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Tipifarnib Shows Promising Clinical Activity in Patients With HRAS-mutant Head and Neck Cancer

BOSTON – The investigational farnesyl transferase inhibitor tipifarnib yielded durable objective responses in patients with recurrent and metastatic head and neck squamous cell carcinoma (HNSCC) harboring HRAS gene mutations, according to data from a phase II clinical trial presented at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, held Oct. 26-30.

“Recurrent and/or metastatic HNSCC is an incurable and devastating disease for which new treatments are needed,” said Alan L. Ho, MD, PhD, medical oncologist at Memorial Sloan Kettering Cancer Center. “If this trial is successful, tipifarnib could represent a targeted drug treatment personalized to the genomics of HNSCC patients’ tumors.”

Although tipifarnib was initially developed more than a decade ago to target tumors that harbor mutations in any of the three RAS genes, studies have shown that HRAS mutant cancers may be uniquely susceptible to tipifarnib, Ho explained. About 5 to 8 percent of patients with advanced HNSCC have tumors with an HRAS mutation, he added. Tipifarnib is a highly selective inhibitor of the enzyme farnesyltransferase, which is needed for the activity of the proto-oncogene HRAS.

“Our data show that for HNSCC patients with HRAS mutations in 20 percent or more of their tumors, 600 mg twice daily dose of tipifarnib administered in alternating weeks generates a high rate of response,” Ho said. “This is another example of how understanding the genomics and biology of a disease can be leveraged to develop new and effective cancer therapies.”

Ho and colleagues recruited patients with HNSCC and squamous cell carcinomas (SCC) in other organs to this phase II trial. All patients had relapsed/refractory disease with a median of two prior treatments and progressed on their previous therapy, including platinum therapy, immunotherapy, or cetuximab with or without chemotherapy.

The trial met its primary objective prior to completion of the study, and was amended to enrich for patients most likely to respond by recruiting only those patients with HNSCC tumors that had HRAS missense mutations at a high variant allele frequency (VAF; 35 percent or higher); those with a VAF of 20 percent or higher were also enrolled if their baseline serum albumin was at least 3.5 g/dL.

Patients received 600 to 900 mg tipifarnib by mouth twice daily on days 1 through 7 and days 15 through 21 of 28-day cycles.

Overall, there were 23 patients with HNSCC and 10 patients with SCC at the time of the presentation of this abstract. Among the 15 patients with HNSCC with high VAF (and therefore met the amended inclusion criteria), the overall response rate was 53 percent, which included eight partial responses and five stable disease.

The median progression-free survival (PFS) in HNSCC patients with high VAF (20 percent or higher) was 5.4 months; 19 months for those with a partial response, and 4.5 months for those with stable disease. By contrast, no objective responses were seen on their last prior therapy, with a median PFS of 3.2 months.

“These results are very gratifying, considering our trial is targeting patients who have stopped responding to other treatments,” Ho said. “Tipifarnib is safe and well tolerated even in patients who have received multiple lines of previous therapies.”

All patients in the study had at least one treatment-emergent adverse event (TEAE). The most frequently observed TEAEs greater than grade 3 were blood and lymphatic system disorders, gastrointestinal disorders, and renal disorders. “The safety of tipifarnib had been extensively evaluated when it was first being developed, and the side effects observed in our trial have been manageable and consistent with the safety profile of those prior studies,” Ho said.

“Tipifarnib may represent a promising new therapy for HRAS-mutant HNSCC patients. The success of the trial also speaks to the promise of utilizing genomic sequencing of diseases to identify highly effective therapies that are personalized to the specific biology of each individual patient’s tumor,” Ho noted.

Limitations of the study include small sample size. “More patients need to be treated to firmly establish the effectiveness of tipifarnib for patients with HRAS-mutant HNSCC,” Ho cautioned.

This study was sponsored by Kura Oncology. The company also provided funding for Ho’s team, and to Ho for travel/housing/conference fees for investigator meetings and for meetings he has attended to present the trial data.