 I think the only other thing on our agenda was the tolerability and safety. You can certainly comment. I’ve treated a number of patients with salivary gland cancer just because I see a fair volume, and patients with head and neck cancer, and overall compared to our other armamentarium, tipifarnib is generally well tolerated. It is an oral option. The schedule is a week on and a week off, 2 weeks on in the totality of a month, 1 on, 1 off. And patients generally feel pretty well. I did mention I’ve noticed some cytopenias, but often those are manageable. If you hold the dose or adjust the dose, it’s something that can be handled. In addition, the only event that’s a bit unique to the agent is the acute kidney injury, which is an increase in creatinine and subsequent BUN [blood urea nitrogen], but again, if you hold the drug, often hydrate the patient, it seems to settle, and then you dose adjust. Those are the dose-limiting issues I’ve run into. I would say on the whole though, people feel quite well on the drug and are often living and working, and it’s well tolerated. I don’t know what your experience has been.

 Yes, identical Glenn, to your experience. It’s exactly what you described, and I agree with what you said.

 It seems like we’ve covered a fair amount. We’ve talked about some exciting opportunities or agents in the head and neck landscape in terms of targeted or molecular therapies, where things stand in the recurrent metastatic setting. We spent a lot of time on how we test and what platforms we use for testing, whether they’re commercial or in-house. I think we agree that as long as you’re testing, that’s probably the most important thing, particularly in the recurrent metastatic setting. We mentioned tipifarnib’s mechanism, the rationale and the rate of 

 mutations in head and neck squamous cell cancers.

Then we summarized the tipifarnib data to date based on the initial trial, which got us to the correct dose and identified a squamous population of interest. Now we’re dealing with the pivotal study, which as you said, is an international effort that’s enrolling patients with 

 mutations regardless of variant allele frequency and has a matched cohort of wild-type patients to compare. Hopefully those results will be compelling and may lead to an indication for this drug in this population. I think that would be potentially the first targeted therapy, true traditional targeted therapy, for head and neck cancer, at least for a small molecule oral inhibitor in the recurrent metastatic setting. So we’re following right behind our lung cancer colleagues.

 Yes. I’m not sure it is right behind them, but I think following them, certainly.

 It is a series of steps. This has been a great discussion. I think we’ve hit the main points, I agree, Glenn. I really look forward a few years from now to reviewing the results of this accruing trial and having a new indication in recurrent metastatic patients. It would be the first really targeted agent, as you have rightfully indicated, and so I’m looking forward to an exciting future. It was a pleasure discussing this with you, and I look forward to more discussions.

 Yes. Take care. It’s always great to see you, Nabil.

Videos

Recommendations for mitigating and managing treatment-related adverse events associated with tipifarnib.

Managing Adverse Events With Tipifarnib

 Perhaps, Glenn, this is all very interesting, but to wrap things up, I was wondering what are your thoughts on future implications? What are your thoughts about how this will fit into the armamentarium in a recurrent metastatic setting and options of combination therapy? It would be nice if we can discuss this.

Yes, I think you made some good points before that it does seem to transcend the HPV [human papillomavirus] biologic boundary. I think we, you and I in particular, think a lot about HPV biology separately and want to try to tailor therapy even in the metastatic setting based on that. It’s also nice to see that patients, as you said, who potentially had initial immunotherapy in the first line or are platinum refractory from our more traditional agents, may benefit. What I’m taking away from this, assuming that this pivotal trial is successful, is that when patients show up with advanced incurable or recurrent metastatic disease, sending molecular profiling is crucial. And certainly, if you identify an alteration or missense mutation in 

, maybe regardless of variant allele frequency, we would hope that tipifarnib would be in our toolbox for those patients and get some durability.

I think further studies will be needed and might be challenging because it’s such a small population as to whether we sequence things differently. Do you give tipifarnib earlier? Should it be in the very first line, or should it be that we give it after immunotherapy? Is there some benefit to priming the immune system or exposing to chemotherapy? I think there are practical challenges; you may not have the sequencing information in front of you when you’re about to make a decision regarding systemic therapy, and you may want to get started with either an immunotherapy or chemoimmunotherapy option. It may naturally end up being more of a second-line drug, but I think that seems reasonable too, because second line right now is a pretty wide-open space for metastatic head and neck cancer. While there is some compelling evidence for cetuximab, plus or minus some other things, a lot of people are resorting to chemotherapy, traditional platinum, taxane doublets. So HRAS inhibition in the right patient would be very smart.

Then I think the same questions you’re hitting on, if someone does have benefit, can we salvage that by adding something else to it, whether that’s a PI3K inhibitor, an EGFR antibody, or some sort of EGFR pathway alteration agent? Or do we add an immunotherapy? It’s a good question, and I think it will be hard to study this population beyond this trial, only because of the small rate of patients who have these mutations. But perhaps we’ll see a subsequent small study that builds on these results as a comparator arm using those rational combinations you talked about. Certainly, the alpelisib plus tipifarnib study will be a nice next step for the evolving story of this. What are your thoughts?

