LBA47 - A phase II study evaluating tipifarnib in mHRAS, recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) (AIM-HN study)

Background

Despite recent advances, prognosis for R/M HNSCC patients (pts) remains poor. HRAS mutations are seen in 4-8% of HNSCCs. HRAS is uniquely farnesylation dependent, making mHRAS tumors susceptible to farnesyl transferase inhibitors. Tipifarnib has activity in pts with HNSCC harboring high variant allele frequency (VAF, ≥20%) mHRAS (Ho et al. JCO 2021). We present data in 50 high VAF pts in AIM-HN.

Methods

Pts received tipifarnib 600 mg BID on days 1-7 and 15-21 of a 28-day cycle. The primary endpoint was objective response rate (ORR) in the high VAF pts by independent review facility (IRF). Histologically confirmed mHRAS HNSCC pts with ≥1 prior platinum-containing regimen were eligible. ORR was assessed in the modified intent to treat (mITT) set (≥1 tipifarnib dose).

Results

Of 59 pts treated with tipifarnib, 50 (85%) had high VAF (median VAF: 34% [range 4-89%]). Twenty-six (44%) received immunotherapy in 1st line (1L). By Investigator assessment, ORR was 30% with 1 pt achieving a CR. By IRF, ORR was 20% with 1 CR (Table). Two responders were on treatment at study close (9 and 29 mos). Median progression-free survival by IRF: 2.6 mos (95% CI: 1.9-4.4); median overall survival: 7.0 mos (95% CI: 4.9-11.5). Grade 3+ treatment-related adverse events (TRAEs) were observed in 33 pts (56%): neutropenia (24%), anemia (20%), leukopenia (14%) and febrile neutropenia (7%). However, only 7% discontinued treatment due to TRAEs. Table: LBA47

*1/9 low VAF pt (< 20% VAF) was also a responder

Conclusions

Tipifarnib was safe and tolerable with anti-tumor activity observed in mHRAS R/M HNSCC pts post-IO and as later-line therapy. Tipifarnib is the first targeted therapy for this rare HNSCC subset. Ongoing combination studies are targeting adaptive resistance pathways (PI3K/mTOR/Akt) to further improve outcomes.

Clinical trial identification

NCT03719690.

Editorial acknowledgement

Legal entity responsible for the study

Kura Oncology, Inc.

Funding

Kura Oncology, Inc.

