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EMEA Says Yes to Everolimus in Renal Cell Cancer
On May 29, 2009, the European Medicines Agency (EMEA) recommended approval of Novartis’s everolimus (Afinitor®), an oral inhibitor of the kinase mammalian target of rapamycin (mTOR), for the treatment of advanced renal cell carcinoma (RCC) that has progressed on or after treatment with vascular endothelial growth factor-targeted therapy. Everolimus was approved by United States Food and Drug Administration (FDA) in March 2009.
New Indication for Pemetrexed in Nonsquamous Non-Small Cell Lung Cancer
On May 29, 2009, the EMEA approved use of Eli Lilly’s pemetrexed (Alimta®) as single-agent therapy for maintenance treatment of locally-advanced or metastatic non-small cell lung cancer (NSCLC) in patients with advanced nonsquamous NSCLC who have stable disease after standard platinum-based chemotherapy. Less than 2 months later, on July 7, 2009, the FDA approved the drug for the same indication.
Ofatumumab: A New Drug for Refractory Chronic Lymphocytic Leukemia
On May 29, 2009, the FDA Oncology Drug Advisory Committee recommended approval for GlaxoSmithKline’s ofatumumab (Arzerra™), a monoclonal antibody targeting a membrane-proximal, small-loop epitope on the CD20 molecule on B cells, for the treatment of chronic lymphocytic leukemia (CLL) that is refractory to fludarabine (Fludara®) and alemtuzumab (Campath®).
The recommendation for approval was based on interim analysis of an international, pivotal phase II trial presented at the 50th Annual Meeting of the American Society of Hematology (ASH) in December 2008. The study included 138 patients with CLL who showed limited or no response to both fludarabine and alemtuzumab treatment (fludarabine/alemtuzumab-refractory) and patients who were refractory to fludarabine and considered inappropriate candidates for alemtuzumab due to bulky disease (>5 cm) in their lymph nodes (bulky fludarabine–refractory). The primary endpoint of the study was response rate. The overall response rate (ORR) seen in patients treated with single-agent ofatumumab was 58% for the fludarabine/alemtuzumab-refractory group (n = 59) and 47% for the bulky fludarabine–refractory group (n = 79). The most common adverse events (AEs) seen with ofatumumab were related to infusion reactions and infections. At the 2009 American Society of Clinical Oncology (ASCO) Annual Meeting, researchers presented an update of the data presented at the 2008 ASH Annual Meeting, with emphasis on the effects of prior exposure to rituximab (Rituxan®/MabThera®). These data confirm that ofatumumab will elicit a response in many patients with refractory CLL for whom rituximab therapy has failed.
FDA’s Full Approval for Dasatinib Use in CML
On May 27, 2009, Bristol-Myers Squibb’s dasatinib (Sprycel®), an oral dual BCR/ABL tyrosine kinase inhibitor, received full FDA approval for the treatment of all phases (chronic, accelerated, or myeloid or lymphoid blast) of chronic myeloid leukemia (CML) resistant or tolerant to previous treatments, including imatinib mesylate (Gleevec®/Glivec®). The full approval was granted, in part, based on results from a phase III, randomized, dose-optimization trial in 670 patients with chronic-phase CML. Of the 167 patients who received the recommended starting dose of 100 mg daily, 63% had a major cytogenetic response (primary endpoint), and of these responders, 91% sustained the response for 18 months.
From the Business World: J&J Boosts Its Global Offerings
On May 21, 2009, Johnson & Johnson (J&J) announced its acquisition of Los Angeles–based Cougar Biotechnology, Inc., a company that is developing drugs for prostate cancer, breast cancer, and multiple myeloma. One of Cougar’s promising drugs, abiraterone, a hormone therapy that inhibits CYP17A1, is in phase III development for prostate cancer.
According to J&J, this deal will strengthen their position as a leader in the global oncology market.
Lapatinib Effective in HER2-Positive Refractory Inflammatory Breast Cancer
Inflammatory breast cancer is highly aggressive with a higher rate of HER2 overexpression (40%) than other breast tumors. Few treatment options exist for patients who are resistant to conventional chemotherapy and trastuzumab treatment. Lapatinib (Tykerb®/Tyverb®), an oral reversible inhibitor of epidermal growth factor receptor (EGFR) and HER2, has demonstrated a 50% response rate in a HER2-positive cohort of 30 patients with recurrent or anthracycline-refractory inflammatory breast cancer in a nonrandomized, open-label, phase II study. Based on these results, the study was expanded to included 126 patients in the HER2-positive cohort to assess further the efficacy and safety of lapatinib 1500 mg once daily in this patient population with refractory disease. Prior therapies included chemotherapy (>99%), trastuzumab (75%), and radiotherapy (70%). The primary objective was to evaluate combined ORR by clinically evaluable skin disease criteria and RECIST criteria, if applicable.
