Expert Point of View: Florian Lordick, MD, PhD

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Florian Lordick, MD, PhD

Florian Lordick, MD, PhD

Florian Lordick, MD, PhD, Professor of Oncology and Director of the University Cancer Center Leipzig, Germany, applauded the positive finding for nivolumab plus chemotherapy in CheckMate 6491 and questioned why nivolumab plus ipilimumab did not meet its endpoint.

“I’m calling this a big step forward in gastric cancer—long awaited and personalized. Since the ToGA trial2 in HER2-positive patients, there have been many other first-line studies, all with negative outcomes. In the past 10 years, CheckMate 649 is the first randomized global phase III study for patients with HER2-negative metastatic gastric cancer that’s positive,” Dr. Lordick said.

Although CheckMate 649 clearly met its primary endpoint of overall survival in the nivolumab/chemotherapy group, showing a hazard ratio of 0.71 in patients with a PD-L1 combined positive score (CPS) ≥ 5 compared with chemotherapy alone, a “dilution effect” was seen in the all-randomized population, where the hazard ratio was 0.80 in the primary analysis. In examining the forest plot, which was published this past summer in The Lancet,3 one can see that patients who have a CPS < 5 did not derive a benefit from the addition of nivolumab to chemotherapy, he said.

“Therefore, the first take-home message is that nivolumab in combination with a fluoropyrimidine- and platinum-based doublet should be [a] new standard of care for the first-line treatment of patients with HER2-negative advanced or metastatic gastric cancer, gastroesophageal junction cancer, or esophageal adenocarcinoma whose tumors express a PD-L1 CPS ≥ 5,” maintained Dr. Lordick.

Nivolumab/Ipilimumab: Comparing CheckMate 648 and 649

According to Dr. Lordick, more questionable is why nivolumab/ipilimumab did not meet its secondary endpoint, despite the findings of a similar study, CheckMate 648, in esophageal squamous cell carcinoma reported at the 2021 ASCO Annual Meeting.4 “That study had a clearly positive primary endpoint (hazard ratio = 0.54) for the population with a tumor proportion score ≥ 1%,” he said. As for why, he said, “It’s probably a mixture of explanations.”

Because of the early termination of the nivolumab/ipilimumab arm due, in part, to safety concerns, the study may have been underpowered to show a benefit, though based on a hazard ratio of 0.89 he deemed that unlikely. The crossover effect may have been somewhat of an issue, since up to 12% of the chemotherapy arm received immunotherapy. It is also possible the study’s PD-L1 assay, IHC 28-8 pharmDx, was “overly sensitive,” since some studies using different assays have resulted in smaller proportions of patients with a CPS ≥ 5 (here, it was 60%). This suggests that patient selection by PD-L1 may have been “inconclusive” and could have affected the results.

The regimen of nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg was also different from that employed in CheckMate 648, nivolumab at 3 mg/kg and ipilimumab at 1 mg/kg. In CheckMate 649, nivolumab/ipilimumab resulted in double the rate of serious treatment-related adverse events over chemotherapy, and this may have contributed to early disease progression and death.

Another important difference from CheckMate 648 is that the crossover of the curves occurred much earlier than in CheckMate 649 (6 months vs 12 months). According to Dr. Lordick, this may have resulted in fewer patients achieving prolonged responses in CheckMate 649.

‘All About Tumor Biology’

“But, at the end of the day, it’s all about tumor biology, and we can’t compare esophageal squamous cell cancer and adenocarcinoma. This is probably the major reason why one study is positive, and one is negative,” Dr. Lordick concluded.

He added that CheckMate 649 does confirm that subpopulations of adenocarcinoma can be highly sensitive to immunotherapy, especially those with high microsatellite instability, who clearly benefited from nivolumab/ipilimumab over chemotherapy; this has been shown with first-line pembrolizumab as well. “The question for this particular population is probably more of whether they really need chemotherapy in addition to checkpoint inhibition.” 

DISCLOSURE: Dr. Lordick has received personal fees from Amgen, Art Tempi, Astellas, AstraZeneca, Bayer, BioNTech, BMS, Lilly, Elsevier, Incyte, Medscape, MedUpdate, Merck, MSD, Roche, Servier, Springer Nature, StreamedUp, and Zymeworks.


1. Janjigian YY, Ajani JA, Moehler M, et al: Nivolumab plus chemotherapy or ipilimumab vs chemotherapy as first-line treatment for advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma: CheckMate 649 study. ESMO Congress 2021. Abstract LBA7. Presented September 19, 2021.

2. Bang YJ, Van Cutsem E, Feyereislova A, et al: Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): A phase 3, open-label, randomised controlled trial. Lancet 376:687-697, 2010.

3. Janjigian YY, Shitara K, Moehler M, et al: First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): A randomised, open-label, phase 3 trial. Lancet 398:27-40, 2021.

4. Chau I, Doki Y, Ajani JA, et al: Nivolumab plus ipilimumab or nivolumab plus chemotherapy versus chemotherapy as first-line treatment for advanced esophageal squamous cell carcinoma: First results of the CheckMate 648 study. 2021 ASCO Annual Meeting. Abstract LBA4001. Presented June 5, 2021.

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