p r i m e l i n e s

On June 25, 2009, the scientific advisory committee of European Medicines Agency (EMEA) issued a positive opinion supporting approval and recommending to grant marketing authorization for vinflunine (Javlor^®), for the second-line treatment of transitional cell carcinoma of the urothelium. Vinflunine is a new vinca alkaloid marketed by Pierre Fabre Médicament. The recommendation for approval was based on results from two phase II studies and the only phase III randomized study ever conducted in patients with metastatic bladder cancer comparing vinflunine and best supportive care versus best supportive care alone in platinum pretreated patients. In the 351 patients treated per protocol in the phase III study, overall survival was significantly longer for vinflunine. Vinflunine will be indicated as monotherapy for the treatment of adult patients with advanced or metastatic transitional cell carcinoma of the urothelial tract after failure of a prior platinum-containing regimen. This drug is not yet approved by the US Food and Drug Administration (FDA).

From the Business World: A Strategic Buy for Bristol-Myers Squibb to Strengthen their Biotech Portfolio?

On July 22, 2009, Bristol-Myers Squibb (BMS) Company and Medarex, Inc. announced that the companies have signed a definitive merger agreement for the acquisition of Medarex by BMS for approximately $2.4 billion. As a result of the merger, BMS will acquire a number of important assets, including

There is no single standard of care for patients with metastatic breast cancer (MBC) and an individualized approach considering tumor biology, growth rate of disease, response to previous treatments, patient characteristics and preference is required for each patient.

Both capecitabine (Xeloda^®) and vinorelbine (Navelbine^®) have demonstrated clinical activity as single agents in the treatment of MBC. Preclinical models suggest that these two agents, which possess different mechanisms of action and non-overlapping safety profiles, may have synergistic antitumor activity. Therefore, the combination of capecitabine with oral vinorelbine is an attractive option for patients with MBC, particularly given that most patients with metastatic disease will have already been treated with an anthracycline and taxane in the adjuvant or neoadjuvant setting.

An international, open-label, phase II trial was conducted to evaluate the activity and safety of this combination as first-line therapy in women with HER2-negative MBC. A total of 54 patients were treated with 3-week cycles of oral vinorelbine (80 mg/m² on day 1 and day 8) plus capecitabine (1000 mg/m² twice daily on days 1-14; patients ≥65 years of age received 750 mg/m² capecitabine) until disease progression. The majority of patients (63%) had received earlier neoadjuvant or adjuvant chemotherapy with an anthracycline-based regimen. Among 49 evaluable patients, the RECIST response rate was an impressive 51%, including complete response in 2 (4%) patients. Median progression-free survival was 8 months, and median overall survival (OS) was 29 months. Moreover, there was a low incidence of alopecia, and the most frequently reported grade 3/4 adverse events were neutropenia (49%) and leukopenia (28%), which were manageable.

Based on these results the authors concluded that this is an effective and well-tolerated first-line regimen in patients with MBC. Given the favorable activity and manageable toxicity profile of this all-oral regimen, it will most likely be well received by patients. However, oral vinorelbine, while approved in Europe, is not yet available in the United States.

In the July 10 issue of the Journal of Clinical Oncology, Jiralerspong and colleagues report the results of a retrospective cohort study to investigate whether metformin, a widely prescribed oral medication used as first-line therapy for type 2 diabetes, improves the pathologic complete response (pCR) rate to neoadjuvant chemotherapy in patients with early-stage breast cancer. Results from population studies have suggested that metformin decreases the incidence of cancer and cancer-related mortality in patients with diabetes. In addition, metformin has been shown to inhibit the growth of breast cancer cells in vitro and inhibit tumor growth in animal models. Although its precise antitumor mechanism(s) of action is not known, metformin is known to activate adenosine monophosphate activated protein kinase (AMPK), which plays a key role in regulating many metabolic pathways in the liver, including gluconeogenesis, and inhibits protein synthesis and cell division. Thus, metformin may inhibit growth of breast cancer either directly via antiproliferative effects or indirectly by reducing hyperinsulinemia associated with type 2 diabetes, but clinical data are lacking. Therefore, the authors hypothesized that metformin might increase the effectiveness of neoadjuvant chemotherapy in diabetic patients with breast cancer.

