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An experimental drug against lung cancer from Akeso and Summit Therapeutics reduced the risk of death by 34% in a closely watched late-stage trial, according to results released Sunday.
When combined with chemotherapy, the drug kept people with squamous non-small cell lung cancer alive for an average of four months longer than the standard combination of immunotherapy and chemotherapy, a result that was statistically significant, according to an abstract published Sunday ahead of a presentation at the American Society of Clinical Oncology annual meeting. The Phase 3 trial was conducted in China and a global Phase 3 study is underway.
“The fact that it shows an improvement in overall survival in a difficult-to-treat patient population is very encouraging,” said Dr. Suresh Ramalingam, executive director of the Winship Cancer Institute at Emory University. “I am aware of the fact that this trial was conducted exclusively in China, and that raises the question of how this data applies to patient populations outside of China, and that will require future research.”
Called ivonescimab, the bispecific antibody targets PD-1, similar to Merck's best-selling drug Keytruda, and VEGF, similar to Roche's Avastin. It has become the subject of intense debate in the oncology and investment communities. Some say ivonescimab and similar drugs could be a successor to Merck's wildly successful cancer drug Keytruda, while others warn it will disappoint like other once-promising ideas, such as drugs targeting TIGIT, an immune receptor.
The dueling narratives are reflected in the share price of US-based Summit Therapeutics, which licensed the rights to ivonescimab outside of China to Akeso. Summit shares have soared nearly 600% in the two years since Summit said ivonescimab controlled tumors more effectively than Keytruda in a separate trial in China. Shares have fallen in the last month on concerns that the drug may not be as effective in a global population.
Targets of anticancer drugs
- PD-1: A protein that helps cancer cells hide from the immune system.
- VEGF: A protein that promotes the growth of new blood vessels and may help cancer cells thrive.
Previous studies have shown that ivonescimab can effectively control tumors, an endpoint known as progression-free survival. That's usually not enough to seek approval from the U.S. Food and Drug Administration, which wants proof that cancer drugs can keep people alive longer. Older VEGF drugs that effectively controlled tumors struggled to improve survival, raising questions about whether ivonescimab's initial promise would hold.
In the Harmoni-6 trial presented Sunday, ivonescimab combined with chemotherapy kept people alive for a median of 27.9 months versus 23.7 months for people who received a standalone PD-1 drug and chemotherapy, an improvement of four months.
“It's not clear how significant this is,” said Dr. Deborah Doroshow, an associate professor of medicine, hematology and medical oncology at the Icahn School of Medicine at Mount Sinai. “It's certainly not two months, but it's not a huge difference either, and I think in terms of whether living four more months is significant or not, it absolutely depends on the person who lives it.”
People who received immunotherapy in the control group lived an average of six months longer than expected, raising questions about whether the trial enrolled a representative patient population and whether the benefit of ivonescimab might be better than that reported in the study, said Doroshow, who is on the steering committee of the ongoing global Harmoni-3 trial of ivonescimab.
One possible reason for the discrepancy is that the study was conducted in China, where people have historically responded better to the standalone drugs PD-1 and VEGF, said Emory's Ramalingam. The only way to determine whether combining the two in one molecule produces different results for broader populations is to conduct additional studies in the West, he said.
Until then, Ramalingam called the trial results “good news” for Chinese patients.
“There is a new approach in squamous cell lung cancer that extends survival by about four months, which is a substantial improvement given that this is a patient population where progress has come in small steps,” he said.
Summit plans to report progression-free survival results of squamous patients in the global Harmoni-3 trial in the second half of this year. He hopes to share results from non-squamous patients in the first half of next year.
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A putative benefit of drugs targeting PD-1/VEGF is the ability to safely administer them to people with squamous lung cancer, a subgroup most commonly caused by smoking. These tumors tend to arise near major blood vessels in the lungs, and blocking VEGF can prevent those blood vessels from repairing themselves, causing life-threatening bleeding.
In the trial presented Sunday, bleeding of any severity occurred in almost a quarter of people in the ivonescimab group, twice as many as in the control group. Less than 3% of cases were considered serious versus about 1% of people who received the PD-1 drug tislelizumab, according to slides to be presented Sunday where the presenter describes the safety of ivonescimab as comparable.
More broadly, both drugmakers and investors want to know whether PD-1/VEGF drugs will succeed Keytruda and similar drugs like Bristol Myers Squibb's Opdivo as mainstream treatments. Checkpoint inhibitors like Keytruda have transformed lung cancer treatment and are now used in dozens of other cancer types. Keytruda alone has 44 indications and generated more than $30 billion in sales for Merck last year.
Replacing Keytruda everywhere it is used today and potentially expanding into new indications would create “a very large market,” said Daina Graybosch, an analyst at Leerink Partners. That prospect has sparked an avalanche of deals.
Licensing deals related to PD-1 drugs reached $30 billion last year, nearly doubling the previous peak of $16 billion in 2017, a few years after Keytruda and Opdivo hit the market. Merck and Bristol Myers Squibb were part of the recent rush, with both companies signing potentially multibillion-dollar deals for PD-1/VEGF drugs.
But ivonescimab and similar drugs are unlikely to be used as widely, said Ethan Smith, Norstella's head of oncology, especially since they face more competition from other emerging drugs such as antibody conjugates than Keytruda had when it entered the market more than a decade ago.
Data from a drug-antibody conjugate from Merck and its partner Kelun will also be presented this weekend at the ASCO meeting. The experimental drug reduced the risk of tumor progression by 65% in a lung cancer study in China, according to an abstract published before the meeting.
While Merck believes there will be places for PD-1/VEGF drugs and is excited about the one it is developing, the company doesn't expect them to become the next Keytruda, said Dr. Marjorie Green, Merck's head of global oncology clinical development.
“It's an exciting time for oncology,” Green said. “I never thought we'd be in a position to debate in lung cancer which of the new therapies is best because there just hasn't been much progress. Keytruda has just been a cornerstone therapy and people are saying, 'What's going to displace it?' And I think it's good news for people who are unfortunately diagnosed with lung cancer that we're in a position to say, you know what, there could be multiple options of things we can do and then hopefully add them up and help even more.”
