PHARMACEUTICAL NEWS

Pazopanib Becomes Sixth Drug Approved for RCC

On October 19, the US Food and Drug Administration (FDA) approved GlaxoSmithKline’s pazopanib (Votrient™) for advanced renal cell carcinoma (RCC), making it the fourth targeted antiangiogenic agent, the third oral multitargeted tyrosine kinase inhibitor, and the sixth drug overall to be approved for advanced RCC since 2005. In a multicenter, randomized, double-blind trial reported at the 2009 American Society of Clinical Oncology Annual Meeting, 435 patients were randomized 2:1 to pazopanib (800 mg/day) or placebo, and pazopanib was shown to significantly improve progression-free survival (PFS) compared to placebo (9.2 months versus 4.2 months; P<.001) and resulted in a 30% response rate. Based on these data, the FDA granted approval. However, because severe liver toxicity was observed in a small number of patients, serum transaminase and bilirubin levels should be closely monitored during treatment with pazopanib.  

Rasburicase Granted Expanded Indication

On October 16, the US Food and Drug Administration granted approval for a supplemental indication of rasburicase (Elitek^®, Fasturtec^®, sanofi-aventis) for the prevention of tumor lysis syndrome caused by increased plasma levels of uric acid in adult patients undergoing treatment for leukemia, lymphoma, and solid tumors. Until now, rasburicase had been approved only for pediatric patients. The approval for adults is based on results from the EFC4978 trial, which demonstrated a significant improvement in uric acid response rates among rasburicase-treated patients compared to allopurinol-treated patients. This approval will provide oncologists with a new option to manage this potentially life-threatening complication in their adult patients.

Second HPV Vaccine Approved for Cervical Cancer Prevention

On October 16, Cervarix^®, GlaxoSmithKline’s recombinant, bivalent human papillomavirus (HPV) vaccine, became the second vaccine to gain approval from the FDA for the prevention of cervical cancer and precancerous or dysplastic lesions caused by  HPV types 16 and 18 in girls and young women age 10 to 25 years. The Vaccines and Related Biological Products Advisory Committee found that the data supported the safety of the vaccine, but recommended further study of a possible increase in the risk of spontaneous abortion.

New Indication for Gardasil

The FDA has also approved Merck & Co. Inc.’s Gardasil^®, a quadrivalent HPV recombinant vaccine to prevent genital warts associated with HPV infection in boys and young men ages 9 to 26 years. Gardasil was originally approved in the US and EU to prevent cervical cancer, dysplastic lesions, and genital warts in girls and young women in 2006. It protects against four strains of HPV (types 6, 11, 16, and 18) and types 6 and 11 have been linked to genital warts in both women and men.

CONFERENCE COVERAGE

Highlights from the 2009 Breast Cancer Symposium in San Francisco

The third annual Breast Cancer Symposium was held this year during Breast Cancer Awareness month in San Francisco, 8-10 October. At this 2.5-day multidisciplinary symposium, more than 1200 specialists and researchers from around the world gathered together to discuss advances in prevention, diagnostic technology, translational research, and treatment of breast cancer.  Reviews of bone health in breast cancer and novel targeted therapies such as PARP inhibitors, heat shock protein-90 inhibitors, and angiogenesis inhibitors were presented.Findings from four important studies were presented and are highlighted below:

