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Everolimus: Approved Treatment for Renal Cell Carcinoma
On March 30, 2009, Novartis’s everolimus (RAD001, Afinitor®), an oral inhibitor of the kinase mammalian target of rapamycin (mTOR), was approved by the US Food and Drug Administration (FDA) for the treatment of advanced renal cell carcinoma (RCC) that is refractory to the tyrosine kinase inhibitors sunitinib and/or sorafenib. The FDA approval was based on robust data from the RECORD-1 trial, which was discontinued early when initial results showed that progression-free survival doubled in patients treated with everolimus compared with those receiving placebo (4 months vs 1.9 months, P<.0001). Results from this study were published in The Lancet (Motzer RJ, et al. Lancet. 2008;372(9637):449-456).
After More Than a Decade, a New Drug for Glioblastoma
On May 5, 2009 Roche’s bevacizumab (Avastin®) won FDA approval for the treatment of recurrent glioblastoma, one of the most aggressive primary brain tumors, with a median survival 3 to 6 months for recurrent disease. Bevacizumab received accelerated approval just 35 days after an advisory panel's unanimous recommendation. Approval was based on significant clinical benefit in pretreated patients with glioblastoma demonstrated in phase II clinical trials. The advisory committee was of the opinion that the apparent benefits of the drug outweighed the risks considering there are no good alternatives for treating patients with relapsed brain cancer.
Bevacizumab is already approved for the treatment of advanced colorectal, lung, and breast cancers.
From the Business World: sanofi-aventis to Enhance Its Pipeline
On April 15, 2009, Paris-based sanofi-aventis announced that it has signed a binding agreement to acquire California-based BiPar Sciences Incorporated, a privately held biopharmaceutical company that is leading the way in developing therapies in the emerging field of DNA repair using poly ADP-ribose polymerase (PARP) inhibitors. Inhibition of PARP has demonstrated significant antitumor effects in a number of cancers; however, its activity does not appear to be harmful to normal, noncancerous cells. BiPar’s leading drug candidate, BSI-201, a potential first-in-class PARP inhibitor, is currently in phase II development for the treatment of triple-negative breast cancer, ovarian cancer, and other malignancies. PARP inhibition is selective for BRCA1 or BRCA2 deficiency, which suggests that PARP inhibitors may be particularly useful for the treatment of cancer with BRCA mutations.
NEWS FROM THE ANNUAL AUA MEETING
Vaccine Improves Survival in Prostate Cancer
Dendreon’s sipuleucel-T (Provenge®) is the first in a new class of active cellular immunotherapies designed to trigger the patient’s own immune system to fight prostate cancer. The highly-anticipated results from the phase III IMPACT (IMmunotherapy for Prostate AdenoCarcinoma Treatment) study of sipuleucel-T were presented during a plenary session at the Annual Meeting of the American Urological Association (AUA) in Chicago, Illinois, on April 28, 2009. In this randomized, double-blind, placebo-controlled trial, men with metastatic castration-resistant prostate cancer who had a life-expectancy of ≥6 months received sipuleucel-T (n = 341) or placebo (n = 171) every 2 weeks for 3 courses. The primary endpoint was overall survival (OS), and the secondary endpoint was time to objective disease progression.
Sipuleucel-T significantly prolonged OS by a median of 4.1 months, reducing the risk of death by 22.5% (hazard ratio [HR], 0.775; 95% confidence interval [CI], 0.614-0.979; P = .032). Furthermore, the 3-year survival rate was 31.7% for patients treated with sipuleucel-T and 23% for those receiving placebo. No statistically significant between-group difference was observed for time to objective disease progression, which, according to the authors, is a difficult endpoint to measure reliably and does not correlate with OS. Most common adverse events (≥5%) occurring at a significantly higher rate in the sipuleucel-T group included chills, fever, headache, influenza-like illness, hypertension, and hyperhydrosis.
Overall, based on these results, sipuleucel-T has a highly favorable benefit/risk profile, and it is the first active immunotherapy to extend OS in patients with advanced prostate cancer.
Cetuximab and Chemotherapy in First-Line Colorectal Cancer: Who Benefits?
Approximately 40% to 50% of patients with newly diagnosed colorectal cancer (CRC) develop metastatic disease. Cetuximab (Erbitux®), an epidermal growth factor receptor (EGFR)–targeted monoclonal antibody, has demonstrated activity when added to irinotecan-based or oxaliplatin-based therapies as first-line treatment in phase I and II studies. Therefore, a randomized (1:1) phase III trial was conducted to assess the efficacy and safety of cetuximab plus FOLFIRI versus FOLFIRI alone as first-line treatment in patients with EGFR-positive metastatic colorectal cancer (mCRC). The primary endpoint was progression-free survival (PFS), and secondary endpoints included OS, rate of best overall response, and safety. Additionally, this study retrospectively investigated the correlation between KRAS gene mutations and response to cetuximab.
