Commentary

Immunotherapy for head and neck cancer an evolving paradigm

The availability and approval of checkpoint inhibitors has transformed the management of metastatic head and neck squamous cell carcinoma.

In 2016, the FDA approved the anti-PD-1 antibodies nivolumab (Opdivo, Bristol-Myers Squibb) and pembrolizumab (Keytruda, Merck) for the treatment of recurrent or metastatic HNSCC.

Since then, these drugs have been adopted as the standard for management of patients after or during progression on platinum-based therapy.

Charu Aggarwal, MD, MPH
Charu Aggarwal

At last year’s European Society for Medical Oncology Congress, Burtness and colleagues presented results of the randomized phase 3 KEYNOTE-048 trial, which compared pembrolizumab alone or in combination with chemotherapy vs. the standard EXTREME regimen.

EXTREME — given in six 3-week cycles — consists of the EGFR inhibitor cetuximab (Erbitux, Eli Lilly) plus chemotherapy.

Pembrolizumab appeared associated with longer survival than EXTREME for patients with tumors that had PD-L1 combined positive score of 1 or higher, as well as those with scores of 20 or higher. In the overall population, pembrolizumab was noninferior to the EXTREME regimen with regard to OS, regardless of PD-L1 expression.

It is worth noting that response rate was higher with EXTREME than pembrolizumab (36% vs. 17%), and grade 3 to grade 5 adverse events were much lower with pembrolizumab monotherapy than the other two groups analyzed.

This clinical trial has important implications for practice.

First, the overall safety and tolerability profile of pembrolizumab monotherapy — coupled with the noninferior OS in the overall population — make it an attractive option for patients regardless of PD-L1 expression.

Additionally, PD-L1 combined positive score testing should be included in the routine clinical management of patients with recurrent/metastatic head and neck squamous cell cancer, based on the robustness of clinical improvement in OS with a higher PD-L1 level.

Two key questions

As immunotherapy with anti-PD-1 antibodies becomes a focal point of therapy in the management of patients with metastatic disease, it opens the door to two questions.

First, are we ready to move these drugs to the locally advanced setting, concurrently with radiation and as consolidation therapy?

Second, how do we manage patients with recurrent or metastatic disease whose disease progressed on anti-PD-1 therapies?

The Society for Immunotherapy of Cancer (SITC) Annual Meeting, held in November in Washington, included presentations of two studies that examined these questions.

Powell and colleagues presented the preliminary safety and efficacy analysis of pembrolizumab combined with low-dose concurrent weekly cisplatin and radiation therapy for patients with stage III or stage IVB HPV-associated HNSCC.

Thirty-four patients with HPV-associated disease — based on p16 immunohistochemistry — were assessable for the primary endpoint of PFS.

Median follow-up was 21 months (range, 8-26). PFS at 1 year was 97.1% (95% CI, 80.9-99.6).

The addition of pembrolizumab to low-dose cisplatin-based chemoradiation therapy in a predominantly intermediate-risk HPV-positive population resulted in promising response and early PFS data.

Results showed minimal added toxicity and, overall, the results looked favorable compared with historical data.

Starting immune modulation before concurrent radiation therapy may ensure T-cell activation before lymphotoxic effect occurs.

In an attempt to maximize this “priming effect” and immune activation, ongoing studies with pembrolizumab, nivolumab and avelumab (Bavencio; EMD Serono, Pfizer) initiate immune-directed therapy before concurrent chemoradiation.

The choice of dosing of the chemotherapy backbone is another area of debate.

Data from a randomized noninferiority trial of concurrent weekly cisplatin compared with high-dose cisplatin indicated that weekly cisplatin may be better tolerated but less effective, with inferior outcomes for disease control and survival.

There has been criticism of this analysis, including the fact that a majority of patients treated on this study had non-HPV-related cancers, and they required adjuvant chemotherapy and radiation after initial surgical resection as opposed to concurrent chemoradiation.

A meta-analysis of trials confirmed this observation; however, other retrospective data — including analysis of outcomes of U.S. military veterans — have suggested similar outcomes with the use of weekly cisplatin concurrently with radiation therapy.

Thus, it remains to be seen if the schedule of chemotherapy administration may affect clinical outcomes when administered with concurrent immunotherapy.

Ongoing clinical trials are exploring both strategies of chemotherapy delivery — weekly and every 3 weeks — in combination with radiation and anti-PD-1 therapy.

For patients with surgically unresectable locally advanced non-small cell lung cancer, 1 year of immunotherapy with the anti-PD-L1 antibody durvalumab (Imfinzi, AstraZeneca) following concurrent definitive chemoradiation therapy has been associated with an OS advantage.

