Sufficiency of Single‐Arm Studies to Support Registration of Targeted Agents in Molecularly Selected Patients with Cancer: Lessons from the Clinical Development of Crizotinib

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Abstract

Clinical development of crizotinib for the treatment of patients with advanced anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) paved the way for approval of molecularly targeted agents by showing that single-arm clinical trials supported by appropriate statistical analyses could be sufficient for regulatory approval in patients with cancer with high unmet medical need and/or rare tumor types, provided the scientific rationale for patient selection is strong and the agent has shown substantial and durable antitumor activity with a favorable safety profile. A major goal of any clinical development program is to implement the most efficient clinical trials that demonstrate the clinical benefit of a new drug, while limiting the number of patients who may be exposed to a treatment with limited effectiveness and/or tolerability. Traditionally, in oncology drug development, in order to achieve this goal and gain regulatory approval of a new drug, sponsors had to first establish short-term safety and antitumor activity in phase I and II clinical trials that could last up to 5 years. Sponsors then had to demonstrate efficacy benefits vs. an active comparator and further characterize the safety profile in randomized controlled phase III studies of cancer patients who were often phenotype-selected rather than genotype-selected. In order to demonstrate a statistically significant and clinically meaningful benefit of one therapy over another, these trials generally enrolled large numbers of patients and lasted 3−5 years or more. Thus, this standard process typically led to a protracted period of upwards of 10 years or more between drug discovery and regulatory approval.1, 2 As the dynamics of oncology drug development are changing with increasing demand for reduced time to drug approval and demonstration of greater clinical benefits, while exposing smaller numbers of patients to potentially toxic agents, the traditional drug development paradigm may benefit from adaptation to the modern era. With a transition from conventional chemotherapy to molecularly targeted agents (MTAs), drugs are now being developed faster for prospectively identified patients whose tumors bear the relevant molecular signatures. Smaller single-arm clinical trials may be sufficient for regulatory approval in the molecularly selected patient population because the treatment effect of an MTA is expected to be much larger than that observed with conventional nonselective agents. In addition, with these new MTAs, there may be situations in which conducting a large randomized phase III clinical trial to gain regulatory approval is impractical or even unnecessary. For example, single-arm clinical trials may be acceptable in situations in which there is a particularly acute medical need (e.g., refractory or resistant patient population) and/or the tumor under treatment is rare. However, clinical trials of MTAs may still be drawn out because a large number of patients may need to be screened to identify and select a small subset of patients with the appropriate molecular signature. Furthermore, the clinical development program may also need to address the requirements for a companion diagnostic test for molecular patient selection in order to secure regulatory approval of the MTA. The MTA crizotinib (Xalkori, Pfizer, New York, NY) is a potent, selective, small-molecule competitive inhibitor of ALK, MET, and ROS13-5 that initially received accelerated approval for the treatment of ALK-positive advanced NSCLC from the US Food and Drug Administration (FDA). Full approvals were subsequently achieved in many countries globally on the basis of results obtained from single-arm phase I and II clinical trials. Herein, we present aspects of the regulatory approval process based on outcomes from single-arm studies. We propose that prospective single-arm clinical trial(s) could be sufficient for the future registration of MTA monotherapies for rare tumors, provided that these agents show rapid, durable, and clinically meaningful activity, preferably together with positive health-related quality of life (HRQOL) and favorable (or at least acceptable) tolerability. As illustrated with crizotinib, new MTAs will also need to demonstrate these findings in a prospective clinical trial of a properly selected patient population based on strong biological rationale, possibly with an appropriate companion diagnostic test. Crizotinib, identified in 2005, was originally synthesized as an MET inhibitor6 and subsequently found to inhibit phosphorylation of NPM-ALK in both Karpas 299 and SU-DHL-1 anaplastic large-cell lymphoma (ALCL) cells.3 The EML4-ALK translocation in NSCLC was discovered in 2007. Commercially available break-apart fluorescence in situ hybridization (FISH) probes for detecting ALK gene rearrangement in anaplastic large-cell lymphoma were