Baseline Plasma Tumor Mutation Burden Predicts Response to Pembrolizumab-based Therapy in Patients with Metastatic Non-Small Cell Lung Cancer

Abstract

Purpose: The role of plasma-based tumor mutation burden (pTMB) in predicting response to pembrolizumab-based first-line standard-of-care therapy for metastatic non-small cell lung cancer (mNSCLC) has not been explored.

Experimental design: A 500-gene next-generation sequencing panel was used to assess pTMB. Sixty-six patients with newly diagnosed mNSCLC starting first-line pembrolizumab-based therapy, either alone or in combination with chemotherapy, were enrolled (Clinicaltrial.gov identifier: NCT03047616). Response was assessed using RECIST 1.1. Associations were made for patient characteristics, 6-month durable clinical benefit (DCB), progression-free survival (PFS), and overall survival (OS).

Results: Of 66 patients, 52 (78.8%) were pTMB-evaluable. Median pTMB was 16.8 mutations per megabase (mut/Mb; range, 1.9-52.5) and was significantly higher for patients achieving DCB compared with no durable benefit (21.3 mut/Mb vs. 12.4 mut/Mb, P = 0.003). For patients with pTMB ≥ 16 mut/Mb, median PFS was 14.1 versus 4.7 months for patients with pTMB < 16 mut/Mb [HR, 0.30 (0.16-0.60); P < 0.001]. Median OS for patients with pTMB ≥ 16 was not reached versus 8.8 months for patients with pTMB < 16 mut/Mb [HR, 0.48 (0.22-1.03); P = 0.061]. Mutations in ERBB2 exon 20, STK11, KEAP1, or PTEN were more common in patients with no DCB. A combination of pTMB ≥ 16 and absence of negative predictor mutations was associated with PFS [HR, 0.24 (0.11-0.49); P < 0.001] and OS [HR, 0.31 (0.13-0.74); P = 0.009].

Conclusions: pTMB ≥ 16 mut/Mb is associated with improved PFS after first-line standard-of-care pembrolizumab-based therapy in mNSCLC. STK11/KEAP1/PTEN and ERBB2 mutations may help identify pTMB-high patients unlikely to respond. These results should be validated in larger prospective studies.

Figure 1.. pTMB and response to pembrolizumab.

A) 45 RECIST-evaluable patients (21 P and 24 PC) at week-9 on therapy were categorized as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD), and pTMB levels assessed. B) 52 RECIST-evaluable patients (26 P and 26 PC) at month-6 on therapy were categorized as durable clinical benefit (DCB; CR, PR, or SD as of 6 months) or no durable benefit (progressive disease; NDB). Horizontal lines indicate median values. C) Kaplan-Meier survival curves using a cutoff of 16 mut/Mb for PFS (above) and OS (below) for 52 pTMB-evaluable patients (26 P and 26 PC). Left panel is all patients, middle includes patients who received P, and right panel includes patients who received PC.

Figure 2.. Mutational analysis and response to pembrolizumab

A) pTMB scores are represented by the height of the bars (red = pTMB≥16 mut/Mb, blue = pTMB<16) and arranged in decreasing order with 29 patients who achieved a durable clinical benefit (left) and 23 patients with no durable benefit (right). Yellow horizontal line indicates pTMB=16 mut/Mb. Rows indicate: pembrolizumab cohort with P in green and PC in yellow, PD-L1 ≥50% patients in purple, patients with a negative predictor mutation in ERBB2, STK11, KEAP1, or PTEN in orange, KRAS or PIK3CA mutations in pink, and fraction genome aneuploidy (FGA; analyzed as a continuous variable) in blue (with lighter blue = lower FGA, darker blue = higher FGA). For negative predictor mutations, capital letter indicates specific mutation detected. B) Forest plots (above) and Kaplan-Meier survival curves (below) for PFS and OS. For the forest plots, black indicates the hazard ratio and 95% confidence interval for pTMB alone, and grey indicates results for pTMB and negative predictors.