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Ref Type Abstract
Authors A.L. Ho D.R. Adkins G.J. Hanna J. Bruce M-J. Ahn L. Iglesias Docampo H. Kang D.J. Wong A. Psyrri M. Gillison I. Braña Y.C. Liu C-Y. Hsieh M.H. Hong Z. Zhang B. Balsara A. Saunders A. Gasco Hernandez S. Dale R. Haddad
Title LBA47 A phase II study evaluating tipifarnib in mHRAS, recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) (AIM-HN study)
Abstract Text 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. 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.


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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
HRAS mutant head and neck squamous cell carcinoma predicted - sensitive Tipifarnib Phase II Actionable In a Phase II trial (AIM-HN), Zarnestra (tipifarnib) demonstrated safety and preliminary activity in patients with recurrent or metastatic head and neck squamous cell carcinoma harboring mutations in HRAS, resulting in an objective response rate of 20% (10/50, 1 complete and 9 partial responses), disease control rate of 48% (24/50), with stable disease in 14 patients, median progression-free survival of 2.6 mo, and median overall survival of 7 mo (Ann Oncol (2023) 34 (suppl_2): S1286-S1287; NCT03719690). detail...