Summit Therapeutics is running late-stage trials for biopharma’s buzziest drug in lung cancer, but some industry experts believe ivonescimab and other PD-1xVEGF bispecifics may better target another type of tumor.
They say a drug that can inhibit PD-1, like Merck’s Keytruda, and VEGF — another important pathway in some colorectal tumors — could be a powerful combination against this type of cancer, which is much harder to treat than lung cancer.
Although Keytruda, Bristol Myers Squibb’s Opdivo and other PD-(L)1 inhibitors have revolutionized cancer treatment, they remain ineffective against most colorectal tumors. VEGF inhibitors, meanwhile, are an established standard for colorectal cancer, and the idea is that both pathways with the same molecule will improve patient outcomes.
Now there’s ivonescimab, which hit like an earthquake last year when it
outperformed
the world’s best-selling drug in a Phase 3 trial in lung cancer. As Summit gets closer to filing that drug with the FDA, industry insiders think ivonescimab will take over Keytruda’s position as the most important cancer therapy in the world, and are questioning whether the drug will work in cancers that don’t respond to PD-1s.
“If it really works broadly in colorectal cancer, the market can be almost as big as lung cancer,” longtime pharma executive David Epstein said. He leads Ottimo Pharma, which is
working on its own
PD-1xVEGFR2 antibody. “If it works there, and if it works in triple-negative breast cancer, which the BioNTech drug seems to do, you’re over $100 billion.”
Along with ivonescimab, which Summit licensed from the Chinese biotech Akeso in 2022, BioNTech and Bristol Myers Squibb are also working on a PD-1xVEGF bispecific called pumitamig. Both drugs are being tested in clinical trials for metastatic colorectal cancer in China, with ivonescimab in Phase 3 and pumitamig in Phase 2.
Given Keytruda’s relative lack of efficacy in colorectal cancer, there’s less competition for these experimental bispecifics, according to Leerink analyst Daina Graybosch. Lung cancer, on the other hand, is one of the most crowded settings in drug development.
“The level of competitive intensity and things that could potentially launch there is much more modest,” Graybosch said of the lung cancer market.
But Epstein is quick to note that the theory has caveats. “They may not work well in every single setting, and determining whether or not they do will take years,” he said. “Then they have to compete on the market.”
Summit executives told
Endpoints News
earlier this year that they don’t plan to advance ivonescimab beyond non-small cell lung cancer on their own.
“We view ivonescimab to have a large potential, and are very excited about the opportunity that ivonescimab can bring to patients with solid tumors,” Summit’s chief business and strategy officer Dave Gancarz said in September before a presentation at the World Conference on Lung Cancer. “And so the very specifics of where we plan to go, we haven’t released that.”
There are two main reasons why PD-(L)1 use has proliferated in lung cancer while remaining scant in colorectal cancer. It comes down to the market size (including the cost it takes to get to commercialization) and the biological rationale for how it works (or doesn’t).
There’s a clearer regulatory path and larger patient population in lung cancer, said Pashtoon Kasi, a GI cancer specialist at City of Hope, who studies the genomics of cancer and how personalized therapies are developed. That leads companies to go after what are perceived to be easier indications.
“I’m going to have my own bias because I am a colorectal cancer oncologist, but I would argue that you could have a bigger impact in a disease type that’s essentially barren when it comes to immunotherapy,” Kasi said.
Keytruda and Bristol Myers’ Opdivo are the only PD-1 drugs approved in colorectal cancer, but only in a setting in which PD-1 expression is high. Opdivo can be given with or without another BMS drug, the CTLA-4 inhibitor Yervoy.
The reason why PD-1s work so much better in lung cancer than colorectal cancer is not well-understood, according to John Heymach, the University of Texas MD Anderson Cancer Center’s chair of thoracic/head and neck medical oncology.
Clinicians theorize that single-agent PD-(L)1 inhibitors like Keytruda simply respond better to tumors that have more mutations like lung cancer and melanoma. It’s also likely that the colon naturally suppresses the immune system more than the lungs and skin, but there’s no clear reason why, he said.
“The tumor mutation burden is one major factor, and the evidence for that is — when colorectal cancer has a lot of mutations, it does respond better to immunotherapy,” Heymach said. “But I think it’s also quite likely there is a suppressive environment where colorectal cancers are more likely to grow.”
Kasi also emphasized just how few mutations exist in common colon cancers — “barely 70,” he said, compared to about 1,800 in the subset of patients for which Keytruda is approved. Fewer mutations means lower expression of PD-1 on cancer cells, and that results in ineffective checkpoint inhibitors.
