Rare targetable drivers (RTDs) in non-small cell lung cancer (NSCLC): Outcomes with immune check-point inhibitors (ICPi)

Elizabeth Dudnik*, Elias Bshara, Ahuva Grubstein, Ludmila Fridel, Tzippy Shochat, Laila C. Roisman, Maya Ilouze, Anna Belilovski Rozenblum, Smadar Geva, Alona Zer, Ofer Rotem, Aaron M. Allen, Nir Peled

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Objectives: Efficacy of immune check-point inhibitors (ICPi) in NSCLC with rare targetable drivers (RTDs) is largely unknown. Materials and Methods: Consecutive patients with NSCLC and RTDs (non-EGFR/ALK, n-82) were selected from the Davidoff Cancer Center database. ORR, PFS, OS with ICPi, OS since advanced disease diagnosis, TMB, MSI, and PD-L1 expression were analyzed; uni- and multivariate PFS and OS analyses were done. OS with ICPi was compared between the RTD cohort and the non-selected NSCLC cohort (n-278). Results: Of 50 tumors tested, 32%, 38%, and 30% were associated with ≥50%, 1–49% and <1% PD-L1 expression, respectively. Median TMB (n-48) comprised 4 muts/Mb (0–57); TMB ≥ 10 muts/Mb was seen in 19% of tumors. Both TMB and PD-L1 expression varied across different RTDs. All the 47 tumors were MSI stable. ORR with ICPi (n-44) was 16%, median PFS was 3.2 months (95% CI, 2.6–5.0), median OS was 16.2 months (95% CI, 8.4-NR). No correlation was seen between OS with ICPi and PD-L1 expression (p > 0.4), TMB (p > 0.8), or RTD type (p > 0.3). In the multivariate analysis, ECOG PS (p-0.005), targeted agents exposure (p-0.005), and ICPi exposure (p-0.04) were the only variables which correlated with OS since advanced disease diagnosis. Median OS since advanced disease diagnosis comprised 32 months (95% CI, 19.9–44.9) and 13 months (95% CI, 6.6–15.9) for patients who were and were not exposed to ICPi, respectively (log-rank test-6.3; p-0.01). In the inter-cohort comparison, for patients matched for ECOG PS (0/1), median OS with ICPi comprised 17.5 months (95% CI, 8.1-NR) and 8.6 months (95% CI, 6.7-NR) for RTD and non-selected patients, respectively (log-rank test-2.4, p-0.1). Conclusion: In NSCLC with RTD, ICPi have favorable efficacy and independent impact on OS. NSCLC with RTD is associated with MSI stable status and variable levels of PD-L1 expression and TMB; their predictive value remains to be determined.

Original languageEnglish
Pages (from-to)117-124
Number of pages8
JournalLung Cancer
StatePublished - Oct 2018


FundersFunder number
Boehringer Ingelheim


    • Immunotherapy
    • Lung cancer
    • Mutation
    • PD-1
    • PD-L1
    • Tumor mutational burden


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