The first annual 2007 Cancer Symposium, held September 7-8 in San Francisco, provided an opportunity for members of the oncology community to discuss major developments in breast cancer treatment and research.
THE 2007 BREAST CANCER SYMPOSIUM
The Combination of Sunitinib Plus Paclitaxel Demonstrates Promising Activity in the First-Line Treatment of Advanced Breast Cancer
Preliminary Results from a Phase I Trial
During a poster session, Mark Kozloff, MD, University of Chicago Medical Center, Chicago, IL and Ingalis Hospital, Harvey, IL, presented the results of a Phase I study evaluating the safety and pharmacokinetics of sunitinib (Sutent) combined with paclitaxel (Taxol) for the first-line treatment of advanced breast cancer. Dr. Kozloff was lead investigator of the study.
Sunitinib is an oral, small-molecule, multi-targeted tyrosine kinase inhibitor. It inhibits cellular signaling by targeting multiple receptor tyrosine kinases (RTKs), including plateletderived growth factor receptors (PDGFRs) and vascular endothelial growth factor receptors (VEGFRs), which play a role in both tumor angiogenesis and tumor-cell proliferation. The simultaneous inhibition of these targets leads to reduced tumor vascularization and cancer cell death. Sunitinib also inhibits KIT—the RTK that drives the majority of gastrointestinal stromal tumors—as well as other RTKs including RET and FLT3. Sunitinib has demonstrated single-agent activity in patients with previously-treated metastatic breast cancer.
Enrollees in the Phase I trial were patients with metastatic or locally recurrent breast cancer. Exclusion criteria included previous cytotoxic therapy for advanced disease and failure of taxane-based adjuvant therapy within 12 months prior to enrollment. Patients received a starting dose of sunitinib of 25 mg/day (continuous dosing schedule; escalation to 37.5 mg/day or reduction to 12.5 mg/day depending on tolerability) plus paclitaxel (1-hour infusion) 90 mg/m2 per week in 4-week cycles (3 weeks on treatment, followed by 1 week off; with reduction to 65 mg/m2 per week as needed).
A total of 20 patients were treated. Median age was 57 years (range, 37 to 74 years). Of these, 17 patients had measurable disease and 7 were chemotherapy-naive. Disease sites included bone (55%), liver (40%), lung (30%), lymph node (55%), and local (40%). A median of 6 cycles were delivered; 9 patients continue on treatment. Eight patients discontinued due to disease progression, 2 due to non—treatment related illness, and 1 due to resection of remaining lesion.
Grade 3 adverse events included fatigue (29%), diarrhea (14%), hand—foot syndrome (10%), and neuropathy (10%). Neutropenia was the primary hematologic toxicity. Granulocyte colony-stimulating factor was given if the neutrophil count fell below 1500/μL, to support delivery of full-dose paclitaxel. Neutrophil nadirs were sharp, with rapid rebound despite continuous sunitinib dosing. Preliminary results indicated no pharmacokinetic interaction between paclitaxel and sunitinib. As of this analysis, there were 5 confirmed objective responses (3 partial and 2 complete) according to Response Evaluation Criteria in Solid Tumors, and 3 patients had stable disease for 6 months or more.
Dr. Kozloff concluded that sunitinib plus paclitaxel was generally well tolerated and showed promising activity in the first-line treatment of advanced breast cancer. He said that a Phase III trial comparing this combination with paclitaxel plus bevacizumab is underway.
The Combination of Capecitabine and Trastuzumab Appears to Be Effective and Safein Heavily Pre-Treated Patients With Metastatic Breast Cancer Further Study Is Warranted
Dr. Rupert Bartsch, First Department of Medicine and Cancer Centre, Clinical Division of Oncology, Medical University of Vienna, Vienna, Austria, presented the results of a preliminary trial that evaluated the efficacy and tolerability of capecitabine (Xeloda) plus trastuzumab (Herceptin) after anthracycline and docetaxel or vinorelbine failure and prior trastuzumab exposure.
In HER2-positive metastatic breast cancer, taxanes or vinorelbine plus trastuzumab are among the most widely applied options in the first-line setting. Capecitabine, a nucleoside analog, is the only FDAapproved oral chemotherapy for both metastatic breast cancer and adjuvant and metastatic colorectal cancer. Although inactive in pill form, capecitabine is enzymatically activated within the body. When it comes into contact with thymidine phosphorylase, a naturally occurring protein, capecitabine is transformed into 5-fluorouracil, a cytotoxic drug.
