primeLINES CLINICAL OPINION POLL

OCTOBER 2010 Issue

PHARMA NEWS

FDA Approves New Dosing for Fulvestrant in Metastatic Breast Cancer

On September 10, 2010, the US Food and Drug Administration (FDA) approved the use of fulvestrant (Faslodex^®, AstraZeneca) injection at a dose of 500 mg intramuscularly per month for hormone receptor–positive metastatic breast cancer in postmenopausal women with disease progression following anti-estrogen therapy. The previously approved dosing regimen was 250 mg monthly. The approval was based on results of the randomized phase III CONFIRM (COmparisoN of Faslodex In Recurrent or Metastatic breast cancer) trial, which demonstrated that fulvestrant at a dose of 500 mg significantly improve progression-free survival (PFS; hazard ratio [HR] = 0.80; P = .006) compared with the 250-mg dose (J Clin Oncol. 2010;28(30):4594-4600). Safety and tolerability were comparable for both doses, and there was no decrease in quality of life at the higher dose.

FROM THE LITERATURE

Cost Effectiveness of BRCA Testing in Young Women with Breast Cancer

Women diagnosed with breast cancer before the age of 50 years are an important subgroup for BRCA mutation testing. Those carrying a BRCA mutation are at high risk for subsequent development of breast and ovarian cancer. However, current guidelines do not recommend BRCA mutation testing unless there is a family history of breast or ovarian cancer.

The study reported by Kwon et al was designed to evaluate the cost-effectiveness of BRCA testing in different subpopulations of younger patients with breast cancer. One option would be to test all patients diagnosed before the age of 50 years. However, the prevalence of BRCA mutations is only 8% in this population, and this strategy had an unfavorable incremental cost-effectiveness ratio (ICER) of $112,908 per quality adjusted life year (QALY) gained. An alternative strategy is to focus on breast cancer subtypes that are associated with a high prevalence of BRCA mutations, namely medullary and triple-negative breast cancer. For example, approximately 24% of women diagnosed before the age of 50 years have triple-negative breast cancer, and it is estimated that 17.5% of these women will be BRCA mutation carriers. The authors found that testing women with triple-negative breast cancer who were younger than 50 years at diagnosis was highly cost effective with an ICER of only $9084 per QALY gained. Based on these results, the author concluded that women diagnosed with triple-negative breast cancer before the age of 50 years should be referred for BRCA mutation testing, regardless of family history or ethnicity. Approximately 50% of these women do not have a family history and would not be routinely tested under current guidelines. Confirmed BRCA mutation carriers can benefit from prophylactic surgery to reduce their subsequent cancer risk, and they may benefit from treatment with novel therapies such as poly(ADP-ribose) polymerase (PARP) inhibitors. Furthermore, their unaffected relatives can be offered genetic testing and interventions to prevent breast and ovarian cancer. Therefore, expanding the criteria for BRCA mutation testing to this subgroup of breast cancer patients is cost effective and could contribute significantly to cancer risk reduction for these women and their families.

J Clin Oncol. 2010;28(27):4214-4220.

Molecular Tools Guiding Patient Selection for Adjuvant Chemotherapy in Colon Cancer

Today, the decision whether to give adjuvant chemotherapy to patients with early stage colon cancer is based largely on pathologic staging. Adjuvant therapy with 5-fluorouracil/leucovorin (5FU/LV) plus oxaliplatin or a capecitabine-based regimen is currently standard for stage III disease, but the benefit of adjuvant therapy is less certain in patients with stage II disease. A number of clinicopathologic factors and biomarkers have been studied in an effort to identify a subpopulation of patients with stage II disease who are at higher risk of recurrence and should receive adjuvant chemotherapy, but no unified prognostic index has emerged. This has spurred efforts to identify quantitative gene expression profiles that correlate with risk of recurrence or predict benefit from adjuvant chemotherapy. Several gene signatures have been described and tested in small cohorts of patients, including the 38-gene signature (ColoPrint™) that has been validated in a cohort of 178 patients and is currently undergoing prospective validation in the PARSC study.

The gene signature described by O’Connell and colleagues is new and was developed (using the same technology as Oncotype DX^® in breast cancer) based on analysis of tumor samples from more than 1500 patients treated in four National Surgical Adjuvant Breast and Bowel Project (NSABP) trials with either surgery alone or surgery plus adjuvant 5FU/LV. From a panel of 761 candidate genes, including 375 genes selected based on their functional importance in colon cancer, the investigators identified 48 genes that were significantly associated with risk of recurrence and 66 genes significantly associated with benefit from 5FU/LV. From these sets, 7 genes associated with risk of recurrence and 6 genes associated with benefit from 5FU/LV were selected for inclusion in an algorithm that characterizes patients as having a low, intermediate, or high risk of recurrence and benefit from 5FU/LV. The algorithm will be validated in tumor samples from patients with stage II colon cancer enrolled in the QUASAR study.

In their editorial, Josep Tabernero and José Baselga suggested that gene expression signatures for colon cancer, if validated, are likely to be useful in daily clinical practice and will improve the management of early-stage colon cancer, similar to how gene expression signatures did in breast cancer. However, they also stressed that these gene signatures need to be validated in cohorts of patients treated with modern adjuvant chemotherapy regimens; and there is an ongoing international effort to do that based on tumor tissue from the MOSAIC and NSABP-07 studies. Based on that validation effort, the genes included in these models may need to be revised. In addition, the nature of the genes identified as prognostic are shedding further light on the biology of colon cancer and may ultimately make the current anatomic staging system obsolete or lead to new therapeutic strategies. Therefore, although much work remains to be done, gene signatures for colon cancer appear promising.

