ADDING THE IMMUNE checkpoint inhibitor pembrolizumab (Keytruda) to standard chemotherapy with pemetrexed (Alimta) and a platinum as first-line therapy was superior to chemotherapy alone in the KEYNOTE-189 trial.1 Induction and maintenance therapies with the new triplet therapy improved overall survival by 51% compared with conventional doublet chemotherapy in patients with metastatic nonsquamous non–small cell lung cancer (NSCLC). Overall survival was improved by the addition of pembrolizumab regardless of the level of programmed cell death ligand 1 (PD-L1) expression.
Leena Gandhi, MD, PhD
Alice T. Shaw, MD, PhD
“IN PATIENTS WITH previously untreated metastatic nonsquamous NSCLC without epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutations, the addition of pembrolizumab to standard chemotherapy with pemetrexed and a platinum-based drug resulted in significantly longer overall survival and progression-free survival than chemotherapy alone. Pembrolizumab plus pemetrexed and a platinum may be a new standard of care for first-line treatment of metastatic nonsquamous NSCLC, irrespective of PD-L1 expression,” stated lead author Leena Gandhi, MD, PhD, Director of Thoracic Medical Oncology at the Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York.
“Halving the risk of death is an unprecedented effect of therapy in the first-line setting for advanced nonsquamous NSCLC without EGFR or ALK alterations,” she added.
“[KEYNOTE-189] establishes the triplet of pembrolizumab/ pemetrexed/platinum as a new standard of care in the front-line setting. The effect on overall survival and progression-free survival regardless of PD-L1 status is striking,” stated Alice T. Shaw, MD, PhD, Director of the Center for Thoracic Cancers at Massachusetts General Hospital in Boston. Dr. Shaw moderated a press conference at the 2018 American Association for Cancer Research (AACR) Annual Meeting, where this paper was discussed. The study was published online in The New England Journal of Medicine to coincide with the presentation at the AACR meeting.2
Pembrolizumab is approved by the U.S. Food and Drug Administration (FDA) for the first-line treatment of advanced NSCLC with a PD-L1 tumor proportion score ≥ 50% and for previously treated advanced NSCLC with a PD-L1 tumor proportion score ≥ 1%. The FDA approval of the pembrolizumab/pemetrexed/platinum triplet is based on phase II data from the KEYNOTE-021 cohort G.3,4 KEYNOTE-189 provides convincing phase III evidence to support the triplet therapy.
“Halving the risk of death is an unprecedented effect of therapy in the first-line setting for advanced nonsquamous NSCLC without EGFR or ALK alterations.”— Leena Gandhi, MD, PhD
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KEYNOTE-189 enrolled 616 patients with untreated stage IV nonsquamous NSCLC and no sensitizing EGFR or ALK alterations. Patients with symptomatic brain metastasis were excluded. Patients were stratified by PD-L1 expression (tumor proportion score < 1% or ≥ 1%) based on samples provided at baseline and were randomized 2:1 to receive treatment with four cycles of pembrolizumab/ pemetrexed/carboplatin or placebo plus the same chemotherapy.
In the experimental arm, patients received pembrolizumab plus pemetrexed as maintenance therapy. In the placebo arm, patients received pemetrexed as maintenance therapy but were allowed to cross over to pembrolizumab if they developed progressive disease.
At baseline, both treatment arms were well balanced for demographic and disease characteristics. There were more males in the experimental arm (62% vs 52.9% in controls). Overall, about 17% had brain metastasis and one-third were untreated.
A clear and highly significant benefit in overall survival was observed when pembrolizumab was added to chemotherapy. Median overall survival was not yet reached in the experimental arm vs 11.3 months in the control arm. At 12 months, 69.2% of patients were alive in the experimental arm vs 49.4% of the control arm. The addition of pembrolizumab achieved a 51% increase in overall survival (P < .00001). All subgroups benefited from the addition of pembrolizumab, but the greatest benefit was in the group expressing high levels of PD-L1 (tumor proportion score ≥ 50%).
