Pembrolizumab a novel treatment alternative for early-stage NSCLC?

In the second interim analysis of the PEARLS/KEYNOTE-091 study, adjuvant pembrolizumab monotherapy provided a clinically meaningful improvement in disease-free survival (DFS) in individuals with stage IB–IIIA non-small cell lung cancer (NSCLC) after complete resection and adjuvant chemotherapy (CT).

 

“To our knowledge, PEARLS/KEYNOTE-091 is the first placebo-controlled trial to find a significant improvement in DFS for a checkpoint inhibitor, and the first trial to show a DFS benefit in a PD-L1-unselected population of patients with completely resected stage IB–IIIA NSCLC who received adjuvant CT per local guidelines,” said the researchers.

 

The overall population comprised 1,177 participants (median age 65 years, 68 percent male). Of these, 333 had PD-L1 TPS* of ≥50 percent. Participants were randomized 1:1 to IV pembrolizumab 200 mg or placebo Q3W for up to 18 cycles. Most patients have received three or four cycles of previous adjuvant CT with either a cisplatin- or carboplatin-based regimen, or both. Median follow-up was 35.6 months. [Lancet Oncol 2022;23:1274-1286]

 

In the overall cohort, median DFS was longer with pembrolizumab vs placebo (53.6 vs 42.0 months; hazard ratio [HR], 0.76; p=0.0014).

 

In the subgroup of patients with PD-L1 TPS of ≥50 percent, median DFS was not reached in either arm (HR, 0.82; p=0.14). The researchers noted that the lack of DFS benefit with pembrolizumab was unexpected, given evidence showing that its relative benefit increases as PD-L1 expression does in the setting of locally advanced or metastatic NSCLC. [Lancet 2016;387:1540-1550; J Thorac Oncol 2021;16:1718-1732; Lancet 2019;393:1819-1830]

 

“Because we could identify no obvious between-arm imbalances in baseline characteristics, including in the distribution of the stratification factors of disease stage and receipt of adjuvant CT, random chance might have led to better-than-expected outcomes in the placebo arm of the PD-L1 TPS of ≥50 percent population,” the researchers explained.

 

“Although an imbalance in unknown factors (eg, molecular biomarkers) might have contributed to the outcomes, the overperformance of the placebo arm probably led to the absence of significant benefit for pembrolizumab in the PD-L1 TPS of ≥50 percent population,” they continued.

 

Safety profile

A third of pembrolizumab recipients reported grade ≥3 adverse events (AEs); the corresponding rate in the placebo arm was 26 percent. “As expected for a placebo-controlled trial, AEs were more frequent in the pembrolizumab than in the placebo arm. AEs were manageable, with participants in the pembrolizumab arm receiving a median of 17 of the planned 18 administrations,” the researchers explained.

 

Treatment discontinuation rate owing to AEs was also higher with pembrolizumab vs placebo (20 percent vs 6 percent). “[This was] higher than that observed in studies of pembrolizumab for advanced or metastatic NSCLC, probably because of longer pembrolizumab exposure in the adjuvant setting and the seemingly lower threshold for treatment discontinuation in the adjuvant than in the advanced/metastatic setting,” said the researchers.

 

There were also more deaths owing to treatment-related AEs in the pembrolizumab vs the placebo arm (n=4 vs 0). The two deaths reported with pembrolizumab were attributed to myocarditis, an immune-mediated AE tied with immune checkpoint inhibitors. [Eur J Heart Fail 2021;23:1739-1747]

 

Immune checkpoint inhibitors as adjuvant therapy

“[This study] adds to the body of evidence supporting the value of checkpoint inhibitors, specifically those that target the PD-1/PD-L1 pathway, in the adjuvant treatment of early-stage NSCLC,” said the researchers. “Our findings support pembrolizumab as a potential new treatment option for patients with stage IB, II, or IIIA NSCLC after complete resection and, when recommended, adjuvant CT, regardless of PD-L1 expression.”

 

Overall survival (OS) data were still immature at the time of this analysis (median not reached in either arm; HR, 0.87; p=0.17). A longer follow-up is thus warranted to ascertain if the DFS benefit will lead to an OS benefit. Further investigation may also shed light on the DFS benefit of pembrolizumab in the PD-L1 strong positive population.