Clinical and molecular features of long-term response to anti-PD-(L)1 therapy in patients with advanced non-small cell lung cancer.
Authors: Thummalapalli Rohit , Ricciuti Biagio , Bandlamudi Chaitanya , Muldoon Daniel , Luo Jia , Alessi Joao Victor Machado , Pecci Federica , Lamberti Giuseppe , Hong Lingzhi , Plodkowski Andrew J. , Ladanyi Marc , Chaft Jamie E. , Rudin Charles M. , Kris Mark G. , Riely Gregory J. , Vokes Natalie I , Awad Mark M. , Schoenfeld Adam Jacob 
Published: June 2023

9107

Background: PD-(L)1 blockade can generate long-term responses in subsets of patients (pts) with advanced non-small cell lung cancer (NSCLC), but the clinical and molecular features of long-term responders (LTR) are not well established. Whereas features predictive of initial response have been rigorously explored, long-term follow up in large cohorts is required to identify features distinguishing LTR from short-term responders (STR). Methods: We analyzed pts with advanced NSCLC treated with anti-PD-(L)1 therapy at three institutions (MSK, DFCI, MDACC) between 2011 and 2022; responses were assessed by RECIST. LTR was defined as partial response (PR) or complete response (CR) ≥ 24 months; STR was defined as PR/CR < 12 months followed by progressive disease (PD). PD-L1 IHC, tumor mutational burden (TMB), next generation sequencing (NGS), and whole exome sequencing (WES) results from subsets of pts were analyzed. High TMB was defined by harmonized TMB z-score ≥ 0 (≥ median TMB in each cohort: ≥ 7.9 for MSK, ≥ 10.5 for DFCI). Results: Among 3240 pts overall (MSK = 1536, DFCI = 1238, MDACC = 466), LTR was achieved in 267 (8.2%, 95% CI 7.3 to 9.2%) and STR was achieved in 213 (6.6%, 95% CI 5.7 to 7.5%), with similar rates from each site. 5-year overall survival (OS) was 83% among LTR and 20% among STR. In univariate analyses, non-squamous histology (non-SQ: odds ratio [OR] 2.13, p = 0.005), peripheral blood derived neutrophil to lymphocyte ratio (dNLR) < 3.0 (OR 2.15, p < 0.001), and high TMB (OR 2.25, p = 0.001) were associated with LTR compared to STR; high PD-L1 (PD-L1 ≥ 50%: OR 1.19, p = 0.494) was not. In multivariate analyses, non-SQ histology (OR 2.56, p = 0.047) and high TMB (OR 2.73, p = 0.001) remained independently associated with LTR over STR. Among LTR compared to patients with best response of PD, dNLR < 3.0 (OR 1.72, p = 0.030), high PD-L1 (OR 5.23, p < 0.001), and high TMB (OR 2.55, p = 0.001) associated with LTR. LTR showed deeper radiographic responses compared to STR (best response of -50% or greater: OR 3.88, p < 0.01). Among 1798 pts with NGS, pathogenic ARID1A alterations were numerically higher among LTR compared to STR, but this was not significant when accounting for multiple hypothesis testing (14% vs 2%, p = 0.022, q = 0.196). Among 73 pts with available WES, both clonal (p = 0.037) and subclonal TMB (p = 0.010) were significantly higher among LTR compared to STR. Conclusions: We report outcomes from > 10 years of advanced NSCLC pts treated with anti-PD(L)1 therapy in a large multicenter cohort, with ongoing response at 2 years associated with > 80% 5-year OS. High TMB was a strong independent predictor of LTR over STR. Non-squamous histology, low dNLR, and depth of response also correlate with LTR, while no individual genomic alterations clearly distinguish LTR. These features may assist in identifying pts more likely to derive durable benefit from anti-PD(L)1 therapy without treatment intensification.