Barbara Burtness, MD, professor of Medicine, Medical Oncology, Disease Aligned Research Team Leader, Head and Neck Cancers Program, co-director of the Developmental Therapeutics Research Program, Yale Cancer Center, discusses the effectiveness of immunotherapy in patients with platinum-refractory head and neck cancers.

The first step in establishing that immunotherapy is active in head and neck cancers was to show that there are targets for the immune system, says Burtness. Evidence suggests that the targets in head and neck cancer can be infiltrated by neoantigenic tumor-associated immune cells with the mutational load seen in human papillomavirus (HPV)—negative and -positive cancers. Data from early trials suggest that the higher the mutational load, the more likely patients will experience a partial or complete response, according to Burtness.

The phase Ib KEYNOTE-012 trial was the first to examine the use of the PD-1 inhibitor pembrolizumab (Keytruda) in patients with head and neck cancer. Results showed that the agent was active in patients with platinum-refractory disease, regardless of HPV status, says Burtness. The phase II KEYNOTE-055 trial followed; results showed that pembrolizumab was also active in patients with cetuximab-refractory disease, according to Burtness.

The phase III CheckMate-141 trial compared the use of the PD-1 inhibitor nivolumab (Opdivo) versus investigator’s choice of standard-of-care chemotherapy in patients with platinum-refractory disease. Results showed the median overall survival was 7.5 months in the nivolumab arm versus 5.1 months in the chemotherapy arm.

These trials present positive evidence supporting the use of PD-1 agents in head and neck cancer, according to Burtness, with modest response rates ranging from 16% to 20%. These data led to FDA approvals in platinum-refractory head and neck cancer, concludes Burtness.

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Barbara Burtness, MD, discusses the effectiveness of immunotherapy in patients with platinum-refractory head and neck cancers. 

Dr. Burtness on the Effectiveness of Immunotherapy in Head and Neck Cancers

Barbara Burtness, MD, professor of Medicine, Medical Oncology, Disease Aligned Research Team Leader, Head and Neck Cancers Program, co-director, Developmental Therapeutics Research Program, Yale Cancer Center, discusses the future of immunotherapy in head and neck cancer.

The logical next step in bringing immunotherapy to the clinic would be to evaluate validated immunotherapy combinations. However, these approaches have not panned out in patients with head and neck cancer, says Burtness. There is a lot of interest in exploring inducible T-cell costimulatory targets and co-inhibitory targets such as OX40. In human papillomavirus-associated cancer, combinations of vaccines and PD-1 inhibitors have shown strong signals of activity.

There is also a lot of interest in exploring the combination of immunotherapy and targeted therapy. There have not been an abundance of data to emerge in this setting, but there are trials evaluating immunotherapeutic agents with cetuximab (Erbitux). Antiangiogenic agents such as ramucirumab (Cyramza), bevacizumab (Avastin), and lenvatinib (Lenvima) also appear to be promising targeted therapies worth exploring in combination with immunotherapy, says Burtness. Moving forward, Burtness is hopeful that the field will place greater emphasis on personalized and sequential treatment strategies.

Barbara Burtness, MD, professor of Medicine (Medical Oncology); Disease Aligned Research Team Leader, Head and Neck Cancers Program; co-director, Developmental Therapeutics Research Program; of Yale Cancer Center, discusses the future of immunotherapy in head and neck cancer.

Dr. Burtness on the Future of Immunotherapy in Head and Neck Cancer

Barbara Burtness, MD, professor of Medicine (Medical Oncology); Disease Aligned Research Team Leader, Head and Neck Cancers Program; co-director, Developmental Therapeutics Research Program; of Yale Cancer Center, discusses the use of biomarkers in metastatic head and neck squamous cell carcinoma (HNSCC).

