Feature

Immunotherapy provides ‘paradigm shift’ for treatment of head and neck cancer

Immunotherapy agents have had a dramatic impact on a variety of cancer types.

Research shows this impact extends to some patients with metastatic head and neck cancer, for whom immunotherapy has been shown to promote durable responses and improve survival compared with conventional chemotherapy.

“Immunotherapy is one of the most promising treatments that came out in the last decade,” Geoffrey Young, MD, PhD, chief of head and neck cancer surgery at Miami Cancer Institute, told HemOnc Today. “There’s so much excitement with everything that is going on. It’s definitely a paradigm shift.”

Geoffrey Young, MD, PhD
Geoffrey Young

In 2016, the FDA approved the PD-1 checkpoint inhibitors nivolumab (Opdivo, Bristol-Myers Squibb) and pembrolizumab (Keytruda, Merck) for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma that progressed after treatment with chemotherapy.

Hundreds of ongoing trials are investigating various immunotherapy agents — alone and in combination — for the treatment of patients with head and neck cancer.

At the American Association for Cancer Research Annual Meeting, Ferris and colleagues presented positive results from the CheckMate 141 trial, showing nivolumab significantly improved median OS compared with investigator’s choice of chemotherapy — which included methotrexate, docetaxel or the EGFR inhibitor cetuximab (Erbitux, Eli Lilly) — among patients with recurrent or metastatic HNSCC who progressed during or after platinum-based therapy (7.7 months vs. 5.1 months; HR = 0.68; 95% CI, 0.54-0.86).

Also at the AACR Annual Meeting, Soulieres and colleagues presented results from the KEYNOTE-040 study that showed pembrolizumab improved median OS compared with standard chemotherapy among patients with recurrent or metastatic HNSCC (8.4 months vs. 6.9 months; HR = 0.8; 95% CI, 0.65-0.98).

Other agents — including durvalumab (Imfinzi, AstraZeneca) and the anti-CTLA-4 agent tremelimumab (MedImmune) — have shown antitumor activity for head and neck cancer. For instance, results from the CONDOR trial showed overall response rates of 9.2% (95% CI, 3.5-19) for durvalumab alone and 7.8% (95% CI, 3.8-13.8) for durvalumab plus tremelimumab therapy.

Researchers also are evaluating several immunotherapies in the frontline setting.

Overall, immunotherapy appears to be better tolerated than chemotherapy, according to Guilherme Rabinowits, MD, medical oncologist and hematologist and co-leader of the head and neck disease management team at Miami Cancer Institute.

Guilherme Rabinowits, MD
Guilherme Rabinowits

HemOnc Today spoke with Rabinowits and Young about the emerging role of immunotherapy in the treatment of head and neck cancer, as well as ongoing studies and things to look forward to in the field.

Question: Before promising studies of immunotherapy for head and neck cancers, what treatment options existed for patients?

Rabinowits: Head and neck cancer treatment options include surgery, radiation, chemotherapy and biotherapy. Early-stage disease is usually managed with monotherapy — either surgery or radiation therapy. Patients with locally advanced disease usually require a combination of different modalities for treatment, which could be surgery and radiation, chemotherapy and radiation, biotherapy and radiation, or even all three modalities, surgery and chemoradiation, depending on the pathology findings after surgery. Patients with distant metastatic disease or those with recurrent, locoregional disease not amenable to surgery or radiation therapy are usually managed with systemic therapy.

A trial that combined platinum, fluorouracil and cetuximab conferred a median OS of about 10 months, representing the first trial in almost a decade that showed a difference in survival when compared with double platinum and fluorouracil therapy. Although outcomes improved, they were still suboptimal, and this is where treatment options remained until immunotherapy came in play.

Young: The advent of robotic surgery also made a lot of highly morbid surgical procedures that almost always received chemoradiation more acceptable for surgical treatment. That change arose in the past 10 years, as well.

Q: What have been the most exciting immunotherapy advances in this setting?

Rabinowits: For the first time, we are seeing a tail on the survival curve among patients with incurable disease, with the majority of responding patients experiencing a prolonged duration of response.

Young: It also is very exciting that these drugs are much better tolerated than chemotherapy.

Q: Does PD-L1 expression play a role in outcomes for patients with head and neck cancer?

Young: Similar to what was seen in melanoma, patients with head and neck cancer whose tumors express PD-L1 tend to do better with immunotherapy than those who do not express PD-L1. However, we see responses in patients whose tumors do not express PD-L1, as well. Whether the tumor expresses PD-L1 or not does not exclude patients from receiving the drug.

Q: Biomarkers, including tumor mutational burden, were a big topic at the AACR Annual Meeting. What additional biomarkers play a role in head and neck cancers?

