Data from KEYNOTE-048 showed that the combination of the checkpoint inhibitor pembrolizumab with platinum-containing therapy improved overall survival vs cetuximab plus chemotherapy in patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC).1 The findings provided hope that the combination of a checkpoint inhibitor with platinum will enhance the effect of radiation in chemoradiation. However, that hope was not realized in the first attempt to advance the definitive treatment of locally advanced HNSCC with immunotherapy, chemotherapy, and radiation.
As reported by Lee et al in The Lancet Oncology2—and summarized in this issue of The ASCO Post—the JAVELIN Head and Neck 100 trial (JAVELIN) evaluating the addition of the PD-L1 inhibitor avelumab to chemoradiotherapy followed by adjuvant avelumab failed to meet its primary objective of prolonging progression-free survival. We are now left with the questions as to why, and will this be true of all ongoing amalgamations of immunotherapy with chemoradiotherapy?
Francis Paul Worden, MD
Michelle Lynn Mierzwa, MD
Previous attempts to enhance the standard backbone of platinum and radiation have been fraught with negative results. In RTOG-0522,3 the addition of cetuximab was anticipated to improve outcomes, as cetuximab had previously added benefit to radiation therapy alone. To the contrary, the addition of this EGFR antagonist added more toxicity and failed to improve local control, progression-free survival, or overall survival when administered with chemoradiotherapy. Albeit toxicity with this combination may have played a detrimental role, there was still concern that cisplatin and cetuximab both inhibit repair of radiation-induced DNA damage and that no additional benefit will be seen in tumors with proficient repair mechanisms. Although increased toxicity was not the issue in the experimental arm of JAVELIN, the addition of avelumab appears to have compromised the benefit of cisplatin and radiation. Was this due to T cell depletion or changes in the immune microenvironment, including the blockage between PD‑L1 and CD80, leading to downregulation of T-lymphocyte activation? The answers remain unknown.
Possible Reasons for Lack of Benefit
Could the lack of effect of benefit, rather, be due to checkpoint inhibitor itself? In the metastatic setting, durvalumab, a PD-L1 inhibitor, administered alone or in combination with the CTLA-4 inhibitor tremelimumab, did not improve survival rates over standard-of-care regimens.4 Spanning several solid tumors, a meta-analysis of 19 studies suggests improvements in survival with PD-1 inhibitors over PD-L1 inhibitors.5 PD-L1 inhibitors forgo the binding of PD-1 to PD-L1, leaving the PD-1 and PD-L2 axis intact. This could invariably inhibit the activation of T cells, leading to the escape of tumors from a heightened immune response. This may be compounded by the benefits of chemotherapy, which appear to be synergistic with the addition of a PD-1 inhibitor rather than a PD-L1 inhibitor, since PD-L1 expression is likely augmented by chemotherapy. But is this enough to suggest that PD-1 inhibitors will add benefit to chemoradiotherapy in patients with locally advanced HNSCC?
The results of the phase II KEYNOTE-799 trial in untreated stage III lung cancer demonstrated robust antitumor activity when pembrolizumab was combined with radiation and two different platinum-based regimens.6 On the other hand, data presented at the 2021 ASCO Annual Meeting by Wise-Draper and colleagues revealed that the addition of pembrolizumab to radiation improved disease-free survival in the adjuvant setting in patients with HNSCC with intermediate-risk pathology7; however, in those with high-risk disease who were treated with adjuvant pembrolizumab in combination with cisplatin and radiotherapy, no improvement in disease-free survival was observed over a historical control.
Whether the lack of improvement in those treated with chemoradiotherapy is due to an effect from immunotherapy is not known. The prospective, randomized data from KEYNOTE-512 are thus eagerly awaited; here, we will learn if a PD-1 inhibitor given with chemoradiotherapy and as adjuvant therapy will improve survival endpoints in patients with locally advanced HNSCC.
The addition of avelumab appears to have compromised the benefit of cisplatin and radiation.— Francis Paul Worden, MD, and Michelle Lynn Mierzwa, MD
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A Matter of Timing?
