According to findings from the CheckMate-032 trial, clinically meaningful and durable antitumor activity was found with nivolumab (Opdivo) alone and nivolumab plus ipilimumab in heavily-pretreated patients with esophagogastric cancer.
Yelena Y. Janjigian, MD
According to findings from the CheckMate-032 trial, clinically meaningful and durable antitumor activity was found with nivolumab (Opdivo) alone and nivolumab plus ipilimumab (Yervoy) in heavily-pretreated patients with esophagogastric cancer.1
In results from this phase I/II, open-label, multicohort trial recently published in theJournal of Clinical Oncology, benefit was seen in Western patients who were refractory to chemotherapy. These results for nivolumab monotherapy are consistent with similar findings in Asian patients in the phase III ATTRACTION-2 study.2
“Taken together with other reports on anti-PD-1 therapy, these findings suggest that despite the morphologic and molecular heterogeneity of esophagogastric cancer, immune checkpoint blockade provides a consistent therapeutic benefit across Asian and Western patients,” lead study author Yelena Y. Janjigian, MD, of Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, and co-authors, wrote.
CheckMate-032 enrolled patients from November 19, 2013 to June 3, 2015 across 18 different centers in the United States and 5 in Europe. To be eligible for the trial, patients had to have a diagnosis of locally advanced or metastatic gastric, esophageal, or gastroesophageal junction (GEJ) adenocarcinoma with disease progression or intolerance to at least 1 chemotherapy treatment.
Patients also had to have an ECOG performance status of either 0 or 1 with adequate organ function. Patients with human epidermal growth factor receptor 2-positive tumors were eligible if they had received a previous treatment of trastuzumab (Herceptin). Patients could not have previously been treated with an immune checkpoint inhibitor therapy.
Overall, 160 patients were enrolled in the trial and assigned to 1 of 3 different arms. Patients either received 3 mg/kg of nivolumab intravenously every 2 weeks (n= 59; NIVO3), 1 mg/kg of nivolumab plus 3 mg/kg of ipilimumab every 3 weeks for 4 cycles (n= 49; NIVO1 + IPI3), or 3 mg/kg nivolumab plus 1 mg/kg ipilimumab every 3 weeks for 4 cycles (n= 52; NIVO3 + IPI1).
All groups also received NIVO3 every 2 weeks for additional treatment until disease progression or an unacceptable adverse event (AE). Dose reductions and modifications were not permitted with either agent,
Overall, 79% of patients enrolled in the trial had received at least 2 prior therapies. In the NIVO3, NIVO1 + IPI3, and NIVO3 + IPI1 groups, 49%, 47%, and 38% of patients received more than 3 prior lines of therapy, respectively.
Investigators also noted more patients in the NIVO3 group had PD-L1positive (38%) and microsatellite instability-high (MSI-H) (28%) tumors, compared to 24% and 9% for the NIVO1 + IPI3 arm, and 30% and 8% in the NIVO3 + IPI1 group, respectively.
Most patients in the NIVO3 + IPI1 group had discontinued treatment at the data cutoff, likely due to disease progression. Only 36% of patients across all groups went on to receive a subsequent anticancer therapy after discontinuing treatment, 84% of which went on to receive chemotherapy.
The primary endpoint was overall response rate (ORR), defined as best response of complete or partial responses divided by number of patients treated. Secondary endpoints included overall survival (OS), progression-free survival (PFS), duration of response (DOR), and safety.
Tumor response was assessed every 6 weeks for 24 weeks, then every 12 weeks until disease progression or treatment discontinuation. The trial was a modified Simon 2-stage study design, which means it was not designed to compare the treatment cohorts.
The ORR was 12% in the NIVO3 arm, 24% in NIVO1 + IPI3, and 8% in NIVO3 + IPI1. The median DOR was 7.1 months (95% CI, 3.0-13.2) in the NIVO3 arm and 7.9 months (95% CI, 2.8-to not estimable) in the NIVO1 + IPI3 arm. The median DOR was not yet reached in the NIVO3 + IPI1 group (95% CI, 2.5-not estimable).
There was a reduction of tumor burden in 29%, 45%, and 27% of patients in the NIVO3, NIVO1 + ILI3, and NIVO3 + ILI1 groups, respectively. Also, 32% to 41% of patients in the trial achieved disease control. In terms of achieving stable disease for a minimum of 12 weeks, this was reached in 67% of patients in the NIVO3 arm, 63% in the NIVO1 + ILI3 arm, and 67% in NIVO3 + ILI1.
