Durvalumab for the Treatment of Locally Advanced, Unresectable, Stage III Non-Small Cell Lung Cancer: An Evidence Review Group Perspective of a NICE Single Technology Appraisal

Abstract

As part of the Single Technology Appraisal (STA) process, the National Institute for Health and Care Excellence (NICE) invited the manufacturer (AstraZeneca) of durvalumab (IMFINZI TM) to submit evidence for the clinical and cost effectiveness of durvalumab for the treatment of patients with locally advanced, unresectable, stage III non-small cell lung cancer whose tumours express programmed death-ligand 1 (PD-L1) on ≥ 1% of tumour cells and whose disease has not progressed after platinum-based chemoradiation therapy. Kleijnen Systematic Reviews Ltd, in collaboration with Maastricht University Medical Centre, was commissioned to act as the independent Evidence Review Group (ERG). This paper summarises the company submission (CS), presents the ERG's critical review on the clinical-and cost-effectiveness evidence in the CS, highlights the key methodological considerations, and describes the development of the NICE guidance by the Appraisal Committee. The CS included a systematic review that identified one randomised controlled trial, comparing durvalumab with SoC. Participants with tumours expressing PD-L1 on ≥ 1% of tumour cells accounted for approximately 40% of the total participants. In this subgroup, a benefit in progression-free survival (PFS) [hazard ratio (HR) 0.44, 95% confidence interval (CI) 0.31-0.63] and overall survival (HR 0.54, 95% CI 0.35-0.81) was reported. Adverse events were comparable between both treatments, but more serious adverse events were reported for durvalumab (64/213 [30%] vs. 18/90 [20%]). The ERG's concerns regarding the economic analysis included a likely overestimation of PFS for the durvalumab arm, the choice of timepoint for treatment waning, as well as the way treatment waning was incorporated in the model, and potential overestimation of utility values without applying an age-or treatment-related decrement. The revised ERG base-case resulted in a deterministic incremental cost-effectiveness ratio of £50,238 per quality-adjusted life-year gained, with substantial remaining uncertainty. NICE recommended durvalumab as an option for use within the Cancer Drugs Fund only in a subpopulation (concurrent platinum-based chemoradiation therapy) with a commercially managed access agreement in place.

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

“…Numerous cost-effectiveness analyses have been published based on both the ITT and the PD-L1 TC ≥ 1% PACIFIC populations. These analyses report a lower range of QALY gains with durvalumab therapy (0.24-1.32 for the PD-L1 TC ≥ 1% population) compared with the original company base-case analysis (2.93) (Table 3 in the ESM) [30,31,[44][45][46][47][48]; this could be explained, in part, by the use of different modelling approaches, decision problems, and/or assumptions regarding long-term survival benefit. The recently published data from PACIFIC (March 2020 DCO) demonstrated a gain in median OS of 27.8 months with durvalumab therapy versus placebo and a sustained OS and PFS benefit with durvalumab at 4 years (PD-L1 TC ≥ 1% population) [34]; the 48-month OS rates were 55 and 38% with durvalumab and placebo, respectively.…”

“…The de novo base-case analysis used a state-transition modelling approach because evidence from PACIFIC indicated that the benefit of durvalumab was primarily driven by PFS [ 22 , 23 , 30 ], whereas post-progression survival (PPS) was similar between the durvalumab and placebo arms [ 30 ]. In the company base-case analysis, durvalumab therapy resulted in an expected gain of 2.93 quality-adjusted life-years (QALYs) compared with standard-of-care active follow-up (placebo), corresponding to a deterministic incremental cost-effectiveness ratio (ICER) of £19,366/QALY gained (after incorporating minor adjustments to correct errors identified by the NICE-commissioned evidence review group [ERG]) [ 30 , 31 ]. Therefore, this ICER fell below the £20,000–30,000/QALY gained willingness-to-pay threshold that NICE applies for cost effectiveness.…”

“…Incremental cost effectiveness of durvalumab versus active follow-up after chemoradiotherapy for the original and updated company base-case analyses DCO data cut-off, ICER incremental cost-effectiveness ratio, LYs life-years, QALYs quality-adjusted LYs a The original model submitted to the UK National Institute for Care and Excellence was adjusted to correct minor errors identified by the evidence review group, yielding a deterministic ICER of £19,366 per QALY gained[30,31] …”

Lenalidomide with Rituximab for Previously Treated Follicular Lymphoma and Marginal Zone Lymphoma: An Evidence Review Group Perspective of a NICE Single Technology Appraisal

“…This may have to do with limitations of the STM approach as discussed above, or the added complexity of implementing both approaches, or other barriers to implementing the TSD 19 recommendation. The ERG, having experienced similar difficulty in a previous STA [ 21 ], therefore argues that care should be taken to justify the employment of this recommendation and feels that perhaps TSD 19 may need further elaboration to detail in what specific cases validation of PSM with STM is indicated. The ERG so far has not seen any STA having successfully cross-validated a PSM by an STM alongside it—or the other way around.…”

Cost-Effectiveness of Durvalumab After Chemoradiotherapy in Unresectable Stage III NSCLC: A US Healthcare Perspective

“…To reflect real-world treatment of unresectable stage III NSCLC in the United States, 36.2% of patients in the cCRT-alone arm were assumed to receive subsequent consolidation with chemotherapy (paclitaxel 1 carboplatin, 33.9%; pemetrexed 1 cisplatin, 2.2%). 27 However, studies have shown that consolidation with chemotherapy does not improve survival 28 ; thus, it was assumed that these patients incurred no survival advantage.…”