then modified to detect the rearrangement in NSCLC.7 This assay and the subsequently developed Vysis fluorescence in situ hybridization test (Abbott Molecular, Abbott Park, IL) enabled patients with ALK-positive NSCLC to be identified for enrollment in crizotinib clinical trials. Modifying an existing assay helped to accelerate development and registration in this specific patient population (Supplementary Figure S1). Accelerated approval by the FDA was achieved in 2011 for the treatment of patients with locally advanced or metastatic ALK-positive NSCLC9 − approximately 4 years after the initial discovery of ALK gene rearrangements in NSCLC and 6 years after the initial discovery of crizotinib. This was based on data from ongoing phase I (PROFILE 1001; NCT00585195) and phase II (PROFILE 1005; NCT00932451) clinical trials in patients with ALK-positive NSCLC. These studies indicated that crizotinib was associated with high objective response rates (ORRs), rapid and durable responses, and a generally tolerable safety profile. At the time of the accelerated approval, two randomized phase III trials were ongoing. Full approval was granted in 2013 by the FDA after the availability of efficacy and safety results from one of these trials (PROFILE 1007; NCT00932893), comparing crizotinib to standard-of-care second-line chemotherapy.9-11 In addition to the United States, crizotinib received conditional approval in the European Union for the treatment of adults with previously treated advanced ALK-positive NSCLC in late 2012 and has since received regulatory approvals in more than 80 other countries. The FDA accelerated approval of crizotinib occurred at the same time as the approval of the companion diagnostic test for ALK gene rearrangement in NSCLC. In all markets, commercial availability of a locally registered ALK assay was required before approval of crizotinib. PROFILE 1001 is a first-in-human, single-arm, phase I clinical trial of crizotinib (Table 1) that originally had two parts7, 12, 14: Part one recruited patients with a variety of advanced solid tumors refractory to standard therapy in order to establish the maximum tolerated dose (MTD) of crizotinib; and part two evaluated the safety and antitumor activity of the maximum tolerated dose, initially among patients screened for tumors that harbored MET amplifications6 and, after discovery of ALK gene rearrangements in NSCLC in 2007, among patients with ALK-positive NSCLC. Emerging data suggested that ALK gene rearrangements were relatively rare (∼3−5% of patients with NSCLC),15, 16 and patients with this genetic event had clinicopathologic characteristics distinct from unselected patients with NSCLC,17 being generally younger never-smokers with tumors having a histology of adenocarcinoma.6, 18 Facilitated by the availability of an ALK test and initial evidence of crizotinib activity in patients with ALK-rearranged NSCLC in part two of PROFILE 1001, an intensive effort began among the clinical sites to screen for this genomic rearrangement. A separate cohort of patients with ALK-positive NSCLC across all lines of standard therapy was consequently added to PROFILE 1001 in 2008.7 In this clinical trial, patients’ baseline demographic and disease characteristics were reflective of the distinct clinicopathologic features that were previously described (Table 2). For the heavily pretreated patients with ALK-positive advanced NSCLC in this trial (median two to three prior systemic therapies), antitumor activity for crizotinib (250 mg twice daily continuously) was found to be consistent as the number of patients enrolled increased: ORR was nearly 60% from the first report based on 19 patients in 2009.14 At the first analysis of progression-free survival (PFS; n = 82), the median had not been reached7; at a later analysis (n = 149), the median PFS was approximately 10 months (95% confidence interval [CI] = 8–13)12 (Table 3). Crizotinib was also well tolerated, and most treatment-related adverse events were grade 1 or 2 in severity. The most common adverse events were vision disorder, nausea, diarrhea, constipation, vomiting, and peripheral edema.12 Based on early results of PROFILE 1001, a single-arm phase II study was initiated in 2010 (PROFILE 1005; Table 1).13 This study evaluated the antitumor activity and safety of crizotinib (250 mg twice daily continuously) in patients with ALK-positive advanced NSCLC whose disease progressed after one or more chemotherapy regimens for locally advanced/metastatic disease. Initial FDA approval of crizotinib in 2011 was primarily based on an ORR of 51%, a median duration of response of 41.9 weeks, and a generally tolerable safety profile from the first 136 patients enrolled in PROFILE 1005 as of February 2011,19 together with favorable efficacy and safety data from PROFILE 1001. Efficacy results from PROFILE 1005 (e.g., ORR; Table 3) were also found to be consistent at different reporting times.13, 19 In this study, treatment-related adverse events were similar to those observed in PROFILE 1001: They were mostly grade 1 or 2 in severity and