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Stage III non-small-cell lung cancer (NSCLC) affects approximately one-third of patients diagnosed with lung cancer each year. Despite curative intent, combined-modality treatment has poor cure rates, ranging from 36% in stage IIIA to 13% in bulky stage IIIC disease (1). There has been no meaningful improvement in stage III lung cancer in more than two decades with dismal median progression-free survival (PFS) of 8.4 months (2) to 11.8 months (3) as seen in START and RTOG 0617 trials. Different definitions of median PFS was used in these studies with randomization starting after and prior chemoradiotherapy respectively in each study.
The impressive PFS benefit observed in the PACIFIC trial with durvalumab was irrespective of PD-L1 expression. The 25% PD-L1 expression cut-off was evaluated before chemoradiotherapy in a patient population that was predominantly PD-L1 negative (4). Similarly, in cohort C of KEYNOTE-021 there was no apparent relationship between PD-L1 expression and response. More than 60% of patients achieved a response across the PD-L1 tumor proportion score subgroups with PFS >10 months (5) suggesting a multiplying effect of chemoimmunotherapy. We now believe that immunogenic cell death (ICD) and radiation abscopal effect may act as a primer to augment an immune-mediated antitumor response and possibly account for the impressive hazard ratio (HR: 0.52) in the PACIFIC trial (6,7). Keynote 189 was the natural Phase III extension in first-line metastatic nonsquamous NSCLC patients. Randomized in a 2:1 fashion, patients received platinum and pemetrexed-based chemotherapy with either pembrolizumab or placebo in the control group.
After a 10.5-month median follow-up; the pembrolizumab arm did not reach its median overall survival (OS); versus 11.3 months in the control group leading to a 51% reduction in death in the pembrolizumab group. The hgh PD-L1 group had a 58% reduction. Impressively, a clear survival benefit was seen across all groups despite a 50% crossover rate (8).
The IMpower150 trial also recently met its co-primary PFS and OS end points. This was seen across all PD-L1 subgroups in front line (nonsquamous) NSCLC with atezolizumab added to a platinum doublet and backbone with or without bevacizumab. The median OS with atezolizumab was 19.2 versus 14.7 months in the bevacizumab, carboplatin and platinum arm (HR: 0.78). This trial also included those with EGFR or ALK genetic alterations who...