Akeso and Summit's lung cancer drug extends survival beyond Keytruda

Akeso (9926.HK) and Summit Therapeutics (SMMT) have reported that their experimental drug ivonescimab cut the risk of death by 27 percent compared with Merck & Co's (MRK) blockbuster Keytruda, strengthening the case for a class of cancer medicines that has drawn billions of dollars in industry investment.

The phase 3 Harmoni-2 trial, conducted in China in patients with previously untreated, PD-L1-positive advanced non-small cell lung cancer, showed patients on ivonescimab lived a median of 30.8 months, against 22.6 months for those on Keytruda. The findings are due to be presented at the World Conference on Lung Cancer in Seoul.

The readout follows the trial's success two years ago on its primary endpoint of progression-free survival, a result that set off a rush among drugmakers to acquire or develop similar bispecific antibodies targeting both PD-1 or PD-L1 and VEGF.

Michelle Xia, chief executive of Akeso, said the data should help physicians see that the approach was "capable of beating current PD-1 standards of care" in the indication, adding that the company had become "something of a bellwether" for the field. A proven survival advantage, she argued, was "a boon to everyone who has bought into PD-1xVEGF, whether that's Summit, Pfizer, AbbVie, Merck & Co, or BMS," referring to Pfizer (PFE), AbbVie (ABBV) and Bristol Myers Squibb (BMY).

The final result improves on the 22.3 percent reduction in risk of death recorded at an unplanned interim analysis requested by Chinese regulators as part of Akeso's drug application, which had disappointed investors. At that point the 398-patient trial had recorded 157 deaths against a demanding significance threshold. With 234 deaths at an August 20 data cutoff, the survival endpoint has now reached statistical significance, with a p-value of 0.009.

Analysts had been divided ahead of the release. Those at Citi and Leerink Partners modeled a survival benefit above 30 percent, while Jefferies and Evercore ISI took a more cautious view. By comparison, Keytruda alone improved survival by 19 percent against chemotherapy in the global Keynote-042 trial in a similar patient population.

Critics have long argued that Harmoni-2 has limited relevance to clinical practice, particularly for patients with low PD-L1 expression, for whom Keytruda plus chemotherapy has become standard treatment. Xia countered that the trial was designed to establish superiority over Keytruda and, with regulatory approval, offered a route to a broad label in China.

The most striking results came in patients with high PD-L1 expression, where Keytruda alone remains the global standard of care and adding chemotherapy offers little extra benefit. In that group, ivonescimab reduced the risk of death by 42 percent; median survival had not yet been reached for ivonescimab, against 23.2 months for Keytruda. In PD-L1-low patients, the advantage narrowed to 15 percent, with median survival extended by 6.4 months to 28.5 months.

Leerink analysts had described the PD-L1-high setting as "a relatively clean test" of whether the bispecific design adds benefit over PD-1 inhibition alone, although they had been skeptical of a strong result there. The outcome bodes well for Summit's global Harmoni-7 trial in the same population.

Ivonescimab also reduced the risk of death by 35 percent in patients with squamous tumors, a subtype in which the established VEGF inhibitor bevacizumab is generally avoided because of bleeding risk. Xia said this supported the view that the bispecific works differently from combining separate PD-1 and VEGF drugs.

In the separate Chinese Harmoni-6 trial, ivonescimab plus chemotherapy cut the risk of death by 34 percent against BeOne Medicines' (ONC) Tevimbra and chemotherapy in first-line squamous disease. When those data were presented at ASCO this year, Julie Brahmer of Johns Hopkins criticized the study for excluding patients whose tumors significantly involved major blood vessels. Such patients were included in Harmoni-2, where squamous histology accounted for 45 percent of participants, a share Xia said reflects real-world practice.

The competitive landscape is nonetheless shifting. At ASCO, Merck's partner Kelun-Biotech (6990.HK) reported that combining Keytruda with its TROP2-directed antibody-drug conjugate, sac-TMT, reduced the risk of disease progression or death by 65 percent versus Keytruda alone in a Chinese phase 3 trial, although survival data remained immature.

Attention now turns to Summit's Harmoni-3 trial, which pairs ivonescimab with chemotherapy in first-line disease, with a final progression-free survival readout from the squamous cohort expected this year. The study recently fell short of statistical significance at an interim analysis, prompting a selloff in Summit shares.

Xia said the two approaches need not compete, since ivonescimab aims to replace PD-1 immunotherapy while antibody-drug conjugates are becoming a better form of chemotherapy. "The next frontier could well be ivo plus an ADC," she said, adding: "Let's conquer one fortress at a time."

Merck appears to be pursuing the same idea. Days before the Harmoni-2 data, it posted its first global trial for its own PD-1xVEGF candidate, MK-2010, a phase 2 study combining the drug with sac-TMT in advanced solid tumors.