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Dec 6, 2010

Late-Stage Clinical Results Presented at ASH

Late-Stage Clinical Results Presented at ASH

Allos, BMS, Celgene, Genentech, Novartis, Pfizer, and Seattle Genetics report on multiple trials.[Alexander Raths-Fotolia.com]

  • The 52nd American Society of Hematology (ASH) Annual Meeting and Exposition kicked off on Saturday in Orlando, Florida. Among the many companies presenting updates on their R&D activities were quite a few with Phase III trial results.

    Celgene presented data from four late-stage trials with Revlimid (lenalidomide) including multiple myeloma and chronic lymphocytic leukemia. The drug was tested in multiple myeloma patients who achieved at least stable disease following autologous stem cell transplant. They received continuous daily treatment with Revlimid 10 mg.

    This trial was halted in December 2009 after the independent Data and Safety Monitoring Committee’s initial interim analysis found that it had met its primary endpoint. Data presented today at ASH is from a third interim analysis.

    Patients in the treatment arm experienced a 60% reduction in risk of disease progression or death when compared to those receiving placebo. The median time to progression (TTP) was significantly higher for the lenalidomide arm at 42.3 months versus 21.8 months. As of December 17, 2009, there had been 13 deaths in the Revlimid-treated group compared to 24 deaths in the placebo arm.

    From a separate study, Celgene reported that Revlimid and dexamethasone in patients with high-risk asymptomatic smoldering multiple myeloma prolonged time to progression to symptomatic disease compared to patients that did not receive treatment and were just observed.

    The results showed an overall response rate of 75%. After a median follow-up of 16 months, disease progression was observed in 3% of patients treated with Revlimid and dexamethasone, while 18% of patients in the observation arm progressed to active myeloma. Eleven of these 21 patients also developed bone lesions due to active myeloma. The median time to symptomatic myeloma was 25 months in patients in the observation arm and has not yet been reached for patients who received Revlimid and dexamethasone (p<0.0001).

    Additionally, two studies of Revlimid either with rituximab or following a rituximab-containing regimen in patients with chronic lymphocytic leukemia (CLL) also demonstrated positive results. In the first study, 38 of 44 patients with previously untreated CLL received six cycles of pentostatin, cyclophosphamide, and rituximab (PCR) every 21 days. Following this treatment regimen, 34 patients continued on to consolidation therapy with daily Revlimid.

    At a median follow-up of 21 months, 21% of those who got at least one cycle of Revlimid consolidation showed an improvement in the quality of their response, including three patients who converted from minimal residual disease (MRD)-positive to MRD-negative disease. The median duration of response has not been reached.

    In the second study, patients with relapsed/refractory CLL received rituximab intravenously, and Revlimid was started on day nine of cycle one on a continuous dosing schedule. The overall response rate was 63%, with 5% achieving a complete response. Additionally, 2% of patients achieved a complete response with incomplete hematological recovery. Fourteen percent of patients achieved nodular partial responses and 42% achieved partial responses.

    More Rituxan data was also presented at ASH. Genentech and Biogen Idec said that in patients with advanced follicular lymphoma, immediate administration of single-agent Rituxan followed by continued use of Rituxan decreased the risk of needing additional therapy by 80% and decreased the risk of disease worsening by 79%.

    The median time to initiation of new therapy (chemotherapy or radiotherapy) for patients managed by watchful waiting was 34 months and the median PFS was 23 months. However, in patients given immediate Rituxan followed by maintenance, the median of these parameters was significantly longer and has not been reached after four years.

    Reporting on Hodgkin lymphoma, Seattle Genetics and Millennium: The Takeda Oncology Company found that brentuximab vedotin (SGN-35) showed positive results in relapsed or refractory disease. Brentuximab vedotin is an antibody-drug conjugate (ADC) targeted to CD30.

    Seattle Genetics plans to submit a BLA in the first quarter of 2011 to seek approval for both relapsed or refractory Hodgkin lymphoma and relapsed or refractory systemic anaplastic large cell lymphoma (ALCL). Millennium has initiated discussions with European regulators to support the submission of an MAA in the first half of 2011.

    Key findings from the trial included 75% of patients achieving an objective response, the primary endpoint of the trial. Thirty-four percent of patients achieved complete remission. The median duration of response was 29 weeks by independent central review and 47 weeks by investigator assessment. Among patients achieving a complete remission, the median duration of response had not yet been reached at a median follow-up of approximately one year.

    Also in the lymphoma space, Allos Therapeutics presented retrospective analyses from its pivotal Propel trial of Folotyn in patients with relapsed or refractory peripheral T-cell lymphoma (PTCL).

    Of the patients who received prior ICE or similar aggressive combinations, objective responses were observed in 40% of patients given Folotyn. Of those whose disease progressed following treatment with first-line CHOP, objective responses were observed in 47% of Folotyn-treated patients.

    Of the patients who received three or more systemic therapies, objective responses and progression-free survival decreased with each line of therapy prior to Folotyn. Following treatment with Folotyn, responses and progression-free survival increased relative to the immediate prior line of therapy, thus reversing the trend of progressive resistance.

    While both Bristol-Myers Squibb (BMS) and Novartis reported that of their marketed drugs for Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML), Sprycel and Tasigna, respectively, were performing well, Pfizer’s investigational therapy did not have the same luck.

    Pfizer’s bosutinib did not meet its primary endpoint of superior complete cytogenetic response but reached its secondary endpoint of achieving a major molecular response. Of patients with newly diagnosed disease treated with bosutinib, 39% experienced a major molecular response (MMR) compared to 26% of patients treated with Novartis’ Glivec. Superior complete cytogenetic response (CCyR) rate at one year versus imatinib was 70% vs. 68%, respectively.

    Bosutinib is an oral dual Src and Abl kinase inhibitor. It is also being studied as a single agent in patients with previously treated chronic phase CML. Interim results from patients who have failed prior Glivec therapy and were resistant or intolerant to BMS’ Sprycel or resistant to Novartis’ Tasigna will also being presented at ASH.

    BMS and Novartis reported that 18-month follow-up studies of Sprycel and Tasigna in untreated Ph+ CML patients showed that the drugs worked better than Glivec.


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