Nivolumab/Ipilimumab Plus Chemotherapy Shows Durable Benefit in Advanced NSCLC


Nivolumab and ipilimumab plus 2 cycles of platinum-based chemotherapy demonstrated durable survival benefit vs chemotherapy alone in patients with advanced non–small cell lung cancer.

Martin Reck, MD, PhD

Martin Reck, MD, PhD

Nivolumab (Opdivo) and ipilimumab (Yervoy) plus 2 cycles of platinum-based chemotherapy demonstrated durable survival benefit vs chemotherapy alone in patients with advanced non–small cell lung cancer (NSCLC), according to findings from a 2-year follow-up analysis of the phase 3 CheckMate 9LA trial (NCT03215706) that were presented during the 2021 ASCO Annual Meeting.

Data from this trial, which initially led to the approval of the combination in patients with either frontline metastatic or recurrent NSCLC who did not harbor EGFR or ALK tumor mutations, were presented by Martin Reck, MD, PhD, of Hospital Grosshansdorf in Germany. These data indicate a benefit of the combination across key patient subgroups characterized by PD-L1 expression, histology, and the presence of central nervous system metastases.

Patients included on the trial were those with stage IV NSCLC without prior systemic therapy for their disease and an ECOG performance status of 0 or 1 (n = 719). Patients were randomized in a 1:1 fashion to either 2 cycles of chemotherapy every 3 weeks with the addition of nivolumab at 360 mg every 3 weeks and ipilimumab at 1 mg/kg every 6 weeks or 3 cycles of chemotherapy. Patients in the chemotherapy arm with nonsquamous histology had the option to continue with pemetrexed maintenance.

The primary end point of the trial was overall survival (OS), with secondary and exploratory outcome measures of progression-free survival (PFS), objective response rate (ORR), efficacy by PD-L1 expression level, and safety. Stratification was performed by PD-L1 expression level (<1% or ≥1%), sex, and histology (squamous or nonsquamous).

In the immunotherapy and chemotherapy-alone arms, 358 and 349 patients, respectively, received active treatment. In the group receiving the experimental regimen, 40% of patients with PFS events (n = 307) went on to receive additional systemic therapy, 8% had subsequent immunotherapy, 37% had chemotherapy, and 22% received platinum-doublet chemotherapy. In the control group, 47% of patients with a PFS event (n = 334) received subsequent systemic therapy, 37% went on to immunotherapy, 24% had any additional chemotherapy, and 4% received platinum-doublet chemotherapy.

With a minimum of 2-years of follow-up, the median OS in the experimental therapy arm was 15.8 months versus 11.0 months with chemotherapy alone (HR, 0.72; 95% CI, 0.61-0.86). Rates of OS at 12- and 24-month time points were also greater for the PD-1/CTLA-4 combination, at 63% and 38%, respectively, compared with 47% and 26% with chemotherapy alone.

Median PFS continued to favor treatment with nivolumab plus ipilimumab compared with chemotherapy, at 6.7 versus 5.3 months, respectively (HR, 0.67; 95% CI, 0.56-0.79). At 12 months, the rate of PFS in the immunotherapy group was 33% versus 20% with chemotherapy. Corresponding rates at 24 months were 19% and 8%.

The ORR in the nivolumab/ipilimumab group was 38.0% with a median duration of response (DOR) of 13.0 months. In the chemotherapy group, the response rate was 24.5% with a DOR of 5.6 months. Patients with an ongoing response at 12 months comprised 52% of the immunotherapy group and 24% of the chemotherapy group; those rates at 24 months were 34% and 12%, respectively.

Reck noted that an increase in median OS was observed with nivolumab/ipilimumab versus chemotherapy across patient subgroups, including those with bone metastases (11.9 vs 8.3 months, respectively; HR, 0.73), CNS metastases (19.9 vs 7.9 months; HR, 0.47), and current/former smokers (16.2 vs 10.4; HR, 0.68).

“In particular, when we look at the stratification factors, the magnitude of survival benefit was independent from histology, and a similar survival benefit was seen across all levels of PD-L1 expression,” said Reck.

Patients with PD-L1­–negative tumors, which included patients with expression in less than 1% of cells, derived significant survival benefit with nivolumab. Median OS in the nivolumab/ipilimumab group was 17.7 months versus 9.8 months in the chemotherapy group (HR, 0.67; 95% CI, 0.51-0.88); median PFS was 5.8 months versus 4.9 months respectively (HR, 0.68; 95% CI, 0.51-0.89). ORR was also greater in the experimental regimen arm (31.1% vs 20.2%, respectively). Notably, 45% of patients who were treated with immunotherapy were still in response at 24 months versus 0% in the chemotherapy group.

In those with tumors with PD-L1 expression in 1% or more of tumor cells, similar benefit with nivolumab/ipilimumab versus chemotherapy was observed for the median OS (15.8 vs 10.9 months; HR, 0.70; 95% CI, 0.56-0.89) and PFS (7.0 vs 5.0; HR, 0.67; 95% CI, 0.53-0.84). Corresponding ORRs were 42.6% and 27.9% with more patients in the immunotherapy arm still in response at 24 months (33% vs 13%).

In tumors with high PD-L1 expression (≥50%), median OS (18.9 vs 12.9 months; HR, 0.67; 95% CI, 0.46-0.97) and PFS (7.5 vs 4.5 months; HR, 0.59; 95% CI, 0.41-0.84) results were consistent with those from the overall patient cohort and other PD-L1 expression subgroups. ORRs were higher in these patients, at 50.0% with nivolumab plus ipilimumab versus 31.6% for chemotherapy alone. At 24 months, 52% of patients remained in response versus just 16% with chemotherapy.

Reck also noted that new data failed to indicate any new safety signals associated with active therapy. Patients in the nivolumab plus ipilimumab arm experienced treatment-related adverse effects (TRAEs) at a rate of 92% versus 88% in those treated with chemotherapy alone; grade 3/4 TRAEs occurred in 48% and 38%, respectively. Treatment discontinuation of any part of the regimen was noted in 22% versus 8% of treated patients, with 17% and 6%, respectively, discontinuing treatment all together.

“There is the concern that the discontinuation of treatment in particular immunotherapies may impact the efficacy of treatment,” said Reck. “Therefore, we performed a post-hoc exploratory analysis for those patients who discontinued all components.”

Looking at patients treated with nivolumab/ipilimumab, a comparison of OS rates for those who discontinued treatment versus all randomized participants showed no decrease in efficacy. At 24 months, rates of OS were 54% and 38%, respectively.

“In the post-hoc analysis, no impact on efficacy was seen for those patients who discontinued all components of the combination therapy related to a treatment-related adverse event,” said Reck. “These results continued to support the combination of nivolumab and ipilimumab together with 2 cycles of chemotherapy as a very efficacious first-line treatment opportunity for patients with advanced non–small cell lung cancer.”


Reck M, Ciulenua T-E, Cobo M, et al. First-line nivolumab (NIVO) plus ipilimumab (IPI) plus two cycles of chemotherapy (chemo) versus chemo alone (4 cycles) in patients with advanced non-small cell lung cancer (NSCLC): Two-year update from CheckMate 9LA. J Clin Oncol. 2021;39(suppl 15):9000. Doi:10.1200/JCO.2021.39.suppl_15.9000

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