Author: Charles Bankhead

Three different checkpoint inhibitors missed the primary endpoints in separate randomized trials of head and neck cancer.

In one trial, adding avelumab (Bavencio) to standard treatment did not significantly improve progression-free survival (PFS) in cisplatin-eligible or ineligible patients with locally advanced head and neck squamous cell carcinoma (HNSCC). In another trial, the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) did not improve overall survival (OS) as first-line treatment for recurrent/metastatic HNSCC.

Both trials were reported during the European Society for Medical Oncology (ESMO) virtual meeting. Although subgroup analyses suggested benefits for certain patients, neither study should influence clinical practice at this point, said ESMO invited discussant Amanda Psyrri, MD, of the University of Athens in Greece.

In the avelumab study, known as GORTEC-REACH, results in cisplatin-eligible patients were consistent with those of the previously reported JAVELIN trial with avelumab, said Psyrri. A signal of benefit was evident in cisplatin-ineligible patients but did not achieve statistical significance.

With regard to the CheckMate 651 trial of nivolumab and ipilimumab, Psyrri said, “Combined PD-1 and CTLA-4 inhibition does not appear to be an effective strategy in recurrent/metastatic HNSCC. Future research efforts may identify predictive biomarkers for response to anti-PD-1 and anti-CTLA-4 combinations in HNSCC.”

Additionally, a smaller trial of pembrolizumab (Keytruda) showed no significant improvement in OS versus chemotherapy for platinum-treated relapsed/metastatic nasopharyngeal carcinoma.

This trial evolved from evidence of potential synergy with PD-1/L1 inhibition, cetuximab (Erbitux), and radiotherapy, said Jean Bourhis, MD, of University Hospital Center Vaudois in Lausanne, Switzerland. The trial included a total of 707 patients with stage III/IV HNSCC, divided into cohorts by eligibility to receive cisplatin. The cisplatin-ineligible cohort comprised 277 patients, and the cisplatin-eligible group included 430 patients.

Cisplatin-ineligible patients all received radiotherapy and cetuximab and were randomized to avelumab or no additional treatment. Cisplatin-eligible patients received cisplatin-based chemoradiation with or without avelumab. The primary endpoint for both cohorts was PFS.

After a median follow-up of 21.3 months in the cisplatin-ineligible cohort, the 2-year PFS rate favored the avelumab arm (44% vs 31%), but the difference did not achieve statistical significance (HR 0.84, 95% CI 0.61-1.15, P=0.14). The difference in the secondary endpoint of metastatic progression did reach statistical significance (14.3% with cetuximab vs 5.4% with avelumab-cetuximab, HR 0.31, P=0.007).

In the cisplatin-eligible group, a planned interim analysis showed a 1-year PFS rate of 73% without avelumab and 64% with the PD-L1 inhibitor, which translated into a hazard ratio of 1.27, crossing the boundary for futility and favoring standard of care, said Bourhis. The key secondary endpoint of OS showed a numerical advantage for the avelumab arm at 2 years (58% vs 54%), but the difference did not achieve statistical significance (P=0.69).

CheckMate 651
This trial followed the progression of treatment standards for relapsed/metastatic HNSCC from chemotherapy, to cetuximab plus chemotherapy, to a migration toward immunotherapy with recent approvals for pembrolizumab with or without chemotherapy, said Athanassios Argiris, MD, of Hygeia Hospital in Marousi, Greece. The combination of nivolumab and ipilimumab has produced durable responses and a survival benefit in several types of advanced solid tumors.

The trial involved 947 patients with untreated platinum-eligible recurrent/metastatic HNSCC. They were randomized to nivolumab-ipilimumab or to the combination of cetuximab, platinum, and 5-fluorouracil. The primary endpoints were OS in all patients and in the patients with a combined positive score (CPS) ≥20 for PD-L1 expression, who accounted for about 38% of the total population.

The primary analysis in all patients showed a median OS of 13.9 months with nivolumab-ipilimumab versus 13.5 months with standard treatment, a nonsignificant difference (P=0.4951). In the CPS ≥20 subgroup, median OS was 17.6 months with nivolumab-ipilimumab and 14.6 months with standard care, representing a 22% reduction in the hazard ratio but did not meet prespecified criteria for statistical significance. The survival benefit in the CPS ≥20 subgroup increased over time, from 63% versus 58% at 1 year to 41% versus 33% at 2 years.

Argiris noted that OS in the control group exceeded expectations based on historical data with standard therapy. Nivolumab-ipilimumab delayed symptom deterioration, was associated with improved overall health status, and had a favorable safety profile versus the control group.

This pembrolizumab study followed favorable results from a phase I trial of patients with heavily treated recurrent/metastatic PD-L1-positive nasopharyngeal carcinoma (NPC). Moreover, NPC has a strong association with Epstein-Barr virus (EBV) infection, which in turn is associated with PD-L1 expression, said Anthony Chan, MD, of the Chinese University of Hong Kong.

The phase III KEYNOTE-122 trial included 233 patients with recurrent/metastatic EBV-positive NPC previously treated with platinum-based chemotherapy. They were randomized to pembrolizumab or investigator’s choice of chemotherapy, which continued until disease progression or intolerable toxicity. The primary endpoint was OS.

About 85% of the patients were Asian, about 40% had CPS ≥10 PD-L1 expression (47% in the pembrolizumab arm), and about 60% of the patients had recurrent metastatic disease.

The primary analysis showed a median OS of 17.2 months with pembrolizumab and 15.3 months with chemotherapy, a nonsignificant difference (HR 0.90, 95% CI 0.67-1.19). The 2-year OS rate favored the pembrolizumab arm (40.2% vs 32.2%). Subgroup analysis showed no consistent pattern of benefit with pembrolizumab, including PD-L1 status. A majority of patients in both arms received one or more subsequent therapies, said Chan.

PFS, objective response rate, disease control rate, and duration of response all did not differ significantly between treatment groups, but trended in favor of the chemotherapy arm.

EBV-positive NPC is a chemosensitive disease; as a result, the chemotherapy control arm was expected to be difficult to top, said ESMO invited discussant Lisa Licitra, MD, of the Istituto Nazionale dei Tumori and University of Milan.

“Immuno-oncology is not lost; anti-PD-1 therapy remains the standard in first line,” she said.

Charles Bankhead is senior editor for oncology and also covers urology, dermatology, and ophthalmology. He joined MedPage Today in 2007