Frontline Nivolumab/Ipilimumab Improves PFS in High TMB NSCLC

Matthew D. Hellmann, MD

The combination of nivolumab (Opdivo) and ipilimumab (Yervoy) improved progression-free survival (PFS) compared with chemotherapy in treatment-naïve patients with high tumor mutation burden (TMB) non—small cell lung cancer (NSCLC).

Bristol-Myers Squibb (BMS), the manufacturer of both immunotherapies, announced the preliminary findings from part 1a of the phase III CheckMate-227 trial in a press release. The company did not report any further data.

“TMB has emerged as an important biomarker for the activity of immunotherapy. For the first time, this phase III study shows superior PFS with first-line combination immunotherapy in a predefined population of NSCLC patients with high TMB,” study investigator Matthew D. Hellmann, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center, said in a statement. “CheckMate-227 showed that TMB is an important, independent predictive biomarker that can identify a population of first-line NSCLC patients who may benefit from the nivolumab plus ipilimumab combination.”

CheckMate-227 is an open-label trial with more than 2500 patients with both nonsquamous and squamous histologies evaluating frontline nivolumab-based regimens versus platinum-doublet chemotherapy in first-line advanced NSCLC. This trial is divided into 3 segments: parts 1a, 1b, and 2. High TMB was defined as ≥10 mutations/megabase.

Part 1a is assessing the nivolumab/ipilimumab combination, as well as nivolumab monotherapy, versus chemotherapy in patients whose tumors express PD-L1. Patients are treated with 3 mg/kg of nivolumab every 2 weeks and 1 mg/kg ipilimumab every 6 weeks.

There are 2 coprimary endpoints in part 1, overall survival (OS) in patients whose tumors express PD-L1 and PFS in patients with high TMB, regardless of PD-L1 expression. Of the evaluable patients, approximately 45% expressed high TMB. BMS noted that the safety findings from CheckMate-227 were consistent with previously reported data for the same dose of nivolumab/ipilimumab in frontline NSCLC.

“We believe these data from CheckMate-227 are a breakthrough in cancer research and a meaningful step forward in determining which first-line lung cancer patients may benefit most from the combination of Opdivo and Yervoy,” Giovanni Caforio, MD, BMS chairman and CEO, said in a press release.

In previously reported findings from the phase I CheckMate-012 trial, patients were assigned to frontline nivolumab monotherapy at 3 mg/kg every 2 weeks of (n = 52), nivolumab (3 mg/kg every 2 weeks) plus 1 mg of ipilimumab every 12 weeks (n = 38), or the same doses of the combination but with ipilimumab administered every 6 weeks (n = 39).¹

At a median follow-up of 22 months for nivolumab monotherapy and 16 months for the combination cohorts, the confirmed objective response rate (ORR) with nivolumab monotherapy was 23% and the median duration of response was not reached. The confirmed ORR in the first-line combined nivolumab plus ipilimumab cohorts was 43%.

Median PFS by tumor PD-L1 expression (overall population, versus PD-L1 expression >1%, versus PD-L1 expression ≥50%) in the monotherapy arm was 3.6 months versus 3.5 months versus 8.3 months, compared to 8.0 months versus 12.7 months versus not reached in the combination arms, respectively.

When efficacy was compared between monotherapy and each of the combination arms in patients with PD-L1 expression ≥1%, median PFS was greatest in the nivolumab every 2 weeks, ipilimumab every 6 weeks interval cohort. Median PFS in this setting was 3.5 versus 10.4 versus 13.2 weeks, in patients receiving monotherapy, ipilimumab every 12 weeks, and ipilimumab every 6 weeks, respectively. Median 1-year OS rates showed a similar pattern; median OS was 69% with monotherapy, 91% with combined ipilimumab given every 6 weeks, and 83% with combined ipilimumab given every 12 weeks.

1. First-line nivolumab monotherapy and nivolumab plus ipilimumab in patients with advanced NSCLC: long-term outcomes from CheckMate-012. Presented at: International Association for the Study of Lung Cancer 17th World Conference on Lung Cancer (WCLC) in Vienna, Austria.