They identified 2529 patients who received neoadjuvant chemotherapy for early-stage breast cancer between 1990 and 2007, including 68 diabetic patients taking metformin and 87 diabetic patients not taking metformin. The pCR and recurrence rates in these two subgroups were compared and were also compared with those in the subgroup of 2374 nondiabetic patients. In addition, various factors predictive of pCR were assessed using a multivariate logistic regression model. They observed that the pCR rate was 24% in the metformin group versus 8% in the nonmetformin group of diabetic patients (P = .007) and 16% in the nondiabetic group. Metformin use was also independently predictive of pCR rate (odds ratio = 2.95; P = .04) after adjusting for a variety of prognostic factors such as body mass index, age, tumor stage and grade, hormone receptor status, and neoadjuvant taxane use. Therefore, the authors concluded that metformin may improve pCR to neoadjuvant chemotherapy, but there were no differences in the rates of disease recurrence among the three groups, and both diabetic groups had worse OS compared with the nondiabetic group (P = .02). Potential confounding factors included different rates of insulin therapy in the two groups of diabetic patients, and potential effects of metformin on hyperinsulinemia.

Based on the results of this study and the accumulated evidence that metformin may play an important role in breast cancer, the National Cancer Institute of Canada has proposed a prospective adjuvant trial to evaluate the effects of metformin on breast cancer outcomes, including recurrence and death. This study will explore whether the potential benefit of metformin is seen across a broad group of diabetic patients (consistent with a direct antiproliferative effect) or whether the benefit is restricted to women with hyperinsulinemia, those with insulin receptor–positive tumors, or those whose insulin levels fall in response to metformin treatment (consistent with an indirect effect). In their editorial, Goodwin and Ligibel commented that the science underlying such a trial is strong, the potential for benefit is large, and that such a trial is warranted.

Selecting Anthracycline-Based Chemotherapy for HER2-Positive Breast Cancer: Is Topo2α the Key?

This question has been a hot topic of investigation for over 10 years, and yet the answer still remains elusive. Over the past decade, numerous investigators have mined the data from a variety of breast cancer trials and found that human epidermal growth factor receptor 2 (HER2) protein overexpression or gene amplification seems to be associated with response to anthracycline-containing chemotherapy regimens and improved disease-free survival (DFS) in early-stage breast cancer. Many of these same investigators subsequently found evidence to suggest that amplification of the topoisomerase II-alfa (Topo2α) gene is also a positive predictive marker for the benefit of anthracycline-containing chemotherapy, and this was thought to explain the association with HER2 amplification because Topo2Α and HER2 are closely linked on chromosome 17, are frequently co-amplified, and Topo2α is a known target of anthracyclines. However, other trials contradicted these results, and the debate has raged on.

In the July issues of the Journal of Clinical Oncology, two studies addressed the question whether Topo2α amplification is associated with a DFS benefit from adjuvant anthracycline-based chemotherapy in women with HER2-positive breast cancer. In the paper reported by Harris and colleagues (J Clin Oncol. 2009;27(21):3430-3436.), based on a prospectively planned correlative study that was part of Cancer and Leukemia Group B (CALGB) Study 8541, the authors came to the conclusion that Topo2α copy number does not explain the observed benefit from increased dose of anthracyclines in HER2-positive breast cancer. Similarly, the study reported by Tubbs and colleagues (J Clin Oncol. 2009;27(24):3881-3886.), based on analysis of the Southwest Oncology Group (SWOG) S9313/Intergroup 0137 study, found that an abnormal Topo2α genotype (either amplification or deletion) was not associated with outcome, but the study confirmed the prognostic value of high-level HER2 amplification in patients treated with anthracycline-based regimens. Therefore, both of these studies cast further doubt on whether Topo2α can explain the benefit of anthracyclines in HER2-positive breast cancer and its role as a prognostic or predictive marker.

