As the American Society of Clinical Oncology (ASCO) annual meeting continued over the weekend, Celgene Corp. made a splash with data from two Phase III studies that analysts believe will convince doctors to use Revlimid (lenalidomide) as maintenance therapy in multiple myeloma (MM).
Some oncologists have been resistant to the idea of maintenance therapy, particularly when it means treating a patient who might otherwise be enjoying a drug-free remission period.
In lung cancer, chemotherapy drug Alimta (pemetrexed, Eli Lilly and Co.) and EGFR-inhibitor Tarceva (erlotinib, OSI Pharmaceuticals Inc./Astellas Pharma Inc. and Genentech Inc./Roche AG) are approved for maintenance use, but analysts don't expect much revenue from this setting due to a lack of enthusiasm among physicians. (See BioWorld Today, April 20, 2010.)
Analysts have no such concerns, however, about Revlimid maintenance therapy for MM. Revlimid is approved for second-line MM as well as for certain myelodysplastic syndromes, but it is used off-label in the MM maintenance setting, which Piper Jaffray analyst Ian Somaiya estimated could be worth $3 billion to $4 billion. And Leerink Swann Research analyst Howard Liang called Celgene's new data at ASCO "practice-changing" and representative of a "real catalyst for increased Revlimid use" in maintenance MM.
Both Phase III trials evaluated the use of Revlimid maintenance therapy following autologous stem cell transplant in MM patients, and both were previously stopped early due to significant efficacy. (See BioWorld Today, Dec. 21, 2009.)
In the CALGB study, 13.8 percent of patients on Revlimid maintenance had disease progression at 12 months, compared to 27.9 percent of placebo patients, representing a 58 percent reduction in the risk of progression (p < 0.0001).
In the IFM study, the Revlimid maintenance group had a 68 percent three-year progression-free survival rate compared to 34 percent in the placebo arm, representing a 54 percent reduction in the risk of progression (HR = 0.46, p < 0.0000001). Liang noted that benefit was seen even in patients already in remission, which could "convert some doubters about the maintenance approach."
Not to be outdone, Millennium/Takeda Pharmaceutical Co. Ltd. presented data from an open-label Phase III MM trial comparing maintenance treatment with their proteasome inhibitor Velcade (bortezomib) plus Celgene's Thalomid (thalidomide) to the standard of care (SOC). Three-year progression-free survival (PFS) was 54 percent for the maintenance group vs. 40 percent for SOC (p = 0.006), and 69 percent of the maintenance patients didn't need second-line treatment at three years, compared to 55 percent for SOC (p = 0.006).
In other maintenance news, Roche AG presented Phase III data supporting the use of Avastin (bevacizumab) maintenance therapy in ovarian cancer. Women who received first-line Avastin plus chemotherapy followed by Avastin maintenance had PFS of 14.1 months compared to 10.3 months with chemotherapy maintenance, resulting in a 39 percent improvement for the Avastin arm (HR = 0.72, p < 0.0001).
Celgene Expands Revlimid Franchise
In addition to the two maintenance studies, Celgene presented several other studies aimed at expanding its already successful Revlimid franchise.
Data from the Phase III MEL200 study showed that Revlimid was as effective as stem cell transplant in multiple myeloma but with fewer side effects. In the trial, 55 percent of patients in the Revlimid group achieved a very good partial response, compared to 53 percent in the transplant arm, and both groups achieved 91 percent PFS at 14 months (p = 0.77). But while 84 percent of transplant patients had neutropenia and thrombocytopenia, and 17 percent had infections, the Revlimid group had a 48 percent incidence of neutropenia, an 8 percent incidence of thrombocytopenia and no infections.
Celgene also presented data from a single-arm Phase II study of Revlimid plus Rituxan (rituximab, Genentech Inc./Roche AG) in newly diagnosed non-Hodgkin's lymphoma. The overall response rate was an impressive 89 percent, with 73 percent of patients achieving a complete response.
Another single-arm Phase II study of Revlimid in first-line chronic lymphocytic leukemia showed an overall response rate of 62 percent, with 15 patients achieving a complete response, and a two-year overall survival rate of 90 percent. Additionally, a retrospective analysis of pooled data from four academic centers in which Revlimid had been used as salvage therapy for diffuse large B-cell lymphoma (DLBCL) showed better responses in nongerminal center B-cell vs. germinal center B-cell phenotypes.
Combos, New Agents for MM
Although Revlimid and Velcade are the current standards for MM, research is ongoing into new combinations as well as new compounds.
At ASCO, Millennium presented data from an open-label Phase I/II trial combining Velcade with Revlimid and dexamethasone for front-line MM treatment. All patients demonstrated a partial response and 57 percent achieved a complete response. Estimated two-year PFS and overall survival rates were 68 percent and 95 percent, respectively.
Celgene presented data from a Phase II trial of pomalidomide plus dexamethasone in multiple myeloma patients who failed both Revlimid and Velcade. In the study, response rate was 54 percent, with 58 percent PFS and 86 percent overall survival at six month follow-up.
Additional data came from Onyx Pharmaceuticals Inc.'s proteasome inhibitor carfilzomib. Interim data from an ongoing single-agent Phase II trial in relapsed and refractory MM showed a response rate of 45 percent to 55 percent in Velcade-naïve patients and 21 percent in patients who had previously failed Velcade.
Array BioPharma Inc. presented Phase I data showing that its kinesin spindle protein inhibitor, ARRY-520, was well tolerated and demonstrated promising single-agent activity in MM patients who had failed Revlimid and Velcade. Out of 20 patients, ARRY-520 induced one partial response and two unconfirmed minor responses.
Also, Novartis AG presented Phase III data showing that bisphosphonate Zometa (zoledronic acid) plus chemotherapy in first-line MM improved overall survival by 16 percent (p = 0.0118) and PFS by 12 percent (p = 0.0179) compared to chemotherapy plus clodronate. Zometa also was significantly superior to clodronate in the prevention of skelatal-related events associated with multiple myeloma, reducing the relative risk 24 percent more than clodronate (p = 0.0004).