The discussant of the PEARLS/KEYNOTE-091 trial, Martin Reck, MD, PhD, underscored the need to do more in the perioperative management of patients with early-stage non–small cell lung cancer (NSCLC) to improve rates of overall survival and relapse after surgery. Dr. Reck is Head of the Department of Thoracic Oncology and Head of the Clinical Trial Department in the Department of Thoracic Oncology at the Lung Clinic Grosshansdorf, Germany.

Martin Reck, MD, PhD

“Despite curative surgery, between 30% and 55% of patients with early-stage NSCLC relapse, and the efficacy of perioperative chemotherapy is modest, with only approximately 5% improvement in 5-year overall survival,” said Dr. Reck.

Cross-Trial Comparisons

In addition to the PEARLS/KEYNOTE-091 trial, Dr. Reck noted that the IMpower010 study, which compared the PD-L1 inhibitor atezolizumab with best supportive care in early-stage NSCLC, demonstrated improvement in disease-free survival, favoring the use of adjuvant checkpoint inhibitors.¹

Analysis of data from both trials, however, suggests several “elephants in the room,” according to Dr. Reck. The first question, he said, is the role of PD-L1 expression as a predictive or prognostic factor. Although the results of the IMpower010 trial showed a “very clear correlation” between PD-L1 expression on tumor cells and the efficacy of atezolizumab, favoring patients with a high PD-L1 expression, the signal from PEARLS/KEYNOTE-091 was unclear. With 18-month disease-free survival rates of 72% and 73%, respectively, efficacy data for pembrolizumab showed a minimal difference between patients with high PD-L1 expression and the intent-to-treat population.

Results of PEARLS/KEYNOTE-091 also differed from previous clinical experience with respect to PD-L1 expression as a prognostic factor, said Dr. Reck. He noted that the disease-free survival rate in the control group (64%) was comparable to the rate in patients with high PD-L1 expression (72%).

“Data from several clinical trials suggest that PD-L1 expression is a poor prognostic marker, but data from PEARLS/KEYNOTE-091 showed a different signal, with a hazard ratio of 0.78 in patients with PD-L1–negative tumors,” stated Dr. Reck. “This is an interim analysis with very early cutoffs of efficacy, so most of these results remain exploratory, but there is a clear need for investigation of additional molecular confounders besides PD-L1 expression in these adjuvant trials of checkpoint inhibitors,” said Dr. Reck.

Although the data are “somewhat convincing” that disease-free survival might be a surrogate marker for overall survival, Dr. Reck noted that the data are for adjuvant chemotherapy alone—not for adjuvant immunotherapy or targeted therapies.

‘Early Days of Adjuvant Immunotherapy’

“We are still in the early days of adjuvant immunotherapy, so assessment of more mature overall survival data is essential,” said Dr. Reck. He added that the future of perioperative immunotherapy might become “very challenging.”

“We already do have many different therapeutic opportunities for untreated patients with metastatic NSCLC, and this might become even more complex in the perioperative setting of early-stage NSCLC,” Dr. Reck continued. “Now, we have data on neoadjuvant immunotherapy, neoadjuvant chemoimmunotherapy, adjuvant immunotherapy, and the combination of neoadjuvant chemotherapy followed by adjuvant chemotherapy. And we didn’t even talk about radiotherapy as a potent radiosensitizer.” 

DISCLOSURE: Dr. Reck reported financial relationships with Amgen, AstraZeneca, BeiGene, BMS, Boehringer Ingelheim, Daiichi Sankyo, Lilly Merck, Mirati, MSD, Novartis, Pfizer, Roche, and Sanofi.

REFERENCE

1. [No authors listed]: Atezolizumab extends DFS after NSCLC relapse. Cancer Discov 11:OF3, 2021.