Abstract 891P
Background
Patients (pts) with advanced HNSCC have an impaired prognosis and often lack specific targets. GA in NOTCH1 have now emerged as targets of novel anti-NOTCH pathway drugs and may impact sensitivity to radio-/chemotherapy or immune checkpoint inhibition (ICPI).
Methods
2,562 pts with clinically advanced and refractory HNSCC underwent comprehensive genomic profiling (CGP) using a hybrid capture based assay (F1CDx). Tumor mutational burden (TMB) and microsatellite instability (MSI) were determined as described. PD-L1 expression in tumor cells (Dako 22C3) was measured by IHC. NOTCH1 mutations were also determined in 220 T-ALL pts by the F1heme test.
Results
426 (16.6%) of the HNSCC pts featured NOTCH1 GA (NOTCH1 mut+) and 2,136 (83.4%) were NOTCH1 WT (NOTCH1 mut-) – compared to 121 mut+ pts (55%) in T-ALL pts. Among T-ALL and HNSCC pts, prevalence of NOTCH1 truncations (7% vs. 1%) and splice site mutations (0 vs. 13%) was significantly different. Three-fourths of HNSCC pts were male gender in both groups. The NOTCH1 mut+ pts were older (P<.0001) and had a higher GA/tumor ratio (P<.0001). At 29% HPV16 DNA was identified more in NOTCH1 mut- than the 15% in NOTCH1 mut+ (P<.0001). NOTCH2 and TERT GA as well as cell cycle regulatory gene inactivations (TP53, CDKN2A) were more common in NOTCH1 mut+ pts (P<.0001). MTOR pathway GA were similar, but PIK3CA GA were more frequent in NOTCH1 mut- pts (P=.03). Targetable kinase GA (EGFR, ERBB2) and MSI High status were infrequent and similar in both groups. The mean TMB was significantly higher in the NOTCH1 mut+ pts as was the frequencies of TMB >10 and >20 mut/Mb (all P<.0001). PD-L1 IHC staining was similarly frequent in both groups. GA reported to predict efficacy (CD274 and PBRM1) and resistance (STK11, MDM2) to ICPI were 3% or lower and similar in both groups.
Conclusions
NOTCH1 GA are associated with significant differences in the genomic landscape of advanced HNSCC pts with less frequent HPV16 positive tumors having higher GA/tumor, more cell cycle disruption and higher TMB. Given the prognostic und predictive potential in particular to ICPI and targeted therapy, advancement of clinical trials appears warranted.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Foundation Medicine Inc.
Disclosure
N.A. Danziger: Financial Interests, Personal, Full or part-time Employment: Foundation Medicine Inc.; Financial Interests, Personal, Stocks/Shares: F. Hoffman La-Roche Ltd. A. Necchi: Financial Interests, Personal, Research Grant: Merck Sharp & Dohme; Financial Interests, Personal, Advisory Role, Consulting fees: Roche; Financial Interests, Personal, Advisory Role, Consulting fees: AstraZeneca; Financial Interests, Personal, Advisory Role, Consulting fees: Bayer; Financial Interests, Personal, Research Grant: Millenium Pharmaceuticals; Financial Interests, Personal, Research Grant: Amgen; Financial Interests, Personal, Research Grant: Novartis Pharmaceuticals; Financial Interests, Personal, Advisory Role, Consulting fees: Merck Sharp & Dohme; Financial Interests, Personal, Research Grant: AstraZeneca. P.E. Spiess: Non-Financial Interests, Personal, Leadership Role: NCCN Panel on bladder and penile cancer; Non-Financial Interests, Personal, Leadership Role: Global Society of Rare GU Tumors. P. Grivas: Financial Interests, Personal, Other, Consulting fees: Bristol-Myers Squibb; Financial Interests, Institutional, Research Grant: Bristol-Myers Squibb; Financial Interests, Personal, Other, Consulting fees: AstraZeneca; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Personal, Other, Consulting fees: Clovis Oncology; Financial Interests, Institutional, Research Grant: Clovis Oncology; Financial Interests, Institutional, Research Grant: Bavarian Nordic; Financial Interests, Institutional, Research Grant: Debiopharm; Financial Interests, Institutional, Research Grant: Immunomedics; Financial Interests, Institutional, Research Grant: OncoGenex Pharmaceuticals; Financial Interests, Personal, Other, Consulting fees: Bayer; Financial Interests, Personal, Other, Consulting fees: GlaxoSmithKline; Financial Interests, Personal, Other, Consulting fees: Merck; Financial Interests, Personal, Other, Consulting fees: Mirati; Financial Interests, Personal, Other, Consulting fees: Pfizer; Financial Interests, Personal, Other, Consulting fees: QED therapeutics; Financial Interests, Institutional, Research Grant: Bayer; Financial Interests, Institutional, Research Grant: GlaxoSmithKline; Financial Interests, Institutional, Research Grant: Merck; Financial Interests, Institutional, Research Grant: Mirati; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Research Grant: QED therapeutics; Financial Interests, Personal, Other, consulting fees: EMD Serono; Financial Interests, Personal, Other, consulting fees: Exelixis; Financial Interests, Personal, Other, consulting fees: F. Hoffman La Roche; Financial Interests, Personal, Other, consulting fees: Foundation Medicine Inc.; Financial Interests, Personal, Other, consulting fees: Genzyme; Financial Interests, Personal, Other, Consulting fees: Heron Therapeutics; Financial Interests, Personal, Other, Consulting fees: Janssen; Financial Interests, Personal, Other, Consulting fees: Seattle Genetics. J.S. Ross: Financial Interests, Personal, Full or part-time Employment: Foundation Medicine Inc.; Financial Interests, Personal, Stocks/Shares: F. Hoffman La Roche Ltd. All other authors have declared no conflicts of interest.