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

Silas Inman @silasinman
Published: Wednesday, Jun 06, 2018

Hossein Borghaei, DO

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–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%).

Across all PD-L1­–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.

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).
  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.


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