Are We Making Progress in Lung Cancer Using Progression-Free Survival as a Surrogate End Point?

Non–small-cell lung cancer (NSCLC) is the secondmost common cancer diagnosed in the United States and the leading cause of cancer-related mortality, with an estimated 221 200 newcases and 158 040deaths anticipated in2015.1Despite advances in treatment, 5-year survival remains lowat 16.8% across all patients, and only 2% in patients with stage 4 disease, indicating a need for novel therapies that affect survival. The identification of driver mutations in lung adenocarcinoma has dramatically changed the therapeutic landscape and improved treatment options for patients with advanced-stage disease, specifically, targeted options for patients with tumors that harbor mutations in the epidermal growth factor receptor (EGFR) gene or rearrangement in the anaplastic lymphoma kinase (ALK) gene. Whereas some targetedagentshavebeenapprovedon thebasisofdata fromrandomized phase 3 trials, theALK inhibitors crizotinib and ceritinibwere grantedpreliminary approval by theFoodandDrug Administration on the basis of early phase 1 data2,3; efficacy of crizotinibwas latervalidated in randomizedphase3 trials.4,5 In this issueof JAMAOncology, Lakdawallaandcolleagues6 discuss the incremental social value of providing early access to newNSCLC treatment on the basis of progression-free survival (PFS) alone. Their analysis finds that early access based on any PFS benefit produces an overall loss of greater than $170 000pernewly treatedpatient permonth,whereas granting access to drugs with PFS benefit between 1 and 3 months is more cost-effective. They also note that PFS benefit correlates with overall survival (OS) benefit in 71% of studies. Thisanalysis raises importantquestions regardingdrugapproval and treatment decisionmodels in the context of inherently limitedhealth care resources. Particularlywith regard to NSCLC, the analysis further raises questions of how to evaluate cost-benefit in the era of targeted therapy. In the Food and Drug Administration’s new drug approvalprocess, cost considerationsare taboo;approval isbased strictly on a thorough assessment of whether the protocolspecified primary end point wasmet, and PFS is increasingly common as a primary end point. At the same time, everincreasing costs of health care have long been the focus of nationwide attention and attempts at reform, begging the question, should such reform give greater weight to incremental social valueof access to treatment?Furthermore, givennet social value as a consideration, which parameters should be included in the value calculation? In the analysis presented by Lakdawalla and colleagues,6 indirect cost of treatment is considered, although not comprehensively; a more accurate picture may require a model with more detailed adjustment for net changes in overall treatment-related costs, such as differences inadverseevents,need for additional clinicvisits orhospitalizations due to therapy, and family member burden. Amore sophisticatedmodel, to consider treatment crossover as well as more detailed consideration of indirect costs, may be particularly important in the era of targeted therapy, given that (1) when purchase price alone is considered, tarRelated article page 196 Research Original Investigation Modeling Access DecisionsWith Surrogate End Points