Join Dr Aarti Bhatia and Dr Deborah Wong for a discussion on the current and evolving treatment landscape in head and neck squamous cell carcinoma (HNSCC), including IO-based therapy, EGFR-targeted bispecific antibodies, antibody–drug conjugates, HPV-targeted vaccines, and novel radiosensitizers. Explore the latest phase III clinical trial data and emerging treatment sequencing strategies shaping the future of care for HPV-positive and HPV-negative patients with head and neck cancer. Listen now to stay ahead of the latest advances in HNSCC treatment.
In this episode, Dr Aarti Bhatia and Dr Deborah Wong discuss the rapidly evolving treatment landscape for recurrent, metastatic, and locally advanced head and neck squamous cell carcinoma (HNSCC), including the growing role of immune checkpoint inhibitors, perioperative treatment strategies, EGFR-targeted bispecific antibodies, antibody–drug conjugates, HPV-targeted vaccines, and novel radiosensitizers. The discussion also explores emerging phase III clinical trials, treatment sequencing considerations, and future precision oncology approaches for HPV-positive and HPV-negative patients with head and neck cancer.
Presenters:
Aarti Bhatia, MD, MPH
Associate Professor of Medicine (Medical Oncology)
Clinical Research Team Leader, Head and Neck Cancers Program
Yale Cancer Center
New Haven, Connecticut
Deborah J. Wong, MD, PhD
Director, Head and Neck Medical Oncology Program
Associate Clinical Professor of Medicine
Division of Hematology/Oncology
University of California, Los Angeles (UCLA)
Los Angeles, California
Link to full program:
https://bit.ly/49kViqg
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This transcript was automatically generated from the audio recording and may contain inaccuracies, including errors or typographical mistakes.
Advanced and Improving Therapies for Head and Neck Squamous Cell Carcinoma
My name is Aarti Bhatia. I am a Medical Oncologist at Yale. I have with me my esteemed colleague, Dr. Wong from UCLA.
We are going to be really talking about the current standard of care in treatment of head and neck cancers, both primarily recurrent metastatic, but also delving into some recent changes that we are seeing with treatment of locally advanced disease. Then we will also talk about some exciting new therapies that are on the horizon and some trials that are investigating these agents. Many of these are in the late phase and phase III now.
Dr. Wong, let me start off by asking you, how do you currently manage your patients with recurrent metastatic disease? How do you see their treatment paradigm in first-line, second-line. Feel free to elaborate based on HPV status or whatever other biomarkers you think are important here?
Dr. Deborah Wong (University of California, Los Angeles): Thanks so much, Dr. Bhatia. I am Dr. Deborah Wong, a Medical Oncologist at UCLA. I have to say and I am sure you agree Dr. Bhatia, it is really exciting times these days for patients and providers of patients with head and neck cancer.
In the setting of recurrent and metastatic head and neck cancer, really the field has changed, I would say, in the last decade or so now with the incorporation of anti-PD-1 immunotherapy in the front-line recurrent and metastatic setting.
We are now seeing exciting practice-changing incorporation of anti-PD-1 immunotherapies in the perioperative space as well. Back to your question as to how do I manage patients with recurrent and metastatic head and neck squamous cell carcinoma?
For these patients right now, our standard of care treatment decisions are really predicated on PD-L1 CPS score, programmed death-ligand one combined positive score. Here, this helps us to prioritize pembrolizumab, how we are going to use primarily immunotherapy in that space.
For patients who have a Pd-L1 CPS score of one or higher, pembrolizumab monotherapy is something that I will treat patients with. Certainly, if patients have a higher CPS score of 20 or higher, I may be more inclined to use pembrolizumab monotherapy. For patients who have bulkier disease or who have a lower CPS score, standard of care I generally use chemotherapy plus immunotherapy.
It is important to note that these standard of care treatments really we are thinking about them in all patients. We know that squamous cell head and neck cancers behave differently depending on other factors, including things like HPV relatedness and things like that.
Some of the exciting things that we are seeing both in later line, but also moving to the front-line setting are emerging data and research looking at novel combinations but distinguishing treatments based not just on PD-L1 status, but based on things like HPV status.
Standard of care is pembrolizumab or pembrolizumab plus platinum-based chemotherapy. What about for you, Dr. Bhatia?
Dr. Bhatia: Yes. No, I completely agree. Of course, prognosis matters and is different based on HPV status, like you mentioned. HPV-positive patients tend to live longer, tend to have more treatment responsive disease.
