Nivolumab plus ipilimumab versus chemotherapy as first-line treatment in advanced non–small-cell lung cancer with high tumour mutational burden: patient-reported outcomes results from the randomised, open-label, phase III CheckMate 227 trial

Abstract

B a c k g r o u n d : I n t h e p h a s e I I I C h e c k M a t e 2 2 7 s t u d y , fi r s t-l i n e nivolumab þ ipilimumab significantly prolonged progression-free survival (co-primary endpoint) versus chemotherapy in patients with advanced nonesmall-cell lung cancer (NSCLC) and high tumour mutational burden (TMB; !10 mutations/megabase). Aim: To evaluate patient-reported outcomes (PROs) in this population. Methods: Disease-related symptoms and general health status were assessed using the validated PRO questionnaires Lung Cancer Symptom Scale (LCSS) and EQ-5D, respectively. LCSS average symptom burden index (ASBI) and three-item global index (3-IGI) and EQ-5D visual analogue scale (VAS) and utility index (UI) scores and changes from baseline were analysed descriptively. Longitudinal changes were assessed by mixed-effect model repeated measures (MMRMs) and time to first deterioration/improvement analyses. Results: In the high TMB population, PRO questionnaire completion rates were w90% at baseline and >80% for most on-treatment assessments. During treatment, mean changes from baseline with nivolumab þ ipilimumab showed early, clinically meaningful improvements in LCSS ASBI/3-IGI and EQ-5D VAS/UI; with chemotherapy, symptoms and health-related quality of life remained stable (LCSS ASBI/3-IGI, EQ-5D UI) or improved following induction (EQ-5D VAS). MMRM-assessed changes in symptom burden were improved with nivolumab þ ipilimumab versus chemotherapy. Symptom deterioration by week 12 was lower with nivolumab þ ipilimumab versus chemotherapy (22.3% versus 35.0%; absolute risk reduction: 12.7% [95% confidence interval 2.4e22.5]), irrespective of discontinuation. Time to first deterioration was delayed with nivolumab þ ipilimumab versus chemotherapy across LCSS and EQ-5D summary measures. Conclusion: First-line nivolumab þ ipilimumab demonstrated early, sustained improvements in PROs versus chemotherapy in patients with advanced NSCLC and high TMB. Clinical trial registration: NCT02477826.

<p>Feasibility and Utility of Incorporating Patient-Reported Outcomes into Surveillance Strategies for Advanced Lung Cancer</p>

“…The differences of HR QoL evaluated with different PROs for patients treated with the two treatments under evaluation and their concordance about the outcome evaluated in the study were reported. 39 Disease progression had a significant adverse impact on many PROs' endpoints; 40 PROs showed that they were useful in identifying patients with advanced NSCLC who are likely to have significantly lower survival. 41 The prognostic power of overall QoL on the survival of lung cancer patients and the advantages for lung cancer survivors reporting to be physically active was demonstrated versus those who were not physically active; 42 the early detection of symptomatic relapse and management of symptoms through a webmediated individualized follow-up strategy provided an improvement in quality of life and overall survival.…”

“…Data on PRO completion rates are available for 20 studies (60.61%) (Table 3), only in 3 studies (15%) was it lower than 80%; 44,47,59 for the others 17 (85%) it was higher than 80%. 35,36,39,40,45,48,49,51,52,[55][56][57][58]61,[66][67][68] Only in one study (5%) did the authors report a completion rate of 100%. 52 In most cases, frequencies decreased over time from baseline to subsequent measurements.…”

“…It must be emphasized that there is much evidence in the literature about the benefits of collecting and using PROs in lung cancer populations, for treatment monitoring, 35,[38][39][40][44][45][46][47][48]51,55,[57][58][59][65][66][67] detection of symptoms, 36,37,41,50,53,54,60,65 the role of patient or pathology characteristics on QoL, 40,42,56,68 to improve patientclinician communication and patient satisfaction. 43,61,62 Only one study about the effect of disease progression on QoL was identified 49 assessing the use of PROs related to efficacy outcomes (PFS, OS).…”

Comparative Efficacy and Safety of Nivolumab and Nivolumab Plus Ipilimumab in Advanced Cancer: A Systematic Review and Meta-Analysis

“…NIVO + IPI showed significant advantages over sunitinib in advanced renal cell carcinoma (Motzer et al, 2018), which led to FDA approval of NIVO + IPI for the treatment of advanced renal cell carcinoma (Schuyler, 2018;Cella et al, 2019). Another study (Reck et al, 2019) showed that first-line NIVO + IPI led to continuous early improvement in patients with advanced NSCLC and high TMB compared with chemotherapy. Japan's single-arm experiment (Namikawa et al, 2018) also highlighted the advantages of NIVO + IPI.…”

Prediction of response to anti-PD-1 therapy in patients with non-small-cell lung cancer by electronic nose analysis of exhaled breath

“…A potential limitation of the present study is represented by its design, in which anti-PD-1 therapy was given in the clinical care setting rather than a randomized controlled trial. Therefore, no comparison has been made to other biomarkers, such as tumor mutational burden [23], as these biomarkers are not yet clinically validated for the selection of treatment [24]. One could argue that this real-world design brings the evaluation of biomarkers closest to daily practice.…”