Hypothetically, a similar advantage will be seen among patients with locally advanced head and neck cancer after completion of concurrent chemoradiation therapy.

Ongoing national and international trials are evaluating this approach, either alone or as continuation of PD-1/PD-L1 inhibitors that were initiated with chemoradiation.

Finally, the KEYCHAIN trial is evaluating a chemotherapy-free approach — pembrolizumab plus radiation therapy vs. chemoradiation — for patients with intermediate-risk p16-positive head and neck cancer.

An important challenge

As we incorporate PD-1/PD-L1 therapies into the management of locally advanced HNSCC, an important challenge will be the treatment of patients with metastatic disease.

What will we offer to patients who experience disease progression despite an initial robust response to immunotherapy?

We will need novel immunotherapy agents and rational combinations that potentially can evade immune resistance.

One such study evaluating a novel immunotherapeutic approach was presented last fall at SITC by Cohen and colleagues.

This phase 1/phase 2 study evaluated the combination of monalizumab (Innate Pharma) and cetuximab in the recurrent/metastatic setting.

Monalizumab is a novel immune checkpoint inhibitor that targets natural killer group 2A (NKG2A).

NKG2A blockade promotes innate anti-tumor immunity mediated by natural killer and CD8-positive T cells and enhances human natural killer cell antibody-dependent cell-mediated cytotoxicity induced by cetuximab.

Patients on this trial were required to have progressed after platinum-based chemotherapy and to have received less than two prior lines of therapy in the recurrent/metastatic setting.

Approximately half of the patients on this trial had received prior anti-PD-1 or anti-PD-L1 therapies. Median follow-up was 8 months.

Researchers reported a 27.5% (95% CI, 16.1-42.8) overall response rate, with 11 confirmed responses (one complete and 10 partial). Median PFS was 5 months (95% CI, 3.7-6.9) and median OS was 10.3 months (95% CI, 7.3-not reached).

Eighteen percent of patients experienced grade 3 or grade 4 adverse events.

These results are interesting, as they offer a potential therapeutic option with robust response rates for patients who previously received immunotherapy. Further work is needed, including results from a larger randomized study to formally evaluate the overall benefit.

We also eagerly await data of trials utilizing other combinations of immunotherapy agents, including CTLA-4 antibodies plus PD-1 inhibitors.

These include the EAGLE trial — designed to compare durvalumab with or without tremelimumab (CP-675,206, MedImmune/AstraZeneca) vs. standard of care as second-line therapy — and KESTREL, designed to compare durvalumab with or without tremelimumab vs. the EXTREME regimen as first-line treatment.

‘An invaluable asset’

Immunotherapy has become an invaluable asset for the management of patients with head and neck cancer. However, the current empiric approach of testing combination immunotherapy drugs has resulted in an unmanageable avalanche of trials for solid tumors in general.

According to one report, there are more than 1,000 open clinical trials evaluating checkpoint inhibitor combinations, and this actually may be counterproductive.

Accrual to these trials already is challenging, time consuming and resource intensive. Some of these trials may provide benefit to only a small percentage of patients.

As we advance into the next stage of postimmunotherapy trials, we must actively participate in and endorse clinical trials that emphasize and build upon a strong scientific rationale.

References:

Antonia SJ, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1809697.

Bauml J, et al. J Clin Oncol. 2017;doi:10.1200/JCO.2016.70.1524.

Bauml JM, et al. J Natl Cancer Inst. 2018;doi:10.1093/jnci/djy133.

Burtness B, et al. Abstract LBA8_PR. Presented at: European Society for Medical Oncology Congress; Oct. 19-23, 2018; Munich.

Cohen R, et al. Monalizumab in combination with cetuximab in recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN): Clinical and translational biomarker results. Presented at: Society for Immunotherapy of Cancer Annual Meeting; Nov. 7-11, 2018; Washington.

Ferris R and Gillison ML. N Engl J Med. 2017;doi:10.1056/NEJMc1615565.

Kaiser J. Science. 2018;doi:10.1126/science.359.6382.1346.

Noronha V, et al. J Clin Oncol. 2018;doi:10.1200/JCO.2017.74.9457.

Powell SF, et al. Abstract O50. Presented at: Society for Immunotherapy of Cancer Annual Meeting; Nov. 7-11, 2018; Washington.

Szturz P, et al. Oral Oncol. 2018;doi:10.1016/j.oraloncology.2017.11.025.

For more information:

Charu Aggarwal, MD, MPH, is Lesley M. Heisler assistant professor of medicine at University of Pennsylvania. She also is a HemOnc Today Editorial Board Member. She can be reached at charu.aggarwal@uphs.upenn.edu.

Disclosure: Aggarwal reports attending advisory boards for Bristol-Myers Squibb, MedImmune and Roche.

