Dual Immunotherapy in First-Line Head and Neck Cancer Treatment: The Current Position

Results from a phase III study called CheckMate 651 addressed an important question in advanced head and neck cancer. The study tested first-line treatment in patients with recurrent or metastatic squamous cell carcinoma of the head and neck using the dual nivolumab/ipilimumab immunotherapy combination.

The previous standard of care was established by EXTREME: cetuximab with cisplatin or carboplatin plus fluorouracil, followed by maintenance cetuximab.

There was no significant overall survival difference between the CheckMate 651 immunotherapy combination results and the historical EXTREME control study. Robert I. Haddad and colleagues reported these findings on 6 December 2022 in Journal of Clinical Oncology.

Results were reported separately for all patients and those with positive PD-L1 CPS scores. The researchers concluded, "CheckMate 651 did not meet its overall survival endpoints in either all randomised patients or those with CPS ≥ 20. Nivolumab plus ipilimumab had a more favourable adverse-effect profile than EXTREME. New treatments remain necessary for recurrent or metastatic squamous cell carcinoma of the head and neck."

Study Details

This open-label study enrolled 947 patients, randomising 472 to nivolumab/ipilimumab and 475 to EXTREME.

• PD-L1 CPS <1: 92 versus 86 patients,
• PD-L1 CPS ≥ 1: 355 versus 372 patients,
• PD-L1 CPS ≥ 20: 185 versus 178 patients.

The primary endpoints, assessed in all patients and those with CPS ≥ 20, were median overall survival.

Key Findings

At the June 2021 analysis, minimum and median follow-up were 27.3 and 39.1 months, respectively.

Primary endpoints:

• Among all randomised patients, there was no statistically significant difference in median overall survival: with nivolumab/ipilimumab it was 13.9 months (95% confidence interval [CI] = 12.1–15.8 months), compared with EXTREME at 13.5 months (95% CI = 12.6–15.2 months), with hazard ratio [HR] = 0.95 (97.9% CI = 0.80–1.13; P = 0.4951).
• CPS ≥ 20 patients likewise showed no statistically significant median overall survival difference: nivolumab/ipilimumab produced 17.6 months (95% CI = 13.8–22.0 months), compared with EXTREME at 14.6 months (95% CI = 12.3–16.0 months), with HR = 0.78 (97.5% CI = 0.59–1.03; P = 0.0469).

Secondary endpoints:

• In patients with CPS ≥ 1, median overall survival was 15.7 months with nivolumab/ipilimumab (95% CI = 13.7–18.8 months) and 13.2 months with EXTREME (95% CI = 11.1–14.6 months), with HR = 0.82 (95% CI = 0.69–0.97).
• Among patients with CPS ≥ 20, median progression-free survival was 5.4 versus 7 months (HR = 1.02; 95% CI = 0.78–1.33).
• Objective response rates were 34.1% versus 36.0%, and median response duration was 32.6 versus 7 months.

Subsequent immunotherapy was given to 9% of the nivolumab/ipilimumab group and 46% of the EXTREME group.

Treatment-related grade 3 or 4 adverse effects occurred in 28.2% of the nivolumab/ipilimumab group and 70.7% of the EXTREME group.

Conclusion and Commentary

Immunotherapy received FDA approvals for advanced head and neck cancer in August and November 2016, for pembrolizumab and nivolumab, respectively. These approvals covered recurrent or metastatic squamous cell carcinoma progressing after platinum-based chemotherapy, where second-line treatment with immunotherapy shows activity and provides substantial benefit.

This raised the question of whether immunotherapies would also be effective first line, leading to the KEYNOTE-048 trial.

Before that study, standard initial treatment for metastatic or recurrent head and neck cancer was platinum-based chemotherapy—cisplatin or carboplatin with 5-fluorouracil (5-FU)—plus the EGFR inhibitor cetuximab. In PD-L1-positive patients with combined positive score [CPS] ≥ 20, median overall survival was 14.9 months with pembrolizumab versus 10.7 months with standard treatment. Regardless of PD-L1 level, overall survival was 13 months with immunotherapy plus chemotherapy versus 10.7 months with standard care. KEYNOTE-048 showed a 23% reduction in the risk of death with the immunotherapy-containing regimen.

In June 2019, the FDA approved pembrolizumab for first-line treatment of metastatic or unresectable recurrent squamous cell carcinoma of the head and neck. Under this approval, pembrolizumab was authorised in combination with platinum and fluorouracil (FU) and as a single agent for all patients with PD-L1 CPS ≥1.

In conclusion, the CheckMate 651 findings discussed here do not change routine practice.

For first-line treatment of advanced squamous cell carcinoma of the head and neck,

• pembrolizumab plus chemotherapy for PD-L1-positive patients,
• chemotherapy plus cetuximab for PD-L1-negative patients

remain the most appropriate initial treatment options.