Did Death, Toxicity Close Phase 3 Trial’s Gastric/GEJ Cancer Arm?

Nivolumab/Chemotherapy Arm Shows No Unexpected Toxicities

Reports have surfaced that BristolMyersSquibbs’ phase 3 CheckMate649 trial in first-line gastric and gastroesophageal junction (GEJ) cancer had to close its nivolumab/ipilimumab (Opidovo/Yervoy) arm early because of undisclosed side effects.

Although patient deaths were recorded, they may not be a result of the combination’s toxicity because the patients had experienced a progression in disease. CheckMate649's nivolumab/ipilimumab arm is listed as closed to enrollment without further details on ClinicalTrials.gov, which was last updated on  May 22, although the arm was apparently closed sometime in 2018.

It is unclear what caused the deaths, and patients are now being followed to track their overall survival (OS). The open-label trial has a targeted enrollment of 2,005-patients, and primary endpoints investigating progression-free survival (PFS) and OS. It is also studying nivolumab plus chemotherapy versus chemotherapy alone.

In June 2018, the trial’s independent Data Monitoring Committee (DMC) recommended that the nivolumab/ipilimumab arm be closed. The DMC also recommended that enrolled patients should continue to receive treatment and be followed for OS.

In the trial, nivolumab’s side effects were as expected and handled directly. When ipilimumab is used in a combination setting, it is at a lower dose than when used in monotherapy, which enables a more predictable side-effect profile.

CheckMate032, an earlier open-label, phase 1/2 basket trial with nivolumab and nivolumab/ipilimumab in the second-line setting, involved 1,620 patients. According to a study by Janjigian et al. (J Clin Oncol 2018; 36(28):2836-2844), 47% of patients who received 1 mg/kg nivolumab plus 3 mg/kg ipilimumab experienced Grade 3 or 4 adverse events, compared with 27% of patients who received 3 mg/kg nivolumab plus 1 mg/kg ipilimumab. Common combination side effects relate to the lung, liver, intestinal and hormone gland issues, among others.

However, CheckMate649 trial patients who are in the nivolumab/chemotherapy arm have experienced no unexpected toxicities. The trial is investigating nivolumab with the chemotherapy combination XELOX (oxaliplatin and capecitabine), as well as the combination of nivolumab plus FOLFOX (leucovorin calcium, fluorouracil, and oxiplatin).

Source: GlobalData, June 6, 2019