The availability and approval of checkpoint inhibitors has transformed the management of metastatic head and neck squamous cell carcinoma.

In 2016, the FDA approved the anti-PD-1 antibodies nivolumab (Opdivo, Bristol-Myers Squibb) and pembrolizumab (Keytruda, Merck) for the treatment of recurrent or metastatic HNSCC.

Since then, these drugs have been adopted as the standard for management of patients after or during progression on platinum-based therapy.

Charu Aggarwal, MD, MPH
Charu Aggarwal

At last year’s European Society for Medical Oncology Congress, Burtness and colleagues presented results of the randomized phase 3 KEYNOTE-048 trial, which compared pembrolizumab alone or in combination with chemotherapy vs. the standard EXTREME regimen.

EXTREME — given in six 3-week cycles — consists of the EGFR inhibitor cetuximab (Erbitux, Eli Lilly) plus chemotherapy.

Pembrolizumab appeared associated with longer survival than EXTREME for patients with tumors that had PD-L1 combined positive score of 1 or higher, as well as those with scores of 20 or higher. In the overall population, pembrolizumab was noninferior to the EXTREME regimen with regard to OS, regardless of PD-L1 expression.

It is worth noting that response rate was higher with EXTREME than pembrolizumab (36% vs. 17%), and grade 3 to grade 5 adverse events were much lower with pembrolizumab monotherapy than the other two groups analyzed.

This clinical trial has important implications for practice.

First, the overall safety and tolerability profile of pembrolizumab monotherapy — coupled with the noninferior OS in the overall population — make it an attractive option for patients regardless of PD-L1 expression.

Additionally, PD-L1 combined positive score testing should be included in the routine clinical management of patients with recurrent/metastatic head and neck squamous cell cancer, based on the robustness of clinical improvement in OS with a higher PD-L1 level.

Two key questions

As immunotherapy with anti-PD-1 antibodies becomes a focal point of therapy in the management of patients with metastatic disease, it opens the door to two questions.

First, are we ready to move these drugs to the locally advanced setting, concurrently with radiation and as consolidation therapy?

Second, how do we manage patients with recurrent or metastatic disease whose disease progressed on anti-PD-1 therapies?

The Society for Immunotherapy of Cancer (SITC) Annual Meeting, held in November in Washington, included presentations of two studies that examined these questions.

Powell and colleagues presented the preliminary safety and efficacy analysis of pembrolizumab combined with low-dose concurrent weekly cisplatin and radiation therapy for patients with stage III or stage IVB HPV-associated HNSCC.

Thirty-four patients with HPV-associated disease — based on p16 immunohistochemistry — were assessable for the primary endpoint of PFS.

PAGE BREAK

Median follow-up was 21 months (range, 8-26). PFS at 1 year was 97.1% (95% CI, 80.9-99.6).

The addition of pembrolizumab to low-dose cisplatin-based chemoradiation therapy in a predominantly intermediate-risk HPV-positive population resulted in promising response and early PFS data.

Results showed minimal added toxicity and, overall, the results looked favorable compared with historical data.

Starting immune modulation before concurrent radiation therapy may ensure T-cell activation before lymphotoxic effect occurs.

In an attempt to maximize this “priming effect” and immune activation, ongoing studies with pembrolizumab, nivolumab and avelumab (Bavencio; EMD Serono, Pfizer) initiate immune-directed therapy before concurrent chemoradiation.

The choice of dosing of the chemotherapy backbone is another area of debate.

Data from a randomized noninferiority trial of concurrent weekly cisplatin compared with high-dose cisplatin indicated that weekly cisplatin may be better tolerated but less effective, with inferior outcomes for disease control and survival.

There has been criticism of this analysis, including the fact that a majority of patients treated on this study had non-HPV-related cancers, and they required adjuvant chemotherapy and radiation after initial surgical resection as opposed to concurrent chemoradiation.

A meta-analysis of trials confirmed this observation; however, other retrospective data — including analysis of outcomes of U.S. military veterans — have suggested similar outcomes with the use of weekly cisplatin concurrently with radiation therapy.

Thus, it remains to be seen if the schedule of chemotherapy administration may affect clinical outcomes when administered with concurrent immunotherapy.

Ongoing clinical trials are exploring both strategies of chemotherapy delivery — weekly and every 3 weeks — in combination with radiation and anti-PD-1 therapy.

For patients with surgically unresectable locally advanced non-small cell lung cancer, 1 year of immunotherapy with the anti-PD-L1 antibody durvalumab (Imfinzi, AstraZeneca) following concurrent definitive chemoradiation therapy has been associated with an OS advantage.

Hypothetically, a similar advantage will be seen among patients with locally advanced head and neck cancer after completion of concurrent chemoradiation therapy.

