According to data from a phase III CheckMate 648 trial (NCT03143153), evaluating treatment with nivolumab (Opdivo®; Bristol Myers Squibb) plus chemotherapy or nivolumab + ipilimumab (Yervoy®; Bristol Myers Squibb) both a dual immunotherapy regimen and a single immunotherapy agent added to chemotherapy extends overall survival (OS) for patients with advanced esophageal squamous cell carcinoma (ESCC), particularly those positive for the immune checkpoint protein PD-L1. The updated data was presented at the annual meeting of the American Society of Clinical Oncology (ASCO), held June 4 – 8, 2021.
Esophageal cancer is the eighth most common cancer and the sixth leading cause of death from cancer worldwide, with approximately 604,000 new cases and over 544,000 deaths in 2020. T
he two most common types of esophageal cancer are squamous cell carcinoma (ESCC) and adenocarcinoma, which account for approximately 90% and 10% of all esophageal cancers, respectively, though esophageal tumor histology can vary by region.
The overall burden of ESCC is concentrated in Asia, where roughly 80% of the global cases occurred in 2020. The majority of esophageal cancer cases are diagnosed in the advanced setting and impact a patient’s daily life, including their ability to eat and drink. ESCC occurs most often in the upper and middle portions of the esophagus, whereas adenocarcinoma begins in the cells of mucus-secreting glands in the esophagus and most often occurs in the lower portion of the esophagus.
The randomized phase III trial CheckMate 648 enrolled 970 patients with previously untreated, unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma. Patients were randomly assigned to receive treatment with nivolumab and chemotherapy (5-fluorouracil and cisplatin); nivolumab and ipilimumab; or chemotherapy alone. Patients randomized to the investigational arms were allowed to receive treatment up to 24 months or until disease progression or unacceptable toxicity.
Primary endpoints were Overall Survival (OS) and Progression-Free Survival (PFS)in patients with tumor cell levels of PD-L1 ≥ 1%. Secondary endpoints included OS and PFS in all randomized patients.
Treatment advances for recurrent or metastatic ESCC or upper GI cancers have been slower than for other cancers. Chemotherapy with cisplatin and 5-fluorouracil is currently the standard of care for initial treatment in patients with advanced ESCC; however, their prognosis remains poor.
“Certain patients with advanced esophageal cancer, who currently have few treatment options, now stand to gain from immunotherapy.” noted ASCO’s Chief Medical Officer and Executive Vice President Julie R. Gralow, MD, FACP, FASCO.
“The dual immunotherapy combination of nivolumab and ipilimumab is the first chemotherapy-free first-line treatment showing benefit for these patients,” she added.
Nivolumab is an immunotherapy agent that belongs to a class of therapies known as checkpoint inhibitors that improve immune systems response to tumor cells by blocking a protein (PD-L1) on the tumor cell surface. Ipilimumab is also a checkpoint inhibitor; it targets CTLA4, a protein on T-cells, also improving response against cancer cells.
Nivolumab has been shown to improve survival in patients with advanced ESCC that is refractory or intolerant to previous chemotherapy.The combination of nivolumab with ipilimumab has demonstrated significant clinical activity across several tumor types, leading investigators to examine the combination for the treatment of ESCC.
The data from CheckMate-648 build upon those from CheckMate-649, together making nivolumab the first and only PD-1/L1 inhibitor to demonstrate superior first-line survival in upper GI cancers across histologies and tumor locations (stomach, gastroesophageal junction, and esophagus). They also add to the existing body of data demonstrating the clinical benefit of Opdivo in esophageal cancer, from the late-line metastatic setting to earlier stages of the disease.
In the study nivolumab plus chemotherapy (cisplatin and 5-fluorouracil) and nivolumab plus ipilimumab both significantly improved OS compared with standard chemotherapy. The co-primary endpoint, OS among patients with PD-L1 ≥ 1%, was significantly better for patients who received nivolumab plus chemotherapy and nivolumab plus ipilimumab compared to chemotherapy alone —15.4 and 13.7 months respectively, compared with 9.1 months.
The study results confirmed that OS was significantly better among all randomized patients with both nivolumab plus chemotherapy and nivolumab plus ipilimumab compared with chemotherapy alone, 13.2, 12.8, and 10.7 months, respectively. In addition, the study results showed that PFS with nivolumab plus chemotherapy was significantly better than with chemotherapy alone in patients with PD-L1 ≥ 1%.
“The clinically meaningful improvements in survival of these two treatment regimens highlight immunotherapy’s impact on cancer care and should bring new therapeutic options to a group of patients that are often diagnosed when the disease has already spread,” said lead author Ian Chau, MD, FRCP, a consultant medical oncologist at the Royal Marsden Hospital in Sutton, United Kingdom.
AEs and serious AEs (≥ grade 3) were comparable between the three groups. Discontinuations (due to any component of a regimen) were more likely for patients receiving nivolumab plus chemotherapy.
As part of the study, participating patients will continue to be followed for OS, PFS, and overall response rate.
A Study to Evaluate Efficacy in Subjects With Esophageal Cancer Treated With Nivolumab and Ipilimumab or Nivolumab Combined With Fluorouracil Plus Cisplatin Versus Fluorouracil Plus Cisplatin (CheckMate 648) – NCT03143153
Highlights of Prescribing Information
Nivolumab (Opdivo®; Bristol Myers Squibb)[Prescribing Information]
Ipilimumab (Yervoy®; Bristol Myers Squibb)[Prescribing Information]
Cisplatin (Platinol, Platinol-AQ; Bristol-Myers Squibb)[Perscription Information]
 Chau I, Doki Y, Ajani JA, Xu J, Wyrwicz L, Motoyama S, Ogata T, Kawakami H, et al. Nivolumab (NIVO) plus ipilimumab (IPI) or NIVO plus chemotherapy (chemo) versus chemo as first-line (1L) treatment for advanced esophageal squamous cell carcinoma (ESCC): First results of the CheckMate 648 study. Abstract LBA4001. Presented at: American Society of Clinical Oncology, held June 4 – 8, 2021. J Clin Oncol 39, 2021 (suppl 15; abstr LBA4001)
 Kato K, Cho BC, Takahashi M, et al. Nivolumab versus chemotherapy in patients with advanced oesophageal squamous cell carcinoma refractory or intolerant to previous chemotherapy (ATTRACTION-3): a multicentre, randomised, open-label, phase 3 trial. Lancet. 20:1506-1517, 2019.
 Klein O, Kee D, Markman B, et al. Immunotherapy of Ipilimumab and Nivolumab in Patients with Advanced Neuroendocrine Tumors: A Subgroup Analysis of the CA209-538 Clinical Trial for Rare Cancers. Clin Cancer Res. 26:4454-4459, 2020
Featured image: 2017 ASCO Annual Meeting – Attendees and poster presenters during Posters Sessions at the American Society of Clinical Oncology (ASCO) Annual Meeting here today. Photo Courtesy: © 2017 ASCO/David Eulitt. Used with permission.