Pembrolizumab May Be Considered as a First-Line Treatment Option in Non-Squamous NSCLC Even in the Presence of KRAS Mutations

Efficacy of pembrolizumab alone or combined with chemotherapy is solid regardless of KRAS mutations in non-squamous non-small cell lung cancer
12 Dec 2019
Cancer Immunology and Immunotherapy;  Lung and other thoracic tumours

Two analyses presented at the ESMO Immuno-Oncology Congress 2019 in Geneva, Switzerland (11-14 December) support pembrolizumab, either as monotherapy or in combination with chemotherapy, as a first-line treatment option in patients with non-squamous non-small cell lung cancer (NSCLC), regardless of the KRAS mutational status.

Findings from the KEYNOTE-042 study

Dr. Gilberto Lopes of the Sylvester Comprehensive Cancer Center at the University of Miami, Miami, FL, USA on behalf of study co-investigators presented results from an analysis of tumour samples from patients participating in the KEYNOTE-042 (NCT02220894) study for somatic KRAS mutations, which have been detected in approximately 15% to 30% of lung adenocarcinomas.

Previous reports have associated KRAS mutations with poorer prognosis in NSCLC

The investigators determined 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 patients with advanced NSCLC that were also PD-L1-positive, as defined by having a tumour proportion score (TPS) ≥1%.

The exploratory analysis conducted by the study team included descriptive analyses of the correlation between the KRAS mutational status and shifts in distributions of tumour mutational burden (TMB) and PD-L1 expression, as well as the association of KRAS and KRAS G12C status with efficacy.

Patients with KRAS mutations also tended to have positive PD-L1 status and higher TMB

The KRAS mutational status and TMB were determined by whole-exome sequencing (WES) in 301 (38%) of patients having available tumour and matched-normal tissue out of 782 patients with non-squamous NSCLC.

KRAS mutations were identified in 69 (23%) patients, including 29 (10%) G12C carriers. Patients with KRAS mutation tended to have a higher PD-L1 TPS; median TPS was 60% (interquartile range [IQR], 10-95) versus 35% (IQR, 10-80) and median TMB 191 mut/exome (IQR, 129-288) versus 105 mut/exome (IQR, 56-226) than in patients without KRAS mutations.  

Patient outcomes strongly favoured pembrolizumab over chemotherapy in patients with non-squamous NSCLC, positive PD-L1 status, and any KRAS or KRAS G12C mutation

Regarding patient outcomes following pembrolizumab versus chemotherapy treatment, 30 patients with any KRAS mutation receiving pembrolizumab had an objective response rate (ORR) of 56.7% (95% confidence interval [CI], 37.4-74.5) versus ORR 18.0% (95% CI, 7.5-33.5) in 39 patients treated with chemotherapy. In the group of patients with KRAS G12C mutation, 12 patients receiving pembrolizumab demonstrated ORR of 66.7% (95% CI, 34.9-90.1) versus ORR 23.5% (95% CI, 6.8-49.9) in 17 patients on chemotherapy. It was noted that the confidence intervals were wide given the modest frequency of KRAS mutation and low frequency of KRAS G12C. In contrast, 127 patients without any KRAS mutation on pembrolizumab had ORR of 29.1% (95% CI, 21.4-37.9) versus 21.1% (95% CI, 13.6-30.0) in 105 patients on chemotherapy.

Median progression-free survival (PFS) in patients with any KRAS mutation, KRAS G12C, and no KRAS mutation was 12 months (95% CI, 8-not reached [NR]) with pembrolizumab versus 6 months  (95% CI, 4-9) with chemotherapy (hazard ratio [HR] 0.51), 15 months (95% CI, 10-NR) with pembrolizumab versus 6 months (95% CI, 4.8) with chemotherapy (HR 0.27), and 6 months (95% CI, 4-7) with pembrolizumab versus 6 months (95% CI, 6-8) with chemotherapy (HR 1.0).

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), NR (95% CI, 23-NR) versus 8 months (95% CI, 5-NR) with KRAS G12C (HR 0.28), and 15 months (95% CI, 12-14) versus 12 months (95% CI, 11-18) with no KRAS mutation (HR 0.86).

