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Patient-reported outcomes of first-line nivolumab + ipilimumab in high tumour mutational burden advanced non-small-cell lung cancer

WCLC 2018
Phase 3, CheckMate 227

Non-squamous non-small-cell lung carcinoma (NSCLC) tumours are tested for driver mutations and rearrangements, typically EGFR, ALK, ROS1, MET, and BRAF. In many centres, it is also common to screen for less frequent but potentially targetable mutations, including RET, ERBB2/HER2, and NTRK fusions [1].

In time, novel immune checkpoint inhibitors (ICIs) will treat growing numbers of driver cell mutations in squamous and non-squamous tumours. Combinations of ICIs alone and with chemotherapy hold promise for prolonging PFS and OS in patients with high PD-L1 expressing tumours. Growing knowledge of the biology of NSCLC is rapidly reshaping treatment advanced disease.

Patient-reported health-related quality of life (HRQoL) outcomes from the CheckMate 227 study [2] suggest rapid and sustained improvements in patients treated with nivolumab + ipilimumab vs chemotherapy.

The phase 3, randomised CheckMate 227 trial enrolled patients with advanced NSCLC and a high tumour mutational burden (TMB; ≥10 mutations/Mb). Those with a PD-L1 level ≥1% were randomised to nivolumab + ipilimumab, nivolumab monotherapy, or chemotherapy. Patients with a tumour PD-L1 expression level of <1% were randomly assigned to receive nivolumab + ipilimumab, nivolumab + chemotherapy, or chemotherapy.

Patient-reported outcomes (PROs) were an exploratory endpoint in CheckMate 227. Eligible chemotherapy-naïve patients had stage 4 or recurrent NSCLC, ECOG performance status 0-1, and no known sensitising EGFR/ALK alterations. Specific outcomes included disease-related symptom deterioration by 12 weeks; time to deterioration in symptoms (by Lung Cancer Symptom Scale [LCSS] Average Symptom Burden Index [ASBI]; and assessment of quality of life and overall health status (by EuroQoL-5 Dimension [EQ-5D] utility index [UI] and visual analogue scale [VAS]). PROs were evaluated each cycle for the first 6 months and every 6 weeks during treatment, and at two follow-up visits. EQ-5D was assessed at survival follow-up visits.

Completion rates were approximately 90% at baseline in the nivolumab + ipilimumab and chemotherapy groups (n=583, for both). They were over 80% for nearly all on-treatment assessments. Fewer patients with high TMB in the nivolumab + ipilimumab arm (n=139) reported symptom deterioration by week 12 vs those who received chemotherapy (n=160). This was so whether they were still receiving therapy or had discontinued it (22.3% vs 35%, absolute RR 12.7%). Time to first deterioration (TTD) either on- or off-treatment was longer in the nivolumab + ipilimumab group vs chemotherapy. The HR for the LCSS ASBI was 0.40. It was 0.56 on the 3-Item Global Index (3-IGI). The estimated benefit in TTD favoured the nivolumab + ipilimumab group for individual symptoms in the ASBI and each item in the 3-IGI (HRs 0.48-0.74). The exception was haemoptysis (HR 1.2), which had a very low burden. The EQ-5D VAS (HR 0.62) and UI (HR 0.50) also showed an advantage for patients who received nivolumab + ipilimumab. In this group, mean changes from baseline indicated rapid and clinically meaningful improvements in the LCSS ASBI/3-IGI and EQ-5D VAS/UI. For patients in the chemotherapy arm, symptoms and HRQoL remained stable (LCSS ASBI/3, EQ-5D UI) or improved after completion of treatment (EQ-5D VAS). Despite the potential for immune-related AEs, there were earlier and more durable improvements in symptoms and HRQoL with immunotherapy vs chemotherapy (see Figure).

Figure: Time to first improvement for LCSS ASBI and all measure on treatment (common assessments) or follow-up in patients with high TMB (≥10 mut/Mb)

WCLC 2018: Figure 10 LCSS ASBI

  1. Doroshow DB, Herbst RS. JAMA Oncol 2018;4:569-570.

  2. Hellmann MD, et al. N Engl J Med 2018;378:2093-2104.

© 2023 The Author(s). Published by Medicom Medical Publishers.
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