primeLINES CLINICAL OPINION POLL

MAY 2010 Issue

PHARMACEUTICAL NEWS

First Cancer Treatment Vaccine Approved for Advanced Prostate Cancer

On April 29, 2010, the US Food and Drug Administration (FDA) approved Dendreon’s sipuleucel-T (Provenge®), an autologous cellular immunotherapy, for the treatment of men with asymptomatic or minimally symptomatic metastatic, castrate-resistant (hormone-refractory) prostate cancer (CRPC). Sipuleucel-T is designed to stimulate T-cell immunity against prostatic acid phosphatase, an antigen expressed in most prostate cancers. Approval was based on results from the phase III IMPACT (IMmunotherapy for Prostate AdenoCarcinoma Treatment) trial, which evaluated 512 men with asymptomatic or minimally symptomatic, metastatic CRPC. Results from IMPACT demonstrated that treatment with Sipuleucel-T increased overall survival (OS) by 4.1 months, with a 24.1 percent reduction in the risk of death (P = .017) when compared with placebo.

CONFERENCE NEWS

IMPAKT 2010: More than Just Another Breast Cancer Meeting

According to Angelo di Leo, MD, PhD (Hospital of Prato in Prato, Italy), scientific committee chair of IMPAKT, the main mission of this interactive conference is to attract young bright breast cancer investigators; indeed, selected young investigators were given the opportunity to present their preclinical and clinical work at an oral abstract or poster presentation session. A pre-IMPAKT training course, specifically designed for young oncologists, focused on an improved understanding of translational research in breast cancer via presentations on DNA (sequencing, comparative genomic hybridization [CGH] array and epigenetics), RNA expression profiles, emerging technologies (miRNA and metabolomics), and circulating markers. Major topics covered in the IMPAKT agenda included drug development based on identification of new therapeutic targets (eg, DNA repair, PI3K and mTOR pathways; breast cancer stem cells; and cancer metabolism), evaluation of biomarkers in terms of therapeutic response, and the potential use of functional imaging to tailor treatment in the future. The challenge of appropriate design of clinical trials evaluating targeted agents was also addressed during the meeting. All of these issues were highlighted in keynote lectures, scientific symposia, and education sessions. A unique and practical aspect of the conference involved the presentation of results from preclinical research followed by discussion of clinical implications of these findings. Though it was clear that the complexity and diversity of breast cancer remains a major challenge for translational research, conferences such as IMPAKT enable an important dialogue between basic scientists and clinical investigators to facilitate progress from the bench to the clinic.

FROM THE LITERATURE

The Older You Are, The Less Treatment You Get

Although cancer incidence and mortality risk increases with advancing age, very little is known about the appropriate treatment of women age 80 years and older with breast cancer due to a dearth of knowledge and clinical trial data in this patient population. In the April 20 issue of the Journal of Clinical Oncology, Schonberg et al evaluated variations in breast cancer tumor characteristics, initial treatments received, and survival among women age 80 to 84, 85 to 89, and ≥90 years with early-stage (stage I or II) breast cancer compared with younger women (age 67 to 79 years). Data was obtained by using the National Cancer Institute’s linked Surveillance, Epidemiology and End Results (SEER)-Medicare data set, which identified 49,616 women age 67 years or older who were diagnosed with stage I/II breast cancer between 1992 and 2003. Tumor characteristics, including tumor grade and hormone-receptor status, were similar across all age groups. Multimodality treatment for early-stage breast cancer (breast-conserving surgery plus radiotherapy) decreased with age, while surgery alone increased with age, especially in patients older than 80 years. This relationship was also observed with comorbidity; women with increasing comorbidity were more likely to receive mastectomy or breast-conserving surgery alone. After a median follow-up of 5.6 years, it was observed that the risk of dying from breast cancer increased significantly with age for women age ≥80 years compared to younger women. It is interesting to note that the risk of dying from other causes was greater than the risk of dying from breast cancer for women at all ages and stages. Among women with ER-negative, lymph node–positive disease, chemotherapy reduced breast cancer mortality. A trend for poorer survival was observed in women 80 years or older who received chemotherapy; this may have been due to more aggressive tumors or increased toxicity. The authors conclude that breast cancer characteristics are similar between women age ≥ 80 years and younger women; however, women age ≥80 years receive less aggressive treatment than younger women and experience higher mortality from early-stage breast cancer. Future studies, focusing on patient and tumor characteristics of the oldest old women with breast cancer, are needed to identify treatments which are likely to yield the most benefit in these patients.

J Clin Oncol. 2010;28(12):2038-2045.

