When is crossover desirable in cancer drug trials and when is it problematic?
Authors: A. Haslam, V. Prasad
Journal: Annals of Oncology (2018)

The use of crossover, as a design feature of randomized trials, is common, with reports indicating that up to 22% of all randomized controlled trials utilize this feature [1.Chan A.-W. Altman DG. Epidemiology and reporting of randomised trials published in PubMed journals.Lancet. 2005; 365: 1159-1162Abstract Full Text Full Text PDF PubMed Scopus (359) Google Scholar]. In cancer medicine, crossover typically refers to uni-directional crossover at the time of progression. Uni-directional: meaning that patients assigned to placebo are offered access to the investigation agent, but not vice versa (bi-directional). Crossover in cancer trials is typically specified by the protocol and occurs before any action taken by the monitoring committee. A positive trial may allow patients to crossover to the active drug after un-blinding, but this use of crossover is a prerequisite to ethical trial design and not the subject of this essay. Instead, we focus on situations where, at the outset and without knowing the trial results, crossover is or is not permitted. Although common, crossover is a confusing and controversial subject. The purported benefits to crossover are that it may make a trial more desirable to participants, aiding in recruitment, or, in certain situations, crossover is considered ethically desirable or necessary. However, elsewhere in the Journal, Chen and Prasad find that crossover trials do not accrue more patients per month [2.Chen E.Y. Prasad V. Crossover is not associated with faster trial accrual.Ann Oncol. 2018; 29: 776-777Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar]. The limitation to crossover is that it can confound end points that are measured after the crossover event, such as the second progression-free survival (PFS2) interval or overall survival (OS). For this reason, crossover has been the topic of several commentaries with varying opinions [3.Henshall C. Latimer N.R. Sansom L. Ward R.L. Treatment switching in cancer trials: issues and proposals.Int J Technol Assess Health Care. 2016; 32: 167-174Crossref PubMed Scopus (12) Google Scholar, 4.Prasad V. Double-crossed: why crossover in clinical trials may be distorting medical science.J Natl Compr Canc Netw. 2013; 11: 625-627Crossref PubMed Scopus (10) Google Scholar, 5.Prasad V. Grady C. The misguided ethics of crossover trials.Contemp Clinl Trials. 2014; 37: 167-169Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar]. Here, we offer a framework to think about crossover using contemporary clinical trial examples. In cancer medicine, crossover may or may not be desirable, depending on the circumstance, and may or may not occur, depending on the trial. In reality, there are errors of both kinds: crossover should have happened but did not, or should not have happened but did. Using Table 1, we wish to clarify these situations.Table 1An explanation of how crossover can occur or not occur, be desirable or problematic, or any combination of these twoCrossover occurredCrossover did not occurUncertainty as to whether crossover occurredCrossover is desirable: Situations in which the experimental drug has ALREADY proven benefit in a later line of therapy or is standard of care in the latter lineKEYNOTE-024 trial [6.Reck M. Rodríguez-Abreu D. Robinson A.G. et al.Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer.N Engl J Med. 2016; 375: 1823-1833Crossref PubMed Scopus (4661) Google Scholar] tested whether platinum doublet or PD-1 antibody was superior in the front line of NSCLC. As PD-1 antibody therapy had already been approved in the second line, the trial is essentially testing whether upfront administration is superior to current standard of care (as second line). In fact, crossover was permitted and 43.7% of control arm crossed over to pembrolizumab.In the LATITUDE trial [7.Fizazi K. Tran N. Fein L. et al.Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer.N Engl J Med. 2017; 377: 352-360Crossref PubMed Scopus (908) Google Scholar], 1199 patients with castrate sensitive metastatic prostate cancer were randomized to receive androgen-deprivation therapy, with or without abiraterone. Before this trial, standard of care was to administer abiraterone to these patients in a later line of therapy. As such, Prasad and Berger wrote 'we cannot be sure that the survival advantage of early treatment would still exist if control patients had fair access to this drug' [13.Prasad V. Berger V.W. Hard-Wired Bias: how even double-blind randomized controlled trials can be skewed from the start.Mayo Clin Proc. 2015; 90: 1171.Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar].The PACIFIC trial [9.Antonia S.J. Villegas A. Daniel D. et al.Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer.N Engl J Med. 2017; 377: 1919-1929Crossref PubMed Scopus (1659) Google Scholar] tested whether, for patients with stage III lung cancer, 12 months of Durvalumab improved PFS and OS. For patients whose disease recurs however, the trial does not specify whether and to what degree they receive PD-1 therapy. Given the trial was conducted at many global sites, one concern is control arm patients may not receive these drugs as they would in the USA. This would not affect the PFS estimate, but may affect OS.**DESIRABLE SITUATION****UNDESIRABLE SITUATION****UNDESIRABLE SITUATION**Crossover is problematic: Situations in which the fundamental efficacy of the experimental agent has not been established in any prior studyIn the randomized trial leading to regulatory approval of sipuleucel-T [9.Antonia S.J. Villegas A. Daniel D. et al.Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer.N Engl J Med. 2017; 377: 1919-1929Crossref PubMed Scopus (1659) Google Scholar], 225 patients were randomized to the vaccine or placebo. Patients who progressed were allowed to receive a similar drug as sipuleucel-T (a frozen salvage product). Disease progression and PFS were not improved, yet overall survival was. This led to the suggestion in an AHRQ report that sipuleucel-T exhibited efficacy not by improving outcomes but rather because crossover harmed the control group by delaying alternate effective therapy. In this case, fewer patients received docetaxel in the control arm and, on average, after a delay.In the CLEOPATRA study [11.Agency for Healthcare Research and Quality. Outcomes of sipuleucel-T therapy. https://www.ahrq.gov/sites/default/files/wysiwyg/research/findings/ta/comments/sipuleucel-t-herapy.pdf (8 November 2017, date last accessed).Google Scholar], patients with HER2-positive metastatic breast cancer were randomly assigned to receive trastuzumab and docetaxel, with or without the addition of pertuzumab. Crossover was not permitted before analysis of overall survival.Occasionally, published trials do not clearly specify if crossover did or did not occur [14.Fassnacht M. Berruti A. Baudin E. et al.Linsitinib (OSI-906) versus placebo for patients with locally advanced or metastatic adrenocortical carcinoma: a double-blind, randomised, phase 3 study.Lancet Oncol. 