1699 - Pan-cancer analysis of clinical acquired resistance (AR) in BRAF-driven real-world cases

Background

BRAF genomic alterations (GA) occur in multiple tumor types and BRAF/MEK targeted therapies are approved in melanoma and NSCLC. Diverse mechanisms of AR to these therapies have been proposed but have not been comprehensively assessed.

Methods

Hybrid-capture based comprehensive genomic profiling (CGP) was performed on FFPE (n = 228,629) or blood-based cell free DNA (cfDNA, n = 15,069) samples for 222,952 patients (pts). Tumor mutational burden (TMB) was determined on 0.8-1.1 Mbp of sequenced DNA. Samples without evidence of tumor DNA or known to have not received RAF/MEK inhibitors were excluded. Paired samples were collected >60 days apart (median 523, range 71-5571).

Results

Paired samples with BRAF V600E (64%) or other activating BRAF GA (36%) were available for 154 pts with NSCLC (20%), melanoma (19%), CRC (15%) myeloma (8.4%) glioma (7.1%) or other (30%) cancers. Acquired GA previously described preclinically or clinically including in BRAF, KRAS, NRAS, MEK1, PIK3CA, PTEN, MET, and CCND1 occurred in 34 cases (Table). 56 additional cases had reportable acquired GA in other genes (eg. STK11, NF1). Median TMB was 4.0 vs 5.2 mut/Mb in the first vs second sample (p = 0.23). In 12% of cases (9 tissue, 9 cfDNA) a BRAF GA was not detected in the second sample. Most AR mechanisms (MET amp, KRAS mut, secondary BRAF GA) were tumor agnostic, but PIK3CA and PTEN GA were enriched in brain samples and absent in CRC, and NRAS mut were exclusive to melanoma (Table). Treatment status was available for a subset of cases. Notably V600E CRC, NSCLC and melanoma each had acquired MET amp post-dabrafenib + trametinib, and a V600E myeloma had acquired MEK C121S post-trametinib + vemurafenib. Additional clinical data will be presented.Table: 1878PD

Indicated for tissue samples only (NA= not applicable); ^#5 cases had AR alterations in multiple genes included here; NSCLC: non-small cell lung cancer, CRC: colorectal carcinoma; CLL: chronic lymphocytic leukemia; UP: unknown primary; AR: acquired resistance; mut: mutation; amp: amplification.

Conclusions

Novel and previously observed potential AR alterations in paired BRAF altered clinical samples were detected using CGP. Most AR mechanisms appeared independent of tumor type and biopsy site. Additional clinical studies to explore effective treatments for these AR subsets are needed.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Foundation Medicine.

Disclosure

F. Pietrantonio: Advisory / Consultancy: Roche; Advisory / Consultancy: Amgen; Advisory / Consultancy: Eli-Lily; Advisory / Consultancy: Bayer; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Servier; Advisory / Consultancy: Merck Serono. J. Lee: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine; Shareholder / Stockholder / Stock options: Roche. L. Boussemart: Advisory / Consultancy: Novartis; Advisory / Consultancy: Pierre Fabre. G. Srkalovic: Speaker Bureau / Expert testimony: Foundation Medicine. R. Madison: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine; Shareholder / Stockholder / Stock options: Roche. J.S. Ross: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine; Shareholder / Stockholder / Stock options: Roche. V.A. Miller: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine; Shareholder / Stockholder / Stock options: Roche; Advisory / Consultancy: Revolution Medicines. B.M. Alexander: Leadership role, Full / Part-time employment: Foundation Medicine; Shareholder / Stockholder / Stock options: Roche. S.M. Ali: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine; Shareholder / Stockholder / Stock options: Roche. A.B. Schrock: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine; Shareholder / Stockholder / Stock options: Roche. All other authors have declared no conflicts of interest.