An accompanying editorial by Laura Hanson and Hyman Muss in the same issue of Journal of Clinical Oncology noted that, while unmeasured variables such as cognitive function, performance status, and patient preferences may have confounded the reported relationships in the retrospective Schonberg study, such analyses are important to identify where clinical trials might be most helpful (eg, defining the role of chemotherapy in women over 80 years old with hormone receptor–negative tumors). It was reiterated that clinical trials are required to accurately define treatment options for older patients, and such trials should include variables that are capable of highlighting population heterogeneity using geriatric assessment instruments and biomarkers. As patient-reported outcomes rise in importance as life expectancy decreases, geriatric oncology trials should generate evidence for benefits beyond survival.

J Clin Oncol. 2010;28(12):1975-1976.

Cisplatin and Gemcitabine: A New Standard of Care for Advanced Biliary Tract Cancer

Biliary tract cancer, a rare malignancy in developed countries, refers to gallbladder and bile duct cancers, as well as periampullary tumors. Surgical resection is the only curative approach for patients with biliary tract cancer; unfortunately, there is no established standard chemotherapy regimen for patients with unresectable or metastatic disease. The use of gemcitabine (Gemzar®) as palliative treatment for biliary tract cancer was precipitated by the efficacy of this chemotherapeutic agent in pancreatic cancer. Cisplatin is known to have an additive or synergistic effect when used in combination with gemcitabine in a variety of tumor types, and a recent pooled analysis of advanced biliary tract cancer trials suggests that gemcitabine plus a platinum compound may improve response rates in this patient population. Indeed, the efficacy of gemcitabine plus cisplatin was confirmed in a phase II study, ABC-01, which demonstrated an improvement in progression-free survival (PFS) with cisplatin plus gemcitabine compared to gemcitabine alone in patients with locally advanced or metastatic biliary tract cancer. Valle et al extended this trial to ABC-02, a randomized phase III trial in which 410 patients with locally advanced or metastatic cholangiocarcinoma, gallbladder cancer, or ampullary cancer received either cisplatin plus gemcitabine (n = 204) or gemcitabine alone (n = 206). After a median follow-up of 8.2 months, the median survival in the cisplatin-gemcitabine group was 11.7 months compared to 8.1 months for the patients receiving only gemcitabine (P<.001). Median PFS was also significantly improved in the cisplatin-gemcitabine arm compared to the gemcitabine-only arm (8.0 months versus 5.0 months; P<.001). In addition, the rate of tumor control was significantly increased in patients who received cisplatin plus gemcitabine, as compared to patients who received gemcitabine alone (81.4% versus 71.8%, P = .049). The incidence of adverse events was comparable in the two treatment groups, though more neutropenia was experienced by patients receiving cisplatin plus gemcitabine.

An accompanying editorial by Brian Wolpin and Robert J. Mayer concluded that cisplatin plus gemcitabine should be considered a standard treatment option for patients with locally advanced or metastatic biliary tract cancer based on the survival advantage and favorable adverse event profile observed in this trial.

N Engl J Med. 2010;362(14):1273-1281.
N Engl J Med. 2010;362(14):1335-1337.

Resistance to Platinum Decreases Sensitivity to PARP Inhibition

BRCA mutations play a key role in the pathogenesis of hereditary ovarian cancer. Defects in BRCA function resulting in aberrant homologous recombination DNA repair have been shown to be associated with cancer cell sensitivity to poly(ADP)-ribose polymerase (PARP) inhibition and platinum-based chemotherapy. Olaparib, a potent oral PARP inhibitor that is selectively cytotoxic to cells lacking BRCA1 or BRCA2 function, has been shown to possess anticancer activity in a phase I study including patients with ovarian, breast, or prostate cancer harboring a BRCA1 or BRCA2 mutation. Fong et al expanded the initial phase I trial to further evaluate the antitumor activity of olaparib in a cohort of BRCA1 and BRCA2 mutation carriers with advanced ovarian cancer; a post hoc analysis was performed to assess an association between response to olaparib and platinum sensitivity. Of the 50 BRCA mutation carriers with ovarian, primary peritoneal, or fallopian tube cancer enrolled in the study, 48 had germline BRCA1/2 mutations; one patient had a BRCA2 germline sequence change of unknown significance, and another had a strong family history of BRCA1/2-associated cancers but declined mutation testing. Treatment with olaparib resulted in 20 patients (40%) achieving RECIST partial response (PR) or CR and/or tumor marker (CA125) response, and 3 patients (6%) experienced disease stabilization for more than 4 months. The overall clinical benefit rate decreased significantly from 69.2% in platinum-sensitive patients to 45.8% in platinum-resistant patients to 23.1% in the platinum-refractory group, demonstrating a significant association between the clinical benefit rate and platinum-free interval. Olaparib was generally well tolerated, with the most common drug-related toxicities consisting of mild gastrointestinal symptoms and fatigue. These results demonstrate that treatment with olaparib results in antitumor activity in patients with BRCA-mutated ovarian cancer, and these responses correlate with platinum sensitivity; however, olaparib has shown modest antitumor activity in platinum-refractory and resistant disease.

