Nivolumab/Ipilimumab Demonstrates OS Benefit in Advanced NSCLC With Brain Metastases

Hossein Borghaei, DO, MS

The combination of nivolumab (Opdivo) and ipilimumab (Yervoy) provided similar clinical benefit to that of chemotherapy when given as a frontline treatment for patients with advanced non–small cell lung cancer (NSCLC) who had stable and treated brain metastases at baseline, according to results from a post-hoc analysis of part 1 of the phase 3 CheckMate-227 trial presented during the 2020 AACR Virtual Annual Meeting II.1

Results showed that the immunotherapy combination led to an improvement in overall survival (OS) in patients with and without brain metastases. The median OS in those with baseline brain metastases was 17.4 months with the nivolumab plus ipilimumab versus 13.7 months with chemotherapy (HR, 0.60; 95% CI, 0.40-0.89). In those without brain metastases at baseline, the median OS in the combination arm was 17.1 months compared with 13.9 months in the control arm (HR, 0.77; 95% CI, 0.67-0.89). Notably, the OS benefit observed with the combination was upheld with 3-year survival rates of over 33%, regardless of brain metastases.

Progression-free survival (PFS) also favored the immunotherapy combination versus chemotherapy in these patient populations. In those with brain metastases at baseline, the median PFS in the investigative arm was 5.4 months compared with 5.8 months in the comparator arm (HR, 0.79; 95% CI, 0.52-1.18). In those without baseline brain metastases, the median PFS was 4.9 months and 5.4 months with the combination versus with chemotherapy, respectively (HR, 0.80; 95% CI, 0.69-0.92).

Additionally, systemic objective response rates (ORRs) and duration of response (DOR) with the combination proved to be comparable between those with baseline brain metastases and those without. The ORR in those with brain metastases was 32.4% with the combination versus 25.8% with chemotherapy; the DOR in this patient population was 24.9 months compared with 8.4 months, respectively. In those without brain metastases, the ORR was 33.6% with nivolumab plus ipilimumab versus 28.2% with chemotherapy; the DOR in this subgroup was 20.4 months with the combination versus 5.8 months with chemotherapy.

“Hazard ratios for OS and PFS favor the combination of nivolumab and ipilimumab, and also systemic overall responses and DORs with the combination were similar in patients with and without brain metastases,” said lead investigator Hossein Borghaei, DO, MS, who is the chief of Thoracic Medical Oncology, a professor in the Department of Hematology/Oncology, and co-director of the Immune Monitoring Facility at Fox Chase Cancer Center, in a poster presentation during the meeting.

Part 1 of the randomized, open-label, phase 3 CheckMate-227 trial enrolled patients with stage IV or recurrent NSCLC who had not previously received systemic therapy, who had no sensitizing EGFR mutations or known ALK aberrations, and who had an ECOG performance score of 0 to 1. Patients with any brain metastases that were adequately treated were eligible for enrollment as long as neurological findings had returned to baseline for at least 2 weeks prior to trial randomization. Additionally, patients were allowed to have received treatment with corticosteroids equivalent to 10 mg or less of daily prednisone, as long as the dose was stable or decreasing for 2 or more weeks before randomization.

Patients were stratified based on histology (nonsquamous versus squamous). In part 1A of the trial, patients with PD-L1 expression of 1% or higher (n = 1189) were randomized 1:1:1 to either nivolumab plus ipilimumab (n = 396), chemotherapy (n = 397), or nivolumab alone (n = 396). In part 1B of the trial, patients with PD-L1 expression of less than 1% (n = 550) were also randomized 1:1:1 to receive the combination (n =187), chemotherapy (n = 186), or nivolumab plus chemotherapy (n = 177). The post-hoc analyses examined patients from both parts of the trial with baseline brain metastases (n = 68, combination; n = 66, chemotherapy) and without baseline metastases (n = 515, combination; n = 517, chemotherapy).

Notably, brain lesions were considered to be nontarget lesions, and thus, data regarding intracranial response were not collected, according to Borghaei.

Baseline characteristics were noted to be generally well balanced between the treatment arms. A larger proportion of patients with brain metastases were aged younger than 65 years; the median age in the combination arm was 60 years compared with 64 years in the combination arm in those without metastases. Additionally, a smaller percentage of patients with brain metastases had squamous histology, at 11.8% of those who received the combination versus 30.1% of those who received the combination and did not have baseline brain metastases.

“Brain radiotherapy was given to control brain metastases prior to study entry; therefore, a greater proportion of patients with brain metastases had received prior radiation [compared with those without brain metastases], and that included non–central nervous system radiotherapy,” noted Borghaei. “The rate ranged from 88% to 90% [between the arms]. In patients without brain metastases, the radiation rates were ranged from 23% to 24%.”

The median treatment duration with the combination was 4.2 months in those with brain metastases at baseline versus 4.2 months in those without metastases; additionally, the median duration of therapy with chemotherapy was 3.6 months versus 2.6 months, respectively.

Notably, smaller proportions of patients with and without baseline brain metastases who were given the immunotherapy combination received subsequent treatment compared with those who were given chemotherapy. In those with brain metastases, 42.6% of those on the combination arm received subsequent treatment versus 66.7% of those in the control arm. In those without baseline brain metastases, 47.4% of those on the combination arm were given subsequent therapy versus 61.1% of those on the control arm.

Additional results broken down by PD-L1 expression showed that the combination provided an OS benefit over chemotherapy in those with a PD-L1 expression of 1% or higher in those with and without brain metastases at baseline.

