Efficacy of immunotherapy in lung cancer with co-occurring mutations in NOTCH and homologous repair genes.

BACKGROUND

Immune checkpoint inhibitors (ICIs) provide significant survival benefits in non-small cell lung cancer (NSCLC). Nevertheless, while some patients obtain a prolonged benefit, a non-negligible fraction of patients experiences an ultrarapid disease progression. Identifying specific molecular backgrounds predicting opposite outcomes is instrumental to optimize the use of these agents in clinical practice.

METHODS

We carried out an observational study with prospective design envisioning targeted next-generation sequencing (NGS) with an approved assay in 55 patients with metastatic NSCLC (Rome cohort), of whom 35 were treated with ICIs. Data from three clinically comparable datasets were collected and combined into a metadataset containing 779 patients. The datasets were related to the Memorial Sloan Kettering Cancer Center (MSKCC) cohort (tissue-based NGS) and the randomized phase II and III POPLAR and OAK trials (blood-based NGS).

RESULTS

In patients treated with ICIs in the Rome cohort, co-occurring mutations in NOTCH1-3 and homologous repair (HR) genes were associated with durable clinical benefit. Using the MSKCC/POPLAR/OAK metadaset, we confirmed the relationship between the NOTCH

CONCLUSIONS

Co-occurring mutations in the NOTCH and HR pathways are associated with increased efficacy of immunotherapy in advanced NSCLC. This genomic predictor deserves further investigation to fully assess its potential in informing therapeutic decisions.

Informations de copyright

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Déclaration de conflit d'intérêts

Competing interests: MM, MF, MO, DM, SS, IT, FS, MP, FR, AG, AB, GS, ADN, EK, MB, SC, MF, FDN, LC, FG, AV, GC, PM and MM-S declare no conflicts of interest. LP received travel grants from Eisai, Roche, Pfizer, Novartis; speaker fees from Roche, Pfizer, Novartis, Gentili. PV received travel grants from Eisai, Roche, Pfizer, Novartis; speaker fees/advisory boards from Roche, Pfizer, Novartis, Gentili. RDM declares to be a scientific advisory board member at ExosomicsSpA (Siena IT), Hibercell Inc. (New York, New York USA), Kiromic Inc. (Houston, Texas, USA) and at Exiris Inc. (Rome, Italy). RG received advisory boards/honoraria/speakers’ fee from AstraZeneca and Roche.