Pembrolizumab Boosts Survival in Metastatic Nonsquamous NSCLC Regardless of KRAS Mutations

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Pembrolizumab showed improvements in overall survival, progression-free survival, and objective response rate compared with pemetrexed or paclitaxel chemotherapy in patients with metastatic nonsquamous non–small cell lung cancer whose tumors are PD-L1–positive, regardless of their KRAS mutational status.

Jonathan Cheng, MD

Jonathan Cheng, MD

Jonathan Cheng, MD

According to an exploratory analysis in the phase III KEYNOTE-042 (NCT02220894) trial, pembrolizumab (Keytruda) showed improvements in overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) compared with pemetrexed or paclitaxel chemotherapy in patients with metastatic nonsquamous non—small cell lung cancer (NSCLC) whose tumors are PD-L1–positive, regardless of theirKRASmutational status. Data from the exploratory analysis were presented at the European Society for Medical Oncology (ESMO) Immuno-Oncology Congress 2019.1

These data demonstrated that single-agent pembrolizumab was associated with improved clinical outcomes regardless of theKRASmutational status compared with chemotherapy. The median OS, the primary end point of the study, in the KRAS-mutated cohort was 28 months with pembrolizumab versus 11 months with chemotherapy (HR = 0.42 [95% CI, 0.22-0.81]). In the cohort without anyKRASmutations, median OS was 15 months versus 12 months with pembrolizumab and chemotherapy, respectively, (HR = 0.86 [95% CI, 0.63-1.18]). Median OS was not reached in the KRASG12C-mutated group (HR = 0.28 [95% CI, 0.09-0.86]).

The ORR was 56.7% versus 18.0% in patients with anyKRASmutation, 66.7% versus 23.5% in patients with the KRASG12C mutation, and 29.1%versus 21.0% in patients without anyKRASmutations with pembrolizumab versus chemotherapy, respectively. Additionally, median PFS in patients with any KRASmutation was 12 months with pembrolizumab compared with 6 months in the chemotherapy arm (HR = 0.51 [95% CI, 0.29-0.87]), and in patients with theKRASG12C, median PFS was 15 months versus 6 months, respectively, (HR = 0.27 [95% CI, 0.10-0.71]). In patients without any KRASmutations, the median PFS was 6 months in each arm (HR = 1.00 [95% CI, 0.75-1.34]).

“KRASmutations occur in approximately 20% of people with NSCLC, and some previous studies have suggested that these mutations are associated with a poorer response to treatment. It was therefore encouraging to see in this exploratory analysis that Keytruda monotherapy was associated with a survival benefit in certain patients with metastatic nonsquamous NSCLC, regardless of KRASmutational status,” said Jonathan Cheng, MD, vice president of Oncology Clinical Research at Merck Research Laboratories, in a statement.

The risk of death was reduced by 58% in patients with anyKRASmutation (HR = 0.42 [95% CI, 0.22-0.81]) and 72% in patients with the KRASG12C mutation (HR = 0.28 [95% CI, 0.09-0.86]) compared with chemotherapy. The exploratory analysis also demonstrated that the safety profile was consistent with previous findings for this patient population.

This exploratory analysis was conducted to assess the association betweenKRASmutations and the efficacy in the KEYNOTE-042 trial. In KEYNOTE-042, 1274 patients with treatment-naïve metastatic nonsquamous NSCLC who had expression of PD-L1 [tumor proportion score (TPS) ≥1%]. Of these patients, 301 had KRASevaluable data, including 232 without aKRASmutation and 69 with any KRASmutation. Additionally, 29 of the 69 patients had a KRASG12C mutation. The KRASmutational status, as well as tissue tumor mutational burden, were determined by whole-exome sequencing of tumor tissue and matched normal DNA blood.

Patients were randomized 1:1 to receive either pembrolizumab at 200 mg intravenously every 3 weeks or investigator’s choice of platinum-based chemotherapy, either pemetrexed or paclitaxel. Patients continued to receive treatment for up to 35 treatments or until disease progression or unacceptable toxicity. The primary end point of the KEYNOTE-042 was OS with a TPS of ≥50%, ≥20%, and ≥1%. Secondary endpoints included PFS and ORR.

To be included in the study, patients had to have a histologically-or cytologically-confirmed diagnosis of advanced or metastatic NSCLC, as well as a PD-L1—positive tumor, measurable disease based on RECIST 1.1 criteria, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and no prior systemic chemotherapy treatments for the advanced or metastatic disease. Patients with anEGFR-sensitizing mutation and/or an ALK gene fusion could not enroll on the trial. They also could not be actively participating or have previously participated in a clinical trial of an investigational agent/device within 4 weeks of the first dose in this study. Additional inclusion and exclusion criteria were also listed.

According to study authors, pembrolizumab monotherapy should be considered a standard of care frontline option for patients with PD-L1—positive advanced NSCLC regardless of theirKRASmutational status.2Pembrolizumab monotherapy has previously been approved by the FDA for a number of indications, including select patient populations with NSCLC and small-cell lung cancer, among other types of cancers.  

References:

  1. Data from Exploratory Analysis Show Merck’s KEYTRUDA® (pembrolizumab) Improved Overall Survival as Monotherapy for the First-Line Treatment of Metastatic Non-Small Cell Lung Cancer Regardless of KRAS Mutational Status. Merck website.https://www.mrknewsroom.com/news-release/oncology/data-exploratory-analysis-show-mercks-keytruda-pembrolizumab-improved-overall-. Published December 12, 2019. Accessed December 16, 2019.
  2. Pembrolizumab May Be Considered as a First-Line Treatment Option in Nonsquamous NSCLC Even in the Presence of KRAS Mutations. ESMO Website.https://www.esmo.org/Conferences/ESMO-Immuno-Oncology-Congress-2019/Congress-Coverage/News-Press-Releases/Pembrolizumab-May-Be-Considered-as-a-First-Line-Treatment-Option-in-Non-Squamous-NSCLC-Even-in-the-Presence-of-KRAS-Mutations. Published December 12, 2019. Accessed December 16, 2019.
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