Response and durability of anti-PD-(L)1 therapy in never- or light-smokers with non-small cell lung cancer (NSCLC) and high PD-L1 expression.

Immunotherapy in non-small cell lung cancer harbouring driver mutations

“…Lung cancer in never or minimal smokers is generally associated with a low TMB, which results in a lack of immunogenic neo-antigens, and thus a non-inflamed ("excluded") microenvironment [13,75]. This is a possible explanation for the more favourable outcomes observed in the KRAS, BRAF non-V600E, and even MET exon14 altered NSCLC patients, as these oncogenes are more frequently observed in smokers.…”

Immunotherapy for oncogenic-driven advanced non-small cell lung cancers: Is the time ripe for a change?

“…Therefore, TMB should be prospectively validated in a large cohort. Of note, oncogenic addicted tumors are usually correlated with a non-or light-smoking habit, and a recent cohort of advanced NSCLC patients reported no significant differences in PD-L1 expression but significant higher TMB in smoker patients compared to light/never-smoker (8.5 Mut/Mb vs. 4.1 Mut/Mb, p = 0.002), respectively, and TMB [30]. This low TMB is especially significant among the oncogenic alterations strongly related with never-smoker habit such as EGFR mutation and ALK rearrangements [31].…”

“…In another smaller cohort of 52 never or light-smoking NSCLC patients (21% KRAS, 12% EGFR, 7% BRAF, and RET/HER2/MET, each 4%), with high PD-L1 expression (≥50% by E1L3N), all treated with anti-PD(L)1 in first-(63%), second-(21%) or ≥third-line (15%), the efficacy measured by RR was 26% with a median duration of response (DoR) of 5.6 months and median PFS and OS of 3.0 and 16.4 months, respectively [30]. Currently, ongoing clinical trials are exploring the use of combination strategies (tyrosine kinase inhibitors or chemotherapy and ICI) in oncogenic-addicted NSCLC patients.…”