None of the patients had a complete response (CR). Forty-nine patients (39%) had partial responses, with a median duration of response of 20.9 weeks. Median progression-free survival (PFS) was 14.6 weeks overall and 25.1 weeks in those patients who responded. At 6 months, 22% of HER2-positive patients remained progression-free. Prior treatment with trastuzumab did not affect the likelihood of response to lapatinib. Patients previously treated with trastuzumab had a combined ORR of 35%; however, response rate measured by RECIST only was 12% for this group. Most AEs were grade 1-3 in severity, with diarrhea being the most commonly reported. The most common serious AEs included dyspnea (n = 8) and pleural effusion (n = 6). Five deaths occurred that were judged to be possibly related to treatment.
Overall, lapatinib monotherapy appears to be active in heavily pretreated patients with HER2-positive inflammatory breast tumors. The authors concluded that the cause of the deaths in this study is difficult to determine given the poor clinical outcome inherent in this patient population.
Lancet Oncol. 2009;10(16):581-588.
Radiotherapy During Adjuvant Trastuzumab Therapy in Breast Cancer: Is It Safe?
The addition of radiotherapy (RT) to adjuvant trastuzumab (H; Herceptin®) raises concerns about increased AEs, particularly cardiac toxicity related to the cumulative effect of adjuvant anthracyclines, H, and breast, chest wall, or regional nodal irradiation. Limited data exist regarding the concurrent administration of adjuvant RT and H. To date, the North Central Cancer Treatment Group (NCCTG) N9831 trial is the largest study with the longest follow-up to assess the potential interactions between RT and H during adjuvant treatment. In this phase III study, patients with early-stage resected HER2-positive breast cancer were randomized to one of the following treatment groups—Arm A: doxorubicin (A) plus cyclophosphamide (C) every 3 weeks for 4 cycles followed by weekly paclitaxel (T) for 12 weeks (AC-T); Arm B: same as Arm A except T was followed by weekly H for 52 weeks (AC-T-H); or Arm C: AC every 3 weeks for 4 cycles followed by T+H every week for 12 weeks followed by weekly H for 40 weeks (AC-TH-H). Radiotherapy criteria (with or without nodal RT) included postlumpectomy breast or (optional) postmastectomy chest wall. Radiotherapy was started within 5 weeks following T, together with H. A total of 1503 irradiated patients were assessed for RT-associated AEs across treatment arms, while cardiac event rates with or without RT were compared within arms.
Overall, there were no statistically significant differences across the 3 treatment arms in the rate of grade ≥1 RT-related AEs, except leukopenia, which was more common with AC-T-H than with AC-T (odds ratio: 1.89; 95% confidence interval [CI], 1.25-2.88). The incidence of grade ≥3 RT-related AEs was low in all 3 treatment arms. At a median follow-up of 3.7 years, RT combined with H did not increase the relative incidence of cardiac events, regardless of whether RT was left or right sided. The cumulative incidence of cardiac events with AC-T-H was 2.7% with or without RT. With AC-TH-H, the cumulative incidence was 1.7% versus 5.9% with or without RT, respectively.
In patients with early-stage breast cancer, RT (with modern techniques that spare cardiac tissue) administered together with adjuvant H does not appear to increase cardiac events or acute RT-related toxicities except leukopenia. Additional follow-up is warranted to evaluate late AEs.
J Clin Oncol.2009;27(16):2638-2644.
Can We Distinguish Luminal A and B Breast Cancer With Immunohistochemistry?
Two biologically distinct estrogen receptor (ER)-positive subtypes of breast cancer, luminal A and luminal B, have been identified by gene expression profiling. Luminal B tumors are characterized by a higher tumor cell proliferation rate and a poorer prognosis than luminal A tumors. A distinction between luminal A and B tumors based on proliferation status among patients with ER-positive luminal tumors may be important to breast cancer biology and prognosis. The high cost of gene expression profiling has limited its incorporation into randomized clinical trials. At present, no practical immunohistochemistry assay is available to distinguish luminal A and luminal B breast cancer subtypes. However, Canadian researchers recently developed such an assay. A group of tumors from 357 patients with invasive breast carcinomas were subtyped by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) gene expression profiling and tested for Ki67 (a cellular proliferation marker) expression by immunohistochemistry to determine a cut-off value that distinguished luminal A and B tumors. In another group, tissue microarray of 4046 breast tumors were assessed immunohistochemically for the expression of ER, progesterone receptor (PR), HER2, and the Ki67 index (percentage of Ki67-positive cancer nuclei) to distinguish tumors by subtype and to determine the prognostic value of these subtypes for recurrence-free survival (RFS) and disease-free survival (DFS).
