Tipifarnib is an orally accessible, potent, and specific inhibitor of the enzyme farnesyl transferase. The drug has previously been investigated in over 5,000 cancer patients and has shown compelling and long-lasting anti-cancer effectiveness in select individuals with a manageable side effect profile. HRAS mutations serve as biomarkers for tipifarnib activity. In the registration-directed AIM-HN study (NCT03719690) of tipifarnib, as of the data cutoff date of June 15, 2023, 59 patients with recurrent or metastatic (R/M) HRAS mutant HNSCC have been recruited, with 50 having a high HRAS mutant variant allele frequency (VAF) and 38 evaluable for effectiveness.

Kura Oncology has presented promising efficacy and safety results at the 2023 European Society for Medical Oncology (ESMO) Congress in Madrid, Spain.  One patient reached a CR while receiving therapy, according to the investigator assessment and Independent Review Facility (IRF). In the R/M setting, patients had a median of two prior lines of therapy (range 0-6). Robust activity was found in second-line and above treatment, with stronger activity in the second line compared to the third line and later treatments. The ORR in second line treatment was 29% [0.13, 0.51] in the IRF assessment. 

Tipifarnib was well accepted and had a controllable safety profile. Cytopenias were the most prevalent grade III/IV treatment-related adverse events (TRAEs) found in at least 10% of patients, and TRAEs caused treatment discontinuation in 7% of patients.

KOL insights

“Broadly speaking for head and neck cancer, it has been an exciting time for treatment for these patients with the advent of immunotherapy. But for patients with recurrent or metastatic disease, this is still an incurable disease and one where there is still a huge need for therapeutics.” –Medical Oncologist, Memorial Sloan Kettering Cancer Center, USA

Conclusion

Head and neck squamous cell carcinoma (HNSCC) is the seventh most common cancer worldwide. In the United States, in 2022, around 66,000 head and neck cancer incident cases were observed. Tipifarnib is targeting a comparatively smaller pool of head and neck cancer. HRAS proto-oncogene occurs in roughly 4%-8% of Head and neck cancer cases. The United States accounted for approximately 3,300 cases for HRAS mutation, in 2022 (DelveInsight’s estimates).

Tipifarnib is effective in extensively pretreated mHRAS R/M HNSCC. It is the first targeted treatment for this underserved group. Data suggests that Tipifarnib ORR was greater in the 2L setting than in the 3L setting (29% vs. 15%). It has a safe and controllable safety profile. Three FDA-approved treatments for HNSCC in the second line had ORRs ranging from 13% to 16%. The PIK3CA-dependent HNSCC patient pool is larger than that of the HRAS segment, hence the company is also investigating tipifarnib with alpelisib in this setting (KURRENT-HN). Roughly 20%–35% of H&N cancer are PIK3CA. Under the collaboration, Kura sponsors the trial and supplies tipifarnib and Novartis supplies alpelisib. Despite the fact that the anti-epidermal growth factor receptor (EGFR) antibody cetuximab was approved more than a decade ago, the development of biomarker-directed therapies in HNSCC has been hampered by the limited number of druggable targets in the genomic landscape as well as the challenge of managing drug-refractory, recurrent/metastatic HNSCC.

For more insight into the patient's burden/epidemiology, treatment, and changing market landscape-related advancements, refer to the Head and Neck cancer (HNC) Market Insight and Forecast Report