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The combination of nivolumab (Opdivo) and low-dose ipilimumab (Yervoy) was superior in overall survival compared with chemotherapy for the first-line treatment of patients with non–small cell lung cancer whose tumors express PD-L1 ≥1%, meeting the co-primary endpoint of part 1a of the phase III CheckMate-227 trial.
Martin Reck, MD, PhD
The combination of nivolumab (Opdivo) and low-dose ipilimumab (Yervoy) was superior in overall survival (OS) compared with chemotherapy for the first-line treatment of patients with non—small cell lung cancer (NSCLC) whose tumors express PD-L1 ≥1%, meeting the co-primary endpoint of part 1a of the phase III CheckMate-227 trial.1
Moreover, the safety profile of the frontline combination was consistent with prior data of nivolumab at 3 mg/kg every 2 weeks plus 1 mg/kg of ipilimumab every 6 weeks in patients with NSCLC. Bristol-Myers Squibb (BMS), the manufacturer of both the PD-1 and CTLA-4 inhibitors, stated in a press release that it will share data from this part of the trial with regulatory authorities, and full findings will be presented at an upcoming medical meeting.
“The nivolumab plus ipilimumab results from part 1a of CheckMate-227 offers the potential for a chemo-sparing regimen that demonstrates an OS benefit to first-line lung cancer patients,” Martin Reck, MD, PhD, CheckMate-227 study investigator, and of the Lung Clinic Grosshansdorf, German Center of Lung Research, stated in a press release. “I am also encouraged to see activity in PD-L1 expressors and non-expressors, and look forward to seeing the full data presented in the future.”
Results of an exploratory analysis from part 1b of the CheckMate-227 trial showed that the combination also led to a benefit in survival in patients with PD-L1­—negative tumors.
However, in part 2 of the CheckMate-227 trial, the company also stated that the combination of nivolumab and chemotherapy did not meet the prespecified primary endpoint of OS compared with chemotherapy alone in patients with nonsquamous NSCLC, regardless of PD-L1 expression status (HR, 0.86; 95% CI, 0.69-1.08).2
In the multi-part, open-label, phase III CheckMate-227 trial, investigators evaluated nivolumab-based regimens compared with platinum-doublet chemotherapy in patients with treatment-naïve advanced NSCLC across nonsquamous and squamous histologies. In part 1a of the study, nivolumab/low-dose ipilimumab or nivolumab alone was compared with chemotherapy in patients with PD-L1—positive tumors; in part 1b, nivolumab/low-dose ipilimumab or nivolumab/chemotherapy was evaluated in patients with PD-L1–negative tumors. The co-primary endpoints of part 1 for nivolumab/ipilimumab versus chemotherapy was OS in PD-L1–positive tumors and progression-free survival (PFS) in patients with tumor mutational burden (TMB) ≥10 mutations/megabase (mut/mB) across the PD-L1 spectrum.
Part 2 of the trial explored the combination of nivolumab/chemotherapy versus chemotherapy in patients, regardless of PD-L1 expression status. OS was the primary endpoint of this part of the trial.
Part 2 results showed that the median OS for patients treated with nivolumab/chemotherapy was 18.83 months versus 15.57 months for chemotherapy, and the 1-year OS was 67.3% compared with 59.2%, respectively. Additionally, in an exploratory analysis of patients with squamous NSCLC, the median OS was 18.27 months for first-line nivolumab plus chemotherapy compared with 11.96 months for chemotherapy (HR, 0.69; 95% CI, 0.50-0.97). There were no new safety signals were observed. BMS stated that full findings of part 2 of the trial will be presented at an upcoming medical meeting.
“While this is not the outcome we had hoped for, the Opdivo plus chemotherapy 1-year landmark overall survival in the nonsquamous population was consistent with the experimental arms in previously-reported trials of IO/chemotherapy combination regimens,” Fouad Namouni, MD, head, Oncology Development, BMS, stated in a press release. “We thank the patients and investigators who participated in this trial.”
In January 2019, BMS withdrew its supplemental biologics license application for the combination of nivolumab and ipilimumab for the first-line treatment of patients with advanced NSCLC with TMB ≥10 mut/Mb following discussions with the FDA.3
The agency had initially accepted the sBLA in June 2018 based on additional data from the phase III CheckMate-227 trial, which showed that the 1-year PFS rate was 43% for patients with high TMB assigned to nivolumab/ipilimumab compared with 13% for those assigned to platinum-doublet chemotherapy.
In October 2018, BMS submitted an exploratory OS analysis to the FDA from part 1 of the CheckMate-227 trial, which comprised a TMB <10 mut/Mb subgroup of patients with stage IV or recurrent NSCLC who had not received prior therapy.
With these updated findings, the FDA extended the review period by 3 months, which made the new action date May 20, 2019. Yet, the new data showed no difference in survival outcomes between patients whose tumors had high or low levels of TMB.
The updated OS data that BMS submitted showed that the median OS for the combination in patients with TMB ≥10 mut/Mb was 23.03 months versus 16.72 months for the chemotherapy arm (HR, 0.77; 95% CI, 0.56-1.06). Among patients with TMB <10 mut/Mb, the median OS was 16.20 months versus 12.42 months, respectively (HR, 0.78; 95% CI, 0.61-1.00).