Scott Gettinger, MD

Martin Reck, MD, PhD

Longer-term follow-up of patients with advanced non–small cell lung cancer (NSCLC) who are treated with immunotherapy have appreciably extended survival at 5 years, suggesting that for some patients, this disease can be managed as a chronic condition. These findings are based on two presentations at the 2019 International Association for the Study of Lung Cancer’s (IASLC) World Conference on Lung Cancer (WCLC).^1,2 Scott Gettinger, MD, of Yale Cancer Center, presented the 5-year outcomes demonstrating a dramatic improvement in overall and progression-free survival with the immune checkpoint inhibitor nivolumab vs docetaxel in patients with advanced NSCLC, based on the pooled results of the CheckMate trials 017 and 057.¹ Martin Reck, MD, PhD, of the Lung Clinic Grosshansdorf, Germany, presented an updated analysis of the KEYNOTE-024 trial, which also showed improved overall survival with another checkpoint inhibitor, pembrolizumab, vs chemotherapy.²

CheckMate Trials 017 and 057

In the pooled analysis of the CheckMate trials 017 and 057, the respective rate of 5-year overall survival was 13.4% for nivolumab vs 2.6% for docetaxel. No new safety signals emerged with longer follow-up.

“CheckMate 017 and 057 are the first phase III trials to report 5-year outcomes for a programmed cell death protein 1 (PD-1) inhibitor in previously treated advanced NSCLC, demonstrating a fivefold increase in 5-year overall survival rates with nivolumab over docetaxel. Nivolumab remained well tolerated,” said Dr. Gettinger.

Historical outcomes for advanced NSCLC have been dismal, with 5-year survival rates below 5% for patients treated with conventional chemotherapy. Nivolumab was approved in 2015 for patients with previously treated advanced NSCLC, based on two phase III trials: CheckMate 017 for squamous cell NSCLC and CheckMate 057 for nonsquamous NSCLC. Both studies showed improved overall survival with nivolumab vs docetaxel.

A total of 854 patients with advanced NSCLC were enrolled in the two trials. All patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and experienced disease progression on first-line platinum-based therapy. They were randomly assigned in a 1:1 ratio to receive nivolumab at 3 mg/kg every 2 weeks or docetaxel at 75 mg/m² every 3 weeks until disease progression or unacceptable toxicity. Once the primary analyses of the trials were completed, patients assigned to docetaxel who experienced disease progression were allowed to cross over to receive nivolumab.

CheckMate Trials: Key Findings

At 5-year follow-up, 50 nivolumab-treated and 9 docetaxel-treated patients were alive.

“There were no baseline clinical or tumor characteristics that clearly distinguished long-term survivors receiving nivolumab,” Dr. Gettinger said at a press conference.

Similar to the primary analysis, nivolumab continued to be associated with a benefit in overall and progression-free survival over docetaxel at 5 years. The 5-year overall survival was 13.4% vs 2.6%, and the 5-year progression-free survival was 8% vs 0%, respectively. Median overall survival was 11.1 months with nivolumab vs 8.1 months with docetaxel, representing a 32% improvement in survival favoring the checkpoint inhibitor.

The survival benefit for nivolumab vs docetaxel was observed across subgroups, including those with PD-L1 expression less than 1%.

Among patients with an objective response to nivolumab or docetaxel (20% vs 11%, respectively), 32.2% of the nivolumab group remained in response at 5 years in the nivolumab arm vs 0% treated with docetaxel; the median duration of response was 19.9 months vs 5.6 months, respectively. Among the 45, 29, and 25 patients treated with nivolumab who had not experienced tumor progression 2 years, 3 years, and 4 years after initiating therapy, 60%, 78%, and 88%, respectively, had not experienced disease progression at 5 years. A total of 10% of the nivolumab 5-year survivors were off study drug (after 8.8–43.5 months of treatment) without recurrence/progression of their disease.

With longer follow-up, there were no new safety concerns. Treatment-related adverse events were reported between 3 and 5 years of follow-up in 26% of the nivolumab-treated patients. The most common adverse events thought to be related to immunotherapy were observed in the skin, and all were grade 1 or 2.

KEYNOTE-024: 3-Year Survival

A separate presentation supported the long-term benefits of immune checkpoint inhibitor therapy for patients with NSCLC. An update of KEYNOTE-024 showed a consistent benefit with a hazard ratio (or risk reduction) of 0.65 favoring pembrolizumab over platinum-based chemotherapy. This study enrolled 305 patients with metastatic NSCLC.

KEYNOTE-024 compared pembrolizumab monotherapy vs platinum-based chemotherapy in untreated patients with metastatic NSCLC and no targetable EGFR/ALK alterations plus a PD-L1 total tumor proportion score (TPS) of at least 50%. Differences favoring pembrolizumab were observed as early as 1 year. At a median follow-up of 11.2 months, patients who received pembrolizumab had a 50% lower risk of disease progression or death and a 40% lower risk of death vs chemotherapy. At 2 years, 51.7% of the pembrolizumab group were alive, compared with 34.2% of the chemotherapy group.

With more than 3 years’ follow-up, first-line pembrolizumab monotherapy continued to provide a durable long-term overall survival benefit vs chemotherapy.

— Martin Reck, MD, PhD

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“With more than 3 years’ follow-up, first-line pembrolizumab monotherapy continued to provide a durable long-term overall survival benefit vs chemotherapy,” said Dr. Reck.“And, pembrolizumab was associated with less toxicity than chemotherapy. Patients who completed 35 cycles of pembrolizumab had a durable clinical benefit, and most were alive at data cutoff. The survival benefit was observed despite 65% of patients assigned to chemotherapy crossing over to pembrolizumab,” he said.

The 3-year survival rate was 43.7% with pembrolizumab vs 24.9% for chemotherapy. At a median follow-up of 44.4 months, median overall survival was 26.3 months with pembrolizumab vs 14.2 months with chemotherapy (P = .001). “We never thought we would see these survival rates in NSCLC. The question is whether we can talk about curing lung cancer after 5 years. I would say we are controlling the tumor with immunotherapy [in some patients],” Dr. Reck noted.

The risk of a treatment-related adverse event of any grade was lower with pembrolizumab: 77% vs 90% for chemotherapy. Grades 3 to 5 treatment-related adverse events occurred in 31% vs 53%, respectively. Serious treatment-related adverse events and events leading to treatment discontinuation were similar in both groups. More immune-mediated and infusion reactions were observed with pembrolizumab than with chemotherapy (34% vs 5%, respectively).

Preliminary results in a subgroup of patients who had a second course of pembrolizumab suggest that this approach may be feasible and may achieve response despite prior exposure to pembrolizumab, noted Dr. Reck. However, he added, this needs to be confirmed. ■

DISCLOSURE: Both CheckMate trials were supported by Bristol-Myers Squibb. Dr. Gettinger reported financial relationships with Bristol-Myers Squibb and Nektar. KEYNOTE-024 was supported by Merck Sharp & Dohme. Dr. Reck reported financial relationships with Roche, Bristol-Myers Squibb, AstraZeneca, Merck Sharp & Dohme, Merck, Boehringer Ingelheim, Celgene, Lilly, Novartis, AbbVie, and Pfizer.

REFERENCES

1. Gettinger S, et al: 2019 World Conference on Lung Cancer. Abstract OA14.04. Presented September 10, 2019.

2. Reck M, et al: 2019 World Conference on Lung Cancer. Abstract OA14.01. Presented September 10, 2019.