• Results from a large US retrospective, population-based study presented by Blake Cady, MD, from Cambridge Hospital in Massachusetts, show that after a median follow up of 12.5 years, nearly 75% of breast cancer deaths occurred in women who did not receive regular screening mammograms compared to only 25% who were regularly screened. Based on these findings, the authors concluded that the most effective method to avoid death from breast cancer is regular screening mammography.
• Another population-based study, performed in Canada and presented by Iwa Kong, MD, FRCPC, from the Odette Cancer Center in Toronto, evaluated risk of local recurrence among younger women after local therapy (breast conserving surgery and irradiation) for ductal carcinoma in situ (DCIS). After a median follow up of 8.5 years, the rate of breast cancer recurrence among women age 44 years and younger was significantly higher than those age 45 to 50 years (20% for those age ≤ 40 years, 19% for those age 40 to 44 years, and 12% for those 45 to 50 years).
• Bedanta Baruah, MBBS, and colleagues from the Cardiff Breast Unit at University Hospital of Wales in the United Kingdom, have shown that the addition of axillary ultrasound and fine needle aspiration biopsy (FNAB) prior to initial breast-conserving surgery spared unnecessary sentinel node biopsy in almost 30% of women where node-positive disease was identified by cytology. As this method has high specific and positive predictive value, the authors concluded that axillary ultrasound and FNAC should be performed routinely in patients with early breast cancer eligible for breast conservation.
• A study, presented by Torsten O. Nielsen, MD, PhD, from the University of British Columbia in Vancouver, Canada, exploring the use of tissue microarrays to identify the biologic subtype of breast cancer and predict value of adjuvant paclitaxel was performed on breast cancer tissue obtained from 2039 women who participated in the CALGB 9344 study. The tissue microarray findings were compared with data on patients’ clinical outcome. They showed that women with intrinsic subtype Luminal A did not benefit from the addition of paclitaxel to their adjuvant therapy, while women with aggressive intrinsic subtypes such as HER2-positive breast cancer or basal breast cancer derived significant benefit from adjuvant paclitaxel. Molecular subtyping may permit tailoring adjuvant chemotherapy in early breast cancer.

FROM THE LITERATURE

Is There a Link Between Aromatase Inhibitor–Associated Arthralgia and Carpal Tunnel Syndrome?

Third-generation aromatase inhibitors (AIs) are now being widely used for the adjuvant treatment of postmenopausal women with endocrine-responsive breast cancer, and have almost completely replaced tamoxifen, the previous 'gold standard' of care in this setting. However, adjuvant hormonal therapy trials have shown that therapy with AIs is associated with an increased incidence of arthralgia compared to treatment with tamoxifen and could adversely affect adherence to therapy. Aromatase inhibitor–associated arthralgia is likely related, at least in part, to estrogen deprivation, given estrogen’s role in collagen maintenance and modulation of pain perception. An editorial by Rowan Chlebowski in the October 20 issue of the Journal of Clinical Oncology explores the relationship between AI-associated arthralgia and carpal tunnel syndrome (CTS) based on a paper by Sestak et al exploring the natural history of CTS in women treated with AIs, and a second paper by Dizdar et al suggesting an association between arthralgia and CTS.

Data presented by Sestak et al (J Clin Oncol. 2009;27(30):4961-4965), based on long-term follow-up data from the Anastrozole, Tamoxifen, Alone or in Combination (ATAC) trial, showed that women in the anastrozole arm had an increased risk of CTS compared to the women in the tamoxifen arm (2.6% versus 0.7%; P<.0001). However, most cases were of mild-to-moderate severity, very few required surgery, no patient discontinued therapy because of CTS, and most cases resolved with continued therapy. These results are consistent with those reported from the Intergroup Exemestane Study. Analysis of a range of known risk factors for CTS showed that the risk was significantly increased among women previously treated with hormone replacement therapy (P = .007) or with chemotherapy (P = .01).  

The paper by Dizdar et al (J Clin Oncol. 2009;27(30):4955-4960) reported a prospective study involving 120 postmenopausal women with breast cancer, of whom 92 were treated with an AI, and 28 were not. Patients in this study received detailed rheumatologic assessments, including autoimmune serology, musculoskeletal sonography, and electromyography (EMG), to test the hypothesis that local tenosynovial inflammation may be a common cause of AI-associated arthralgia and CTS. This study found, as expected, that 33% of patients treated with an AI reported new-onset or worsening arthralgia, most commonly in the knee (70%), wrist (70%), and small joints of the hand (63%), and that AI therapy resulted in increased tendon thicknesses compared with controls (P<.001). Moreover, compared to AI-treated patients without arthralgia and the control group, those with AI-associated arthralgia had a higher rate of wrist effusions (P = .037), and more patients with AI-associated arthralgia had EMG findings consistent with CTS compared to AI-treated patients without arthralgia (P = .024). Autoimmune markers were all similar for those treated and those not treated with an AI, which supports prior reports against an autoimmune etiology of AI-associated arthralgias. These findings are very informative and begin to shed light on the etiology of AI-associated arthralgia and CTS, which is critical to the development of more effective interventions.