Disclosure

A.L. Ho: Financial Interests, Personal, Invited Speaker, discussed head and neck cancer therapies: Chinese American Hematologist and Oncologist Network; Financial Interests, Personal, Invited Speaker, Discussed salivary cancer therapies: Lurie Cancer Center (Northwestern); Financial Interests, Personal, Invited Speaker, discussed thyroid cancer therapies: Physician Education Resource; Financial Interests, Personal, Invited Speaker, Discussed thyroid cancer therapies: Endocrine Society; Financial Interests, Personal, Invited Speaker, Discussed head and neck cancer therapies: University of Pittsburgh Medical Center; Financial Interests, Personal, Invited Speaker, Discussed thyroid cancer therapeutics: New York University; Financial Interests, Personal, Advisory Board, Serve on DSMC: Affyimmune; Financial Interests, Personal, Other, Serve on the NCI Head and Neck Steering Committee: National Cancer Institute; Financial Interests, Personal, Advisory Board, Member of advisory board: Exelixis, Remix Therapeutics, Elevar Therapeutics, Prelude Therapeutics, Eisai, Ayala, Kura Oncology; Financial Interests, Personal, Other, Member of Safety Monitoring Committee: Kura Oncology; Financial Interests, Personal, Advisory Board, Member of advisory board.: Merck; Financial Interests, Personal, Other, Consultant: ExpertConnect; Financial Interests, Personal, Advisory Board, Member of advisory board and consulting.: Rgenta; Financial Interests, Personal, Full or part-time Employment: Memorial Sloan Kettering Cancer Center; Financial Interests, Personal, Stocks/Shares, options: Rgenta Therapeutics; Financial Interests, Institutional, Other, Listed as inventor for: Memorial Sloan Kettering Cancer Center; Financial Interests, Institutional, Coordinating PI, Serve as PI. also served on paid advisory board: Ayala; Financial Interests, Institutional, Coordinating PI, Serve as trial PI, also serve on paid SMC/advisory board: Kura Oncology; Financial Interests, Institutional, Local PI, Trial PI and served on an advisory board: Elevar Therapuetics; Financial Interests, Institutional, Coordinating PI, PI of IIT: Novartis, Merck, Bristol Meyer Squibb; Financial Interests, Institutional, Coordinating PI, PI of several IIT trials: Bayer; Financial Interests, Institutional, Coordinating PI, PI of trial: Bioatla, TILT Biotherapeutics, Genentech Roche, Astellas, Celldex; Financial Interests, Institutional, Local PI, PI of trial: OncC4; Financial Interests, Institutional, Coordinating PI, PI of several IITs: AstraZeneca; Financial Interests, Institutional, Coordinating PI, PI of trial and was part of paid advisory board: Eisai; Financial Interests, Institutional, Local PI, co-PI of trial: Poseida Therapuetics; Financial Interests, Institutional, Local PI: Hookipa; Non-Financial Interests, Advisory Role: Cellestia, Inxmed; Non-Financial Interests, Member of Board of Directors: International Thyroid Oncology Group; Non-Financial Interests, Leadership Role: International Rare Cancer Initiative; Non-Financial Interests, Leadership Role, for the head and neck working group: Alliance for Clinical Trials in Oncology. D.R. Adkins: Non-Financial Interests, Institutional, Advisory Role: Kura Oncology. G.J. Hanna: Financial Interests, Institutional, Speaker, Consultant, Advisor, research/advisor: Kura Oncology, Inc. J. Bruce: Non-Financial Interests, Personal, Advisory Board: Kura Oncology, Inc. M. Ahn: Financial Interests, Personal, Advisory Board: AstraZeneca, Takeda, MSD, Yuhan, Amgen, Alpha Pharmaceutical, Janssen, BMS, Roche, Daiichi Sankyo, Merck, Boronoi. L. Iglesias Docampo: Non-Financial Interests, Personal, Advisory Board: Kura Oncology, Inc. H. Kang: Non-Financial Interests, Personal, Advisory Board: Kura Oncology, Inc. D.J. Wong: Financial Interests, Personal, Advisory Board: Merck, Sharp & Dohme, Sanofi Genzyme; Financial Interests, Institutional, Local PI: KURA Oncology, Merck, Sharp & Dohme, BICARA therapeutics, FSTAR therapeutics, TopAlliance, Gilead, Roche, Lilly, AstraZeneca, Checkmate Pharamaceuticals, Pfizer, Bristol Myers Squibb; Financial Interests, Institutional, Steering Committee Member: Genentech. A. Psyrri: Financial Interests, Personal, Invited Speaker: MSD, Merck Serono; Financial Interests, Personal, Advisory Board: Pfizer, Sanofi, MSD, AstraZeneca, BMS, Leo, Rakuten, eTheRNA immunotherapies, Merck Serono; Financial Interests, Personal and Institutional, Local PI: AstraZeneca, Pfizer, GSK, Genesis, MSD, Incyte, Amgen, Debiopharm, Jannsen, Lilly, Regeneron, Sanofi, BI, Roche, Peregrine, Oncolytics Biotech; Financial Interests, Coordinating PI: AstraZeneca; Financial Interests, Personal and Institutional, Steering Committee Member: Iovance, Pfizer, Roche; Financial Interests, Institutional, Steering Committee Member: Kura Oncology; Financial Interests, Steering Committee Member: Kura Oncology; Financial Interests, Personal and Institutional, Funding: Kura Oncology, BMS, Roche, Demo, Amgen, BI, Genesis, BMS, Pfizer, Oncolytics Biotech; Financial Interests, Institutional, Funding: Merck Serono, Pfizer; Financial Interests, Personal, Other, Educational activity: Medscape, PrimeOncology; Financial Interests, Institutional, Local PI: Novartis, Replimmune; Non-Financial Interests, Project Lead, Medical Education with honoraria: Medscape. M. Gillison: Non-Financial Interests, Personal, Advisory Board: Kura Oncology, Inc. I. Braña: Financial Interests, Personal, Advisory Board: Achilles Therapeutics, Bristol Myers Squibb, Cancer Expert Now, eTheRNA Immunotherapies, Merck Serono, Merck Sharp & Dohme (MSD), Rakuten Pharma, Boehringer Ingellheim, PCI Biotech, Guidepoint; Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb, Merck Serono, Merck Sharp & Dohme (MSD), Roche; Financial Interests, Institutional, Local PI: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, GSK, Gliknik, Incyte, ISA pharmaceuticals, Janssen Oncology, Kura, Merck Serono, Debiopharm, Merck Sharp & Dohme (MSD), Nanobiotix, Novartis, Northern Biologics, Regeneron, Pfizer, Seattle Genetics, Shattuck Labs, VCN Biosciences, Roche, Immutep, MacroGenics, Sanofi, PharmaMar, Odonate Therapeutics, Bicycle Therapeutics, Dragonfly therapeutics, Gilead; Non-Financial Interests, Principal Investigator, Basket of baskets: Cancer Core Europe; Non-Financial Interests, Member, Head and Neck Group: EORTC; Non-Financial Interests, Member: SEOM, ASCO. Y.C. Liu: Non-Financial Interests, Personal, Advisory Board: Kura Oncology, Inc. Z. Zhang: Financial Interests, Personal, Full or part-time Employment: Kura Oncology, Inc. B. Balsara: Financial Interests, Personal, Full or part-time Employment: Kura Oncology, Inc. A. Saunders: Financial Interests, Personal, Full or part-time Employment: Kura Oncology, Inc. A. Gasco Hernandez: Financial Interests, Personal, Full or part-time Employment: Kura Oncology, Inc. S. Dale: Financial Interests, Personal, Full or part-time Employment: Kura Oncology, Inc. R. Haddad: Financial Interests, Personal, Advisory Board: BMS, Merck, EMD Serono, Boehringer Ingelheim, Eisai, Bayer, Merus, AstraZeneca, Genentech, Pfizer, Genmab, Exelexis, Coherus; Financial Interests, Personal, Other, Data Safety Monitoring Board ( DSMB): nanobiotix, psi, Hookipa; Financial Interests, Personal, Royalties: up to date; Financial Interests, Institutional, Local PI, grant to hospital for clinical trials: Merck BMS, EMD, AstraZeneca, Incyte, Kura; Non-Financial Interests, Other, panel chair guidelines: NCCN. All other authors have declared no conflicts of interest.