Although the number of patients eligible for genome-driven treatment has increased over time, these drugs have helped a minority of patients with advanced cancer. To accelerate progress in precision oncology, novel trial designs of genomic therapies should be developed, and broad portfolios of drug development, including immunotherapeutic and cytotoxic approaches, should be pursued.

IMPORTANCE Approximately one-third of cancer drugs are approved based on response rate (RR)-the percentage of patients whose tumors shrink beyond an arbitrary thresholdtypically assessed in a single-arm study. OBJECTIVE To characterize RR end points used by the US Food and Drug Administration (FDA) for cancer drug approval. DESIGN, SETTING, AND PARTICIPANTS A retrospective review of FDA-approved drug indications in oncology from 2006 to 2018. EXPOSURES Data related to cancer type, line of therapy (first-line, second-line, or third-or-later-line treatment for advanced/metastatic disease), type of FDA approval pathway, trial design, sample size, and level of innovation were extracted. MAIN OUTCOMES AND MEASURES The primary outcome was the RR used as the basis for FDA approval. The secondary outcome was rate of complete response. RESULTS Eighty-five indications for 59 cancer drugs were identified, 32 (38%) received regular approval, and 53 (62%) were granted accelerated approval. Twenty-nine (55%) accelerated approvals were later converted to regular approval. Of these, 6 (21%) approvals showed overall survival benefit, 16 (55%) later established progression-free survival benefit, and 7 (24%) continued to use RR but gained regular approval. The median RR among the 85 indications was 41% (interquartile range [IQR], 27%-58%). Among them, 14 of 85 (16%) had an RR less than 20%, 28 of 85 (33%) had an RR less than 30%, and 40 of 85 (47%) had an RR less than 40%. The median complete RR for 81 participants was 6% (IQR, 2%-22%). The median sample size among studies leading to approval was 117 (IQR, 76-182; range, 18-1052 participants). Drugs with accelerated approval pending confirmatory data had lower RR compared with drugs that have completed most postmarketing efficacy requirements (median, 28%; IQR, 15%-50% vs median, 42%; IQR, 31%-58%; P = .02). CONCLUSIONS AND RELEVANCE Many cancer drugs approved on the basis of response rate offer numerically low or modest response rates. Most premarket studies accrue more than 100 patients. Some of these drugs could potentially be tested in premarket randomized clinical trials measuring directly end points that demonstrate clinical benefit.

Although prior studies have shown underuse of appropriate therapy in patients with hepatocellular carcinoma (HCC), no studies to date have assessed the prevalence and clinical impact of therapeutic delays among patients with HCC. The goal of this study was to characterize and identify factors associated with underuse and delays in treatment of these patients. A retrospective cohort study was conducted of patients with cirrhosis diagnosed with HCC at a large urban safety net hospital between January 2005 and June 2012. Dates for HCC diagnosis and any treatments were recorded. Univariate and multivariate analysis was used to determine factors associated with treatment underuse and delayed treatment, which was defined as time from diagnosis to treatment exceeding 3 months. The authors identified 267 treatment-eligible patients with HCC, of whom only 62% received HCC therapy. On multivariate analysis, tumor stage (odds ratio [OR], 0.48; 95% CI, 0.36–0.65), Child-Pugh class (OR, 0.49; 95% CI, 0.28–0.84), and black race (OR, 0.55; 95% CI, 0.31–0.99) were associated with lower rates of treatment use. The median time to treatment was 1.7 months, with 31% of patients experiencing delayed treatment. Delayed treatment was associated with the presence of ascites (hazard ratio [HR], 2.8; 95% CI, 1.3–6.1) and current treatment with transarterial chemoembolization (HR, 4.8; 95% CI, 1.8–12.5). After adjusting for tumor stage and Child-Pugh class, treatment underuse (HR, 0.33; 95% CI, 0.24–0.46) and delayed treatment (HR, 0.50; 95% CI, 0.30–0.84) were both associated with significantly worse survival. Results showed that, in addition to one-third of patients not receiving HCC-directed therapy, another 30% experienced significant therapeutic delays, leading to worse survival.

IMPORTANCE Surrogate end points in oncology trade the advantage of reducing the time needed to conduct clinical trials for the disadvantage of greater uncertainty regarding the treatment effect on patient-centered end points, such as overall survival (OS) and quality of life. OBJECTIVE To quantify the amount of time saved through the acceptance of surrogate end points, including response rate (RR) and progression-free survival (PFS). DESIGN, SETTING, AND PARTICIPANTS This retrospective study of US Food and Drug Administration (FDA) oncology approvals and their drug registration trials based on actual publication analyzed the original and updated clinical trials data that led to FDA-approved drug indications in oncology from 2006 to 2017 by using existing publications, conference abstracts, and package inserts from the FDA. Data related to cancer type, line of therapy (first-line, second-line, and third-or later-line treatment of advanced or metastatic disease), FDA approval type, end point basis for approval (RR, PFS, or OS/quality of life), sample size, accrual rate, and drug RR were extracted by March 23, 2018. All data were analyzed by July 13, 2018. MAIN OUTCOMES AND MEASURES The main outcome was the study duration needed to complete the primary end point analysis used for each drug indication approval. This was estimated from reported enrollment dates, analysis cutoff dates, time to response, median duration of response, median PFS, and median OS. RESULTS In total, 188 distinct indications among 107 cancer drugs were identified. The RR was more often used for FDA approval in subsequent lines of therapy (17 of 71 drug indications [24%] in first-line therapy vs 34 of 77 drug indications [44%] in second-line therapy vs 19 of 24 drug indications [79%] in third-or later-line therapy, P < .001). Study duration for PFS (median, 31 [range, 10-104] months) was similar to that for OS (median, 33 [range, 12-117] months; P = .31), whereas study duration for RR (median, 25 [range, 11-54] months) was shorter than that for OS (P = .001). In multivariate analysis, compared with using OS, use of PFS as the end point was associated with study durations that were shorter by a mean of 11 months (95% CI, 5-17 months), and the use of RR as the end point was associated with study durations that were shorter by a mean of 19 months (95% CI, 13-25 months). CONCLUSIONS AND RELEVANCE From the findings of this study, an estimated 11 months appeared to be needed (ie, approximately 12% longer in the drug development cycle) to assess the OS benefit of a cancer drug. This study's findings suggest that this must be weighed against the downside of increased uncertainty of clinical benefit arising from using surrogate end points.

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