Corey J. Langer, MD
There has been a major paradigm shift with the combination of immunotherapy and chemotherapy in non–small cell lung cancer (NSCLC), according to Corey J. Langer, MD.
Although impressive single-agent data have been seen with agents such as pembrolizumab (Keytruda) versus chemotherapy in a high–PD-L1 population, the combination of PD-L1 inhibitors and chemotherapy may prove to be beneficial in a broader group of patients.
KEYNOTE-021 cohort G was part of a large phase II study combining pembrolizumab with various chemotherapy combinations and targeted therapies—a trial that set the stage for this therapeutic approach and was the basis for the FDA approval of frontline pembrolizumab with carboplatin/pemetrexed in May 2017. The standard arm was pembrolizumab plus carboplatin for 4 cycles, with or without pembrolizumab, given at a fixed dose for up to 2 years with pemetrexed given as maintenance in the absence of toxicity or progression.
Updated findings from KEYNOTE-021 cohort G were presented at the 2018 ASCO Annual Meeting.1
The overall response rate (ORR) with pembrolizumab plus carboplatin and pemetrexed was 56.7% versus 30.2% with carboplatin and pemetrexed (P
= .0016). The addition of pembrolizumab to carboplatin and pemetrexed resulted in a greater progression-free survival (PFS; HR, 0.53; 95% CI, 0.33-0.86; P
= .0049). The median PFS for pembrolizumab plus chemotherapy was 24.0 months (95% CI, 8.5-NR), compared with 9.3 months (95% CI, 6.2-14.9) for chemotherapy alone.
Median overall survival (OS) for the chemoimmunotherapy combination was not reached (95% CI, 24.5-NR) and was 21.1 months (95% CI, 14.9-NR) for carboplatin and pemetrexed alone.
“These are unprecedented findings,” said Langer, director of thoracic oncology and professor of medicine at the Hospital of the University of Pennsylvania. “Granted, this is a small, randomized, phase II trial that is in mostly academic centers, but this trial accrued ahead of schedule. We had no trouble findings patients for this effort.”
These results laid the framework for KEYNOTE-189, which Langer said is essentially the phase III version of the phase II trial. The eligibly criteria are identical, enrolling nonsquamous patients without common oncogenic drivers. However, Langer noted that there are some salient differences. This was a 2:1 randomization, there was a choice of carboplatin or cisplatin, and it was a placebo-controlled study. Crossover was built into this trial as it was in KEYNOTE-021 cohort G.
Data from KEYNOTE-189 presented at the 2018 AACR Annual Meeting and published in the New England Journal of Medicine
showed that combining pembrolizumab with standard chemotherapy in the frontline setting reduced the risk of death by more than 50% in patients with nonsquamous NSCLC without EGFR or ALK abnormalities.2,3
The estimated 12-month OS rate was 69.2% (95% CI, 64.1%-73.8%) in the pembrolizumab arm compared with 49.4% (95% CI, 42.1%-56.2%) in the control group (HR, 0.49; 95% CI, 0.38-0.64; P
<.001) at a median follow-up of 10.5 months.
The median PFS in the pembrolizumab group was 8.8 months (95% CI, 7.6-9.2) versus 4.9 months (95% CI, 4.7-5.5) in the control arm (HR, 0.52; 95% CI, 0.43 to 0.64; P
<.001). Median OS was not reached in the pembrolizumab group, while it was 11.3 months (95% CI, 8.7-15.1) in the control arm.
“One very interesting observation that had not been heralded in the randomized phase II trial was renal toxicity,” Langer noted. “Instances of renal insufficiency were 5% in the pembrolizumab combination versus the control arm.”
Most of the adverse events (AEs) in all patients were grades 1/2, with nausea, anemia, and fatigue being the most common.
Langer said that these results pose the question of what to give patients with a PD-L1 expression ≥50%: singleagent pembrolizumab or the triplet? There is a rationale for pembrolizumab monotherapy, there is no head-to-head of the single-agent versus the doublet, and KEYNOTE-021 cohort G was a relatively small randomized phase II study, he noted. “Clearly, single-agent pembrolizumab has less toxicity, much lower cost, and is much more convenient, and it doesn’t preclude the option of going to pembrolizumab plus carboplatin with or without bevacizumab at the time of progression,” said Langer.
He argued, however, that the response rate from KEYNOTE- 021 cohort G was 80%, and over 60% in KEYNOTE-189, which compared favorably to single-agent pembrolizumab in the same setting. There were also very low rates of primary progression, and initial PFS is increasing over time in the phase II trial.
“The worst conversation that we have in clinic is the progression conversation; it stops the clinic cold. Not only does it contribute to a detrement in the patient and their family’s quality of life, it [also] decreases our quality of life—the doctors, nurses, and physician’s assistants that are taking care of them,” said Langer.