We see some of our worst prognosis is associated with bulky locoregionally recurrent HPV-negative tumors. For these patients, we know their median overall survival, on the lower side, it is about a year. That is where we really need new paradigms, new treatment options, newer drugs to improve their cure outcomes at the time of locally advanced disease and to give us better longevity, better duration of response and better overall survival in the recurrent metastatic space.
I agree with your management. We follow a very typical and similar pattern of treatment with either pembrolizumab monotherapy or in combination with chemotherapy based on PD-L1 status and tumor bulk. Of course, an exciting development has been our ability to offer now pembrolizumab in the perioperative space like you hinted at.
Two key trials: KEYNOTE-689 and NIVOPOST-OP, both showed that adding immunotherapy to perioperative treatment seems to improve three-year disease-free survival, three-year event-free survival. Those were the endpoints of those trials.
In the United States, immunotherapy, pembrolizumab in particular has been approved by the FDA. Any patient with stage III up to IVa locally advanced, especially HPV-negative head and neck cancers that are being planned for surgery, we are now offering two cycles of preoperative pembrolizumab too, if their PD-L1 CPS is one or higher. Then the pembrolizumab continues in the post-operative stage with radiation with or without chemotherapy based on the pathologic risk stratification.
Then pembrolizumab continues for up to one year. That is what the KEYNOTE-689 trial demonstrated to that these patients who got the pembrolizumab, had improved event-free survival at three years.
To your point, about 40% patients will still have recurrence or metastases and will need better treatment options in the recurrent metastatic space. Again, these are patients who are poor prognosis, especially the HPV-negative. What do you think are some of the upcoming exciting treatments that we are starting to see in early phase trial and hopefully will be replicated in late phase trials too?
Dr. Wong: Yes, that is a great question. I will say that in the perioperative space, our management for surgically resectable patients is quite similar. It introduces a lot of new and exciting challenges with regard to workflow and incorporating immunotherapies into the perioperative space.
Hopefully, with the incorporation of anti-PD-1 immunotherapy in the curative setting, we are able to cure patients with fewer patients relapsing. However, of course, we know that in the setting of relapsed patients still need great good treatment options.
In that regard, thinking about HPV-negative disease and we know that these are patients who have the worst prognosis, as you mentioned, really exciting data have emerged really looking at anti-EGFR targeting strategies.
This is really built on data evaluating cetuximab in combination with pembrolizumab or nivolumab in several studies that demonstrated that the combination, particularly in HPV-negative patients, really improved outcomes in terms of response rate and progression-free survival, compared to historical controls with pembrolizumab.
Now there are several newer generation anti-EGFR antibodies and targeted approach that are being incorporated, all of which have been very exciting, particularly for HPV-negative patients. Some of the ones for which we have emerging early data and that have now moved into late phase trials include bifunctional antibodies.
One example is ficerafusp alfa, or BCA101, which is being evaluated in combination with pembrolizumab. In the phase I study, the objective response rate was 54%. The really exciting thing is that not just was progression-free survival good, but median duration of response was about 21 months. The median overall survival from this early phase study was nearly 22 months.
We put that in perspective with what we know about survival for pembrolizumab monotherapy or pembrolizumab, even with chemotherapy from KEYNOTE-048, where median overall survival there only is 13 months for all comers. If you look at the HPV-negative patients. With pembrolizumab monotherapy, overall survival is much more modest. Here, potentially we are seeing a significant improvement in outcomes.
This is only one example. Petosemtamab is a second agent. That is a bispecific antibody targeting EGFR and LGR5. Petosemtamab as monotherapy, has shown very exciting response rate data. This is post-platinum and post PD-1 in many cases. Similarly, this has now given rise to ongoing phase III trials, both in the front-line and second-line setting.
Of course, a third bispecific antibody is amivantamab, which you may be familiar with from lung cancer, but this is a EGFR cMet antibody, and they have an ongoing study with multiple different cohorts, but amivantamab as a single-agent in the post-platinum post PD-1 setting had very impressive responses of about 40% or so as well.
Three different examples of novel strategies targeting EGFR that really are exciting in this space and have now moved into frontline setting as well.
What about your thoughts, Dr. Bhatia?
Dr. Bhatia: No, I completely agree. All these agents have generated a lot of excitement with their early phase data. Like you mentioned, their phase III trials are enrolling slightly different patient populations. It is important to note that because based on the patient you see, one trial might be better suited than another.
Then petosemtamab is in both frontline and in late line, so second and third-line treatment option. In the first-line, that is the LiGeR-HN1 trial. It is a randomized design again, pembrolizumab monotherapy versus pembrolizumab and petosemtamab given in combination. The trial allows HPV-positive patients to enroll as well.
