Frontline Pembrolizumab and Chemotherapy a New Standard of Care in Metastatic Squamous NSCLC

Frontline Pembrolizumab and Chemotherapy a New Standard of Care in Metastatic Squamous NSCLC

Dr. Luis G. Paz-Ares
Combining pembrolizumab with conventional chemotherapy in the first-line setting significantly prolongs median overall survival (OS) in patients with metastatic squamous non–small cell lung cancer (NSCLC), according to data from the global phase III KEYNOTE-407 trial presented during the “Compelling Combinations: Raising the Bar With Immunotherapy” Clinical Science Symposium, held June 3 (Abstract 105).

The median OS reached 11.3 months with carboplatin and paclitaxel/nab-paclitaxel but increased to 15.9 months when pembrolizumab was paired with the chemotherapy (HR 0.64, 95% CI [0.49, 0.85]; p = 0.0008). The OS benefit observed with the pembrolizumab/chemotherapy regimen persisted across all relevant patient subgroups, including those with tumor PD-L1 expression categorized as low (< 1%; HR 0.61, 95% CI [0.38, 0.98]), intermediate (1%-49%; HR 0.57, 95% CI [0.36, 0.90]), and high (≥ 50%; HR 0.64, 95% CI [0.37, 1.10]).

“These data suggest pembrolizumab plus carboplatin and paclitaxel or nab-paclitaxel should become a new standard of care for the first-line treatment of metastatic squamous NSCLC across all the different levels of PD-L1 expression,” Luis G. Paz-Ares, MD, PhD, of the Hospital Universitario 12 de Octubre, Spain, said during his presentation.

KEYNOTE-407 follows on the heels of the positive KEYNOTE-189 clinical trial, which demonstrated that adding pembrolizumab to standard first-line chemotherapy significantly improved median OS regardless of PD-L1 tumor expression in patients with metastatic nonsquamous NSCLC.1 KEYNOTE-407 aimed to do the same, but in untreated metastatic squamous NSCLC.

A total of 559 patients enrolled in KEYNOTE-407. PD-L1 expression in tumor tissue was not a prerequisite for entry; however, patients were stratified prior to randomization based on tumor PD-L1 expression (< 1% vs. ≥ 1%) as well as the choice of taxane (paclitaxel vs. nab-paclitaxel) and geography (East Asia vs. rest of world). Individuals were randomly assigned to receive four cycles of carboplatin and paclitaxel/nab-paclitaxel plus either pembrolizumab or placebo. Thereafter, patients received pembrolizumab or placebo maintenance therapy in accord with the assigned induction regimen. Patients in the placebo arm who developed disease progression could cross over to receive pembrolizumab monotherapy at any time.

The results reported by Dr. Paz-Ares come from a second interim analysis of the KEYNOTE-407 data after patients had been followed for a median of 7.8 months and enough events occurred to evaluate both OS and progression-free survival (PFS), the coprimary endpoints of the trial.

Consistent with OS, the pembrolizumab/chemotherapy combination significantly improved median PFS over chemotherapy alone (6.4 vs. 4.8 months; HR 0.56, 95% CI [0.45, 0.70]; p < 0.0001), again, across all PD-L1 expression subgroups. Patients in the pembrolizumab/chemotherapy arm also demonstrated a significantly higher objective response rate than those who received chemotherapy alone (58.4% vs. 35.0% at the first interim analysis; p = 0.0004) as well as a more durable response to treatment (median, 7.7 vs. 4.8 months).

Dr. Paz-Ares commented that the frequency of adverse events was mostly similar between thepembrolizumab/chemotherapy and chemotherapy-alone arms both for overall events (98.2% vs. 97.9%) and grade 3-5 events (69.8% vs. 68.2%). The observed events matched the known safety profiles of both pembrolizumab and chemotherapy. For example, the most common adverse events in both arms included anemia, alopecia, neutropenia, nausea, and thrombocytopenia, with the cytopenias comprising the majority of grade 3-5 adverse events in each arm.

Immune-mediated adverse events and infusion reactions did occur more frequently with the addition of pembrolizumab to chemotherapy, compared with both overall (28.8% vs. 8.6%) and for grade 3-5 adverse events (10.8% vs. 3.2%). The most common immune-mediated adverse events (incidence ≥ 5%) associated with the pembrolizumab regimen included hypothyroidism (7.9%), hyperthyroidism (7.2%), and pneumonitis (6.5%).

“This trial is clearly a win,” discussant Charles G. Drake, MD, PhD, of the Columbia University Herbert Irving Comprehensive Cancer Center, said, adding that the pembrolizumab/chemotherapy combination will become a new frontline standard of care. From a scientific perspective, Dr. Drake thinks it will be intriguing to determine whether pairing chemotherapy and pembrolizumab confers additive activity or whether the combination promotes immunogenic cell death that leads to immune memory and a sustained long-term response.  

–Kara Nyberg, PhD