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Immunotherapy Benefits Survival, Improves Safety, vs Platinum-Based Chemotherapy for PD-L1–Expressing NSCLC


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IMMUNOTHERAPY WITH pembrolizumab (Keytruda) improved overall survival compared with investigator’s choice of platinum-based chemotherapy as first-line treatment for patients with advanced non–small cell lung cancer (NSCLC) in the KEYNOTE-042 trial. Median overall survival was improved by 4 to 8 months in patients enrolled in the trial, all of whom had tumors with programmed cell death ligand 1 (PD-L1) expression of 1% or more. Moreover, immunotherapy with pembrolizumab was associated with fewer severe side effects than chemotherapy (17.8% vs 41%, respectively). The results were numerically higher for patients with higher levels of PD-L1 expression, but even patients with very low levels of PD-L1 expression had greater benefit from pembrolizumab than chemotherapy. These results were presented at the Plenary Session during the 2018 ASCO Annual Meeting.1 

Gilberto Lopes, MD

Gilberto Lopes, MD

“The vast majority of patients with lung cancer [and no driver mutations] have a new treatment option with better efficacy and fewer side effects than standard chemotherapy. Our study shows that pembrolizumab provides more benefit than chemotherapy for two-thirds of all people with the most common type of lung cancer,” said lead author Gilberto Lopes, MD, a medical oncologist at the Sylvester Comprehensive Cancer Center, University of Miami Health System, Miami. 

“KEYNOTE-042 is the first study with a primary endpoint of overall survival to demonstrate superiority of pembrolizumab over platinum-based chemotherapy in patients with previously untreated advanced/metastatic NSCLC without sensitizing epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutations and PD-L1 Tumor Proportion Score (TPS) ≥ 1%. These data confirm and potentially extend the role of pembrolizumab monotherapy as a standard first-line treatment for PDL1–expressing advanced/metastatic NSCLC,” Dr. Lopes stated. “We have to commit that every single patient who can benefit has access to this therapy,” he told listeners. 

Previously, the smaller KEYNOTE-024 trial showed that pembrolizumab improved outcomes in patients with NSCLC and high PD-L1 expression (at least 50%). The larger KEYNOTE-042 trial found that pembrolizumab was also effective in patients with a much lower level of PD-L1 expression (ie, 1% or higher). 

Currently, pembrolizumab is the only U.S. Food and Drug Administration (FDA)-approved immunotherapy for initial treatment of NSCLC as monotherapy or in combination with chemotherapy. 

“Our study shows that pembrolizumab provides more benefit than chemotherapy for two-thirds of all people with the most common type of lung cancer.”
— Gilberto Lopes, MD

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Study Details and Results 

THE STUDY, conducted at 213 sites in 32 countries, randomly assigned 1,274 patients with locally advanced or metastatic NSCLC to receive up to 35 cycles of pembrolizumab at 200 mg every 3 weeks or investigator’s choice of chemotherapy (ie, up to 6 cycles of paclitaxel plus carboplatin or pemetrexed [Alimta] plus carboplatin with optional pemetrexed maintenance for nonsquamous NSCLC). Patients were stratified by geographic region (East Asia vs non–East Asia), Eastern Cooperative Oncology Group performance ptatus (0 vs 1), histology (squamous vs nonsquamous), and PD-L1 (tumor proportion score [TPS] ≥ 50% vs 1% vs 49%). A total of 599 patients (47%) had a TPS ≥ 50%; 818 patients had a TPS ≥ 20%. At a median follow-up of 12.8 months, 13.7% were still receiving pembrolizumab compared with 4.9% on pemetrexed maintenance. 

Pembrolizumab was significantly superior to chemotherapy in all subgroups of PD-L1 expression. In patients with a PD-L1 TPS ≥ 50%, pembrolizumab significantly improved survival: median overall survival of 10 months vs 12.2 for chemotherapy (P = .0003). In patients with a PD-L1 TPS ≥ 20%, median overall survival was 17.7 months vs 13 months, respectively (P = .0020). In those with the lowest level of PD-L1 expression, TPS > 1%, median overall survival was 16 months vs 12.1 months, respectively (P = .0018). 

The response rate was higher in patients with a TPS ≥ 50%: 39.5% for pembrolizumab vs 32% for chemotherapy. For patients with a TPS ≥ 20%, response rates were 33.4% and 28.9%, respectively. For a TPS > 1%, response rates were 27.3% and 26.5%, respectively. In all three PD-L1 subgroups, the duration of response to pembrolizumab was 20.2 months vs 8 to 10 months for chemotherapy. 

KEYNOTE-042 Findings

  • Pembrolizumab monotherapy improved overall survival compared with chemotherapy as first-line treatment for patients with advanced lung cancer with a PD-L1 level ≥ 1%.
  • The side-effect profile of pembrolizumab was more favorable than with chemotherapy, suggesting it is an appropriate treatment option for those whose tumors have any level of PD-L1 positivity.
  • The formal discussant of this trial recommended the use of biomarkers to select the best individual treatment option for each patient.

Safety 

TREATMENT-RELATED adverse events were reported in 62.7% of the pembrolizumab arm and 89.9% of the chemotherapy arm. Grades 3 to 5 adverse events occurred in 17.8% vs 41%, respectively. Immune-mediated adverse events were reported in 27.8% of the pembrolizumab arm and 7.2% of the chemotherapy arm. Grades 3 to 5 immune-related adverse events occurred in 8% and 1.5%, respectively. The most common immune-related adverse events of any grade were hypothyroidism, pneumonitis, and hyperthyroidism. 

Dr. Lopes was enthusiastic about the safety findings. “The vast majority of patients treated with pembrolizumab did not have toxicity. Grades 3 to 5 toxicity occurred in 17%, and just 2% died; one was an immune-related death, but the patient also had progressive disease. We have learned to manage immune-related toxicities with experience,” he noted. 

Additional Comments on Safety 

ASCO EXPERT John Heymach, MD, PhD, of The University of Texas MD Anderson Cancer Center, Houston, weighed in on the safety of pembrolizumab as well. “These numbers don’t capture the impact on patients’ lives. We have fewer grade 3 and higher adverse events with immunotherapy than with chemotherapy. For grade 3 adverse events with chemotherapy, patients may have to be hospitalized for weeks. Patients on immunotherapy have a dramatically better quality of life,” he told listeners at an ASCO press conference. 

Ongoing trials will evaluate whether pembrolizumab plus chemotherapy is superior to pembrolizumab alone in patients whose tumors express PD-L1; the use of adjuvant pembrolizumab; and combinations of immunotherapy with bevacizumab (Avastin)-containing combination regimens as first-line therapy in NSCLC. ■

DISCLOSURE: Dr. Lopes has received institutional research funding from Merck Sharp & Dohme, EMD Serono, and AstraZeneca. Dr. Heymach reported no conflicts of interest. 

REFERENCE 

1. Lopes G, Wu Y-L, Kudaba I, et al: Pembrolizumab versus platinum-based chemotherapy as first-lone therapy for advanced metastatic NSCLC with a PD-L1 tumor proportion score ≥ 1%: Open-label, phase 3 KEYNOTE-042 study. 2018 ASCO Annual Meeting. Abstract LBA4. Presented June 3, 2018.


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“THIS STUDY represents a true milestone in the field of lung cancer. For the first time, the vast majority of patients with non–small cell lung cancer (NSCLC) can receive immunotherapy with pembrolizumab (Keytruda),” said ASCO expert John Heymach, MD, PhD, of MD...

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