Tipifarnib Targets HRAS-Mutant Cancers

The experimental farnesyltransferase inhibitor tipifarnib (Kura Oncology) may be effective in treating HRAS-mutant head and neck squamous cell carcinoma (HNSCC), according to results presented at the 2019 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in Boston, MA, October 26–30. These findings suggest that after more than a decade of trying, researchers may have finally developed a drug that targets mutant HRAS within the elusive RAS–RAF–MAPK pathway—and they've done so in a population of patients with few treatment options.

HRAS mutations occur in 5% to 8% of patients with advanced HNSCC. Farnesyltransferase is an enzyme that catalyzes the binding of farnesyl groups to RAS proteins, enabling them to localize to the cell membrane and initiate oncogenic activity. Tipifarnib blocks this activity.

“There have been several lines of preclinical evidence suggesting that while NRAS and KRAS are susceptible to certain biological processes that allow them to circumvent [farnesyltransferase inhibitor] action, indeed HRAS mutations are not susceptible to those mechanisms,” explained Alan Ho, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, NY, who presented the findings. This notion was supported by studies of tipifarnib in mouse models of skin and thyroid cancers, which led Ho and his colleagues to test the agent in the clinic.

A phase II trial enrolled patients with HNSCC tumors that had HRAS missense mutations at a high variant allele frequency (VAF; at least 35%, or a minimum of 20% if baseline serum albumin was at least 3.5 g/dL). Patients had received a median of two prior therapies: 90.5% had received a platinum agent, 61.9% had received an immune checkpoint inhibitor, and 52.4% had received cetuximab (Erbitux; Eli Lilly).

Overall, tipifarnib elicited partial responses in 10 of 18 evaluable patients and led to stable disease in the others. Four responses lasted more than a year, and six responses lasted at least 6 months. Responders had a median progression-free survival (PFS) of 8.3 months, and those with stable disease had a median PFS of 4.5 months. Notably, with their last therapy prior to joining the tipifarnib trial, patients had a median PFS of 3.2 months, and none had partial responses. Historical response rates for these patients are 13% to 15% for immune checkpoint inhibitors and less than 10% for chemotherapy or cetuximab, Ho said.

All patients experienced adverse events, and more than 10% experienced hematologic side effects, namely anemia, neutropenia, and leukopenia. These were also the most common adverse events of grade 3 or higher.

“We have very compelling antitumor activity in a heavily pretreated cohort of these recurrent metastatic head and neck cancer patients with HRAS mutations,” Ho said. Next, researchers will test tipifarnib in the pivotal phase II AIM-HN/SEQ-HN trial of HRAS-mutant HNSCC. They also plan to explore tipifarnib in combination with other agents, including chemotherapy, immune checkpoint inhibitors, and targeted therapies—particularly in patients with HRAS mutations at a VAF of less than 20%.

Targeting the RAS–RAF–MAPK pathway “has been one of the holy grails of cancer, given the high frequency of RAS mutations in tumors such as colorectal, pancreas, and melanoma,” said William Sellers, MD, of the Broad Institute of Harvard and MIT in Cambridge, MA, who was not involved in the trial. Sellers added that the tipifarnib trial, along with others testing agents that act on the same pathway, “emphasizes the excitement … of what's happening in the cancer field in general, and in particular in the RAS pathway.” –Catherine Caruso

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