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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.