Late breaking Abstract – ESMO 2019 OPDIVO® Improves Overall Survival in Advanced Esophageal Cancer Regardless of PD-L1 Expression

SUMMARY: The American Cancer Society estimates that in 2019, about 17,650 new cases of esophageal cancer will be diagnosed in the US and about 16,080 individuals will die of the disease. It is the sixth most common cause of global cancer death. Squamous Cell Carcinoma is the most common type of cancer of the esophagus among African Americans, while Adenocarcinoma is more common in caucasians. About 20% of patients survive at least 5 years following diagnosis. Patients with advanced esophageal cancer following progression on first line chemotherapy have limited treatment options and have a poor prognosis, with a 5-year relative survival rate of 8% or less.

The FDA in July 2019 approved KEYTRUDA® (Pembrolizumab) for patients with recurrent, locally advanced or metastatic Squamous Cell Carcinoma of the Esophagus (ESCC), whose tumors express PD-L1 (Combined Positive Score-CPS of 10 or more). This approval was based on the Phase III KEYNOTE-181 global trial in which KEYTRUDA® significantly improved Overall Survival compared with chemotherapy, as second line therapy for patients with advanced esophageal cancer, with PD-L1 CPS of 10 or higher. The median Overall Survival in the Intent-To-Treat population was however was not statistically significant.

OPDIVO® (Nivolumab) is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the T cells. OPDIVO® in a Phase II study showed promising antitumor activity and safety profile among patients with advanced refractory Squamous Cell Carcinoma of the Esophagus (ESCC). ATTRACTION-3 is a multicentre, randomized, open-label, Phase III trial in which 419 patients with unresectable advanced or recurrent ESCC refractory or intolerant to one prior Fluoropyrimidine/Platinum-based chemotherapy, regardless of PD-L1 expression, were enrolled. Patients were randomly assigned (1:1) to either OPDIVO® 240 mg IV every 2 weeks (N=210) or investigator’s choice of Paclitaxel 100 mg/m2 IV once per week for 6 weeks then 1 week off or Docetaxel 75 mg/m2 IV every 3 weeks (N=209). Both treatment groups were well balanced and nearly 90% of the patients were male and 96% were Asian. Approximately 85% of patients were current or former smokers, about half of patients had prior surgery and about 70% had prior radiotherapy. Approximately 50% of patients had tumor PD-L1 expression of 1% or more. The Primary endpoint was Overall Survival (OS), in the intent-to-treat population that included all randomized patients.

At a minimum follow-up of 17.6 months, OPDIVO® showed a statistically significant improvement in OS, with a 23% reduction in the risk of death, compared to chemotherapy. The median Overall Survival was 10.9 months in the OPDIVO® group versus 8.4 months in the chemotherapy group (HR for death=0.77, P=0.019). The proportion of patients alive at 18 months was numerically larger with OPDIVO® versus chemotherapy (31% vs 21%). The OS benefit with OPDIVO® over chemotherapy was noted across tumor PD-L1 expression levels (PD-L1 1% or more, HR=0.69; PD-L1 less than 1%, HR=0.84). The Objective Response Rate was similar in both treatment groups (19% vs 22%). However the median duration of response with OPDIVO® was 6.9 months, versus 3.9 months with chemotherapy, suggesting that the responses were substantially more durable with OPDIVO® compared to chemotherapy. There was no significant difference in the Progression Free Survival between the treatment groups. Grade 3 or 4 adverse events occurred in 18% of the OPDIVO® group and 63% of the chemotherapy group.

It was concluded that OPDIVO® was associated with a significant improvement in Overall Survival with a favorable safety profile compared with chemotherapy, in previously treated patients with advanced Esophageal Squamous Cell Carcinoma, regardless of PD-L1 expression, and represents a potential new standard second-line treatment option for this patient group. Nivolumab versus chemotherapy in advanced esophageal squamous cell carcinoma (ESCC): the phase 3 ATTRACTION-3 study. Cho BC, Kato K, Takahashi M, et al. Presented at ESMO 2019: September 27-October 1, 2019; Barcelona, Spain. Abstract LBA 11.