Nivolumab Plus Ipilimumab Versus EXTREME Regimen as First-Line Treatment for Recurrent/Metastatic Squamous Cell Carcinoma of the Head and Neck: The Final Results of CheckMate 651

Abstract

PURPOSE CheckMate 651 (ClinicalTrials.gov identifier: NCT02741570 ) evaluated first-line nivolumab plus ipilimumab versus EXTREME (cetuximab plus cisplatin/carboplatin plus fluorouracil ≤ six cycles, then cetuximab maintenance) in recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). METHODS Patients without prior systemic therapy for R/M SCCHN were randomly assigned 1:1 to nivolumab plus ipilimumab or EXTREME. Primary end points were overall survival (OS) in the all randomly assigned and programmed death-ligand 1 combined positive score (CPS) ≥ 20 populations. Secondary end points included OS in the programmed death-ligand 1 CPS ≥ 1 population, and progression-free survival, objective response rate, and duration of response in the all randomly assigned and CPS ≥ 20 populations. RESULTS Among 947 patients randomly assigned, 38.3% had CPS ≥ 20. There were no statistically significant differences in OS with nivolumab plus ipilimumab versus EXTREME in the all randomly assigned (median: 13.9 v 13.5 months; hazard ratio [HR], 0.95; 97.9% CI, 0.80 to 1.13; P = .4951) and CPS ≥ 20 (median: 17.6 v 14.6 months; HR, 0.78; 97.51% CI, 0.59 to 1.03; P = .0469) populations. In patients with CPS ≥ 1, the median OS was 15.7 versus 13.2 months (HR, 0.82; 95% CI, 0.69 to 0.97). Among patients with CPS ≥ 20, the median progression-free survival was 5.4 months (nivolumab plus ipilimumab) versus 7.0 months (EXTREME), objective response rate was 34.1% versus 36.0%, and median duration of response was 32.6 versus 7.0 months. Grade 3/4 treatment-related adverse events occurred in 28.2% of patients treated with nivolumab plus ipilimumab versus 70.7% treated with EXTREME. CONCLUSION CheckMate 651 did not meet its primary end points of OS in the all randomly assigned or CPS ≥ 20 populations. Nivolumab plus ipilimumab showed a favorable safety profile compared with EXTREME. There continues to be a need for new therapies in patients with R/M SCCHN.

Novel Immunotherapeutic Approaches to Treating HPV-Related Head and Neck Cancer

“…The study randomized a total of 947 patients and, at a minimum follow-up of 27.3 months, did not find a statistically significant improvement in OS regardless of CPS score or HPV status when compared to the EXTREME regimen. However, grade 3 and 4 adverse events occurred in 28.2% of patients in the combination arm and 70.7% in the EXTREME arm [ 70 ]. Although CheckMate-651 did not meet its primary endpoint of OS, the combination arm demonstrated a more favorable safety profile.…”

“…Examples include targeting IDO1 [ 74 ], TLR8 agonists [ 75 ], OX40 [ 76 ], and B7-H3 [ 77 ], the detailing of which are beyond the scope of this review. Major trials regarding ICIs and HPV-related OPSCC are demonstrated in Table 1 [ 51 , 63 , 65 , 66 , 67 , 69 , 70 , 71 , 72 ].…”

Deep spatial-omics to aid personalization of precision medicine in metastatic recurrent Head & Neck Cancers

“…Immunotherapy and more specifically check-point inhibitors (ICIs) have revolutionized the management of solid tumors but despite the great advancements, ICIs have been limited by a lack of ability to confidently identify patients who are likely or unlikely to positively respond to treatment 1 . A prime example is mucosal Head and Neck Squamous Cell Carcinomas (HNSCCs) where multiple studies have failed to show a benefit of ICIs over standard chemotherapy [2][3][4] . This failure is partially explained by the high inter-and intra-tumor heterogeneity of mucosal HNSCCs with different tumor microenvironments (TME) influenced by the location of primary site and etiology (i.e., HPV + vs HPV -) 5 .…”

Combination Immunotherapy in Head and Neck Cancer—Checkmate or a Draw?

“…The study population in CheckMate 651 included only patients with platinum-eligible disease (no prior platinum treatment or platinum treatment during curative-intent therapy recurrence or metastasis greater than 6 months after curative therapy) . Although not meeting its statistical boundary, this study demonstrated a convincingly favorable outcome for the primary end point, survival in the combination arm compared with the EXTREME regimen in patients with combined positive score (CPS) greater than 20, and for patients with CPS greater than 1, a secondary end point .…”