J Clin Oncol. 2010;28(15):2512-2519.

Ofatumumab: Effective New Treatment for Refractory CLL

Fludarabine (Fludara®) has become an essential component of chronic lymphocytic leukemia (CLL) treatment regimens; patients who become refractory to fludarabine-based therapy may derive benefit from alemtuzumab (Campath®), a CD52 monoclonal antibody. Patients with fludarabine-and-alemtuzumab–refractory (FA-ref) CLL or patients with fludarabine-refractory CLL with bulky (>5 cm) lymphadenopathy (BF-ref) who are less suitable for alemtuzumab treatment typically have a poor prognosis. Single-agent ofatumumab, a human monoclonal antibody that targets a unique epitope on the CD20 molecule on the surface of B lymphocytes, has demonstrated efficacy in a phase I/II study evaluating patients with relapsed or refractory CLL. Wierda et al recently reported data from a planned interim analysis of an international, multicenter phase II study of ofatumumab in patients with FA-ref (n = 59) and BF-ref CLL (n = 79). The overall response rate (ORR) was 58% in the FA-ref patients and 47% in the BF-ref patients; in patients who had previously received rituximab (Rituxan®/MabThera®), the ORR was 54% and 44% in the patients with FA-ref and BF-ref disease, respectively. The median PFS was 5.7 months in the FA-ref patients and 5.9 months in the BF-ref patients; median OS was 13.7 months and 15.4 months, respectively. Treatment with ofatumumab resulted in a favorable safety profile in this patient population, with the most common adverse events consisting primarily of grade 1/2 infusion reactions and infections. Overall, these results demonstrate significant activity of single-agent ofatumumab in patients with heavily pretreated FA-ref CLL and BF-ref CLL—poor-risk patient populations. The use of ofatumumab in this setting is further warranted by the observation that similar response rates were observed regardless if patients had received prior rituximab or were refractory to fludarabine plus cyclophosphamide and rituximab, a standard regimen used for earlier treatment of CLL.

J Clin Oncol. 2010;28(10):1749-1755.

Addition of Rituximab to Dexamethasone Improves Outcomes in ITP

Treatment options for adult immune thrombocytopenic purpura (ITP), an acquired autoimmune disease, have historically consisted of glucocorticoids in the first-line and splenectomy as salvage therapy. Thrombopoietin receptor agonists have recently demonstrated efficacy in chronic ITP; but these agents do not target the underling pathophysiology of ITP, and continual administration is required to maintain therapeutic efficacy. Dexamethasone monotherapy given as first-line treatment in adult patients with ITP has resulted in sustained responses, and several studies have reported substantial activity of single-agent rituximab as salvage treatment for ITP. In the April 8 issue of Blood, Zaja et al report results from a prospective phase III study that compared the efficacy of dexamethasone plus rituximab versus dexamethasone alone in treatment-naïve adult patients with ITP. A total of 101 evaluable, previously untreated patients with a platelet count of ≤20 x 10⁹/L were randomized to receive 40 mg/day dexamethasone for 4 days with or without 375 mg/m² rituximab weekly for 4 weeks. The primary objective of the study was to compare the rates of sustained response (SR), defined as a platelet count ≥50 x 10⁹/L at month 6 after treatment initiation. It was found that SR was greater in patients treated with dexamethasone plus rituximab compared to those treated with dexamethasone alone (63% versus 36%; P = .004). Patients initially randomized to receive single-agent dexamethasone who failed to achieve SR received salvage treatment with dexamethasone plus rituximab; in this subgroup, the combination regimen was an effective salvage therapy in 56% of these dexamethasone-refractory patients. The trial was stopped early since the primary efficacy goal had already been achieved at the first interim analysis; thus, the safety evaluation was performed during a shorter period than initially planned. Overall, both treatment arms were well tolerated; patients receiving dexamethasone plus rituximab experienced more grade 3/4 adverse events and drug-related adverse events. The combination of dexamethasone and rituximab may represent an effective treatment option for second-line therapy, particularly in patients not responding to steroids and as an alternative to splenectomy, in adult patients with ITP.

Blood. 2010;115(14):2755-2762.

