Immunotherapy Gains Frontline Foothold in NSCLC

Corey J. Langer, MD

Less than 2 years after checkpoint blockade immunotherapy first became available for patients with non—small cell lung cancer (NSCLC), the PD-1 inhibitor pembrolizumab (Keytruda) is poised to reshape the treatment paradigm for previously untreated individuals without molecular mutations.

On May 10, the FDA granted an accelerated approval to pembrolizumab for use in combination with pemetrexed plus carboplatin as a frontline treatment for patients with metastatic or advanced nonsquamous NSCLC, regardless of PD-L1 expression, based on a cohort from the KEYNOTE-021 study.¹ The decision amplifies the frontline role for the drug following the FDA’s October 2016 approval for pembrolizumab monotherapy in patients with metastatic NSCLC with greater than 50% PD-L1 expression as a result of the KEYNOTE-024 trial.²

The expanded indications make pembrolizumab part of the first-line treatment considerations for the estimated 80% of patients with NSCLC whose tumors do not harbor EGFR mutations or ALK rearrangements, and cap a rapid rise for antibodies that target the PD-1/ PD-L1 pathway in NSCLC (Timeline). Looking forward, researchers are anticipating results from randomized phase III combination trials involving checkpoint blockade agents.

Timeline. FDA Checkpoint Immunotherapy Approvals in NSCLC

Pivotal Clinical Trial Findings

“This approval marks an important milestone in the treatment of lung cancer. Now, pembrolizumab in combination with pemetrexed and carboplatin can be prescribed in the first-line setting for patients with metastatic nonsquamous non—small cell lung cancer, irrespective of PD-L1 expression,” Corey J. Langer, MD, principal investigator on the pivotal KEYNOTE-021 trial, said in a statement. “Physicians should continue to use each patient’s individual characteristics—including biomarker status, histology, and other clinical factors—to determine the best treatment plan for each person.” The evolving role of checkpoint blockade immunotherapy has been evident since the approval of pembrolizumab monotherapy. “As of October 2016, we saw a major shift in the therapeutic landscape in advanced NSCLC,” Langer, director of thoracic oncology and professor of medicine at the Hospital of the University of Pennsylvania in Philadelphia, said in an interview with OncologyLive® that took place before the latest approval. “KEYNOTE-024, at least in individuals with 50% or higher expression, documented a clear-cut outcome advantage for pembrolizumab versus standard platinum-based chemotherapy combinations.”Findings from the phase II KEYNOTE-021 cohort study are scheduled to be updated at the 2017 American Society of Clinical Oncology Annual Meeting (Abstract 9094). In the trial, 123 patients were randomized to receive pemetrexed and carboplatin alone (n = 63) or in combination with pembrolizumab (n = 60). In the investigational arm, pembrolizumab was continued for 24 months.

In data submitted for the FDA’s approval, the pembrolizumab triplet elicited an objective response rate (ORR) of 55% compared with 29% with the chemotherapy agents alone (P = .0032). The median progression-free survival (PFS) was 13.0 months with the addition of pembrolizumab versus 8.9 months for chemotherapy alone (HR, 0.53; 95% CI, 0.31-0.91; P = .0205).

After 10.6 months of follow-up, 88% of those in the pembrolizumab arm remained alive and progression free compared with 78% for the chemotherapy agents alone. The median time to response was 1.5 months with pembrolizumab compared with 2.7 months for the chemotherapy agents alone. Overall, a response of at least 6 months was seen for 92% of patients in the pembrolizumab group compared with 81% of those in the control arm.

The 6-month PFS rate was 77% with pembrolizumab (95% CI, 64-86) compared with 63% for chemotherapy alone (95% CI, 49-74). At the time of the analysis, 78% of patients remained alive in each arm, with no discernible differences in survival between the 2 groups (HR, 0.90; 95% CI, 0.42-1.91; P = .39). The 6-month overall survival (OS) was 92% in both arms. However, this analysis was likely confounded by crossover, since 74% of patients in the chemotherapy alone arm went on to receive a subsequent PD-1 or PD-L1 inhibitor compared with none in the pembrolizumab arm.

