Immunotherapy Likely New Standard in Advanced Esophageal Cancer


Nivolumab (Opdivo) plus chemotherapy and nivolumab plus ipilimumab (Yervoy) were superior to standard chemotherapy in improving overall survival in patients with advanced esophageal squamous cell carcinoma (ESCC), new results of a phase 3 trial show.

The benefit was particularly pronounced for the subgroup of patients who were positive for PD-L1 (n = 473).

Among all patients (n = 970), overall survival was statistically significantly better for those who received nivolumab plus chemotherapy (13.2 months) and nivolumab plus ipilimumab (12.8 months), as compared with chemotherapy alone (10.7 months).

“Nivolumab is the first PD-1 inhibitor to demonstrate superior overall survival in combination with either chemotherapy or ipilimumab vs chemo alone, in previously untreated patients with advanced esophageal squamous cell carcinoma,” said lead author Ian Chau, MD, a consultant medical oncologist at the Royal Marsden Hospital in Sutton, United Kingdom, noting that there were no new safety signals with either of these agents.

“Nivolumab plus chemotherapy and nivolumab plus ipilimumab each represent a new potential first-line standard of care for patients with advanced esophageal squamous cell carcinoma,” he said.

Chau presented the results of the study at the 2021 American Society of Clinical Oncology virtual Annual Meeting.

Before this trial of first-line use, nivolumab had shown efficacy in previously treated patients with advanced ESCC, say Chau and colleagues. In the ATTRACTION-3 trial, the checkpoint inhibitor was associated with a significant improvement in overall survival, as well as a favorable safety profile, as compared with chemotherapy.

On the basis of those results, the US Food and Drug Administration in June 2020 approved nivolumab in previously treated patients with advanced ESCC.

Survival Improved With Immunotherapy, Especially Those With Tumor Cell PD-L1 ≥1%

The CheckMate-648 trial, a randomized phase 3 study, was conducted among treatment-naive patients with advanced ESCC to determine if dual immunotherapy or a single immunotherapy agent added to chemotherapy improved overall survival, as compared with standard chemotherapy.

The cohort involved 970 patients with previously untreated, unresectable advanced, recurrent, or metastatic ESCC. Patients were randomly assigned to nivolumab 240 mg plus chemotherapy (consisting of fluorouracil and cisplatin) or nivolumab 3 mg/kg plus ipilimumab 1 mg/kg, or chemotherapy alone.

The primary endpoints were overall survival (OS) and progression-free survival (PFS) per blinded independent central review in patients with tumor cell PD-L1 ≥1%. Secondary endpoints included OS and PFS in all patients.

At 13 months minimum follow-up, patients in the immunotherapy groups achieved a statistically significant improvement in OS, in the group with tumor cell PD-L1 ≥1%, and in all patients included in those two nivolumab-containing arms.

Overall survival for patients with tumor cell PD-L1 ≥1% was as follows: nivolumab plus chemotherapy 15.4 months (hazard ratio [HR] 0.54; P < .0001), nivolumab plus ipilimumab 13.7 months (HR, 0.64; P = .001), and chemotherapy alone), as compared with chemotherapy alone 9.1 months.

There was also a statistically significant PFS benefit observed for patients in the nivolumab plus chemotherapy group vs chemotherapy alone (HR, 0.65; P = .0023) in patients with tumor cell PD-L1 ≥1%. However, PFS in the nivolumab plus ipilimumab group vs chemotherapy did not meet prespecified boundary for significance. (HR, 1.02).

“Among those who achieved a complete response, the proportion was three times higher in the nivolumab plus chemotherapy arm compared to the chemotherapy arm,” said Chau.

No new safety signals were observed and serious adverse events of grade 3 or higher were comparable between the three groups. However, patients in the nivolumab plus chemotherapy group were more likely to discontinue therapy as compared with the other two groups.

“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 disease has already spread,” said Chau.

New Standard of Care?

Commenting on the study, Samuel J. Klempner, MD, a gastrointestinal medical oncologist at the Massachusetts General Hospital Cancer Center, Boston, Massachusetts, noted that the “prospect of a chemo-free regimen for advanced ESCC with the well-studied combination of ipilimumab and nivolumab would represent a welcome addition to our treatment armamentarium. The CheckMate-648 trial provides the first phase 3 support for this combination in ESCC patients and future regulatory evaluation is anticipated.”  

These findings further validate the superiority of chemotherapy in combination with anti-PD-1 agents over chemotherapy alone in ESCC, he explained. “The outcomes from the chemotherapy-free combination of ipilimumab plus nivolumab in CM-648 suggest we may soon have another option for many of our ESCC patients.

“The results of CheckMate-648 provide clear evidence that chemotherapy in combination with anti-PD-1 represents the new standard for frontline therapy for our advanced esophageal squamous cell cancer patients,” Klempner added.

Another expert also weighed in on the results.

Joseph Chao, MD, associate clinical professor in the Department of Medical Oncology & Therapeutics Research at City of Hope in Duarte, California, agreed that these data show that nivolumab plus chemotherapy represents a new standard of care — but for advanced ESCC in patients with tumor cell PD-L1 ≥1% expression.

“For this treatment combination and study subpopulation, the co-primary endpoints of overall survival and progression-free survival were clearly improved over chemotherapy,” he said.

While the data were encouraging in all study patients, results in patients with tumor cell PD-L1 <1% expression will likely need to be analyzed to better ascertain risks and benefits of adding nivolumab to chemotherapy for this subgroup of patients, he commented. 

“Nivolumab plus ipilimumab also demonstrated a significant improvement in overall survival in this subgroup, but the progression-free survival did not meet the study’s predefined statistical boundary for significance,” Chao said. “Nivolumab plus ipilimumab may still emerge as a treatment option in patients with contraindications to chemotherapy but is still appropriate for a dual-immunotherapy combination.”

Therefore, further analysis will still be worthwhile to elucidate the clinical activity of dual immunotherapy vs chemotherapy in the tumor cell PD-L1 <1% subpopulation, he said.

“Lastly, assessing PD-L1 expression by counting positive both tumor cells and immune cells has appeared more reliable as a predictive biomarker for immunotherapy benefit across other major advanced ESCC studies,” said Chao. “Thus, analyzing the treatment outcomes for each arm in the CheckMate-648 trial population by this methodology may provide more insight into where a new standard of care should be applied for first-line treatment of advanced ESCC.”

The study was funded by Bristol-Myers Squibb (BMS).

Chau has declared the following: honoraria from Lilly; a consulting or advisory role with AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Incyte, Lilly, Merck Serono, MSD Oncology, OncXerna Therapeutics, Pierre Fabre, and Roche/Genentech; receiving research funding from Janssen-Cilag (Inst), Lilly (Inst); travel/ accommodations/expenses from Bristol-Myers Squibb, Lilly, Merck Serono, and MSD.

Klempner has disclosed a consulting/advisory role with Merck, Bristol-Myers Squibb, Astellas, Daiichi-Sankyo, Eli Lilly, and Natera; and stock ownership in Turning Point Therapeutics.

American Society of Clinical Oncology (ASCO) Annual Meeting: Abstract 4001. Presented June 3, 2021.

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