primeLINES CLINICAL OPINION POLL

MARCH 2010 Issue

PHARMACEUTICAL NEWS

European Approval for Pazopanib: A New Option for Renal Cell Carcinoma

On February 18, 2010, the European Medicines Agency (EMEA) adopted a positive opinion regarding the use of GlaxoSmithKline’s pazopanib (Votrient™) for the first-line treatment of advanced renal cell carcinoma (RCC) and for patients who have received prior cytokine therapy for advanced RCC. The favorable recommendation, following US Food and Drug Administration (FDA) approval on October 19, 2009, is based on results from a pivotal double-blind, phase III study in which pazopanib demonstrated significant improvement in progression-free survival (PFS) and tumor response compared with placebo in treatment-naïve and cytokine-pretreated patients with advanced and/or metastatic RCC.

A Second Anti-CD20 Antibody Available in Europe for Chronic Lymphocytic Leukemia

On January 20, 2010, GlaxoSmithKline and Genmab’s novel anti-CD20 antibody, ofatumumab (Arzerra™), received a positive recommendation from the EMEA for use in patients with chronic lymphocytic leukemia (CLL) who are refractory to fludarabine and alemtuzumab; ofatumumab was approved by the FDA on October 26, 2009.

Expanded Indication for Rituximab

On February 18, 2010, the FDA approved Genentech’s rituximab (Rituxan^®/MabThera^®) in combination with fludarabine and cyclophosphamide (FC) for the treatment of previously untreated and previously treated patients with CD20-positive CLL. This new indication for rituximab is based on results from two randomized multicenter open-label phase III trials, CLL8 and REACH, that demonstrated clinically meaningful and statistically significant increases in PFS in patients treated with FC plus rituximab compared with patients treated with FC alone. Rituximab was initially approved for single-agent treatment of relapsed or refractory low-grade or follicular CD20-positive non-Hodgkin lymphomas (NHL). Subsequently, its indication was extended to include first-line therapy in combination with chemotherapy for follicular and diffuse, large B-cell CD20-positive NHL and as maintenance therapy after response to induction therapy for follicular NHL.

FROM THE LITERATURE

Can Aspirin Improve Survival in Breast Cancer?

Much publicity has recently been given to a study evaluating whether aspirin use among women with breast cancer decreased their risk of death from breast cancer. Results of this prospective observational analysis by Michelle Holmes et al were published in the March 20 edition of the Journal of Clinical Oncology. While animal and in vitro studies have demonstrated that aspirin may inhibit breast cancer metastasis, it is not clear if such a relationship exists in women with breast cancer. The current study sought to address this issue by obtaining data regarding aspirin use from 4164 female registered nurses in the Nurses’ Health Study (NHS) who were diagnosed with stages I, II, or III breast cancer between 1976 and 2002 and were observed until death or June 2006, whichever came first. There were 341 breast cancer deaths, 400 distant recurrences (including the 341 breast cancer deaths), and 732 deaths from any cause in this patient population.

Among women living at least 1 year after a diagnosis of breast cancer, the risk reduction for distant metastasis was 43% and 60% for patients receiving aspirin 6-7 days per week and 2-5 days per week, respectively. In comparison to nonusers, aspirin use was associated with a 64% reduction in the risk for breast cancer–related mortality for patients using aspirin 6-7 days/week and 71% for those receiving aspirin 2-5 days/week. These results did not differ substantially when stratified by stage, body mass index, menopausal status, or estrogen receptor status. The authors conclude that, if further studies confirm these data, the therapeutic options available to reduce breast cancer–related morbidity and mortality may be expanded. Indeed, while these data are promising, important questions must be addressed before a change in clinical practice takes place: How does aspirin improve survival? What dose, and for how long, should be aspirin given to achieve the desired results? It is important to note that the current study does not include details on aspirin dose; only the frequency of use is reported. The authors acknowledge this limitation and state that the size of the effect observed in the current study may have been diminished because frequent aspirin users are more likely to be low-dose users attempting to prevent heart disease. The unknown efficacy of aspirin as breast cancer prophylaxis was also discussed, with the authors stating that the association between aspirin use and breast cancer incidence remains inconclusive, despite meta-analyses where either aspirin or nonsteroidal anti-inflammatory (NSAID) use has shown a 9% to 30% reduced risk for breast cancer incidence.

