ESMO 2020 Ushers in Immunotherapy for Gastric and Esophageal Cancers

By Christina Bennett, MS

At ESMO Virtual Congress 2020, the results from three randomized phase 3 clinical trials — CheckMate 649, ATTRACTION-4, and KEYNOTE-590 — made one thing clear: Immunotherapy benefits patients with gastric and esophageal cancers. As for the adjuvant setting, which had no standard of care, the results from the phase 3 CheckMate 577 trial point to nivolumab as a new option.

CheckMate 649: Survival Benefit Seen in First-line Setting with Nivolumab in HER2-Negative Gastric Cancer, Gastroesophageal Junction Cancer, and Esophageal Adenocarcinoma

The addition of nivolumab to chemotherapy in the first-line setting led to a survival benefit for patients with unresectable, HER2-negative advanced gastric cancer, gastroesophageal junction cancer, or esophageal adenocarcinoma, especially for tumors expressing high amounts of PD-L1.

The CheckMate 649 trial included 1,581 patients, of whom 955 had a PD-L1 combined positive score (CPS) ≥5. Among the PD-L1 CPS ≥5 subgroup, patients who received nivolumab and chemotherapy (n=473) had a 29% reduced risk of death compared with patients who received chemotherapy alone (n=484; HR=0.71; 98.4% CI, 0.59 – 0.86; P<0.0001) and a 3-month gain in overall survival (OS; 14.4 vs 11.1 months).

The PD-L1 CPS ≥5 subgroup also had a 32% reduced risk of disease progression or death for the nivolumab and chemotherapy arm compared with the chemotherapy alone arm (HR=0.68; 98.0% CI, 0.56 – 0.81; P<0.0001)

The PD-L1 CPS ≥5 subgroup had a higher frequency of grade 3 or 4 adverse events (59% vs 44%) and treatment-related adverse events (TRAEs) leading to discontinuation (38% vs 25%) for the nivolumab and chemotherapy arm compared with the chemotherapy alone arm.

Based on the trial results, the addition of nivolumab to chemotherapy will become the standard of care for first-line treatment of patients with HER2-negative gastric cancer, gastroesophageal junction cancer, or esophageal adenocarcinoma with a PD-L1 CPS ≥5, commented Salah-Eddin Al-Batran, MD, Director, Institute of Clinical Cancer Research and Director of GI Oncology, Krankenhaus Nordwest-University Cancer Centre, Frankfurt, Germany. He was not involved in the trial.

“The open question is the effect in patients who have a PD-L1 CPS <5,” he added.

For the overall study population, the OS benefit was significant and favored the nivolumab and chemotherapy arm but was less pronounced (HR=0.80; 99.3% CI, 0.68 – 0.94; P=0.0002), as was the case for the PD-L1 CPS ≥1 subgroup (HR=0.77; 99.3% CI, 0.64 – 0.92; P=0.0001).

ATTRACTION-4: Nivolumab in the First-line Setting Showed Improvement in PFS in HER2-Negative Gastric/Gastroesophageal Patients

The addition of nivolumab to chemotherapy in the first-line setting improved progression-free survival (PFS) but not OS for Asian patients with HER2-negative advanced or recurrent gastric/gastroesophageal junction cancer, according to the phase 3 portion of the randomized phase 2/3 ATTRACTION-4 trial.

The trial met its primary endpoint, showing that patients on the nivolumab plus chemotherapy arm (n=362) had a 32% reduced risk of disease progression or death compared with the chemotherapy alone arm (n=362; HR=0.68; 98.51% CI, 0.51 – 0.90; P=0.0007) and a median PFS gain of approximately 2 months (10.5 vs 8.3 months). Also, a higher proportion of patients in the nivolumab plus chemotherapy arm achieved a response compared with the chemotherapy alone arm (57.5% vs 47.8%; P=0.0088).

However, no difference in OS was seen between arms (HR=0.90; 95% CI, 0.75 – 1.08; P=0.257) with both arms showing a median OS of approximately 17 months. Also, the frequency of grade 3 or worse TRAEs was higher in the nivolumab plus chemotherapy arm compared with the chemotherapy alone arm (57.9% vs 49.2%).

Not involved in the trial, Dr. Al-Batran speculated about the lack of OS benefit, saying, “Overall survival was not improved, possibly because all-comers were treated or because patients in Asia receive more subsequent therapies than Western populations.”

KEYNOTE-590: Pembrolizumab Prolonged Survival in Locally Advanced or Metastatic Esophageal Carcinoma

The addition of pembrolizumab to chemotherapy in the first-line setting for locally advanced or metastatic esophageal carcinoma prolonged survival, showed data from the phase 3 KEYNOTE-590 trial.

On the basis of the trial results, Roy Baynes, MD, PhD, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories said in a press release statement, “We look forward to engaging regulatory authorities as quickly as possible.”

The trial enrolled 749 patients with locally advanced or metastatic esophageal carcinoma, most of whom had esophageal squamous cell carcinoma (73%); the rest had adenocarcinoma of the esophagus or Siewert type 1 esophagogastric junction adenocarcinoma. Patients were randomized to receive a standard chemotherapy regimen of cisplatin plus 5-fluorouracil (n=376) or pembrolizumab plus standard chemotherapy (n=373).

The trial met its primary endpoint, showing that at a median follow-up of 10.8 months, patients with esophageal squamous cell carcinoma and a PD-L1 CPS ≥10 had a 43% reduced risk of death with the addition of pembrolizumab to chemotherapy (HR=0.57; 95% CI, 0.43 – 0.75; P<0.0001) and lived a median of 5 months longer (13.9 vs 8.8 months).

An OS benefit favoring pembrolizumab and chemotherapy was also seen for the entire study population (HR=0.73, 95% CI, 0.62 – 0.86; P<0.0001), patients with a CPS ≥10 (HR=0.62; 95% CI, 0.49 – 0.78; P<0.0001), and patients with esophageal squamous cell carcinoma (HR=0.72; 95% CI, 0.60 – 0.88; P=0.0006).

Similarly, a PFS benefit favoring pembrolizumab and chemotherapy was seen for the entire study population (HR=0.65; 95% CI, 0.55 – 0.76; P<0.0001), patients with a CPS ≥10 (HR=0.51; 95% CI, 0.41 – 0.65; P<0.0001), and patients with esophageal squamous cell carcinoma (HR=0.65; 95% CI, 0.54 – 0.78; P<0.0001).

For the overall study population, a significantly higher response rate was seen in the pembrolizumab and chemotherapy arm compared with the chemotherapy alone arm (45.0% vs 29.3%; P<0.0001).

The frequency of grade 3 or worse TRAEs was similar between the pembrolizumab and chemotherapy arm and chemotherapy alone arm (72% vs 68%), though the discontinuation rate was higher for the pembrolizumab and chemotherapy arm (19% vs 12%).

Not involved in the trial, Dr. Al-Batran commented that he expects that KEYNOTE-590 will change practice for patients with metastatic squamous cell carcinoma or adenocarcinoma of the esophagus who have PD-L1 CPS ≥10 tumors, for whom pembrolizumab added to chemotherapy will become the standard of care in the first-line.