Immunotherapy and Biomarker Testing in R...

Dr. Emrullah Yilmaz reviews the latest evidence and recommendations for health care providers on biomarker testing and immunotherapy for head and neck cancers. He discusses the ASCO Expert Panel’s recommendations for biomarkers for the selection of patients with head and neck squamous cell carcinoma for anti-PD-1 immune checkpoint inhibitor therapy. Additionally, he reviews recommended treatment options, including first-line treatment based on PD-L1 status, therapies for platinum-refractory disease, options for patients with nasopharyngeal cancer, the role of radiation therapy for oligometastatic head and neck cancer, and immunotherapy for rare head and neck cancers. Dr. Yilmaz also explores future areas of research for therapeutic options for patients with head and neck squamous cell carcinoma.

Read the full guideline, “Immunotherapy and Biomarker Testing in Recurrent and Metastatic Head and Neck Cancers: ASCO Guideline” at www.asco.org/head-neck-cancer-guidelines.

TRANSCRIPT

Brittany Harvey: Hello, and welcome to the ASCO Guidelines podcast series, brought to you by the ASCO Podcast Network; a collection of nine programs, covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at: asco.org/podcasts.

My name is Brittany Harvey, and today I'm interviewing Dr. Emrullah Yilmaz, from Cleveland Clinic in Cleveland, Ohio, lead author on, 'Immunotherapy and Biomarker Testing in Recurrent and Metastatic Head and Neck Cancers: ASCO Guideline’.

Thank you for being here today, Dr. Yilmaz.

Dr. Emrullah Yilmaz: Thank you so much.

Brittany Harvey: Then first, I'd like to note that ASCO takes great care in the development of its guidelines, and ensuring that the ASCO Conflict of Interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology.

Dr. Yilmaz, do you have any relevant disclosures that are directed related to this guideline topic?

Dr. Emrullah Yilmaz: No, I don't have a relevant disclosure.

Brittany Harvey: Thank you. Then let's dive right into this guideline.

So, generally, what is the purpose and the scope of this guideline?

Dr. Emrullah Yilmaz: Immunotherapy with anti-PD-1 immune checkpoint inhibitors has become one of the most important treatment options for patients with recurrent metastatic head and neck cancers. And in the last few years, there has been new studies leading to new indications such as combinations with chemotherapy, or single-agent immunotherapy in the first-line treatment. And moreover, several studies also shown the effectiveness of immunotherapy for patients with nasopharyngeal carcinoma. All these advances in this complex disease group made it necessary to have an evidence-based guideline. So, that was the basis of building this guideline.

Brittany Harvey: Understood. And then this evidence-based guideline addresses six clinical questions. So, I'd like to review the key recommendations for each of those questions for our listeners. So, let's start with the first question. What did the expert panel recommend regarding biomarkers for selecting patients with head and neck squamous cell carcinoma for anti-PD-1 immune checkpoint inhibitor therapy?

Dr. Emrullah Yilmaz: Biomarkers are key for selection of treatment for immunotherapies, especially for the first-line treatment for head and neck cancer patients. PD-L1 is measured by immunohistochemistry and reported as Combined Positive Score, CPS, or Tumor Proportion Score, TPS. CPS is slightly different than TPS, and it includes lymphocyte and macrophage PD-L1 expression, in addition to tumor cells. Head and neck cancer studies have shown that CPS is a better marker for predicting response to immune checkpoint inhibitors, and key head and neck trials started to use CPS for reporting PD-L1 status. Therefore, we recommend CPS for recurrent metastatic head and neck cancers for PD-L1 reporting. This also makes it important for the oncologists to have a communication with the pathologists to make sure the right PD-L1 scoring is reported for head and neck cancer patients. Tissue tumor mutation burden is another emerging biomarker when CPS is not available, or for rare head and neck tumors, tumor mutation burden can be used as a biomarker as well.

Brittany Harvey: Great. And then based on that PD-L1 status that you just mentioned, what is the optimal first-line treatment regimen for patients with recurrent or metastatic head and neck squamous cell carcinoma?

