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Medical writer: Stijn van den Borne, MSc | Last updated: 21 April 2018 | In: Lung Cancer, Oncology, Chemotherapy, Immunotherapy, Translational Research
Article Keywords
PD-1, pemetrexed, PD-L1, CTLA4, Bristol-Myers Squibb, Oncology News, NSCLC, non-squamous cell lung cancer, nivolumab, platinum-doublet, cisplatin, squamous cell lung cancer, ipilimumab, AACR 2018, carboplatin, TMB, gemcitabine, BMS
First-line nivolumab (OpdivoⓇ) plus ipilimumab (YervoyⓇ) was associated with a more than tripled 1-year progression-free survival (PFS) rate compared to platinum-based chemotherapy for patients with tumour mutation burden (TMB)-high non-small cell lung cancer (NSCLC) in the Phase III CheckMate 227 trial. The results were presented during the 2018 AACR Annual Meeting with simultaneous online publication in the New England Journal of Medicine (NEJM).
“In this study of TMB-high non–small cell lung cancer, we found that nivolumab plus ipilimumab significantly improved progression-free survival compared to chemotherapy,”
~Matthew D. Hellman, MD, Memorial Sloan Kettering Cancer Center
Study Design
The CheckMate 227 (NCT02477826) initially was a multipart study comparing various immunotherapeutic regimens of programmed death 1 (PD-1) inhibitor nivolumab with chemotherapy (Figure 1). Eligible patients had Stage IV or recurrent NSCLC and not received prior systemic treatment. Participants were stratified as squamous NSCLC and non-squamous NSCLC. Subjects with insufficient tissue available for testing of PD-1 ligand (PD-L1) could not participate in the study.
Upon successful study-registration, participants were divided into a low PD-1 ligand (PD-L1) expression-group [PD-L1<1%] and high PD-L1 expression-group [PD-L1≥1%] and randomised to either nivolumab plus ipilimumab, chemotherapy alone, or nivolumab alone. Patients in the PD-L1<1% group and allocated to the nivolumab-arm received concomitant chemotherapy (Figure 1).
Based on the results of the CheckMate 012 and 032 studies, which showed efficacy of nivolumab plus ipilimumab in TMB-high lung cancer, the study was amended to include the co-primary progression-free survival endpoint comparing the immunooncology combination (IO-IO) with chemotherapy in patients with TMB-high (≥10 mutations per megabase [mut/Mb]).
Figure 1. Study design of the CheckMate 227 study. Platinum-doublet chemotherapy was subject to the histological subtype. Patients with non-squamous NSCLC received pemetrexed (500 mg/m2) plus cisplatin (75 mg/m2) or carboplatin (area under the concentration-time curve [AUC] 5 or 6), every 3 weeks (q3w) for up to four cycles. Maintenance therapy with pemetrexed 500 mg/m2 after chemotherapy or with nivolumab 360 mg q3w plus pemetrexed 500 mg/m2 after nivolumab plus chemotherapy was optional. Patients with squamous NSCLC received gemcitabine (1000 or 1250 mg/m2) plus cisplatin (75 mg/m2), or gemcitabine (1000 mg/m2) plus carboplatin (AUC 5) q3w for up to four cycles.
Progression-Free Survival
In patients with TMB-high NSCLC the 1-year PFS rate was 43% for nivolumab plus ipilimumab compared with 13% for platinum-doublet chemotherapy (Figure 2). The median PFS was 7.2 months (nivolumab plus ipilimumab) versus 5.5 months (chemotherapy), a 42% risk reduction for disease progression or death (hazard ratio [HR]=0.58, P<0.001; 97.5%CI, 0.41-0.81).
mPFS nivolumab plus ipilimumab: 7.2 months (95%CI, 5.5-13.2)
1-year PFS-rate nivolumab plus ipilimumab: 42.6%
mPFS chemotherapy: 5.5 months (95%CI, 4.4-5.8)
1-year PFS-rate chemotherapy: 13.2%
Figure 2. Progression-free survival (PFS) for chemotherapy vs ipilimumab plus nivolumab in TMB-high NSCLC, the co-primary endpoint of the CheckMate 227 study (NCT02477826). The combination IO-IO was associated with a 42% reduction of risk for disease progression or death (HR=0.58, P<0.001; 97.5% confidence interval [CI], 0.41-0.81). mPFS: median PFS.
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Figure 3a. Response rates with nivolumab plus ipilimumab combination in TMB-high NSCLC.
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Figure 3b. Response rates with chemotherapy in TMB-high NSCLC.
Objective Response Rate
The nivolumab-ipilimumab combination showed an objective response rate (ORR) of 45.3%. Responses were durable, 68% had an ongoing response after 1 year. In the chemotherapy-arm, the ORR was 26.9% and 25% of responders had an ongoing response at 1 year.