J Clin Oncol. 2010;28(9):1467-1472.

Neoadjuvant Trastuzumab for Locally Advanced and Inflammatory HER2-Positive Breast Cancer

Amplification and/or overexpression of HER2, which is associated with aggressive course of disease and poor prognosis, is observed in 35% of patients with locally advanced and metastatic breast cancer and 40% of inflammatory breast cancers. Trastuzumab (Herceptin^®), a monoclonal antibody targeting HER2, has demonstrated efficacy in patients with HER2-positive early and metastatic breast cancer and is currently approved for use in metastatic and early disease, but not specifically for patients with locally advanced or inflammatory breast cancer. Luca Gianni et al recently reported results from the phase III randomized NeOAdjuvant Herceptin (NOAH) study, which assessed efficacy of neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab (n = 117) versus neoadjuvant chemotherapy alone (n = 118) in patients with HER2-positive locally advanced or inflammatory breast cancer. The neoadjuvant chemotherapy regimen consisted of 3 cycles of doxorubicin-paclitaxel therapy, followed by 4 cycles of paclitaxel, and ended with 4 cycles of CMF (cyclophosphamide/ methotrexate/fluorouracil). After positive results of adjuvant trastuzumab trials became available, HER2-positive patients who had been randomized to chemotherapy alone were offered 1 year of adjuvant post-surgery trastuzumab. A parallel HER2-negative cohort (n = 99) received the same chemotherapy as the HER2-positive group, but without trastuzumab.

After a median follow-up of 3.2 years, data from NOAH demonstrated that addition of trastuzumab to chemotherapy significantly improved event-free survival (EFS), the primary endpoint of the study, in patients with HER2-positive breast cancer (3-year EFS, 71% with trastuzumab versus 56% without; HR = 0.59; P = .013). Subgroup analysis including patients with inflammatory breast cancer demonstrated a consistent advantage in favor of trastuzumab with respect to EFS. Event-free survival was comparable in patients with HER2-positive disease who were not given trastuzumab and patients with HER2-negative cancer receiving the same regimen. Local, regional, and distant recurrences occurred less frequently in patients with HER2-positive breast cancer treated with trastuzumab compared to those with HER2-positive cancer treated with chemotherapy alone. The addition of trastuzumab to chemotherapy significantly improved rates of pathologic complete response (in breast and axilla) in patients with HER2-positive disease (38% versus 19%, P = .001); only 16% of the HER2-negative patients had complete pathologic responses. Interestingly, adverse events were similar in the 3 treatment groups. There was no increase in grade 3 and 4 noncardiac toxic effects in patients receiving trastuzumab, and, despite concurrent administration with doxorubicin, only 2 patients (1.7%) developed symptomatic cardiac failure; indeed, the observed incidence of symptomatic cardiac failure was less than expected based on previously reported data from adjuvant trials of trastuzumab. These data support increasing evidence that trastuzumab can be given concurrently with anthracyclines with a low frequency of symptomatic cardiac dysfunction. The authors conclude that the addition of 1 year of trastuzumab (starting as neoadjuvant and continuing as adjuvant) to neoadjuvant chemotherapy should be offered to patients with HER2-positive locally advanced or inflammatory breast cancer.

Lancet. 2010;375(9712):377-384.

