When are randomized controlled trials needed to assess novel anticancer drugs? An illustration based on the development of selpercatinib, a RET inhibitor
Authors: J. Gill, V. Prasad
Journal: Annals of Oncology (2020)

A debate persists in medicine: are randomized controlled trials (RCTs) always necessary to demonstrate efficacy? In oncology, this discussion arises when new drugs demonstrate impressive preliminary results from early phase, single-arm trials. While RCTs minimize bias and confounding factors and are important in determining clinical efficacy, opponents contend that for novel drugs with remarkable single-agent activity, RCTs are unnecessary, perhaps even unethical. This editorial offers steps to resolve this dispute. To determine whether an RCT is necessary for a specific oncology drug, one must first establish when RCTs are appropriate in medicine generally, and then review available data to determine the following. (i) Does the current preliminary evidence of efficacy predict clinically meaningful outcomes? (ii) How do the preliminary results compare to results of alternative therapies? As an example, we will determine whether an emerging cancer drug, selpercatinib, should be investigated in an RCT. On 9 September 2019, Eli Lilly and Company announced that selpercatinib, a RET inhibitor, demonstrated a 68% overall response rate (ORR) among heavily pretreated, RET fusion-positive patients with non-small-cell lung cancer (NSCLC) in the LIBRETTO-001 Phase I/II trial.1Lilly Announces Positive Results for Selpercatinib (LOXO-292), Demonstrating a 68 Percent Objective Response Rate and Sustained Durability in Heavily Pretreated RET Fusion-Positive Non-Small Cell Lung Cancer.https://investor.lilly.com/news-releases/news-release-details/lilly-announces-positive-results-selpercatinib-loxo-292Date: 2019Google Scholar Median duration of response was 20.3 months and median progression-free survival (PFS) was 18.3 months among 105 patients.1Lilly Announces Positive Results for Selpercatinib (LOXO-292), Demonstrating a 68 Percent Objective Response Rate and Sustained Durability in Heavily Pretreated RET Fusion-Positive Non-Small Cell Lung Cancer.https://investor.lilly.com/news-releases/news-release-details/lilly-announces-positive-results-selpercatinib-loxo-292Date: 2019Google Scholar The sponsors announced that an RCT in the frontline would test selpercatinib against chemotherapy for patients with RET fusion NSCLC. Some have questioned this randomized study. Is selpercatinib so transformative that an RCT would be inappropriate? We begin answering this question by reflecting on the role of RCTs in medical research. RCTs are ideal tools for investigating interventions predicted to have modest to marginal effect sizes. This excludes medical practices that are so obviously beneficial that it would be ridiculous to subject them to an RCT. A parachute, for instance, has such a high likelihood of preventing death when jumping from an airplane (99.999%)2Hayes M.J. Kaestner V. Mailankody S. Prasad V. Most medical practices are not parachutes: a citation analysis of practices felt by biomedical authors to be analogous to parachutes.CMAJ Open. 2018; 6: E31-E38Crossref PubMed Scopus (22) Google Scholar that there is no need to test this through randomization, and it would be unethical to do so. Unfortunately, most interventions do not offer parachute-sized benefits. An analysis by Perrera et al.3Pereira T.V. Horwitz R.I. Ioannidis J.P. Empirical evaluation of very large treatment effects of medical interventions.JAMA. 2012; 308: 1676-1684Crossref PubMed Scopus (168) Google Scholar found, in the entire Cochrane database, that only one intervention out of 80 000 had a large treatment effect on all-cause mortality.2Hayes M.J. Kaestner V. Mailankody S. Prasad V. Most medical practices are not parachutes: a citation analysis of practices felt by biomedical authors to be analogous to parachutes.CMAJ Open. 2018; 6: E31-E38Crossref PubMed Scopus (22) Google Scholar Even practices that have been touted 'parachutes' by medical providers are often exaggerated and only carry modest to marginal effect sizes.2Hayes M.J. Kaestner V. Mailankody S. Prasad V. Most medical practices are not parachutes: a citation analysis of practices felt by biomedical authors to be analogous to parachutes.CMAJ Open. 2018; 6: E31-E38Crossref PubMed Scopus (22) Google Scholar The general principle holds that randomization is needed for interventions with modest or marginal effect sizes, but not those with large effect sizes. With so few parachutes in biomedicine, randomization should be the rule with few exceptions. Prior interventions that many believed improved outcomes were later found to be lacking in randomized studies. The CAST trial, for instance, investigated antiarrhythmic drugs prescribed for premature ventricular contractions after myocardial infarction.4Echt D.S. Liebson P.R. Mitchell L.B. et al.Mortality and morbidity in patients receiving encainide, flecainide, or placebo.N Engl J Med. 1991; 324: 781-788Crossref PubMed Scopus (2662) Google Scholar Many thought the trial was unethical because these antiarrhythmic drugs were lifesaving. Some physicians refused to randomize their patients for fear they would receive placebo. CAST found that these commonly used drugs (encainide and flecainide) led to excess mortality and the trial was halted.4Echt D.S. Liebson P.R. Mitchell L.B. et al.Mortality and morbidity in patients receiving encainide, flecainide, or placebo.N Engl J Med. 1991; 324: 781-788Crossref PubMed Scopus (2662) Google Scholar The lesson is to be cautious of hailing promising treatments as parachutes and to require a high standard for this declaration. After establishing when RCTs are appropriate in general, we can review the current data on selpercatinib that has led to criticism of the ongoing RCT. LIBRETTO-001 measured ORR, duration of response (DOR), and PFS for NSCLC patients receiving selpercatinib. These measures are surrogate end points for overall survival (OS), a true patient-centered end point. In a 2006 surrogate validation study evaluating end points from 191 trials on lung cancer, the coefficient of determination (r2) between ORR and OS was 0.16, denoting that only 16% of variability in the change in OS is explained by change in ORR.5Johnson K.R. Ringland C. Stokes B.J. et al.Response rate or time to progression as predictors of survival in trials of metastatic colorectal cancer or non-small-cell lung cancer: a meta-analysis.Lancet Oncol. 