Putting all of colorectal cancer under one umbrella is also not constructive, Kasi said. There are at least five different subgroups of colon cancer that all come with genetic and phenotypic differences, further complicating potential treatments. Colorectal tumors can even respond differently depending on where they are located in the colon.
“To group them into just one group of diseases makes it not do justice to some of the challenges,” Kasi said. “The more common type — garden-variety colorectal cancer — does not respond to the checkpoint blockade.”
Meanwhile, anti-VEGF therapy has long been the standard of care, with Roche’s Avastin being the go-to metastatic colorectal cancer treatment since it was first approved in 2004. Colorectal cancer patients are typically given a regimen of three to five chemotherapy drugs and Avastin, regardless of tumor type, Kasi said.
Researchers have tried using separate PD-1 and VEGF inhibitors in colorectal cancer, but the drugs have largely failed or provided only incremental benefit. Kasi pointed to a recent study from Bristol Myers that
didn’t pan out
. It tested Avastin and chemo with or without its PD-1 drug Opdivo.
Avastin also comes with a notable side effect that can be counterintuitive when given with immunotherapy, Heymach said. It can restrict the body’s ability to close surgical wounds and create scar tissue.
Why, then, have ivonescimab and other anti-VEGF bispecifics arrived with such a splash? Much of the hype has to do with the molecule designs that could theoretically overcome some of the immunosuppressive challenges found in most colon cancers, Epstein said. Most of the designs fall into one of three categories.
First, there’s ivonescimab, which is “Keytruda plus Avastin slammed together” on the same molecule, according to Epstein. There’s also BMS and BioNTech’s pumitamig, which is Roche’s Tecentriq plus Avastin “slammed together.” And then there’s the third category: a PD-1 drug bound to an inhibitor of VEGFR2, which is what Epstein’s Ottimo is researching.
With all of these “flavors” of drug, the market is wide enough for biopharma companies to go big or small when picking which indications to pursue, Epstein added.
“If you want to be the next Merck, you’re probably gonna have to do a very broad program,” Epstein said. “If you want to be like Regeneron’s Libtayo — they have one or two indications — you could be very focused. So there’s room to do both.”
Ivonescimab came to Summit from a license with Akeso, a startup in China where lung cancer is by far the most common cancer. So far, most of its clinical trial successes have come in China-only studies. The first data for Western patients, revealed last month,
disappointed Wall Street
and forced executives to
play defense for the first time
.
Still, if Summit ends up translating that success to the US, it could represent a tectonic shift in the standard of care for lung cancer patients — and a boon for whichever large company ends up partnering on the drug. Earlier this summer,
Bloomberg
reported
that AstraZeneca was in discussions for a $15 billion partnership with Summit.
But lung cancer is one of the most crowded settings in drug development, according to Graybosch. Trying to upend the longstanding standard of care comes with immense risk. But going after colorectal cancer presents a different kind of risk, since there are fewer treatments and a more complex immunotherapy landscape.
The FDA has approved Keytruda for five non-small cell lung cancers, including in the first-line and adjuvant populations. NSCLC makes up about 87% of all lung cancers, according to the
American Cancer Society
.
However, in colorectal cancer, Keytruda has just that one approval for a subset of patients with certain mutations. About 5% to 15% of all colorectal cancer diagnoses can be treated with Keytruda. Keytruda works very well in this setting — it
reduces
the risk of death or disease progression by 40% compared to chemo.
And so for the rest of colorectal cancers, PD-1xVEGF bispecifics may work better in combination with other therapies rather than PD-1s alone. Based on the data released so far, Graybosch — who is Summit’s most bearish sell-side analyst — believes the bispecifics will not replace PD-(L)1 checkpoint inhibitors outright in colorectal cancer.
“PD-1 was a lightning in a bottle, just because it sets a baseline for an immune therapy that we just didn’t have before, and now everything’s adding on top of that,” Graybosch said. “I don’t think we’ll have a Merck again because I think it’s going to be about combinations, and those combinations are more likely to start to diverge now and fragment.”
A two- or three-month overall survival benefit may be enough for bispecifics to displace checkpoint inhibitors in lung cancer, according to Epstein. It’s why ivonescimab has investors excited about the potential for dethroning Keytruda and its $30 billion in annual sales.
But it’s still an open question whether ivonescimab and other bispecifics will live up to the hype — both in lung cancer and colorectal cancer. Akeso is set to present additional data from the China-only HARMONi-6 trial in lung cancer at ESMO’s annual meeting this week in Berlin.
“You’ve been to the movie theater and you’ve gone in and someone’s overhyped the movie, and you’ve seen the movie, and it was a good movie. But maybe, maybe you left disappointed,” Epstein said. “So when you ask the question, ‘Will it be as good as what people expect?’ It all depends upon what the expectations are.”