Tipifarnib in HRAS-mutant Head and Neck Squamous Cell Carcinoma - Episode 1

The Evolving Treatment Landscape of HNSCC


A brief overview of treatment advances for HRAS-mutated head and neck squamous cell carcinoma.

Glenn J. Hanna, MD: Hello, my name is Glenn Hanna. I’m a medical oncologist in the Center for Head and Neck Oncology at Dana-Farber Cancer Institute in Boston, Massachusetts. I’m joined today by Dr Nabil Saba. He is the head and neck cancer program director at Emory University in Atlanta, Georgia. We’re thrilled to talk to you a bit today about the HRAS-mutated head and neck cancer landscape.

Thanks for joining, Nabil. I think our first task is to talk a bit about how we would describe the current landscape of head and neck cancer and what we think are the most unmet needs in our disease at this time. Maybe you want to start, and I’m happy to jump in after you’ve given some of your thoughts.

Nabil F. Saba, MD, FACP: Hi, Glenn. It’s nice to see you. We’re still in a virtual situation here, but I’m glad to be part of this discussion. I think the landscape is very interesting and certainly very exciting. Over the last 4 years, we’ve seen the big excitement with immunotherapy being approved, with 2 PD-1 inhibitors approved in the recurrent metastatic setting. We’re seeing this moving now to the definitive therapy setting with trials that are accruing. We’re seeing an unprecedented, I think, international collaboration in head and neck cancer, with centers from Europe, Southeast Asia, China, and the United States participating in landmark studies, and hopefully that will make a big difference for patients.

We’re starting also to decipher the molecular characteristics of head and neck cancer and focus on specific targets. I think the topic of today is HRAS, but I think the field is open to additional discoveries in the future. I’m very glad to be part of this, and I look forward to changing the standard of care for a much-needed patient population. As you know, patients with head and neck cancer don’t have a large number of approved agents, certainly in the recurrent metastatic setting. As an introduction, Glenn,what do you think about the state of targeted therapies in this disease? I think it would be nice to have an overview of this.

Glenn J. Hanna, MD: When I was reflecting on your comments, just before I go into that, about unmet need, for me some of the interesting areas, as you said, first and foremost, in the recurrent metastatic setting, we lack significant amount of molecular targeted options. For better or worse, we rarely subdivide patients based on those molecular options to tailor treatment, unlike something such as lung cancer, where there’s quite a large pie and there are a number of different actionable molecular alterations. The other 2 spaces where I’m, in my career, hoping to see evolution are in the HPV [human papillomavirus]-negative or carcinogen-related head and neck cancer definitive population where we’re aiming for cure. For those patients, we’re still thinking about how we can tailor or add to chemoradiation to improve outcomes. One example has been some interesting data from the SMAC mimetic, the Debio 1143 compound, so hopefully that may turn out positive. Then the other space for me is the recurrent resectable group, so people who have definitive treatment and then are candidates for salvage surgery when they relapse. That’s a really high-risk group, and I know there’s a lot of interest in helping that particular population before they become truly incurable.

In terms of the targeted therapies and the landscape right now, there are a number of things I think about. Going through a bit of history, there was the addition of bevacizumab, the VEGF monoclonal antibody, to chemotherapy that unfortunately in the advanced setting didn’t really pan out in terms of improved outcomes and had increased bleeding risk. We saw that in an ECOG trial a few years ago.

Of course, we can call cetuximab in some context a targeted therapy. It’s an EGFR monoclonal antibody, which I think what’s been really exciting has been the first-line data that were shared by Assuntina Sacco, MD, in her recent publication and then by Christine Chung, MD, at Moffitt Cancer Center looking at PD-1 inhibition with cetuximab in the first-line advanced setting for patients who are recurrent or metastatic. Those data are pretty compelling with response rates, at least from those 2 phase 2 multicenter trials, ranging from about 38% to 45%, so I’m hopeful about that synergism.

From more traditional targeted agents, of course we’re going to spend time talking about tipifarnib. HRAS mutations occur in about 3% to 8% of patients with recurrent metastatic head and neck cancer, so that oral targeted therapy will be the focus of our discussion for some of this talk. But that’s obviously exciting and is a group of patients we want to match to their HRAS mutation. Some other areas of interest, the HGFR monoclonal antibody, ficlatuzumab, in combination with cetuximab, and also the NKG2A or CD94 monoclonal, monalizumab, in combination with cetuximab. Those antibodies have shown some promise.

Palbociclib is of interest, a CDK4/6 inhibitor. There’s been a lot of interest even though head and neck cancer is a microsatellite stable disease traditionally, and we don’t see a lot of instability. There is a question of how much DNA repair issues in head and neck cancer may be important and whether to utilize PARP inhibitors alone or in combination. I think there’s a lot of interest in that. A couple of other things, you mentioned immunotherapy, and we’re now seeing the addition of multitargeted VEGF inhibitors, like lenvatinib, in combination with immunotherapy, so I think that’s of interest.

Then an old drug, probably the last one I can think of right now, is targeting the PI3K pathway. There’s been a lot of interest in earlier drugs like buparlisib, the pan-PI3K inhibitor, copanlisib, and now alpelisib, and some of the more isoform-specific PI3K small molecule inhibitors or tyrosine kinase inhibitors. What’s been unfortunate is, it looks like at least in some studies alone or in combination, while there may be some signal for potential benefit, to my understanding there hasn’t been a great correlation with PI3K amplification or alteration. And we saw that from the BERIL-1 trial in follow-up when they analyzed the molecular data. While small and ad hoc, there wasn’t a great correlation with benefit based on PI3K amplification or mutation. That was a long list, but those are the drugs I can think of that will probably be of interest if we’re thinking about molecular therapies in head and neck. Did you have others, Nabil?

Nabil F. Saba, MD, FACP: I was reflecting on what you said. You’re absolutely right, this has been a frustrating path for head and neck oncologists, and you see the different molecular targeted agents that are available in different diseases. Certainly, the pace of progress has been slower for head and neck cancer. However, I always remember the era when the EGFR mutation was just discovered in lung cancer, and this opened the door for different mutations and different targeted agents. Even though HRAS, which is the topic of our discussion today, is present as you said, in 3% to 8% of patients with head and neck cancer, I think it’s a big step forward. Because, as you also rightfully mentioned, cetuximab, we think of it as a targeted agent. It’s not really a targeted agent because you’re not really targeting a molecular alteration. It happens that EGFR is expressed in head and neck cancer, and it happens that cetuximab is clinically active. But as you very well know, all the data on EGFR expression, and whether it correlates with benefit to cetuximab treatment or any EGFR inhibition, have basically failed to show any promise there.

I think the data we’re seeing with HRAS really open a new door for a newer targeted agent. You mentioned many, which I think all are exciting, but also have been disappointing in a sense that they did not lead to a clinical.... These molecular alterations are quite common. If you look at PI3 kinase, FGFR, essentially those are fairly common in the genomic picture of head and neck cancer. Perhaps the example of cetuximab, and PEMBRO [pembrolizumab], and as you mentioned, our study with cetuximab and NIVO [nivolumab], would be something of interest in the future, given that immunotherapy has I think changed the equation completely. Now we’re in a situation where combination therapy with immunotherapy probably makes sense in many cases. That’s all I have to say. I don’t want to expand too much on this, but clearly, we’re still in a very exciting field despite the slow progress relative to other diseases.

Transcript Edited for Clarity