PD-L1 expression, tumor mutational burden, and response to immunotherapy in patients with MET exon 14 altered lung cancers

Abstract

<div class="section"> <a class="named-anchor" id="s1"> <!-- named anchor --> </a> <h5 class="section-title" id="d776580e383">Background</h5> <p id="d776580e385"> <i>MET</i> exon 14 alterations are actionable oncogenic drivers. Durable responses to MET inhibitors are observed in patients with advanced <i>MET</i> exon 14-altered lung cancers in prospective trials. In contrast, the activity of immunotherapy, PD-L1 expression and tumor mutational burden (TMB) of these tumors and are not well characterized. </p> </div><div class="section"> <a class="named-anchor" id="s2"> <!-- named anchor --> </a> <h5 class="section-title" id="d776580e394">Patients and methods</h5> <p id="d776580e396">Patients with <i>MET</i> exon 14-altered lung cancers of any stage treated at two academic institutions were identified. A review of clinicopathologic and molecular features, and an analysis of response to single-agent or combination immune checkpoint inhibition were conducted. PD-L1 immunohistochemistry was carried out and TMB was calculated by estimation from targeted next-generation sequencing panels. </p> </div><div class="section"> <a class="named-anchor" id="s3"> <!-- named anchor --> </a> <h5 class="section-title" id="d776580e402">Results</h5> <p id="d776580e404">We identified 147 patients with <i>MET</i> exon 14-altered lung cancers. PD-L1 expression of 0%, 1%–49%, and ≥50% were 37%, 22%, and 41%, respectively, in 111 evaluable tumor samples. The median TMB of <i>MET</i> exon 14-altered lung cancers was lower than that of unselected non-small-cell lung cancers (NSCLCs) in both independently evaluated cohorts: 3.8 versus 5.7 mutations/megabase ( <i>P</i> &lt; 0.001, <i>n</i> = 78 versus 1769, cohort A), and 7.3 versus 11.8 mutations/megabase ( <i>P</i> &lt; 0.001, <i>n</i> = 62 versus 1100, cohort B). There was no association between PD-L1 expression and TMB (Spearman’s rho=0.18, <i>P </i>= <i> </i>0.069). In response-evaluable patients ( <i>n</i> = 24), the objective response rate was 17% (95% CI 6% to 36%) and the median progression-free survival was 1.9 months (95% CI 1.7–2.7). Responses were not enriched in tumors with PD-L1 expression ≥50% nor high TMB. </p> </div><div class="section"> <a class="named-anchor" id="s4"> <!-- named anchor --> </a> <h5 class="section-title" id="d776580e435">Conclusion</h5> <p id="d776580e437">A substantial proportion of <i>MET</i> exon 14-altered lung cancers express PD-L1, but the median TMB is lower compared with unselected NSCLCs. Occasional responses to PD-1 blockade can be achieved, but overall clinical efficacy is modest. </p> </div>