2024 Top Story in Oncology: Pembrolizumab Plus Concurrent Chemoradiotherapy for HNSCC

For patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) that is PD-L1–expressing, the PD-1 inhibitor pembrolizumab, given alone or in combination with chemotherapy, improves survival compared with chemotherapy plus cetuximab.¹ This finding immediately raised the question of whether the addition of an immune checkpoint inhibitor to standard-of-care therapy in the curative setting would also provide an advantage. A number of trials have addressed this, and, to date, the JAVELIN Head and Neck 100 trial adding avelumab to chemoradiation² and the IMvoke010 trial adding atezolizumab maintenance after definitive surgical or radiation therapy³ were negative. These trials used PD-L1 inhibitors that were not approved for HNSCC. Therefore, the results of the KEYNOTE-412 trial using pembrolizumab⁴ were keenly awaited.

This trial enrolled patients with stage III to IV HNSCC suitable for high-dose cisplatin and radiation; for patients with HPV-associated oropharynx cancer, either T4 or N3 stage was required. Similarly to previous trials, the study did not require PD-L1 expression on tumor or immune cells. Among 804 patients enrolled and followed for a median of 47.7 months, the median event-free survival was not reached (95% CI, 44.7 months–not reached) in the pembrolizumab group and was 46.6 months (27.5–not reached) in the placebo group (HR, 0.83 [0.68–1.03]; log-rank P = .043). However — and this is again similar to prior trials — effects were greater among patients with positive PD-L1 expression (combined positive score [CPS] ≥10) than among those with PD-L1 CPS <1 (HR, 0.80 vs 1.09) as well as among those with HPV-negative versus HPV-associated cancers (HR, 0.83 vs 0.89). Taking these findings together with those from prior trials, there is a strong case to be made for studying immune checkpoint inhibition in the definitive management of PD-L1–expressing HNSCC. There is also an argument to be made for focusing such studies on HPV-negative HNSCC, as the benefit of adding immune checkpoint inhibition is greater in patients with HPV-negative HNSCC in both JAVELIN Head and Neck 100 and KEYNOTE-412. This is likely the case because of the higher event rate and shorter event-free survival in patients with HPV-negative HNSCC, as well as because of the biologic features of HPV-associated HNSCC, which result in immune silencing.⁵ The recent press release of KEYNOTE-689⁶ indicates an event-free survival benefit with the use of preoperative pembrolizumab, and this highlights the potential benefit of using immune checkpoint inhibition prior to definitive therapy that ablates the tumor-draining lymph nodes. Thus, a longer exposure to the immune checkpoint inhibitor may be beneficial. At present, the JADE trial (NCT06256588) is a phase III trial studying the use of dostarlimab following chemoradiation in patients with PD-L1–expressing tumors, providing some promise for advancing immune checkpoint inhibitor therapy for patients receiving potentially curative chemoradiation.