: Yes, fascinating. I agree with what was stated. I always go back to what has happened in other diseases, like lung cancer. Even though this is such a rare situation, let’s remember also that the EGFR inhibition, when it started in lung cancer more than a decade ago, was very restricted to a certain group of patients who were difficult to probably get to. Then fast forward to the current situation where you have second-generation agents, you have agents that are used in the adjuvant setting. Those resulted from big international collaborations, and I think the way I look at tipifarnib and HRAS inhibition is basically the same way.

I’d like to see 5, 10 years from now a situation where we are at a better understanding of where exactly we have to use these drugs, and the field is wide open. What about definitive therapy? A patient with an 

 alteration, should this patient be treated the same way as we currently do for patients with radiation and chemotherapy? What about maintenance therapy? What about adjuvant therapy post- definitive therapy? All these are important questions. I understand head and neck cancer is not as common as lung cancer, for example, worldwide, but certainly there’s a large number of patients with recurrent metastatic disease. I think it’s going to take a lot of effort to answer these questions, but I think we’re in the first steps of this effort, and I really hope that this will make a huge difference in patients’ lives down the line. It is already doing that.

Glenn J. Hanna, MD, and Nabil F. Saba, MD, FACP, highlight potential new therapies for head and neck squamous cell carcinoma in various patient populations.

Future Directions in HRAS-Mutated Head and Neck Cancer

 We can talk a bit about the follow-up study, you alluded to it. It branched out of the initial trial, and this is the pivotal trial, the so-called AIM-HN [head and neck] or TIP-007 trial. Do you want to talk about how that trial involves or differs from the parent study?

 The new study, as you mentioned, looks deeper into the molecular alterations of the 

 alterations in head and neck cancer, so it looks at mutations but looks also at VAF [variant allele frequency]. I think that will give us better answers because if you look at the data from the first study, these patients, as you rightfully mentioned, do seem to benefit depending on the frequency of this alteration. The new study will be basically digging deeper into looking at these subgroups of patients to see whether the approval or the use of tipifarnib should be in all of these patients versus a certain group of patients. If you look at the responders in the first study, all of them had alterations, and all of them had a VAF that exceeded the threshold I believe of 30%. This is an indication that the type of test that we get matters for future prediction of clinical activity.

It will be a larger study, a definitive study, as you said. It will look deeper also into the tolerance of the treatment, the clinical activity of the treatment, and it’s focused on head and neck cancer, given the responses we’ve seen in the first trial. I think the very interesting aspect you also mentioned is that interaction with EGFR and the PI3 kinase. There is clearly an interaction between the 

 and these. These tumors appear to not be having 

 alterations when you look at the genomic characteristics; these tumors appear to be somewhat excluding patients with 

. So, there’s something we need to learn about the biology, how to dig deeper into identifying a subset of patients with head and neck cancer who should be targeted differently. The interesting part also is it seems to be cutting across the HPV [human papillomavirus]-positive and negative, more so HPV-negative group. We look forward to of course seeing results and to improving accrual and getting an FDA approval. I think the FDA priority status of tipifarnib is a good indication that even if you have a small study, that is making a difference for patients who have otherwise very few options of care. Certainly, that is a path to approval, and it is really nice to see that.

 I thought it was interesting that with the companion piece to the study, the so-called AIM component with the active drug for patients with 

 mutations, they’re also looking at this 

 wild-type, the SEQ component of the trial, the SEQ-HN part, which is another few hundred patients. They’re collecting disease history and first-line outcome data to prospectively match with the 

-mutated folks to compare response rates and trajectory. I think that’s meaningful. It’s always great to see a molecularly targeted agent deliver a response rate and durability for a small group of patients, but it’s also valuable to see how that compares to patients who are on our other standard options more generally, like immunotherapy or in the platinum-refractory setting. I thought that was an interesting component of the design, that they’re doing a matched, sort of synchronous or analogous study in the 

Glenn J. Hanna, MD, and Nabil F. Saba, MD, FACP, discuss the design and potential clinical implications of the AIM-HN trial of tipifarnib in head and neck cancers.

Pivotal AIM-HN Clinical Trial of Tipifarnib in HNSCC

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 

 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 

. But it does seem quite effective in patients with 

 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 

 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 

 mutations and how that evolved into the more recent AIM-HN study?

: This is, as you indicated, a very interesting history of 

 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 

 mutation, has become of significant interest, given, as you mentioned, the differences in 

The initial study focused on tumors that had 

 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 

 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 

 expression. Preclinical data suggest that tumors that harbor the 

 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.

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 

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 

 amplifications or alterations who might benefit from alpelisib plus an HRAS inhibitor maybe, and then those who are 

 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.

Potential implications for treating patients with HRAS-mutated head and neck cancer with tipifarnib, based on results demonstrated by the RUN-HN study.

Tipifarnib in HRAS-Mutated HNSCC

 Speaking of the pros and cons or the limits and benefits of targeted options for head and neck cancer, albeit somewhat less compelling than other spaces right now, how are you incorporating molecular testing in your practice? Are you using a commercial or an in-house assay? Who are you testing, is it everyone with recurrent, incurable, or metastatic disease? Are you selective, or even do you do it sooner than that?

