Tipifarnib in Head and Neck Squamous Cell Carcinoma With HRAS Mutations

Abstract

Purpose: Mutations in the HRAS (mHRAS) proto-oncogene occur in 4%-8% of patients with recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). Tipifarnib is a farnesyltransferase inhibitor that disrupts HRAS function. We evaluated the efficacy of tipifarnib in patients with R/M mHRAS HNSCC.

Methods: We enrolled 30 patients with R/M HNSCC in a single-arm, open-label phase II trial of tipifarnib for mHRAS malignancies; one additional patient was treated on an expanded access program. After an ad hoc analysis of the first 16 patients with HNSCC with mHRAS variant allele frequency (VAF) data, enrollment was limited to those with a mHRAS VAF of ≥ 20% (high VAF). The primary end point was objective response rate. Secondary end points included assessing safety and tolerability. Patients received tipifarnib 600 or 900 mg orally twice daily on days 1-7 and 15-21 of 28-day cycles.

Results: Of the 22 patients with HNSCC with high VAF, 20 were evaluable for response at the time of data cutoff. Objective response rate for evaluable patients with high-VAF HNSCC was 55% (95% CI, 31.5 to 76.9). Median progression-free survival on tipifarnib was 5.6 months (95% CI, 3.6 to 16.4) versus 3.6 months (95% CI, 1.3 to 5.2) on last prior therapy. Median overall survival was 15.4 months (95% CI, 7.0 to 29.7). The most frequent treatment-emergent adverse events among the 30 patients with HNSCC were anemia (37%) and lymphopenia (13%).

Conclusion: Tipifarnib demonstrated encouraging efficacy in patients with R/M HNSCC with HRAS mutations for whom limited therapeutic options exist (NCT02383927).

