In its first global phase 3 readout, Akeso and Summit Therapeutics’ closely watched PD-1xVEGF bispecific antibody ivonescimab reduced the risk of progression or death by 48% in patients with previously treated EGFR-mutated nonsquamous non-small cell lung cancer (NSCLC).
Ivonescimab improved progression-free survival (PFS) outcomes when added to chemotherapy and compared with chemotherapy alone. The patients in the study had progressed following treatment with a third-generation EGFR tyrosine kinase inhibitor (TKI).
The HARMONi trial readout (PDF) marks the fourth phase 3 study result for ivonescimab in NSCLC.
“We think it is fairly clear that this is a drug!” Cantor Fitzgerald analyst Eric Schmidt said in a Friday note.
“In each of these four trials, the data posted by ivonescimab appear differentiated from and superior to PD-1 therapy,” Schmidt said.
Previously, in the China-only HARMONi-A trial in a similar post-TKI EGFR setting, ivonescimab reduced patients' risk of progression or death by 54%. In a Friday press release, Summit described the findings between the two studies as “consistent.”
Patients in HARMONi-A who had failed on third-generation TKI were included in the analysis of the global HARMONi trial.
A 21% reduction in the risk of death for ivonescimab in HARMONi did not reach statistical significance at this point, Summit said. An analysis run by Jefferies analyst Kelly Shi, Ph.D., found that the overall survival endpoint still has chance to reach statistical significance in the future as data on patients from outside of China mature, if those remaining patients continue to show consistent survival benefits.
The median follow-up time for Western patients was less than the median overall survival at the time of the analysis, Summit noted. Both Asian and North American patients demonstrated a positive trend in overall survival, the company said.
About 38% of HARMONi participants were randomized from Western countries.
Based on the HARMONi results, Summit said it intends to seek an approval from the FDA. The company will “consider the timing” of its Biologics License Application (BLA) filing based on its discussions with the agency, Summit added.
“The FDA noted that a statistically significant overall survival benefit is necessary to support marketing authorization, which will weigh into Summit’s considerations regarding the timing of a potential BLA filing,” Summit noted.
The overall survival data at this analysis likely disappointed investors, as Summit's stock price dropped about 26% Friday as of publication time.
The ivonescimab data drop comes just days after an FDA advisory committee panel voted that a phase 3 diffuse large B-cell lymphoma dataset from Roche’s Columvi is not applicable to a U.S. population. The study in question, coded Starglo, enrolled 52% of its participants from countries outside Asia, including 9% from the U.S.
Still, EGFR mutations are more prevalent in the Asian patient population. The frequency is estimated to be around 40% to 50% in Asian NSCLC patients, compared with 10% to 15% in Caucasians. Besides, as Summit noted, HARMONi’s 38% ex-Asia enrollment rate is consistent with past multiregional phase 3 trials in EGFR-mutated NSCLC.
With the HARMONi readout, Akeso and Summit effectively crashed the American Society of Clinical Oncology annual meeting, just as they did last year with the bombshell news that ivonescimab topped Merck & Co.’s PD-1 king Keytruda in the head-to-head HARMONi-2 trial.
HARMONi-2 is an ongoing China phase 3 trial in first-line, PD-L1-positive NSCLC. The trial has met its PFS endpoint, with its overall survival data remaining immature.
Because ivonescimab was developed by Akeso in China, the drug had only generated Chinese data until now.
Despite the strong PFS results in China, skeptics have questioned whether ivonescimab’s efficacy can be replicated in a Western population.
“We can’t completely rule out this bear argument today, but today’s press release reports a best possible outcome between ivonescimab’s consistency of effect across the two different populations,” Schmidt said in his note.
As Schmidt pointed out, post-TKI EGFR-mutant NSCLC is a relatively small indication, with around $500 million to $1 billion in annual sales potential. Some people will likely argue that EGFR-driven cancer is different from wild-type NSCLC, which is a much larger population with more than $10 billion in annual market opportunity in the first-line setting, Schmidt noted.