Elsevier

The Lancet Oncology

Volume 17, Issue 11, November 2016, Pages 1497-1508
The Lancet Oncology

Articles
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

https://doi.org/10.1016/S1470-2045(16)30498-3Get rights and content

Summary

Background

Limited evidence exists to show that adding a third agent to platinum-doublet chemotherapy improves efficacy in the first-line advanced non-small-cell lung cancer (NSCLC) setting. The anti-PD-1 antibody pembrolizumab has shown efficacy as monotherapy in patients with advanced NSCLC and has a non-overlapping toxicity profile with chemotherapy. We assessed whether the addition of pembrolizumab to platinum-doublet chemotherapy improves efficacy in patients with advanced non-squamous NSCLC.

Methods

In this randomised, open-label, phase 2 cohort of a multicohort study (KEYNOTE-021), patients were enrolled at 26 medical centres in the USA and Taiwan. Patients with chemotherapy-naive, stage IIIB or IV, non-squamous NSCLC without targetable EGFR or ALK genetic aberrations were randomly assigned (1:1) in blocks of four stratified by PD-L1 tumour proportion score (<1% vs ≥1%) using an interactive voice-response system to 4 cycles of pembrolizumab 200 mg plus carboplatin area under curve 5 mg/mL per min and pemetrexed 500 mg/m2 every 3 weeks followed by pembrolizumab for 24 months and indefinite pemetrexed maintenance therapy or to 4 cycles of carboplatin and pemetrexed alone followed by indefinite pemetrexed maintenance therapy. The primary endpoint was the proportion of patients who achieved an objective response, defined as the percentage of patients with radiologically confirmed complete or partial response according to Response Evaluation Criteria in Solid Tumors version 1.1 assessed by masked, independent central review, in the intention-to-treat population, defined as all patients who were allocated to study treatment. Significance threshold was p<0·025 (one sided). Safety was assessed in the as-treated population, defined as all patients who received at least one dose of the assigned study treatment. This trial, which is closed for enrolment but continuing for follow-up, is registered with ClinicalTrials.gov, number NCT02039674.

Findings

Between Nov 25, 2014, and Jan 25, 2016, 123 patients were enrolled; 60 were randomly assigned to the pembrolizumab plus chemotherapy group and 63 to the chemotherapy alone group. 33 (55%; 95% CI 42–68) of 60 patients in the pembrolizumab plus chemotherapy group achieved an objective response compared with 18 (29%; 18–41) of 63 patients in the chemotherapy alone group (estimated treatment difference 26% [95% CI 9–42%]; p=0·0016). The incidence of grade 3 or worse treatment-related adverse events was similar between groups (23 [39%] of 59 patients in the pembrolizumab plus chemotherapy group and 16 [26%] of 62 in the chemotherapy alone group). The most common grade 3 or worse treatment-related adverse events in the pembrolizumab plus chemotherapy group were anaemia (seven [12%] of 59) and decreased neutrophil count (three [5%]); an additional six events each occurred in two (3%) for acute kidney injury, decreased lymphocyte count, fatigue, neutropenia, and sepsis, and thrombocytopenia. In the chemotherapy alone group, the most common grade 3 or worse events were anaemia (nine [15%] of 62) and decreased neutrophil count, pancytopenia, and thrombocytopenia (two [3%] each). One (2%) of 59 patients in the pembrolizumab plus chemotherapy group experienced treatment-related death because of sepsis compared with two (3%) of 62 patients in the chemotherapy group: one because of sepsis and one because of pancytopenia.

Interpretation

Combination of pembrolizumab, carboplatin, and pemetrexed could be an effective and tolerable first-line treatment option for patients with advanced non-squamous NSCLC. This finding is being further explored in an ongoing international, randomised, double-blind, phase 3 study.

Funding

Merck & Co.

Introduction

Currently, the standard first-line therapy for patients with advanced non-squamous non-small-cell lung cancer (NSCLC) without targetable genetic aberrations is platinum-doublet chemotherapy. With the exception of bevacizumab,1, 2 and despite extensive study of multiple targeted and cytotoxic agents, the addition of a third agent to platinum-doublet chemotherapy has not been shown to improve progression-free or overall survival over platinum-doublet chemotherapy alone in randomised studies.

Research in context

Evidence before this study

We searched PubMed on Sept 4, 2016, using the following terms: “PD-1 OR PD-L1 OR MK-3475 OR pembrolizumab OR lambrolizumab OR Keytruda OR nivolumab OR BMS-936558 OR Opdivo OR atezolizumab OR MPDL3280A OR Tecentriq OR durvalumab OR MEDI4736 OR avelumab” AND “platinum-doublet chemotherapy OR triple chemotherapy OR triple therapy OR maintenance therapy OR carboplatin and pemetrexed OR cisplatin AND pemetrexed” AND “advanced non–small-cell lung cancer OR NSCLC”. The search was not limited by date, but was limited to articles and abstracts published in English only. We also searched the abstracts for the 2015 and 2016 American Society of Clinical Oncology Annual Meetings, the 2015 European Cancer Congress, and the 2015 World Conference for Lung Cancer using the same search terms. Similar to the phase 1 cohorts of KEYNOTE-021, these two studies suggested that addition of anti-PD-1 or anti-PD-L1 therapy to platinum-doublet chemotherapy had a manageable safety profile and promising antitumour activity. A thorough review of the literature showed that most large, randomised, controlled clinical studies did not show superior efficacy or a favourable benefit-risk profile for the addition of a third agent to platinum-doublet chemotherapy in the first-line advanced non-small-cell lung cancer setting. One notable exception is the addition of bevacizumab to platinum-doublet chemotherapy, which showed superior efficacy to platinum-doublet chemotherapy alone and a manageable safety profile in randomised, controlled clinical studies.