BRIEF REPORTS

Long-Term Outcome of Gemcitabine in T-cell Lymphoma

Zinzani et al reported the long-term update of 39 heavily pretreated patients with T-cell lymphoma (n = 19 with mycosis fungoides; n = 20 with peripheral T-cell lymphoma) who had been treated with single-agent gemcitabine salvage therapy. The ORR was 51%; the CR and PR rates were 23% and 28%, respectively. These data suggest that gemcitabine provides a long-term clinical benefit in patients with mycosis fungoides and peripheral T-cell lymphoma, regardless of prior treatment failures.

Ann Oncol. 2010;21(4):860-863.

A Single Circulating Tumor Cell Can Predict Survival in Breast Cancer

Using the CellSearch system, Bidard et al prospectively detected circulating tumor cells (CTC) before and after neoadjuvant chemotherapy in 115 patients with nonmetastatic large operable or locally advanced breast cancer in a randomized phase II trial. At baseline, 23% of patients were CTC positive, but only 10% had >1 CTC/7.5 mL of blood. After a median follow-up of 36 months, it was found that pretreatment CTC detection was an independent prognostic factor for both OS (P = .007) and distant metastasis-free survival (P = .01) in this patient population. These findings suggest that detection of a single CTC in the neoadjuvant setting is associated with the subsequent development of metastases. It is hoped that the ongoing GeparQuattro study, a neoadjuvant phase III trial combined with CTC detection, will provide more data and confirm the current results.

Ann Oncol. 2010;21(4):729-733.

Everolimus in Patients with Previously Treated Metastatic Gastric Cancer

Doi et al recently published results from a phase II study evaluating the efficacy and safety of everolimus monotherapy in pretreated patients with advanced gastric cancer. The disease control rate (DCR; CR + PR + stable disease) was 56.0%, and 45% of patients experienced a decrease in tumor size compared to baseline. The median PFS was 2.7 months; at a median follow-up of 9.6 months, median OS was 10.1 months. Adverse events were consistent with reported safety profile of everolimus. Based on these results, further evaluation of everolimus monotherapy in this patient population is warranted in a phase III trial. The authors state that DCR was selected as the primary endpoint in this study because it reflects clinical practice, where disease progression typically leads to a change of treatment.

J Clin Oncol. 2010;28(11):1904-1910.

ADDITIONAL PUBLICATIONS WORTH READING

• Korde LA, Zujewski JA, Kamin L, et al. Multidisciplinary meeting on male breast cancer: Summary and research recommendations. J Clin Oncol. 2010;28(12):2114-2122. This article summarizes a multidisciplinary international meeting on male breast cancer, highlighting differences and similarities of breast cancer in males and females, and provides recommendations for management of this rare disease and future international research in the context of the International Male Breast Cancer Program.
• Neville-Webbe HL, Coleman RE. Bisphosphonates and RANK ligand inhibitors for the treatment and prevention of metastatic bone disease. Eur J Cancer. 2010;46(7):1211-1222. This review article discusses the use of personalized therapy for the management of metastatic bone disease, including the use of bone markers to guide frequency of bisphosphonate administration in metastatic bone disease and bone-targeting agents such as denosumab. Proposed mechanisms of anticancer effects of bisphosphonates and their possible role in early cancers are highlighted.
• Okines A, Sharma B, Cunningham D. Perioperative management of esophageal cancer. Nat Rev Clin Oncol. 2010;7(4):231-238. Since there is currently no international consensus on the optimal management of operable esophageal cancer, this review article summarizes available data from clinical trials and meta-analyses and frames it in the context of current clinical practice.
• Pagani O, Senkus E, Wood W, et al. International guidelines for management of metastatic breast cancer: Can metastatic breast cancer be cured? J Natl Cancer Inst. 2010;102(7):456-463. This commentary summarizes a discussion and related recommendations of the European School of Oncology–Metastatic Breast Cancer Task Force regarding the available therapeutic options for patients with metastatic breast cancer; in particular, options that may be associated with cure in selected patients are highlighted.
• Rades D, Schild SE, Abrahm JL. Treatment of painful bone metastases. Nat Rev Clin Oncol. 2010;7(4):220-9. This review article provides a practical guide for the management of cancer-associated painful bone metastases. In particular, useful recommendations are given regarding the appropriate use of single or multi-fraction radiotherapy.
• Tejpar S, Bertagnolli M, Bosman F, et al. Prognostic and predictive biomarkers in resected colon cancer: Current status and future perspectives for integrating genomics into biomarker discovery. Oncologist. 2010;15(4):390-404. Despite significant methodological progress, colorectal cancer research has not yet provided biomarkers for clinical use in guiding adjuvant colon cancer treatment. This article provides an overview of the current status of biomarker research in the field of colon cancer and discusses the role of integrating genomics into biomarker identification.

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