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	Gynecologic Cancer

primeLINES CLINICAL OPINION POLL

September 2011 Issue

At Long Last, Treatment Options for Advanced Melanoma Are Expanding

On August 17, 2011, the US Food and Drug Administration (FDA) approved vemurafenib (Zelboraf^®, Genentech, Inc/Hoffman-La Roche) for patients with unresectable or advanced melanoma harboring the BRAF^V600E mutation and also approved a companion diagnostic test (Cobas^® 4800 BRAF V600 Mutation Test, Roche Diagnostics). In the pivotal trial in 675 patients with BRAF^V600E mutation, vemurafenib, in comparison to dacarbazine, significantly improved response rate (48% vs 5%, P<.001) and reduced the risk for disease progression and death by 74% and 63%, respectively (P<.001). Additionally, on July 14, 2011, European regulators approved the anti-CTLA4 antibody ipilimumab (Yervoy^®, Bristol-Myers Squibb) for the treatment of patients with previously-treated advanced melanoma based on results from a randomized phase III trial that demonstrated a significant overall survival benefit in this setting. Ipilimumab was approved by the FDA earlier this year and received a broader indication to include first-line therapy of advanced melanoma.

Brentuximab Vedotin Approved for Progressive Hodgkin Disease and Anaplastic Large Cell Lymphoma

On August 19, 2011, the FDA granted accelerated approval to brentuximab vedotin (SGN-35, Adcetris^®, Seattle Genetics) to treat Hodgkin lymphoma (HL) and a rare type of non-Hodgkin lymphoma known as systemic anaplastic large cell lymphoma (ALCL). Brentuximab vedotin combines an anti-CD30 antibody with a powerful cytotoxin (monomethyl auristatin E) to target lymphoma cells. The approved indication is for patients with HL whose disease has progressed after autologous stem cell transplant or for patients who cannot receive a transplant and for whom at least 2 prior chemotherapy regimens have failed. For patients with ALCL, brentuximab vedotin may be used if their disease has progressed after one prior chemotherapy. Both indications were approved based on results of single-arm trials for progressive HL and ALCL with high overall response rates of 73% and 86%, respectively. Brentuximab vedotin represents the first new treatment option for these patient populations in many years and confirmatory trials are ongoing.

FDA Approves Crizotinib for ALK-Positive Non-Small Cell Lung Cancer

On August 26, 2011, the FDA granted accelerated approval to crizotinib (Xalkori^®, Pfizer), an oral anaplastic lymphoma kinase (ALK) inhibitor, for patients with non-small cell lung cancer (NSCLC) harboring a gene rearrangement involving the ALK oncogene. Crizotinib safety and efficacy were evaluated in two multicenter phase II clinical trials with 255 patients with ALK-positive metastatic NSCLC. In both studies, a response rate over 50% and duration of response of more than 40 weeks were demonstrated. Similar to vemurafenib, crizotinib is effective only in a selected patient population with the abnormal ALK gene; approximately 7% of NSCLCs are ALK-positive (roughly 10,000 cases per year in the United States). Fluorescence in situ hybridization (FISH) is required to detect the chromosomal translocation that activates ALK. Therefore, the FDA also approved a companion diagnostic test called the Vysis ALK Break Apart FISH Probe Kit (Abbott Molecular).

Olaparib Active in Ovarian Carcinomas With and Without BRCA Mutations

The clinical development of poly(ADP-ribose) polymerase (PARP) inhibitors in oncology has a solid biologic rationale based on their activity in BRCA1-deficient and BRCA2-deficient tumors. Roughly 5% to 10% of breast and ovarian cancers have a germline BRCA mutation. However, it has long been suspected that PARP inhibitors might also have activity in some sporadic tumors because of somatic BRCA mutations. The tumors long thought to be good candidates are sporadic triple-negative breast cancer (TNBC) with a basal-like phenotype and high-grade serous ovarian carcinoma because they share many pathologic and molecular features with breast and ovarian cancers harboring hereditary BRCA mutations. That hypothesis was directly tested by Karen Gelmon (British Columbia Cancer Agency, Vancouver, Canada) and colleagues in a phase II study. They observed objective responses in 24% of patients with advanced high-grade serous and/or undifferentiated ovarian carcinoma without a germline BRCA mutation who were treated with oral olaparib (400 mg twice daily). In contrast, no objective responses were observed in 16 patients with non-BRCA TNBC.

