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ESMO20: Keytruda, Opdivo boost survival in Phase III gastroesophageal cancer trials

Ref: ESMO, Business Wire

PUBLISHED: SEPTEMBER 21, 2020

Anna Bratulic

Findings from two Phase III studies presented Monday at the European Society for Medical Oncology (ESMO) virtual congress demonstrated that first-line use of immunotherapies by Merck & Co. and Bristol Myers Squibb led to superior overall survival (OS) and progression-free survival (PFS) rates in patients with gastroesophageal cancers. Merck's Keytruda and Bristol Myers Squibb's Opdivo (nivolumab), which were assessed in the KEYNOTE-590 and CheckMate -649 trials, respectively, cut the risk of death by 27% and 29% versus chemotherapy alone, with researchers concluding that each drug represents a new standard of care in the treatment of the disease.

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The KEYNOTE-590 trial tested first-line use of Keytruda plus chemotherapy, versus chemotherapy alone, in 749 patients with locally advanced/unresectable or metastatic adenocarcinoma or oesophageal squamous cell carcinoma (ESCC) or Siewert type 1 oesophagogastric junction adenocarcinoma. Merck reported in August that the study hit its main goals of OS and PFS.

Prolonged OS for higher PD-L1 expression

After a median follow-up of 10.8 months, the median OS among patients who received Keytruda was 12.4 months, compared to 9.8 months for chemotherapy alone, translating to a 27% lower risk of dying. Keytruda-treated patients whose tumours expressed a PD-L1 combined positive score (CPS) of at least 10 had better odds of survival, with a 38% lower risk of mortality than those given chemotherapy alone. The median OS for these groups was 13.5 months and 9.4 months, respectively. Results for ESCC patients were similar to the overall study population, but among those ESCC patients with CPS of at least 10, Keytruda cut the risk of death by 43%. These patients had a median OS of 13.9 months, versus 8.8 months for chemotherapy alone.

The risk of disease progression or death was reduced by 35% in the Keytruda arm, where median PFS was 6.3 months, versus 5.8 months in the comparator group. When just looking at subjects having CPS of at least 10, Keytruda-treated patients achieved median PFS of 7.5 months compared to 5.5 months for chemotherapy alone, for a hazard ratio of 0.51. Meanwhile, the respective overall response rates for the two groups overall was 45% and 29.3%, with median duration of response being 8.3 months versus 6 months.

In the study, serious drug-related adverse events (AEs) occurred at rates of 72% for the Keytruda arm versus 68% for chemotherapy, while discontinuation rates as a result of drug-related side effects were 19% and 12%, respectively.

Roy Baynes, chief medical officer at Merck Research Laboratories, said the results were "particularly impressive" given that OS improvement was seen across all patient populations. Keytruda is currently approved in the US, China and Japan as monotherapy for the second-line treatment of ESCC in patients with PD-L1 CPS of at least 10.

Merck previously reported that Keytruda significantly improved OS compared to chemotherapy when used as monotherapy in the KEYNOTE-181 study for second-line oesophageal or oesophagogastric junction carcinoma in patients with CPS of at least 10. Prior to that, it had failed to significantly prolong OS and PFS in the Phase III KEYNOTE-061 gastric cancer trial.

CheckMate -649 study

Meanwhile, the CheckMate -649 trial enrolled adults with previously untreated, unresectable advanced or metastatic gastric cancer, gastroesophageal junction cancer or esophageal adenocarcinoma, regardless of their PD-L1 expression levels. There were 1581 patients randomised to receive Opdivo plus chemotherapy or chemotherapy alone, including 60% with PD-L1 CPS of at least 5. Bristol Myers Squibb announced in August that the study met its co-primary endpoints of OS and PFS in patients whose tumours have a CPS of at least 5.

Results from an interim analysis presented at ESMO showed that in patients whose tumours have a CPS of at least 5, and after a minimum follow-up of 12 months, the risk of death was reduced by 29% in the Opdivo group, where median OS reached 14.4 months, compared with 11.1 months for chemotherapy alone. Opdivo-treated patients with a CPS of at least 5 also saw a 32% improvement in PFS at 7.7 months, versus 6 months for chemotherapy alone.

Benefit seen in lower PD-L1 CPS

Researchers noted that a significant OS benefit was also observed in patients with PD-L1 CPS of at least 1 and in the total population as well. Looking at the subgroup of patients with a CPS of at least 1, the study found that those on Opdivo survived a median of 14 months, compared to 11.3 months for chemotherapy alone, translating to a 23% reduction in mortality risk. For the overall study population, median OS was 13.8 months, representing a 20% lower risk of death versus patients on chemotherapy alone, where the median OS was 11.6 months.

With regards safety, results showed that Grade 3/4 AEs occurred in 59% of patients given Opdivo plus chemotherapy, compared to 44% for chemotherapy alone. Meanwhile, AEs that led to discontinuation of treatment occurred at rates of 38% and 25% in the two groups, respectively.

Ian Waxman, development lead for gastrointestinal cancers at Bristol Myers Squibb, said "these available results of the CheckMate -649 study will be discussed with global health authorities." Opdivo was awarded accelerated approval in June for use in patients with unresectable advanced, recurrent or metastatic ESCC after prior fluoropyrimidine- and platinum-based chemotherapy.