Added value of this study

Results of this cohort of KEYNOTE-021 show that addition of pembrolizumab to carboplatin and pemetrexed improves efficacy and has a favourable benefit-to-risk profile in patients with chemotherapy-naive, advanced non-squamous NSCLC. Not only do these data represent, to the best of our knowledge, the first published report of a randomised, controlled clinical trial in NSCLC to prospectively show a benefit of addition of a PD-1 pathway inhibitor to chemotherapy, they are also among the only randomised data to show a benefit of adding a third agent to platinum-doublet chemotherapy.

Implications of all the available evidence

Our data suggest that the addition of pembrolizumab to platinum-doublet chemotherapy is an effective treatment option with a manageable, predictable safety profile for patients with chemotherapy-naive, advanced, non-squamous NSCLC. The efficacy and safety of addition of pembrolizumab to platinum-doublet chemotherapy as first-line therapy for advanced NSCLC is being further explored in two ongoing international, randomised, double-blind, phase 3 studies: the KEYNOTE-189 study of platinum and pemetrexed with or without pembrolizumab in patients with non-squamous non–small-cell lung cancer (NCT02578680) and the KEYNOTE-407 study of carboplatin and paclitaxel or nab-paclitaxel with or without pembrolizumab in patients with squamous NSCLC (NCT02775435).

When used as monotherapy in patients with advanced NSCLC, drugs targeting programmed death 1 (PD-1) and its ligand, PD-L1, have shown a manageable safety profile and robust efficacy, including a significant prolongation of overall survival compared with docetaxel in patients whose disease progressed on platinum-based chemotherapy.3, 4, 5, 6, 7, 8, 9, 10 One of these therapies is pembrolizumab, a humanised, monoclonal antibody against PD-1 that prevents PD-1 from binding to its ligands, PD-L1 and PD-L2. Evidence for the efficacy and safety of pembrolizumab in both treatment-naive and previously treated advanced NSCLC initially came from the large, multicohort KEYNOTE-001 study, which showed a correlation between PD-L1 expression on tumour cells and response to pembrolizumab.3, 4 The efficacy and safety of pembrolizumab monotherapy was confirmed in the international, randomised KEYNOTE-010 study, in which pembrolizumab yielded superior overall survival compared with docetaxel in patients with previously treated, PD-L1-expressing (ie, PD-L1 tumour proportion score ≥1%), advanced NSCLC.5

Increasing evidence suggests that the antitumour activity of chemotherapy is mediated not only though cytotoxic effects, but also through immunological effects, including reducing T-regulatory cell activity and enhancing cross-presentation of tumour antigens.11, 12, 13 Chemotherapy has also been shown to induce PD-L1 expression on tumour cells.14, 15, 16 Combining immunotherapy and chemotherapy could thus synergistically improve the anticancer activity of anti-PD-1 and anti-PD-L1 monotherapy.11, 12, 13 Early clinical data for combinations of chemotherapy with PD-117, 18 and PD-L119 inhibitors have suggested that these regimens have manageable toxicity and promising antitumour activity as first-line therapy for advanced NSCLC with non-overlapping toxicity profiles. In the international, multi-cohort, phase 1/2 KEYNOTE-021 study (ClinicalTrials.gov number NCT02039674), the safety and anti-tumour activity of pembrolizumab added to either carboplatin and paclitaxel (cohort A), carboplatin, paclitaxel, and bevacizumab (cohort B), or pemetrexed and carboplatin (cohort C) were assessed.18 All three combinations showed promising antitumour activity irrespective of tumour PD-L1 expression, with manageable safety profiles observed in cohorts A and C. The greatest antitumour activity was observed in cohort C (N=24), where the combination of pembrolizumab, carboplatin, and pemetrexed resulted in 17 (71%) of 24 patients achieving an overall response and a median progression-free survival of 10·2 months (95% CI 6·2–15·2).18

Based on these results and to further explore the potential synergy of combining chemotherapy with immunotherapy, we aimed to compare the efficacy and safety of pembrolizumab at a fixed intravenous dose of 200 mg plus carboplatin and pemetrexed versus those of carboplatin and pemetrexed alone as first-line therapy for patients with advanced NSCLC of non-squamous histology as part of KEYNOTE-021.

Section snippets

Study design and participants

This randomised, controlled, phase 2 study was done at 26 academic medical centres in the USA and Taiwan (appendix p 2). Eligibility criteria stipulated no previous systemic treatment for histologically or cytologically confirmed non-squamous, stage IIIB or IV NSCLC and the absence of targetable EGFR mutations or ALK translocations. Other eligibility criteria included Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (a 5-point scale where higher numbers indicate greater

Results

Between Nov 25, 2014, and Jan 25, 2016, 219 patients were screened for enrolment at 23 sites in the USA and three sites in Taiwan (figure 1). 123 (56%) of these patients met all eligibility criteria and were randomly assigned; 60 (49%) were allocated to pembrolizumab plus carboplatin and pemetrexed and 63 (51%) to carboplatin and pemetrexed alone (figure 1). One patient in the pembrolizumab plus chemotherapy group had deterioration in their ECOG performance status to a score of 2 after

Discussion

The addition of pembrolizumab to standard-of-care carboplatin and pemetrexed followed by pembrolizumab for 2 years and indefinite pemetrexed maintenance therapy significantly improved the proportion of patients who achieved an objective response compared with carboplatin and pemetrexed alone in patients with chemotherapy-naive, advanced non-squamous NSCLC. In addition, this combination also significantly prolonged progression-free survival in this non-squamous NSCLC population. These data

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Investigators listed in the appendix (p 2)

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