Revisiting anti-CTLA-4 antibodies in combination with PD-1 blockade for cancer immunotherapy
M Sznol, I Melero
In this issue of Annals of Oncology, Perets et al.1 report on a phase I/II trial of a new immunoglobulin G1 (IgG1) anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) monoclonal antibody (mAb) (MK-1308, quavonlimab) administered in combination with pembrolizumab [anti-programmed cell death protein 1 (PD-1)] in an all-comer dose escalation design in previously untreated, advanced non-small-cell lung cancer (NSCLC).1 For the phase II component, accrual was alternated between four regimens of MK-1308. Objective response rates were similar in all four arms, and based on the safety profile, MK-1308 25 mg every 6 weeks in combination with pembrolizumab 200 mg every 3 weeks was chosen for further testing in NSCLC and other malignancies.
In first-line advanced NSCLC, two other anti-CTLA-4 agents in combination with a PD-1 or programmed death-ligand 1 (PD-L1) antagonist have already been tested in phase III trials.2,3 The ipilimumab IgG1 mAb administered in combination with nivolumab (anti-PD-1) improved overall survival compared with chemotherapy and was approved in the USA for patients with tumors expressing PD-L1 ≥ 1%. In contrast, the anti-CTLA-4 IgG2 tremelimumab, when combined with durvalumab (anti-PD-L1), did not improve progression-free or overall survival compared with chemotherapy. The differences in outcome between the two trials remain unexplained. In addition to the differences in the IgG subtype, tremelimumab was given at 1 mg/kg every 4 weeks for up to four doses; ipilimumab was dosed at 1 mg/kg every 6 weeks for up to 2 years. Potential immunobiological differences may also exist in combining an anti-CTLA-4 with an anti-PD-1 versus an anti-PD-L1...