Two therapies are positioned to become fierce rivals in non-small cell lung cancer: ivonescimab, a bispecific antibody drug, and sac-TMT, an antibody-drug conjugate.
And this one-on-one battle could offer insights about how two of the hottest drug categories in oncology — ADCs and bispecifics — will find their place in the wider market. But it may not be a case of winner-takes-all for the dueling drug classes.
While the drugs would compete for market share if approved, they may also become complementary therapies, said Nkiru Ibeanu, an oncology analyst at Citeline.
“In clinical trials the question being asked is about which one should be used over the other,” she said. “But I think there's still room for a broader conversation of ADC plus bispecific or ADC then bispecific rather than ADC versus bispecific.”
Both modalities have seen heavy funding and M&A activity. Billions of investment dollars have flowed into bispecific antibodies, which are designed to simultaneously hit two targets. Activity ramped up when ivonescimab, a PD-1 and vascular endothelial growth factor (VEGF) combination being developed by Summit Therapeutics and Akeso, showed potential to beat Merck & Co.’s Keytruda in a lung cancer trial in 2024.
ADCs have also attracted major attention, fueled by the success of blockbusters like Daiichi Sankyo’s Enhertu, most recently approved for a challenging type of HER2-positive breast cancer. These so-called smart chemo drugs are designed to deliver potent cancer-killing payloads while limiting damage to healthy tissues. They’ve made headway taking on once “undruggable” targets and showing what one expert called “dramatic efficacy.”
At the ASCO meeting earlier this month, Merck presented new data for sac-TMT from a phase 3 lung cancer trial in China, showing that the ADC in combination with Keytruda slashed the risk of disease progression by 65% compared to Keytruda alone. In its abstract, researchers noted that the data for overall survival were “not mature” but that a “favorable trend was observed.”
Akeso and Summit also showcased recent late-stage results at ASCO for ivonescimab in lung cancer. In the China-based trial, the bispecific cut the risk of death by 34% when combined with chemotherapy and triggered a “significantly prolonged” overall survival rate of nearly 79% at 12 months.
And bispecifics may have an edge when it comes to side effects. ADCs were initially hampered by serious side effects and still carry risks, including lung inflammation and mouth sores known as stomatitis. But the side effect profile of individual ADCs varies and doctors are learning how to manage troubling symptoms more effectively, Ibeanu said.
Side effects aren’t the only differentiator. ADCs may have the upper hand in flexibility because they seem capable of targeting a broader range of cancers, Ibeanu said.
“What we have seen is that sac-TMT does have a more extensive clinical trial program beyond NSCLC, and that's basically because the biomarker that they’re looking for, TROP-2, is highly expressed in a lot of different cancers,” Ibeanu said.
In addition to advancing sac-TMT, which is in phase 3 for seven indications, Merck is also co-developing another ADC, raludotatug deruxtecan, with Daiichi Sankyo. The treatment is in late-stage development for ovarian cancer and in mid-stage studies in several other indications.
But, bispecifics could have broader potential in other indications, such as liver cancer and gastric cancers. Bispecifics, including ivonescimab, are also in testing for colorectal cancer, breast and brain cancers, among others.
The road to approval
How ivonescimab and sac-TMT fare if they make it to market will depend on several factors, including physician preference, which is often driven by assessing the balance between safety and efficacy. But payer access will also come into play, Ibeanu said.
Provided there are no surprises, ivonescimab and sac-TMT are both poised to gain approval in the near future. Ivonescimab may hit the market faster because the BLA is filed and the drug already has a November PDUFA date.
“Ivonescimab does seem to have the upper hand, but sac-TMT is not going to be very far behind,” Ibeanu said. The FDA awarded sac-TMT a drug priority review voucher, which will accelerate its FDA review.
Beyond the fate of the individual drugs, a broader question remains about how ADCs and bispecifics will fit into the wider oncology market. Researchers are exploring not only where each approach works best, but whether the two modalities could be used in combination.
“Mechanistically, ADCs can prepare the immune system for, or make the immune system more susceptible to a bispecific therapy,” Ibeanu said. “A protocol might include an ADC first in one line of therapy, followed by a bispecific rather than have these two drug classes directly compete with each other.”
A number of trial readouts are expected by the end of this year. One key question is whether ivonescimab’s results from a China-only trial will translate to global populations. Those data, along with others, could help clarify the future role of both drug classes, she said.