An accompanying editorial by Melanie Seal and Stephen Chia commented on the NOAH trial, specifically the significance of low rates of cardiotoxicity. An earlier pivotal study by Dennis Slamon et al demonstrated a 27% cardiotoxicity rate in patients with HER2-positive breast cancer receiving concurrent anthracycline and trastuzumab for advanced breast cancer; thus, there became a perception that these 2 agents could not be safely administered together in clinical practice. This is in contrast to the NOAH trial, in which only 2 patients had clinical congestive heart failure (1.7%) and another 2 patients (1.7%) experienced a fall in left ventricular function. Similar low rates of cardiotoxicity were observed in 2 other neoadjuvant trials combining trastuzumab and epirubicin. The authors state that concomitant administration of trastuzumab and anthracyclines could be considered in patients with high-risk disease, specifically locally advanced or inflammatory breast cancer, due to the sensitivity of HER2-positive breast cancer to anthracyclines and additive or synergistic effects of this combination. Factors such as low cumulative dose of anthracycline and high baseline left ventricular ejection fraction might contribute to decreased rate of cardiotoxicity. It was also noted that neoadjuvant trials should be increasingly pursued and should challenge the dogma of our current strategies of therapeutic trials in early-stage breast cancer.

Lancet. 2010;375(9712):349-350.

mTOR Inhibition: A New Therapeutic Target in Waldenström Macroglobulinemia

Waldenström Macroglobulinemia (WM) is a rare and incurable B-cell hematologic malignancy that is characterized by bone marrow infiltration with lymphoplasmacytic cells and the demonstration of immunoglobulin M (IgM) monoclonal gammopathy. Patients with a disease- related hemoglobin level of less than 100 g/L, platelet count less than 100 x 10⁹/L, bulky adenopathy or organomegaly, symptomatic hyperviscosity, severe neuropathy, amyloidosis, cryoglobulinemia, cold-agglutinin disease, or evidence of disease transformation should be considered for therapy. Front-line treatment options for WM include oral alkylators, nucleoside analogues, rituximab, and combinations of these agents. In the salvage setting, the re-use or use of an alternative front-line regimen can be considered, as well as bortezomib, alemtuzumab, and stem cell transplantation.

Preclinical studies in lymphoma and multiple myeloma have demonstrated that mammalian target of rapamycin (mTOR) inhibition has a significant antiproliferative effect on malignant B cells. Response rates of 40% have been demonstrated in clinical trials evaluating the use of temsirolimus, an mTOR inhibitor, in patients with mantle cell lymphoma and other B-cell NHLs. Studies have also demonstrated that Akt, a key member of the phosphatidylinositol 3-kinase (PI3K) pathway upstream of mTOR, is constitutively activated in bone marrow from patients with WM. These laboratory and clinical data provided the impetus for Irene Ghobrial et al to perform a phase II clinical trial evaluating the antitumor activity and safety of single-agent everolimus (Afinitor^®), an oral mTOR inhibitor, in patients with relapsed/refractory WM. Fifty patients, treated with 10 mg everolimus daily, were eligible for analysis; the median age was 63 years. Ninety-six percent of patients had received prior rituximab-based therapy and 64% of the patients had received prior alkylator-based therapies. The overall response rate was 70% [complete response (0%), partial remission (42%) and minimal response (28%)], and 16% of patients experienced disease stabilization while receiving treatment with everolimus. The median duration of response and progression-free survival had not been reached at the time of publication, which is particularly encouraging based on previously reported median durations of response from monotherapy with rituximab or bortezomib as 12 months or less in this patient population. Grade 3 or higher toxicities were observed in 56% of patients, with the most common adverse events occurring as hematologic toxicities with cytopenias. Dose reductions due to toxicity occurred in 52% of patients, and pulmonary toxicity was observed in 10% of patients. Based on the high level of single-agent efficacy and manageable toxicity observed with everolimus, the authors conclude that mTOR inhibition may offer a new therapeutic strategy for patients with relapsed/refractory WM. However, since no patients in this trial achieved a complete response, further studies are needed to elucidate mechanisms of potential resistance to mTOR inhibition in lymphoplasmacytic cells.

J Clin Oncol. 2010;28(8):1408-1414.