2015; 16: 426-435Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar].**UNDESIRABLE SITUATION****DESIRABLE SITUATION****UNDESIRABLE SITUATION** Open table in a new tab Crossover is desirable in settings where a drug has already proven benefit in a subsequent line of therapy and an attempt is being made to advance it to an earlier line. Such was the case in the KEYNOTE-024 trial, where patients with non-small-cell lung cancer (NSCLC) and high expression of PD-L1 received either pembrolizumab or a platinum-based chemotherapy in the front line [6.Reck M. Rodríguez-Abreu D. Robinson A.G. et al.Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer.N Engl J Med. 2016; 375: 1823-1833Crossref PubMed Scopus (4661) Google Scholar]. Before this study, PD-1 antibody therapy had shown improved overall survival over docetaxel in second line NSCLC, and had become standard of care. Thus, in KEYNOTE-24, participants were allowed to crossover to pembrolizumab, if they had disease progression. KEYNOTE asks the clinical relevant question: is there a survival advantage to administering PD-1 antibody therapy for these patients upfront versus giving the same drug as second line, as is current practice? The trial answered this question with a positive conclusion. Conversely, other studies have not provided the experimental drug in a later line, despite the fact that such agents represent global best practice or standard of care. In the LATITUDE trial [7.Fizazi K. Tran N. Fein L. et al.Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer.N Engl J Med. 2017; 377: 352-360Crossref PubMed Scopus (908) Google Scholar], patients with castrate sensitive prostate cancer received androgen-deprivation therapy with or without abiraterone acetate. The treatment led to an improvement in overall survival. However, trial participants did not receive abiraterone for progressive prostate cancer, as was standard of care in the USA and other nations. In response to LATITUDE, De Bono et al. write, 'the majority of men in the control groups in the STAMPEDE and LATITUDE trials died without exposure to abiraterone or enzalutamide. Thus, the drugs used in these control groups were inconsistent with current prevailing standards of care. This has implications for the conclusions of the trials…' [8.de Bono J. Eisenberger M. Sartor O. Abiraterone in metastatic prostate cancer.N Engl J Med. 2017; 377: 1694.Crossref PubMed Scopus (7) Google Scholar]. Finally, at other times, crossover is desirable, but it is unclear whether and to what extent it occurred. In a global trial of PD-1 antibody consolidation for patients with stage III NSCLC, a PFS benefit was shown, while overall survival remains immature [9.Antonia S.J. Villegas A. Daniel D. et al.Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer.N Engl J Med. 2017; 377: 1919-1929Crossref PubMed Scopus (1659) Google Scholar]. However, it is not reported how often patients in the control arm had access to PD-1 antibody therapy if their cancer recurred as metastatic disease. Knowledge of this fact is important, just as in KEYNOTE-024, where the clinically relevant question is whether consolidation is superior to receipt of the drug as current standard of care for metastatic disease. Crossover is problematic in trials that seek to establish the basic efficacy of a therapy (see Table 1). In a randomized trial of sipuleucel-T or placebo for metastatic prostate cancer [10.Higano C.S. Schellhammer P.F. Small E.J. et al.Integrated data from 2 randomized, double‐blind, placebo‐controlled, phase 3 trials of active cellular immunotherapy with sipuleucel‐T in advanced prostate cancer.Cancer. 2009; 115: 3670-3679Crossref PubMed Scopus (627) Google Scholar], patients who progressed were allowed a frozen version of the vaccine, though efficacy of this therapy was not established. This meant there were more patients in the control arm than the active therapy arm who did not receive docetaxel or received it after a delay. Docetaxel had already shown a survival benefit in this cancer. Response rate and PFS, end points not affected by crossover, were not improved by the therapy, while survival was. In this case, allowing crossover (72% for patients in the control arm of this study) resulted in ambiguity whether prolonged survival was because the treatment was truly effective or because of a delay in alternative and effective therapy for those in the control arm. This was noted in an Agency for Healthcare Research & Quality (AHRQ) report on sipuleucel-T [11.Agency for Healthcare Research and Quality. Outcomes of sipuleucel-T therapy. https://www.ahrq.gov/sites/default/files/wysiwyg/research/findings/ta/comments/sipuleucel-t-herapy.pdf (8 November 2017, date last accessed).Google Scholar]. Alternatively, in the CLEOPATRA trial [12.Swain S.M. Kim S.B. Cortés J. et al.Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study.Lancet Oncol. 2013; 14: 461-471Abstract Full Text Full Text PDF PubMed Scopus (656) Google Scholar], patients with HER2-positive metastatic breast cancer received trastuzumab and docetaxel with or without pertuzumab. Crossover was not permitted until overall survival was resulted, permitting for a clear measurement of therapeutic effect. Much of the difficulty in interpreting crossover studies arises from the fact that crossover can be desirable or undesirable, depending on the situation. Modern trials have had errors of both kinds: omission of crossover when it is needed, or inclusion when it is undesirable. Also, in some trials, the presence of or rate of crossover is not provided. Understanding these situations is invaluable for interpreting cancer clinical trials, and using crossover appropriately ensures clinical trials answer questions that impact clinical decisions. None declared.