Figure 3a shows the response rates for nivolumab plus ipilimumab in TMB-high NSCLC and Figure 3b the response rates for chemotherapy in TMB-high NSCLC.
Comparison with Overall Population
In the overall population, ipilimumab plus nivolumab was associated with a higher 1-year PFS rate (30.9% vs 17.0%; HR=0.83; 95%CI, 0.72-0.96). However, the median PFS for IO-IO did not significantly differ from chemotherapy: 4.9 vs 5.5 months, respectively. In the subset of participants with TMB-low tumours (<10 mut/Mb), the median PFS was 3.2 months with the IO-IO vs 5.5 months with chemotherapy (HR=1.07; 95%CI, 0.84-1.35).
Overall Survival
At the time of database-lock on January 24, 2018, the overall survival (OS) data were not yet mature. Despite censoring of over 50% of the data points, the preliminary HR for OS in TMB-high patients was 0.79 (95%CI, 56-1.10) favouring the IO-IO combination over chemotherapy.
Cross Over
More than 24% of patients treated with IO-IO nivolumab plus ipilimumab for TMB-high NSCLC continued treatment at the time of database-lock, compared with 3.1% of chemotherapy-treated patients. Notably, 30% of CheckMate 227 patients on chemotherapy were treated with subsequent immunotherapy.
Figure 3a. Response rates with nivolumab plus ipilimumab combination in TMB-high NSCLC.
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Figure 3b. Response rates with chemotherapy in TMB-high NSCLC.
Figure 4a. CheckMate 227 TMB analysis as by the FoundationOne companion diagnostic (CDx).
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Figure 4b. CheckMate 227 PD-L1 level expression was evenly distributed across the TMB-high (PD-L1<1%: 21%; PD-L1≥1% 79%) and TMB-low groups (PD-L1<1%: 21%; PD-L1≥1% 79%), represented in this figure as total proportions.
Biomarker Analysis
A total of 1004 tissue samples were successfully tested for TMB-analysis by the FoundationOne companion diagnostic (CDx) (Figure 4a). In total, 444 (25.5%) samples of 1739 participants in the CheckMate 227 had ≥10 mut/Mb.
PD-L1 level expression was independent of the TMB-classification and equally distributed across the two TMB subgroups. In the TMB-high subgroup, 21% of the samples tested for PD-L1 were found to have a <1% level expression, and 79% were found to have a PD-L1≥1% level expression. The distribution of PD-L1 <1% and ≥1% level expression was similar in the TMB-low group; 21% and 79%, respectively (Figure 4b).
Subgroup analysis showed that nivolumab plus ipilimumab improved PFS among all patients regardless of PD-L1 expression or histologic (squamous vs non-squamous) subtypes. “This suggests TMB is an important independent biomarker,” commented the authors in the NEJM.
Safety
The safety of nivolumab plus ipilimumab was similar as reported in other trials of the IO-IO combination. Grade 3/4 treatment-related adverse events (TRAEs) occurred in 31% of the nivolumab plus ipilimumab-treated patients. In this group, rash, diarrhoea, and anaemia (1.6% each) were the most frequently observed TRAEs. In the chemotherapy-arm, 36% of patients experienced grade 3/4 TRAEs. Treatment discontinuation due to TRAEs occurred more often in the IO-IO combination-group than in the chemotherapy-group: 12% vs 4.9%, respectively.
References
- Hellmann MD et al. N Engl J Med. DOI: 10.1056/NEJMoa1801946.
- Hellmann MD et al. Abstract CT077. Presented at 2018 AACR Annual Meeting; April 14-18, 2018.
Figure 4a. CheckMate 227 TMB analysis as by the FoundationOne companion diagnostic (CDx).
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Figure 4b. CheckMate 227 PD-L1 level expression was evenly distributed across the TMB-high (PD-L1<1%: 21%; PD-L1≥1% 79%) and TMB-low groups (PD-L1<1%: 21%; PD-L1≥1% 79%), represented in this figure as total proportions.
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Disclaimer
This article is not medical advice. Patients should seek personal assessment by a licenced specialist. Physicians are recommended to read the full publication(s) as cited in the article before making medical decisions. This article does not supersede nor replace the published article(s).
© Copyright 2018 MediPaper Medical Communications Ltd. – AACR 2018: First-line Nivolumab-Ipilimumab in TMB-high NSCLC CheckMate 227 / NCT02477826.
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© Copyright 2018 MediPaper Medical Communications Ltd. – AACR 2018: First-line Nivolumab-Ipilimumab in TMB-high NSCLC CheckMate 227 / NCT02477826.
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