Durvalumab Combinations Push the Response Envelope in Unresectable NSCLC
Patients with unresectable stage III non-small cell lung cancer (NSCLC) had a higher response rate and better progression-free survival when novel targeted agents were added to treatment with durvalumab (Imfinzi), a phase II randomized trial showed.
Objective response rate improved from 17.9% with durvalumab alone to 30.0% with the addition of the anti-CD73 agent oleclumab and to 35.5% with durvalumab plus the NKG2A inhibitor monalizumab, following standard chemoradiation therapy.
The addition of a targeted agent to the immune checkpoint inhibitor reduced the hazard for disease progression or death by 56%-58%, reported Roy S. Herbst, MD, PhD, of the Yale Cancer Center in New Haven, Connecticut, and co-authors, in the Journal of Clinical Oncology.
Grade ≥3 treatment-emergent adverse events (TEAEs) were similar with durvalumab alone versus its combination with oleclumab and less common with the monalizumab combination.
“We’re building on the PACIFIC regimen, which has already been shown to improve survival in stage III disease,” Herbst told Medpage Today. “Now we’re adding a drug to durvalumab … for patients who have had chemo and radiation and did not progress. This is their first immunotherapy, not a refractory situation. With this platform, we’re able to test an immune-pristine environment, and that allows us to look for combinations that might be more active.
“Lo and behold, in this trial, both of these combos were positive in this phase II study, so I guess we picked well. It allows us to do two things: Take these combinations to phase III, which we need to confirm the results, and then of course, move forward with other combinations, maybe test combinations in the metastatic setting and so forth.”
Known as the COAST trial, the study was part of a clinical trial platform to evaluate immunotherapy-based combinations in different clinical settings. As reported at the recent American Association for Cancer Research meeting, the NeoCOAST trial showed that the rate of major pathologic response tripled with the addition of targeted agents to durvalumab for operable NSCLC.
The COAST trial evaluated durvalumab alone or in combination with agents that target different contributors to lung cancer progression. Upregulation of CD73 increases extracellular adenosine production, leading to local immunosuppression in multiple types of cancer. Monalizumab blocks the inhibitory receptor NKG2A to HLA-E to reduce inhibitory effects on natural killer and CD8+ T cells, Herbst and co-authors noted in the background information of their article.
The study involved patients with unresectable stage III NSCLC that did not progress after upfront concurrent chemoradiation. Investigators in the multicenter trial randomized patients 1:1:1 to durvalumab alone or combined with oleclumab or monalizumab. The primary endpoint was objective response rate (ORR).
The planned interim analysis included 189 patients who had a median follow-up of 11.5 months. Response data showed objective responses in 12 of 67 (17.9%) patients randomized to single-agent durvalumab, 18 of 60 (30%) assigned to durvalumab plus oleclumab, and 22 of 62 (35.5%) of those treated with durvalumab plus monalizumab. Median duration of response had yet to be reached in any group.
Best response was stable disease for 50%-55% of patients in each group. Analysis of the secondary endpoint of disease control rate (DCR) at 16 weeks showed a DCR of 58.2% with single-agent durvalumab, 77.4% with the addition of monalizumab, and 81.7% with oleclumab.
Progression-free survival (PFS) was prolonged in both combination arms versus durvalumab alone. Adding oleclumab to durvalumab was associated with a 56% reduction in the hazard for progression or death (95% CI 0.26-0.75) and a 58% reduction in the hazard ratio with monalizumab (95% CI 0.24-0.72). The 12-month PFS was 33.9% with durvalumab alone, 62.6% with oleclumab, and 72.7% with monalizumab. Median PFS had yet to be reached with durvalumab plus monalizumab versus 15.1 months with durvalumab plus oleclumab, and 6.3 months with single-agent durvalumab.
Grade ≥3 TEAEs occurred in 40.7% of patients treated with durvalumab and oleclumab, 27.9% of those assigned to monalizumab, and 39.4% with durvalumab alone.
Although the specific results apply only to durvalumab-containing combinations, Herbst said he sees no reason that combinations with other anti-PD1/L1 drugs would not produce similar results.
“I would think that PD-1, PD-L1 combinations can be somewhat interchangeable,” he said.
The COAST study was supported by AstraZeneca.
Herbst disclosed relationships with AstraZeneca, Genentech/Roche, Merck, Pfizer, AbbVie, Biodesix, Bristol Myers Squibb, Lilly, EMD Serono, Heat Biologics, Junshi Pharmaceuticals, Loxo, Nektar, NextCure, Novartis, Sanofi, Seattle Genetics, Shire, Spectrum Pharmaceuticals, Symphogen, Tesaro, Neon Therapeutics, Infinity Pharmaceuticals, ARMO Biosciences, Genmab, Halozyme, Tocagen, Bolt Biotherapeutics, I-Mab, Mirati Therapeutics, Takeda, Cybrexa Therapeutics, DynamCure Biotechnology, eFFECTOR Therapeutics, Candel Therapeutics, Oncternal Therapeutics, STCube Pharmaceuticals, WindMIL, Xencor, Bayer, Checkpoint Therapeutics, Foundation Medicine, Gilead-Forty Seven, HiberCell, Immune-Onc Therapeutics, Johnson & Johnson, Ocean Biomedical, Oncocyte, Refactor Health, Ribbon Therapeutics, and Ventana Medical Systems.
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