Although AI-associated arthralgias represent a substantial problem, most women are able to continue their AI treatment regimen. Oncologists should carefully observe their patients for development of arthralgias, clearly express to their patients the benefits of continued adherence to therapy, and provide available therapies for management.

J Clin Oncol. 2009;27(30):4932-4934.

Asymptomatic Metastatic Colorectal Cancer: Is Resection of the Primary Tumor Necessary?

For years, the standard approach to the treatment of advanced metastatic colorectal cancer (mCRC) has been surgical resection of the primary tumor followed by systemic chemotherapy. This therapeutic approach is supported by retrospective studies, largely conducted before the development of modern chemotherapy regimens, suggesting that resection of the primary tumor improves survival. In patients with symptomatic mCRC, surgical resection of the primary tumor can rapidly palliate symptoms and decrease morbidity related to bleeding, obstruction, or perforation of the colon, and in patients with limited metastatic disease, surgery may have curative intent. However, the value of surgical resection in patients with asymptomatic primary lesions and extensive unresectable metastatic disease is less clear, particularly in light of the efficacy of modern systemic therapies and of nonsurgical modalities to manage intestinal complications. The morbidity and mortality associated with colectomy must be weighed against the potential survival benefit in an incurable disease where <10% of patients survive 5 years.

Given that modern chemotherapy regimens incorporating oxaliplatin (Eloxatin^®) and irinotecan (Camptosar^®) in combination with biologic agents such as bevacizumab (Avastin^®) and cetuximab (Erbitux^®) have dramatically improved both response rates and survival in patients with advanced mCRC, the authors of this review argue that it is perfectly reasonable to consider systemic therapy without removing the primary tumor. Indeed, that approach is currently being investigated by the National Surgical Adjuvant Breast and Bowel Project in a prospective phase II study (NSABP C-10). Patients with unresectable stage IV colon cancer and a synchronous asymptomatic primary tumor will be treated with 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) plus bevacizumab. The goal is to determine if this approach leads to an increase in “major morbidity” defined as any event related to the intact primary tumor necessitating surgery or resulting in patient death. The results of this study should be very informative. Finally, the authors summarize current recommendations regarding treatment of mCRC, which are supported by the existing literature.

Current recommendations:

1. Patients with evidence of significant obstruction, perforation, or uncontrolled bleeding should undergo resection of the symptomatic lesion.
2. Patients who are unfit for surgery, or who decline surgery, should undergo endoscopic management with stents or ablation to palliate symptoms.
3. Patients with potentially resectable metastases should undergo resections of both the primary tumor and the metastases (typically, sequentially).
   1. Chemotherapy may be administered preoperatively to assess the natural history of the underlying malignancy.
   2. If disease controlled is obtained with chemotherapy, resection of primary and secondary lesions should be considered.
4. In patients who have diffuse, metastatic CRC with unresectable metastases, modern polychemotherapy with targeted agents will offer disease control without the mortality and morbidity of surgery directed at the primary lesion.

Oncologist. 2009;14(10):963-969.

Long-Acting Release Octreotide Delays Progression of Neuroendocrine Tumors

In his editorial, Kjell Öberg of Sweden, one of the world’s leading experts in neuroendocrine tumors (NETs), poses the question of whether it is time to consider wider use of somatostatin analogues for the treatment of these rare tumors. Somatostatin analogues, including octreotide long-acting release (LAR) (Sandostatin-LAR^®), are standard therapy for patients with functional NETs of the small intestine that are often associated with carcinoid syndrome. The question posed by Öberg was prompted by the long awaited results of a randomized double-blind trial known as PROMID (Placebo-Controlled Prospective Randomized Study on the Antiproliferative Efficacy of Octreotide LAR in Patients with Metastatic Neuroendocrine Midgut Tumors).