Then in late line, patients should have progressed on both anti-PD-1 therapy and platinum-based chemotherapy randomized to petosemtamab or investigator's choice systemic therapy, which can be cetuximab or 5FU or a taxane. Again, both HPV positive and negative patients are being enrolled.
Then amivantamab in phase III, OrigAMI-5. That is a slightly different design. It is randomized phase III in first-line only, allows all PD-L1 expressing patients. The petosemtamab and ficerafusp trials allow just PD-L1 CPS one or higher, but with OrigAMI-5, they allow any PD-L1 expression. That is because their control arm is pembrolizumab and platinum doublet, an FDA-approved regimen for first-line recurrent metastatic treatment.
Hopefully, you can enroll your patients to one of these options. It might offer them the added benefit of a dual targeting EGFR agent. Hopefully fewer toxicities, better response rates, and hopefully improved overall survival. Always very exciting times, I think after a long time where we have so many different agents on the horizon, especially for HPV negative patients.
Dr. Wong: A lot of the exciting studies are really focused on the frontline setting with anti-EGFR targeting strategies. What are you excited about in the second-line and third-line space for these HPV-negative patients?
Dr. Bhatia: Yes, absolutely. There is an ongoing phase III trial. It is called the FIERCE-HN. We all know in the second-line space beyond progression on immune checkpoint therapy and chemotherapy, really our go to standard of care for HPV-negative patients is cetuximab. This trial is a randomized design. It is exploring the combination of cetuximab and ficlatuzumab, which is a HGF/c-Met pathway targeting monoclonal antibody.
The control arm is cetuximab alone. Initially, the trial was exploring two different dose levels of ficlatuzumab in combination with cetuximab. They have narrowed down to the more effective dose, which is the higher dose and that combination is now being compared head-to-head with cetuximab alone.
They had a phase II trial which explored a similar randomized design of the combination of two agents versus ficlatuzumab. The ficlatuzumab arm closed early, but then the combination of the two agents showed a 38% response rate in HPV-negative, which I consider very exciting again, if you think about cetuximab in this space.
Then you mentioned in other second-line trials, there is a lot of exciting antibody drug conjugates on the horizon now. A couple that come to mind are CRB-701, It is a Nectin-4 targeting next-generation antibody drug conjugate. It was explored in both HPV-positive and negative patients who had no standard of care treatment options.
They presented results from two dose levels at ESMO last year. The response rates were 33% and 47% for the higher dose level. The common side effects that you expect with these antibody drug conjugates can be keratitis, which was seen with this agent as well. You can also expect to see some neuropathy, maybe cytopenias because the payload is vedotin. It is a microtubule inhibitor.
Then similarly there is a ROR2-targeting antibody drug conjugate, that is ozuriftamab vedotin. Those updated results were recently presented at the Head and Neck Conference in February. They are looking to explore that mainly in the oropharynx cancer population. Their initial objective response rate was 45% in 11 patients.
That is also going to be interesting to look at as they move into hopefully phase III soon.
Dr. Wong: Yes. Also I agree with you, in the second-line space, lots of excitement around antibody drug conjugates. Nice to see that at least with the ROR2 ADC, we are perhaps starting to think about tailoring therapies based on not just what the patients have been previously exposed to, PD-L1 status, but now maybe even HPV status. Maybe moving towards an era where we are thinking about treatments based on disease biology more.
What about in the frontline space for HPV-positive disease?
Dr. Bhatia: Yes. There are a couple HPV 16 specific therapeutic vaccines which contain HPV 16 oncoprotein neoantigens, which are expected to improve responses to immune checkpoint therapy. Two such vaccines come to mind. There is the PDS Biotechnology vaccine in phase II trial data, which was a high response rate in patients with treatment-naive HPV-positive recurrent metastatic disease.
These patients were treated with a combination of pembrolizumab and the PDS Biotechnology vaccine. They are expecting to start enrolling into phase III pretty soon.
Another vaccine is the BioNTech drug. It is BNT113, which is also in phase III. Their safety lead-in cohort had showed a response rate of about 40% in combination with pembrolizumab. They currently are hopefully about to end soon enrolment of phase III. It is a randomized design for pembrolizumab versus pembrolizumab plus the HPV vaccine.
Absolutely, and for the first time stratify treatment, not just based on PD-L1 status, but also based on HPV status, because we have known for a while these diseases are biologically distinct. They behave differently. They respond to treatments differently. Hopefully, we will have more tailored treatment options for these patients in the future.