Two editorials on this topic discuss the complexity of the data and its interpretation. Kathleen Pritchard (J Clin Oncol. 2009;27(24):3875-3876.), after thoughtful review of all the relevant data, concludes that HER2 and/or Topo2α amplification/alteration are not ready for routine clinical use in selecting anthracycline-containing chemotherapy. She provides a good historical perspective, points out what we have learned from the studies reported, and clarifies that the analysis of the SWOG study is unable to shed light on the predictive value of Topo2α because patients in both arms received an anthracycline-based regimen. In his editorial, Francisco Esteva (J Clin Oncol. 2009;27(21):3416-3417.) comes to a similar conclusion that Topo2α expression can be used as a prognostic marker, but currently available evidence does not support the use of Topo2α gene amplification or deletion to select patients for adjuvant anthracycline-based chemotherapy. He also brings up the issue of a selective publication bias with respect to this question, pointing out that several negative studies, including NSABP B-15 and B-23, have not been published.

Capecitabine, an oral prodrug of 5-fluorouracil, is used to treat a variety of cancers, including breast, colorectal, stomach, and nasopharyngeal cancer and its use continues to increase worldwide. Although capecitabine is generally well tolerated, it is associated with hand-foot syndrome (palmoplantar erythema [PPE]), and the skin reactions associated with PPE can, on occasion, result in a loss of fingerprints. While it is uncertain when and if this happens, patients receiving treatment with capecitabine should be warned of this if they have plans for international travel to countries that require fingerprint identification to gain entrance. According to the published case report, a letter from the treating oncologist describing the condition and the treatment would be helpful for patients to avoid any inconvenience while travelling internationally.

Small molecule inhibitors of the vascular endothelial growth factor receptor (VEGFR) signaling pathway have become the new standard of care for the treatment of advanced clear-cell renal cell carcinoma (RCC), and sunitinib (Sutent^®) is currently the preferred first-line therapy for intermediate-risk patients. Sorafenib (Nexavar^®) is another multitargeted kinase inhibitor that blocks VEGFR-2, VEGFR-3, and platelet-derived growth factor receptor beta (PDGFR-β). Based on positive phase II data demonstrating that sorafenib improved progression-free survival (PFS) in RCC, the phase III multicenter Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGET) was initiated. This randomized, double-blind, placebo-controlled study (N = 903) evaluated sorafenib in patients with metastatic clear-cell RCC who had progressed following one prior systemic therapy (interleukin-2 or interferon-α). In January 2005, a preplanned interim analysis demonstrated that sorafenib significantly improved PFS compared with placebo (5.5 months versus 2.8 months; P<.000001). On the basis of that analysis, the data safety monitoring board stopped the trial, leading to patients still on placebo crossing over to sorafenib; and the FDA and other regulatory authorities approved sorafenib for the treatment of advanced RCC.

Subsequently, OS was determined at two planned interim analyses and one final analysis, with a secondary OS analysis conducted by censoring placebo patients who crossed over to sorafenib. The interim survival analyses did not meet the preplanned statistical criteria for statistical significance. In the July 10 issue of the Journal of Clinical Oncology, the authors reported the final survival analysis at a median of 16 months after unblinding and the analysis censoring placebo cross-over patients. The final OS analysis of the intent-to-treat population also failed to show a significant survival advantage associated with sorafenib (median 17.8 months for sorafenib versus 15.2 months for placebo; hazard ratio [HR] = 0.88; P = .146). However, when placebo cross-over patients were censored, the OS advantage was statistically significant (17.8 months versus 14.3 months, respectively; HR = 0.78; P = .029). The authors concluded that this demonstrates a significant cross-over effect and the results suggest that sorafenib improves OS when used as second-line therapy for metastatic clear-cell RCC. In addition, prognostic value of VEGF was confirmed in this study. Patients with high and low baseline VEGF both benefit from sorafenib in terms of PFS, but patients with high-VEGF benefit more.

