893P - Clinico-genetic profiling of HRAS mutant head and neck squamous cell carcinoma (HNSCC)

Background

HNSCC is the 6^th most common non-skin cancer worldwide. Recent development of Ras pathway inhibitors has made HRAS the first possible actionable oncogene in HNSCC. Tipifarnib, a farnesyl transferase inhibitor, demonstrated an ORR of 55% in recurrent/metastatic (R/M) HNSCC patients with HRAS mutations (mHRAS). However, little is known about the prevalence, patient characteristics, mutation and co-occuring mutation profiles for this molecularly-defined population.

Methods

We identified mHRAS HNSCC cases in 3 datasets: MD Anderson Cancer Center (MDACC), KURA KO-TIP-001 trial participants, and Foundation Medicine (FMI)-profiled cases. We extracted patient demographics, HRAS mutation type and co-occurring mutations for each cohort.

Results

The median age in years for mHRAS HNSCC was 55 (MDACC), 61 (KURA) and 65 (FMI); females comprised 46, 27, and 35% of cases per cohort, respectively. For tumors with available HPV status, 50, 28, and 21% of the cases were HPV-positive, respectively. The table provides a summary of the HRAS mutations per cohort. The number of cases and percent occurrence of the exact HRAS mutation are indicated. Table: 893P

In the FMI cohort, mHRAS had a prevalence of 3.3% (155 of 4,759 cases). Mutations at codon 13 also included two G13_V14 frameshift mutations. The most frequent mutation was HRAS G12S (MDACC, 31%; KURA, 33%; FMI, 26%). Co-occurring mutations occurred most frequently in TP53 (MDACC, 46%; KURA, 32%; FMI, 53%) and CDKN2A (MDACC, 15%; KURA, 10%; FMI, 53%). A 26% loss of CDKN2A was likewise observed in the FMI cohort. Compared to mKRAS, STK11 mutations (5, 3.1%) were rare in the FMI cohort, and were not seen in the other cohorts. No KEAP1 mutation was observed.

Conclusions

mHRAS occurred at 3-4% in R/M HNSCC in FMI; G12S was the most common mutation in all 3 cohorts. Co-occuring TP53 or CDKN2A alterations were common, but not KEAP1 or STK11. mHRAS are present in both HPV-positive and -negative HNSCC.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