Of the 357 tumors subtyped by gene expression profiling, 101 (28%) were luminal A and 69 (19%) were luminal B. The best Ki67 index cutoff value to distinguish luminal B was 13.25%. Of the 4046 breast tumors in the microarray series, 2598 were ER/PR positive. Of the ER/PR-positive tumors subtyped by HER2 and Ki67 immunohistochemistry, 1530 (59%) were luminal A, 846 (33%) luminal B, and 222 (9%) as luminal–HER2 positive. Luminal B and luminal–HER2-positive breast tumors were statistically significantly associated with poor breast cancer DFS and RFS in all adjuvant systemic treatment categories. In particular, for women receiving tamoxifen as their only adjuvant systemic therapy (n = 976), the 10-year breast cancer-specific survival was 79% for luminal A, 64% for luminal B, and 57% for luminal–HER2 subtypes.
Overall, this immunohistochemistry assay of 4 biomarkers (ER, PR, HER2, and Ki67 index) seems to be able to distinguish luminal A from luminal B breast cancer subtypes. Further research is warranted to determine the clinical utility of this assay.
J Natl Cancer Inst. 2009;101(10):736-750.
Hepatic Resection and Improved Chemotherapy Lead to Better Outcomes in Metastatic Colorectal Cancer
The overall survival (OS) of patients with metastatic colorectal cancer (CRC) treated only with fluorouracil/leucovorin is 8 to 12 months. However, with an increase in surgical resections of liver-limited metastases and development of new chemotherapies, indirect evidence suggests that patient outcomes are improving for the broader metastatic CRC population, although the incremental gain has yet to be quantified. To evaluate the changes in survival in patients with metastatic CRC and to associate these changes with hepatic resection utilization and improvements in chemotherapy, a retrospective analysis was conducted of 1) 2470 patients with newly diagnosed metastatic CRC treated at 2 academic centers (1990 through 2006) and 2) a similar population of 49,459 patients from the Surveillance Epidemiology and End Results (SEER) registry (1990 through 2005). Landmark analysis determined the association of diagnosis year and hepatic resection with OS.
For patients who received their primary treatment at the 2 academic centers, median OS for those diagnosed from 1990 to 1997 was 14.2 months, increasing to 18, 18.6, and 29.3 months for patients diagnosed from 1998 to 2000, 2001 to 2003, and 2004 to 2006, respectively. Similarly, 5-year OS increased from 9.1% in 1990-1997 to 19.2% in 2001 to 2003. Improved outcomes from 1998 to 2004 were due to increased hepatic resections, which were performed in one fifth of the patients. Furthermore, improvements from 2004 to 2006 were temporally associated with increased utilization of new chemotherapies. Comparable to the institutional findings, the SEER registry also showed an increased OS in the most recent time period.
This retrospective analysis revealed substantial improvements in outcome for patients with metastatic CRC that appear to be linked to the increased use of hepatic resection in selected patients (1998 to 2006) and advances in chemotherapy (2004 to 2006).
In a recent review article, the combination of surgery and chemotherapy in the treatment of CRC patients with liver metastases was discussed (Ann Oncol. 2009;20(6):985-992). The international expert panel comprising liver surgeons and medical oncologists reviewed available evidence and recommended that most patients with CRC liver metastases should be treated upfront with chemotherapy, regardless of the initial resectability of the metastases.
J Clin Oncol. 2009 May 26. [Epub ahead of print]
Addition of Docetaxel to Induction Chemotherapy Improved Survival in Locally Advanced Head and Neck Cancer
Nearly 25% of all head and neck cancer arise in the larynx or hypopharynx, and patients with laryngeal or hypopharyngeal cancer (LHC) represent an important subgroup that shares overlapping clinical management strategies and similar treatment concerns. This challenging disease is usually treated with complex, combined-modality regimens including surgery and/or radiation therapy as well as chemotherapy. The standard neoadjuvant chemotherapy regimen has consisted of a platinum agent and 5-fluorouracil (a regimen known as PF); however, more recently, the addition of a taxane such as docetaxel to the PF regimen (a triple combination known as TPF) is emerging as a more effective standard for induction chemotherapy. In the phase III TAX 324 study, TPF induction chemotherapy followed by chemoradiotherapy significantly reduced the risk of death by 30% (P = .006) and the risk of disease progression or death by 29% (P = .004) compared with PF followed by chemoradiotherapy. To compare OS, PFS, laryngectomy-free survival (LFS) in operable patients, site of treatment failure, and surgery rate between TPF and PF treatment groups, a subgroup analysis was conducted in 166 patients with LHC enrolled in the TAX 324 trial.
