1. Fuerst, Mark L.

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BOSTON-An investigational farnesyl transferase inhibitor, tipifarnib, yields durable responses in patients with recurrent and metastatic head and neck squamous cell carcinoma (HNSCC) harboring HRAS gene mutations, according to a new study.

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Tipifarnib is a potent, highly selective inhibitor of farnesyltransferase, a critical enzyme for the activity of the proto-oncogene HRAS. It was initially developed more than a decade ago to target tumors that harbor mutations in any of the three RAS genes. Studies subsequently showed that HRAS-mutant cancers may be uniquely susceptible to tipifarnib.


About 5-8 percent of patients with advanced HNSCC have tumors with an HRAS mutation, said Alan L. Ho, MD, PhD, a medical oncologist at Memorial Sloan Kettering Cancer Center. "Recurrent and/or metastatic HNSCC is an incurable and devastating disease for which new treatments are needed. If this trial is successful, tipifarnib could represent a targeted drug treatment personalized to the genomics of HNSCC patients' tumors."


Ho presented the results of a phase II clinical trial at a press briefing before the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics.


"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."


Research Results

The researchers recruited patients with HNSCC and squamous cell carcinomas (SCC) in other organs into 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.


Initially, the trial included two cohorts, one cohort of thyroid cancer patients and the second cohort of patients with HRAS solid tumors, among other types. The patients showed "rapid, durable responses despite resistance to chemotherapy," noted Ho.


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) of 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.


Of the 21 HNSCC patients treated so far, 18 patients, median age 64 years, were evaluable for efficacy. "These patients were heavily pretreated, with a median of two prior regimens," said Ho. "More than half had had prior anti-cancer therapy." Patients received 600 to 900 mg of oral tipifarnib twice daily on days 1 through 7 and days 15 through 21 of 28-day cycles.


Tipifarnib treatment resulted in a 56 percent overall response rate, including 10 partial responses (PRs) and two other unconfirmed PRs. "Many responses were deep and durable. No patients progressed on tipifarnib," said Ho. Four patients have maintained responses for more than 1 year, and six patients for more than 6 months.


He noted that a combination of the immunotherapies nivolumab and ipilimumab yields a 13 percent response rate. Among responders, the median progression-free survival was 8.3 months; the median progression-free survival was 4.5 months in those with stable disease.


"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 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 commented.


"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."


The study's limitations include the small sample size. "More patients need to be treated to firmly establish the effectiveness of tipifarnib for patients with HRAS-mutant HNSCC," said Ho.


In conclusion, "tipifarnib demonstrated compelling antitumor activity in a heavily pretreated cohort of recurrent/metastatic HNSCC carrying HRAS mutations. Activity was seen in disease resistant to chemotherapy, immunotherapy, and cetuximab. The majority of grade 3 or higher TEAEs were hematological events managed with best supportive care," he stated.


Based on these data, an ongoing pivotal study is evaluating the efficacy of tipifarnib in HRAS-mutant HNSCC and the impact of HRAS mutations on first-line HNSCC therapies. Data support further testing of single-agent tipifarnib in a high HRAS allele patient subset, which represents less than 5 percent of the HNSCC cohort, Ho said. "Additional opportunities for combination with immunotherapy, chemotherapy, and/or cetuximab in the low (1-20%) HRAS VAF subset are under consideration."


Mark L. Fuerst is a contributing writer.