Pembrolizumab Benefit Not Altered by KRAS Status in Nonsquamous NSCLC

Gilberto Lopes, MD

Two analyses presented at the 2019 ESMO Immuno-Oncology Congress provided data supporting pembrolizumab (Keytruda), either as monotherapy or in combination with chemotherapy, as a first-line treatment option in patients with nonsquamous non—small cell lung cancer (NSCLC), regardless of KRAS mutational status.

Patient outcomes strongly favored pembrolizumab monotherapy over chemotherapy in patients with nonsquamous NSCLC, and any KRAS or KRAS G12C mutation in an analysis of the KEYNOTE-042 study.¹ Thirty patients on the trial with any KRAS mutation receiving pembrolizumab had an objective response rate (ORR) of 56.7% (95% CI, 37.4-74.5) versus an ORR of 18.0% (95% CI, 7.5-33.5) in 39 patients treated with chemotherapy.

In patients with KRAS G12C mutations, 12 patients who received pembrolizumab demonstrated a 66.7% ORR (95% CI, 34.9-90.1) versus an ORR of 23.5% (95% CI, 6.8-49.9) in 17 patients on chemotherapy. In contrast, 127 patients without any KRAS mutation on pembrolizumab had an ORR of 29.1% (95% CI, 21.4-37.9) versus 21.1% (95% CI, 13.6-30.0) in 105 patients on chemotherapy.

The median duration of response (DOR) in responding patients with any KRAS mutation was 18 months (95% CI, 11—not reached [NR]) with pembrolizumab versus 10 months (95% CI, 6–NR) with chemotherapy; in patients with KRAS G12C mutations, the median DOR was 20 months (95% CI, 11—NR) versus 9 months (95% CI, 6–NR), respectively. The median DOR in patients without KRAS was not reached (95% CI, 13—NR) versus 9 months (95% CI, 7–NR) with pembrolizumab versus chemotherapy, respectively.

“Findings of this descriptive exploratory analysis suggest that pembrolizumab monotherapy should be considered as a standard first-line treatment option for PD-L1—positive advanced nonsquamous NSCLC, regardless of KRAS mutational status,” Gilberto Lopes, MD, associate director of Global Oncology at Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, said in a presentation during the meeting. “Studies have shown variable results with chemotherapy and immunotherapy in NSCLC with KRAS mutations.”

Lopes and colleagues analyzed tumor samples from patients in the phase III KEYNOTE-042 study to determine the prevalence of KRAS mutations in these patients and the association between the presence of mutations and their impact on pembrolizumab efficacy. KEYNOTE-042 evaluated first-line pembrolizumab monotherapy compared with platinum-based chemotherapy in 1274 patients with advanced NSCLC that were also PD-L1—positive, defined by having a tumor proportion score (TPS) ≥1%. The trial’s data were the basis for the FDA’s April 2019 decision to approve single-agent pembrolizumab for the frontline treatment of patients with stage III NSCLC who are ineligible for surgery or definitive chemoradiation, or metastatic NSCLC, with a PD-L1 expression level of ≥1% and do not harbor EGFR or ALK aberrations.

The exploratory analysis included descriptive analyses of the correlation between KRAS mutational status and shifts in distributions of tumor mutational burden and PD-L1 expression, as well as the association of KRAS and KRAS G12C status with efficacy. KRAS status and TMB were determined by whole-exome sequencing (WES) in 301 (38%) patients having available tumor and matched-normal tissue out of 783 patients with nonsquamous NSCLC.

KRAS mutations were identified in 69 (22.9%) patients, 29 (9.6%) of whom were G12C carriers. Patients with KRAS mutations tended to have a higher PD-L1 TPS; the median TPS was 60% (interquartile range [IQR], 10-95) versus 35% (IQR, 10-80) with a median TMB of 191 mutations/exome (IQR, 129-288) versus 105 mutations/exome (IQR, 56-226) in patients with and without KRAS mutations, respectively. The prevalence of KRAS mutations was 46.3% in patients having high TMB and higher levels of PD-L1 expression.

In KEYNOTE-042, median progression-free survival (PFS) was longer across both groups of patients with KRAS mutations who were treated with pembrolizumab compared to those receiving chemotherapy. Patients with any KRAS mutation demonstrated a median PFS of 12 months (95% CI, 8—NR) with pembrolizumab versus 6 months (95% CI, 4-9) with chemotherapy (HR, 0.51; 95% CI, 0.29-0.87). Those with KRAS G12C mutations had a median PFS of 15 months (95% CI, 10—NR) with pembrolizumab versus 6 months (95% CI, 4-8) with chemotherapy (HR, 0.27; 95% CI, 0.10-0.71). In patients without KRAS, the median PFS was 6 months (95% CI, 4-7) with pembrolizumab versus 6 months (95% CI, 6-8) with chemotherapy (HR, 1.00; 95% CI, 0.75-1.34).

Median overall survival (OS) with pembrolizumab versus chemotherapy, respectively, was 28 months (95% CI, 23—NR) versus 11 months (95% CI, 7-25) in patients with any KRAS mutation (HR, 0.42; 95 CI, 0.22-0.81). Median OS was not reached (95% CI, 23—NR) versus 8 months (95% CI, 5–NR) in those with KRAS G12C (HR, 0.28; 95% CI, 0.09-0.86), and 15 months (95% CI, 12-24) versus 12 months (95% CI, 11-18) without KRAS (HR, 0.86; 95% CI, 0.63-1.18).