Results from this study showed that first-line treatment of mCRC patients with cetuximab plus FOLFIRI (n = 599), versus FOLFIRI alone (n = 599), significantly reduced the risk of progression by 15% (HR, 0.85; P = .048). Furthermore, the addition of cetuximab to FOLFIRI resulted in a response rate of 46.9%, which was nearly 10% higher than that observed in the control arm. However, there was no significant difference between treatment groups for OS. There was a significant interaction between treatment group and KRAS status for response to cetuximab plus FOLFIRI (P = .03) but not for PFS or OS. Patients with wild-type KRAS tumors in the cetuximab plus FOLFIRI group had a 32% reduced risk of progression compared with those in the FOLFIRI group (HR, 0.68; 95% CI, 0.50-0.94). The toxicity profile of cetuximab plus FOLFIRI was as expected. The incidence of grade 3/4 skin reactions, infusion-related reactions, and diarrhea was significantly higher with cetuximab plus FOLFIRI versus FOLFIRI alone.
First-line treatment of mCRC patients with cetuximab plus FOLFIRI reduced the risk of disease progression compared to treatment with FOLFIRI alone. It appears that only patients with wild-type KRAS tumors benefited from cetuximab.
N Engl J Med. 2009;360(14):1408-1417.
Denosumab: A Promising Bone-Targeted Therapy
Elevated levels of urinary N-telopeptide (uNTx), a marker of excessive bone resorption, have shown to be a predictor of skeletal-related events (SREs), cancer progression, and death in patients with bone metastases regardless of primary tumor type. In a phase II study, treatment with denosumab, a human monoclonal antibody that specifically inhibits the receptor activator of nuclear factor κB ligand (RANKL), resulted in notable suppression of uNTx and other bone turnover markers in women with bone-metastatic breast cancer who have never received intravenous (IV) bisphosphonates (BPs). Herein, results are presented from a randomized, phase II study conducted to assess the effect of denosumab in patients with ≥1 bone metastases from prostate, breast, or other cancer and elevated uNTx levels (>50 nmol/L bone collagen equivalents [BCE]/mM creatinine) despite ongoing IV BP therapy. Patients were stratified by tumor type and screening uNTx levels (50-100 or >100 nmol/L BCE/mM creatinine) and randomized to receive IV BPs every 4 weeks or subcutaneous denosumab 180 mg every 4 or 12 weeks.
Overall, a significantly larger proportion of patients in the denosumab arm, versus IV BP arm, achieved the primary endpoint of uNTx levels <50 nmol/L BCE/mM creatinine at week 13 (71% [13 of 49] vs 29% [10 of 35]; P<.001). This benefit of denosumab over IV BP was sustained through week 25 (secondary endpoint; 64% vs 37%; P = .01). Furthermore, at week 25, the incidence of first on-study SREs was 50% lower with denosumab versus ongoing IV BP (8% vs 17%). Adverse event rates were comparable between the 2 treatment groups.
Results from this study demonstrated that in patients with bone metastases who had elevated uNTx levels regardless of IV BP therapy, denosumab normalized uNTx levels more often than ongoing IV BPs.
An accompanying editorial discussed RANKL as a bone-targeted therapy.
J Clin Oncol.2009;27(10):1564-1571.
J Clin Oncol.2009;27(10):1534-1536.
Bortezomib: A Good Option for Refractory/Relapsed Mantle Cell Lymphoma
Mantle cell lymphoma (MCL) is an aggressive, rapidly progressive subtype of non-Hodgkin lymphoma for which there is currently no well defined standard of care. Bortezomib (Velcade®), a novel proteosome inhibitor, is approved in the US for the treatment of patients with MCL who have received at least 1 prior therapy, and for patients with multiple myeloma. Approval of the MCL indication was based on initial phase II data from the PINNACLE study, the largest prospective study to date in this population. One hundred fifty-five patients with relapsed or refractory MCL (with a maximum of 2 prior therapies) were given bortezomib monotherapy 1.3 mg/m2 twice weekly for 2 weeks every 21 days for up to 1 year. Initial results showed a 33% overall response rate, 8% complete response rate, a median duration of response (MDR) of 9.2 months, and a MDR of 13.5 months in those who achieved a complete response.
Recently, updated data from this study revealed that, after a median follow-up of 26.4 months, the median time to progression (TTP) was 6.7 months, median time to next therapy (TTNT) was 7.4 months, and median OS was 23.5 months. In responders, median TTP was 12.4 months, median duration of response (DOR) was 9.2 months, median TTNT was 14.3 months, and median OS was 35.4 months. In complete responders, median TTP and DOR were not reached, and median OS was 36.0 months. One-year survival rate was 69% overall and 91% in responders. After a median follow-up of 63.7 months, median OS from diagnosis was 61.1 months. Bortezomib-associated toxicity was manageable and comparable to that previously reported.