Forty patients were enrolled in the trial. All had prior exposure to an anthracycline, at least one antimicrotuble agent (ie, a taxane or vinorelbine), and one earlier trastuzumabcontaining treatment regimen for metastatic disease. Capecitabine was administered at a daily dose of 2500 mg for 2 consecutive weeks every 3 weeks, with dose modifications if necessary. Trastuzumab was administered in 3 weekly cycles. The primary endpoint was time to progression (TTP). Response was evaluated every three months using Union International Contre Cancer (UICC) criteria. Overall survival (OS) was assessed secondarily.
Median TTP was 8 months, (range, 2 to 21 months). Median OS was 24 months (range, 3 to 42 months). Complete response was observed in 2.5% of patients, partial response in 17.5%, and stable disease for 6 months or more in 50%, resulting in a clinical benefit rate of 70%.
Diarrhea (5%) and hand—foot syndrome (15%) were the only treatment-related adverse events that occurred with grade 3 or 4 severity. Three patients (7.5%) developed cerebral metastases as the first site of disease progression while on the combination regimen.
Dr. Bartsch concluded that capecitabine plus trastuzumab appears to be an effective and safeoption in this heavily pre-treated population. These results compare well with those from studies evaluating the combination of capecitabine plus lapatinib (GW572016, GlaxoSmithKline).
Phase III Study of Gemcitabine Plus Paclitaxel vs Paclitaxel Alone in Patients with Unresectable, Locally Recurrent, or Metastatic Breast Cancer Gemcitabine Is a Valid Treatment Option for Patients Who Require Rapid Cytoreduction
During a poster session, Allen S. Melemed, MD, Medical Director for Global Oncology, Eli Lilly, Indianapolis, IN, presented the results of a Phase III trial that compared overall survival (OS) with gemcitabine (Gemzar, Eli Lilly) plus paclitaxel (Taxol, Bristol-Myers Squibb) vs. that with paclitaxel alone in patients with unresectable, locally recurrent, or metastatic breast cancer after one previous adjuvant or neoadjuvant anthracycline-containing chemotherapy regimen. Secondary objectives included time to progression (TTP), overall response rate (ORR), and toxicity. Dr. Melemed was lead investigator of the study.
Gemcitabine, a nucleoside analog, has demonstrated efficacy in metastatic breast cancer in Phase II studies, both as a single agent and in combination with paclitaxel.
A total of 529 women were enrolled, of whom 266 were randomized to receive gemcitabine 1250 mg/m2 on Days 1 and 8 with paclitaxel 175 mg/m2 on Day 1, and 263 were randomized to receive paclitaxel alone, 175 mg/m2 every 21 days. The median age of enrollees was 53 years (range, 23 to 83 years). The majority of patients had metastatic (97% per arm) and visceral (73% per arm) disease.
The median OS was significantly better for the combination of gemcitabine plus paclitaxel than for paclitaxel alone (18.6 months vs 15.8 months, = 0.0489), as was TTP (6.1 months vs 4.0 months, = 0.0002) and ORR (41.4% vs 26.2%, = 0.0002).
Hematologic toxicity was more common in the combination group, particularly grade 3-4 neutropenia (47.9% vs 11.5%). Grade 3-4 fatigue, motor neuropathy, and transaminase elevations were also more common in the combination group. One patient per arm died from possible drug-related toxicities (non-neutropenic septicemia and severe asthenia).
Dr. Melemed concluded that the combination of gemcitabine plus paclitaxel “is one of a select number of regimens to demonstrate a significant survival advantage in patients with advanced breast cancer and prior anthracycline-based (neo)adjuvant therapy.” These results establish the combination of gemcitabine plus paclitaxel as a valid treatment option for patients needing rapid cytoreduction with manageable toxicity, and warrant further study of this combination regimen in the adjuvant setting.