Dr. Emrullah Yilmaz: If PD-L1 is positive, which is CPS more than one, there are two different options. Both pembrolizumab, single agent or pembrolizumab plus chemotherapy with platinum and 5-Fluorouracil can be offered. KEYNOTE-048 study showed an overall survival benefit with pembrolizumab alone for patients with CPS more than one, which was greater for the patients with CPS 20 or more. However, the pembrolizumab plus chemotherapy has showed benefit for the patients regardless of the PD-L1 status. So, if an early response is needed for a patient with high disease burden, pembrolizumab with chemotherapy could be an option, even if the PD-L1 is positive. For patients with negative PD-L1, which is CPS less than one, we recommend pembrolizumab and chemotherapy.

There was a recent subgroup analysis of KEYNOTE-048 for CPS-low patients. Patients with CPS less than one subgroup did not have significant survival difference with pembrolizumab plus chemotherapy when compared to cetuximab plus chemotherapy. This included a small number of patients, and this study was not powered to look at this subgroup, but cetuximab and chemotherapy can also be considered in the PD-L1 negative patient.

Brittany Harvey: Understood. It's important to recognize which patients benefit from these treatments more than others in different subgroups. So, following that, what is the effect of immunotherapy compared to other systemic treatments in platinum-refractory recurrent, or metastatic head and neck squamous cell carcinoma?

Dr. Emrullah Yilmaz: Platinum-refractory disease is defined as recurrence within six months of platinum-based chemotherapy. And effectiveness of immunotherapy was actually proven in this disease group first, several years ago. The effectiveness of immunotherapy as a single agent was proven in two similarly designed phase III trials in this setting. CheckMate 141 trial compared nivolumab to standard-of-care methotrexate, cetuximab, or docetaxel, and KEYNOTE-040 trial compared pembrolizumab to similar standard-of-care agents. And both studies showed overall survival benefit when compared to standard-of-care systemic agents, and the responses were independent from the PD-L1 expressions. So, nivolumab or pembrolizumab, are options as single-agent immunotherapy treatments for the patients with platinum-refractory head and neck squamous cell carcinoma, regardless of their PD-L1 expression.

Brittany Harvey: Understood, and thank you for getting into those options for those patients. Getting into the specifics for nasopharyngeal carcinoma, what did the panel recommend regarding the role of immunotherapy for patients with recurrent or metastatic nasopharyngeal carcinoma?

Dr. Emrullah Yilmaz: So, the combination of immunotherapy with cisplatin and gemcitabine was shown to be effective in first-line treatment of recurrent metastatic nasopharyngeal carcinoma, in several phase III studies from Asia in the last few years. JUPITER-02 study used toripalimab, CAPTAIN-1 study used camrelizumab, and RATIONALE-309 study used tislelizumab in combination with cisplatin and gemcitabine in the first-line treatment, and all these studies showed progression-free survival benefit with addition of immunotherapy to chemotherapy.

Since these agents are not available in the United States as of now, our panel members recommend that pembrolizumab or nivolumab may be offered in combination with chemotherapy for the first-line treatment of recurrent or metastatic nasopharyngeal carcinoma. But the role of immunotherapy in the platinum-refractory nasopharyngeal carcinoma without the prior immunotherapy use is not well established yet. There are phase II studies that have shown that responses to immunotherapy are comparable to chemotherapy with a better safety profile. So, single-agent immunotherapy could be considered in a platinum-refractory setting if a PD-1 inhibitor was not used before.

Brittany Harvey: Those are excellent points that you just made. So, following that, the next question that the panel considered is, what is recommended regarding the use of radiation therapy in combination with immunotherapy versus immunotherapy alone, for the treatment of locoregionally recurrent or oligometastatic head and neck squamous cell carcinoma?