A PD-L1 combined positive score (CPS) ≥20 is likely to become a biomarker that will drive treatment decisions for patients with metastatic HNSCC in the near future, says Burtness. With the promise of immunotherapy in this setting, many institutions are now doing PD-L1 testing, says Burtness. PD-L1 expression can either be reported in terms of the proportion of tumor cells stained for PD-L1 or the proportion of stromal cells that stain for PD-L1. Looking at the proportion of positive cells on either tumor cells or immune cells is a novel way for the pathologist to test for the biomarker, says Burtness.

Though, assessing CPS ≥20 is going to require a different reporting algorithm, Burtness notes. If it is going to go forward as a companion biomarker with PD-L1, that will add some complexity to the landscape. Currently, looking at PD-L1 seems to be the standard of care as response rates with pembrolizumab (Keytruda) and nivolumab (Opdivo) are low in the unselected population.

Barbara Burtness, MD, professor of Medicine (Medical Oncology) Disease Aligned Research Team Leader, Head and Neck Cancers Program co-director, Developmental Therapeutics Research Program of Yale Cancer Center, discusses the use of biomarkers in metastatic head and neck squamous cell carcinoma.

Dr. Burtness on the Use of Biomarkers in Metastatic HNSCC

Barbara Burtness, MD, professor of Medicine (Medical Oncology); Disease Aligned Research Team Leader, Head and Neck Cancers Program; co-director, Developmental Therapeutics Research Program; of Yale Cancer Center, discusses the promise of frontline pembrolizumab (Keytruda) in the treatment of patients with metastatic head and neck squamous cell carcinoma (HNSCC).

Although the EXTREME regimen had previously been the best treatment option available in this setting, Burtness says no one actually liked using it due to its toxicity. Patients who receive it are at risk of neutropenia or they can develop rash, and there can be days where they just simply feel ill. The regimen has a response rate of approximately 36% and a median overall survival of about 10.7 months, Burtness says, which are not data that patients are particularly encouraged by. As such, the PD-1 inhibitor can really fill an unmet need.

Moreover, the field is anticipating forthcoming studies combining PD-1 inhibition with chemoradiation in early-stage disease, with the goal of preventing patients from reaching the recurrent metastatic setting. For now, however, it is important to see single-agent pembrolizumab have improved efficacy with no additional toxicity than what is observed with EXTREME. Burtness concludes that the next steps for research will be to generate even more durable responses.

Barbara Burtness, MD, professor of Medicine (Medical Oncology); Disease Aligned Research Team Leader, Head and Neck Cancers Program; co-director, Developmental Therapeutics Research Program; of Yale Cancer Center, discusses the promise of frontline pembrolizumab in the treatment of patients with metastatic head and neck squamous cell carcinoma.

Dr. Burtness on Promise of Frontline Pembrolizumab in Metastatic HNSCC

Barbara Burtness, MD, professor of medicine, Yale Cancer Center, discusses the benefit of pembrolizumab (Keytruda) as a treatment for patients with recurrent metastatic head and neck squamous cell carcinoma.

In the phase III KEYNOTE-048 trial, frontline pembrolizumab was tested as a single-agent and in combination with chemotherapy versus 6 cycles of a platinum agent with 5-FU and cetuximab (Erbitux) followed by cetuximab alone—–known as the EXTREME regimen. When investigators looked at the overall survival (OS) benefit with pembrolizumab and chemotherapy compared with the EXTREME regimen in the biomarker-unselected population, they found a benefit for the early use of pembrolizumab.

OS was improved by about 2 months in the pembrolizumab arm compared with in the EXTREME arm. Response rates were comparable, and the amount of grade 3 to 5 and overall toxicity was fairly similar, Burtness says. This demonstrates that early use of pembrolizumab in patients with recurrent metastatic cancer leads to an improvement in OS, adds Burtness. Findings from the study demonstrated that patients who express PD-L1 do better with pembrolizumab monotherapy and those who are not biomarker-enriched do better with the combination of pembrolizumab and chemotherapy.