Findings from the KEYNOTE-189 study

Dr. Delvys Rodriguez-Abreu of the Complejo Hospitalario Universitario Insular Materno-Infantil de Gran Canaria and Universidad de Las Palmas de Gran Canaria, Gran Canaria, Spain presented the findings on the prevalence of KRAS mutations and evaluation of the association with pembrolizumab efficacy from an exploratory analysis of the KEYNOTE-189 (NCT02578680) study of first-line treatment with pembrolizumab plus pemetrexed and platinum chemotherapy compared to placebo plus pemetrexed and platinum chemotherapy in patients with metastatic non-squamous NSCLC.

Using samples from patients having available tumour and matched-normal tissue, the investigators performed WES to determine the KRAS and TMB in patients with metastatic non-squamous 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 (47%) had evaluable WES data from both tumour and normal DNA, which established that 89 (31%) of patients had KRAS mutation, including 37 (13%) patients who were G12C carriers. Patients with KRAS mutations also had higher PD-L1 median TPS of 30% (IQR, 1-71] versus median 5% (IQR, 0-60) and higher median TMB of 204 mut/exome (IQR, 137-276) versus 141 mut/exome (IQR, 85-252) than patients without any KRAS mutation, respectively.

Responses were higher with pembrolizumab plus chemotherapy versus chemotherapy regardless of KRAS mutational status

Fifty-nine patients with any KRAS mutation treated with pembrolizumab plus chemotherapy had an ORR of 40.7% (95% CI, 28.1-54.3) versus 26.7% (95% CI, 12.3-45.9) in 30 patients treated with placebo/chemotherapy. In the group of patients with KRAS G12C mutation, 26 patients receiving pembrolizumab/chemotherapy demonstrated an ORR of 50.0% (95% CI, 29.9-70.1) versus 18.2% (95% CI, 2.3-51.8) in 11 patients on chemotherapy. It was noted that the confidence intervals were wide given the modest frequency of KRAS mutation, particularly KRAS G12C, and the 2:1 randomisation that resulted in small populations for placebo plus chemotherapy. In the patients without KRAS mutation, 145 patients receiving pembrolizumab/chemotherapy had ORR 47.6% (95% CI, 39.2-56.0) versus 10.9% (95% CI, 4.1-22.3) in 55 patients receiving chemotherapy.

Survival across the 3 mutational groups followed a similar pattern favouring pembrolizumab/chemotherapy in most mutational groups

Median PFS in patients with any KRAS mutation, KRAS G12C, and no KRAS mutation was 9 months (95% CI, 7-14) with pembrolizumab/chemotherapy versus 5 months  (95% CI, 5-9) with chemotherapy (HR 0.47), 11 months (95% CI, 6-18) with pembrolizumab/chemotherapy versus 5 months (95% CI, 5-NR) with chemotherapy (HR 0.48), and 9 months (95% CI, 7-14) with pembrolizumab/chemotherapy versus 5 months (95% CI, 4-5) with chemotherapy (HR 0.40).

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), 18 months (95% CI, 11-NR) versus 25 months (95% CI, 8-NR) with KRAS G12C (HR 1.14), and 23 months (95% CI, 19-NR) versus 9 months (95% CI, 7-17) in patients harbouring no KRAS mutation (HR 0.55).

Conclusions

Dr. Lopes concluded thatthe findings from the KEYNOTE-042 descriptive exploratory analysis suggest that pembrolizumab monotherapy should be considered as a standard first-line treatment option for patients with PD-L1-positive advanced NSCLC regardless of KRAS mutational status. A pembrolizumab-containing regimen is a clinically relevant comparator for studies of KRAS-targeted therapy administered as first-line treatment of NSCLC.

According to Dr. Rodriguez-Abreu, the descriptive exploratory analysis of the KEYNOTE-189 demonstrated that pembrolizumab plus chemotherapy comprising pemetrexed and a platinum should be a standard first-line treatment for patients with metastatic non-squamous NSCLC regardless of KRAS mutation status.

 

Disclosure

Both studies were funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. 

References

  • LBA4 - 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.
  • LBA5 – Gadgeel S, Rodriguez-Abreu D, Felip E, 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.

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