Young: The accumulation of genetic changes absolutely plays a role in head and neck cancers. In alcohol- and tobacco-related cancers, we see more genetic mutations than with HPV-related cancers, which tend to have their own specific profile of gene mutations. However, immunotherapy is beneficial to both. We have great response rates, but combinatorial therapy may increase those response rates, which is where biomarkers factor in. We are getting into individualized medicine through which we can tailor therapy to a patient based on their specific tumor and its gene expression and biomarker profile. In addition, targeted therapies, such as those that target LAG3 and other proteins, can be used in combination with immune checkpoint inhibitors. So, biomarkers play two roles.

Rabinowits: Unfortunately, we do not have a predictive biomarker for immune checkpoint inhibitors yet, but we are getting there. As I mentioned before, although anti-PD-1/PD-L1 treatment responses are higher for those whose tumors express PD-L1, responses are also seen in patients whose tumors’ PD-L1 expression is less than 1%. The investigators of KEYNOTE-040 went a step further and analyzed PD-L1 expression not only in the tumor cells, but in the immune cells, as well. For the combined cohort with PD-L1 greater than 1%, the median OS was better with pembrolizumab than with standard-of-care chemotherapy (8.7 months vs. 7.1 months; P = .0078). Further, for those whose tumor cells’ PD-L1 expression is greater than 50%, median OS was 11.6 months with pembrolizumab. Given the complexity of the tumor biology and its microenvironment, it is more likely that the prediction of response will result from a combination of different biomarkers.

Q: HPV-related head and neck cancer incidence is on the rise. Has immunotherapy been studied in this population?

Rabinowits: Immunotherapy studies included patients with both HPV-positive and HPV-negative disease. Despite the lower tumor mutation burden seen with HPV-associated disease, HPV is, by itself, immunogenic. Similar to what was seen with chemotherapy and radiation therapy, patients with HPV-associated HNSCC tend to respond better to immunotherapy than those with HPV-negative disease.

Young: It goes back to the fact that the HPV-associated disease has a different biology. One hypothesis why is that HPV infects the tonsillar crypts, where there is PD-L1 expression, making that an immune-privileged site. So, HPV is linked with the PD-L1 pathway way before it develops a tumor. The different disease biology and the immune response of HPV should make it very amenable to treatment with immunotherapy. However, to my knowledge, no prospective trial has gone forward evaluating only HPV-positive patients.

Q: What is the rationale for combining different immunotherapies for metastatic head and neck cancer?

Young: A lot of the rationale is in identifying additional targets and pathways and seeing what will work in combination therapy. However, most trials are in the early phase 1 or phase 2 stages, so we will have to wait and see results from these studies.

Q: What impact has immunotherapy had when added to chemoradiation in the curative setting?

Rabinowits: Unfortunately, we do not have the answer for that yet. Studies evaluating the combination of immunotherapy and chemoradiation therapy in HNSCC are ongoing and results are eagerly awaited.

Q: How does immunotherapy affect the role of surgery for the treatment of head and neck cancer?

Young: For patients with HPV-positive disease, we are looking at ways to de-escalate treatment after surgery, with the goal of improving acute and long-term toxicity without sacrificing outcome. Clinical trials are evaluating lower radiation doses after surgery and the use of adjuvant immunotherapy instead of chemotherapy in order to achieve that goal. Surgery also is used as salvage in the event of locoregional recurrences. Patients who have inoperable tumors at baseline and respond to neoadjuvant treatment may then become candidates for surgery However, this remains experimental.

Q: What key immunotherapy trials are underway?

Rabinowits: The large majority of trials in HNSCC now involve immunotherapy. It is a complete paradigm shift. Some very exciting trials include the combination of immunotherapy and chemoradiation in the curative-intent setting, IDO1 inhibition plus anti-PD-1, the anti-CTLA-4 in combination with anti-PD-1 in the metastatic setting, and a trial combining a vaccine (ISA101, Isa Pharmaceuticals) with an anti-PD-1 inhibitor in HPV-associated HNSCC. – by Cassie Homer

References:

Ferris RL, et al. Abstract CT116. Presented at: American Association for Cancer Research Annual Meeting; April 14-18, 2018; Chicago.

Sui L, et al. Abstract 1. Presented at Multidisciplinary Head and Neck Cancers Symposium; Feb. 15-17, 2018; Scottsdale, Ariz.

Soulieres D, et al. Abstract CT115. Presented at: American Association for Cancer Research Annual Meeting; April 14-18, 2018; Chicago.

For more information:

Geoffrey Young, MD, PhD, and Guilherme Rabinowits, MD, can be reached at 8900 N. Kendall Drive, Miami, FL 33176.

Disclosures: Young reports no relevant financial disclosures. Rabinowits reports advisory board roles with EMD Serono and Pfizer, as well as stock ownership in Regeneron and Syros Pharmaceuticals.

