BETHESDA, MdThe Oncologic Drugs Advisory Committee (ODAC) has recommended that the FDA approve Targretin capsules (bexarotene, Ligand Pharmaceuticals) for the treatment of advanced cutaneous T cell lymphoma (CTCL) but not for early stage CTCL.
The panel voted after reviewing two historically controlled studies presented by the company. One trial, a high- vs low-dose study, involved 58 patients with stage IA, IB, and IIA disease, 15 of whom received 650 mg/m²/d. The rest received 300 mg/m²/d. The committee decided that evidence from this study was insufficient to support Targretin as beneficial in early stage CTCL.
The second trial, an open-label, multicenter study, involved 94 advanced CTCL patients (stage IIB, III, IVA, and IVB) who were initially assigned to receive either 300 or 650 mg/m²/d. However, patients in the high-dose group were dropped to the lower dose because of dose-limiting toxicities, primarily hypertriglyceridemia and neutropenia.
CTCL is an uncommon disease. About 1,000 new cases, or 2.2% of all lymphomas, are diagnosed annually in the United States, and the estimated US prevalence is 16,000 to 20,000 cases, Francine M. Foss, MD, associate professor of hematologyoncology, New England Medical Center, Boston, told the panel.
The 10-year survival prognosis at diagnosis ranges from essentially 100% for very early stage disease to 41% for advanced stage disease. CTCL is incurable, except in a subset of early stage patients, but disease palliation provides significant benefit to patients even without a documented increase in survival, Dr. Foss said.
Primary efficacy assessments for the two studies were made by a physicians global assessment (PGA), a composite assessment (CA) of index lesion severity, and a primary endpoint classification (PEC) of responsea response on either PGA or CA. Secondary efficacy assessments included time to response, duration of response, and time to disease progression.
The trial protocols, in the view of the FDA staff, required very specific photographic supportglobal photographs (half-body fields, anterior and posterior)of the primary and secondary efficacy assessments. These were to be obtained at baseline and every 4 weeks during treatment and at the follow-up visit. This requirement became a major issue during the ODAC review.
The company presented data from the advanced CTCL study that showed a total response rate among the 94 patients of 50% and a complete response rate of 2%, as determined by PGA. According to the CA assessment, the total response rate was 35%, with a complete response rate of 6%.
The FDA analysis put the CA total response rate at 29% and accepted a complete response rate of 6%. But the review team refused to assess the PGA response rates because of a failure by the company to provide the required full-body photographs, said FDA medical officer Oluwole Odujinrin, MD. He noted that in some close-up photographs, lesions surrounding the healing index area seem to be worsening. Without the full-body photos, he added, the FDA could not confirm the PGA responses claimed by the company.
Speakers for the sponsor said that researchers had decided to use more tightly focused photographs during the study in order to document a better view of the extent and clearing of lesions.
Photographs validated one or both of the primary endpoints, said Richard C. Yocum, MD, Ligands senior medical director for clinical research. He added that it was never the intent of the study designs to rely on photographs as the primary means of determining response. According to Dr. Yocum, researchers in the two studies had a 95% compliance rate for the number of photos and that the FDA had been provided 6,142 pictures in support of the efficacy claims.
Ligand and the FDA review team generally agreed on the safety data in both studies. Among patients who received 300 mg/m²/d of Targretinthe dose regimen proposed for labelingthe most common adverse events were hyperlipidemia (79%), hypercholesterolemia (32%), headache (30%), hypothyroidism (29%), pruritus (25%), asthenia (20%), pain (18%), leukopenia and rash (17%), infection (13%), exfoliative dermatitis (10%), and diarrhea (7%).
During committee discussion, ODAC chair Richard L. Schilsky, MD, associate dean for clinical research, University of Chicago Medical Center, said the crux of the issue was whether patients benefited from Targretin. I think there is a general sense among all the parties involved that this agent has biological activity, he said.
However, several members expressed concern about whether benefit could be determined, given the high patient withdrawal rate as the result of adverse events30% in the early stage study and 35% in the late stage study.
These are not virgin patients from the point of view of treatment, said Derek Raghavan, MD, PhD, head of medical oncology, University of Southern California. I think the discontinuation rate for people who have already been through several lines of treatment is actually not that high.
The ODAC members advised the FDA to negotiate with Ligand to ensure that the company carry out a phase IV study if the agency grants the drug marketing approval and urged that, if approved, Targretin should be compared to another systemic therapy in a randomized clinical trial.