Research study shows merits of using Pembrolizumab as first line treatment of patients with advanced non-small-cell lung cancer and high PD-L1 expression

Pembrolizumab is set to become a new option for first line treatment of patients with advanced lung cancer and high PD-L1 expression, according to the results of the phase III KEYNOTE-024 trial presented at the ESMO 2016 Congress in Copenhagen1 and published in the New England Journal of Medicine.

”Pembrolizumab is a PD-1 antibody approved for second line treatment of patients with advanced non-small-cell lung cancer (NSCLC) and PD-L1 expression in their tumour cells,” said lead author Professor Martin Reck, chief oncology physician, Department of Thoracic Oncology, Lung Clinic Grosshansdorf, Germany. “KEYNOTE-024 is the first phase III trial of pembrolizumab as first line treatment in patients with high PD-L1 expression, who represent 27–30% of those with advanced NSCLC.”

KEYNOTE-024 investigated the efficacy of pembrolizumab compared to standard of care with platinum-based chemotherapy in untreated patients with advanced NSCLC and high PD-L1 expression (defined as expression in at least 50% of tumour cells). Patients with EGFR activating mutations and ALK translocations were excluded from recruitment. “There is a substantial need to find better options than chemotherapy for these patients,” said Reck.

The trial included 305 patients from 16 countries who were randomised 1:1 to pembrolizumab or chemotherapy. Patients in the chemotherapy arm who progressed were eligible to crossover to pembrolizumab as second line treatment – this occurred in 44% of these patients.

The investigators found that pembrolizumab significantly improved the primary endpoint of progression-free survival by approximately four months compared to chemotherapy (10.3 months versus 6.0 months, hazard ratio [HR] 0.50). The secondary endpoint of overall survival was also significantly prolonged, and 80% of patients on pembrolizumab were alive at six months compared to 72% on chemotherapy (HR=0.60).

“The significant improvement in overall survival with pembrolizumab was remarkable given that more than 40% of patients crossed over from the control arm to pembrolizumab after progression of the disease,” said Reck.

Pembrolizumab was associated with a higher overall response rate compared to chemotherapy (45% versus 28%), a longer duration of response, and lower incidences of all and serious (3/4) adverse events.

“This data will completely change the management of patients with advanced NSCLC,” said Reck. “All endpoints of efficacy and tolerability favoured treatment with pembrolizumab, suggesting it should become one standard of care for first line treatment of patients with advanced NSCLC and high PD-L1 expression. This is primarily an opportunity for patients without oncogenic alterations. More information is needed for those with alterations.”

He concluded: “This is a landmark trial for the 30% of patients with advanced NSCLC who are high expressers of PD-L1. The new treatment algorithm should include upfront testing for PD-L1 expression to identify patients who will benefit from first line treatment with pembrolizumab.”
Commenting on the results, Professor Johan Vansteenkiste, Professor of Medicine, Catholic University Leuven, and Chief Oncology Physician, Unit of Respiratory Oncology, University Hospital  KU Leuven, Belgium, said: “This study may change current practice for the treatment of patients with advanced NSCLC. It is the first time a therapy has improved progression-free survival over the current standard first line treatment with platinum-based doublet chemotherapy.”

“The reason KEYNOTE-024 met its primary endpoint, in contrast with other studies, is probably because the trial only included patients who had PD-L1 expression of at least 50% and were therefore optimal candidates for treatment with pembrolizumab,” he added.

“A study is needed to confirm these findings in patients with high PD-L1 expression,” continued Vansteenkiste. “Additional research should be done to find out whether patients with lower levels of PD-L1 expression also benefit more from pembrolizumab than chemotherapy.”

Adapted from press release by ESMO

Chemotherapy and pembrolizumab combination significantly improves outcomes in advanced non-small-cell lung cancer

The addition of PD-1 antibody pembrolizumab to standard first-line chemotherapy for treatment-naïve advanced non-small-cell lung cancer significantly improves response rates and progression-free survival, researchers reported at the ESMO 2016 Congress in Copenhagen today.

Pembrolizumab is a class of immunotherapeutic anti-cancer drugs called checkpoint inhibitors, which target the mechanism the tumor uses to shut down the body’s immune response.
“Pembrolizumab enables T cells to ‘reactivate’ and accomplish what they are designed to do – facilitate tumor cell killing,” said principal investigator Dr Corey Langer, director of the Thoracic Oncology Program at the Abramson Cancer Center at the University of Pennsylvania, US.

Research Study

In the phase II KEYNOTE-021 study, researchers randomized 123 patients with stage IIIB/IV, chemotherapy-naive, nonsquamous non-small-cell lung cancer to receive four cycles of carboplatin and pemetrexed (500 mg/m2 every three weeks), with or without 24 months treatment with pembrolizumab (200mg every three weeks).

After a median follow-up of 10.6 months, researchers observed a significantly greater objective response rate (55% vs. 29%, P = 0.0016) in the patients who received pembrolizumab as well as chemotherapy, compared to those treated with chemotherapy alone. While patients were not selected by the amount of PD-L1 expression in their tumor, researchers did note a higher response rate (around 80%) for the pembrolizumab and chemotherapy combination in tumors with PD-L1 expression greater than or equal to 50%.

Participants in the pembrolizumab arm also experienced an improved progression-free survival (median 13.0 months vs. 8.9 months) although overall survival rates were similar between the two arms (6 month survival rate = 92%), in this early landmark assessment.

There was a higher incidence of adverse events of grade 3 severity or above in the pembrolizumab arm compared to the chemotherapy alone arm (39% vs. 26%), but this had no impact on treatment discontinuation rates (10% for the pembrolizumab arm compared to 13% for the chemotherapy only arm) or treatment-related deaths. The most common treatment-related adverse events were fatigue and nausea, which were more common in patients receiving pembrolizumab, and anemia, which was more common in the chemotherapy alone arm of the study.

“This is the first randomized phase II trial in advanced, treatment-naïve non-squamous non-small-cell lung cancer to assess the benefit of adding a monoclonal antibody targeting PD1 to standard chemotherapy,” said Langer. “If these benefits are confirmed in an ongoing phase III trial, the results may radically alter the treatment paradigm in advanced non-small-cell lung cancer.”

Commenting on the study, Dr Raffaele Califano, Consultant in Medical Oncology at The Christie Hospital and University Hospital of South Manchester in Manchester, UK said: “Data for the combination of chemotherapy plus pembrolizumab in this population is certainly encouraging, and it is reassuring to see that the addition of pembrolizumab to first-line chemotherapy has a manageable toxicity profile and doesn’t increase the incidence of treatment-related adverse events or deaths.”

“Notably, the progression-free survival reported in the standard arm was much longer than expected and nearly doubled when compared to historical data, which could be due to patient selection or other clinical/molecular characteristics of the patients enrolled in this study,” Califano said.

“In order to establish if this strategy should be adopted in clinical practice, these results should be investigated further in a phase III randomized study with a similar design, adequately powered for progression-free survival and with robust assessment of patient’s reported outcomes.”

Adapted from press release by ESMO