Immunotherapy agents have had a dramatic impact on a variety of cancer types.

Research shows this impact extends to some patients with metastatic head and neck cancer, for whom immunotherapy has been shown to promote durable responses and improve survival compared with conventional chemotherapy.

“Immunotherapy is one of the most promising treatments that came out in the last decade,” Geoffrey Young, MD, PhD, chief of head and neck cancer surgery at Miami Cancer Institute, told HemOnc Today. “There’s so much excitement with everything that is going on. It’s definitely a paradigm shift.”

Geoffrey Young, MD, PhD
Geoffrey Young

In 2016, the FDA approved the PD-1 checkpoint inhibitors nivolumab (Opdivo, Bristol-Myers Squibb) and pembrolizumab (Keytruda, Merck) for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma that progressed after treatment with chemotherapy.

Hundreds of ongoing trials are investigating various immunotherapy agents — alone and in combination — for the treatment of patients with head and neck cancer.

At the American Association for Cancer Research Annual Meeting, Ferris and colleagues presented positive results from the CheckMate 141 trial, showing nivolumab significantly improved median OS compared with investigator’s choice of chemotherapy — which included methotrexate, docetaxel or the EGFR inhibitor cetuximab (Erbitux, Eli Lilly) — among patients with recurrent or metastatic HNSCC who progressed during or after platinum-based therapy (7.7 months vs. 5.1 months; HR = 0.68; 95% CI, 0.54-0.86).

Also at the AACR Annual Meeting, Soulieres and colleagues presented results from the KEYNOTE-040 study that showed pembrolizumab improved median OS compared with standard chemotherapy among patients with recurrent or metastatic HNSCC (8.4 months vs. 6.9 months; HR = 0.8; 95% CI, 0.65-0.98).

Other agents — including durvalumab (Imfinzi, AstraZeneca) and the anti-CTLA-4 agent tremelimumab (MedImmune) — have shown antitumor activity for head and neck cancer. For instance, results from the CONDOR trial showed overall response rates of 9.2% (95% CI, 3.5-19) for durvalumab alone and 7.8% (95% CI, 3.8-13.8) for durvalumab plus tremelimumab therapy.

Researchers also are evaluating several immunotherapies in the frontline setting.

Overall, immunotherapy appears to be better tolerated than chemotherapy, according to Guilherme Rabinowits, MD, medical oncologist and hematologist and co-leader of the head and neck disease management team at Miami Cancer Institute.

Guilherme Rabinowits, MD
Guilherme Rabinowits

HemOnc Today spoke with Rabinowits and Young about the emerging role of immunotherapy in the treatment of head and neck cancer, as well as ongoing studies and things to look forward to in the field.

PAGE BREAK

Question: Before promising studies of immunotherapy for head and neck cancers, what treatment options existed for patients?

Rabinowits: Head and neck cancer treatment options include surgery, radiation, chemotherapy and biotherapy. Early-stage disease is usually managed with monotherapy — either surgery or radiation therapy. Patients with locally advanced disease usually require a combination of different modalities for treatment, which could be surgery and radiation, chemotherapy and radiation, biotherapy and radiation, or even all three modalities, surgery and chemoradiation, depending on the pathology findings after surgery. Patients with distant metastatic disease or those with recurrent, locoregional disease not amenable to surgery or radiation therapy are usually managed with systemic therapy.

A trial that combined platinum, fluorouracil and cetuximab conferred a median OS of about 10 months, representing the first trial in almost a decade that showed a difference in survival when compared with double platinum and fluorouracil therapy. Although outcomes improved, they were still suboptimal, and this is where treatment options remained until immunotherapy came in play.

Young: The advent of robotic surgery also made a lot of highly morbid surgical procedures that almost always received chemoradiation more acceptable for surgical treatment. That change arose in the past 10 years, as well.

Q: What have been the most exciting immunotherapy advances in this setting?

Rabinowits: For the first time, we are seeing a tail on the survival curve among patients with incurable disease, with the majority of responding patients experiencing a prolonged duration of response.

Young: It also is very exciting that these drugs are much better tolerated than chemotherapy.

Q: Does PD-L1 expression play a role in outcomes for patients with head and neck cancer?

Young: Similar to what was seen in melanoma, patients with head and neck cancer whose tumors express PD-L1 tend to do better with immunotherapy than those who do not express PD-L1. However, we see responses in patients whose tumors do not express PD-L1, as well. Whether the tumor expresses PD-L1 or not does not exclude patients from receiving the drug.

Q: Biomarkers, including tumor mutational burden, were a big topic at the AACR Annual Meeting. What additional biomarkers play a role in head and neck cancers?

