Table 1.

An explanation of how crossover can occur or not occur, be desirable or problematic, or any combination of these two

	Crossover occurred	Crossover did not occur	Uncertainty as to whether crossover occurred
Crossover 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 line	KEYNOTE-024 trial [6] 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], 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].	The PACIFIC trial [9] 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 study	In the randomized trial leading to regulatory approval of sipuleucel-T [9], 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], 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].
	**UNDESIRABLE SITUATION**	**DESIRABLE SITUATION**	**UNDESIRABLE SITUATION**