2006; 7: 741-746Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar The correlation of PFS and OS was similar with r2 = 0.19. A more recent surrogate validation study of NSCLC by the US Food and Drug Administration (FDA) found that correlations between ORR and OS, and PFS and OS were even lower (r2 = 0.09 and r2 = 0.08, respectively).6Blumenthal G.M. Karuri S.W. Zhang H. et al.Overall response rate, progression-free survival, and overall survival with targeted and standard therapies in advanced non–small-cell lung cancer: US Food and Drug Administration trial-level and patient-level analyses.J Clin Oncol. 2015; 33: 1008-1014Crossref PubMed Scopus (150) Google Scholar Currently, data available for selpercatinib are regarding surrogate end points that have poor correlation with subsequent OS gains. If the only data available are on surrogate outcomes with poor correlations to OS, then the data must be so superior to current outcomes that there leaves little doubt of efficacy. Selpercatinib, with an ORR of 68% and a median PFS of 18.3 months, shows promise, but is it exceptional enough to discourage conducting an RCT? Let us consider the response of the population receiving standard treatment of RET fusion-positive NSCLC. A 2016 retrospective review found that patients with RET-rearranged lung cancers receiving pemetrexed-based therapies had an ORR of 45% (5/11) and a median PFS of 19 months (n = 18).7Drilon A. Bergagnini I. Delasos L. et al.Clinical outcomes with pemetrexed-based systemic therapies in RET-rearranged lung cancers.Ann Oncol. 2016; 27: 1286-1291Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar Therefore, ORR and PFS from chemotherapy are similar to selpercatinib. One cannot formulate strong conclusions of comparative efficacy in comparing these datasets, but the side-by-side results help to rule out the idea that selpercatinib is a 'parachute' drug. Median ORR was 45% versus 68% and median PFS was 19 months versus 18.3 months when comparing chemotherapy with selpercatinib. While promising, selpercatinib does not clearly improve survival for RET fusion-positive NSCLC patients as a parachute would. As a comparison, let us review the groundbreaking imatinib in chronic myelogenous leukemia (CML). In 2001, a phase I study found that 53 of 54 CML patients (98%) treated with 300+ mg of imatinib experienced complete hematologic responses, which were maintained by 51 patients for a median of 265 days.8Druker B.J. Talpaz M. Resta D.J. et al.Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia.N Engl J Med. 2001; 344: 1031-1037Crossref PubMed Scopus (4445) Google Scholar Such exceptional responses are rare in oncology, and imatinib was lauded as a revolutionary drug. It was granted accelerated approval in 2.5 months, the fastest FDA approval to date. Imatinib ended up being a highly beneficial drug. Patients with CML now have life expectancy nearing that of the general population, when 30 years ago CML diagnosis meant up to 25 years of life lost.9Bower H. Björkholm M. Dickman P.W. Höglund M. Lambert P.C. Andersson T.M.-L. Life expectancy of patients with chronic myeloid leukemia approaches the life expectancy of the general population.J Clin Oncol. 2016; 34: 2851-2857Crossref PubMed Scopus (472) Google Scholar Still, compared with generally high hematologic responses of patients treated with interferon-alpha plus cytarabine (66%–92%), imatinib could not be deemed a parachute and multiple RCTs were conducted to determine survival benefit.10Hochhaus A. Larson R.A. Guilhot F. et al.Long-term outcomes of imatinib treatment for chronic myeloid leukemia.N Engl J Med. 2017; 376: 917-927Crossref PubMed Scopus (705) Google Scholar After reviewing current data on selpercatinib and comparing them with standard care in NSCLC, we have concluded that, while promising, the drug needs to be investigated in an RCT. As more oncology drugs are developed and clinically tested, many promising preliminary results will emerge. Excitement over treatments may drive oncologists to advocate for quick market approval and oppose randomizing patients to controls. Yet accepting single-arm studies without further investigation is a potentially detrimental path. Without RCTs, the efficacy, comparative effectiveness, and cost-effectiveness of a therapy cannot be known. A number of oncology drugs have already received regular FDA approval based on single-arm trials measuring response,11DeLoughery E.P. Prasad V. The US Food and Drug Administration's use of regular approval for cancer drugs based on single-arm studies: implications for subsequent evidence generation.Ann Oncol. 2018; 29: 527-529Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar leaving less incentive for manufacturers to perform post-marketing RCTs. Therefore, it is essential that leaders in oncology act as proponents for evidence-based medicine and make recommendations based on unbiased and logical processes.