Advancing Education, Research, and Quality of Care for the Head and Neck oncology patient.
Background: Head and neck squamous cell carcinoma (HNSCC) is the most common subtype of head and neck cancers and the seventh most common cancer worldwide, according to recent GLOBOCAN estimates. HNSCC is associated with a high incidence and mortality, accounting for 890,000 new cases and 450,000 deaths annually. For many years, the standard of care (SOC) treatment was systemic chemotherapy with a combination of cisplatin and 5-fluorouracil. However, in 2019, the SOC shifted drastically when the anti-PD-1 antibody pembrolizumab was approved by the FDA for the treatment of recurrent/metastatic (RM) HNSCC. The remarkable success of pembrolizumab in the KEYNOTE-048 trial spurred a series of studies analyzing immune checkpoint inhibitors (ICIs) for HNSCC treatment. While many promising results emerged in the RM setting, this was not the case for locally advanced HNSCC (LA HNSCC). Two pivotal trials, KEYNOTE-412 and JAVELIN Head and Neck 100, yielded negative results. This study aims to further evaluate the efficacy of ICIs in the treatment of LA HNSCC.
Methods: We conducted a comprehensive literature search using PubMed, EMBASE, and Cochrane databases from inception through September 6th, 2024. Phase II and III randomized controlled trials (RCTs) evaluating ICIs plus chemoradiation in the treatment of LA HNSCC were included. The primary outcome was progression-free survival (PFS). A generic inverse variance method was used to calculate the estimated pooled hazard ratio (HR) for PFS with 95% confidence interval (CI). Heterogeneity was assessed with Cochran’s Q test. Fixed effects model was applied.
Results: A total of 1,501 patients from two phase III RCTs (KEYNOTE-412, n=804; JAVELIN Head and Neck 100, n=697), were incorporated into the final analysis. Both trials used a 1:1 randomization ratio. The studies compared ICIs (either avelumab or pembrolizumab) plus chemoradiotherapy versus chemoradiotherapy alone. HR for 2-year PFS in the PD-L1 positive cohort reached statistical significance with HR of 0.78 (95% CI: 0.63-0.97; P=0.02), indicating improved PFS in the immunotherapy arm compared to the control arm. Interestingly, subgroup analysis in the PD-L1 negative cohort showed potential harmful effects of ICIs, as the result was near statistical significance with HR of 1.31 (95% CI: 0.99-1.75, P=0.06). HRs for 2-year PFS in all other subgroups, including HPV negative, HPV positive, age > 65, age < 65, males, females, North Americans, cancer subtypes: hypopharyngeal, pharyngeal, oropharyngeal, oral cavity, and overall population, were not statistically significant.
Conclusions: This study revealed improved PFS in PD-L1 positive patients with LA HNSCC treated with ICIs + chemoradiotherapy compared to chemoradiotherapy alone. It also suggests a possible harmful effect of ICI addition to SOC in patients with PD-L1 negative status, which may explain why the overall results from the included studies were negative. The findings in this study favor the addition of ICIs to SOC treatment of PD-L1 positive LA HNSCC, and suggest their avoidance in the PD-L1 negative setting. Additional studies are needed in the future to further evaluate the efficacy of ICIs in LA HNSCC