Conflict of interest statement

Alan L. HoConsulting or Advisory Role: Bristol-Myers Squibb, Eisai, Genzyme, Merck, Novartis, Sun Pharma, Regeneron, TRM Oncology, Ayala Pharmaceuticals, AstraZeneca, Sanofi, CureVac, Prelude Therapeutics, Kura Oncology, McGivney Global Advisors, Rgenta, Exelixis, Genentech/Roche, AffyimmuneSpeakers' Bureau: Medscape, Omniprex America, NovartisResearch Funding: Lilly, Genentech/Roche, AstraZeneca, Bayer, Kura Oncology, Kolltan Pharmaceuticals, Eisai, Bristol-Myers Squibb, Astellas Pharma, Novartis, Merck, Pfizer, Ayala Pharmaceuticals, Allos Therapeutics, Daiichi Sankyo, Elevar TherapeuticsTravel, Accommodations, Expenses: Janssen Oncology, Merck, Kura Oncology, Ignyta, Ayala Pharmaceuticals, Klus Pharma Irene BranaConsulting or Advisory Role: Merck Sharp and Dohme, Rakuten Medical, Sanofi, Achilles Therapeutics, eTheRNA Immunotherapies, Cancer Expert NowSpeakers' Bureau: Bristol-Myers Squibb, Merck Serono, RocheResearch Funding: AstraZeneca, Bristol-Myers Squibb, Celgene, Gliknik, GlaxoSmithKline, Janssen Oncology, Kura Oncology, Merck Sharp and Dohme, Novartis, Orion Pharma GmbH, Pfizer, Roche, Shattuck Labs, Nanobiotix, Seattle GeneticsTravel, Accommodations, Expenses: AstraZeneca Spain, Merck Serono Robert HaddadEmployment: Dana-Farber Cancer InstituteLeadership: NCCNConsulting or Advisory Role: Celgene, Merck, Eisai, Bristol-Myers Squibb, AstraZeneca, Pfizer, Loxo, Genentech, Immunomic Therapeutics, GlaxoSmithKline, Gilead Sciences, Vaccinex, EMD Serono, BioNTech AG, Achilles TherapeuticsResearch Funding: Boehringer Ingelheim, Merck, Bristol-Myers Squibb, Celgene, AstraZeneca, VentiRx, Genentech, Pfizer, Kura OncologyPatents, Royalties, Other Intellectual Property: UpToDateOther Relationship: Nanobiotix, ISA Pharmaceuticals Jessica BaumanConsulting or Advisory Role: Pfizer, Bayer, AstraZeneca, Kura OncologyResearch Funding: Bristol-Myers SquibbTravel, Accommodations, Expenses: Trident Pharmaceuticals Sjoukje OostingResearch Funding: Celldex Deborah J. WongConsulting or Advisory Role: Bristol-Myers Squibb, Genentech/Roche, Sanofi/Aventis, Blueprint MedicinesResearch Funding: BioMed Valley Discoveries, Merck Serono, Merck Sharp and Dohme, ARMO BioSciences, AstraZeneca/MedImmune, Kura Oncology, Regeneron, Genentech/Roche, Bristol-Myers Squibb, FSTAR, Pfizer, Astellas Pharma, Enzychem Lifesciences, Lilly, Elevar Therapeutics Myung-Ju AhnHonoraria: AstraZeneca, Lilly, MSD, TAKEDAConsulting or Advisory Role: AstraZeneca, Boehringer Ingelheim, Lilly, MSD, TAKEDA, Alpha pharmaceutical Caroline EvenConsulting or Advisory Role: Innate Pharma, Bristol-Myers Squibb, MSD Oncology, Merck Serono Jerome FayetteHonoraria: AstraZeneca, Bristol-Myers Squibb, Merck Sharp and Dohme, Merck Serono, Innate Pharma, RocheConsulting or Advisory Role: AstraZeneca, Bristol-Myers Squibb, Merck Sharp and Dohme, Merck Serono, Innate Pharma, RocheResearch Funding: Bristol-Myers SquibbTravel, Accommodations, Expenses: Bristol-Myers Squibb, AstraZeneca, Merck Sharp and Dohme Kevin HarringtonHonoraria: Merck Sharp and Dohme, Amgen, Merck Serono, AstraZeneca/MedImmune, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Replimune, Oncolys BioPharma, MersanaConsulting or Advisory Role: Merck Sharp and Dohme, Merck Serono, AstraZeneca/MedImmune, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, ReplimuneSpeakers' Bureau: Merck Sharp and Dohme, Merck Serono, Bristol-Myers SquibbResearch Funding: AstraZeneca, Merck Sharp and Dohme, Boehringer Ingelheim, Replimune Sung-Bae KimHonoraria: DAEHWA Pharmaceutical, ISU ABXISConsulting or Advisory Role: Lilly, AstraZeneca, DAEHWA Pharmaceutical, ISU AbxisResearch Funding: Novartis, Dongkook Pharma, Genzyme Lisa LicitraConsulting or Advisory Role: Eisai, Boehringer Ingelheim, AstraZeneca, SOBI, Novartis, Bayer, MSD, Merck Serono, Roche, Bristol-Myers Squibb, Incyte, Doxapharma, GlaxoSmithKline, Nanobiotix, Debiopharm Group, Amgen, IpsenResearch Funding: AstraZeneca, Novartis, Roche, MSD, Eisai, Merck Serono, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Exelixis, IRX Therapeutics, Medpace, Pfizer, Debiopharm Group, RocheTravel, Accommodations, Expenses: Merck Serono, Bayer, Bristol-Myers Squibb, MSD, Eisai, AstraZeneca Nabil F. SabaHonoraria: Merck, Lilly, Pfizer, Bristol-Myers Squibb, CUE Biopharma, GlaxoSmithKline, Aduro Biotech, Kura Oncology, Genentech/RocheConsulting or Advisory Role: Pfizer, Bristol-Myers Squibb, Merck, Lilly, Bluprint, BiontechResearch Funding: Bristol-Myers Squibb, ExelixisTravel, Accommodations, Expenses: Bristol-Myers Squibb, Merck, Pfizer, Lilly, GlaxoSmithKline, Genentech/Roche, Bluprint Francis WordenHonoraria: Merck Sharp & Dohme, Eisai, Bristol-Myers Squibb, Bayer, RegeneronConsulting or Advisory Role: Merck, Loxo, Bristol-Myers Squibb, Eisai, Bayer, CUE Biopharma, Rakuten Medical, RegeneronResearch Funding: Pfizer, Merck, Eisai, Bristol-Myers Squibb, Loxo, Oragenics, LillyTravel, Accommodations, Expenses: Merck Sharp & Dohme, Bayer Binaifer BalsaraEmployment: Kura OncologyStock and Other Ownership Interests: Kura Oncology Mollie LeoniEmployment: Kura Oncology, Kyowa Kirin InternationalStock and Other Ownership Interests: Kura OncologyTravel, Accommodations, Expenses: Kura Oncology, Kyowa Kirin International Catherine ScholzEmployment: Kura Oncology, H3 BiomedicineStock and Other Ownership Interests: Kura OncologyPatents, Royalties, Other Intellectual Property: Methods of Treating Cancer Patients With Farnesyltransferase Inhibitors (FTI treatment of H-Ras mutant cancers), co-Inventor (014168-0011-999), Methods of Treating Cancer With Farnesyltransferase Inhibitors (FTI treatment of a CXCL12-expressing cancer), co-Inventor (014168-0021-999), Methods of Treating Cancer Patients With Farnesyltransferase Inhibitors (FTI treatment of Casitas B cell lymphoma [CBL] mutant cancers), co-Inventor (014168-0024-228), Therapies For Squamous Cell Carcinomas (FTI treatment of SCC with high frequencies of H-Ras mutant allele frequency), co-Inventor (014168-0051-888)Travel, Accommodations, Expenses: Kura OncologyNo other potential conflicts of interest were reported.

Figures

FIG 1.

Study overview. HNSCC, head and neck squamous cell carcinoma; PD, progressive disease; PR, partial response; SCC, squamous cell carcinoma; SD, stable disease; VAF, variant allele frequency.

FIG 2.

Efficacy outcomes. Red, PR; blue, SD; green, not evaluable for efficacy; diamond, patient initiated treatment at 600 mg twice a day; cross, patient withdrew consent; arrow in bar, start of response; arrow, active treatment. Numbers at the end of the bars represent VAF for each patient. (A) Maximal change in tumor size. (B) Duration of response to treatment. (C) Kaplan-Meier analysis of PFS. Tick marks indicate censored data. PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease; VAF, variant allele frequency.