An experimental lung cancer drug, ivonescimab, developed by Akeso and Summit Therapeutics, demonstrated improved survival in the Harmoni-6 Phase 3 trial conducted in China, according to results being presented at the American Society of Clinical Oncology (ASCO) annual meeting. The bispecific antibody targets both PD-1, similar to Merck's best-selling drug Keytruda, and VEGF, akin to Roche's Avastin. This class of PD-1/VEGF drugs has become a hotly debated emerging class of medicines within the medical and investment communities.
Results released Sunday indicated that ivonescimab reduced the risk of death by 34% in this closely watched late-stage trial, according to the findings. When administered in combination with chemotherapy, the drug extended the lives of individuals with squamous non-small-cell lung cancer by a median of four months longer than the standard treatment regimen of immunotherapy and chemotherapy. This outcome was deemed statistically significant, according to an abstract released Sunday ahead of its presentation at ASCO's annual meeting. The Phase 3 trial was conducted exclusively in China, with a global Phase 3 study currently ongoing.
Dr. Suresh Ramalingam, executive director of the Winship Cancer Institute of Emory University, expressed encouragement regarding the findings. He said, "The fact that it shows an improvement in overall survival in a difficult-to-treat patient population is very encouraging." However, Dr. Ramalingam also acknowledged the trial's geographical limitation, stating, "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."
Ivonescimab has become a focal point of intense discussion among oncology specialists and investors. Some proponents suggest that ivonescimab and similar drugs could potentially succeed Merck's widely successful cancer treatment, Keytruda. Conversely, others warn that these drugs might ultimately disappoint, drawing parallels to other once-promising concepts like TIGIT-targeting drugs that did not meet expectations.
These contrasting viewpoints are reflected in the stock performance of U.S.-based Summit Therapeutics, which licensed the rights for 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. However, the stock has experienced a decline in the past month due to concerns regarding the drug's potential efficacy in a global patient population.
Previous studies have showed ivonescimab can effectively control tumors, an endpoint known as progression-free survival. This alone is typically insufficient for seeking approval from the U.S. Food and Drug Administration (FDA), which generally requires evidence that cancer drugs prolong patients' lives. Older VEGF drugs, despite effectively controlling tumors, struggled to demonstrate improved survival, which had raised doubts that ivonescimab's early promise would translate into better overall survival.
In the Harmoni-6 trial, ivonescimab combined with chemotherapy extended the median survival to 27.9 months, compared to 23.7 months for patients who received a standalone PD-1 drug and chemotherapy, representing an improvement of four months. Dr. Deborah Doroshow, associate professor of medicine, hematology, and medical oncology at the Icahn School of Medicine at Mount Sinai, commented on this difference, stating, "It's not clear how meaningful that is." She added that while "it's certainly, it's not two months, but it's also not a huge difference," the meaningfulness of living four months longer "absolutely depends on the person who is living it."
Dr. Doroshow, who serves on the steering committee for the ongoing Harmoni-3 global trial of ivonescimab, noted that people receiving immunotherapy in the control group lived an average of six months longer than expected. This observation, she said, puts attention on whether the trial enrolled a truly representative patient population and if ivonescimab's advantage might be better than reported in the study. Emory's Dr. Ramalingam suggested one possible reason for this discrepancy is that the study was conducted in China, where people have historically responded better to standalone PD-1 and VEGF drugs. He said the only way to determine whether combining the two targets in one molecule produces different results for broader populations is to run additional studies in the West. Until then, Ramalingam called the trial results "good news" for Chinese patients, emphasizing that "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 and expects to share results from non-squamous patients in the first half of next year.
Safety Profile and Market Dynamics
One purported benefit of PD-1/VEGF-targeting drugs is their ability to be given 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, potentially leading to fatal hemorrhaging. In the trial 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 are keen to understand whether PD-1/VEGF drugs will succeed Keytruda and similar treatments like Bristol Myers Squibb's Opdivo as mainstay therapies. 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 Leerink Partners analyst Daina Graybosch. This prospect has prompted a rush of dealmaking, with licensing deals involving PD-1 drugs reaching $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 this recent surge, both signing potentially multibillion-dollar deals for PD-1/VEGF drugs.
However, Ethan Smith, oncology director at Norstella, said it is unlikely that ivonescimab and similar drugs will be as broadly used. He noted they face increasing competition from other emerging drugs, such as antibody drug conjugates, a challenge Keytruda did not encounter when it entered the market over 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. Green characterized it as an "exciting time in oncology," adding that it is "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."
