6MO - Pan-cancer characterization of Receptor Tyrosine Kinases alterations to sort targetable drivers from passengers.

Background

Receptor tyrosine kinases (RTK) or ligands have frequent genetic alterations in cancers. Either amplifications, missense mutations or fusions of RTK are biomarkers for some targeted therapies in a fraction of cancers, with heterogeneous responses to tyrosine kinase inhibitors (TKI), monoclonal antibodies (mabs) or andibody-drug conjugates (ADC).

Methods

An analysis of pan-cancer molecular and clinical outcome in RTK-altered cancers was conducted for 16 selected targetable RTK (EGFR, HER2, KIT, FLT3, TRKA-B-C, ROS1, ALK, RET, MET, and FGFR1-2-3-4). The molecular landscape of RTK-altered cancers was analyzed in pan-cancer public databases (MSK-impact / MSK-MET-Tropism) and institutional databases (DNA-targeted sequencing in PROFILER, PROFILER-2 (NCT03163732), RNA-seq FFPE database). The clinical profile and therapeutic activity of TKI, mabs, ADC monotherapy in genomic-driven clinical trials was analyzed through a systematic review of phase I-II-III studies published up to January 2022. Clinical efficacy of the best quality trials across cancer types, with efficacy defined as n>5 patients objective response rate (ORR) of 30% and/or median progression free survival (PFS) >6months.

Results

RTK-alterations encompass a variety of situations since only 2% (19/884) of cancers have a \"frequent” (prevalence >10%) RTK-alteration. On the whole, clinical efficacy of TKI-targeting strategies in RTK-altered cancers is not associated with RTK prevalence, but is shaped by the type of RTK-alterations (Table) and molecular co-alterations. Some of the main clinical and molecular characteristics of RTK-alterations in cancers are summarized in the table. The type of RTK-alterations have also variable genomic background in term of tumor mutation count, tumor mutational burden, tumor fusion burden, fraction genome altered. Mutual exclusivity was found statistically significant only in RTK-translocations and mutations of EGFR with KIT and FGFR3. Most of RTK copy number variations are co-occurrent. Despite strong clinical benefit a few number of RTK-translocations with atypical partners and/or underlying genomic instability challenge the notion of histology-agnosticism of RTK-translocations. Table: 6MO

Conclusions

These analyses reveal the wide heterogeneity of RTK alterations pan-cancer defining clinical and genomic biomarkers to select patient for targeted therapies for unlabeled rare tumors/alterations. Single agent TKI may be proposed 1) fusions of RTK with expressed partner and few other genetic alterations 2) activating missense mutations in RTK involved in normal cell lineage physiology. ADC or mab+chemo may be preferred for amplifications.

Clinical trial identification

Soma data analyzed here provide from: 1) Public database from MSK-IMPACT trial (NCT03208374); 2) Institutional database from PROFILER (NCT01774409) and PROFILER 02 (NCT03163732) clinical trials.

Legal entity responsible for the study

The authors.

Funding

Funding of PROFILER and PROFILER 02 trials: partial funding by Roche, Fone panels (Fone or CDX) were performed by Foundation Medicine free of charge the Integrated Cancer Research Site LYriCAN (INCa-DGOS-Inserm_12563), NetSARC (INCA & DGOS), InterSARC (INCA), LabEx DEvweCAN (ANR-10-LABX 0061), PIA Institut Convergence Francois Rabelais PLAsCAN (PLASCAN, 17-CONV-0002), Fondation ARC contre le Cancer, La Ligue contre le Cancer (Canopée), and EURACAN (EC 739521).

Disclosure

M. Brahmi: Financial Interests, Institutional, Research Grant: Bayer, GSK. A. Dufresne: Financial Interests, Institutional, Principal Investigator: GSK, Bayer. P. Cassier: Financial Interests, Personal, Expert Testimony: Itéos, Amgen, Janssen; Non-Financial Interests, Personal, Advisory Role: OSE Immunotherapeutics; Financial Interests, Institutional, Research Grant: Bayer, GSK, Janssen, Lilly, AstraZeneca, Roche, Merck Serono, Toray industries, Novartis, Bristol Myers Squibb, Innate, Loxo, Blueprint, Celgene, AbbVie, Merck Sharp & Dohme. O. Tredan: Financial Interests, Institutional, Research Grant: BMS, MSD; Financial Interests, Personal, Expert Testimony: Roche, Pfizer, Novartis-Sandoz, Lilly, AstraZeneca, Pierre Fabre, Seagen, Daiichi Sankyo, Gilead, Eisai, Stemline. J. Blay: Financial Interests, Personal, Expert Testimony: GSK, AstraZeneca, Bayer, Novartis; Financial Interests, Institutional, Research Grant: GSK, AstraZeneca, Bayer, Novartis. All other authors have declared no conflicts of interest.