Despite advances in the management of recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) and the introduction of immune checkpoint inhibitors in the treatment algorithm, the prognosis remains poor for most patients. While the molecular landscape of SCCHN has been largely elucidated, the majority of genetic alterations are not ‘druggable’. Cetuximab is currently the only approved targeted therapy for R/M SCCHN, and there is a high unmet need for biomarker-selected personalized therapies to improve patient outcomes.

Approximately 4 – 8% of patients with R/M SCCHN harbor activating mutations in HRAS, a member of the RAS family of oncogenes. Targeting RAS has proved challenging; however, recent research indicated that tipifarnib – a first-in-class, potent selective inhibitor of farnesyltransferase – has activity in HRAS-mutated SCCHN preclinical models. Farnesyltransferase is an essential enzyme for RAS signaling function. Hence, research to evaluate HRAS as a potential therapeutic target for patients with HRAS-mutated SCCHN is ongoing.

An open-label phase II study that evaluated the objective response rate (ORR) of tipifarnib in patients with incurable HRAS-mutated solid tumors, detected a potential efficacy signal for tipifarnib in patients with SCCHN with high mutant HRAS variant allele frequency (high-VAF). Thus, a further assessment was undertaken of the efficacy of tipifarnib treatment in a cohort of HRAS-mutated SCCHN patients, and results from this cohort were published recently. Thirty patients with R/M SCCHN received tipifarnib in the study, and one additional patient was treated in an expanded-access program. Among these 30 patients, 22 had high-VAF (≥ 20%). An albumin level of ≥ 3.5 g/dL was also required for patients with HRAS VAF of 20 – 35% as a marker of patient fitness to sustain treatment; no minimum albumin level was required for patients with HRAS VAF > 35% since it was premised that this group would be particularly susceptible to tipifarnib treatment. Patients had received a median of two prior lines of systemic therapy, including cetuximab (50%), immunotherapy (63%), or both (23%). Of the 22 patients with high-VAF, 20 patients were evaluable for response, and ORR was 55% (11 patients). Of note, the majority of patients who were previously treated with immunotherapy responded to tipifarnib. Furthermore, a statistically significant improvement in median progression-free survival (PFS) was seen in patients treated with tipifarnib versus last prior therapy: 5.6 versus 3.6 months, respectively (P = 0.0012). Median overall survival (OS) was 15.4 months. Based on previous trial data, the initial oral dose of tipifarnib was 900 mg twice a day on days 1 – 7 and 15 – 21 of 28-day cycles. However, due to grade 3 toxicities that required dose reduction, the dose was subsequently reduced to 600 mg twice a day. The most frequently observed grade ≥ 3 adverse events in ≥ 10% of patients, regardless of VAF or albumin levels, were hematologic toxicities, with anemia being the most frequent (37%), and gastrointestinal disorders such as nausea (10%). There were no tipifarnib-related deaths. No high-VAF patients discontinued tipifarnib due to adverse events.

The investigators conclude that tipifarnib in heavily pretreated SCCHN patients with high mutant HRAS VAF showed encouraging anti-tumor activity and was well tolerated. They note that the ‘unprecedented’ ORR of 55%, with a longer median OS than previously reported for treatments used in a similar setting, supports the ongoing pivotal trial of tipifarnib in HRAS-mutant SCCHN. This ongoing trial will also evaluate the validity of VAF as a predictive biomarker for tipifarnib efficacy. An accompanying editorial highlights the significance of these results given the limited number of successful targeting strategies for RAS alterations and the paucity of personalized treatment strategies in SCCHN. The successful targeting of HRAS would mark significant progress for precision oncology care for patients with HRAS-mutated R/M SCCHN.

References

Ho AL, et al. J Clin Oncol. 2021; March 22. [Online ahead of print].

Pearson AT, Vokes MD. J Clin Oncol. 2021; April 20. [Online ahead of print].