X. Le: Financial Interests, Advisory Role: EMD Serono; Financial Interests, Advisory Role: AstraZeneca; Financial Interests, Advisory Role: Spectrum Pharmaceutics; Financial Interests, Advisory Role: Eli Lilly; Financial Interests, Advisory Role: Boehringer Ingelheim; Financial Interests, Advisory Board: Bristol-Myers Squibb; Financial Interests, Advisory Role: Celgene; Financial Interests, Research Grant: Eli Lilly; Financial Interests, Research Grant: Boehringer Ingelheim. J. Hopkins: Financial Interests, Full or part-time Employment: Foundation Medicine Inc.; Financial Interests, Stocks/Shares: Roche Holding AG. B. Balsara: Financial Interests, Full or part-time Employment: Kura Oncology. M. Leoni: Financial Interests, Full or part-time Employment: Kura Oncology. D.S. Hong: Financial Interests, Research Grant: AbbVie; Financial Interests, Research Grant: Adaptimmune; Financial Interests, Research Grant: Adlai Nortye; Financial Interests, Research Grant: Amgen; Financial Interests, Research Grant: AstraZeneca; Financial Interests, Research Grant: Bayer; Financial Interests, Research Grant: Bristol Myers Squibb; Financial Interests, Research Grant: Daiichi-Sankyo; Financial Interests, Research Grant: Eisai; Financial Interests, Research Grant: Eli Lilly; Financial Interests, Research Grant: EMD Serono; Financial Interests, Research Grant: Erasca; Financial Interests, Research Grant: Fate Therapeutics; Financial Interests, Research Grant: Genentech; Financial Interests, Research Grant: Genmab; Financial Interests, Research Grant: GlaxoSmithKline; Financial Interests, Research Grant: Ignyta; Financial Interests, Research Grant: Infinity; Financial Interests, Research Grant: Kite; Financial Interests, Research Grant: Kyowa; Financial Interests, Research Grant: LOXO; Financial Interests, Research Grant: Merck; Financial Interests, Research Grant: MedImmune; Financial Interests, Research Grant: Millenium; Financial Interests, Research Grant: Mirati; Financial Interests, Research Grant: miRNA; Financial Interests, Research Grant: Molecular Templates; Financial Interests, Research Grant: Mologen; Financial Interests, Research Grant: Navier; Financial Interests, Research Grant: NCI-CTEP; Financial Interests, Research Grant: Novartis; Financial Interests, Research Grant: Numab; Financial Interests, Research Grant: Pfizer; Financial Interests, Research Grant: Seattle Genetics; Financial Interests, Research Grant: Takeda; Financial Interests, Research Grant: Turning Point Therapeutics; Financial Interests, Research Grant: Verstatem; Financial Interests, Research Grant: VM Oncology; Financial Interests, Advisory Role: Alpha Insights; Financial Interests, Advisory Board: Acuta; Financial Interests, Advisory Role: Amgen; Financial Interests, Advisory Board: Axiom; Financial Interests, Advisory Role: Adaptimmune; Financial Interests, Advisory Role: Baxter; Financial Interests, Advisory Role: Bayer; Financial Interests, Advisory Role: Boxer Capital; Financial Interests, Advisory Role: COG; Financial Interests, Advisory Role: Ecor1; Financial Interests, Advisory Role: Genentech; Financial Interests, Advisory Role: GLG; Financial Interests, Advisory Role: Group H; Financial Interests, Advisory Role: Guidepoint; Financial Interests, Advisory Role: HCW Precision; Financial Interests, Advisory Role: Infinity; Financial Interests, Advisory Role: Janssen; Financial Interests, Advisory Role: Merrimack; Financial Interests, Advisory Role: Medscape; Financial Interests, Advisory Role: Numab; Financial Interests, Advisory Role: Pfizer; Financial Interests, Advisory Role: Prime Oncology; Financial Interests, Advisory Role: Seattle Genetics; Financial Interests, Advisory Role: ST Cube; Financial Interests, Advisory Role: Takeda; Financial Interests, Advisory Role: Tavistock; Financial Interests, Advisory Role: Trieza Therapeutics; Financial Interests, Advisory Role: WebMD; Financial Interests, Ownership Interest, Advisor: Molecular Match; Financial Interests, Ownership Interest, Founder: OncoResponse; Financial Interests, Ownership Interest, Advisor: Presagia Inc; Financial Interests, Other, Travel, Accommodations, Expenses: AACR; Financial Interests, Other, Travel, Accommodations, Expenses: Amgen; Financial Interests, Other, Travel, Accommodations, Expenses: ASCO; Financial Interests, Other, Travel, Accommodations, Expenses: AstraZeneca; Financial Interests, Other, Travel, Accommodations, Expenses: Bayer; Financial Interests, Other, Travel, Accommodations, Expenses: Celgene; Financial Interests, Other, Travel, Accommodations, Expenses: Eli Lilly; Financial Interests, Other, Travel, Accommodations, Expenses: Genentech; Financial Interests, Other, Travel, Accommodations, Expenses: Genmab; Financial Interests, Other, Travel, Accommodations, Expenses: GlaxoSmithKline; Financial Interests, Other, Travel, Accommodations, Expenses: Janssen; Financial Interests, Other, Travel, Accommodations, Expenses: LOXO; Financial Interests, Other, Travel, Accommodations, Expenses: miRNA; Financial Interests, Other, Travel, Accommodations, Expenses: Pfizer; Financial Interests, Other, Travel, Accommodations, Expenses: Philips; Financial Interests, Other, Travel, Accommodations, Expenses: SITC; Financial Interests, Other, Travel, Accommodations, Expenses: Takeda. L.A. Albacker: Financial Interests, Stocks/Shares: Roche Holding AG; Financial Interests, Full or part-time Employment: Foundation Medicine Inc. M. Gillison: Financial Interests, Advisory Board, Scientific/Advisory Committee: Sensei; Financial Interests, Advisory Board, Member: Mirati Therapeutics; Financial Interests, Advisory Board, Consulting: BioNTech AG; Financial Interests, Advisory Board, Consulting: Shattuck Labs Inc.; Financial Interests, Advisory Board, Consulting: EMD Serono Inc.; Financial Interests, Advisory Board, Consulting: Debiopharm; Financial Interests, Advisory Board, Consulting: Kura Oncology; Financial Interests, Advisory Board, Consulting: Merck Co.; Financial Interests, Advisory Board, Consulting: Ipsen Biopharmaceuticals Inc.; Financial Interests, Advisory Board, Consulting: Bristol-Myers Squibb; Financial Interests, Advisory Board, Consulting: Bicara Therapeutics; Financial Interests, Advisory Board, Consulting: Bayer HealthCare Pharmaceuticals; Financial Interests, Advisory Board, Consulting: Roche; Financial Interests, Advisory Board, Speaker/Preceptorship: Roche Diagnostics GmbH; Financial Interests, Advisory Board, Consulting: Genocea Biosciences, Inc.; Financial Interests, Advisory Board, Consulting: NewLink Genetics Corporation; Financial Interests, Advisory Board, Consulting: Aspyrian Therapeutics; Financial Interests, Advisory Board, Consulting: TRM Oncology; Financial Interests, Advisory Board, Consulting: Amgen Inc.; Financial Interests, Advisory Board, Consulting: AstraZeneca Pharmaceuticals; Financial Interests, Advisory Board, Consulting: Celgene Corp; Financial Interests, Research Grant: Genocea; Financial Interests, Research Grant: BMS; Financial Interests, Research Grant: Kura; Financial Interests, Research Grant: Cullinan; Financial Interests, Research Grant: Genentech; Financial Interests, Research Grant: BioNtech; Financial Interests, Research Grant: Gilead. All other authors have declared no conflicts of interest.