1212PD - Lung sarcomatoid carcinoma (LSC) harbors targetable genomic alterations and high mutational burden as observed by comprehensive genomic profiling (...

Date 09 October 2016
Event ESMO 2016 Congress
Session NSCLC, metastatic
Topics Translational Research
Non-small-cell lung cancer
Basic Principles in the Management and Treatment (of cancer)
Presenter Balazs Halmos
Citation Annals of Oncology (2016) 27 (6): 416-454. 10.1093/annonc/mdw383
Authors B. Halmos1, D.A. Fabrizio2, J. Suh3, E. Braun4, R. Mehra5, S. Buck6, J.A. Bufill4, N. Peled7, N.A. Karim8, P. Fishkin9, J. Knost9, S.I. Ou10, J.S. Ross11, P.J. Stephens12, V.A. Miller13, S.M. Ali13, A.B. Schrock13
  • 1Oncology, Montefiore Medical Center, 10461 - New York/US
  • 2Bioinformatics, Foundation Medicine, Inc., Cambridge/US
  • 3Pathology, Foundation Medicine, Inc., 02141 - Cambridge/US
  • 4Michiana, Hematology-Oncology, Mishawaka/US
  • 5Oncology, Fox Chase Cancer Center, Philadelphia/US
  • 6Medical Oncology, Tulsa Cancer Institute, Tulsa/US
  • 7Thoracic Cancer Unit, Davidoff Cancer Center, Petach Tiqwa/IL
  • 8Division Of Hematology/oncology, The University of Cincinnati, Cincinnati/US
  • 9Medical Oncology, Illinois Cancer Care, Peoria/US
  • 10Department Of Medicine, Division Of Hematology Oncology, UC Irvine School of Medicine, Irvine/US
  • 11Pathology, Foundation Medicine, Inc., Cambridge/US
  • 12Clinical Genomics, Foundation Medicine, Inc., Cambridge/US
  • 13Clinical Development, Foundation Medicine, Inc., Cambridge/US

Abstract

Background

LSC is a rare, clinically aggressive, heterogeneous and poorly differentiated subtype of non-small cell lung cancer (NSCLC), which is typically difficult to diagnose and resistant to conventional therapies. We queried whether CGP could guide LSC patients to novel targeted therapies.

Methods

Hybrid-capture based CGP was performed on 6,923 consecutive FFPE NSCLCs during the course of clinical care and 91 (1.3%) LSCs were identified.

Results

In this series the median age was 67 years (range 32-86), 59% were male, and 82% of tumors were stage 4. Overall, 57% of cases involved a genomic alteration (GA) in KRAS (34%) or one of 7 genes now recommended for testing in the NSCLC NCCN guidelines including: MET (8.8%), BRAF (7.7%), EGFR (6.6%), ERBB2 (2.2%) or RET (1.1%). No alterations were detected in ALK or ROS1. BRAF alterations included amplification and mutation at V600 or G469. EGFR alterations included amplification, exon 19 deletion, exon 20 insertion, and activating L858R mutation. Notably, MET exon 14 skipping alterations were enriched in this series (7/91, 7.7%) compared to non-LSC NSCLCs (2.8%). In 39 cases that were wild-type for the 7 NCCN genes and KRAS, potentially actionable GAs were most commonly detected in PTEN (10.3%), PIK3CA (7.7%), FGFR1 (7.7%), and PDGFRA (7.7%). Median tumor mutation burden (TMB) was 8 mutations/megabase (range: 0-165, mean: 14), and 21% (19/91) of cases had high TMB ≥ 20. Clinical outcomes were available for a subset of patients and we report clinical benefit in 4 LSC patients treated with targeted therapy whose tumors harbored alterations in MET, BRAF, and EGFR, as well as an ongoing response to anti-PD-1 therapy in one patient with TMB = 31.

Conclusions

Targetable GAs, including MET exon 14 alterations, were found in a majority of LSC patients, some of which occur at greater frequency than that observed in non-LSC NSCLCs. An important portion of LSC cases had high TMB, which has been associated with increased likelihood of response to immunotherapy. Thus, CGP can lead to selection of appropriate targeted therapies in this population of patients, which has historically been poorly characterized and difficult to treat.

Clinical trial identification

Legal entity responsible for the study

Foundation Medicine

Funding

Foundation Medicine

Disclosure

G.M. Frampton, J. Suh, J.S. Ross, P.J. Stephens, V.A. Miller, S.M. Ali, A.B. Schrock: is an employee and has stock ownership in Foundation Medicine. S-H.I. Ou: has received honoraria as an advisory board and speaker bureau member for Boehringer Ingelheim. All other authors have declared no conflicts of interest.