In an accompanying editorial, Melinda Telli (Stanford University School of Medicine, Stanford, California, United States) commented that this study appears to confirm the hypothesis that subsets of patients with common sporadic tumors may be sensitive to PARP inhibitors. Indeed, this is the first study to demonstrate single-agent clinical activity of a PARP inhibitor in sporadic tumors without germline BRCA mutations. These findings suggest that a substantial proportion of high-grade serous and/or undifferentiated ovarian carcinomas may be good candidates for treatment with a PARP inhibitor. The absence of objective responses to single-agent olaparib in women with sporadic TNBC is also an important finding. Although the numbers were small and patients were heavily pretreated, this casts further doubt on whether sporadic TNBC is truly "BRCA-like". Dr Telli concluded that PARP inhibitors have encountered many obstacles in their clinical development pathway, but this study "marks a new beginning to what will hopefully be a long and fruitful future for PARP inhibitors as they make their move beyond BRCA."

Lancet Oncol. 2011;12(9):852-861.

Lancet Oncol. 2011;12(9):827-828. (Editorial)

The Importance of Biopsy in Melanoma Patients With New Lung Lesions

This retrospective analysis of 229 patients with melanoma who underwent biopsy of a suspicious new lung lesion from 1996 to 2009 at Memorial Sloan-Kettering Cancer Center set out to examine factors predictive of biopsy results positive for melanoma. The investigators also wanted to find out if positron emission tomography (PET) scanning might decrease the need for biopsy of such lesions. The results showed that, in 31% of patients, the new lung lesions were not melanoma. In 12% of cases they were benign lesions, and in 19% they were malignant nonmelanoma lesions (14% were potentially curable primary lung cancers). Multivariate analysis showed that 4 variables were significantly associated with the lung lesions being metastatic melanoma, including stage II or greater melanoma at initial diagnosis, nonsmoking status, no prior malignancy, and the presence of multiple lung nodules. Moreover, PET scans did not differentiate between benign and malignant lesions or between melanoma and nonmelanoma lesions. Therefore, the authors concluded that a PET scan adds little information and that current National Comprehensive Cancer Network guidelines recommending biopsy of new lung lesions should be followed to obtain an accurate histologic diagnosis prior to treatment planning.

Ann Oncol. 2011 Aug 4. [Epub ahead of print].

Rituximab Plus Bendamustine for Elderly Patients With Aggressive B-Cell Lymphoma

Rituximab plus combination chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is widely recommended for the treatment of aggressive B-cell lymphoma. However, elderly patients are often not eligible for this aggressive chemotherapy regimen and there is a need for alternative treatment options for these patients. In a small phase II study, investigators from Germany tested rituximab plus bendamustine in 14 elderly patients (≥80 years of age) with aggressive B-cell lymphomas who were either not eligible for R-CHOP (at their physicians' discretion) or did not agree to aggressive treatment. Seven patients (54%) had a complete response and two (15%) had a partial response. Although the median overall survival was only 7.7 months, 6 patients (43%) were alive without disease 20 months to 72 months from the start of treatment. More importantly, the toxicity of this regimen was low. The most severe toxicity was neutropenia (17% grade 3 and 6% grade 4). Therefore, the authors concluded that rituximab plus bendamustine may be a good alternative for elderly patients who are not eligible for R-CHOP.

Ann Oncol. 2011;22(8):1839-1844.