The PROMID study is the first prospectively randomized study to investigate the antitumor efficacy of octreotide LAR in patients with well-differentiated NETs of the midgut (proliferation index <2%). The study enrolled 85 patients over 8 years and randomized 43 patients to receive monthly treatment with intramuscular octreotide LAR (30 mg) and 42 patients to placebo. Importantly, the study enrolled patients with both functional and nonfunctional NETs, and the vast majority had liver metastases. This landmark study reported by Rinke et al (J Clin Oncol. 2009;27(28):4656-4663) showed that treatment with octreotide LAR significantly delayed tumor progression (14.3 months versus 6.0 months; P = .00007) compared to placebo. After 6 months of treatment, 67% of patients in the octreotide LAR group had stable disease compared to 37% of patients in the placebo group. These results demonstrate the antitumor benefit of octreotide LAR in this group of patients, and more importantly showed that patients with nonfunctional tumors could benefit to the same extent as those with functional tumors. However, the benefit was primarily restricted to a subset of patients with resected primary tumors and low hepatic tumor load (<10%), and overall survival (OS) could not be assessed. Based on these findings, the authors and Dr Öberg conclude that patients with surgically resected, well-differentiated NETs of the small intestine with low hepatic tumor burden should be candidates for treatment with octreotide LAR regardless of the functional status of the tumor. This study will undoubtedly result in wider use of somatostatin analogues for the study-defined patient population, but further research is needed to define the benefit in other patient subsets.

J Clin Oncol. 2009;27(28):4635-4636.

What Is the Optimal Cisplatin Doublet for Recurrent Cervical Cancer?

Cisplatin-based doublet chemotherapy is current standard salvage treatment for recurrent stage IVB surgically unresectable cervical cancer. The combination of paclitaxel plus cisplatin (PC) has been the standard of therapy since 2004 based on a Gynecologic Oncology Group (GOG) study showing that the addition of paclitaxel to cisplatin significantly improves objective response rate (36% versus 19%; P = .002) and median progression-free survival (PFS) (4.8 months versus 2.8 months; P<.001) compared with cisplatin alone. However, the difference in median OS was minor (9.7 months for combination and 8.8 months for cisplatin alone). Several recent studies have reported promising results when cisplatin was combined with other agents, including topotecan, vinorelbine, or gemcitabine. Therefore, the GOG conducted a 4-arm, phase III, randomized trial to compare standard PC with either topotecan/cisplatin (TC), vinorelbine/cisplatin (VC), or gemcitabine/cisplatin (GC) on a 3-week cycle.

A total of 513 patients had been enrolled when a planned interim analysis prompted early closure of the trial for futility. The response rate was 29% with PC compared with 26%, 22%, and 23% for VC, GC, and TC, respectively. The median PFS was 5.82 months for PC and 3.98, 4.70, and 4.57 months for VC, GC, and TC, respectively. Median survival was 13 months with PC compared with approximately 10 months for the other three regimens. Of the three experimental regimens, VC was associated with significantly less alopecia compared to PC, whereas GC was associated with a substantially lower incidence of hematologic toxicity (primarily leukopenia and neutropenia) compared with PC. However, the arms were fairly comparable with respect to toxicity. Overall, all three experimental regimens did not show superiority over PC; in contrast, a trend in response rate, PFS, and OS favors PC. 

Although this is an important study in defining optimal therapy for advanced and recurrent cervical cancer, pre-existing morbidity and toxicity should be taken into account to individualize therapy. In addition, there is an obvious need to further evaluate targeted and biologic therapies in cervical cancer. Bevacizumab has demonstrated positive results in a recent phase II study, and it is hoped that emerging GOG trials focusing on combining chemotherapy with bevacizumab will lead to further improvement in survival.

J Clin Oncol. 2009;27(28):4649-4655.