In those with baseline brain metastases and a tumor PD-L1 expression level of 1% or higher, the median OS with the combination was 20.6 months versus 13.7 months with chemotherapy and 12.0 months with nivolumab alone (HR, 0.60; 95% CI, 0.37-0.96). In those without baseline brain metastases with the same PD-L1 expression, the median OS with the nivolumab plus ipilimumab was 16.7 months versus 15.0 months with chemotherapy and 16.1 months with nivolumab monotherapy (HR, 0.83; 95% CI, 0.70-0.99).

With regard to PFS, the HRs with the combination in patients with a tumor PD-L1 expression of 1% or higher with and without brain metastases were 0.88 (95% CI, 0.55-1.42) and 0.82 (95% CI, 0.69-0.98), respectively.

Furthermore, in those with a PD-L1 expression of 1% or higher, the DOR was extended with the combination compared with chemotherapy in patients with and without brain metastases at baseline. In those with brain metastases, the ORR was 38.8% with the combination versus 31.3% with chemotherapy and 25.0% with nivolumab alone. The median DOR was 15.5 months versus 8.4 months and 31.0 months, respectively. In those without brain metastases, the ORR was 36.0% with nivolumab plus ipilimumab versus 30.1% with chemotherapy, and 27.9% with nivolumab alone; here, the median DOR was 24.5 months with the combination versus 6.1 months with chemotherapy and 15.3 months with nivolumab.

No new safety signals were reported in this analysis. All-cause nervous system toxicities were observed in 46.9% of patients with brain metastases who received the combination and 42.4% of those who were given chemotherapy. Treatment-related nervous system disorders were experienced by 15.6% of patients with brain metastases who received the immunotherapy combination versus 16.7% of those who received chemotherapy.

“No new safety signals were observed and the findings from this post-hoc analysis were consistent with what has previously been reported in terms of the benefit from the combination in patients with baseline brain metastases,” said Borghaei.

In May 2020, the FDA approved the combination of nivolumab plus ipilimumab for use as a first-line treatment in patients with metastatic NSCLC without EGFR or ALK aberrations and whose tumors express a PD-L1 level of 1% or higher, as determined by an FDA-approved test.2 The decision was based on earlier findings from part 1 of CheckMate-227, which suggested that a dual immunotherapy approach could result in long-term survival for select patients with metastatic disease.3,4

The median OS with nivolumab and ipilimumab versus chemotherapy was 17.1 months and 14.9 months, respectively (HR, 0.79; 95% CI, 0.67-0.94; P = .0066). Moreover, the median OS was 17.1 months with the combination and 14.9 months with chemotherapy in all randomized patients, regardless of PD-L1 status (HR, 0.73; 95% CI, 0.64-0.84).

Three-year follow-up data were presented during the 2020 ASCO Virtual Scientific Program and showed that patients with advanced disease and a tumor PD-L1 expression of 1% or higher or less than 1% experienced durable and long-term efficacy from frontline treatment with the combination over chemotherapy.5

After a median follow-up of 43.1 months, patients with a PD-L1 expression of 1% or higher experienced a 21% reduced risk of death when treated with the combination versus 10% with chemotherapy (HR, 0.79; 95% CI, 0.67-0.93) and nivolumab monotherapy (HR, 0.90; 95% CI, 0.77-1.06). The median OS was 17.1 months in the combination arm versus 15.7 months and 14.9 months in the nivolumab-alone and chemotherapy arms, respectively. The 3-year OS rates observed with the combination was 33% versus 29% with nivolumab monotherapy, and 22% with chemotherapy.

“The OS benefit with this combination was maintained with 3-year survival rates, at over 30%, regardless of baseline brain metastases,” concluded Borghaei.

References

1. Borghaei H, Pluzanski A, Caro RB, et al. Nivolumab (nivo) + ipilimumab (ipi) as first-line (1L) treatment for patients with advanced non-small cell lung cancer (NSCLC) with brain metastases: results from the CheckMate 227. Presented at: AACR Virtual Annual Meeting II; June 22-24, 2020; Virtual. Abstract CT221.
2. US Food and Drug Administration approves Opdivo (nivolumab) + Yervoy (ipilimumab) as first-l­ine treatment of patients with metastatic non-small cell lung cancer whose tumors express PD-L1≥1%. News release. FDA May 15, 2020. Accessed June 23, 2020. bit.ly/3bAJkYD.
3. Peters S, Ramalingam S, Paz-Ares L, et al. Nivolumab + low-dose ipilimumab versus platinum-doublet chemotherapy as first-line treatment for advanced non–small cell lung cancer: CheckMate-227 part 1 final analysis. Ann Oncol. 2019;30(suppl 5):LBA4_PR. doi:10.1093/annonc/mdz394.075
4. Hellmann MD, Paz-Ares L, Carbo RB, et al. Nivolumab plus ipilimumab in advanced non–small-cell lung cancer. N Eng J Med. 2019;381(21):2020-2031. doi: 10.1056/NEJMoa1910231
5. Ramalingam S, Ciuleanu TE, Pluzanski A, et al. Nivolumab + ipilimumab versus platinum-doublet chemotherapy as first-line treatment for advanced non-small cell lung cancer: three-year update from CheckMate 227 Part 1. J Clin Oncol. 2020;38(suppl 15):9500. doi: 10.1200/JCO.2020.38.15_suppl.9500