLC. But the combo comes with a lot of toxicities, meaning there’s room for the bispecific approach, Dana Farber Cancer Institute oncologist Pasi Jänne told Endpoints News . Meanwhile, a third bispecific maker called Instil Bio $TIL saw its stock jump a whopping 493% in the week after Summit’s data readout. On Monday, Instil spelled out its own plans for a PD-L1xVEGF bispecific antibody that it licensed from Shanghai-based ImmuneOnco. The biotech expects to file an application in the US later this year to start mid-stage studies of IMM2510 as a monotherapy in second-line NSCLC. If these studies are successful, the partners may start global Phase 3 studies in first-line non-small cell lung cancer, where they could potentially also go head-to-head with Keytruda, and/or in triple-negative breast cancer, according to the company release , which did not provide timelines. The flurry of data comes around a week after Summit said ivonescimab cut the risk of progression or death by up to 49% in certain lung cancer patients in China versus Keytruda. If the results can be replicated in a study with US patients and then approved, ivonescimab could be used in the first-line NSCLC setting in place of Keytruda, the world’s top-selling cancer drug. Going head-to-head against Keytruda was “a bold move, and it’s paid off for Summit,” Jänne said. Merck, Keytruda’s maker, this week pointed to safety concerns with Summit’s drug. The results are “really exciting” but VEGF inhibitors are known to come with a lot of safety issues, Merck Chief Medical Officer Eliav Barr said in an interview . The goal is to “create a molecule that provides the VEGF effect but doesn’t end up with toxicity that causes more harm than good,” he added. In Summit’s Phase 3 trial, around 29% of patients treated with ivonescimab had grade 3 or higher adverse events versus around 16% in the Keytruda arm. In BioNTech’s Phase 2 study, 31% of patients had adverse events that disrupted the dosing of BNT327. However, Jänne said that the side effects of this drug class weren’t “off the charts” and seemed to be manageable. Summit’s market value more than doubled to $23.5 billion in the span of about a week, though the company had a tiny, austere booth at the medical meeting. It’s unclear whether these efficacy results can be replicated in larger, global studies, and other companies are paying close attention to what happens next with bispecific VEGFs. Izzy Lowy, Regeneron’s SVP of translational and clinical sciences in oncology, told Endpoints at ESMO that he found the ivonescimab data “provocative.” When asked whether such an approach would be something Regeneron would consider, Lowy said, “These are more complicated, multi-specific antibodies. If it really makes sense to do that, then I imagine that we will engage.” When asked, AstraZeneca head of oncology R&D Susan Galbraith didn’t say whether the company was looking to pursue this particular approach. She did say, however, that AstraZeneca is developing several PD-1 bispecifics, including rilvegostomig, which also targets TIGIT, and volrustomig, which also targets CTLA4. The company is studying these candidates as monotherapies and in combination with its anti-VEGF bevacizumab as part of the GEMINI clinical trial program in various cancers. Combining separate VEGF and PD-L1 agents has led to mixed results in the past, Jänne said. The combo of bevacizumab, Roche’s PD-L1 Tecentriq and chemo is approved in the US for metastatic non-squamous NSCLC, However, Phase 3 trials in Japan and China in certain lung cancer patients failed. There may be an advantage to having a two-pronged “all-in-one molecule” compared with two separate drugs “where you don’t know that both of them will make it in the same way to where you want them to act,” Jänne said. In general, the science behind bispecifics targeting both VEGF and PD-1 or PD-L1 is murky and more data are needed on how they work, he added. “When we’ve thought about bispecifics, we’ve generally thought about them as bridging cells of interest,” Regeneron’s Lowy said. “Targeting different molecules on the same cell — we thought was a little complicated because you don’t know what the optimum engagement affinity for one target is versus another.” “But at the end of the day, if it works, it works,” he said.

The deal terms mean Insitil will gain the rights to both candidates everywhere outside of Greater China. Instil Bio has been a biotech in search of a pipeline after it scrapped its lead assets over the last couple of years. Now, it seems to have found a pair of clinical-stage candidates from China to instill it with new purpose.The Dallas-based biotech is paying $50 million in upfront and near-term payments—with potentially up to $2 billion to follow in milestones—to China’s ImmuneOnco Biopharmaceuticals for therapies dubbed IMM2510 and IMM27M.IMM2510 is a bispecific antibody combining an anti-PD-L1 antibody with a vascular endothelial growth factor (VEGF) receptor “trap” that binds VEGF. Academic researchers have already shown that anti-PD-1 therapy together with anti-VEGF can effectively block the PD-1/PD-L1 axis and synergistically suppress tumor growth, especially when it comes to tumors with VEGF hypersecretion.According to the two companies, what sets IMM2510 apart from other PD(L)1xVEGF antibodies in development is its ability to bind multiple VEGF receptor ligands beyond VEGF-A.VEGF-A is a protein known to stimulate the formation of blood vessels. Roche’s eye disease blockbuster Vabysmo suppresses VEGF-A, while at one point Moderna and AstraZeneca were looking at an mRNA cardiovascular drug with the same target.The companies also said that IMM2510 has a “smaller molecular weight allowing for potentially better tumor penetration, and enhanced antibody-dependent cellular cytotoxicity designed to improve tumor killing.” IMM2510 has completed a phase 1 dose-escalation trial in advanced solid tumors, where it demonstrated a response in the likes of patients with squamous non-small cell lung cancer whose cancer had not been effectively treated by PD-1 inhibitors.The other candidate helping to fill out Instil’s empty pipeline, IMM27M, is a next-generation anti-CTLA-4 antibody that the companies said has been designed to “promote intratumoral regulatory T cell depletion to enhance the efficacy and reduce the toxicity associated with first-generation anti-CTLA-4 antibodies.”As well as completing a phase 1 dose-escalation study of IMM27M to show its anti-tumor potential, ImmuneOnco also launched a trial last month to assess the anti-CTLA-4 antibody in combination with IMM2510.The deal terms mean Instil will gain the rights to both candidates everywhere outside of greater China. On top of the combined $2.05 billion in biobucks up for grabs, ImmuneOnco will also be in line for low double-digit percentage royalties on sales.Instil needed to restock its pipeline after the biotech scrapped its lead tumor-infiltrating lymphocyte therapy and four corresponding programs—along with 60% of its staff—at the end of 2022. That left the company with only its ITIL-306 program, but the company announced earlier this year that even this was being shut down.