Amivantamab-VMJM

None\n The detailed results from the HARMONi trial—the first global phase 3 data set for the world’s first PD-1xVEGF bispecific, ivonescimab—have sparked a mix of hopes and concerns, leading to a 25% stock plunge for the drug’s U.S. developer, Summit Therapeutics.The highly debatable data, along with the trial design flaws and unfortunate execution that they reflect, plus a rapidly evolving competitive landscape, all point to one conclusion: Summit must partner with a Big Pharma company as soon as possible.Summit probably understands this reality, if the rumored deal talks with AstraZeneca two months ago were true. But back then, investors’ expectations of the value of a deal for ivonescimab were incredibly high, fueled partly by BioNTech and Bristol Myers Squibb’s up-to-$11 billion collaboration on a rival PD-L1xVEGF bispecific. Now, as the HARMONi readout has brought down Summit’s stock price, the company may be able to negotiate a more reasonable price from a buyer’s perspective—one that also wouldn\'t be too big of a disappointment to Summit investors.Meanwhile, The New York Times’ report today that the Trump administration is weighing a crackdown on licensing deals around China-invented experimental medicines may add extra urgency for Summit to find a partner. Ivonescimab was developed and is sold in China by Chinese biotech Akeso.Although a White House spokesperson told the NYT that the administration was not “actively considering” the reported draft executive order, which would scrutinize biotech deals involving Chinese assets, we’re all too familiar with how things can quickly change with this administration. The trial readout We can’t talk about the need for Summit to seek Big Pharma help without addressing the HARMONi data in second-line EGFR-mutated non-small cell lung cancer (NSCLC). The global phase 3 study met one of its dual primary endpoints, progression-free survival (PFS), but missed its other main goal, overall survival (OS).Heading into the trial readout, industry watchers were looking for evidence on whether the tumor progression benefit observed from ivonescimab—and the PD-(L)1xVEGF class by extension—in Chinese patients would translate to a Western population and to an improvement on the gold-standard metric of overall survival. But, after Sunday’s presentation at the 2025 World Conference on Lung Cancer (WCLC), people may realize that HARMONi has fallen into an awkward situation: It didn’t really prove or disprove any new theories with certainty. Wall Street analysts have to lean on a certain amount of guesswork to reach their inconclusive opinions on what the results tell us and about ivonescimab’s chances at an FDA approval.On the primary analysis of PFS, ivonescimab and chemo delivered a statistically significant 48% improvement over chemo alone in the overall trial. The readout only included 18 PFS events from patients outside of China, constituting 6.5% of the total PFS events recorded.So, Summit did another analysis, one with an additional 7.4 months of median follow-up. It showed a 33% PFS improvement for Western patients, notably lower than the 45% recorded in Chinese patients. The 12-percentage-point difference exceeded the 10-point threshold that multiple analysts said would indicate consistency of effect.The PFS improvement in Western patients, though weaker than expected, can still be viewed as clinically meaningful. But Summit has found itself in a precarious situation with the FDA mainly because of HARMONi’s OS findings.The trial has failed to meet OS at its final analysis, which is itself a problem because the FDA has previously told Summit that a statistically significant OS would be necessary to seek an approval in second-line EGFR-mutated NSCLC, according to a May release from the biotech.At the time, Summit argued that longer follow-up was needed because the median follow-up time for the Western population, at 9.2 months, was shorter than the overall median OS, which was 14 months for the control arm and 16.8 months for the experimental arm at the time of the primary analysis. Updated findings After a longer follow-up, ivonescimab’s death-risk reduction has expanded from 21% at the final OS analysis to 22%, with a nominal p-value of 0.0332, which doesn’t bear statistical significance because the final analysis has passed.When looking at subgroups, the risk reduction was 16% for North American and EU patients, 30% for North American patients specifically, and 24% for Chinese patients. The median OS was 17 months and 16.7 months for ivonescimab patients in the North American/EU and China groups, respectively, and the result wasn’t reached for those in North America specifically. In the control arm, median OS was 14 months.This is a major argument for Summit to support its consistency-of-benefit claims in and out of China. Even though the subgroup analyses were not statistically powered by design, they can be informative, Summit’s clinical development head, Jack West, M.D., said during an investor call Monday.