Exploring the Benefits of Neoadjuvant Chemotherapy in Serous Endometrial Cancer

The serous histopathologic subtype of endometrial cancer accounts for only about 10% of all cases, but is particularly aggressive and has a high propensity for transperitoneal spread. Although a small minority of patients present with surgical stage IV disease, these patients have a very poor prognosis (5-year survival rate of 0% to 10%). In current practice, patients with stage IV endometrial cancer receive only systemic treatment or primary debulking surgery, which is associated with up to 39% of postoperative complications. This study sought to explore the benefit of neoadjuvant chemotherapy followed by interval debulking surgery (IDS) in patients with stage IV endometrial cancer and transperitoneal spread (90% of whom have serous histopathology). Thirty patients were treated with 3-4 cycles of neoadjuvant chemotherapy (primarily paclitaxel plus carboplatin). Response evaluated according to RECIST criteria was as follows: complete response (CR) in 2 (7%) patients, partial response (PR) in 20 (67%) patients, stable disease (SD) in 6 (20%) patients. Progressive disease (PD) was shown in 2 (7%) patients and these patients were not operated upon. Importantly, after neoadjuvant chemotherapy, 24 (80%) patients had optimal debulking surgery, of whom 22 (92%) were without residual tumor following IDS, and only 4 (13%) patients were considered inoperable. Median PFS and OS were 13 months and 23 months, respectively. Only 1 patient (4%) needed re-laparotomy and 3 (13%) had minor postoperative complications.

The investigators found that neoadjuvant chemotherapy led to a high rate of optimal surgical debulking and favorable outcomes in patients with stage IV endometrial cancer. The results of this study are particularly noteworthy because the amount of residual tumor following IDS is a significant prognostic factor for survival in patients with this disease. Historically, 28% to 48% of patients with stage IV disease do not receive optimal debulking, and 18% to 38% of patients are considered inoperable. The current study also showed that the degree of tumor regression in response to neoadjuvant chemotherapy is a significant prognostic factor. The investigators, therefore, concluded that neoadjuvant chemotherapy followed by IDS offers a valuable new treatment option for patients with stage IV endometrial cancer.

Single-Agent Bortezomib: Efficacy and Peripheral Neuropathy in Previously Untreated Multiple Myeloma

Bortezomib (Velcade^®) has demonstrated substantial activity in combination with other agents in the treatment of newly diagnosed multiple myeloma (MM), but also as a single agent for a relapsed/refractory MM. Bortezomib’s safety profile is well characterized in MM, with one of the key toxicities being peripheral neuropathy (PN). Additionally, the disease itself has been reported to be associated with PN in 3% to 13% of patients. The goals of this study was to evaluate the efficacy and safety of single-agent bortezomib in previously untreated patients with MM; to assess the prevalence, incidence, and severity of PN by standard toxicity and modified consensus criteria based on extensive neurologic examination, neurophysiologic testing, and measurements of epidermal nerve fiber densities; and to identify potential molecular markers associated with response to bortezomib and emergence of PN. Patients received bortezomib at a dose of 1.3 mg/m² on days 1, 4, 8, and 11 of every 21-day cycle for up to 8 cycles.

Among 64 newly diagnosed patients with MM enrolled in the study, overall response rate was 41% including 9% CR/nearCR and 17% very good partial response (VGPR). Median duration of response was 8.4 months and did not differ according to the cytogenetic abnormalities. Median time to progression was 17.3 months. Median OS was not reached, but the 30-month survival probability was 79%. Toxicity was manageable and safety profile was similar to that previously reported for single-agent bortezomib in relapsed/refractory MM. Interestingly, 20% of patients had sensory PN at baseline, which is a larger percentage than historical data would suggest, and 64% of patients developed new or worsening sensory PN during treatment, including 2 (3%) patients with grade 3 symptoms. The low rate of grade 3 PN was probably due to rigorous monitoring and use of established dose-modification guidelines. Importantly, PN was not only manageable but resolved completely in the majority (85%) of patients within a median of 98 days.

The authors concluded that single agent bortezomib is effective in previously untreated MM, but better efficacy has been reported for bortezomib-based combination regimens; baseline myeloma-associated PN may be more common than previously reported; and that bortezomib-associated neuropathy, although common, is reversible in most patients. Molecular markers of response and treatment-emergent neuropathy were identified by pharmacogenomic analysis but will require further study.

Mantle cell lymphoma is treated similarly to other B-cell non-Hodgkin lymphomas (NHLs), but unlike the more indolent histologic subgroups, mantle cell lymphoma is associated with a poor prognosis. Few patients achieve a durable remission with standard first-line and second-line chemotherapy regimens, with or without rituximab (eg, R-CHOP), and patients with relapsed/refractory disease have few treatment options. On a molecular level, mantle cell lymphoma is characterized by a chromosomal translocation t(11;14) (q13;q32) that results in overexpression of cyclin D1, which is thought to be regulated by the mammalian target of rapamycin (mTOR). This provides a strong biologic rationale for investigating temsirolimus (Torisel^®), a specific mTOR inhibitor, in the treatment of mantle cell lymphoma. Moreover, phase II studies suggested that it produced response rates comparable to other available therapies in the relapsed/refractory setting and was associated with a favorable safety profile.