The median PFS was 1.4 months (95% CI, 1.2-1.5 months) in the nivolumab alone arm, compared to 1.4 (95% CI, 1.2-3.8 months) for the NIVO1 + ILI3 arm and 1.6 months (95% CI, 1.4-2.6) in the NIVO3 + ILI1 arm. Also, 12-month PFS was reached in 8% (95% CI, 3%-17%), 17% (95% CI, 8- 29), and 10% (95% CI, 3-20), respectively.
Median OS was 6.2 months (95% CI, 3.4- 12.4-) with NIVO3 with 39% (95% CI, 26- 52) of patients achieving a 12-month OS, compared to an OS of 6.9 (95% CI, 3.7 to 11.5 months) and 4.8 months (95% CI, 3.0- 8.4) with 35% (95% CI, 22-49) and 24% (95% CI, 13- 37) of patients reaching 12-month OS in the NIVO1 + ILI3 and NIVO3 + ILI1 arms, respectively.
In regard to safety, the drugs were generally well tolerated with manageable toxicities. Sixty-nine percent of patients in the NIVO3 arm experienced treatment-related adverse events (TRAEs), versus 84% in the NIVO1 + IPI3 arm and 75% in the NIVO3 + IPI1 arm. The most common TRAEs across all treatment groups included fatigue, pruritus, rash, diarrhea, decrease appetite, and an increase in ALT and AST levels.
Approximately 17%, 47%, and 27% of the patients experience grade 3/4 TRAEs in the NIVO3, NIVO1 + IPI3, and NIVO3 + IPI1 arms, with these TRAEs leading to discontinuation in 3%, 20%, and 13% of patients, respectively.
There was 1 death due to tumor lysis syndrome possibly related to treatment. The patient was part of the NIVO3 + IPI1 group. Serious TRAEs were experienced in 10% of NIVO3 patients, 43% in the NIVO1 + IPI3 arm, and 25% in the NIVO3 + IPI1 arm. Pneumonitis was reported as a serious TRAE in the NIVO3 + IPI1 group for 8% of patients.
The NIVO1 + IPI3 regimen has previously been approved by the FDA for the treatment of melanoma. Results from this trial demonstrated that despite a higher ORR of 24% in the NIVO1 + IPI3 group and 12% in the NIVO3 group, there was a similar median OS found between both groups.
“One explanation for this observation may be the higher proportion of patients with MSI-H and PD-L1positive tumors in the NIVO3 group,” the study authors wrote. “The enhanced clinical benefit observed with NIVO1 + IPI3 was accompanied by a numerically higher incidence of grade 3/4 AEs than observed with NIVO3.”
NIVO3 + IPI1 was also comparable to the nivolumab alone group in terms of clinical activity, but the rates of AEs were higher in this group.
“On the basis of the numerically higher overall response and landmark OS rates in the NIVO1 + IPI3 arm, this combination was considered more likely to offer clinical benefit relative to currently available treatment regimens for first-line metastatic esophagogastric cancer and was selected for further evaluation in the phase III CheckMate-649 study (NCT02872116),” wrote the authors.
Tumor PD-L1 and MSI-H status were investigated as potential biomarkers for response to these treatment regimens. In the ATTRACTION-2 trial, tumor PD-L1 was not predictive of survival when looking at patients with gastric cancer or GEJ adenocarcinoma.
Investigators on the CheckMate-032 trial found that although the ORR seemed numerically higher in patients with PD-L1positive versus PD-L1–negative tumors, the sample size was small, with overlapping CIs between these subgroups.
The analysis also found that responses were observed in patients with both MSI-H and nonMSI-H tumors. While ORR seemed numerically higher in the MSI-H subgroup, investigators noted these data are hypothesis generation and more research is needed in in larger patient subsets.
“In summary, our findings suggest that nivolumab and nivolumab plus ipilimumab represent a potential therapeutic approach for patients with advanced esophagogastric cancer. Ongoing phase III studies are investigating nivolumab in the adjuvant setting (NCT02743494) and NIVO1 + IPI3 in the first-line setting (NCT02872116) in patients with esophagogastric cancer,” the investigators concluded.