ImmuneOnco Biopharmaceuticals (Shanghai), Inc.

iStock, Naeblys Summit Therapeutics’ ivonescimab has the potential to challenge Merck’s blockbuster checkpoint inhibitor in non-small cell lung cancer, but experts stress the need for diverse and overall survival data. Summit Therapeutics wowed attendees at the World Conference on Lung Cancer with late-stage data for its in-licensed bispecific ivonescimab, declaring victory over Merck’s blockbuster Keytruda, which has historically led the non-small cell lung cancer treatment space. Since Summit’s Sept. 9 presentation , eager investors have sent Summit’s stock skyrocketing as much as 140%. Still, some analysts urged caution, as the data was from a trial run only in China. “Results may or may not be generalizable beyond the China-focused patient population initially assessed,” BMO Capital Markets analyst Evan Seigerman wrote in a note to investors, adding that FDA consideration will likely require U.S. data. Summit has already announced it will take its bispecific into a multi-regional study of non-small cell lung cancer (NSCLC) in early 2025. And at the 2024 European Society for Medical Oncology (ESMO) annual meeting this week, Summit reported that ivonescimab also showed promising anti-tumor activity in small trials for colorectal cancer, triple negative breast cancer and head and neck squamous cell carcinoma—all indications where Keytruda is also approved. Ryan Schoenfeld, CEO of The Mark Foundation for Cancer Research, said it’s not too early to get excited about the NSCLC data. Despite checkpoint inhibitors shifting the curve for lung cancer patients, there are still patients with a lot of unmet need, so “this is a really big deal,” he told BioSpace . It’s reasonable to think that ivonescimab might be competitive with Keytruda plus chemo, Schoenfeld added, potentially sparing patients from chemotherapy treatments, which come with a host of side effects including fatigue, nausea and low blood cell counts. John Heymach, head of the Heymach Laboratory at MD Anderson Cancer Center, which specializes in NSCLC research, agreed. “By any measure, the data is impressive,” he told BioSpace . Still to Prove: Overall Survival Heymach noted that Summit’s HARMONi-2 trial is one of the few instances of a candidate successfully taking on Keytruda head-to-head in a population where the latter is approved. He said that he and other investigators had previously believed Summit to be overly optimistic in in how it powered its HARMONi-2 trial , but that the latest results have largely put those concerns to bed. The trial was run by Summit’s development partner Akeso and pitted ivonescimab, a bispecific antibody combining the powers of anti-PD-1 and anti-VEGF, against Keytruda, itself an anti-PD-1 checkpoint inhibitor, as a first-line treatment for patients withadvanced NSCLC. Median progression free survival after nine months of follow-up was 11.14 months in the treatment arm vs. 5.82 months in the Keytruda group. Summit’s bispecific cut the risk of disease progression or death by nearly 50% compared to Keytruda. HARMONi-2 included a variety of patient subgroups, including high and low PD-L1, and squamous and non-squamous cancer. Ivonescimab was effective across all groups, with no obvious outlier driving results, Heymach said. An earlier study echoed this efficacy in a different setting of NSCLC patients with EGFR mutations on platinum chemotherapy. HARMONi-A compared patients receiving chemo alone to patients on chemo plus ivonescimab, with the latter showing significantly improved progression-free survival (PFS). Heymach noted that this is a subgroup in which Keytruda had been tested and did not show benefit. “That’s two consecutive, randomized Phase III [trials] where [ivonescimab] overperformed compared to expectations,” he told BioSpace . After a string of attempted checkpoint combo attempts were “horribly unsuccessful,” Christiana Bardon, co-managing partner at MPM BioImpact, said, “this is really the first data of something that’s worked beyond that first crop. And it’s pretty shocking that it works.” While Bardon called Summit’s data “definitive,” she said they are lacking the holy grail of trial results—overall survival (OS). Summit stated in its press release that OS data was not yet mature and would be evaluated in the future. Heymach said that although improvements to PFS have sometimes not translated into OS improvement, given the magnitude of PFS benefit, it would be surprising if it was not reflected in this outcome measure. Summit will also likely need to demonstrate an improvement on the therapeutic index, which could be achieved from combining an anti-VEGF with an anti-PD-1 as separate agents for treatment, Schoenfeld said. According to Summit, ivonescimab does more than just combine two treatments into one. The bispecific antibody has a unique cooperative binding that results in a higher affinity in the presence of both PD-1 and VEGF. Diverse Data Needed With the current results coming from China-only trials, all three experts who spoke with BioSpace agree that the FDA will need to see more data from a diverse population in order to consider approval. The use of China-only data can be skewed by factors such as variation in genetics, less patient follow up and cultural differences in reporting side effects. Bardon emphasized that safety/side effects in particular could be a concern for the FDA when reviewing China-only data. For example, in HARMONI-2, there were very few grade 3 adverse events. “[Adverse events] are probably underestimated compared to what we would see in a Western-based population,” Bardon said. If the data indeed hold up in a broader population, Summit could tap into a portion of Keytruda’s $25 billion in overall annual sales. While Akeso has already garnered approval for ivonescimab in China where it holds the rights, Summit’s license extends to the U.S., Canada, Europe, Japan, Central, South America and a handful of other markets. Of course, Summit is not the only bispecific developer to announce impressive results of late. On Saturday, BioNTech reported at ESMO 2024 that its own bispecific targeting both PD-L1 and VEGF-A, BNT327, elicited a 57.8% confirmed objective response in a Phase II trial of 64 Chinese patients with EGFR-mutant NSCLC, according to Endpoints News . Meanwhile, Instil Bio, and its China-based partner ImmuneOnco Biopharmaceuticals, are gearing up to begin a Phase II trial of their own bispecific antibody SYN-2510/IMM2510 in NSCLC and triple-negative breast cancer. “This [bispecific] therapeutic modality has definitely arrived,” Schoenfeld said.

