The PD-1 inhibitor pembrolizumab may be a better first-line treatment than chemotherapy for many patients with advanced non–small cell lung cancer: In a phase III trial, patients with PD-L1 expression of 1% or higher treated with the drug had better overall survival, a longer duration of response, and fewer side effects than patients who received chemotherapy alone.

The PD-1 inhibitor pembrolizumab (Keytruda; Merck)—not chemotherapy—may be the best first-line treatment for most patients with advanced non–small cell lung cancer (NSCLC), according to research presented on June 3 at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, IL. In a phase III trial, patients with PD-L1 expression of 1% or higher treated with the drug had better overall survival (OS), a longer duration of response (DOR), and fewer side effects than patients who received chemotherapy.

Pembrolizumab is already approved as a first-line monotherapy for patients with metastatic NSCLC who have PD-L1 expression at or above 50%, based on positive results in the phase III KEYNOTE-024 trial. Gilberto Lopes, MD, of the Sylvester Comprehensive Cancer Center in Miami, FL, and his team designed the KEYNOTE-042 trial to expand on KEYNOTE-024 by assessing the efficacy of pembrolizumab in patients with PD-L1 expression of at least 1%, a group that accounts for two thirds of patients.

The researchers assigned 1,274 patients with advanced squamous and nonsquamous NSCLC to receive pembrolizumab or standard chemotherapy as first-line therapy. Patients with PD-L1 expression of 1% or higher treated with pembrolizumab had a median OS of 16.7 months, compared with 12.1 months for those who received chemotherapy. Overall response rates (ORR) were similar in both groups, but patients treated with pembrolizumab had a median duration of response of 20.2 months, compared with 8.3 months for those on chemotherapy—and they experienced fewer treatment-related adverse events (63% vs. 90%). Gains were similar for patients with PD-L1 expression of 20% or higher (median OS of 17.7 months, ORR of 33.4%, and DOR of 20.2 months vs. 13 months, 28.9%, and 8.3 months for chemotherapy), and 50% or higher (median OS of 20 months, ORR of 39.5%, and DOR of 20.2 months vs. 12.2 months, 32%, and 10.8 months for chemotherapy).

In an exploratory analysis not powered for statistical significance, patients with PD-L1 expression between 1% and 49% treated with pembrolizumab had a median OS of 14.4 months and an ORR of 16.6%, compared with a median OS of 12.1 months and an ORR of 21.7% in patients who received chemotherapy. Patients treated with pembrolizumab, however, still had a longer DOR—17.4 months versus 8.2 months for chemotherapy.

“What we can conclude is that pembrolizumab is an option for patients with expression of 1% and above,” Lopes said, but based on the exploratory analysis, “it seems like the benefit is larger for patients with greater than 50% expression.”

Lopes pointed out that in the phase III KEYNOTE-189 trial, pembrolizumab plus chemotherapy extended OS and progression-free survival in patients with metastatic nonsquamous NSCLC compared with chemotherapy alone, regardless of PD-L1 status—in fact, the combination is FDA-approved for this indication. Moreover, in preliminary results from the phase III KEYNOTE-407 trial presented at the ASCO meeting, patients with metastatic squamous NSCLC treated with the combination, compared with chemotherapy alone, had a higher ORR (58.4% vs. 35%) and were more likely to respond for at least 6 months (65.8% vs. 45.6%). Thus, for fit patients with PD-L1 expression below 50%, Lopes thinks pembrolizumab plus chemotherapy will likely be the standard of care. However, he emphasized the need to identify better biomarkers than PD-L1.

“What seems to be happening is patients who respond to pembrolizumab do it very well,” he said. “The question is, how can we identify those patients before we actually give the treatment? It seems that PD-L1 alone is not the whole answer.”

Nathan Pennell, MD, PhD, of Cleveland Clinic in Ohio, who was not involved in the trial, praised it for testing pembrolizumab as a first-line monotherapy in a broader patient group, and expects the results will lead to expansion of the drug's FDA approval. Although he thinks that most patients with PD-L1 expression between 1% and 49% would be better served by pembrolizumab plus chemotherapy, pembrolizumab alone could be preferable in some cases.

“In the real world, advanced lung cancer patients tend to be much older than what you see in clinical trials, they have a lot more comorbidities, they have a poorer performance status,” Pennell said. “It is highly relevant to be able to give an effective, less-toxic therapy.”

For Benjamin Levy, MD, of Johns Hopkins University in Baltimore, MD, the trial, along with KEYNOTE-189, signals a broader shift in first-line treatment of patients with PD-L1 expression below 50%.

“Before this trial, we struggled with, ‘Should I add pembrolizumab to chemotherapy, or should I just give chemotherapy alone?’ Now, we struggle with, ‘Should I give pembrolizumab alone, or should I give chemotherapy plus pembrolizumab?’” he explained. “I think chemotherapy alone is out the door.” –Catherine Caruso

©2018 American Association for Cancer Research.
2018
American Association for Cancer Research.