Pembrolizumab After Completion of Locally Ablative Therapy for Oligometastatic Non-Small Cell Lung Cancer: A Phase 2 Trial

Abstract

Importance: Patients with oligometastatic non-small cell lung cancer (NSCLC) may benefit from locally ablative therapy (LAT) such as surgery or stereotactic radiotherapy. Prior studies were conducted before the advent of immunotherapy, and a strong biological rationale for the use of immunotherapy exists in a minimal residual disease state.

Objective: To evaluate whether the addition of pembrolizumab after LAT improves outcomes for patients with oligometastatic NSCLC.

Design, setting, and participants: This single-arm phase 2 trial of pembrolizumab therapy was performed from February 1, 2015, through September 30, 2017, at an academic referral cancer center. The 51 eligible patients enrolled had oligometastatic NSCLC (≤4 metastatic sites) and had completed LAT to all known sites of disease. Data were analyzed from February 1, 2015, to August 23, 2018.

Interventions: Within 4 to 12 weeks of completing LAT, patients began intravenous pembrolizumab therapy, 200 mg every 21 days, for 8 cycles, with provision to continue to 16 cycles in the absence of progressive disease or untoward toxic effects.

Main outcomes and measures: The 2 primary efficacy end points were progression-free survival (PFS) from the start of LAT (PFS-L), which preceded enrollment in the trial, and PFS from the start of pembrolizumab therapy (PFS-P). The study was powered for comparison with historical data on the first efficacy end point. Secondary outcomes included overall survival, safety, and quality of life as measured by the Functional Assessment of Cancer Therapy-Lung instrument.

Results: Of 51 patients enrolled, 45 (24 men [53%]; median age, 64 years [range, 46-82 years]) received pembrolizumab. At the time of analysis, 24 patients had progressive disease or had died. Median PFS-L was 19.1 months (95% CI, 9.4-28.7 months), significantly greater than the historical median of 6.6 months (P = .005). Median PFS-P was 18.7 months (95% CI, 10.1-27.1 months). Eleven patients died. Overall mean (SE) survival rate at 12 months was 90.9% (4.3%); at 24 months, 77.5% (6.7%). Neither programmed death ligand 1 expression nor CD8 T-cell tumor infiltration was associated with PFS-L. Pembrolizumab after LAT yielded no new safety signals and no reduction in quality of life.

Conclusions and relevance: Pembrolizumab after LAT for oligometastatic NSCLC appears to improve PFS with no reduction in quality of life.

Trial registration: ClinicalTrials.gov identifier: NCT02316002.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Bauml reported receiving research funding to his institution from Merck & Co, Incyte Corp, Carevive Systems, Novartis International AG, Bayer, Janssen Pharmaceutica, AstraZeneca, Takeda Pharmaceutical Company, Ltd, and Amgen, Inc; performing consultative services for Bristol-Myers Squibb, AstraZeneca, Celgene Corporation, Merck & Co, Janssen Pharmaceutica, Genentech, Inc, Guardant Health, Inc, Boehringer Ingelheim, Takeda Pharmaceutical Company, Ltd, and Regeneron Pharmaceuticals, Inc. Dr Aggarwal reported receiving research funding to her institution from Genentech/Roche, Incyte Corp, MacroGenics, Inc, and Medimmune, LLC; performing consultative services for Genentech, Inc, Bristol-Myers Squibb, and Eli Lilly and Company; and having an immediate family member on a speakers’ bureau with Genentech, Inc, Novartis International AG, and Pfizer, Inc. Dr Evans reported serving on a speaker’s bureau for Merck & Co, AstraZeneca, and Genentech, Inc; serving on an advisory board for Guardant Health, Inc; and having a spouse on a speaker’s bureau for Genentech, Inc. Dr Deshpande reported serving on a speaker’s bureau for Merck & Co and performing consultative services for Targos Molecular Pathology GmbH. Ms Knepley reported serving on a speaker’s bureau for Astra Zeneca. Dr Cohen reported receiving research funding to his institution from Merck & Co, Celldex Therapeutics, Inc, Innate Pharma, MacroGenics, Inc, Heat Biologics, Genocea Biosciences, Inc, and Xencor, Inc, and performing consultative services for Takeda Pharmaceutical Company, Ltd, Heat Biologics, Innate Pharma, and Genocea Biosciences, Inc. Dr Langer reported receiving research funding to his institution from Merck & Co, Advantagene, Inc, Clovis Oncology, Inc, Celgene Corporation, Inovio Pharmaceuticals, Inc, ARIAD Pharmaceuticals, GlaxoSmithKline, Genentech/Roche, and StemCentRx; performing consultative services for Genentech/Roche, Eli Lilly and Company/ImClone, Merck & Co, Abbott Biotherapeutics, Bayer/Onyx, Clarient, Clovis Oncology, Inc, Celgene Corporation, Cancer Support Community, Bristol-Myers Squibb, ARIAD Pharmaceuticals, and Takeda Pharmaceutical Company, Ltd; receiving honoraria from Bristol-Myers Squibb, Genentech/Roche, and Eli Lilly and Company/ImClone; and receiving compensation as a Data Safety Monitoring Committee member for Eli Lilly and Company, Amgen, Inc, Peregrine Pharmaceuticals, and Synta Pharmaceuticals, Inc. No other disclosures were reported.

Figures

Figure 1.. CONSORT Diagram

Figure 2.. Progression-Free and Overall Survival

Progression-free survival (PFS) was measured separately from the start of locally ablative therapy (LAT) (A) and from the start of pembrolizumab therapy (B). Overall survival (OS) was measured from the start of LAT (C).