DALLAS, TX, USA and SHANGHAI, China I September 16, 2024 I Instil Bio, Inc. (Nasdaq: TIL, “Instil”) and ImmuneOnco Biopharmaceuticals (Shanghai) Inc. (HKEX:1541, “ImmuneOnco”) announced today the global registrational strategy for the PD-L1xVEGF bispecific antibody SYN-2510/IMM2510 in combination with chemotherapy in front-line non-small cell lung cancer (NSCLC) and in front-line triple-negative breast cancer (TNBC). In China, ImmuneOnco is accelerating the development of IMM2510/SYN-2510 in front-line NSCLC by targeting initiation in late 2024 of a Phase 1b/2 front-line chemo combination study. This study is expected to enroll patients with driver gene mutation-negative non-squamous and squamous NSCLC. ImmuneOnco is also accelerating development of IMM2510/SYN-2510 in front-line TNBC with initial Phase 1b/2 chemotherapy combination studies targeted to begin in early 2025. In the United States, Instil is prioritizing development of SYN-2510/IMM2510 in NSCLC and TNBC. US IND submission is targeted for late 2024, starting with a Phase 2 trial of SYN-2510/IMM2510 monotherapy in second-line non-squamous and squamous NSCLC. With potential positive proof-of-concept data, ImmuneOnco and Instil may initiate joint global randomized Phase 3 chemotherapy combination trials in first-line non-squamous and squamous NSCLC and/or first-line TNBC. “There are significant unmet medical needs in NSCLC and TNBC cancer patients which may be addressed by IMM2510,” said Dr. Wenzhi Tian, PhD, CEO and CSO of ImmuneOnco. “This practical and accelerated registrational strategy, which is aligned with Instil, paves a clear pathway to a potential regulatory approval for us in China and for Instil Bio globally.” “SYN-2510 may have the opportunity to meaningfully improve on the current standard of care in NSCLC and TNBC,” said Bronson Crouch, CEO of Instil. “Our expectation for the initial US study of SYN-2510 is that it would lay a foundation for the efficient enrollment of potential global Phase 3 studies.” About SYN-2510/IMM2510 SYN-2510/IMM2510 is a PD-L1xVEGF bispecific antibody in development for the treatment of multiple solid tumor cancers. SYN-2510/IMM2510 is differentiated from other PD-(L)1xVEGF bispecific antibodies by its VEGF trap, which binds multiple VEGF receptor ligands beyond VEGF-A, a bispecific structure which leverages PD-L1 as an anchor in the tumor microenvironment (TME), and enhanced antibody-dependent cellular cytotoxicity (ADCC) to direct killing of PD-L1-positive tumor cells. About Instil Bio Instil Bio is a clinical-stage biopharmaceutical company focused on developing a pipeline of novel therapies. Instil’s lead asset, SYN-2510, is a novel and differentiated PD-L1xVEGF bispecific antibody in development for the treatment of multiple solid tumor cancers. For more information, visit www.instilbio.com . About ImmuneOnco ImmuneOnco is a clinical-stage biotech company focused on discovery and development of biologics to treat cancers and other diseases. With 10+ assets all originated in-house and the most advanced asset in phase III right now, ImmuneOnco is pursuing innovative therapies to improve patients’ health. For more information visit www.immuneonco.com . SOURCE: ImmunoOnco

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.