: Very good question. I want to say that things have progressed and improved over time. I think a few years back we were not testing many patients, but since the approval of immune checkpoint inhibitors, we have been testing more and more. At our center, I can tell you not every patient is getting a genomic analysis, which is something I think we strive to achieve, at least, because I believe with the 

 story, certainly it makes sense to check for recurrent metastatic patients. If you go to other histologic types, we check everyone, like for thyroid cancer, for example, saliva gland carcinomas, there’s a very low threshold of checking, and I would say we check on all patients.

But squamous cell cancer of the head and neck, we have not really gotten there to check on everyone, even though I think we should be getting there. Glenn, you may want to comment. Perhaps at your center it’s a little different. We’re all in academic large tertiary centers, but the practices may differ among the different centers. To answer your question about whether we use an internal test, we do it for certain tumor types. Like lung cancer, we have our internal panel. We could certainly use it as well for other diseases, including head and neck squamous cell carcinoma, but we’re also partnering with commercial entities. Our cancer center as a whole has partnered with commercial entities to basically do this in an easier way. We have ongoing discussions to improve on the frequency of testing and on structuring this in a way that benefits patients the most. As you know, it’s a work in progress.

 I would say we’re approaching molecular testing similarly. On the whole, my group has been proactive about sequencing anyone with recurrent, incurable, or metastatic disease, trying to capture everyone. But certainly, if they felt the patient was well enough to potentially receive something in that context, we definitely test them, if tissue is available and not exhausted. We try to prioritize a more recent biopsy. Obviously, a fresh sample is always great, but we’re often testing archival tissue from a biopsy that proves recurrent metastatic disease. But we will test the original resection or original tumor if that’s all we have.

Luckily, it seems like a lot of head and neck mutations are earlier events, where there may not be resistance evolution in some of the founder events like 

alterations, or tumor suppressor alterations. I feel like we’re comfortable checking the primary tumor in many patients. I would say we do use a mix of commercial assay or in-house testing. We do also have an in-house panel test that covers almost 400 genes and 60 introns or rearrangements, so I would say it’s a mixed bag. Sometimes the commercial tests can be a little more streamlined because they’re a more refined program or entity. It’s mixed, but they usually report, thankfully, the same information, as you alluded to. We usually are able to get PD-L1 status for immune marker, and then we get the mutations of interest, as you mentioned, 

, all of those alterations, and any amplifications. 

 amplification, although it may be a bit unusual, can be of interest if you’re thinking about using something like an EGFR antibody or whatnot.

I think it’s across the board, I agree with you. I think community oncologists are starting to recognize that we, as head and neck oncologists, do value the genomic testing results beyond just PD-L1 immune testing. I’ve seen a lot more patients come to me with squamous cell head and neck cancers in the advanced setting with testing in hand from commercial vendors or commercial platforms, which is great because it streamlines care a bit. Do you ever repeat testing in the trajectory of a patient’s course if someone is no longer responding, or are there any time points where you repeat testing?

 Fascinating question. I tend to do that, yes, in certain situations where, for example, the patient has now recurrent metastatic disease. They were treated 5 years ago for locally advanced disease, and we have tissue from that time. I think those are clearly patients who need additional testing, who need another look. Even in patients who may have new onset of recurrent metastatic disease, for example, I tend to want to rely more on the most recent biopsy to try to get a more accurate answer as far as what’s driving the disease. Even though, as you know, in squamous cell cancer, the changes over time do happen, but the lack of actionable mutations or the paucity of these I think has resulted in people not checking too much. To follow up on what you said, I think cancer centers in general should lead the way to set the example, if I can use this term, for others to follow through. Certainly, PD-L1, PD-1, no question, that needs to be done on every patient with recurrent metastatic disease. This is the situation we’re in, but to answer your question, yes, I do tend to sometimes retest.

 I would say maybe I would do it more if resources were also permissive. Also, as you pointed out, if we knew there was some sort of event that predicted, or we knew someone was going to develop resistance, and there were some predictable resistance mutations or pathway alterations, it might be more compelling. This is the case in lung cancer, where sequential genomic testing is employed, whether in the tissue or in the bloodstream or plasma. I’m hopeful that someday we’ll get there with head and neck cancer.

Guidance for incorporating initial and repeat molecular testing in head and neck cancers into clinical practice.

Molecular Testing in HNSCC

 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 

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.

: 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 

, 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.

 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. 

 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 

 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 

 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 

 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?

 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 

 mutation was just discovered in lung cancer, and this opened the door for different mutations and different targeted agents. Even though 

, 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.

 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.

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

Nabil F Saba, MD, FACP, Emory University

Articles

Managing Adverse Events With Tipifarnib

Future Directions in HRAS-Mutated Head and Neck Cancer

Pivotal AIM-HN Clinical Trial of Tipifarnib in HNSCC

Tipifarnib in HRAS-Mutated HNSCC

Molecular Testing in HNSCC

The Evolving Treatment Landscape of HNSCC