“There’s really not a situation where one subgroup is an outlier, or the study results were driven by a specific subset of patients,” West said.Jefferies analyst Clara Dong, Ph.D., agreed. In a Monday note, Dong argued that even Summit’s new OS cut—performed freshly this month—is “not a totally fair direct comparison” because about 79% of patients in the Chinese cohort had passed away, whereas fewer than 50% of Western patients had died. In HARMONi-A, which enrolled exclusively Chinese patients in second-line EGFR NSCLC, the death risk reduction was 20% for the ivonescimab-chemo regimen at 52% data maturity. That 20% is “comparable” to the 16% observed in Summit’s Western population, especially considering that the control arm performed consistently across patient subgroups, Dong said.Nevertheless, Dong didn’t go any further than saying the WCLC data “hinted” that ivonescimab could bring survival benefits regardless of geographic regions and that the results are “file-able” with the FDA. FDA uncertainties Problem is, merely hinting at promising outcomes may not be enough to convince the FDA to grant an approval.As Leerink Partners analyst Daina Graybosch, Ph.D., noted in her Tuesday note to clients, in Summit’s longer OS follow-up, the 95% confidence interval for the Western subgroup was wide and crossed 1.0 by a large margin. Graybosch was even less convinced because Summit didn’t provide a survival curve for Western patients, which would have offered a more vivid depiction of how patients had fared so far.For both the Western population and North Americans specifically, the upper bound of the 95% confidence interval for OS reached or exceeded 1.3. A value above 1 suggests harm. This means, we’re 95% confident that the true outcome could land in a range that includes a sizable portion that’s unfavorable to ivonescimab, including as high as a 30% increased risk of death.Obviously, this suggestion of potential harm could be detrimental to Summit’s case in front of the FDA.The FDA has recently put an increased emphasis on OS and has grown hawkish on Chinese data in the absence of sufficient representation of a U.S. population in clinical trials.The agency recently declined to approve Roche’s Columvi, used in combination with chemo, in second-line diffuse large B-cell lymphoma, after criticizing its U.S. data, which was echoed by a negative FDA advisory committee vote. In Columvi’s phase 3 Starglo trial, which met its OS endpoint, U.S. patients only made up 9% of the trial population, versus 48% in Asia.Granted, the Starglo trial showed a negative OS trend in non-Asian countries. Unlike the Roche trial, HARMONi’s OS trend in Western patients is favorable. However, as discussed above, the potential for OS harm also exists by a fairly significant margin in HARMONi.Given the controversies around the data set, an FDA advisory committee is likely if Summit decides to file ivonescimab based on the current data. Summit plans to finalize its regulatory strategy in the coming weeks, Chief Business and Strategy Officer Dave Gancarz said on Monday’s call. Data debate Feedback from doctors also suggests a tough sell.It’s clear that the addition of non-Asian patients “diluted” the PFS outcomes for ivonescimab, Suresh Ramalingam, M.D., from Emory University, a renowned expert in lung cancer, said as an invited discussant of HARMONi at the WCLC conference.Besides, the level of PFS benefit observed in HARMONi is comparable to studies that have evaluated separate VEGF inhibitors in NSCLC, with “no clear evidence of PD-1 blockade as a contributor to the efficacy,” Ramalingam said.“Is this a new symphony? I don’t think so,” Ramalingam concluded, alluding to the ivonescimab study name.Summit’s West argued that Ramalingam “really minimized the […] understandable issue of the overall survival cut, the relative immaturity of the [original] OS data” and that he focused on the “negative range of the confidence intervals of fairness as you could get within the admittedly ambiguous setting of the trial.” During his presentation, Ramalingam said he wouldn’t attach much significance to the promising nominal p-value from the longer-term OS follow-up because it was not part of the rigorous trial design.West, who joined Summit in 2023 as a practicing thoracic oncologist at City of Hope, said other doctors have been congratulatory to him.“To my colleagues who are treating patients going back to their clinics this week and seeing patients with EGFR mutation-positive disease, they say that they would be very eager to use the HARMONi regimen,” West said.“I think we are always, as clinicians, looking for truth within the reality that the trials don’t always provide clear answers,” he added.