Nivolumab Plus Low-Dose Ipilimumab Shows Durable Responses for PD-L1-Negative, TMB-High NSCLC

Hossein Borghaei, DO, MS

The combination of nivolumab (Opdivo) and low-dose ipilimumab (Yervoy) reduced the risk of progression or death by 52% compared with standard platinum doublet chemotherapy for patients with metastatic PD-L1—negative, tumor mutation burden (TMB)-high non–small cell lung cancer (NSCLC), according to findings from the phase III CheckMate 227 trial presented at the 2018 ASCO Annual Meeting.¹

In the PD-L1—negative (<1% expression), TMB-high (≥10 mutations/megabase) subgroup, regardless of histology, median progression-free survival (PFS) with nivolumab/ipilimumab was 7.7 months compared with 5.3 months for chemotherapy and 6.2 months for nivolumab and chemotherapy. The 1-year PFS rate was 45% with nivolumab/ipilimumab compared with 27% for nivolumab/chemotherapy and just 8% for chemotherapy.

In the TMB-high/PD-L1&shy;—negative group, 93% of patients continued to respond to the nivolumab/ipilimumab for ≥1 year. "These responses are extremely durable," said lead investigator Hossein Borghaei, DO, MS. In the nivolumab/chemotherapy arm, 33% of patients continued to respond at ≥1 year compared with a not calculable duration in the chemotherapy alone group. Kaplan-Meier curves for duration of response to chemotherapy did not extend past 12 months.

"TMB testing may be clinically relevant in selecting patients for IO [immuno-oncology] plus chemo or IO plus IO," said Borghaei, chief of Thoracic Medical Oncology at Fox Chase Cancer Center. "Responses were more durable, and the 1-year PFS rates were higher with nivolumab plus ipilimumab versus nivolumab and chemotherapy in patients with high TMB and less than 1% PD-L1 expression, and there were fewer grade 3/4 treatment-related adverse events."

Across the full unselected population, median PFS was 5.6 months with nivolumab plus chemotherapy compared with 4.7 months for chemotherapy alone (HR, 0.74; 95% CI, 0.58-0.94). The median PFS with nivolumab/ipilimumab was 4.4 months (HR vs chemo, 0.79; 95% CI, 0.62-1.01). The 1-year PFS rates were 29% for nivolumab/ipilimumab, 26% with nivolumab/chemotherapy, and 14% for chemotherapy alone.

"This is consistent with some of the other studies that we've seen in the PD-L1—negative subgroup of patients," Borghaei said.

Part 1b of the CheckMate 227 trial enrolled 550 patients with PD-L1—negative metastatic NSCLC, regardless of histology. Patients were randomized to the combination of nivolumab and ipilimumab (n = 187) or histology-based chemotherapy with nivolumab (n = 177) or without (n = 186). In the chemotherapy-free arm, nivolumab was given at 3 mg/kg every 2 weeks and ipilimumab was dosed at 1 mg/kg every 6 weeks. In the chemoimmunotherapy group, nivolumab was given at 360 mg every 3 weeks.

Baseline characteristics were well-balanced across the arms. The median age of patients was approximately 64 years, and roughly two-thirds of patients had an ECOG performance status of 1. Most patients were current or former smokers (~85%) and the most common histology was non-squamous (75%). TMB was considered high for nearly half of patients (42% to 45%).

At the analysis, 72% of patients continued to respond for ≥1 year in the nivolumab/ipilimumab combination arm. The duration of response was similar between the other groups. Twenty-eight percent of patients receiving nivolumab/chemotherapy responded for ≥1 year compared with 24% for chemotherapy alone.

Consistent benefits were seen with the PD-1/chemotherapy combination across subgroups of patients; however, there was just an 8% reduction in the risk of progression or death in those with squamous histology (HR, 0.92) compared with a 32% drop for patients with non-squamous NSCLC.

When compared with chemotherapy alone, the nivolumab/chemotherapy combination elicited a 44% reduction in the risk of progression or death for patient with tumors with high TMB (HR, 0.56; 95% CI, 0.35-0.91) compared with a 13% reduction for those with low TMB (HR, 0.87; 95% CI, 0.57-1.33). Similarly, when compared with chemotherapy, nivolumab/ipilimumab showed a 52% reduction in the risk of progression or death in the TMB-high group (HR, 0.48; 95% CI, 0.27-0.85). There was no benefit in the TMB-low arm (HR, 1.17; 95% CI, 0.76-1.81).