Dr. Emrullah Yilmaz: This is a great question, and radiation therapy is used a lot in head and neck cancers for different purposes. And immunotherapy and SBRT combinations were not shown to increase efficacy for abscopal effect for the treatment of oligometastatic disease in head and neck cancers. So, radiation therapy should not be given to increase the effectiveness of immunotherapy in recurrent metastatic head and neck cancers. However, there are several ongoing studies to evaluate the efficacy of radiation such as SBRT with immunotherapy for locoregional recurrence. So, although radiation therapy is safe to give the patients with recurrent and metastatic cancers, with immunotherapy, it should be considered for palliation or local control until the results of these trials are available.

Brittany Harvey: Great. And yes, we'll look forward to the results of those trials to find some more definitive results for these patients. So, then, the last clinical question that the panel addressed, what is recommended for the role of immunotherapy for rare head and neck cancers?

Dr. Emrullah Yilmaz: The role of the immunotherapy for rare head and neck cancers depends on the biomarkers. KEYNOTE-158 study has shown the effectiveness of pembrolizumab in advanced cancer patients, which included different types of cancers with high tissue TMB defined as more than 10 mutations per megabase. And looking at the results from that study for the patients with advanced rare head and neck cancers with limited treatment options, such as, salivary gland cancers or sinonasal cancers, if high TMB, which is Tumor Mutational Burden, is identified, then pembrolizumab may be considered for those patients. And pembrolizumab was also shown to have activity in salivary gland cancer patients expressing more than 1% PD-L1. So, that makes it an option for these patients as well.

Brittany Harvey: It sounds like understanding the biomarker status of these patients with rare head and neck cancers is essential for determining their therapy options. I want to thank you so much for reviewing all of those recommendations.

So, in your view, Dr. Yilmaz, what is the importance of this guideline, and how will it impact clinicians and patients with head and neck squamous cell carcinoma?

Dr. Emrullah Yilmaz: This guideline was written by panel members, experts in their field, including medical oncologists, radiation oncologists, head and neck surgeons, pathologists, and radiologists. It is really important for oncologists to communicate the treatment options to their patients clearly while planning treatment of head and neck cancers. So, this guideline can help the clinicians to provide evidence-based resource when to use the immunotherapy for their head and neck cancer patients. So, that can be really helpful to the clinicians.

Brittany Harvey: Excellent. Yes, it's important to have a multidisciplinary group working on these guidelines to help clinicians in all capacities.

Finally, what outstanding questions or ongoing research are you interested in for future therapeutic options in head and neck squamous cell carcinoma?

Dr. Emrullah Yilmaz: Our guideline focuses on recurrent metastatic head and neck cancers since it is the only area where the immunotherapy is approved as of now. We've had a few studies in the curative intent setting, which has not shown the benefit of addition of immunotherapy to radiation therapy, or chemoradiation. There's still several studies ongoing to investigate the effectiveness of immunotherapy in the curative intent setting, and the neoadjuvant setting, or adjuvant setting, or different combinations with the radiation therapy, with the immunotherapy, with the different sequences. So, it will be interesting to see the results of those studies in the future. So, that might be another area that the field might be moving in the future.

There are also studies ongoing to improve effectiveness of the immunotherapy in the recurrent and metastatic disease. Chemoimmunotherapy seems to be among the strongest systemic treatment options right now that we have, but there are several other combination strategies that are being developed combined with the PD-1 inhibitors, including combinations with EGFR inhibitors, angiogenesis inhibitors, intratumoral injections, vaccine developments, and there are a lot of different novel checkpoint inhibitors being developed. So, the field is advancing in that area as well. So, those are the areas that research are ongoing at this point.

Brittany Harvey: Definitely. We'll look forward to the results of those ongoing trials to inform future updates and future guidelines in this area.

So, I want to thank you so much for all of your work that you put into developing these evidence-based guidelines and thank you for your time today, Dr. Yilmaz.

Dr. Emrullah Yilmaz: Thank you so much.

Brittany Harvey: And thank you to all of our listeners for tuning to the ASCO Guidelines podcast series. To read the full guideline, go to: www.asco.org/head-neck-cancer-guidelines.

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