Tipifarnib in HRAS-Mutated HNSCC

Glenn J. Hanna, MD: In the interest of time, we’ll start talking about our potential targeted option of interest. This is tipifarnib, and tipifarnib is utilized in this situation for targeting HRAS mutations. HRAS is overexpressed and mutated in a small percentage of head and neck cancers, around 3% to 8%. We know that that oncogene activity is highly dependent on what’s called post-translational modification, or the protein gets modified as it reaches the surface of the cell in a process called farnesyltransferase enzymes, causing what’s called prenylation.

Tipifarnib inhibits some of that process, whereby it blocks farnesyltransferase, or the transfer of those groups to the surface, or modification of the protein. It has a bit of a unique mechanism compared to some other more traditional tyrosine kinase inhibitors or inhibitors of phosphorylation. It inhibits a post-translational event on the protein and disrupts the HRAS function. It’s actually a repurposed drug. It was looked at in a number of other cancers early on, particularly colorectal cancer, given the interest in targeting KRAS. But it does seem quite effective in patients with HRAS oncogene addiction. When it was repurposed, that was the basis of the initial TIP-001, or the RUN-Head and Neck study, using tipifarnib in patients with head and neck cancer who have HRAS mutations. Nabil, do you want to talk a little about that initial study that Alan Ho, MD, PhD, and colleagues ran, looking at solid tumors with HRAS mutations and how that evolved into the more recent AIM-HN study?

Nabil F. Saba, MD, FACP: This is, as you indicated, a very interesting history of HRAS. As you rightfully mentioned, the RAS oncogene is one of the most commonly altered oncogenes in solid tumors. It’s refreshing to see that reviving tipifarnib, which was basically a dead drug back in the ’90s, for targeting of HRAS mutation, has become of significant interest, given, as you mentioned, the differences in HRAS compared to other RAS mutations.

The initial study focused on tumors that had HRAS alterations, including thyroid cancer, bladder cancer, and squamous cell carcinoma of the head and neck. As you know, there was also a cohort of, I think, saliva gland cancers as well. The trial did show evidence of clinical benefit with the tipifarnib in some of these tumors. The squamous cell carcinoma of the head and neck responses that were reported, were up to 50%. Let’s remember this is in a heavily pretreated population of patients. Most of these patients had failed multiple lines of therapy. I think a number of them failed immunotherapy. The question of whether we ought to use this after immunotherapy failure seems to indicate, by the data that were presented, that yes, these targeted agents continue to work even following immunotherapy failure. It seems to be regardless also of HPV [human papillomavirus] status. We know that the HRAS alteration seems to be more enriched in patients who do have HPV-negative disease, perhaps more so in oral cavity cancers. If you look at the data, they do not seem to indicate that you should not check it, for example, in an HPV-positive patient who has failed therapy. I’m encouraging the team on the new study to essentially check on probably every patient with recurrent metastatic disease to see if this alteration is present.

The other fascinating thing is the duration of response we observed. As you recall, in this squamous cell population, the duration of response I think was up to 15 months, which is really impressive in a previously treated population. If you look at progression-free survival, for example, in the first-line recurrent metastatic setting, 15 months is what you get with the first-line KEYNOTE-048 trial. To have a treatment that has such generous maintenance of the clinical benefit is a departure from what we see in the recurrent metastatic setting.

I think this has opened the question to multiple items on the list. We can talk about these if you like. What is the future of combination therapy? There have been data on whether EGFR inhibition is linked to HRAS expression. Preclinical data suggest that tumors that harbor the HRAS tend to be resistant to cetuximab. These are PDX [patient-derived xenograft] data. Our own data basically looked at wild-type head and neck cancer because we were interested in that interaction. We also have seen some evidence of cetuximab resistance in this group. The question of combination with EGFR, is there a role for combination with immunotherapy? All these are very interesting questions.

However, as you very well know, accrual to the trial has been challenging. This is an international effort, and even though we’re checking on many of our patients, I think they are few and far between who end up being able to go on the therapeutic trial, which has been a source of frustration. I guess this is the way to go, especially that this agent seems to be beneficial in multiple tumor types. The good thing about the initial study is it proved its effectiveness in multiple tumor types, regardless of the primary tumor. Even though to different degrees perhaps, squamous cell head and neck cancer appears to be showing a very strong signal. But I think it goes to say that the molecular testing of tumors is very important in directing oncologic care rather than sometimes looking mostly at the primary disease sites.

Glenn J. Hanna, MD: I think the only thing I would add to the discussion about the original study, or the parent trial that walked us into squamous cell head and neck subgroup was that there were 2 interesting pieces to that study beyond the exceptional response rate that you mentioned and the durability. One was that the variant allele frequency of mutation seemed to matter. Patients who had upward of 20%, 35% or so allele fraction of the mutation seemed to do better. I’ve thought about why that would be the case, and the thought in talking to others is that perhaps there’s more of a driver role, or a driver function, or so-called oncogene addiction for that HRAS protein, that if you’re inhibiting the farnesyltransferase molecule that you’re shutting down that pathway.

The other piece is that they settled on a 600-mg twice daily dosing, on-off schedule, 1 week on and off, based on some toxicity that we can talk about. I would say on the whole though, it’s generally a well-tolerated medication compared to many of the cytotoxic agents that you and I are probably used to giving. What’s also interesting about the combination approach is that exactly as you said, besides the EGFR resistance mechanism of potential RAS activation, there’s a similar adaptive upregulation of the PI3K pathway. We’ve seen patients who have RAS inhibition for some time with any particular agent, and that pathway developed PI3K amplification or upregulation.

Kura Oncology, Inc, the company that sponsors tipifarnib, is launching a trial using a combination of tipifarnib with alpelisib, the pan-PI3K inhibitor. That study is their KURRENT [TIP-013] trial, which will combine those 2 agents to get at exactly your point, this idea of increasing capture. We know there are more patients with de novo PI3K amplifications or alterations who might benefit from alpelisib plus an HRAS inhibitor maybe, and then those who are HRAS amplified, or overexpressing, or mutated may get tipifarnib and perhaps get the benefit of the PI3K inhibitor if that’s a mechanism of resistance.

I know they’re looking to combine those 2 agents, but you’re right, it will be interesting to see if immunotherapy with a small molecular inhibitor is a good option or targeting with something like a next-generation EGFR molecule would be of interest. Those are all great points, and that would increase the capture because, as you pointed out, even though it’s an international effort, the trial has been slow to enroll for the follow-up study because it’s still only 3% to 8% of a relatively rare disease. We see a lot of head and neck cancer, but I think at each center, finding those patients and sequencing many patients to get 1 is what we’re all experiencing.

Transcript Edited for Clarity