Associations of Tissue Tumor Mutational Burden and Mutational Status With Clinical Outcomes With Pembrolizumab Plus Chemotherapy Versus Chemotherapy For Metastatic NSCLC

Abstract

Introduction: We evaluated tissue tumor mutational burden (tTMB) and mutations in STK11, KEAP1, and KRAS as biomarkers for outcomes with pembrolizumab plus platinum-based chemotherapy (pembrolizumab-combination) for NSCLC among patients in the phase 3 KEYNOTE-189 (ClinicalTrials.gov, NCT02578680; nonsquamous) and KEYNOTE-407 (ClinicalTrials.gov, NCT02775435; squamous) trials.

Methods: This retrospective exploratory analysis evaluated prevalence of high tTMB and STK11, KEAP1, and KRAS mutations in patients enrolled in KEYNOTE-189 and KEYNOTE-407 and the relationship between these potential biomarkers and clinical outcomes. tTMB and STK11, KEAP1, and KRAS mutation status was assessed using whole-exome sequencing in patients with available tumor and matched normal DNA. The clinical utility of tTMB was assessed using a prespecified cutpoint of 175 mutations/exome.

Results: Among patients with evaluable data from whole-exome sequencing for evaluation of tTMB (KEYNOTE-189, n = 293; KEYNOTE-407, n = 312) and matched normal DNA, no association was found between continuous tTMB score and overall survival (OS) or progression-free survival for pembrolizumab-combination (Wald test, one-sided p > 0.05) or placebo-combination (Wald test, two-sided p > 0.05) in patients with squamous or nonsquamous histology. Pembrolizumab-combination improved outcomes for patients with tTMB greater than or equal to 175 compared with tTMB less than 175 mutations/exome in KEYNOTE-189 (OS, hazard ratio = 0.64 [95% confidence interval (CI): 0.38‒1.07] and 0.64 [95% CI: 0.42‒0.97], respectively) and KEYNOTE-407 (OS, hazard ratio = 0.74 [95% CI: 0.50‒1.08 and 0.86 [95% CI: 0.57‒1.28], respectively) versus placebo-combination. Treatment outcomes were similar regardless of KEAP1, STK11, or KRAS mutation status.

Conclusions: These findings support pembrolizumab-combination as first-line treatment in patients with metastatic NSCLC and do not suggest the utility of tTMB, STK11, KEAP1, or KRAS mutation status as a biomarker for this regimen.

Keywords: Biomarker; Metastatic non‒small-cell lung cancer; Pembrolizumab; Single-gene genetic alterations; Tissue tumor mutational burden.

Figure 1

Association of tTMB with efficacy outcomes in (A) and (B) KEYNOTE-189 and (C) and (D) KEYNOTE-407. In panels A and C, the graph illustrates the area under the ROC curve for ORR. Panels B and D provide p values for OS, PFS, and ORR in each respective study from logistic regression analysis. ^ap values were calculated using the Wald test and are one-sided for pembrolizumab-combination (a priori hypothesis that tTMB was positively associated with improved outcomes for pembrolizumab-combination) and two-sided for placebo-combination (no a priori hypothesis regarding the direction of the association between tTMB and outcomes) with significance level set at 0.05 and no multiplicity adjustment. tTMB was graphed on a log₁₀ scale for the ROC curve. AUC, area under the curve; CI, confidence interval; ORR, objective response rate; OS, overall survival; PD-L1, programmed death-ligand 1; PFS, progression-free survival; r, correlation coefficient; ROC, receiver operating characteristics; tTMB, tissue tumor mutational burden; TPS, tumor proportion score.

Figure 2

Clinical utility of tTMB for OS and PFS in each study at cutpoints of greater than or equal to 175 mut/exome and less than 175 mut/exome. Kaplan-Meier estimates of OS (A) and PFS (B) in KEYNOTE-189. Kaplan-Meier estimates of OS (C) and PFS (D) in KEYNOTE-407. Chemo, chemotherapy; CI, confidence interval; HR, hazard ratio; mut, mutation; NR, not reached; OS, overall survival; PFS, progression-free survival; tTMB, tissue tumor mutational burden.

Figure 3

Kaplan-Meier estimates of OS and PFS by STK11 status in the single-gene mutation-evaluable population in KEYNOTE-189. (A) OS and (B) PFS. Chemo, chemotherapy; CI, confidence interval; HR, hazard ratio; mut, mutation; NR, not reached; OS, overall survival; mut, mutation; Pembro, pembrolizumab; PFS, progression-free survival; wt, wild-type.

Figure 4

Kaplan-Meier estimates of OS and PFS by KEAP1 status in the single-gene mutation-evaluable populations. OS in (A) KEYNOTE-189 and (B) KEYNOTE-407. PFS in (C) KEYNOTE-189 and (D) KEYNOTE-407. Chemo, chemotherapy; CI, confidence interval; HR, hazard ratio; mut, mutation; NR, not reached; OS, overall survival; Pembro, pembrolizumab; PFS, progression-free survival; wt, wild-type.

Figure 5

Kaplan-Meier estimates of OS and PFS by KRAS status in the single-gene mutation-evaluable population in KEYNOTE-189. (A) OS and (B) PFS. Chemo, chemotherapy; CI, confidence interval; HR, hazard ratio; mut, mutation; NR, not reached; OS, overall survival; Pembro, pembrolizumab; PFS, progression-free survival; wt, wild-type.