In assessments of PD-L1 staining, those with expression of less than 1% had an ORR of 57% with the pembrolizumab combination (12 of 21) compared with 13% in the chemotherapy arm (3 of 23). In those with expression on greater than 1% of cells, the ORR was 54% with pembrolizumab and chemotherapy (21 of 39) compared with 38% in the chemotherapy-alone arm. The ORRs were 80% and 35% in those with ≥50% expression for the pembrolizumab (16 of 20) and chemotherapy arms (6 of 17), respectively.

The role of PD-L1 as a biomarker in NSCLC remains an unanswered question since patients with low or no expression have responded to checkpoint blockade therapy. Langer said approximately one-third of patients in clinical trials have PD-L1 expression levels ≥50%, one-third are between 1% and 50%, and one-third are at <1%. “That’s been a consistent theme across clinical trials in terms of where expression levels generally end up,” he said.

Langer said PD-L1 expression is “an imperfect biomarker” but that it is becoming integrated into diagnostic workups. “PD-L1 testing is here to stay,” he said. “It’s been very helpful in my institution. Now it’s reflex—the pathologists will do it automatically the same way they would obtain ER [estrogen receptor] and PR [progesterone receptor] testing in breast cancer.”

Other considerations in the combination immunotherapy regimens involve toxicities, Langer said. In terms of adverse events (AEs), the incidence of grade 3 or higher treatment-related AEs was higher in the pembrolizumab plus chemotherapy group (39%) than in the chemotherapy-alone group (26%).

Frequently observed all-grade treatment-related AEs in the pembrolizumab and chemotherapy arms, respectively, included fatigue (71% vs 50%), nausea (68% vs 56%), constipation (51% vs 37%), rash (42% vs 21%), vomiting (39% vs 27%), dyspnea (39% vs 21%), diarrhea (37% vs 23%), and decreased appetite (31% vs 23%). AEs led to treatment discontinuations for 10% of those in the pembrolizumab arm versus 13% in the control group.

First-Line Combination Trials on Horizon

The most common grade ≥3 treatment-related AEs were decreased lymphocytes (23% with pembrolizumab vs 28% with chemotherapy alone), hemoglobin decreased (17% vs 19%), decreased neutrophil count (14% vs 8%), and platelets decreased (9% vs 10%).The accelerated approval for pembrolizumab in combination with chemotherapy is contingent on results from a confirmatory trial.

The phase III KEYNOTE-189 study is currently exploring platinum-based chemotherapy plus pemetrexed with or without pembrolizumab for patients with untreated nonsquamous NSCLC. In this study, investigators will be able to choose between cisplatin or carboplatin as their platinum-based chemotherapy. The primary endpoint is PFS, with an accrual goal of 570 patients and an estimated completion date of March 2019 (NCT02578680).

Other ongoing first-line phase III checkpoint blockade combination trials in NSCLC include the CheckMate-227 study, which is comparing platinum-based doublet chemotherapy with nivolumab (Opdivo) monotherapy, the combination of nivolumab and ipilimumab (Yervoy), and the combination of nivolumab and platinum-based chemotherapy (NCT02477826).

In the IMpower130 study, the combination of atezolizumab (Tecentriq) plus nab-paclitaxel and carboplatin is being compared with the chemotherapy doublet in 724 chemotherapy-naïve patients with stage IV nonsquamous NSCLC (NCT02367781).

The phase III MYSTIC trial is evaluating the combination of the PD-L1 inhibitor durvalumab (Imfinzi) with the CTLA-4 inhibitor tremelimumab. In January, the primary endpoint was adapted to include OS in addition to PFS. At this time, the MYSTIC trial is no longer recruiting new participants (NCT02453282).

References

1. Langer CJ, Gadgeel SM, Borghaei H, et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016;17(11):1497-1508. doi: 10.1016/S1470-2045(16)30498-3.
2. Reck M, Rodríguez-Abreu D, Robinson AG, et al; KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1—positive non–small-cell lung cancer. N Engl J Med. 2016;375(19):1823-1833. doi: 10.1056/NEJMoa1606774.