The median OS was significantly longer for TPF than PF (59 months vs 24 months, respectively; P = .024). Similarly, patients in the TPF group showed a significantly prolonged median PFS versus those in the PF group (21 months vs 11 months, respectively; P = .032). Among operable patients, LFS was significantly greater with TPF (hazard ratio: 0.59; 95% CI, 0.37-0.95; P = .030). Furthermore, in operable patients, the 3-year LFS with TPF was 52% compared to 32% for PF, and significantly fewer patients receiving TPF underwent surgery (22% vs 42%, P = .030).
This subgroup analysis demonstrated that sequential therapy with induction TPF significantly improved PFS and OS, reduced locoregional surgery rates, and, in operable patients, significantly improved LFS. These findings support the use of sequential TPF followed by chemoradiotherapy as a treatment option for organ preservation or to improve survival in locally-advanced LHC.
Ann Oncol. 2009;20(5):921-927.
Casopitant Effective for Cisplatin-Based Chemotherapy-Related Nausea and Vomiting
Cisplatin-based chemotherapy is effective in treating many cancers; however, it is also highly emetogenic chemotherapy (HEC). Successful management of the associated chemotherapy-induced nausea and vomiting (CINV) continues to be a concern for both patients and clinicians. Improvements in the control of CINV have been achieved through advances in pharmacotherapy, such as the addition of 5HT3 receptor antagonists to the treatment regimen and, more recently, the NK1-receptor antagonists. Casopitant (Rezonic™/Zunrisa™) is a potent and selective antagonist of the NK1 receptor that is currently being assessed for the prevention of CINV. Preliminary data suggest that casopitant in combination with ondansetron and dexamethasone decreases delayed CINV. A randomized, double-blind, placebo-controlled, phase III trial was conducted to determine the safety and efficacy of casopitant as a single oral dose (150 mg, n = 271) or a 3-day intravenous (IV)/oral dose (90 mg IV on day 1 plus 50 mg oral on days 2 and 3, n = 270) versus placebo (n = 269) when added to standard ondansetron plus dexamethasone for preventing CINV in chemotherapy-naïve patients receiving cisplatin-based HEC regimens. The primary endpoint was the proportion of patients with CR (ie, no vomiting, retching, or use of rescue medications) in the first 120 hours following HEC.
During the first HEC cycle, CR rates were significantly greater in both the single oral dose (86%, P<.0001) and 3-day IV/oral (80%, P = .0004) casopitant groups versus placebo (66%). This improvement was sustained over multiple HEC cycles. In addition patients administered casopitant had an improved quality of life, as assessed by Functional Living Index–Emesis (FLIE) scores, compared with patients in the control group. Adverse event rates were comparable between the 3 groups. The most common serious adverse events among the 3 groups were those associated with cisplatin-based chemotherapy including neutropenia, febrile neutropenia, and dehydration and the incidence in all treatment groups was within the expected range for the given chemotherapy regimen.
Results from this study demonstrated that a single oral dose or 3-day IV/oral dose of casopitant added to a standard regimen of ondansetron plus dexamethasone prevented CINV (during overall, acute, and delayed phases) in 14% to 20% more patients than ondansetron plus dexamethasone alone. Furthermore, casopitant demonstrated an acceptable safety profile with manageable side effects.
Lancet Oncol. 2009;10(6):549-558.
Goldhirsch A, Ingle JN, Gelber RD, et al. Thresholds for therapies: Highlights of the St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2009. Ann Oncol. 2009 April 17. [Epub ahead of print]. This article reports opinions from the expert consensus meeting on the primary treatment of early breast cancer held during the final session of the St. Gallen Breast Cancer Conference in Switzerland on March 14, 2009.
Delmonte A, Ghielmini M, Sessa C. Beyond monoclonal antibodies: New therapeutic agents in non-Hodgkin’s lymphomas. The Oncologist. 2009;14(5):511-525. This review article aimed to identify and discuss novel nonmonoclonal antibody agents based on mechanism of action and clinical results.
Halabi S, Vogelzang NJ, Ou SS, et al. Progression-free survival as a predictor of overall survival in men with castrate-resistant prostate cancer. J Clin Oncol. 2009;27(17):2766-2771. This retrospective analysis of pooled data from 9 CALGB trials that enrolled 1296 men with castration-resistant prostate cancer (CRPC) from 1991-2004 was designed to evaluate whether PFS or biochemical PFS could predict OS in men with CRPC. The authors found that PFS at 3 and 6 months and biochemical progression at 3 months do, in fact, predict OS. They noted, however, that these observations require prospective validation.
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