Nivolumab plus ipilimumab and chemotherapy efficacious in patients with advanced NSCLC and brain metastases
Post-hoc analysis from the CheckMate 9LA trial in patients with advanced non-small cell lung cancer (NSCLC) demonstrates that systemic efficacy outcomes all favour the combination of nivolumab (NIVO) plus ipilimumab (IPI) and chemotherapy (chemo) versus chemo alone, regardless of baseline brain metastases. Consistent with systemic efficacy, among patients with baseline brain metastases, intracranial efficacy was also improved with the NIVO + IPI + chemo combination.
Brain metastases are diagnosed in 10% of patients with non-small cell lung cancer (NSCLC) and are associated with poor prognosis. In the randomised phase III CheckMate 9LA trial, first-line nivolumab (NIVO) + ipilimumab (IPI) combined with chemotherapy (chemo) significantly improved overall survival (OS) versus chemo alone in patients with advanced NSCLC (two-year OS rate of 38% vs. 26%). At the 2021 World Conference on Lung Cancer, a post hoc analysis of efficacy and safety outcomes from CheckMate 9LA in patients with and without brain metastases at baseline, with a minimum follow-up of two year was presented.
CheckMate 9LA study design
Eligible patients were adults with stage IV or recurrent NSCLC, ECOG performance status ≤1, and no known sensitising EGFR mutations or known ALK alterations. Patients with adequately treated brain metastases who were asymptomatic for ≥2 weeks prior to first treatment were eligible; corticosteroids were permitted if the dose was stable or decreasing at ≤10 mg daily prednisone (or equivalent) for ≥2 weeks prior to first study treatment. Patients were randomly assigned (1:1) to NIVO 360 mg Q3W + IPI 1 mg/kg Q6W + chemo (2 cycles) or chemo alone (4 cycles); treatment was until disease progression, unacceptable toxicity, or 2 years for immunotherapy. Brain MRI/CT was performed in all patients at baseline, and in patients with history/symptoms of brain metastases during treatment, at 2 follow-up visits, and every 3 months thereafter until disease progression.
Efficacy of the NIVO + IPI + chemo combination
Of the 719 randomised patients in the CheckMate 9LA study, 101 (14%) had baseline brain metastases. Baseline characteristics were generally well-balanced between patients with and without baseline brain metastases and between treatment arms, except for a slightly greater proportion of patients who had never smoked (NIVO + IPI + chemo arm) and patients with liver metastases (chemo arm) in the baseline brain metastases subgroup. There was a clinically significant improvement in median OS from 6.8 months in the chemo arm to 19.3 months in the NIVO + IPI + chemo arm for patients with baseline brain metastases (HR[95%CI]: 0.43[0.27-0.67]). Two-year landmark survival rates were respectively 12% and 35%. Also for patients without baseline brain metastases, the difference in median OS was in favour of the NIVO + IPI + chemo combination (HR[95%CI]: 0.79[0.65-0.95]). The median systemic progression-free survival (PFS) in patients with baseline brain metastases was 10.6 months in the NIVO + IPI + chemo arm, as compared to 4.1 months in the chemo arm (HR[95%CI]: 0.40[0.25-0.64]). In patients without brain metastases, the median systemic PFS was fairly similar between treatment arms (5.8 vs. 5.4 months, respectively). Among patients with baseline brain metastases, almost twice as many responders were observed in the NIVO + IPI + chemo arm versus the chemo arm (43% vs. 24%) with an almost four times longer median duration of response (DoR, 15.5 vs. 4.4 months).
In terms of intracranial PFS in patients with baseline brain metastases, there was again a significant clinical difference with 51% of patients without intracranial progression at one year in the NIVO + IPI + chemo arm, compared to only 11% of patients in the chemo arm. This translates into a median intracranial PFS of 13.5 vs. 4.6 months and a hazard ratio of 0.36 (95%CI: 0.22-0.60). An objective response rate of 39% was obtained in the NIVO + IPI + chemo arm in patients with baseline brain metastases, including 5 complete responses (10%) and 15 partial responses (29%). Median time to response was 2.8 months and median intracranial DoR was 22.3 months. The median change in tumour volume was 41% in the NIVO + IPI + chemo arm, compared to 28% in the chemo arm. Overall, patients with baseline brain metastases were more likely to develop new brain lesions, as compared to those patients without baseline brain metastases. However, in the NIVO + IPI + chemo arm there were approximately half as many new brain lesions that developed as compared to the chemotherapy arm in both patients with and without baseline brain metastases. Furthermore, median time to development of new brain lesions in patients who already had brain metastases at baseline was twice as long for patients treated with NIVO + IPI + chemo (9.0 vs. 4.6 months).
No new safety signals were observed in patients with baseline brain metastases. In these patients, any-grade neurological treatment-related adverse events occurred in 22% and 10% of the NIVO + IPI + chemo and chemo arms, respectively; most were grade 1/2.
In the post-hoc analysis of the CheckMate 9LA study, first-line NIVO + IPI + chemo for advanced NSCLC demonstrated durable survival benefit versus chemotherapy alone in patients with or without baseline brain metastases. Among patients with baseline brain metastases, intracranial efficacy was improved with NIVO + IPI + chemo versus chemo, consistent with systemic efficacy. In addition, fewer patients developed new brain lesions with the combination regimen as compared to chemotherapy alone. No new safety signals were observed in patients with baseline brain metastases. These data further support the use of NIVO + IPI + chemo as an efficacious first-line treatment option in patients with advanced NSCLC, including those with brain metastases.
Carbone DP, Ciuleanu TE, Cobo M, et al. First-line Nivolumab + Ipilimumab + Chemo in Patients With Advanced NSCLC and Brain Metastases: Results From CheckMate 9LA. Presented at the 2021 World Conference on Lung Cancer; Abstract OA09.01.