Moving on a bit from the recurrent metastatic space now. There are some newer radiosensitizing agents as well that are in development. Unfortunately, the last agent that was looked at in this space that was xevinapant, encouraging results in phase II, but then did not quite hold up in phase III. There is a great unmet need for these patients, right?
We have cisplatin, but a lot of patients are not able to receive cisplatin. We definitely need less toxic and more effective radiosensitizing agents for these patients. Are you aware of any interesting agents in this space? Anything you are excited about?
Dr. Wong: Yes, most definitely. Not all patients are candidates for perioperative. They are not surgically resectable. Even amongst that, as you pointed out, for the patients who only are left with definitive chemoradiation as a potentially curative option, not all of those patients will be candidates for the tried and true cisplatin. Really standard of care options there would be radiation alone.
In selected cases, we may consider cetuximab in combination with radiation. We know that outcomes are not very good if we are not able to use cisplatin chemotherapy.
One exciting agent is an agent that really seeks to enhance the radiosensitivity of tumors. You mentioned xevinapant, very exciting, however, did not bear out in phase III studies. We have another molecule quite different and quite novel, JNJ-1900, formerly known as NBTRXR3, which is a radio enhancer.
Essentially, it is composed of functionalized hafnium oxide nanoparticles. These are administered as an intratumoral injection, both in the primary tumor as well as the involved lymph nodes as a one-time dose and before start of radiation. There is an ongoing randomized phase II/III study, in which patients who are ineligible for platinum-based chemotherapy can enroll on this study.
Patients are randomized to either standard of care, which can be radiation alone or radiation with cetuximab or standard of care, plus this intratumoral injection. The idea being that incorporation of JNJ-1900 will enhance the efficacy of radiation for these patients.
This is something that we have been very excited about. Patients are really excited about it as well as it is a one-time procedure. They then proceed with their standard treatments. The mechanism is just so cool and novel.
Dr. Bhatia: Right. In theory, this could be scaled to any other tumor type as well that needs radiation treatment. Definitely stay tuned for that.
Dr. Bhatia, let us say five years from now, hopefully the treatment landscape will look much different. What do you anticipate the treatment landscape will look like, and how would you think about sequencing treatment for your patients?
Dr. Bhatia: Yes. Great question. I would hope that we have an EGFR bispecific antibody that is approved in the next year or two. Hopefully, we have an HPV 16 specific vaccine that is approved around the same time point.
Presuming these results that we are seeing in early phase trials hold up in phase III as well and these patients truly have a benefit in terms of response rate and overall survival, then, of course, for an HPV-negative patient, I might start treatment with an EGFR bispecific and pembrolizumab as long as they are PD-L1 CPS positive.
Beyond progression on that, we might have options like chemotherapy which will be pushed to second-line, of course. There is also hopefully an option of an antibody drug conjugate if one is approved by then. It offers us a few other options for these patients.
If you have more than one EGFR bispecific approved, of course, that question is going to come up, how do you sequence an EGFR bispecific after another one. I think, and this is a bit premature to know, of course, but because the second target of all these EGFR agents is different, maybe after sandwiching another systemic therapy like a chemotherapy or an antibody drug conjugate in second and third-line, we may end up wanting to try another EGFR bispecific down the line.
Those would be how I sequence HPV-negative patients. How do you foresee sequencing treatment for HPV-positive patients?
Dr. Wong: Yes, that is a great question. If I had my wish list, we would have something like one of our vaccine studies that will read out positively. For such patients, I would envision an HPV-targeted strategy, perhaps a vaccine in combination with pembrolizumab for patients who are PD-L1 positive.
Hopefully, at least the rationale is that if we can better interrogate the immune system, we are going to have a very durable responses here. Hopefully, not very many of them will require additional therapies. But should they require additional therapies, then similar to what we have available, cytotoxic chemotherapy remains an option, and antibody drug conjugates, perhaps one specifically targeting with activity in HPV-positive patients such as the ROR2 antibody drug conjugate.
Overall, the strategies we have right now are really focused on patients with PD-L1 CPS positive disease, which, based on the KEYNOTE-048 data, comprises 85% of patients. That still leaves a significant population of patients who would not be eligible for what is currently available in terms of a chemo-free regimen.
There is more to be done there. There is also a lot more to be done for patients in the curative intent setting who have locally advanced disease, but in particular those who are not candidates for surgical resection. Hopefully things like better agents in the curative intent setting, be they EGFR-targeted antibodies or vaccine type approaches might also come to the fore. That is going to further complicate in a good way the idea of treatment sequencing as well.