What Defines “Resistance” to Tyrosine Kinase Inhibitors in Metastatic Renal Cell Carcinoma?

An interesting case report presented by Alain Ravaud et al illustrates the challenge presented by defining “resistance” to vascular endothelial growth factor receptor-platelet derived growth factor receptor (VEGFR-PDGFR) tyrosine kinase inhibitors (TKIs). Previous reports suggest that patients with metastatic renal cell carcinoma (mRCC) should be treated in the first-line with sunitinib (Sutent^®), and patients progressing on sunitinib or sorafenib (Nexavar^®), or both, should be given everolimus. It is assumed that progression on sunitinib and/or sorafenib indicated resistance to this class of agents; however, the following clinical scenario requires reconsideration of this dogma.

A 60-year-old male patient underwent nephrectomy for clear cell RCC, and was considered to be in the intermediate-risk group. Due to lung and mediastinal lymph node metastases, he was treated initially with sorafenib; however, this was prematurely stopped due to a severe cutaneous reaction. Treatment was then followed by sunitinib, resulting in a prolonged (12 months) RECIST-confirmed partial response. At the time of disease progression, he received everolimus, which produced stable disease for 5 months; ultimately, there was progression of all tumor sites and appearance of new lesions in the brain and bones. It was thought that re-exposing this patient to sunitinib 50 mg/day, which was the most active agent in his medical history, could induce a clinical benefit. Indeed, sunitinib was initiated and partial response according to RECIST criteria was observed. At the time of report, this patient is still on sunitinib at 7 months. The authors state this demonstrates that a change in treatment, and subsequent rechallenge with initial treatment, could lead to optimization of sequential therapies in patients with mRCC.

Ann Oncol. 2010;21(2):431-432.

ADDITIONAL PUBLICATIONS WORTH READING

• Bladé J, Dimopoulos M, Rosiñol L, Rajkumar SV, Kyle RA. Smoldering (asymptomatic) multiple myeloma: Current diagnostic criteria, new predictors of outcome, and follow-up recommendations. J Clin Oncol. 2010;28(4):690-697. This publication provides a comprehensive overview of smoldering (asymptomatic) multiple myeloma, including diagnosis, predictors and pattern of progression, and overall outcome.
• Casper C, Englund J, Boeckh M. How I treat influenza in patients with hematologic malignancies. Blood. 2010;115(7):1331-1342. This report summarizes the clinical manifestations of seasonal and 2009 H1N1 influenza, and focuses on current diagnostic, treatment, and prevention options in immunocompromised patients.
• Robson ME, Storm CD, Weitzel J, et al. American Society of Clinical Oncology policy statement update: Genetic and genomic testing for cancer susceptibility. J Clin Oncol. 2010;28(5):893-901. In response to significant developments in the field of genetics, the American Society of Clinical Oncology released an updated statement regarding cancer genetic testing, including topics such as informed consent, privacy, and counseling.

RECENTLY PUBLISHED, PREVIOUSLY REPORTED

A new feature in primeLINES, the RECENTLY PUBLISHED, PREVIOUSLY REPORTED section will provide links to published articles of important clinical trials that have been previously reported in primeLINES when initially presented at major international conferences.

• Blackwell KL, Burstein HJ, Storniolo AM, et al. Randomized study of lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer. J Clin Oncol. 2010;28(7):1124-1130. Previously reported in the July 2008 and January 2010 issues of prIMELINES.
• Burstein HJ, Sun Y, Dirix LY, et al. Neratinib, an irreversible ErbB receptor tyrosine kinase inhibitor, in patients with advanced ErbB2-positive breast cancer. J Clin Oncol. 2010;28(8):1301-1307. Previously reported in the December 2008/January 2009 issue of prIMELINES.
• Sternberg CN, Davis ID, Mardiak J, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: Results of a randomized phase III trial. J Clin Oncol. 2010;28(6):1061-1068. Previously reported in the June 2009 issue of prIMELINES.

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