“[KEYNOTE-189] establishes the triplet of pembrolizumab/pemetrexed/platinum as a new standard of care in the front-line setting. The effect on overall survival and progression-free survival regardless of PD-L1 status is striking.”— Alice T. Shaw, MD, PhD
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Progression-free survival was significantly improved in the pembrolizumab combination group: median progression-free survival was 8.8 months vs 4.9 months for controls, representing a 51% improvement. The 1-year progression-free survival rate was 34.1% vs 17.3%, respectively (P < .00001).
The progression-free survival benefit was greater in patients with a tumor proportion score ≥ 50%, and those with a score of 1% to 49% also had a significant progression-free survival benefit. A progression-free survival benefit was less clear in those with a score < 1%.
A similar pattern was seen for objective response rate. For the whole study population, the objective response rate was 47.6% for the pembrolizumab combination vs 18.9% for controls (P < .00001). Responses were seen at all levels of PD-L1 expression, but objective response rate was highest among those with a PD-L1 tumor proportion score ≥ 50%: 61.4% vs 22.9%, respectively (P < .0001).
THE RATE OF adverse events was similar across both treatment arms. About 99% of patients experienced at least 1 adverse event, and about two-thirds had a grade 3 to 5 adverse event.
“Overall, no more grade 3 to 5 adverse events were seen [with the pembrolizumab combination] than with pembrolizumab monotherapy,” Dr. Gandhi said. Rates of treatment discontinuation due to adverse events were 13.8% in the pembrolizumab combination arm vs 7.9% in the control arm.
Immune-mediated adverse events were greater with the pembrolizumab combination: 22.7% vs 11.9%, respectively. Grade 3 to 5 acute renal injury was more frequent in the pembrolizumab arem: 5.2% vs 0.5% in the control arm. Grade 3 to 4 nephritis was reported in 1.5% vs 0%.
“The rate of nephritis was higher in this trial than in other studies [of pembrolizumab], but all three drugs in the combination regimen can cause renal toxicity,” Dr. Gandhi said.
Dr. Gandhi commented that although the pembrolizumab combination improved survival in all subgroups, in her opinion, PD-L1 testing is still needed.
“We would be hesitant to give up on that biomarker. PD-L1 may be part of a biomarker, perhaps added to tumor mutational burden,” Dr. Gandhi stated. “In the United States, we routinely get PD-L1 testing for most patients with nonsquamous NSCLC. We also typically order next-generation sequencing, which can estimate tumor mutational burden.” ■
DISCLOSURE: Dr. Gandhi has received research funding from Merck and has served on scientific advisory boards for Merck, Genentech/Roche, Pfizer, Ignyta, Syndax, AbbVie, AstraZeneca, and Bristol-Myers Squibb. Dr. Shaw reported no conflicts of interest.
1. Gandhi L, Rodriguez-Abreu D, Gadgeel S, et al: KEYNOTE-189: Randomized, double-blind, phase 3 study of pembrolizumab or placebo plus pemetrexed and platinum as first-line therapy for metastatic NSCLC. 2018 AACR Annual Meeting. Abstract CT075. Presented April 16, 2018.
2. Gandhi L, Rodriguez-Abreu D, Gadgeel S, et al: Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. April 16, 2018 (early release online).
3. Langer C, Gadgeel S, Borghaei H, et al: Carboplatin and pemetrexed with or without pembrolizumab for advanced non-squamous, non-small-cell lung cancer: A randomized phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol 17:1497-1508, 2016.
4. Borghaei H, Langer CJ, Gadgeel S, et al: Updated results of KEYNOTE-021 cohort G: A randomized, phase II study of pemetrexed and carboplatin with or without pembrolizumab as first-line therapy for advanced nonsquamous NSCLC. 2017 ESMO Congress. Abstract LBA49. Presented September 8, 2017.
FORMAL DISCUSSANT of the KEYNOTE-189 trial, Roy S. Herbst, MD, PhD, Chief of Medical Oncology at Smilow Cancer Hospital, Yale Cancer Center, New Haven, heartily endorsed the new triplet combination of pembrolizumab, pemetrexed, and a platinum in advanced nonsquamous non– small cell lung cancer...