Survival Boost With First-Line Immunotherapy for Esophageal Cancer

Immunotherapy-containing combinations significantly improved survival in advanced esophageal cancer as compared with standard chemotherapy, a large randomized trial showed.

Median overall survival (OS) in patients with PD-L1 expression ≥1% increased from 9.1 months with chemotherapy alone to 15.4 months with the addition of nivolumab (Opdivo). The combination of nivolumab and ipilimumab (Yervoy) led to a median OS of 13.7 months. The two immunotherapy arms also outperformed chemotherapy in an analysis of all randomized patients.

Nivolumab plus chemotherapy also improved progression-free survival in the PD-L1-positive subgroup, but the dual-immunotherapy regimen did not, reported Ian Chau, MD, of the Royal Marsden Hospital in London, at the American Society of Clinical Oncology (ASCO) virtual meeting.

“For both nivolumab plus ipilimumab and nivolumab plus chemotherapy, responses are much longer compared to those achieved by chemotherapy alone,” Chau said during a press briefing prior to the ASCO meeting. “With overall survival benefits seen in both our primary patient population of PD-L1-positive patients, as well as all randomized patients, nivolumab plus chemotherapy and nivolumab plus ipilimumab each represents a new potential first-line standard of care for patients with esophageal squamous cell carcinoma (ESCC).”

The trial made a case for use of either immunotherapy combination as initial treatment for advanced esophageal cancer, said Julie Gralow, MD, ASCO chief medical officer.

“There have been very few treatment advances for esophageal or upper GI [gastrointestinal] cancers,” she said following Chau’s presentation. “The CheckMate 648 study found two regimens that improved overall survival beyond the current standard of care, which is chemotherapy alone for recurrent or metastatic esophageal cancers, particularly those that express PD-L1, which was found in about half of the tumors.”

“Both (immunotherapy regimens) significantly extended survival and should be considered superior treatments as first-line treatment of esophageal squamous-cell carcinoma,” Gralow added. “The dual immunotherapy combination without chemo is the first chemo-free first-line treatment showing benefit for these patients.”

In a prior randomized, phase III trial, single-agent nivolumab significantly improved OS versus chemotherapy in previously treated advanced ESCC. CheckMate 648 moved the clinical evaluation of immunotherapy for ESCC into the first-line setting and was the first phase III trial to compare an immuno-oncology combination and dual immunotherapy against standard-of-care chemotherapy.

Investigators in CheckMate 648 enrolled patients with unresectable advanced, recurrent, or metastatic ESCC, irrespective of PD-L1 expression status. Patients were randomly allocated to receive cisplatin-containing chemotherapy, nivolumab plus chemotherapy, or nivolumab plus ipilimumab. Treatment continued for a maximum of 24 months or until disease progression or development of unacceptable toxicity.

The trial had two primary endpoints: OS and PFS in the PD-L1-positive patients, as determined by a blinded independent review committee (BIRC). The key secondary efficacy outcomes were OS and PFS in all randomized patients, also adjudicated by BIRC.

Data analysis included 970 randomized patients (473 with PD-L1-positive tumors), each of whom had a minimum follow-up of 13 months.The primary analysis showed statistically significant improvement versus chemotherapy alone with nivolumab plus chemotherapy (HR 0.54, 99.5% CI 0.37-0.80, P<0.0001) and with the dual-immunotherapy regimen (HR 0.64, 98.6% CI 0.46-0.90, P=0.0010). The 12-month OS was 58% with nivolumab plus chemotherapy, 57% with nivolumab and ipilimumab, and 37% with chemotherapy.

The secondary OS analysis in all randomized patients yielded median values of 13.2 months with nivolumab plus chemotherapy, 12.8 months with nivolumab plus ipilimumab, and 10.7 months with chemotherapy. The differences represented hazard ratio reductions of 26% and 28% in favor of the nivolumab-chemotherapy and nivolumab-ipilimumab arms, respectively (P=0.0021, P=0.0110).

PD-L1-positive patients treated with nivolumab and chemotherapy had a 35% reduction in the survival hazard versus chemotherapy (95% CI 0.46-0.92). The nivolumab-ipilimumab arm did not meet the PFS endpoint (HR 1.02, 95% CI 0.73-1.43).

Objective response rates in PD-L1-positive patients were 53% with nivolumab-chemotherapy, 35% with nivolumab-ipilimumab, and 20% with chemotherapy. Corresponding rates in all randomized patients were 47%, 28%, and 27%.

Grade 3/4 treatment-related adverse events (TRAEs) occurred more often with the nivolumab-chemotherapy regimen (47% vs 32% for nivolumab-ipilimumab and 36% with chemotherapy). More patients in the nivolumab-chemotherapy group discontinued because of TRAEs (34% vs 18% vs 19%).

Although not formally compared, the nivolumab-chemotherapy regimen appeared more active than the dual-immunotherapy regimen. In response to a question, Chau said nivolumab-ipilimumab might be preferable for patients with significant comorbidities, such as renal impairment and neuropathy. In contrast, nivolumab-chemotherapy would be the choice for patients with high symptomatic burden, so long as they could tolerate the chemotherapy, as they had higher response rates with that combination, he added.