Activity Seen With Tipifarnib in HRAS-Mutant HNSCC in Proof-of-Concept Study

ALAN L. HO, MD, PHD

Tipifarnib demonstrated encouraging antitumor activity among patients withHRAS-mutant head and neck squamous cell carcinoma (HNSCC), according to preliminary results of an ongoing phase II proof-of-concept trial (NCT02383927). In a presentation during the 2017 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, held in Philadelphia, Pennsylvania, Alan L. Ho, MD, PhD, said that the farnesyltransferase inhibitor (FTI) produced partial responses in 4 of 6 patients in a cohort of patients with HNSCC harboring anHRASmutation.¹

“This evidence is the first to really demonstrate that mutantHRASis a target in cancer with FTIs,” said Ho, a medical oncologist and the Geoffrey Beene Junior Faculty Chair at Memorial Sloan Kettering (MSK) Cancer Center. “The activity we’ve seen [with tipifarnib] is rapid and durable and has translated into clinical benefit in a number of different ways.”

FTIs were previously of interest to target all RAS mutations, Ho said. “All 3 RAS isoforms—KRAS/NRAS/HRAS—even when mutated require membrane localization for the activation of downstream signaling. That process was dependent upon a posttranslational addition of hydrophobic groups to the C-terminal tail of those proteins in a process known as prenylation,” he explained. “Recognizing that farnesyltransferase catalyzes the predominant form of prenylation for RAS, it was hypothesized that inhibiting that process and inhibiting that enzyme would result in delocalization of RAS in mutant tumors and rendering it oncogenically inert.”

However, FTIs did not demonstrate efficacy among patients with NRAS and KRAS mutations, as both are susceptible to redundant forms of prenylation. Only HRAS is dependent on farnesyltransferase for membrane localization, as James A. Fagin, MD, also of MSK, demonstrated in preclinical models.²

Tipifarnib is a first-in-class potent/highly selective inhibitor of farnesyltransferase that competitively binds to the CAAX motif.

The phase II trial investigated tipifarnib in patients withHRAS-mutant solid tumors across 3 cohorts. Cohort 1 included patients with thyroid cancer, and enrollment is ongoing for this cohort. Cohort 2 is for patients with HNSCC and other solid tumors. While the study was originally intended to focus only on 2 cohorts, a third was added for patients with squamous cell carcinoma (SCC) not of the head and neck, and an HNSCC extension was added to the second cohort as well; enrollment is ongoing for both.

Patients across all cohorts had no curative treatments available to them and had an ECOG performance status of 0 to 1, even after progressing on previous regimens. The primary endpoint for the study was objective response rate (ORR). The study had a 2-stage design and was considered to be positive when 4 responses were observed in any cohort.

The trial focused on the HNSCC population, especially because patients with HNSCC harboring anHRASmutation are characterized as being a unique molecular subset of the disease. Only 5% to 6% of patients with HNSCC have anHRASmutation, but these patients typically are enriched forCASP8mutations and are not likely to haveTP53mutations. Additionally, Ho suggested that cetuximab (Erbitux) resistance might be correlated with the acquisition of aRASmutation.

As of data cutoff on October 4, 2017, 6 patients with HNSCC had been enrolled in cohort 2, all of whom had received chemotherapy, cetuximab, radiation, and/or immunotherapy for their disease. Tipifarnib was given orally to all patients at 900 mg twice daily on days 1 to 7 and 15 to 21 of a 28-day cycle.

Four of the 6 patients in the second cohort achieved a partial response, for an ORR of 67% (95% CI, 22%-95%), which Ho said “is a remarkable response rate for a previously treated patient population.”

Of these responders, 2 were durable and lasted for over a year; 1 response was ongoing after 21 cycles with tipifarnib. The other 2 patients in the cohort experienced stable disease, and all patients achieved some degree of tumor reduction. Ho also noted that this activity was observed in diseases that were resistant to chemotherapy, cetuximab, and immunotherapy.

A patient with cutaneous SCC of the skin in cohort 3 also experienced stable disease, but no other patients from this or the first cohort were discussed during the presentation.

“Impressively, we’ve also seen patients with very large volume metastases with rapid and impressive responses,” Ho said. He addressed the case of a recently enrolled patient with metastatic laryngeal SCC with metastases to the muscle, adrenal gland, lung, bone, and mediastinal lymph nodes who experienced a 22% reduction in overall tumor volume by cycle 2, as 1 example.

He noted that the adverse events (AEs) seen in the trial were consistent with the safety profile seen with tipifarnib in previous trials. Among 27 patients across all 3 cohorts, observed grade ≥3 treatment-emergent AEs included myelosuppression (neutropenia in 31%, anemia in 19%, thrombocytopenia in 15%), gastrointestinal disturbances in 15%, and increased creatinine in 11%.

Two patients with HNSCC required dose reductions for grade 2 peripheral neuropathy. Three patients (11%) discontinued because of AEs: 2 due to grade 3 renal AEs, and 1 due to a grade 3 gastrointestinal AE.

References

1. Ho A, Chau N, Wong DJ, et al. Preliminary results from a phase 2 proof of concept trial of tipifarnib in tumors with HRAS mutations. Presented at: 2017 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; October 26-30, 2017; Philadelphia, PA. Abstract LBA10. abstractsonline.com/pp8/#!/4557/presentation/618.
2. Chen Xu, Makarewicz JM, Knauf JA, Johnson LK, Fagin JA. Transformation by Hras(G12V) is consistently associated with mutant allele copy gains and is reversed by farnesyl transferase inhibition.Oncogene.2014;33(47):5442-5449. doi: 10.1038/onc.2013.489.