“The findings also suggest that a pembrolizumab-containing regimen is a clinically relevant comparator for studies of KRAS-targeted therapy given as first-line treatment of NSCLC,” said Lopes.

In a second analysis, Delvys Rodriguez-Abreu, MD, of the Department of Medical Oncology, Complejo Hospitalario Universitario Insular de Canarias, Gran Canaria, Spain, and co-investigators used data from the phase III KEYNOTE-189 to demonstrate that KRAS mutational status does not decrease the efficacy of first-line pembrolizumab plus pemetrexed and platinum-based chemotherapy in patients with metastatic nonsquamous NSCLC.² In August 2018, the FDA granted a full approval to frontline pembrolizumab for use in combination with standard chemotherapy for patients with metastatic nonsquamous NSCLC, based on findings from the phase III KEYNOTE-189 trial.

Results of this analysis showed that, in a group of 59 patients with any KRAS mutation treated with pembrolizumab plus chemotherapy, the ORR was 40.7% (95% CI, 28.1-54.3) versus an ORR of 26.7% (95% CI, 12.3-45.9) in 30 patients treated with placebo/chemotherapy. In patients with KRAS G12C mutations, 26 patients on pembrolizumab demonstrated an ORR of 50.0% (95% CI, 29.9-70.1) versus an ORR of 18.2% (95% CI, 2.3-51.8) in 11 patients on chemotherapy. In patients without KRAS mutations, 145 patients on pembrolizumab plus chemotherapy had an ORR of 47.6% (95% CI, 39.2-56.0) versus 10.9% (95% CI, 4.1-22.3) in 55 patients receiving chemotherapy.

Rodriguez-Abreu set the frequency of KRAS mutations at approximately 15% to 30% in lung adenocarcinomas, and noted that they may be a prognostic factor in NSCLC. His research team determined the prevalence of KRAS mutations and evaluated the association with pembrolizumab efficacy in an exploratory analysis of the KEYNOTE-189 study of first-line treatment with pembrolizumab plus pemetrexed and platinum-based chemotherapy compared with placebo plus pemetrexed and platinum-based chemotherapy in patients with metastatic nonsquamous NSCLC.

Using samples from patients having available tumor and matched-normal tissue, investigators performed WES to determine KRAS and TMB status in patients with metastatic nonsquamous NSCLC. Descriptive analyses of the association of KRAS and KRAS G12C status with efficacy were included as part of this exploratory analysis, as was correlation between KRAS mutational status and shifts in TMB and PD-L1 expression distributions.

Of 616 patients, 289 had evaluable WES data, which established that 89 (30.8%) of patients had KRAS mutations, including 37 (12.8%) patients who were KRAS G12C carriers. Patients with KRAS mutations also had higher median PD-L1 TPS of 30% (IQR, 1-71) versus median 5% (IQR, 0-60), as well as a higher median TMB of 204 mutations/exome (IQR, 137-276) versus 141 mutations/exome (IQR, 85-252) than patients without any KRAS mutation, respectively.

The median PFS in patients with any KRAS mutation, KRAS G12C, and no KRAS mutation was 9 months (95% CI, 7-14) with pembrolizumab plus chemotherapy versus 5 months (95% CI, 5-9) with chemotherapy alone (HR, 0.47; 95% CI, 0.29-0.77); 11 months (95% CI, 6-18) with pembrolizumab plus chemotherapy versus 5 (95% CI, 5—NR) with chemotherapy alone (HR, 0.48; 95% CI, 0.22-1.06), and 9 months (95% CI, 7-14) with pembrolizumab plus chemotherapy versus 5 months (95% CI, 4-5) with chemotherapy alone (HR, 0.40; 95% CI, 0.29-0.57).

Median OS with pembrolizumab/chemotherapy versus chemotherapy, respectively, was 21 months (95% CI, 16—NR) versus 14 months (95% CI, 8–NR) in patients with any KRAS mutation (HR, 0.79; 95% CI, 0.45-1.38), 18 months (95% CI, 11—NR) versus 25 months (95% CI, 8–NR) with KRAS G12C mutations (HR, 1.14; 95% CI, 0.45-2.92), and 23 months (95% CI, 19-NR) versus 9 months (95% CI, 7-17) in patients harboring no KRAS mutations (HR, 0.55; 95% CI, 0.37-0.81).

“This exploratory analysis demonstrated that pembrolizumab plus chemotherapy comprising pemetrexed and a platinum should be considered as a standard first-line treatment for patients with metastatic nonsquamous NSCLC, regardless of KRAS mutation status,” said Rodriguez-Abreu.

References

1. Herbst RS, Lopes G, Kowalski DM, et al. Association of KRAS mutational status with response to pembrolizumab monotherapy given as first-line therapy for PD-L1-positive advanced non-squamous NSCLC in KEYNOTE-042. Presented at: 2019 ESMO Immuno-Oncology Congress; December 11-14, 2019; Geneva, Switzerland. Abstract LBA4.
2. Gadgeel S, Rodriguez-Abreu D, et al. KRAS mutational status and efficacy in KEYNOTE-189: Pembrolizumab (pembro) plus chemotherapy (chemo) vs placebo plus chemo as first-line therapy for metastatic non-squamous NSCLC. Presented at: 2019 ESMO Immuno-Oncology Congress; December 11-14, 2019; Geneva, Switzerland. Abstract LBA5.