included gastrointestinal (nausea, vomiting, and diarrhea) and ophthalmologic (visual impairment, photopsia, blurred vision, and vitreous floaters) events. Clinically meaningful improvements were also observed in key lung cancer symptoms, such as cough, pain in chest, and dyspnea, and in global HRQOL.13 PROFILE 1001 and PROFILE 1005 represented the first studies of any MTA in patients with NSCLC prospectively selected for a specific genetic event – in this case, ALK gene rearrangement. Although clinical trials of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib had taken place before PROFILE 1001 and PROFILE 1005, these studies were prospectively conducted in unselected patients with NSCLC, with retrospective analyses of patients with EGFR mutation-positive NSCLC.20-24 PROFILE 1001 and PROFILE 1005 were also notable because of the large clinical benefits observed, further supported by retrospective analyses described below, led to approval of crizotinib before the availability of randomized phase III study data. Consistently robust data from two global single-arm clinical trials were important for regulatory agencies at the time when making their benefit−risk assessments. Although the rapid clinical development and approval of crizotinib was successful, the development of this MTA was associated with unique challenges – not the least of which was the rarity of ALK-positive NSCLC. Additionally, historical data on typical end points (ORR, PFS, or overall survival [OS]) for other cancer therapies in this specific patient population were lacking. Data were also lacking on the natural history of ALK-positive NSCLC. As such, several questions arose regarding interpretation of the results, including in the absence of a comparator arm, how did the crizotinib data from these single-arm studies in ALK-positive NSCLC patients compare with data from standard therapies, and was the ALK gene rearrangement a predictor of clinical outcome with standard chemotherapies or TKI therapy? We addressed each of these questions using retrospective efficacy data analyses performed at different times during the drug development process, as described below. In the absence of comparative data, it was unclear whether the distinct clinicopathologic characteristics of patients with ALK-positive NSCLC noted above might be contributing to the observed antitumor activity of crizotinib. To put the efficacy results from PROFILE 1001 and PROFILE 1005 into perspective, covariate-matched and covariate-adjusted modeling analyses25, 26 were retrospectively performed to simulate outcomes of randomized controlled studies of crizotinib vs. standard advanced NSCLC treatment (Pfizer, data on file).27 These analyses utilized data from the control arms of three Pfizer-sponsored phase III studies evaluating first-line paclitaxel − carboplatin or gemcitabine − cisplatin and second-line or later-line erlotinib regimens in patients with advanced unselected NSCLC.28-30 In the covariate-matched analyses (Pfizer, data on file),27 the efficacy outcomes of patients with ALK-positive advanced NSCLC in PROFILE 1001 and PROFILE 1005 were compared with those from patients with similar baseline characteristics in the control arms of the three aforementioned phase III studies.28-30 Baseline characteristics for matching, based on the known clinicopathologic characteristics of patients with ALK-positive disease and potential predictors of outcome, included histology, race, smoking classification, and age. The covariate-adjusted modeling analyses (Pfizer, data on file)27 were performed to retrospectively “predict” the antitumor efficacy of patients with advanced ALK-positive NSCLC in PROFILE 1001 and PROFILE 1005 as if they had received one of the treatment regimens from the control arms of the phase III studies described above,28-30 and then compare them with the efficacy outcomes of patients in PROFILE 1001 and PROFILE 1005. A logistic regression model was used to The model was used to PFS and Baseline characteristics for this in addition to those used in the covariate-matched included disease and In PROFILE 1001, the observed ORR in patients treated with crizotinib = the from control patients in the covariate-matched analyses of for patients paclitaxel − carboplatin or gemcitabine − and for patients Figure 1 and Table in the covariate-adjusted for the control treatment regimens described above were than that observed with crizotinib in PROFILE 1001 as by ORR The median PFS for patients in PROFILE 1001 was months (95% = across all lines of In covariate-matched and median PFS for historical first-line treatment between and months for paclitaxel − carboplatin or gemcitabine − and and months for erlotinib (Table In addition, PFS for crizotinib vs. any of the three control regimens in the covariate-matched or covariate-adjusted analyses from to (Table Although for patients was still and the median was not at the time of PROFILE 1001 the for crizotinib compared with any of the three standard-of-care regimens were similar for the covariate-adjusted and covariate-matched analyses and between