Tipifarnib Exhibits Enriched Activity in HRAS-Mutant Head and Neck Cancer

Tipifarnib (Zarnestra) demonstrated encouraging antitumor activity in patients with recurrent and metastatic head and neck cancer with high HRAS-mutant variant allele frequency (VAF), according to results of the phase 2 KO-TIP-001 trial,¹ surpassing historical competitors in the second- or later-line settings, said lead study author, Alan L. Ho, MD, PhD.

The trial was divided into 2 cohorts: patients with thyroid cancer (cohort 1; n = 13) and other solid tumors (cohort 2; n = 13). Following an initial signal of activity in patients with head and neck cancer, investigators opened an extension of cohort 2 for up to 30 patients with head and neck cancer.

Tipafarnib is a potent and highly selective inhibitor of farnesyltransferase, an enzyme that is responsible for HRAS function. In December 2019, the FDA granted a fast track designation to the agent for the treatment of patients with HRAS-mutant head and neck cancer after progression on platinum therapy.²

In the trial, patients received a starting dose of 600 mg or 900 mg of oral tipifarnib twice daily on days 1-7 and 15-21 every 28 days until disease progression or unacceptable toxicity.

The objective response rate (ORR) in the intention-to-treat population (n = 21) was 42.9% (95% CI, 21.8%-66.0%), and the ORR in response-evaluable patients (n = 17) was 47.1% (95% CI, 23.0%-72.2%).

The median duration of response (DOR) in patients with high HRAS-VAF, including 1 patient who was treated off protocol, was 14.7 months (95% CI, 2.1-not reached).

The median progression-free survival was 5.9 months (95% CI, 3.5-19.2), and the median overall survival (OS) was 15.4 months (95% CI, 7.0-46.4).

The phase 2 registrational KO-TIP-007 trial (NCT03719690) evaluating tipifarnib in patients with head and neck cancer with highHRAS-mutant VAF is currently enrolling.

“If we can verify this initial signal in the registrational trial, we’ll have another effective therapeutic that’s available for our patients with head and neck cancer,” said Ho. “This would give us a targeted therapy that is far superior than other second-line therapeutic options that patients currently have access to.”

In an interview with OncLive, Ho, a medical oncologist and Geoffrey Beene Junior Faculty Chair at Memorial Sloan Kettering (MSK) Cancer Center, discussed the development of tipifarnib in solid tumors and the activity that has been reported to date in patients with head and neck cancer.

OncLive: Could you provide some background on tipifarnib?

Ho: Farnesyltransferase inhibitors were developed more than 10 years ago to target RAS. Unfortunately, those initial studies really didn’t yield a lot of efficacy. Based upon preclinical data from several groups, including some groups at MSK, we believed the reason why those initial trials failed was because they didn’t enrich for HRAS mutations.

There are three different isoforms of RAS that exist, HRAS being the least common in cancer. Kura Oncology brought this concept of re-evaluating the efficacy of tipifarnib forward in HRAS-mutant solid tumors.

What was the design of the trial?

The trial was a 2 cohort, basket trial. In cohort 1, we evaluated tipifarnib in HRAS-mutant thyroid cancers. In cohort 2, we evaluated tipifarnib in any HRAS-mutant solid tumor other than thyroid cancer. We saw an initial signal in patients with head and neck cancer in cohort 2 that led us to focus on those patients.

What did the results show?

We found that the drug had a lot of activity in patients with head and neck cancer with a high VAF of HRAS. In total, we enrolled 21 patients with head and neck cancer with high VAF. In the response-evaluable patient population, the ORR was 50%. These responses were quite durable. Among the patients who had responses, the DOR was greater than 14 months. Even more exciting was that the median OS was over 15 months. That, in and of itself, is quite remarkable given that all these patients were primarily treated in the second- or later-line settings.

The median OS with historical competitors in this setting is between 5 to 8 months. We’re really excited by these preliminary results which served as the basis for the ongoing phase 2 registration trial in these patients.

What was the safety profile of the agent?

A lot of the safety and toxicity data we have with the agent was commensurate with what had been observed in the previous clinical trials. Dose adjustments were made in the protocol. Initially, patients were treated with 900 mg twice daily. When we did an interim analysis of the first 16 patients, we found that the median dose was 600 mg twice daily. Our preliminary data really demonstrate that this dose is still effective and probably better tolerated.

One of the things that’s been really gratifying about being part of this study is the fact that it’s a real representation of how you can use basic science to translate that into effective therapeutics. We’re really encouraged and so excited that Kura Oncology wanted to take on this question again, especially with a drug whose development had ended years ago. Now, we’re bringing it back and evaluating it in the right genomically selected patient population, that is in patients with HRAS-mutant head and neck cancer.

References

1. Ho AL, Hanna GJ, Scholz CR, et al. Preliminary activity of tipifarnib in tumors of the head and neck, salivary gland and urothelial tract with HRAS mutations. J Clin Oncol. 2020;38(15 suppl):6504. doi:10.1200/JCO.2020.38.15_suppl.6504

2. Kura Oncology receives fast track designation for tipifarnib in HRAS mutant HNSCC and provides enrollment guidance for AIM-HN trial. News release. San Diego, California. December 16, 2019. Accessed July 17, 2020. bit.ly/3fzFWA6.