H. Jack West, MD
In the setting of advanced non–small cell lung cancer (NSCLC), the choice of up-front immunotherapy or chemotherapy, or combinations of both, is aided by findings from several trials discussed during a recent expert panel presentation on the OncLive®
Agents such as pembrolizumab (Keytruda), nivolumab (Opdivo), ipilimumab (Yervoy), and atezolizumab (Tecentriq), alone or in combination, offer the promise of improved response rates but need to be considered in the context of PD-L1 expression, the panel noted.
Some of the results from KEYNOTE-042, -189, and -407; CheckMate-227; and IMpower150 are practice-changing, according to the panel, moderated by H. Jack West, MD, medical director of the Thoracic Oncology Program at the Swedish Cancer Institute in Seattle, Washington. The panel discussed how these findings are likely to shape treatment and considered yet-unanswered questions.
In patients with nondriver mutations, KEYNOTE-042 results showed the difference high PD-L1 expression can make in the efficacy of frontline immune monotherapy. “The dramatic benefit with pembrolizumab monotherapy was in the 50% [PD-L1] or higher subset, and it diluted progressively as you added patients with a 20% cutoff or a 1% cutoff. And when you look at just the group of patients with 1% to 49% PD-L1, there was really no difference,” West said.
In KEYNOTE-042, compared with chemotherapy, frontline pembrolizumab improved median overall survival (OS) in correlation with PD-L1 expression for patients with advanced non–small cell, squamous, or nonsquamous disease: tumor proportion score (TPS) ≥50% (20 vs 12.2 months; HR, 0.69; 95% CI, 0.56-0.85; P
= .0003), TPS ≥20% (17.7 vs 13.0 months; HR, 0.77; 95% CI, 0.64-0.92; P
= .002), and TPS ≥1% (16.7 vs 12.1 months; HR, 0.81; 95% CI, 0.71-0.93; P
However, across all patients with PD-L1 TPS of 1% to 49%, pembrolizumab improved median OS by just over 1 month (13.4 vs 12.1; HR, 0.92; 95% CI, 0.77-1.11).
In the phase III trial, patients with locally advanced or metastatic NSCLC were randomly assigned to pembrolizumab (n = 637) or chemotherapy (n = 637) with paclitaxel plus carboplatin or pemetrexed (Alimta) plus carboplatin. Patients with both squamous and nonsquamous cancers were included, but those who had cancers with genetic changes that could be treated with targeted therapies, such as EGFR and ALK inhibitors, were not eligible. West noted that there was no significant difference between the treatment groups for median OS in the TPS 1% to 49% population.
Crossover rates between arms were relatively low in KEYNOTE-042, less than would be expected in the United States, where access to advanced drugs is generally higher. West said that 19.8% of patients who were enrolled globally were allowed to cross over from the chemotherapy arm to the pembrolizumab arm.
Crossover rates would be higher in his own clinical practice, West said. “I think mostly in the United States, where we have much better access and an expectation that if you didn’t get it as first-line [treatment] and you were ever a candidate for immunotherapy, you’d get it second line,” he said.
Results of the phase III KEYNOTE-407 made a quiet splash at the 2018 American Society of Clinical Oncology Annual Meeting, owing to delayed publicity, but those data amounted to one of the most important presentations at the meeting, panelists said. Regardless of PD-L1 status, the combination of immunotherapy plus platinum-based chemotherapy improved OS and several other measures of response compared with chemotherapy alone. Also, adverse events were similar between the arms.
In adults with metastatic squamous NSCLC, pembrolizumab was given in combination with frontline carboplatin/paclitaxel or nab-paclitaxel (Abraxane) versus standard solvent-based paclitaxel with either placebo or pembrolizumab in patients with metastatic NSCLC.2
The median OS was 15.9 months (95% CI, 13.2-not evaluable) with pembrolizumab versus 11.3 months (95% CI, 9.5-14.8) with chemotherapy alone (HR, 0.64; 95% CI, 0.49-0.85; P
= .0008). The OS benefit was observed regardless of PD-L1 expression level, choice of taxane, age, sex, and ECOG performance status.
Compared with chemotherapy alone, the addition of pembrolizumab resulted in a 1.6-month improvement in median PFS (6.4 vs 4.8 months; HR, 0.56; 95% CI, 0.45-0.70; P
<.0001). Investigators observed a correlation between higher PD-L1 levels and greater PFS benefit, and the benefit was present across all PD-L1 expression levels.
The objective response rate (ORR) was 57.9% in the pembrolizumab arm with a complete response (CR) rate of 1.4% and a partial response (PR) rate of 56.5%. In the control arm, the ORR was 38.4%, with a CR rate of 2.1% and a PR rate of 36.3%. The duration of response was 7.7 months (range, 1.1+ to 14.7+) versus 4.8 months (1.3+ to 15.8+), favoring the pembrolizumab arm.