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Akeso’s experimental lung cancer drug and summit therapeutics Results published Sunday showed a 34% reduction in the risk of death in a carefully monitored late-stage trial.
When used with chemotherapy, the drug led to a statistically significant median survival of four months longer for patients with squamous non-small cell lung cancer than the standard combination of immunotherapy and chemotherapy, according to abstracts published Sunday ahead of presentation at the annual meeting of the American Society of Clinical Oncology. Phase 3 trials were conducted in China, and global Phase 3 trials are underway.
“The fact that we have shown improved overall survival in this difficult-to-treat patient population is very encouraging,” said Dr. Suresh Ramalingam, executive director of Emory University’s Winship Cancer Institute. “We are mindful of the fact that this trial was conducted only in China, which raises the question of how these data apply to patient populations outside of China and will require future investigation.”
The bispecific antibody, called ivonecimab, targets PD-1, similar to Merck & Co.’s best-selling drug Keytruda, and VEGF, similar to Roche’s Avastin. This is the subject of intense debate in the oncology and investment communities. Some say ivonecimab and similar drugs could be a successor to Merck & Co.’s hugely successful cancer drug Keytruda, but others warn that they will be as disappointing as other once-promising ideas, such as drugs targeting the immune receptor TIGIT.
This dueling saga is reflected in the stock price of US-based Summit Therapeutics, which licensed the rights to ivonescimab outside of China from Akeso. Summit’s stock price soared nearly 600% in two years after the company announced that ivonecicimab controlled tumors more effectively than Keytruda in a separate Chinese trial. Stocks have fallen over the past month on concerns that the drug is not as effective for the world’s population.
Cancer drug targets
Previous studies have shown that ivonecicimab can effectively control tumors, with an endpoint known as progression-free survival. Normally, this is not enough to get a drug approved by the U.S. Food and Drug Administration, but the agency wants evidence that a cancer drug can extend people’s lives. Older VEGF drugs that effectively controlled tumors have struggled to improve survival rates, raising questions about whether the early promise of ivonecicimab will hold up.
In the Harmoni-6 trial published on Sunday, median survival was 27.9 months for patients treated with ivonecicimab and chemotherapy, compared with 23.7 months for patients who received a single PD-1 drug and chemotherapy, an improvement of four months.
“It’s not clear how meaningful that is,” says Dr. Deborah Doroshaw, associate professor of medicine, hematology, and oncology at the Icahn School of Medicine at Mount Sinai. “Sure, it’s not two months, but it’s not a huge difference either. I think it’s absolutely up to the person who’s living whether it makes sense to live four months longer.”
Doroshow, who is on the steering committee for Harmoni-3, the ongoing global trial of ivonecicimab, said people receiving immunotherapy in the control arm lived on average six months longer than expected, raising questions about whether the trial enrolled a representative patient population and whether the benefits of ivonecicimab were superior to those reported in the study.
One possible reason for this discrepancy is that the study was conducted in China, where stand-alone PD-1 and VEGF drugs have historically responded better, Emory’s Ramalingam said. The only way to determine whether combining the two in one molecule would yield different results in a broader population is to conduct additional studies in Western countries, he said.
Until then, Ramalingam had called the trial results “good news” for Chinese patients.
“There is a new approach for squamous cell carcinoma of the lung that extends survival by about four months, which is a significant improvement given the incremental progress made in this patient population,” he said.
Summit plans to report progression-free survival results for squamous patients in the global Harmoni-3 trial in the second half of this year. The company plans to share results for non-squamous patients in the first half of next year.
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One of the purported advantages of PD-1/VEGF-targeted drugs is that they can be safely administered to patients with squamous cell carcinoma of the lung, which is most commonly caused by smoking. These tumors tend to develop near major blood vessels in the lungs, and inhibiting VEGF can prevent blood vessels from self-repairing, leading to potentially fatal hemorrhages.
In the trial, published Sunday, nearly a quarter of patients in the ivonescimab group experienced bleeding of any severity, twice as many as in the control group. Less than 3% of cases were considered serious, while about 1% of patients received the PD-1 drug tislelizumab, according to slides released Sunday.
More broadly, drug companies and investors alike want to know whether PD-1/VEGF drugs will become mainstream treatments, replacing similar drugs such as Keytruda and Bristol-Myers Squibb’s Opdivo. Checkpoint inhibitors like Keytruda have revolutionized the treatment of lung cancer and are now used in dozens of other cancers. Keytruda alone has 44 indications and generated sales of more than $30 billion for Merck last year.
Daina Graybosch, an analyst at Leerink Partners, said the potential to replace Keytruda everywhere it is currently used and expand into new indications would create a “very large market.” The prospect triggered a rush of deals.
Licensing deals for PD-1 drugs reached $30 billion last year, nearly double the previous peak of $16 billion in 2017, a few years after Keytruda and Opdivo hit the market. Merck & Co. and Bristol-Myers Squibb have also joined in the recent rush, with the two companies inking potentially multibillion-dollar deals for PD-1/VEGF drugs.
But it’s unlikely that ivonecicimab or similar drugs will see such widespread use, especially since there is more competition from other emerging drugs, such as antibody-drug conjugates, than when Keytruda entered the market more than a decade ago, said Ethan Smith, Norstera’s director of oncology.
Data from one antibody-drug conjugate from Merck and partner Cologne will also be presented at this weekend’s ASCO meeting. The experimental drug reduced the risk of tumor progression by 65% in a lung cancer study conducted in China, according to an abstract published ahead of the conference.
Dr. Marjorie Green, head of global oncology clinical development at Merck, said Merck believes there is room for PD-1/VEGF drugs and is excited about the drugs the company is developing, but does not expect them to become the next Keytruda.
“Oncology is at an exciting time right now,” Green said. “I never thought I’d be in a position in the field of lung cancer to debate which new treatments are best, because there hasn’t been much progress. Keytruda is just the cornerstone treatment, and people are thinking, ‘What’s going to replace it?’ And I think the good news is that for people who are unfortunately diagnosed with lung cancer, we’re in a position to say that there may be multiple options for what we can do, and hopefully we can combine them to help even more.”
