Tiragolumab

The Bristol Myers setback follows another similar one by AstraZeneca's Imfinzi. Another attempt at improving upon AstraZeneca’s Imfinzi in stage 3, unresectable non-small cell lung cancer (NSCLC) has gone up in flames. The latest failure comes from a phase 3 trial conducted by Bristol Myers Squibb. The company’s Opdivo, used with concurrent chemoradiotherapy, followed by Opdivo plus BMS’ Yervoy, failed to beat Imfinzi maintenance in unresectable stage 3 NSCLC, BMS said Friday. The Imfinzi regimen features chemoradiation alone followed by Imfinzi during the maintenance phase of treatment. Approved by the FDA in early 2018, unresectable stage 3 NSCLC has been Imfinzi’s main indication, and it’s where the AZ PD-L1 inhibitor is the standard of care for patients whose cancer has not progressed after chemoradiation. BMS tried to challenge AZ’s dominance by launching the phase 3 CheckMate-73L trial in 2019. The company figured that because chemoradiotherapy increases PD-L1 expression, concurrent immune checkpoint inhibition may improve outcomes. But, now, the study found the Opdivo-Yervoy-concurrent-chemoradiation regimen couldn’t extend the time before tumor progression or death versus the Imfinzi maintenance approach. The adverse events observed were generally consistent with the known profiles of each component in the combination, BMS said. The CheckMate-73L study features another arm testing Opdivo monotherapy during the maintenance phase. But because its primary endpoint measures progression-free survival for the Opdivo-Yervoy arm, the entire study is now considered negative. The study’s many secondary endpoints include overall survival for either experimental arm against Imfinzi and for the two Opdivo arms against each other. The BMS setback follows another similar one by Imfinzi itself. Because the current Imfinzi regimen is given only to patients who have not progressed after initial chemoradiotherapy, AZ had tried to expand the drug’s patient base by giving Imfinzi and chemoradiation concurrently. However, that regimen recently failed to beat Imfinzi maintenance in the phase 3 PACIFIC-2 trial. Besides those regimens, China’s CStone Pharmaceuticals in 2022 reported positive phase 3 results from the GEMSTONE-301 trial for its China-approved PD-L1 inhibitor Cejemly (sugemalimab) when used after chemoradiotherapy in unresectable stage 3 NSCLC. However, that study was conducted solely in China, and the drug was pitted against placebo, not Imfinzi, so the results are not considered meaningful for the U.S. market. Now, market watchers are turning their attention to Merck & Co.’s PD-1 king Keytruda. The phase 3 KEYLYNK-012 trial is testing concurrent use of chemoradiation and Keytruda, followed by Keytruda with or without AZ and Merck’s PARP inhibitor Lynparza, versus Imfinzi maintenance in unresectable stage 3 NSCLC. However, the regimen doesn’t look very promising after a pair of phase 3 flops for the PD-1/PARP combo in metastatic NSCLC. There’s also Roche’s PD-L1 inhibitor Tecentriq. The Swiss pharma is running the phase 3 SKYSCRAPER-03 trial pairing Tecentriq with the company’s closely watched TIGIT inhibitor tiragolumab in the maintenance setting following concurrent platinum-based chemoradiation. The trial finished enrollment about a year ago and bears a primary completion date this October, according to Roche. AZ isn’t giving up its expansion efforts, either. The PACIFIC-9 trial is evaluating Imfinzi together with either the company’s anti-CD73 antibody oleclumab or Innate Pharma-partnered anti-NKG2A antibody monalizumab as a maintenance therapy. A readout from that phase 3 study could be two years away.

Merck is continuing with four other phase 3 lung cancer trials involving vibostolimab. Merck & Co. has bailed early on a phase 3 test of the anti-TIGIT antibody vibostolimab after a high rate of discontinuations rendered the trial's success unlikely.  The Big Pharma had been evaluating vibostolimab in combination with anti-PD-1 immunotherapy Keytruda in the KeyVibe-010 trial as an adjuvant treatment for patients with resected high-risk melanoma. But a higher rate of discontinuations mainly due to “immune-mediated adverse experiences” among patients taking the combination regimen meant it was “highly unlikely that the trial could achieve a statistically significant improvement” in the primary endpoint of recurrence-free survival, the company said. As a result, the independent data monitoring committee recommended that Merck unblind the trial and offer all patients the option of receiving just Keytruda. The study had originally been expected to read out in 2026. “Through our clinical development program, we continue to ask the tough questions in an effort to fully explore the potential of novel co-formulations and combinations that build on the foundation of Keytruda, with a goal to improve upon current standards of care and help even more patients with cancer,” Marjorie Green, senior vice president and head of oncology, global clinical development at Merck Research Laboratories, said in the May 13 release. This is not the first time vibostolimab has run into problems in the clinic. Last year, Merck revealed that a combination of vibostolimab and Keytruda was numerically less effective than the chemotherapy docetaxel in terms of progression-free survival among non-small cell lung cancer patients. It’s still not the end of the road for vibostolimab, however. Merck has four other phase 3 lung cancer trials involving the antibody ongoing with a combined total of about 3,000 patients enrolled. None of these trials are expected to be altered in the wake of today’s news, the company stressed. Talking to investors at an event back in December 2023, Merck’s chief medical officer Eliav Barr, M.D., identified phase 3 as where TIGITs would need to prove their worth. “We have to acknowledge that there have been phase 2 studies that have looked good, and then there's been phase 3s that have been more complex. So, the way I see the compound is we would wait to see phase 3 and go from there,” Barr said at the time. Merck’s executives can take some comfort from the fact that their Big Pharma peers have also struggled to demonstrate the effect of TIGIT blockade on cancer, despite the high hopes once heaped on the modality. Still, the year got off to a decent start with Roche posting a phase 3 win for tiragolumab in esophageal cancer, even if the use of a comparator that is no longer the standard of care complicates efforts to tease out the antibody's impact.