This led to the multicenter, randomized, phase III trial conducted by Hess et al. One hundred sixty-two patients with relapsed/refractory mantle cell lymphoma were randomized to receive one of two temsirolimus dosing regimens (175 mg weekly for 3 weeks followed by either 75 mg or 25 mg weekly) or investigator’s choice of therapy (from a list of prospectively approved options). The investigator’s choice arm was designed to reflect typical daily practice. The results showed that temsirolimus significantly improved PFS and objective response rate compared with investigator’s choice of treatment and that the high-dose temsirolimus regimen was more effective than the low-dose regimen. Median PFS was 4.8 months with high-dose temsirolimus (175/75 mg), 3.4 months with low-dose (175/25 mg), and 1.9 months with investigator’s choice of treatment. The comparison of 175/75 mg temsirolimus versus investigator’s choice was highly statistically significant (hazard ratio = 0.44; P = .0009). Objective response rate was also significantly higher in the 175/75-mg group (22%) compared with investigator’s choice (2%; P = .0019). Although this response rate with standard treatment regimens is very low compared with other reported studies, the authors noted that the patient population was heavily pretreated, and the regimens used in the investigator’s choice arms were those commonly used in clinical practice. Therefore, based on these results in a population of heavily pretreated patients, temsirolimus appears to have clinically meaningful activity in patients with relapsed/refractory mantle cell lymphoma, and the benefit appears to be even greater in less heavily pretreated patients. Temsirolimus has also demonstrated activity in other NHL subtypes, and the investigators plan to continue exploring the best use of this agent for the treatment of B-cell lymphoma.

Positron-emission tomography (PET) has long been used for preoperative staging of non-small cell lung cancer (NSCLC). However, since 2001, combined PET and computed tomography (CT) has rapidly replaced PET alone. The major advantages of PET-CT are more accurate tumor staging and, to a lesser extent, lymph-node staging. Accurate staging of NSCLC is critical for determining the appropriate treatment and assessing prognosis; however, there are limited prospective data to indicate whether the improved diagnostic accuracy of PET-CT improves management of the disease compared with PET alone.

Recently, Fischer and colleagues reported on a randomized study designed to evaluate the clinical utility of PET-CT for preoperative staging of NSCLC. The primary end point of this study was the number of futile thoracotomies, defined as any one of the following: a thoracotomy with the finding of pathologically confirmed mediastinal lymph-node involvement (stage IIIA [N2]), stage IIIB or stage IV disease, or a benign lung lesion; an exploratory thoracotomy; or a thoracotomy in a patient who subsequently had recurrent disease or died from any cause within 1 year after randomization. One hundred eighty-nine patients were randomized to either PET-CT or conventional staging and were followed for up to 12 months or until death. After PET-CT, 38 patients were classified as inoperable and only 18 patients after conventional staging. Overall, 60 patients in the PET-CT group versus 73 in the conventional-staging group underwent thoracotomy (P = .004). Among those thoracotomies, 21 (35%) in the PET-CT group versus 38 (52%) in the conventional-staging group were futile (P = .05). The number of justified thoracotomies and survival were similar in the two groups. The authors concluded that the use of PET-CT for preoperative staging of NSCLC reduced both the total number of thoracotomies and the number of futile thoracotomies but did not affect overall mortality.

OTHER prIME ACTIVITIES

Exploring New Horizons in Renal Cell Carcinoma and Prostate Cancer 20 September 2009 \| Berlin, Germany	Breast Cancer: Evaluating Current Standards and Formulating Strategies for the Next Decade 20 September 2009 \| Berlin, Germany	Breast Cancer Treatment on the Cutting Edge: Understanding the Options 21 September 2009 \| Berlin, Germany


Expert Practice in Breast Cancer 10 October 2009 \| Prague, Czech Republic	Expert Practice in Genitourinary Malignancy 10 October 2009 \| Brussels, Belgium	These IME activities feature expert interviews focusing on important data from the recent oncology literature in Breast Cancer, GIST, and CML. Go to the Virtual Journal Club