and (Table findings for PFS, and were observed with PROFILE 1005 data 2 and Table Pfizer, data on of patients with rare tumors – such as ALK-positive NSCLC – present in of conducting clinical trials. European in such it is appropriate to a time to tumor in which on the last prior therapy is compared with on and be and PFS analyses were performed in patients with ALK-positive NSCLC in PROFILE 1005 (Pfizer, data on A analysis compared the outcomes of patients who received second-line or regimens for second-line treatment of before into PROFILE 1005 with those of patients who received second-line crizotinib in that A compared the outcomes of the same patients who received second-line or before enrollment in PROFILE 1005 with their outcomes to or treatment with crizotinib in this In both the median with therapy was months (95% = The median PFS with crizotinib therapy was not (95% = in the analysis and was months (95% = in the for crizotinib vs. for baseline were (95% = and (95% = (Table 3). these retrospective analyses in the ALK-positive NSCLC population suggested that treatment with crizotinib in the second-line treatment to PFS times compared with standard second-line or a that was later in a randomized phase III trial, as below. At the time that PROFILE 1001 and PROFILE 1005 were there were data on the potential clinical benefit of standard therapy regimens for patients with ALK-positive NSCLC. In the absence of comparative clinical on prior systemic therapies for patients with advanced ALK-positive NSCLC subsequently treated in PROFILE 1001 or PROFILE 1005 were compared with from historical data in unselected patients with advanced NSCLC (Table The findings that on standard chemotherapy and EGFR in patients with ALK-positive NSCLC were to those in patients with unselected NSCLC (Table suggested that ALK-positive is not a response predictor for standard chemotherapy regimens or TKI found that ALK gene rearrangement did not to be a of clinical outcome because was similar between patients with ALK-positive tumors and patients with tumors that were for ALK and retrospective small patient suggested that may be more as a agent or in with chemotherapy in patients with advanced ALK-positive to these large retrospective analyses that evaluated ORR and with chemotherapy in patients with ALK-positive NSCLC before crizotinib in PROFILE 1005 much smaller that were consistent with those for patients with unselected NSCLC 3). This further supported the that ALK-positive was not to be a predictor of clinical outcome for that was later in the randomized phase III trial below, the ORR for patients treated with was than expected in this of PROFILE also that the interpretation of results from the single-arm phase I and II studies associated retrospective efficacy analyses results was outcomes of PROFILE supported the by to approval of crizotinib based on the data from single-arm clinical trials. These results from PROFILE supported the of accelerated approval of crizotinib to approval in the United Based on we that consistent evidence of and durable antitumor activity with a favorable safety profile from prospective single-arm clinical trial(s) could be sufficient for approval of MTAs for rare tumors, for tumors that the in the large of or for prospectively molecularly selected patients with common advanced tumors provided there is high unmet medical an approval process accelerated patient to new treatment studies a number of benefits, including a for smaller numbers of patients and generally study duration than randomized clinical still a of clinical In the of crizotinib, the time from the discovery of ALK-positive NSCLC to initial regulatory approvals was approximately 4 years. with ALK-positive NSCLC were to gain to this MTA much than been the had a traditional drug development been Accelerated approval of crizotinib in the United the European and approval in other was granted based on the rapid and durable and clinically meaningful in prospective single-arm phase I and II clinical trials in prospectively selected patients with ALK-positive NSCLC. These approvals of crizotinib were also based on the evidence that the observed results were a antitumor effect of crizotinib based on strong scientific rationale and observed Additionally, for an MTA to be based on single-arm clinical the drug show at least an acceptable safety preferably with positive on quality of life as In the of crizotinib, the generally favorable safety profile that early in development was by later studies and after of 12, A safety of patients from PROFILE 1001 and 136 from PROFILE was sufficient for crizotinib in the this could for other agents on such as the rarity of the disease or and the of the treatment Crizotinib also positive on in PROFILE which were later an active control in PROFILE Although data are not for approval based on single-arm clinical they data to efficacy and safety assessments. For in which patient selection is a large of patients not the genetic event of the development of a companion diagnostic test is key to patients most to In the of crizotinib, the