https://www.ajmc.com/conferences/asco-2018/keynote042-confirms-firstline-pembrolizumab-superior-to-chemotherapy-in-pdl1mdashlow-advanced-nsclc
KEYNOTE-042 Confirms First-Line Pembrolizumab Superior to Chemotherapy in PD-L1–Low Advanced NSCLC

Surabhi Dangi-Garimella, PhD

A late-breaking abstract presented Sunday at the 2018 American Society of Clinical Oncology Annual Meeting confirmed that pembrolizumab significantly improved the primary endpoint of overall survival (OS) over platinum-based chemotherapy in treatment-naïve advanced/metastatic non–small cell lung cancer (NSCLC). The effect, the authors found, was agnostic of PD-L1 expression, meaning the monoclonal antibody was effective for tumors expressing PD-L1 at ≥50%, ≥20%, and ≥1%.1

However, the secondary outcome of progression-free survival (PFS) was not met at data cut-off on February 26, 2018.

Pembrolizumab monotherapy has shown significant improvement in OS over docetaxel as second-line treatment in metastatic NSCLC with PD-L1 tumor proportion score (TPS) ≥1%. Additionally, patients whose NSCLC had a PD-L1 TPS of ≥50% saw significant improvements in both PFS and OS with first-line pembrolizumab, compared to platinum-based chemotherapy (KEYNOTE-024).

Results from the Keynote-189 study, published earlier this year, emphasized the advantage of combining chemotherapy with pembrolizumab: the researchers showed that the combination approach as first-line in patients with metastatic NSCLC, without EGFR or ALK alterations, was significantly better than chemotherapy alone and was agnostic of PD-L1 expression.2

“Our trial, Keynote-042, is evaluating pembrolizumab monotherapy against platinum-based chemotherapy for metastatic NSCLC with low expression of PD-L1,” said lead author Gilberto Lopes, MD, MBA, Sylvester Comprehensive Cancer Center, University of Miami Health System. The trial was designed to develop a more effective and tolerable first-line treatment for metastatic NSCLC, he said.

Eligibility criteria included locally advanced or metastatic tumors with PD-L1 TPS ≥1%, without EGFR or ALK alterations. The Eastern Cooperative Oncology Group or ECOG status had to be 0 or 1; patients had to be free of untreated or unstable CNS metastases.  

Treatment-eligible patients were randomized 1:1 to ≤35 cycles of pembrolizumab 200 mg every 3 weeks or investigator’s choice of ≤6 cycles of paclitaxel + carboplatin or pemetrexed + carboplatin with optional pemetrexed maintenance (nonsquamous only). Primary end-points were OS in pts with TPS ≥50%, ≥20%, and ≥1%. Secondary endpoints were PFS and objective response rate for all 3 TPS; safety in TPS ≥1%.

At 12.8-months median follow-up, 13.7% of patients were still on pembrolizumab and 4.9% were receiving pemetrexed maintenance treatment.

In the TPS ≥50% subset, median OS at 24 months was 20 months (range, 15.4-24.9) in the pembrolizumab-treated patients (event rate: 44.7%) and 12.2 months (range, 10.4-14.2) in those treated with chemotherapy (event rate: 30.1%). Similarly, in the TPS ≥20% subset, median OS at 24 months was 17.7 months (range, 15.3-22.1) in the pembrolizumab-treated patients (event rate: 40.5%) and 13.0 months (range, 11.6-15.3) in those treated with chemotherapy (event rate: 29.6%). Among patients whose tumors expressed a low level of PD-L1 (TPS ≥1%), median OS at 24 months was 16.7 months (range, 13.9-19.7) in the pembrolizumab-treated arm (event rate: 39.3%) and 12.1 months (range, 11.3-13.3) in those treated with chemotherapy (event rate: 28.0%).

Lopes shared the PFS data in the TPS ≥20% cohort. Median PFS at 12 months was 6.2 months (range, 5.1-7.8) in the pembrolizumab-treated arm (event rate: 32.4%) and 6.6 months (range, 6.2-7.3) in those treated with chemotherapy (event rate: 28.8%).

Grade 3-5 drug-related adverse events were less frequent with pembrolizumab, Lopes said (17.8% vs 41.0% for chemotherapy). However, the rate of discontinuation (about 9.0%) and treatment-related deaths (about 2.0%) were similar between the 2 groups. Immune-related adverse events or irAEs are a significant concern with using immune checkpoint inhibitors such as pembrolizumab. Lopes shared that about 27.8% of patients treated with pembrolizumab experienced irAEs, and 1 patient died as a result. Only 7% of patients in the chemotherapy arm had irAE flare-ups.

“Keynote-042 is the first study with a primary end-point of overall survival to demonstrate superiority of pembrolizumab over platinum-based chemotherapy in patient with previously untreated advanced/metastatic NSCLC without sensitizing EGFR or ALK alterations and a PD-L1 TPS ≥1%,” the authors concluded.

“Our data confirm and potentially extend the role of pembrolizumab monotherapy as a standard first-line treatment for patients with PD-L1–expressing tumors,” said Lopes. He shared that based on the advice of their external drug monitoring committee, the trial continues to evaluate PFS in this trial population.

Leena Gandhi, MD, currently the director of Thoracic Medical Oncology and an associate professor of medicine at the New York University School of Medicine, who will soon be joining Eli Lilly and Company, was the discussant for this abstract.

Comparing the performance of nivolumab, the other PD-1 inhibitor, with pembrolizumab, Gandhi questioned whether the crossover allowed in the Checkmate-026 study may have resulted in the failure of nivolumab as first-line treatment in advanced/metastatic NSCLC. “Overall, the studies are more similar than they are different,” she said. However, Checkmate-026 allowed 60.4% of patients in the chemotherapy arm to cross over to the nivolumab arm, whereas only 19.8% in Keynote-042 who received chemotherapy were subsequently treated with pembrolizumab.

She identified several caveats with the Keynote-042 results: References
  1. Lopes G, Wu Y, Kudaba I, et al. Pembrolizumab (pembro) versus platinum-based chemotherapy (chemo) as first-line therapy for advanced/metastatic NSCLC with a PD-L1 tumor proportion score (TPS) ≥ 1%: Open-label, phase 3 KEYNOTE-042 study. J Clin Oncol. 2018;36(suppl; abstract LBA4).
  2. Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al; Keynote-189 investigators. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018;378(22):2078-2092. doi: 10.1056/NEJMoa1801005.
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