AstraZeneca has stopped a phase 3 trial of volrustomig in lung cancer based on interim efficacy data, narrowing the opportunity for a bispecific designed to replace current immune checkpoint inhibitors.
Investigators randomized 895 people to receive volrustomig or Merck & Co.’s Keytruda in combination with chemotherapy as a first-line treatment for metastatic non-small cell lung cancer. By enrolling people with PD-L1-low or PD-L1-negative disease, AstraZeneca aimed to validate its PD-1xCTLA-4 bispecific in a subpopulation of patients who have limited responses to current checkpoint inhibitors.
But a planned review of the results led the Independent Data Monitoring Committee (IDMC) to conclude the volrustomig regimen was unlikely to meet either of the dual primary endpoints. The endpoints looked at progression-free and overall survival in patients with PD-L1-negative tumors.
AstraZeneca’s statement lacks data from the trial or comments on other efficacy endpoints, including its assessments of survival in the broader population of PD-L1-low patients. Based on the IDMC’s advice, AstraZeneca said it is discontinuing the trial.
The drugmaker is continuing phase 3 trials of volrustomig in cervical cancer, head and neck squamous cell carcinoma and mesothelioma. Safety data from the discontinued lung cancer study were positive for the ongoing trials, with AstraZeneca reporting the absence of new signals and a profile consistent with the individual medicines.
Volrustomig’s failure to deliver efficacy alongside predictable safety ends AstraZeneca’s attempt to serve an unmet need in lung cancer. With PD-L1-low and PD-L1-negative patients having less durable responses to single-agent checkpoint inhibitors, researchers have explored combining the drugs with CTLA-4 inhibitors, such as Bristol Myers Squibb’s Yervoy. However, toxicity is a barrier to the combination.
AstraZeneca bet that a bispecific could boost CTLA-4 inhibition at tolerable doses by increasing blockade of the immune checkpoint protein on PD-1-positive T cells. The mix of antitumor activity and acceptable tolerability seen in a phase 1/2 study, especially in PD-L1-negative patients, led AstraZeneca to start a phase 3 trial in 2023.
Earlier this year, AstraZeneca used the American Society of Clinical Oncology annual meeting to tout early evidence that volrustomig can achieve durable responses. However, in a June 2 note to investors, Guggenheim Securities analysts said their expectations remained low. These low expectations, which the analysts said are shared by the investors they speak to, extend to AstraZeneca’s PD-1xTIGIT bispecific rilvegostomig.