First-Line Nivolumab plus Ipilimumab Combined with 2 Cycles of Chemotherapy in Patients with Stage IV/Recurrent NSCLC: 2-Year Update of CheckMate-9LA

Long-term outcomes for patients with advanced non–small-cell lung cancer (NSCLC) are often poor, despite the advent of new therapies or combinations of therapies. Anti–PD-L1 drugs, such as pembrolizumab, nivolumab (NIVO; plus ipilimumab [IPI]), and atezolizumab have improved outcomes.¹ Therefore, the investigators of CheckMate-9LA examined whether dual immunotherapy combined with a limited course of 2 cycles of chemotherapy could control disease early in the disease process and provide durable survival benefit while lessening the adverse events associated with chemotherapy alone.^1,2

The CheckMate-9LA study was a randomized, international, phase 3 trial with patients (N = 719) who had histologically confirmed squamous or nonsquamous stage IV or recurrent NSCLC and had not received prior systemic anticancer treatment for advanced/metastatic disease.¹ Patients received either chemotherapy alone (every 3 weeks for 4 cycles) or NIVO 360 mg intravenously (IV) every 3 weeks plus IPI 1 mg/kg IV every 6 weeks plus platinum doublet chemotherapy (either carboplatin plus paclitaxel for squamous histology or carboplatin plus pemetrexed or cisplatin plus pemetrexed for nonsquamous) every 3 weeks limited to 2 cycles.¹

The primary end point was overall survival (OS), and the secondary end points were progression-free survival (PFS) and objective response rate (ORR). Therapy continued until disease progression, unacceptable toxicity, or 2 years (end of protocol).¹

In the initial prespecified interim analysis with a minimum follow-up of 8.1 months, the primary end points were met, showing statistically significant improvements in addition to a manageable safety profile.² The median OS was 14.1 months (95% confidence interval [CI], 13.2-16.2) in the NIVO plus IPI plus limited chemotherapy group compared with 10.7 months (95% CI, 9.5-12.4) in the chemotherapy group (hazard ratio [HR], 0.69; 96.71% CI, 0.55-0.87; P = .00065). The median PFS was 6.8 months (95% CI, 5.6-7.7) in the NIVO plus IPI group compared with 5.0 months (95% CI, 4.3-5.6) in the chemotherapy group (HR, 0.70; 97.48% CI, 0.57-0.86; P = .00012).¹

ORR was reported in 37.7% (95% CI, 32.7-42.9) of patients in the NIVO plus IPI plus limited chemotherapy group compared with 25.1% (95% CI, 20.7-30.0) of patients in the chemotherapy-alone group (P = .00030).¹

The 2-year follow-up study investigated the continued efficacy with the regimen of NIVO plus IPI plus chemotherapy and the PFS after the next line of therapy (PFS2), to determine the impact of that therapy. In addition, an analysis of treatment-related adverse events (TRAEs) by treatment cycle and outcomes of patients who discontinued treatment secondary to TRAEs was performed.²

With a minimum follow-up of 24.4 months, the OS at 2 years was 38% for the NIVO plus IPI plus chemotherapy group compared with 26% for the chemotherapy-alone group (HR, 0.72; 95% CI, 0.61-0.86), including across key subgroups (by PD-L1 expression levels and histology).² The PFS at 2 years was 20% for the NIVO plus IPI plus limited chemotherapy group compared with 8% for the chemotherapy-alone group.² The ORR was 38% for the NIVO plus IPI plus limited chemotherapy group versus 25.4% in the chemotherapy-alone group.²

The median PFS2 was 13.9 months in the NIVO plus IPI plus limited chemotherapy group and 8.7 months in the chemotherapy-alone group (in all randomized patients) (HR, 0.66; 95% CI, 0.56-0.78).² The 1-year PFS2 rate was 55% in the NIVO plus IPI plus limited chemotherapy group and 37% months in the chemotherapy-alone group; the 2-year PFS2 rate was 35% in the NIVO plus IPI plus limited chemotherapy group and 21% in the chemotherapy- alone group. When evaluated by subgroups (PD-L1 expression and histology), PFS2 was also better in the NIVO plus IPI plus limited chemotherapy group compared with the chemotherapy- alone group.²

At 2 years, safety data were consistent with the original 1-year data. TRAEs of any grade occurred in 92% of the NIVO plus IPI plus chemotherapy group and in 88% of the chemotherapy-alone group. Grade 3/4 TRAEs occurred in 48% of the NIVO plus IPI plus chemotherapy group compared with 38% in the chemotherapy-alone group.² The onset of grade 1/2 TRAEs was similar between the 2 treatment groups in respective cycles. The onset of most of the grade 3/4 TRAEs occurred in the first 2 cycles in the NIVO plus IPI plus chemotherapy group (during the course of platinum-doublet chemotherapy) compared with cycles 7 to 8 in the chemotherapy-alone group.²

In the post-hoc analysis of the patients who discontinued therapy (NIVO plus IPI plus limited chemotherapy) secondary to TRAEs, the median duration of treatment was 4.4 months. The median OS was 27.5 months with a 2-year OS rate of 54%. Median PFS was 5.1 months; 1-year PFS rate was 44%; ORR was 51% (responses maintained for median of 14.5 months [95% CI, 2.86-not reached] after treatment discontinuation).² These patients remained treatment-free for a median of 11.9 months (95% CI, 3.8-21), with a 48% chance of being treatment-free at 1 year.²

The researchers concluded that NIVO plus IPI in combination with 2 cycles of chemotherapy continued to show durable efficacy compared with 4 cycles of chemotherapy alone for first-line treatment of advanced NSCLC. This was found to be true across histologies and regardless of PD-L1 expression.²

References

1. Paz-Ares L, Ciuleanu TE, Cobo M, et al. First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial. [Published correction appears in Lancet Oncol. 2021;22:e92.] Lancet Oncol. 2021;22:198-211.
2. Reck M, Ciuleanu TE, Cobo M, et al. First-line nivolumab plus ipilimumab with two cycles of chemotherapy versus chemotherapy alone (four cycles) in advanced non-small-cell lung cancer: CheckMate 9LA 2-year update. ESMO Open. 2021;6:100273.