early availability of a companion diagnostic test enabled patients to be more and potentially more selected for enrollment in the clinical trial the development for this MTA. analyses may be important to standard analyses of data from single-arm studies. For example, with crizotinib, there were unique challenges in the interpretation of findings from the early clinical including the of comparative historical data for other therapies in the population of patients with ALK-positive NSCLC. However, not all of the analyses for crizotinib may be for future approval of could prospectively prior of patients enrolled in the single-arm clinical trials or comparing data from single-arm clinical trials with those from historical studies. However, it is important to show that having the molecular of is not of clinical outcome with standard therapy and not a Additionally, not on the to regulatory approval, activity of new MTAs in patients with disease be In the of crizotinib, of patients with prospectively identified NSCLC is The randomized phase III clinical trial PROFILE the efficacy and safety of consistent with findings from the single-arm phase I and II studies in patients with ALK-positive NSCLC, including with the retrospective efficacy analyses retrospective statistical analyses the efficacy outcomes of PROFILE this study, in also the retrospective statistical the that results from single-arm clinical trials may be sufficient for the regulatory approval of MTA In PROFILE 1001, patients with ALK-positive NSCLC were enrolled in the study of treatment In PROFILE 1005, patients with second-line or later-line NSCLC were Although there were a small number of patients with NSCLC enrolled in PROFILE 1001, it was to that the of the ORR results of treatment may well been sufficient for crizotinib to gain a across treatment the was supported by the results of the ongoing randomized phase III study PROFILE that significant in PFS for crizotinib vs. standard-of-care chemotherapy in the first-line treatment of patients with locally advanced or metastatic ALK-positive Traditionally, the end in any cancer clinical development program has been As described the approval of crizotinib approval in approval in was based on objective response and duration of rather than on However, it be noted that with crizotinib were rapid and durable, were clinically and the outcomes were by the biological rationale for the MTA and selected patient Furthermore, consistent with the ORR data, crizotinib also meaningful improvements in for the potential of ORR as a end for single-arm clinical trials of MTAs was provided in a of studies of advanced NSCLC to the FDA since of which MTAs in molecularly selected patient In this a strong was found between ORR and PFS, between ORR and or PFS and were potentially because of and survival after disease in the studies of MTAs in molecularly selected patient The of regulatory approvals based on single-arm studies began in when received FDA approval based on the results of single-arm A the high response observed with crizotinib in PROFILE 1001 led to the that one single-arm clinical trial could be sufficient for early approval of the way for even times to approval of other This to with the ALK which received accelerated approval in the United years after of one single-arm study in patients with or ALK-positive metastatic the ALK was in than 4 years after of one single-arm study in ALK patients with advanced ALK-rearranged A of an accelerated is that approval may a of the of an as in the of which was originally in 2012 based on results of a single-arm in this and single-arm clinical trial, high rates of first to of in by with a in this to be an accelerated approvals of cancer drugs by the FDA between 2011 and early were based on single-arm clinical trials targeted or molecularly selected patient and 4 unselected patient these conditional of requirements and to approval has as of been achieved for crizotinib. The of the MTAs for the treatment of patients with cancer described above has led of the the cancer and cancer and treatment to propose a of for whether a single-arm study is robust to traditional These the of being supported by a strong scientific the treatment being for a patient the demonstration of substantial durable tumor those of available and a favorable benefit−risk of on clinical trial data were also included the of ORR as a for clinical which be in randomized and the need to identify a comparative data for as a historical Additionally, a of whether adverse events are to the into the or other will be The studies and retrospective statistical analyses that supported accelerated approval of crizotinib, as described to these and addressed the a study of their they the of prospective single-arm studies for approval of MTAs, the need for randomized controlled trials under these was provided by and at York, and an and was by and are of and and and/or of and Data analysis and and and approval of and been not The is not for the or of any by the than be to the for the

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