Secondary Cancers Resurface In Updated Revlimid Maintenance Trial Data

Trial investigators proclaim the drug's benefits outweigh its risks and predict maintenance will become the standard of care in multiple myeloma, but investors remain unconvinced.

Celgene Corp.'s Revlimid (lenalidomide) has shown an overall survival benefit in a major study of maintenance treatment - an important achievement - but investors registered their concern by sending the big biotech's share price down more than 3% after the data were released at a multiple myeloma conference in Paris on Thursday, May 5.

Revlimid is currently approved for second-line treatment of multiple myeloma, but it is being positioned for first-line and maintenance settings and is already widely used in newly diagnosed patients in the U.S.

Celgene filed an application for newly diagnosed patients in Europe in December 2010 and plans to file in the U.S. in this segment in the second half of this year.

Updated data from three major randomized controlled trials for longer-term use of Revlimid were presented at the 13 annual International Myeloma Workshop on May 5 in Paris. Two of the studies, CALGB 100104 and IFM-0502, examined patients following stem cell transplant and the third, MM-015, was done in patients who had not undergone transplant.

The data confirmed higher rates of secondary malignancies for patients treated longer with Revlimid, compared to control groups, news that sent the company's stock price down by $2.10, nearly 3.5%, to $58.85. Despite the company's success in building a hematological oncology franchise in recent years, investors have been lukewarm about the stock, in particular since questions about secondary cancers in Revlimid patients surfaced in late 2010 at the American Society of Hematology meeting.

The ASH data confirmed a more than doubling of progression-free survival with extended use of Revlimid, but in all three studies there was a higher rate of secondary malignancies, ranging from 3% to 6.5%, compared to 1% to 2.6% for placebo.

All of the patients in the studies had received the alkylating agent melphalan at some point, and one theory has held the melphalan responsible for the higher rates.

After the ASH data release, the company's stock price dipped, despite payers noting that cancer drugs could be expected to have risks and some clinicians saying they were less concerned about risk of secondary malignancies if an overall survival benefit could be demonstrated (" (Also see "Revlimid In Limbo: Market Slams Celgene, Physicians And Payers Take Wait And See Approach" - Pink Sheet, 13 Dec, 2010.)).

Thursday's stock decline contrasts with Revlimid's blockbuster status, with sales of $738 million in the first quarter of 2011, up by 39% from the same time last year. In 2010, Celgene had sales of $2.6 billion, a figure that has been expected to rise to $8 billion in 2015, partly thanks to expanded use of Revlimid (Also see "Celgene Flexes Its Muscles" - In Vivo, 1 Mar, 2011.).

New Standard Of Care?

At a press conference held by the International Myeloma Foundation, leading clinicians said they supported maintenance treatment with Revlimid based on the latest data. Trial investigators predicted a paradigm change founded on evidence of significant benefits for longer-term treatment with Revlimid.

In the post-ASCT CALGB study of patients who received a variety of induction therapies, those in the treatment arm received continuous daily treatment with Revlimid until relapse. At a median follow-up of 28 months, there was a 90% overall survival rate for those on Revlimid compared to 83% on placebo, according to the study, which was backed by the National Cancer Institute.

Median time to progression was significantly higher at 48 months versus 30.9 months for placebo, equivalent to a 56% reduction in risk of disease progression for patients on Revlimid. Time to progression was longest in patients who had received Revlimid as an induction therapy and as a maintenance treatment.

All patients benefited from treatment regardless of the degree of completeness of their response to treatment, said CALGB investigator Kenneth Anderson of the Dana-Farber Cancer Institute at the meeting.

Anderson described the results as a "tremendous advance."

"This is an extraordinary benefit. We want patients to live longer without cancer but we obviously also want them to live longer in general.... This is a historic moment for the treatment of this disease," Anderson said.

As a well-tolerated oral agent that can be used for maintenance for many years, the drug will change the paradigm for treatment of patients, he predicted.

Secondary Cancer Rates

In the updated CALGB study, there were reports of 29 new cancers, including 7 that occurred prior to randomization. Of the rest, 8 of 231 on Revlimid developed blood cancers, versus none of the 229 patients on placebo. And 10 of 231 on Revlimid developed secondary solid cancers, versus only 4 of 229 for placebo.

However, Anderson concluded the benefits far outweigh the risks.

Speaking on behalf of the IMF study group, Mario Boccadoro of the University of Torino in Italy said that updated data from this study show a doubling of progression free survival. An overall survival benefit has not been shown yet but is expected, Boccadoro said.

Updated data were also released from the MM-015 study, which compared combinations of treatments: melphalan/prednisone; melphalan/prednisone/Revlimid; and melphalan/prednisone/Revlimid plus Revlimid maintenance. Secondary cancer rates respectively were 2.6% (4 cases); 5.9% (9 cases); and 8% (12 cases) for those on the MPR-R.

IMF Chairman Brian Durie suggested that the secondary malignancies seen in the Revlimid treatment arms were probably due to patients living longer.

Writing in a research note, JP Morgan analyst Geoff Meacham said the meeting has further de-risked the Street's two biggest fears: first-line EU approval and the risk of treatment duration limitation. But investors showed once again they're not ready to buy in, despite the optimism of analysts, doctors, and Celgene itself.

- Emily Hayes ([email protected])