Key Points Question Can surrogate end points, such as progression-free survival, be used to estimate overall survival in immunotherapy trials? Findings This systematic review and meta-analysis using data from 60 published immunotherapy randomized clinical trials in advanced solid cancers found that 6-month progression-free survival in the immunotherapy arm estimated 12-month overall survival well using a statistical model that accounts for tumor type. Meaning These findings suggest that this model could assist with selecting immunotherapy agents for further testing in large randomized clinical trials and with regulatory approvals in rare cancers for which randomized trials are not feasible.
Background: Recent trials of novel agents in 'rare' molecular subtypes of non-small cell lung cancer (NSCLC) have used single-arm trial designs and benchmarked outcomes against historical controls. We assessed the consistency of historical control outcomes using docetaxel data from published NSCLC randomized controlled trials (RCTs). Material and methods: Advanced NSCLC RCTs including a docetaxel monotherapy arm were included. Heterogeneity in tumor objective response rates (ORRs), progression-free survival (PFS) and overall survival (OS), and correlations between outcomes and year of trial commencement were assessed. Results: Among 63 trials (N ¼ 10,633) conducted between 2000 and 2017, ORR ranged from 0% to 26% (I 2 ¼ 76.1%, p heterogeneity < .0001). Mean of the median PFS was 3.0 months (range: 1.4-6.4), 3month PFS ranged from 25% to 85% (I 2 ¼ 86.0%, p heterogeneity < .0001). Mean of the median OS was 9.1 months (range: 4.7-22.9), 9-month OS ranged from 23% to 79% (I 2 ¼ 83.0%, p heterogeneity < .0001). Each later year of trial commencement was associated with 0.3% (p ¼ .046), 0.5% (p ¼ .11) and 0.9% (p ¼ .001) improvement in ORR, 3-month PFS and 9-month OS rates, respectively. Conclusions: There was significant heterogeneity and an improving trend in docetaxel outcomes across trials conducted over 20 years. Benchmarking biomarker-targeted agents against historical controls may not be a valid approach to replace RCTs. Innovative study designs involving a concurrent control arm should be considered.
Background: Next-generation sequencing is used to increase targeted treatment opportunities, particularly for patients who have exhausted standard options. Where randomized controlled trial evidence for a targeted therapy is available for molecular alterations in one tumor type, the dilemma for the clinician is whether ‘matching’ targeted agents should be recommended off-label for the same molecular alterations detected in other tumor types, for which no trial data are available to guide practice. To judge the likely benefits, it may be possible to extrapolate evidence from cancers where treatment benefits have been established. Methods: We present a framework for assessing the appropriateness of extrapolation using trastuzumab, an anti-HER2 antibody, for HER2-amplified tumors where trastuzumab use would be off-label as an illustrative example. Results: The following should be considered for the tumor type where trastuzumab would be off-label: (a) reliability of the NGS assay for detecting HER2 amplification; (b) criteria for defining HER2 positivity; (c) strength of evidence supporting the actionability of HER2 amplification and trastuzumab; (d) whether better clinical outcomes with trastuzumab are due to a more favorable natural history rather than trastuzumab effect; (e) signals of trastuzumab activity and whether it translates to clinically meaningful benefit; (f) whether the safety profile of trastuzumab differs from established indications; and (g) discussion points for shared decision making (SDM) to facilitate informed consent. Conclusion: We present a systematic approach for appraising evidence to support extrapolating trastuzumab benefits from established indications to off-label applications. Extrapolation criteria and areas of uncertainty to inform SDM are outlined. This framework is potentially generalizable to other tumor-agnostic biomarker-targeted therapy scenarios. It is a practical approach for clinicians to apply in routine practice and should be considered by molecular tumor boards who make off-label recommendations.
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