Of the 260 posters and presentations offered up by Celgene Corp. researchers during this year's American Society of Hematology (ASH) meeting, the biggest buzz surrounded blockbuster multiple myeloma drug Revlimid's potential to expand from second-line into front-line and maintenance use.
Revlimid (lenalidomide) currently is approved for second-line multiple myeloma (MM) as well as for certain myelodysplastic syndromes. The immune modulator garnered $1.71 billion in 2009 and $1.76 billion in the first nine months of 2010. Analysts have predicted a front-line label could add $1 billion in mostly overseas sales, while a maintenance label would be worth $3 billion to $4 billion.
At the American Society of Clinical Oncology (ASCO) annual meeting in June, Celgene presented data from two Phase III trials of Revlimid maintenance therapy following autologous stem cell transplant. Both trials, CALGB and IFM, showed a greater than 50 percent reduction in the risk of disease progression, and both had been stopped early due to their significant efficacy. (See BioWorld Today, June 8, 2010.)
Additional data from both studies were presented at ASH. CALGB showed a 60 percent reduction in the risk of disease progression (p < 0.0001) and a median time to progression of 42.3 months for Revlimid vs. 21.8 months for placebo. The survival benefit – 13 deaths on Revlimid vs. 24 deaths on placebo (p < 0.052) – barely missed statistical significance due to placebo patients crossing over.
In the IFM study, Revlimid patients showed a 50 percent reduction in the risk of disease progression, with median progression-free survival of 42 months for Revlimid vs. 24 months for placebo and five-year overall survival of 81 percent for both arms.
Investors, however, were focused on a risk of secondary malignancies that cropped up in both trials. ISI Group analyst Mark Schoenebaum noted that, pooled together, there were 25 new malignancies in the Revlimid arms of the trials vs. eight in the placebo arms. Yet he added that the imbalance could have been artificially created by the trial designs, which followed Revlimid patients longer, and that overall survival – "the single most important data point for measuring clinical benefit" – numerically favored Revlimid in CALGB.
Piper Jaffray & Co. analyst Ian Somaiya was similarly unconcerned, noting that an independent satellite symposium polling some 400 physicians indicated 71 percent would give Revlimid maintenance post-transplant and 69 percent would use Revlimid maintenance in transplant ineligible patients – the larger section of the maintenance market.
Even so, investors pushed Celgene's stock down about 9 percent in midday trading and were closely watching a Monday late afternoon presentation of Phase III data from the MM-015 front-line trial. Promising interim data were presented at the European Haematology Association annual meeting in June, but Schoenebaum reported that the new data presented at ASH also showed a slight imbalance in secondary malignancies.
Schoenebaum called the new data a surprise because, while CALGB and IFM had been designed and run by cooperative research groups, MM-015 was a Celgene-run trial expected to have better patient screening. Additionally, while CALGB and IFM were both post-transplant studies and stem cell transplants are known to increase the risk of secondary malignancy, MM-015 did not involve transplants.
Shares of Celgene (NASDQ:CELG) closed down $4.95, or 8.2 percent, at $55.64 on Monday – but the stock continued to slide after-hours as investors weighed the risk that extended use of Revlimid might be good for treating MM but bad in terms of causing other cancers.
Any safety concerns plaguing Revlimid may bode well for competitor Velcade (bortezomib, Takeda Pharmaceutical Co. Ltd.), which is approved for front-line and second-line MM. Phase III data presented at ASH showed 36-month progression-free survival of 48 percent and overall survival of 78 percent with a Velcade maintenance regimen, compared to 40 percent and 70 percent with a Thalomid (thalidomide, Celgene) maintenance regimen. A separate Phase III trial showed progression-free survival of 13.8 months to 18.4 months in elderly MM patients receiving Velcade maintenance after a variety of Velcade-containing first-line regimens.
Additional Revlimid data presented at ASH included a study in newly diagnosed MM patients given Revlimid plus low-dose or high-dose dexamethasone. Patients younger than 65 years of age showed 92 percent two-year survival on low-dose and 86 percent on high-dose, while patients 65 and older showed 85 percent two-year survival on low-dose and 72 percent on high-dose.
Outside of MM, Celgene presented Phase III data showing a 75 percent overall response rate in high-risk asymptomatic smoldering multiple myeloma patients treated early with Revlimid and dexamethasone. Additionally, two studies of Revlimid plus Rituxan (rituximab, Roche AG and Biogen Idec Inc.) in chronic lymphocytic leukemia showed strong response rates and survival. And a pivotal Phase II trial of Istodax (romidepsin) showed a 26 percent response rate in peripheral T-cell lymphoma with a 12-month median duration of response, paving the way for a label expansion beyond cutaneous T-cell lymphoma.