Timing of checkpoint inhibitor therapy may perhaps be the key to improvements in survival, especially if future reports of combinations of immunotherapy and chemoradiation fail to show improved outcomes. Data from the PACIFIC trial in lung cancer demonstrated the benefit of durvalumab following definitive chemoradiotherapy for stage III disease.8 Following suit, a recent report of adjuvant nivolumab vs placebo following neoadjuvant chemoradiation and surgery reported doubling of progression-free survival in patients with resected esophageal or gastroesophageal junction cancer who received the checkpoint inhibitor.9 Alterations in the immune microenvironment due to the inflammation caused by chemoradiotherapy may likely bolster the activity of PD-1 inhibitors, providing the opportunity for dendritic cell priming in lymph nodes, cytotoxic T cell entry, and reactivation of T cells.10
Furthermore, as the authors of the JAVELIN trial noted, the subgroup of patients with high PD-L1 expression had better outcomes than those with low or no expression. With the study permanently closed with no plan for continued follow-up, we will never know, however, if a survival benefit exists for this group of patients or for the avelumab arm collectively. So, if timing becomes relevant to checkpoint inhibitor therapy administration, it will be imperative for providers to identify the patient populations who will derive clinical benefit.
In Search of the Ideal Combination for Radiation Sensitization
Finally, cisplatin and pembrolizumab may not be the ideal combination for radiation sensitization. While cisplatin remains as the standard radiation sensitizer of choice, newer combinations of targeted therapy and immunotherapy could prove to be more efficacious.
In the metastatic setting, Sacco et al reported a response rate of 45% with the combination of cetuximab and pembrolizumab.11 In the GORTEC 2017-01 (REACH) study (ClinicalTrials.gov identifier NCT02999087), patients with locally advanced HNSCC in platinum-eligible and platinum-ineligible cohorts have been randomly assigned to receive radiation therapy with standard high-dose cisplatin and radiation therapy with cetuximab as the standard of care, respectively, each vs radiation therapy with cetuximab and avelumab followed by adjuvant avelumab. The safety phase of this trial was published in 202012 and demonstrated tolerability of the immunotherapy and cetuximab combination, giving the investigators approval to continue enrollment in the efficacy phase; results are awaited. While GORTEC 2007-0113 demonstrated improvement in progression-free survival, but not overall survival, with carboplatin, fluorouracil, and cetuximab in combination with radiation over cetuximab and radiation, it will be some time before we know whether targeted therapy and a checkpoint inhibitor therapy provides a similar advantage or improves overall survival.
Although cisplatin remains the standard radiation sensitizer of choice, newer combinations of targeted therapy and immunotherapy could prove to be more efficacious.— Francis Paul Worden, MD, and Michelle Lynn Mierzwa, MD
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Since we have been unable to move the field for treatment of locally advanced HNSCC beyond cisplatin and radiation, the results of the JAVELIN trial are very disappointing. We must remain optimistic and keep looking for combination regimens of immunotherapy and chemotherapy or immunotherapy and targeted therapy that will provide us with opportunities beyond our current standard of care. From the words of Winston Churchill, “Failure is not fatal, success is not final; it is the courage to continue that counts.”
Dr. Worden is Professor in the Department of Internal Medicine, Division of Hematology and Oncology, and Dr. Mierzwa is Associate Professor in the Department of Radiation Oncology, both at Rogel Cancer Center, University of Michigan Health System, Ann Arbor.
DISCLOSURE: Dr. Worden has received honoraria from Bayer, Bristol Myers Squibb, Eisai, Merck Sharp & Dohme, and Regeneron; has served as a consultant or advisor to Bayer, Bristol Myers Squibb, Cue Biopharma, Eisai, Loxo, Merck, Rakuten, and Regeneron; has received research funding from Bristol Myers Squibb, Eli Lilly, Loxo, and Oragenics; has received institutional research funding from Eisai, Merck, and Pfizer; and has been reimbursed for travel, accommodations, or other expenses by Bayer and Merck Sharp & Dohme. Dr. Mierzwa receives study drug from Bristol Myers Squibb.
REFERENCES
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