Durvalumab shows OS benefit over chemo in NSCLC
First-line therapy with the anti-programmed death ligand-1 (PD-L1) monoclonal antibody durvalumab improved overall survival (OS) in patients with metastatic non-small-cell lung cancer (NSCLC) compared with platinum-based chemotherapy (CT), according to results from two analyses of the MYSTIC* trial presented at ELCC 2019.
This phase 3 trial randomized immunotherapy/CT-naïve individuals 1:1:1 to receive durvalumab 20 mg/kg Q4W alone or with the anti-CTLA-4** antibody tremelimumab 1 mg/kg Q4W (four cycles), or platinum-based CT (up to six cycles).
OS in relevant subgroups
In a subgroup analysis evaluating 488 participants, durvalumab alone generated OS improvement compared with CT across most clinical subgroups, including those aged ≥65 years (hazard ratio [HR], 0.66), with non-squamous histology (HR, 0.70), with PD-L1 tumour cell (TC) ≥25 percent (HR, 0.63), and with ECOG performance status 0 (HR, 0.54). The durvalumab-tremelimumab combination provided a similarly improved OS vs CT across the same subgroups (HR, 0.72, 0.84, 0.64, and 0.76, respectively). [ELCC 2019, abstract LBA3]
The favourable HRs for durvalumab were consistent with the overall primary analysis results, which reflected a clinically meaningful OS improvement with durvalumab vs CT in individuals with PD-L1 TC ≥25 percent (median, 16.3 vs 12.9 months, HR, 0.76, 97.54 percent confidence interval [CI], 0.56–1.02; p=0.036). Albeit nonsignificant, the durvalumab-tremelimumab combination also generated a numerical improvement compared with CT (HR, 0.85, 98.77 percent CI, 0.61–1.17; p=0.202).
However, the durvalumab-tremelimumab combo was associated with the highest incidence of treatment-related*** adverse events (TRAEs) leading to discontinuation (13.2 percent), followed by CT and durvalumab monotherapy (9.4 percent and 5.4 percent, respectively). Immune-mediated# AEs were also highest with durvalumab-tremelimumab (28.3 percent) compared with durvalumab monotherapy and CT (13.6 percent and 3.4 percent, respectively).
Nonetheless, the safety profile of durvalumab was deemed manageable and consistent with previous studies, noted the researchers, highlighting the higher incidence of grade ≥3 TRAEs in the CT vs the durvalumab arms (33.8 percent vs 14.9 percent [durvalumab monotherapy] and 22.9 percent [durvalumab + tremelimumab]).
A majority of durvalumab and CT recipients received subsequent therapy (44.8 percent and 58.6 percent, respectively), most of whom starting within 2 months of discontinuing treatment. Of these, 13.7 and 67.4 percent of those respective groups received immunotherapy, the most common being nivolumab and pembrolizumab. [ELCC 2019, abstract LBA4]
After adjusting for the effect of subsequent immunotherapy using a two-stage model, the OS benefit observed with durvalumab vs CT improved compared with the overall primary analysis results (median, 16.2 vs 11.5 months, HR, 0.66, 97.54 CI, 0.49–0.90; p=0.002).
However, the significantly higher proportion of CT-treated patients who received subsequent immunotherapy might have confounded the primary OS outcome, potentially masking the true efficacy of durvalumab, pointed out the researchers, hence the need for further evaluation.