Dr. Burtness on the Benefit of Pembrolizumab in Head and Neck Cancer

Barbara Burtness, MD, professor of medicine, Yale Cancer Center, discusses the potential of using immunotherapy for frontline treatment of patients with head and neck cancer.

With the FDA’s approval of pembrolizumab (Keytruda) and nivolumab (Opdivo) for the treatment of patients with head and neck cancer in the second-line setting, it is well known that immunotherapy can be beneficial for certain patients with these rare cancers.

Investigators involved in the KEYNOTE-048 study sought to determine if immunotherapy would prove safe and effective for frontline treatment. Researchers feel this is where it would have the most impact, as many patients with head and neck cancer are not fit enough to move on to second-line therapy, Burtness says. She adds that high PD-L1 expression has been a predictive biomarker of immune response in this tumor type.

Findings from the randomized 3-arm KEYNOTE-048 study were presented by Burtness at the 2018 ESMO Congress. The study sought to answer 2 questions—could pembrolizumab alone have an impact on PD-L1—high patients as a frontline treatment, and would it be beneficial to combine pembrolizumab with chemotherapy? Burtness adds that chemotherapy has proven effective in terms of disease control for symptomatic patients with head and neck cancer.

Barbara Burtness, MD, professor of medicine, Yale Cancer Center, discusses frontline immunotherapy in head and neck cancer.

Dr. Burtness on Frontline Immunotherapy in Head and Neck Cancer

Barbara Burtness, MD, professor of medicine, Yale Cancer Center, discusses findings from the KEYNOTE-048 in head and neck squamous cell carcinoma (HNSCC).

Interim findings from the phase III KEYNOTE-048 trial presented at the 2018 ESMO Congress showed that frontline pembrolizumab (Keytruda) monotherapy improved overall survival and duration of response versus standard therapy in patients with PD-L1—positive recurrent or metastatic HNSCC. There was not a similar improvement in progression-free survival or overall response rate with the PD-1 inhibitor, though.

This open-label, randomized study evaluated whether pembrolizumab could prolong survival and slow disease progression versus the standard of care EXTREME regimen in the recurrent or metastatic setting. EXTREME consists of platinum-based chemotherapy with cisplatin or carboplatin, 5-fluorouracil (5-FU), and cetuximab (Erbitux).

Dr. Burtness on Findings of KEYNOTE-048 in Head and Neck Cancer

Barbara Burtness, MD, professor of medicine, Yale Cancer Center, discusses challenges regarding immunotherapy for patients with head and neck cancer.

Although immunotherapy can lead to durable responses, there are still a population of patients who do not see any responses, explains Burtness.

According to Burtness, more research needs to be conducted in an attempt to make all patients respond to immunotherapy or to determine a targeted therapy to better support the immune system.

Dr. Burtness on Challenges Facing Immunotherapy in Head and Neck

Barbara Burtness, MD, professor of medicine, Yale Cancer Center, discusses immunotherapy resistance in head and neck cancer.

 Immunotherapy is producing durable responses across malignancies, but there are still many patients who do not respond.

 Burtness asks if the community has turned their back on targeted therapy too quickly. There may be promise in synthetic lethal approaches with targeted therapies, she adds.

Dr. Burtness on Immunotherapy Resistance in Head and Neck Cancer

Barbara Burtness, MD, professor of medicine, Yale Cancer Center, discusses immunotherapy combinations for patients with head and neck cancer.

There are different combination approaches being investigated for patients with head and neck cancer, Burtness explains. Immunotherapy has been integrated in to the standard approach to build on the existing responses, such as with chemoradiation or chemotherapy and cetuximab (Erbitux) for recurrent metastatic disease.

Combinations of PD-1/PD-L1 inhibitors with CTLA-4 inhibitors have also been investigated in large phase III trials, states Burtness.

Barbara Burtness, MD, professor of Medicine, Yale Cancer Center, discusses immunotherapy combinations for patients with head and neck cancer.

Barbara Burtness, MD

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