Overall, bortezomib demonstrated prolonged responses and remarkable survival in patients with relapsed or refractory MCL, with notable TTP and TTNT in responders, suggesting substantial clinical benefit. Therefore, bortezomib provides a valuable treatment option for these patients.
Ann Oncol. 2009;20(3):520-525.
Azacitidine Prolongs Survival in Higher-Risk Myelodysplastic Syndromes
Myelodysplastic syndromes (MDS) are malignant diseases of myeloid stem cells, characterized by ineffective hemopoiesis resulting in peripheral-blood cytopenias. Patients with intermediate-2 or high-risk MDS have a poor prognosis, with median survival of 1.2 years or 0.4 years, respectively, and a high-risk for conversion to acute myeloid leukemia. With the exception of allogeneic stem cell transplantation (ASCT), no treatment strategies are curative and are merely able to slow disease progression and alleviate symptoms. Azacitidine (Vidaza®) is a hypomethylating agent that in a CALGB trial suggested improved overall survival in patients with MDS compared to best supportive care.
To assess the effect on OS of azacitidine compared to the 3 most common conventional care regimens, a phase III, multicenter, open-label trial was conducted in 358 patients with higher-risk MDS. Patients were randomized 1:1 to receive azacitidine (75 mg/m2/day for 7 days every 28 days) or conventional care (best supportive care, low-dose cytarabine, or intensive chemotherapy). The primary endpoint was OS. After a median follow-up of 21.1 months, median OS was 24.5 months for azacitidine-treated patients versus 15.0 months for those receiving conventional care, a significant difference of 9.5 months (HR, 0.58; 95% CI 0.43-0.77; P = .0001). At the time of last follow-up, 82 patients treated with azacitidine had died versus 113 patients treated with conventional care regimens. Furthermore, based on Kaplan-Meier estimates, a significantly greater percentage of patients in the azacitidine group were alive at 2 years relative to those in the conventional care group (50.8% vs 26.2%, P<.0001). Across all treatments, peripheral cytopenias were the most common grade 3/4 adverse events.
Overall, azacitidine therapy significantly prolongs OS in higher-risk MDS patients compared to treatment with conventional care regimens. These findings are encouraging since azacitidine is the first treatment option to show a significant OS advantage in this patient population, with the exception of ASCT, which is indicated in only a small percentage of patients with MDS.
Lancet Oncol. 2009;10(3):223-232.
Non-Small Cell Lung Cancer Histology Important When Choosing Therapy
In recent studies of pemetrexed (Alimta®), non-small cell lung cancer (NSCLC) histology (nonsquamous vs squamous) was identified as a predictor of response to treatment. Therefore, 2 large, randomized phase III trials were retrospectively analyzed to assess the differential efficacy of pemetrexed based on NSCLC histology. One study compared pemetrexed with docetaxel in previously treated patients (n = 571) while the other study compared cisplatin plus pemetrexed versus cisplatin plus gemcitabine in chemotherapy-naïve patients (n = 1725) with advanced NSCLC. In both studies, the primary endpoint was OS, and secondary endpoints included comparisons of PFS, TTP, time to treatment failure (TTF), tumor response rate (RR), duration of response, and toxicity.
In both studies, treatment-by-histology interactions (THIs) were statistically significant (P<.005) for both OS and PFS. Patients with nonsquamous disease treated with pemetrexed-based therapy had longer survival than those treated with comparator drugs (HR, 0.78 and 0.84, respectively), while patients with squamous disease had shorter survival (HR, 1.56 and 1.23, respectively). Furthermore, no other chemotherapeutic agent has consistently shown differential efficacy according to NSCLC histology. In both studies, pemetrexed was well tolerated across histologic groups.
Results from these 2 studies showed a significant interaction between NSCLC histology and pemetrexed treatment effect, regardless of comparator agents. The uniformity of the results across the 2 studies corroborates the predictive effect of histology for pemetrexed, as well as the survival benefit for pemetrexed in patients with nonsquamous NSCLC.
Oncologist.2009;14(3):253-263.
Adjuvant Imatinib Improves Survival in Patients with GIST
A large, randomized, phase III clinical study was conducted to determine the efficacy of imatinib 400 mg (Glivec®/Gleevec®) versus placebo in 713 patients who underwent surgical resection of a primary gastrointestinal stromal tumor (GIST; ≥3 cm in size, Kit protein (CD117)-positive). Imatinib administered post-surgery significantly improved recurrence-free survival at 1 year compared with placebo (98% vs 83%; HR 0.35; P<.0001). For more information on this study, please visit PRIME Oncology’s GIST Virtual Journal Club with Peter Pisters, MD.
Lancet.2009;373(9669):1097-1104.
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