Ongoing national and international trials are evaluating this approach, either alone or as continuation of PD-1/PD-L1 inhibitors that were initiated with chemoradiation.

Finally, the KEYCHAIN trial is evaluating a chemotherapy-free approach — pembrolizumab plus radiation therapy vs. chemoradiation — for patients with intermediate-risk p16-positive head and neck cancer.

An important challenge

As we incorporate PD-1/PD-L1 therapies into the management of locally advanced HNSCC, an important challenge will be the treatment of patients with metastatic disease.

What will we offer to patients who experience disease progression despite an initial robust response to immunotherapy?

We will need novel immunotherapy agents and rational combinations that potentially can evade immune resistance.

PAGE BREAK

One such study evaluating a novel immunotherapeutic approach was presented last fall at SITC by Cohen and colleagues.

This phase 1/phase 2 study evaluated the combination of monalizumab (Innate Pharma) and cetuximab in the recurrent/metastatic setting.

Monalizumab is a novel immune checkpoint inhibitor that targets natural killer group 2A (NKG2A).

NKG2A blockade promotes innate anti-tumor immunity mediated by natural killer and CD8-positive T cells and enhances human natural killer cell antibody-dependent cell-mediated cytotoxicity induced by cetuximab.

Patients on this trial were required to have progressed after platinum-based chemotherapy and to have received less than two prior lines of therapy in the recurrent/metastatic setting.

Approximately half of the patients on this trial had received prior anti-PD-1 or anti-PD-L1 therapies. Median follow-up was 8 months.

Researchers reported a 27.5% (95% CI, 16.1-42.8) overall response rate, with 11 confirmed responses (one complete and 10 partial). Median PFS was 5 months (95% CI, 3.7-6.9) and median OS was 10.3 months (95% CI, 7.3-not reached).

Eighteen percent of patients experienced grade 3 or grade 4 adverse events.

These results are interesting, as they offer a potential therapeutic option with robust response rates for patients who previously received immunotherapy. Further work is needed, including results from a larger randomized study to formally evaluate the overall benefit.

We also eagerly await data of trials utilizing other combinations of immunotherapy agents, including CTLA-4 antibodies plus PD-1 inhibitors.

These include the EAGLE trial — designed to compare durvalumab with or without tremelimumab (CP-675,206, MedImmune/AstraZeneca) vs. standard of care as second-line therapy — and KESTREL, designed to compare durvalumab with or without tremelimumab vs. the EXTREME regimen as first-line treatment.

‘An invaluable asset’

Immunotherapy has become an invaluable asset for the management of patients with head and neck cancer. However, the current empiric approach of testing combination immunotherapy drugs has resulted in an unmanageable avalanche of trials for solid tumors in general.

According to one report, there are more than 1,000 open clinical trials evaluating checkpoint inhibitor combinations, and this actually may be counterproductive.

Accrual to these trials already is challenging, time consuming and resource intensive. Some of these trials may provide benefit to only a small percentage of patients.

As we advance into the next stage of postimmunotherapy trials, we must actively participate in and endorse clinical trials that emphasize and build upon a strong scientific rationale.

References:

Antonia SJ, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1809697.

Bauml J, et al. J Clin Oncol. 2017;doi:10.1200/JCO.2016.70.1524.

Bauml JM, et al. J Natl Cancer Inst. 2018;doi:10.1093/jnci/djy133.

Burtness B, et al. Abstract LBA8_PR. Presented at: European Society for Medical Oncology Congress; Oct. 19-23, 2018; Munich.

Cohen R, et al. Monalizumab in combination with cetuximab in recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN): Clinical and translational biomarker results. Presented at: Society for Immunotherapy of Cancer Annual Meeting; Nov. 7-11, 2018; Washington.

Ferris R and Gillison ML. N Engl J Med. 2017;doi:10.1056/NEJMc1615565.

Kaiser J. Science. 2018;doi:10.1126/science.359.6382.1346.

Noronha V, et al. J Clin Oncol. 2018;doi:10.1200/JCO.2017.74.9457.

Powell SF, et al. Abstract O50. Presented at: Society for Immunotherapy of Cancer Annual Meeting; Nov. 7-11, 2018; Washington.

Szturz P, et al. Oral Oncol. 2018;doi:10.1016/j.oraloncology.2017.11.025.

For more information:

Charu Aggarwal, MD, MPH, is Lesley M. Heisler assistant professor of medicine at University of Pennsylvania. She also is a HemOnc Today Editorial Board Member. She can be reached at charu.aggarwal@uphs.upenn.edu.

Disclosure: Aggarwal reports attending advisory boards for Bristol-Myers Squibb, MedImmune and Roche.

    See more from HemOnc Today's PharmAnalysis