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An experimental lung cancer drug 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 a median of four months longer than the standard combination of immunotherapy and chemotherapy, a result that was statistically significant, according to an abstract released Sunday ahead of a presentation at the American Society of Clinical Oncology’s annual meeting. The Phase 3 trial was conducted in China, and a global Phase 3 study is ongoing.
“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 of Emory University. “I’m mindful of the fact that this trial was done exclusively in China, and that brings up the question of how do these data apply to patient populations outside of China, and that will require future investigations.”
Called ivonescimab, the bispecific antibody targets PD-1 — similar to Merck’s best-selling drug Keytruda —and VEGF — similar to Roche’s Avastin. It’s 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’ll disappoint like other once-promising ideas such as drugs targeting TIGIT, an immune receptor.
The dueling narratives are reflected in the stock price of U.S.-based Summit Therapeutics, which licensed the rights to ivonescimab outside of China from Akeso. Shares of Summit have skyrocketed nearly 600% in the two years since Summit said ivonescimab more effectively controlled tumors than Keytruda in a separate China trial. The stock has slid in the past month over concerns the drug won’t be as effective in a global population.
Cancer drug targets
Previous studies have showed ivonescimab can effectively control tumors, an endpoint known as progression-free survival. That’s typically 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, which raised doubts that ivonescimab’s early promise would hold.
In the Harmoni-6 trial being 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 meaningful that is,” said Dr. Deborah Doroshow, associate professor of medicine, hematology and medical oncology at the Icahn School of Medicine at Mount Sinai. “It’s certainly, it’s not two months, but it’s also not a huge difference, and I think in terms of whether or not living four months longer is meaningful absolutely depends on the person who is living it.”
People receiving 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 advantage of ivonescimab might be better than reported in the study, said Doroshow, who serves on the steering committee for the ongoing Harmoni-3 global trial of ivonescimab.
One possible reason for the discrepancy is that the study was conducted in China, where people have historically responded better to standalone PD-1 and VEGF drugs, said Emory’s Ramalingam. The only way to determine whether combining the two in one molecule produces different results for broader populations is to run 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 from squamous patients in the global Harmoni-3 trial in the second half of this year. It expects to share results from non-squamous patients in the first half of next year.
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One purported benefit of PD-1/VEGF-targeting drugs is the ability to give them safely to people with squamous lung cancer, a subset most commonly caused by smoking. These tumors tend to crop up near major blood vessels in the lungs, and blocking VEGF can prevent those blood vessels from repairing themselves, leading to potentially fatal hemorrhaging.
In the trial being presented Sunday, bleeding of any severity occurred in almost one-quarter of people in the ivonescimab group, twice as much as in the control group. Less than 3% of the cases were considered severe versus about 1% of people who received the PD-1 drug tislelizumab, according to slides that will be presented Sunday where the presenter describes ivonescimab’s safety as comparable.
More broadly, drugmakers and investors alike want to know whether PD-1/VEGF drugs will succeed Keytruda and similar drugs like Bristol Myers Squibb’s Opdivo as mainstay treatments. Checkpoint inhibitors like Keytruda have transformed the treatment of lung cancer and are now used in dozens of other cancers. Keytruda alone has 44 indications and generated more than $30 billion in sales for Merck last year.
Replacing Keytruda everywhere it’s used today and potentially expanding into new indications would create “a very large market,” said Leerink Partners analyst Daina Graybosch. That prospect has prompted a rush of dealmaking.
Licensing deals involving 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 reached 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 it’s unlikely that ivonescimab and similar drugs will be as broadly used, said Ethan Smith, oncology director at Norstella, especially as they face more competition from other emerging drugs like antibody drug conjugates than Keytruda had when it entered the market more than a decade ago.
Data from one antibody drug conjugate from Merck and partner Kelun is also being presented this weekend at the ASCO meeting. The experimental drug cut the risk of tumor progression by 65% in a study of lung cancer conducted in China, according to an abstract released ahead of the meeting.
While Merck thinks there will be places for PD-1/VEGF drugs and is excited about the one it’s 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 in oncology,” said Green. “I never thought that we would be in a position in lung cancer to debate about which of the new therapies is the best because there just have not been a lot of advances. Keytruda has just been a cornerstone therapy and people are like, ‘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 position to say, you know what, there might be multiple options of things that we can do, and then hopefully add them together and help even more.”