Young: The accumulation of genetic changes absolutely plays a role in head and neck cancers. In alcohol- and tobacco-related cancers, we see more genetic mutations than with HPV-related cancers, which tend to have their own specific profile of gene mutations. However, immunotherapy is beneficial to both. We have great response rates, but combinatorial therapy may increase those response rates, which is where biomarkers factor in. We are getting into individualized medicine through which we can tailor therapy to a patient based on their specific tumor and its gene expression and biomarker profile. In addition, targeted therapies, such as those that target LAG3 and other proteins, can be used in combination with immune checkpoint inhibitors. So, biomarkers play two roles.

PAGE BREAK

Rabinowits: Unfortunately, we do not have a predictive biomarker for immune checkpoint inhibitors yet, but we are getting there. As I mentioned before, although anti-PD-1/PD-L1 treatment responses are higher for those whose tumors express PD-L1, responses are also seen in patients whose tumors’ PD-L1 expression is less than 1%. The investigators of KEYNOTE-040 went a step further and analyzed PD-L1 expression not only in the tumor cells, but in the immune cells, as well. For the combined cohort with PD-L1 greater than 1%, the median OS was better with pembrolizumab than with standard-of-care chemotherapy (8.7 months vs. 7.1 months; P = .0078). Further, for those whose tumor cells’ PD-L1 expression is greater than 50%, median OS was 11.6 months with pembrolizumab. Given the complexity of the tumor biology and its microenvironment, it is more likely that the prediction of response will result from a combination of different biomarkers.

Q: HPV-related head and neck cancer incidence is on the rise. Has immunotherapy been studied in this population?

Rabinowits: Immunotherapy studies included patients with both HPV-positive and HPV-negative disease. Despite the lower tumor mutation burden seen with HPV-associated disease, HPV is, by itself, immunogenic. Similar to what was seen with chemotherapy and radiation therapy, patients with HPV-associated HNSCC tend to respond better to immunotherapy than those with HPV-negative disease.

Young: It goes back to the fact that the HPV-associated disease has a different biology. One hypothesis why is that HPV infects the tonsillar crypts, where there is PD-L1 expression, making that an immune-privileged site. So, HPV is linked with the PD-L1 pathway way before it develops a tumor. The different disease biology and the immune response of HPV should make it very amenable to treatment with immunotherapy. However, to my knowledge, no prospective trial has gone forward evaluating only HPV-positive patients.

Q: What is the rationale for combining different immunotherapies for metastatic head and neck cancer?

Young: A lot of the rationale is in identifying additional targets and pathways and seeing what will work in combination therapy. However, most trials are in the early phase 1 or phase 2 stages, so we will have to wait and see results from these studies.

Q: What impact has immunotherapy had when added to chemoradiation in the curative setting?

Rabinowits: Unfortunately, we do not have the answer for that yet. Studies evaluating the combination of immunotherapy and chemoradiation therapy in HNSCC are ongoing and results are eagerly awaited.

PAGE BREAK

Q: How does immunotherapy affect the role of surgery for the treatment of head and neck cancer?

Young: For patients with HPV-positive disease, we are looking at ways to de-escalate treatment after surgery, with the goal of improving acute and long-term toxicity without sacrificing outcome. Clinical trials are evaluating lower radiation doses after surgery and the use of adjuvant immunotherapy instead of chemotherapy in order to achieve that goal. Surgery also is used as salvage in the event of locoregional recurrences. Patients who have inoperable tumors at baseline and respond to neoadjuvant treatment may then become candidates for surgery However, this remains experimental.

Q: What key immunotherapy trials are underway?

Rabinowits: The large majority of trials in HNSCC now involve immunotherapy. It is a complete paradigm shift. Some very exciting trials include the combination of immunotherapy and chemoradiation in the curative-intent setting, IDO1 inhibition plus anti-PD-1, the anti-CTLA-4 in combination with anti-PD-1 in the metastatic setting, and a trial combining a vaccine (ISA101, Isa Pharmaceuticals) with an anti-PD-1 inhibitor in HPV-associated HNSCC. – by Cassie Homer

References:

Ferris RL, et al. Abstract CT116. Presented at: American Association for Cancer Research Annual Meeting; April 14-18, 2018; Chicago.

Sui L, et al. Abstract 1. Presented at Multidisciplinary Head and Neck Cancers Symposium; Feb. 15-17, 2018; Scottsdale, Ariz.

Soulieres D, et al. Abstract CT115. Presented at: American Association for Cancer Research Annual Meeting; April 14-18, 2018; Chicago.

For more information:

Geoffrey Young, MD, PhD, and Guilherme Rabinowits, MD, can be reached at 8900 N. Kendall Drive, Miami, FL 33176.

Disclosures: Young reports no relevant financial disclosures. Rabinowits reports advisory board roles with EMD Serono and Pfizer, as well as stock ownership in Regeneron and Syros Pharmaceuticals.

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