Lenalidomide: Another Effective Salvage Option for Relapsed/Refractory Indolent NHL

Patients with indolent, low-grade, follicular non-Hodgkin lymphoma (NHL) are generally treated with anthracycline-based chemotherapy and/or rituximab (Rituxan^®, MabThera^®). The addition of rituximab to standard chemotherapy regimens has improved response rates and durability, but patients will inevitably experience disease recurrence and require additional therapy. Radioimmunotherapy with either 90Y-labeled ibritumomab tiuxetan (Zevalin^®) or 131I-labeled tositumomab (Bexxar^®) is often used as second-line or third-line therapy. Although these agents are effective in the majority of patients with relapsed indolent NHL, OS benefits have been modest, and there remains a need for new salvage agents. Lenalidomide (Revlimid^®) is an immunomodulatory agent with proven activity in a variety of B-cell malignancies, including multiple myeloma and NHL.

The report by Witzig et al describes the results of a multicenter phase II trial of single-agent lenalidomide in 43 patients with relapsed/refractory indolent NHL who had received a median of 3 prior regimens (range, 1-17). Nearly all patients (91%) had received prior chemotherapy or rituximab, and half had not responded to their most recent therapy. Patients in this study received oral lenalidomide (25 mg/day) for 21 consecutive days out of every 28-day cycle, which yielded a 23% response rate (3 [7%] complete and 7 [16%] partial responses). Median duration of response had not been reached at the time of publication, but was at least 16.5 months. In addition, 16 patients (37%) had stable disease, and median PFS was 4.4 months. This regimen was well tolerated, and the most frequent grade 3/4 adverse events were neutropenia and thrombocytopenia. Based on these data, the authors concluded that oral lenalidomide may have a role in the treatment of relapsed/refractory indolent NHL, despite the modest response rate observed in this study. Although studies with radioimmunotherapy or bendamustine in similar heavily pretreated patient populations have demonstrated higher response rates with duration of 8 months to 9 months, the durability of response to lenalidomide is noteworthy. Thus, the authors concluded that further investigation of lenalidomide as maintenance therapy or in combination with other agents is warranted.

J Clin Oncol. 2009;27(32):5404-5409.

ADDITIONAL PUBLICATIONS WORTH READING

• Radich JR. How I monitor residual disease in chronic myeloid leukemia. Blood. 2009;114(16):3376-3381. Answers to frequently asked questions about the value of molecular monitoring as a tool to document treatment effect and predict relapse in CML.
• Hurwitz J, McCoy F, Scullin P, Fennell D. New advances in the second-line treatment of small cell lung cancer. Oncologist. 2009;14(10):986-994. This article reviews the current evidence for the use of second-line cytotoxic therapy and the emerging role of novel targeted agents in small cell lung cancer, particularly those targeting the Bcl-2 protein family.
• Specht J, Gralow JR. Neoadjuvant chemotherapy for locally advanced breast cancer. Semin Radiat Onco.l 2009;19(4):222-228.This review explores the efficacy of various preoperative systemic therapy regimens and research opportunities afforded by this approach.
• Siena S, Sartore-Bianchi A, Di Nicolantonio F, et al. Biomarkers predicting clinical outcome of epidermal growth factor receptor–targeted therapy in metastatic colorectal cancer.J Natl Cancer Inst. 2009;101(19):1308-1324. This review article explores the value of molecular biomarkers in predicting response to EGFR inhibitors.
• Coate L, John T, Tsao M-S, Shepherd F. Molecular predictive and prognostic markers in non-small-cell lung cancer. Lancet Oncol. 2009;10(10):1001-1010. The authors review and assess the potential clinical use of predictive and prognostic biomarkers in non-small cell lung cancer and explore recent data pertaining to a genome-wide approach to treatment selection.

UPCOMING LIVE EVENTS
Expert Practice in Breast Cancer 28 November 2009 | Nice, France	Variations on Central Themes in Breast Oncology 11 December 2009 San Antonio, Texas	Hematologic Malignancies Demystified: The Series A Critical Appraisal of Data from 2009 and ASH

AVAILABLE ONLINE NOW
Expert Perspectives on Clinical Practice: Daily Clinical Updates from the 60th Annual Meeting of the AASLD	New in the Virtual Journal Club: Expert Interviews on Data from Recent Oncology Literature: Breast Cancer, GIST, and CML	Expert Perspectives in Non-Small Cell Lung Cancer: Advances and Updates in Adjuvant Therapy for Resectable NSCLC