“This couldn’t be said to be a slam dunk. So it’s subject to interpretation,” West said at one point. The larger pointSo, how did we get to this awkward situation—and back to the point that Summit needs to promptly find a Big Pharma partner?It all traces back to Summit’s decision to roll over a large number of patients (62% of HARMONi) from Akeso’s HARMONi-A trial. That China-only study already had its own PFS data cutoff—which later yielded a positive readout—in March 2023, about two months before the official launch of the global HARMONi trial. This effectively led to a sequential enrollment—first in China and then in the West—and an unavoidably longer follow-up of the Chinese population.The issue was compounded by the fact that the Western portion of HARMONi enrolled slower than expected. So, when the PFS and OS results reached enough total events to read out under the trial’s statistical plan, they were both premature for the Western population. The longer OS follow-up now compensates for what would have happened in the Western group had the trial had accrued as originally expected, according to West.“Summit was a completely unknown company, and ivonescimab was a completely unknown drug in the U.S. and globally, and that it just took longer than anticipated to get a toehold and start generating data,” West said in an interview with Fierce.Kudos to Summit for identifying ivonescimab and the PD-1xVEGF bispecific concept as a promising asset based on some Chinese clinical data before any large pharma company was willing to buy into the field. Kudos to Summit, as a then little-known biotech, for wanting to bring ivonescimab to patients as quickly as possible by coming up with the unique single- to multiregion trial design. But the HARMONi situation shows that ivonescimab is too complicated, and its development task too tall, for a small biotech like Summit to handle despite its $13 billion market cap today or $23 billion at peak.It’s not that large pharmas don’t make mistakes—case in point, Roche’s Starglo setback—but Summit’s experience mirrors two intrinsic shortfalls of a small biotech: lack of cash and influence. Those two factors are even more important for ivonescimab’s goal of supplanting the world’s best-selling drug, Merck & Co.’s Keytruda, as the new immuno-oncology treatment backbone.Acceleration of clinical development is one thing, but Summit arguably cut corners and enrolled a relatively small number of Western patients also because it needed to preserve cash. For reference, for Johnson & Johnson’s Rybrevant, which was approved a year ago alongside chemo in second-line EGFR-mutated NSCLC, its phase 3 Mariposa-2 trial enrolled 657 patients across three arms, including about 50% outside of Asia. That’s compared to 438 patients and 38% for HARMONi. And, thanks to the novel trial design, the number of enrolled patients who can be credited to Summit was just 165, leading to the company\'s current dilemma of having to discern a signal from a few events.Just ask yourself, would a large pharma company pinch pennies and take this kind of risk for the very first indication of a first-of-its-kind drug that’s billed as the next Keytruda? The company would want to deliver a bang. It would want clinical evidence to be decisive to establish a strong reputation from the get-go.Granted, subsequent HARMONi trials are larger and do not have this flawed sequential trial design. But larger trials require more cash and even more sophisticated clinical expertise to avoid the myriad pitfalls associated with oncology drug development.In August, Summit laid out a plan to raise up to $360 million by selling new shares of its stock from time to time. While the money “could provide the company with temporary alleviation of their cash overhang,\" it \"does not preclude the need to partner,” Leerink’s Graybosch said at the time.The two Summit co-CEOs, Bog Duggan and Maky Zanganeh, are credited for the successful development of the hugely popular blood cancer drug Imbruvica, which was the centerpiece of AbbVie’s $21 billion acquisition of Pharmacyclics 10 years ago. But solid tumors are a whole new territory from both the R&D and commercialization perspectives.As a potential follower, BioNTech, a larger company than Summit with a much deeper pipeline, already realizes that it cannot carry the weight of a PD-(L)1xVEGF drug on its own, hence its high-profile BMS tie-up.Granted, Summit is no longer a nobody in the oncology world. But it will still need to fight for clinical resources against the likes of BioNTech-BMS, Pfizer and Merck.What’s more, the future of these PD-(L)1xVEGFs may lie in their ability to be combined with other drugs. And the deep pipelines of those Big Pharma companies have given investors reasonable concerns that Summit—with ivonescimab as its lone asset—might lose out in the long run.BioNTech and BMS have already launched early-stage trials to combine their PD-L1xVEGF agent, pumitamig, with antibody-drug conjugates, and Pfizer has indicated its plans to do the same across multiple tumor types.As Leerink’s Graybosch pointed out when the AZ deal rumor emerged in July, competition of the PD-(L)1xVEGF class should also be judged by each drug’s portfolio of combo partners, and Summit is losing.