Durvalumab After Sequential Chemoradiotherapy in Stage III, Unresectable NSCLC: The Phase 2 PACIFIC-6 Trial.

INTRODUCTION: On the basis of the findings of the phase 3 PACIFIC trial (NCT02125461), durvalumab is standard of care for patients with stage III, unresectable NSCLC and no disease progression after concurrent chemoradiotherapy (cCRT). Many patients are considered unsuitable for cCRT owing to concerns with tolerability. The phase 2 PACIFIC-6 trial (NCT03693300) evaluates the safety and tolerability of durvalumab after sequential CRT (sCRT). METHODS: Patients with stage III, unresectable NSCLC and no progression after platinum-based sCRT were enrolled to receive durvalumab (1500 mg intravenously) every 4 weeks for up to 24 months. The primary end point was the incidence of grade 3 or 4 adverse events possibly related to treatment occurring within 6 months. Secondary end points included investigator-assessed progression-free survival (PFS; Response Evaluation Criteria in Solid Tumors version 1.1) and overall survival. RESULTS: Overall, 117 patients were enrolled (59.8% with performance status >0, 65.8% aged ≥65 y, and 37.6% with stage IIIA disease). Median treatment duration was 32.0 weeks; 37.6% of patients remained on treatment at data cutoff (July 15, 2021). Grade 3 or 4 AEs occurred in 18.8% of patients. Five patients had grade 3 or 4 possibly related adverse events within 6 months (incidence: 4.3%; 95% confidence interval: 1.4-9.7), including two pneumonitis cases. Two patients (1.7%) had grade 5 AEs of any cause. Survival data maturity was limited. Median PFS was 10.9 months (95% confidence interval: 7.3-15.6), and 12-month PFS and overall survival rates were 49.6% and 84.1%, respectively. CONCLUSIONS: Durvalumab after sCRT had a comparable safety profile with that observed with durvalumab after cCRT in PACIFIC and had encouraging preliminary efficacy in a frailer population.

Cost Effectiveness of Durvalumab in Unresectable Stage III NSCLC: 4-Year Survival Update and Model Validation from a UK Healthcare Perspective.

BACKGROUND: In the phase III PACIFIC study, durvalumab improved survival versus placebo in patients with unresectable stage III non-small-cell lung cancer (NSCLC) whose disease had not progressed after platinum-based concurrent chemoradiotherapy. The appraisal by the UK's National Institute for Health and Care Excellence (NICE) included a cost-effectiveness analysis based on an early data readout from PACIFIC [March 2018 data cut-off (DCO); median follow-up duration 25.2 months; range 0.2-43.1]. Uncertainties regarding long-term survival outcomes with durvalumab led to some challenges in estimating the cost effectiveness of this therapy. OBJECTIVE: Here, we validate the survival extrapolations used in the original company base-case analysis by benchmarking them against updated survival data from the 4-year follow-up analysis of PACIFIC (i.e. approximately 4 years after the last patient was randomised; March 2020 DCO; median follow-up duration 34.2 months; range 0.2-64.9). Moreover, we update the original analysis with these more mature survival data to examine the consistency of key economic outputs with the original analysis. METHODS: The original analysis used a semi-Markov (state-transition) approach and was based on patients whose tumours expressed programmed cell death-ligand 1 on ≥ 1% of cells (to reflect the European licence for durvalumab). We benchmarked the survival extrapolations used in the original company base-case analysis against survival data from the 4-year follow-up of PACIFIC and updated the cost-effectiveness analysis with these more mature survival data. Early deaths avoided by the adoption of durvalumab into the UK Cancer Drugs Fund (CDF) in March 2019 were estimated using the 4-year follow-up survival data and an assumed uptake of 125 patients/year (lower estimate) and 367 patients/year (higher estimate). RESULTS: The original company base-case analysis had a good visual fit with the observed overall survival (OS) distribution for the durvalumab arm and accurately predicted the 48-month OS rate (predicted 55%; observed 55%); by comparison, the fit was less precise for the placebo arm, for which the analysis underestimated the 48-month OS rate (predicted 32%; observed 38%). In the updated company base-case analysis, durvalumab yielded 2.51 incremental quality-adjusted life-years (QALYs) (- 0.43 vs. the original company base-case analysis), corresponding to an incremental cost-effectiveness ratio of £22,665/QALY (+£3298 vs. the original analysis), which falls within the upper bound of NICE's willingness-to-pay threshold (£30,000/QALY gained). We estimate that between 31 and 91 early patient deaths may have been avoided by the adoption of durvalumab into the CDF. CONCLUSIONS: These findings reinforce the patient benefit observed with durvalumab in unresectable stage III NSCLC, support the routine use and cost effectiveness of this therapy, and demonstrate how appropriate modelling can inform the early adoption of therapies by payers to achieve patient benefit.

Based on the results of a clinical trial, the European Medicines Agency approved durvalumab for the treatment of adults with a specific type of advanced lung cancer whose tumours cannot be removed surgically and whose disease has not progressed after chemotherapy and radiotherapy. The UK's National Institute for Health and Care Excellence (NICE) invites companies to submit cost-effectiveness analyses to help with decision making about adopting new therapies. The company included an analysis based on early trial data that suggested durvalumab was cost effective compared with other previous treatments. As patients in the study at the time of the initial submission to NICE were only followed for approximately 2 years, the long-term survival benefit that could be achieved with durvalumab was uncertain. Therefore, NICE recommended durvalumab for use within the Cancer Drugs Fund (CDF) to allow patients to access the drug while more data were being collected. Here, we demonstrate that the original cost-effectiveness model accurately predicted the rates of long-term survival for patients receiving durvalumab and that durvalumab remains a cost-effective use of healthcare resources based on recently published data from the trial (which added approximately 2 further years of follow-up). Moreover, we estimate that adopting durvalumab into the CDF may have avoided 31­91 early patient deaths from lung cancer. These findings support NICE's early decision to make durvalumab available within the CDF and the adoption of durvalumab for routine use within the UK national health service.