PET-CT Predictive for Clinical Outcome in Follicular Lymphoma

Investigators from the Prospective Primary Rituximab and Maintenance (PRIMA) study conducted a retrospective analysis to determine the prognostic significance of [¹⁸F]fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) performed after first-line immunochemotherapy in patients with follicular lymphoma. Although the utility of PET-CT for assessing response to induction therapy is well documented in Hodgkin lymphoma and diffuse large B-cell lymphoma, its role in follicular lymphoma remains unproven. The results of their analysis clearly showed that patients who remained positive by PET-CT after induction therapy had significantly worse progression-free survival at 42 months (32.9% versus 70.7%) and inferior overall survival (hazard ratio = 7.0; P = .0011) compared with patients who were PET-CT negative. In a multivariate Cox proportional hazards model, PET-CT−positive status was also an independent predictor of lymphoma progression. The authors concluded that in patients with follicular lymphoma, PET-CT status after induction immunochemotherapy is strongly predictive of clinical outcome and should be considered a meaningful clinical endpoint in future studies.

J Clin Oncol. 2011;29(23):3194-3200.

Should The Method for Cervical Cancer Screening Change?

Liquid-based cervical cytology is the standard method for cervical cancer screening in most developed countries, but more sensitive and cost-effective methods are needed. Assays for human papillomavirus (HPV) DNA testing are also used as an adjunct to cytology in wealthier nations, and their role in cervical cancer screening and triage for colposcopy continues to evolve. The ATHENA (Addressing THE Need for Advanced HPV diagnostics) substudy reported in the August 23 issue of The Lancet Oncology by Philip Castle (American Society for Clinical Pathology Institute, Washington, DC, United States) and colleagues examined the screening performance of the second-generation Cobas^® HPV Test for separate HPV-16 and HPV-18 genotype detection in comparison to liquid-based cytology on cervical specimens from 41,955 women aged 25 years or older. The primary endpoint for this substudy was histologically confirmed cervical intraepithelial neoplasia grade 3 (CIN3) or worse.

The results of this analysis showed that in women who had colposcopy performed, the Cobas HPV Test was more sensitive than cytology for detection of CIN3 or worse. However, as a triage test to identify CIN3 or worse in HPV-positive women, sensitivity and positive predictive value were similar to abnormal cytology. Importantly, however, HPV test results were much more consistent than cytology across assessment laboratories. Addition of cytology to HPV testing increased sensitivity for CIN3 or worse but at the cost of increasing the number of screen positives by 35.2%. The authors concluded that HPV testing with separate HPV-16 and HPV-18 detection could provide an alternative, more sensitive and efficient strategy for cervical cancer screening than methods based solely on cytology. In his editorial, Guglielmo Ronco (Centre of Cancer Prevention, Turin, Italy) indicated that co-testing of HPV and cytology will probably be replaced by stand-alone HPV testing as the primary screening test in high income countries, because the addition of cytology seems to provide little additional sensitivity.

Lancet Oncol. 2011;12(9):880-889.

Lancet Oncol. 2011;12(9):831-832. (Editorial)

Exploring Autoimmunity Associated With Cancer Immunotherapy. Immunotherapy is a new emerging treatment option for several cancers, but can lead to immune reactions against normal tissues ranging from minor conditions, such as vitiligo, to severe reactions against the liver, bowel, and lung. This review describes current immunotherapeutic approaches to cancer treatment, provides details of associated toxicities, and discusses potential ways to mitigate these side effects. Blood. 2011;118(3):499-509.
Advances in the Diagnosis, Classification, and Treatment of NSCLC. This comprehensive review covers a wide range of important advances in the pathology and classification, diagnosis, and treatment of NSCLC over the past 10 years. Lancet. 2011 May 10. [Epub ahead of print].
The Changing Therapeutic Landscape of Castration-Resistant Prostate Cancer (CRPC). This review describes recent advances in the treatment of CRPC, which include: the novel taxane, cabazitaxel; the vaccine, sipuleucel-T; the CYP17 inhibitor, abiraterone; the novel androgen-receptor antagonist, MDV-3100; and the radioisotope, alpharadin. The authors also propose a treatment pathway and strategies to optimize the use of these agents, including the incorporation of predictive and intermediate-endpoint biomarkers. Nat Rev Clin Oncol. 2011 Aug 9. [Epub ahead of print].