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Romidepsin Therapy Over 5 Years in a Clinical Setting-Real-world Experience.

This issue of JAMA Oncology reports a strategy for managing romidepsin therapy in patients with cutaneous T-cell lymphoma (CTCL), asking, what should we do to maintain remission? Cutaneous T-cell lymphoma has long been managed as a chronic disease—and patients are treated for life. MartinezEscala and colleagues1 suggest an approach taken in the management of patients with CTCL treated with romidepsin at Northwestern University over a 5-year span. The approval of romidepsin by the US Food and Drug Administration (FDA) for CTCL in 2009 was based on 2 phase 2 trials with similar results, 1 conducted at the National Cancer Institute (NCI) and the other by Gloucester Pharmaceuticals.2,3 Both observed an overall response rate of 34% with median durations of 13.7 and 15 months, respectively. Now, in a retrospective review of medical records of CTCL patients who received romidepsin between 2010 and 2015, we get a glimpse of romidepsin real-world use.1 Among 47 patients, including 9 with atypical CTCL, an overall response rate (ORR) of 53% was noted, including 7 (15%) complete remissions (CRs) and 18 partial remissions. Among the 38 patients with classical mycosis fungoides or Sézary syndrome, a 61% ORR was observed. These response rates are noteworthy—exceeding that in the 2 phase 2 studies, with almost 3 times as many complete remissions; the duration of response exceeded 1 year. Some may take exception to the retrospective, observational nature of this report. But I would note that a 47-patient single-institution observational study in a rare disease over 5 years likely represents the majority of patients who could be candidates for this therapy—without much selection. Furthermore, this real-world experience included a patient population that was equally if not more challenging than those enrolled in the trials that made up the FDA submission. With a median age of 64 years (vs 59 years for the NCI trial and 57 for the pivotal trial, respectively), a median of 4 prior therapies (vs 3 and 4), and stage IIB or greater in 89% (vs 88% and 71%), it is hard to detect bias.1-3 Now, one may argue that a “complete remission” might not be so rigorously defined in a retrospective setting, and a handful of patients did receive light or radiation therapy as an adjunct (Figure in Martinez-Escala et al1). But 17 patients received romidepsin for more than 6 months, and for a median of 15 months (7-34 months), clearly establishing the value of this therapy. Because multiple topical therapies are standard for CTCL, it will be important to learn whether and which skin-directed strategies combine well with romidepsin as part of multimodality management. Clinical trials conducted after FDA approval are typically designed to either (1) expand the indication or (2) meet regulatory requirements. They are not designed to see how an agent fares in the real-world setting, where patients often have more advanced disease, or more comorbidities than seen on clinical trials. Japan has an active postmarketing all-patient surveillance requirement following each drug approval, in which the toxicity and efficacy must be tracked in a predetermined number of patients. This type of effectiveness research is likely to emerge as an area of research of increasing importance in the coming years.4 Indeed, therapeutic benefit in clinical trials, termed “efficacy,” has been distinguished from that due to treatment in daily practice, termed “effectiveness.” The romidepsin results are especially noteworthy because many newly approved drugs encounter inferior results in the postmarketing setting: fewer responses, more toxicity, or reduced dosing. Notable examples include (1) sunitinib for renal cell cancer, with a 31% pivotal trial ORR, vs a 16% expanded access study ORR5; (2) lenalidomide for multiple myeloma, which was discontinued for rash in 3% or less of patients in a clinical trial vs 28.7% in a Global Drug Safety database6; and (3) sorafenib for hepatocellular cancer, which was administered at half the approved dose in a real-world setting.7 The investigators reported their approach to maintaining the responses. Patients in response who had received romidepsin for 6 months could be switched from day 1, 8, and 15 dosing to every other week dosing (6 patients) or once per month (3 patients).1 The duration of treatment in these patients ranged from 12 to 34 months. This strategy is a different approach from that taken in the NCI study, in which patients were given treatment breaks after remission. In some cases retreatment was required only after years-long intervals.2 These 2 approaches reflect different and incomplete understanding of CTCL biologic features and response. Breaks imply that disease has been reduced to a minimum, with perhaps an epigenetic effect. Maintenance therapy implies that CTCL is an indolent disease requiring long-term suppression. Prospective testing, an understanding of the genesis of CTCL, and a better understanding of romidepsin’s mechanism of action will be required to distinguish these. Here we must state the obvious. This was a small study. Cutaneous T-cell lymphoma is a rare disease. But bigger is not always better. In discussing effectiveness studies, Sargent writes, “In the presence of bias, large sample sizes are of little benefit, and in fact may only make us more confident in the ‘wrong’ answer.”4(p22) If larger is not always better, perhaps a retrospective study design is not always flawed. One could argue that in some settings the FDA and the European Medicines Agency might want to consider observational effectiveness data from postmarketing real-world surveillance. Given the complexity of the weekly 4-hour intravenous infusions, the uptake of romidepsin in the oncology community after its approval by the FDA remained uncertain. A novel Related article Romidepsin and Real-World Experience Invited Commentary