1374P - Survival and therapy analysis of small-scale ROS1-mutant non-small cell lung cancer (NSCLC) patients

Background

ROS1 fusions are well treatable aberrations in NSCLC. Besides solvent-front mutations (SFM) in resistance to targeted therapy, small-scale ROS1 mutations are largely unknown. We exploratively analyzed the clinicopathological characteristics, survival and therapy of small-scale ROS1 mutations in NSCLC patients without activating ROS1 fusions or SFMs.

Methods

Next-generation sequencing was performed on tissue samples from NSCLC patients within the Network Genomic Medicine. Patients with ROS1 fusions and SFMs were excluded. We analyzed the characteristics of the patients, their survival and their response to systemic therapy.

Results

Of 10,396 patients analyzed, 101 (1.0%) patients harbored small-scale ROS1 mutations. Most patients were male (73.3%) and smokers (96.6%). Nearly half of the patients presented with squamous-cell carcinoma (SqCC, 40.4%). Most mutations were transversions (50.5%), and 66% were in the kinase domain. Besides TP53 mutations (65.3%), KRAS (22.8%), EGFR (5.9%), PIK3CA (9.9%) and FGFR1-4 mutations (8.9%) co-occurred. In 10 (9.9%) patients, ROS1 mutation was the only aberration detected. The median overall survival (mOS) of all stage IV patients was 10.5 months and the survival differed significantly in patients with or without KRAS co-mutations (9.7 vs 21.5 months, p=0.02, HR 2.6, 95% CI: 1.1-5.9). Altough not significant, the most common KRAS mutation in this cohort G12V (n=7/17) worsened survival (4.4 versus 9.7 months). Patients significantly benefited from treatment with immune-checkpoint blockade (21.5 vs 4.4 months, p=0.003, HR 0.14, 95% CI: 0.03-0.6). KRAS co-mutant patients treated with ICB only had an mOS of 8 months. In three patients with co-occurring mutations, qualifying for and having received targeted therapy (2x EGFRmut, 1x MET fusion), mOS was 23.5 months (95% CI: NA).

Conclusions

The cohort’s clinical characteristics contrasted ROS1-fused cohorts. Co-occurrence of KRAS mutations led to shortened survival and patients benefited from ICB. Our data does not support the idea of ROS1 small-scale mutations as strong oncogenic drivers in NSCLC, but rather as relevant bystanders altering the efficacy of treatment approaches.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Matthias Scheffler.

Funding

German Cancer Aid (DKG).

Disclosure

L. Nogova: Financial Interests, Personal, Advisory Role: Pfizer. R.N. Fischer: Financial Interests, Personal, Advisory Role, finance of scientific research: MSD, BMS. S. Michels: Financial Interests, Personal, Funding: Novartis. R. Riedel: Financial Interests, Personal, Funding: Boehringer Ingelheim, Loxo Oncology, Novartis. R. Büttner: Financial Interests, Personal, Advisory Role, lecture fees and honoraria for SABs: AbbVie, Amgen, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Illumina, Janssen, Lilly, Merck-Serono, MSD, Novartis, Pfizer, Roche. J. Wolf: Financial Interests, Personal, Other, Honoraria: AbbVie. AstraZeneca, BMS, Boehringer Ingelheim, Chugai, Ignyta, Lilly, MSD, Novartis, Pfizer, Roche. M. Scheffler: Financial Interests, Personal, Advisory Role, honoraria: BMS, Boehringer Ingelheim, Takeda, Roche, Amgen, AstraZeneca. All other authors have declared no conflicts of interest.