Tipifarnib induces responses in HRAS-mutant head and neck squamous cell carcinoma
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Tipifarnib induced durable objective responses among patients with metastatic or recurrent head and neck squamous cell carcinoma with HRAS mutations, according to results of a single-arm phase 2 study presented at AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics.
“Recurrent and/or metastatic HNSCC is an incurable and devastating disease for which new treatments are needed,” Alan L. Ho, MD, PhD, medical oncologist at Memorial Sloan Kettering Cancer Center, said in a press release. “If this trial is successful, tipifarnib could represent a targeted drug treatment personalized to the genomics of HNSCC patients’ tumors.”
Tipifarnib (Kura Oncology), an investigational farnesyltransferase inhibitor, targets tumors that have mutations in any of the three RAS genes. Previous studies have shown that cancers with HRAS mutations, which occur in 5% to 8% of patients with HNSCC, may be particularly sensitive to the drug, Ho said.
In the phase 2 trial, Ho and colleagues treated patients with HNSCC and other squamous cell carcinomas with tipifarnib at a starting dose of 600 mg to 900 mg twice daily on days 1 to 7 and 15 to 21 of 28-day cycles.
All patients had relapsed or refractory disease with a median two prior therapies, including platinum therapy, immunotherapy and cetuximab (Erbitux, Eli Lilly) with or without chemotherapy.
The trial met its primary objective before its completion and, based on the preliminary efficacy results, underwent amendment to enroll only patients with HNSCC tumors that had HRAS missense mutations at a high variant allele frequency (35% or 20% or higher with baseline serum albumin of 3.5 g/dL).
Twenty-one patients (median age, 64 years; range, 20-89; 66.7% men) with HNSCC met the HRAS mutation high variant allele frequency criteria.
Among 18 of these patients evaluable for efficacy, researchers observed an overall response rate of 56% (95% CI, 0.31-0.78), with 10 confirmed partial responses and six patients with stable disease.
Patients experiencing partial responses demonstrated median PFS of 8.3 months, whereas those with stable disease had median PFS of 4.5 months.
On their last previous therapy, these patients had no objective responses and median PFS of 3.2 months, researchers noted.
All patients experienced at least one treatment-emergent adverse event. The most common grade 3 or higher treatment-related adverse events included blood and lymphatic system disorders, gastrointestinal disorders and renal disorders.
A pivotal study based on these results is investigating the efficacy of tipifarnib in HRAS-mutant HNSCC and how HRAS mutations impact first-line therapies of HNSCC.
“These results are very gratifying, considering our trial is targeting patients who have stopped responding to other treatments,” Ho said in the press release. “Tipifarnib is safe and well-tolerated even in patients who have received multiple lines of previous therapies.”– by John DeRosier
Reference:
Ho A, et al. Preliminary results from a phase 2 trial of tipifarnib in squamous cell carcinomas (SCCs) with HRAS mutation. Presented at: AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; Oct. 26-30, 2019; Boston.
Disclosures: Ho reports consultant roles with AstraZeneca, Ayala Pharmaceuticals, Bristol-Myers Squibb, Eisai, Genentech, Genzyme, Ignyta, Janssen, Klaus Pharmaceutical, Kura Oncology, Merck, Novartis, Regeneron, Sanofi Aventis, Sun Pharmaceuticals and TRM Oncology; grant/research support from Allos Pharm, AstraZeneca, Ayala Pharmaceuticals, Bayer, Bristol-Myers Squibb, Daiichi Sankyo, Eisai, Eli Lilly, Genentech/Roche, Koltan Pharmaceuticals, Kura Oncology and Merck; and speakers bureau roles with Medscape, Novartis and Omniprex America LLC. Please see the abstract for all other researchers’ relevant financial disclosures.