Immunotherapy and chemo-immunotherapy for non–small cell lung cancer with novel actionable oncogenic driver alterations.

Background: Immune checkpoint inhibitors (IO) single agent or in combination with platinum chemotherapy (CT-IO) are standard of care for Stage IV non-small cell lung cancer (NSCLC) according to PD-L1 expression. While the efficacy of IO among patients (pts) with common EGFR and ALK alterations appears to be limited, its activity in pts with novel oncogenic drivers alterations is not well characterized. Compared to non-oncogene-addicted NSCLC, the overall response rate (ORR) seems to be similar in BRAF and c-MET altered NSCLC, lower in RET altered NSCLC, while data are less consistent in HER2 and EGFR exon 20 (EGFRex20) altered NSCLCs. Methods: From January 2016 to January 2022, we retrospectively enrolled pts with Stage IV NSCLC that received IO or combination CT– IO in any line, ECOG PS 0 - 2 and detection of MET exon 14 skipping mutations (METex14), BRAF mutations (V600E or non-V600E), RET rearrangement, HER2 point mutations (HER2mut)/exon 20 insertions (HER2ex20) or uncommon EGFR mutations (uEGFRmut)/EGFRex20. A review of clinicopathologic and molecular features and an analysis of response to combination or single-agent IO were conducted. Results: Among sixty-four pts enrolled, 20 (31%) had METex14, 19 (30%) had EGFR alterations [12 (19%) EGFRex20, 7 (11%) uEGFRmut], 8 (12%) had BRAF mutation (3 V600E and 5 non-V600E), 13(20%) had HER2 alterations [7 (11%) HER2ex20, 6 (10%) HER2mut] and 4 (6%) were RET rearranged. 43 received IO single agent and 21 received CT-IO. With a median follow up of 22 months (m), median progression free survival (mPFS) was 5.40 m (0.95 CI 4.73-6.9) overall, 6.77m in CT-IO arm (0.95 CI 5.37-NA) and 5.10m in IO arm (0.95 CI 2.60-6.7), with a trend to better mPFS for CT-IO (p 0.054). Regarding specific mutations irrespectively from treatment arm, NSCLC harboring METex14 showed a mPFS of 5.33 m (0.95 CI, 2.30-13.9), BRAF 9.9 m (0.95 CI, 6.70-NA), EGFR 4.93 m (0.95 CI, 1.80-6.9), HER2 11.4 (0.95 CI, 4.2-NA), RET 5.28 (0.95 CI, 1.42-NA). Disease control rate (DCR) was better in the CT-IO arm vs IO one in the overall population (84.2% vs 50%, p 0.013). Conclusions: Novel driver alterations seem to show a benefit from IO treatments. CT-IO seems to have a better outcome in terms of DCR. Therefore, IO-based treatment should be evaluated also in tumors harboring novel driver alterations