In those with high TMB tumors, the ORR with nivolumab and chemotherapy was 60.5% compared with 36.8% with nivolumab/ipilimumab and 20.8% with chemotherapy. In those with low TMB, the ORR was 27.8% with nivolumab/chemotherapy and 22.0% with chemotherapy alone. The ORR for this subgroup was not presented for nivolumab and ipilimumab.

"In patients with low PD-L1 expression, PFS benefit from nivolumab plus chemo versus chemo was enhanced in the high TMB group," said Borghaei. "Patients with low TMB and low PD-L1 did not appear to have PFS benefit from nivolumab in combination with either chemo or ipilimumab."

Treatment-related adverse events (TRAEs) of any grade occurred in 92% of patients treated with nivolumab and chemotherapy, compared with 74% with nivolumab and ipilimumab and 77% with chemotherapy alone. Grade 3/4 TRAEs occurred in 52%, 25%, and 35% of patients across treatment groups, respectively, which led to discontinuation rates of 8%, 10%, and 9%.

The most common grade 3/4 TRAEs with nivolumab plus chemotherapy were anemia (17%), neutropenia (12%), decreased neutrophil count (10%), fatigue (5%), hepatic (3%), decreased appetite (2%), nausea (2%), gastrointestinal (2%), diarrhea (1%), skin (1%), and endocrine (0.6%). In the nivolumab/ipilimumab group, the most common grade 3/4 TRAEs were hepatic (8%), gastrointestinal (3%), endocrine (3%), skin (3%), diarrhea (2%), anemia (2%), fatigue (1%), asthenia (1%), and nausea (1%).

"This is consistent with what has been previously reported," said Borghaei. "We had the anticipated side effect you might see with a chemotherapy regimen. The treatment-related adverse events [with nivolumab and ipilimumab] were consistent with an immunotherapy-based regimen and were not unanticipated."

Findings from the CheckMate 227 trial were previously reported at the 2018 AACR Annual Meeting and published in the New England Journal of Medicine.^2,3 This report included Part 1b along with patients from Part 1a who had PD-L1—positive NSCLC (≥1% expression).

The 1-year PFS rate was 43% with nivolumab/ipilimumab in patients with TMB-high NSCLC across groups compared with 13% for chemotherapy. The median PFS was 7.2 versus 5.5 months (HR, 0.58; 97.5% CI, 0.41-0.81; P <.001).

Part 2 of the trial is currently recruiting. In this arm, nivolumab plus chemotherapy is being compared with chemotherapy alone for patients with NSCLC, regardless of PD-L1 or TMB status (NCT02477826).

References:

1. Borghaei H, Hellmann MD, Paz-Ares LG, et al. Nivolumab (Nivo) + platinum-doublet chemotherapy (Chemo) vs chemo as first-line (1L) treatment (Tx) for advanced non-small cell lung cancer (NSCLC) with <1% tumor PD-L1 expression: Results from CheckMate 227. J Clin Oncol. 2018;36 (suppl; abstr 9001).
2. Hellman MD, Ciuleanu T, Pluzanski A, et al. Nivolumab (nivo) + ipilimumab (ipi) vs platinum-doublet chemotherapy (PT-DC) as first-line (1L) treatment (tx) for advanced non-small cell lung cancer (NSCLC): initial results from CheckMate 227. Presented at: 2018 AACR Annual Meeting; April 14-18, 2018; Chicago, Illinois. Abstract CT077. 2017;35(suppl 4S; abstr 350).
3. Hellman MD, Ciuleanu T, Pluzanski A, et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden [published online April 16, 2018]. N Engl J Med. doi: 10.1056/NEJMoa1801946.

Across all PD-L1&shy;—negative patients (N = 550), the objective response rate (ORR) with the nivolumab/chemotherapy combination was 36.7% compared with 23.1% with chemotherapy alone. The median duration of response was 7.2 versus 4.7 months for the nivolumab/chemotherapy and chemotherapy alone arms, respectively. The ORR with nivolumab plus ipilimumab was 25.1% with a median duration of response was 18.0 months.