Frontline Nivolumab/Ipilimumab Shows Clinical Benefit in NSCLC With Poor Prognosis

Fabrice Barlesi MD, PhD

First-line treatment with nivolumab (Opdivo) combined with low-dose ipilimumab (Yervoy) was safe and showed encouraging overall survival (OS), regardless of PD-L1 expression, in patients with advanced non—small cell lung cancer (NSCLC), including those with comorbidities or poor ECOG performance status, according to findings from the phase IIIb CheckMate-817 trial reported at the 2019 ESMO Immuno-Oncology Congress.

Results of the OS analysis showed that, with a minimum follow-up of 21 months, 391 patients in a cohort of patients with advanced NSCLC and an ECOG performance status of 0 to 1 (cohort A) demonstrated a median OS of 17.0 months (95% CI, 14.7-22.4). The 12- and 18-month OS rates were 60% and 49%, respectively. Patients in cohort A with PD-L1 expression ≥1% demonstrated a median OS of 21.4 months (95% CI, 14.8—not reached [NR]) and a 12- and 18-month OS rate of 61% and 53%, respectively. In those with PD-L1 <1%, the median OS was 15.3 months (95% CI, 12.5-18.7); the 12- and 18-month OS rates were 58% and 44%, respectively.

At a median follow-up of 14.1 months, 198 patients with advanced NSCLC and an ECOG performance status of 2, or a performance status of 0 to 1 plus comorbidities (in cohort A1; AOSP) of asymptomatic untreated brain metastases, hepatic or renal impairment, or HIV infection had a median OS of 9.9 months (95% CI, 7.0-13.7). The median OS specifically in patients who had an ECOG performance status of 2 was 9.0 months (95% CI, 5.5-12.9) and was 12.9 months (95% CI, 8.1—NR) in those with ASOP.

Cohort A1 patients with PD-L1 ≥1% had a median OS of 6.9 months (95% CI, 3.6-12.8) and those with PD-L1 <1 had a median OS of 10.5 months (95% CI, 7.0-15.6). The 12-month OS rates were 41% and 48%, respectively.

“Flat-dose nivolumab and a lower, weight-based dose of ipilimumab was safe and improved OS, including in patients with NSCLC who are traditionally not eligible for clinical trials, such as those who had either a comorbid condition or poor ECOG performance status,” said Fabrice Barlesi MD, PhD, head of the Multidisciplinary Oncology and Therapeutic Innovations Department, Assistance Publique Hôpitaux de Marseille, France.

In the multicohort, single-agent, phase IIIb CheckMate-817 trial, investigators evaluated the safety of flat-dose nivolumab plus a weight-based dose of ipilimumab in patients with advanced NSCLC. Patients with previously untreated stage IV or recurrent NSCLC and no known sensitizing EGFR or ALK alterations were enrolled, and all patients were unselected for PD-L1 expression status. All patients received nivolumab at 240 mg every 2 weeks plus ipilimumab at 1 mg/kg every 6 weeks for 2 years or until disease progression or unacceptable toxicity.

Except for ECOG performance status and comorbidities, baseline characteristics were similar between cohorts. Among 391 and 198 treated patients in cohorts A and A1, respectively, 60% versus 64% of patients were male and the median age was 65 years (range, 26-89) versus 67 years (range, 39-90). PD-L1 expression status in cohort A versus cohort A1, respectively, was ≥50% in 18% versus 19% of patients, ≥1% in 49% and 44% of patients, and <1% in 51% versus 56% of patients. Tumor mutational burden (TMB) was evaluable in 39% versus 43% of patients in the respective cohorts; 48% versus 43% had TMB of ≥10 mutations/megabase and TMB was <10 mutations/megabase in 52% versus 57% of patients.

Most patients in cohort A had an ECOG performance status of 0 to 1, with just 1% of patients having a performance status of 2, whereas 70% of patients in cohort A1 had ECOG performance status of 2. Many patients in cohort A1 also had a specified comorbidity, such as asymptomatic untreated brain metastases (25%), hepatic impairment (4%), renal impairment (4%), or HIV infection (2%).

The primary endpoint was safety in cohort A; efficacy was a secondary endpoint. Exploratory endpoints included efficacy and safety in the A1 cohort. “Importantly, the treatment-related select AE profile with the flat-dose nivolumab and weight-based ipilimumab was consistent across cohorts A and A1,” said Barlesi.

The safety profile, which consisted of the type and rate of treatment-related adverse events (TRAEs), was similar across both cohorts. Any-grade TRAEs occurred in 77% of patients in cohort A and 67% of patients in cohort A1. Thirty-five and 28% of patients in cohort A and A1, respectively, had grade 3/4 TRAEs.

“The onset of select TRAEs occurred early on during treatment,” Barlesi noted.

Select AEs in cohort A included skin (n = 122) endocrine (n = 92), gastrointestinal (n = 88), pulmonary (n = 41), hepatic (n = 39), hypersensitivity (n = 34), and renal (n = 7). In cohort A, the median time to onset of select TRAEs ranged from 2.1 weeks for hypersensitivity to 26.4 weeks for renal AEs. The majority (68% to 90%) of select TRAEs resolved, excepting for endocrine AEs where 40% of patients had resolution and the median time to resolution was not reached (95% CI, 46.6—NR).

In cohort A1, the same select AEs occurred, including skin (n = 52) endocrine (n = 36), gastrointestinal (n = 37), pulmonary (n = 5), hepatic (n = 20), hypersensitivity (n = 5), and renal (n = 5). The median time to onset of select TRAEs ranged from 2.1 weeks for hypersensitivity to 20.7 weeks for pulmonary. The majority (73% to 89%) of select TRAEs resolved, excepting for endocrine AEs where 47% of patients had resolution.

“First-line nivolumab and ipilimumab resulted in durable OS outcomes in cohort A patients with advanced NSCLC that were comparable to reports from the overall patient population in CheckMate-227,” concluded Barlesi. “While comorbidities and/or poor performance status impacted OS outcomes in cohort A1, this special population had a promising efficacy outcome with a 1-year OS rate of 47%.”

Barlesi F, Audigier-Valette C, Felip E,&#8239;et al.&#8239;Nivolumab plus low-dose ipilimumab as first-line treatment of advanced NSCLC: overall survival analysis of CheckMate 817. Ann Oncol. 2019;30(suppl_11):xi33-xi47. doi: 10.1093/annonc/mdz451.