J Clin Oncol. 2010;28(25):3937-3944.

J Clin Oncol. 2010;28(25):3904-3907 (editorial).

To Use or Not to Use Consolidative Radiotherapy in Diffuse Large B-Cell Lymphoma? An Age Old Question

Six to eight cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone in combination with rituximab (R-CHOP) with or without consolidation with involved-field radiotherapy (IFRT) or three cycles of R-CHOP with IFRT for early-stage, nonbulky disease are considered as the current standard of care options for patients with diffuse large B-cell lymphoma (DLBCL). However, studies evaluating the role IFRT in early-stage DLBCL were done before the rituximab era, and today many oncologists opt not to use IFRT in favor of additional cycles of R-CHOP. The issue of whether IFRT adds benefit also to the R-CHOP regimen was addressed by the authors of a retrospective analysis of data from 469 patients with histologically confirmed DLBCL treated at M. D. Anderson Cancer Center between 2001 and 2007. The majority of patients (327) included in this analysis received 6 to 8 cycles of R-CHOP, and among 190 patients with stage I or II disease, 54% received IFRT (30 Gy to 39.6 Gy) after complete response to chemotherapy. In stages III and IV, where IFRT is not commonly used, only 39 of 279 patients (14%) received radiotherapy. The variables included in the analysis were age, sex, Ann Arbor disease stage, bulky disease status, standardized uptake values on positron emission tomography (PET), International Prognostic Index (IPI), and Ki67. The benefit of IFRT was seen in both univariate and multivariate analysis across all disease stages and regardless of disease bulk. In the subset of patients with stage I or II disease, addition of IFRT significantly (P = .007) improved both 5-year PFS (82% vs 73%) and 5-year overall survival (92% versus 73%) compared with R CHOP alone.

In the accompanying editorial, Joachim Yahalom from Memorial Sloan-Kettering Cancer Center discussed the weight of evidence from this retrospective analysis in the context of a long line of studies conducted over the years that demonstrate the benefit of adding IFRT to CHOP chemotherapy in patients with early stage, nonbulky DLBCL. Although the results of this retrospective study strengthen the role of IFRT, the saga of radiotherapy in early-stage DLBCL has not yet ended said Yahalom, and it is unlikely that a randomized study to confirm the role of IFRT will happen soon. He also emphasized that results from M. D. Anderson Center regarding radiotherapy in advanced DLBCL are interesting and the value of consolidation radiotherapy in advanced-stage disease should be revaluated in an intelligently designed trial using the new lymphoma and radiation oncology tools that have been developed in the last two decades.

J Clin Oncol. 2010;28(27):4170-4176.

J Clin Oncol. 2010;28(27):4105-4107 (editorial).

Targeting Mutant BRAF: An Effective Treatment Strategy for Melanoma

The long search for a viable target in melanoma seems finally to be over. Although it has been known since 2002 that approximately 50% of melanomas have an activating mutation in BRAF (the V600E mutation), the first BRAF inhibitor, sorafenib, has not demonstrated substantial activity in melanoma. However, the data presented by Flaherty et al suggest that inhibition of mutant BRAF with a novel inhibitor known as PLX4032 may have tremendous therapeutic potential against melanoma that harbors the V600E mutation. These investigators reported impressive response rates in a phase I/II dose-escalation study. In the dose-escalation phase (N = 55), the major dose-limiting toxicity was grade 2 or 3 rash, fatigue, and arthralgia. Most notably, among 32 melanoma patients with confirmed V600E mutations who were enrolled in the extension cohort and treated at the recommended phase II dose of 960 mg twice daily, 24 (75%) had a partial response and 2 (6%) had a complete response. The estimated median PFS among all patients was more than 7 months. Indeed, numbers like this in metastatic melanoma are exciting.

In the accompanying editorial, Keiran Smalley and Vernon Sondak from the H. Lee Moffitt Cancer Center and Research Institute in Florida discuss some caveats to the enthusiasm over these results. First and foremost is the issue of acquired and intrinsic resistance. As seen with other BRAF inhibitors, tumor cells can rapidly acquire resistance through a variety of escape routes that allow the MAP kinase pathway to remain active or shift signaling to other pathways. Possible reasons for intrinsic resistance in patients with V600E BRAF mutation could be lack of phosphatase and tensin homologue (PTEN) function or cyclin D1 amplification which enable melanoma cells to survive and proliferate when BRAF is inhibited. Therefore, it may be necessary to target multiple signaling molecules within the MAP kinase pathway and/or simultaneously inhibit alternative pathways. A multitargeted approach, as in combining CTLA4 blockade with BRAF inhibition may be the way to achieve durable clinical responses and meaningful improvements in overall survival. They also point out that screening for BRAF mutations is critical because, for reasons that are not well understood, treating a tumor that has wildtype BRAF mutation with an inhibitor such as PLX4032 can paradoxically stimulate MAP kinase-mediated proliferation in cell lines lacking BRAF mutation. This phenomenon also may account for the high incidence of keratoacanthomas (a cutaneous form of squamous-cell carcinoma) among patients treated with PLX4032. In this study, approximately 30% of patients developed these secondary tumors. Nevertheless, Smalley and Sondak acknowledge that the data reported by Flaherty et al represent a major breakthrough in the treatment of metastatic melanoma, and that prospects for patients with metastatic melanoma have never been brighter, but also the need for further translational research has never been greater.

N Engl J Med. 2010;363(9):809-819.

N Engl J Med. 2010;363(9):876-878 (editorial).