On the eve of the American Society of Clinical Oncology’s annual meeting last week, a piece of news set off vigorous discussions. A bispecific antibody from China appears to have done the unthinkable: beating Merck & Co.’s PD-1 inhibitor Keytruda, the world’s best-selling medicine, in a head-to-head phase 3 trial in non-small cell lung cancer.
The drug is ivonescimab, a PD-1 x VEGF bispecific developed by Chinese biotech Akeso and out-licensed to Summit Therapeutics in the U.S. in late 2022 in a deal worth up to $5 billion. The China-only trial, coded HARMONi-2, found that ivonescimab significantly extended patients' progression-free survival (PFS) time compared with Keytruda those whose tumors have positive PD-L1 expression, Summit said in release Thursday.
Before this result, no single drug had ever beaten Keytruda in a head-to-head phase 3 NSCLC trial.
Summit CEO Bob Duggan went as far as calling the readout “the beginning of a paradigm change” in the treatment of cancer in general. Analysts are doing their best to sort out the financial ramifications, and biopharma insiders are eager to see the exact data. But what does Merck think?
“Good news for patients or maybe another [treatment] option,” Eliav Barr, M.D., chief medical officer at Merck Research Laboratories, said in an interview with Fierce Pharma at the ASCO 2024 meeting.
“The issue,” Barr continued, is that “there’s been a lot of data looking at VEGF inhibitors in lung cancer. And we’ve done, God knows, a lot of studies of VEGF inhibition with [Keytruda]. In many of our studies, PFS was positive, including in lung. But [overall survival] was a little more difficult to show.”
“Patients, regulators, payers […] will focus on OS,” Barr continued. “So, we’ll see. It’s possible that this is going to be something interesting.”
Indeed, in the phase 3 LEAP-007 trial in first-line PD-L1-positive NSCLC, Merck and partner Eisai’s combination of Keytruda and Lenvima led to a statistically significant 22% reduction in the risk of disease progression or death but a negative 10% trend in overall survival compared with Keytruda alone. Lenvima is a kinase inhibitor targeting VEGF receptors and many other proteins involved in cancer.
As Barr indicated, an overall survival win would likely be needed for the Akeso/Summit drug to win an approval from the FDA in first-line NSCLC.
Trouncing Keytruda in its home turf would be a huge deal, considering the drug’s $25 billion in sales across numerous indications in 2023.
“I think everyone’s curious about what the Summit data is going to show—that’s so explosive a couple days ago,” P.K. Morrow, Takeda’s newly installed head of the oncology therapeutic area unit, said during an interview on the sidelines of ASCO 2024.
Keytruda won its FDA approval as a monotherapy to treat PD-L1-positive NSCLC in 2016. But Barr noted that most doctors today only use Keytruda monotherapy in PD-L1-high disease, where the single agent’s effect is bigger.
As for cases with a lower PD-L1 expression below a TPS score of 50%, Keytruda’s various combinations with chemotherapy represent the current practice. That means in those patients, an ivonescimab regimen will need to beat Keytruda and chemo.
“Will they? Maybe. I don’t know. We’ll have to see,” Barr said.
Meanwhile, it’s a common understanding in the oncology world that a China-only study such as HARMONi-2, or a trial conducted predominantly in one country outside the U.S., alone likely couldn’t support a U.S. filing, especially in a large indication such as NSCLC. The FDA’s oncology chief, Richard Pazdur, M.D., reiterated that position on the sidelines of the ASCO 2024 meeting.
When reviewing a clinical dataset, the FDA typically performs its analysis across different trial sites to look for differences and consistencies, Pazdur explained in response to a question about the ivonescimab readout during a Stat event Friday.
“This builds confidence in a system,” Pazdur said. “And when you’re bringing in data where we don’t have confidence, we need that confidence here.”
In addition, a trial conducted in China wouldn’t reflect the ethnic diversity of a U.S. population, the FDA official added.
Akeso’s HARMONi-2 readout might have benefited from its Chinese population, Jefferies analysts argued in a Friday note, pointing to past trial experiences where anti-VEGF treatments did better in Asian patients than for non-Asian populations.
According to Summit, ivonescimab’s PFS benefit was seen across patient subgroups, including in PD-L1-low, PD-L1 high, squamous, nonsquamous and high-risk patients. Detailed results will be shared at a future medical meeting.