GeparQuattro: A Phase III Trial Evaluating the Efficacy of Capecitabine and Trastuzumab Given Concomitantly or in Sequence to EC-Doc as Neoadjuvant Treatment of Primary Breast Cancer Interim Safety Analysis
GeparQuattro is a German Breast Group neoadjuvant trial designed to explore the effect of simultaneous or sequential use of capecitabine (Xeloda) with docetaxel (Taxotere) after 4 cycles of epirubicin/cyclophosphamide (EC-Doc) as well as simultaneous trastuzumab (Herceptin) on pathologic complete response of previously untreated Stage I-III breast cancer.
Gunter von Minckwitz, MD, Associate Professor of Gynecology at the University of Frankfurt, Frankfurt, Germany, and Chair, German Breast Group, presented the results of an interim safety analysis of the GeparQuattro trial during a general poster session. Dr. von Minckwitz was lead investigator of the study.
Between August 2005 and December 2006, 1512 patients received 4 cycles of EC (90 mg/ m2/600mg/m2) and were then randomized to either: (Arm 1) 4 cycles of docetaxel (100 mg/m2) (n=109); (Arm 2) 4 cycles of docetaxel plus capecitabine (75 mg/m2/1800mg/m2) (n=110); or (Arm 3) 4 cycles of docetaxel (75 mg/m2) followed by 4 cycles of capecitabine (1800mg/m2) (n=110). Patients with HER2/neu-positive tumors (n=109) received trastuzumab concomitantly with all chemotherapy. A total of 329 patients (mean age, 51 years) received a composite total of 2725 cycles.
Grade 3-4 neutropenia was observed in 57.1%, 42.4%, and 41.3% of patients in arms 1-3, respectively. Grade 3-4 thrombocytopenia was observed in 3.4%, 2.0%, and 2.4% of patients, respectively. Hand—foot–syndrome was observed in 6.9%, 27.6%, and 8.5%, respectively. Grade 3-4 nail changes were observed in 2.2%, 5.3%, and 5.1%, respectively. Grade 3-4 dysphagia was observed in 3.4%, 5.4%, and 0%, respectively. Grade 3-4 diarrhea was seen in 2.2%, 7.6%, and 5.2%, respectively. Grade 3-4 nausea was observed in 6.3%, 10.9%, and 9.9%, respectively. Sensory neuropathy was seen in 3.1%, 3.2%, and 1.0%, respectively. Among patients who received trastuzumab, Grade 3 cardiac toxicity was noted in 1.7%, 3.6%, and 4.7%, respectively, and among those who did not receive trastuzumab, Grade 3 cardiac toxicity was noted in 0%, 3.1%, and 3.6%, respectively. Capecitabine dose delays in Arm 2 were double those in Arm 3 (6.3% vs. 3.7%).
Dr. von Minckwitz concluded that hematologic toxicities were more frequent with docetaxel (100 mg/m2) alone, whereas non-hematologic toxicity increased incrementally with the sequential and simultaneous addition of capecitabine. Simultaneous addition of trastuzumab to EC/Doc/capecitabine was feasible without additional cardiotoxicity. Dr. von Minckwitz reported that as a result of the interim analysis, no safety concerns were raised and the trial is proceeding as planned.
Phase III Study of Ixabepilone plus Capecitabine in Patients with Metastatic Breast Cancer Resistant to Anthracyclines and Taxanes Positive Outcomes Demonstrated in Both ER and ER— Patients
During a general poster session, Dr. Xavier B. Pivot, Centre Antoine Lacassagne, Nice, France, presented the results of subgroup analysis evaluating the effectiveness of ixabepilone plus capecitabine in patients with metastatic breast cancer resistant to anthracyclines and taxanes. Dr. Pivot was lead investigator of the trial.
The epothilones are a new class of microtubule- stabilizing agents designed to overcome drug resistance. Ixabepilone is a semisynthetic analog of epothilone B.
In the trial, a total of 752 patients with metastatic breast cancer were randomized to receive either ixabepilone (40 mg/m2 IV over 3 hours on day 1, every 3 weeks) plus capecitabine (2000 mg/m2 po on days 1-14) or capecitabine alone (2500 mg/m2 po on days 1-14).
In a subgroup analysis, progression-free survival (PFS) and objective response rate (ORR) were assessed for ER— patients. Ixabepilone plus capecitabine was superior to capecitabine alone, with a 25% reduction in the risk of disease progression in the entire patient population. Fiftythree percent of patients had ER–tumors. PFS was also prolonged with the combination regimen in the ER–subgroup, with a 35% reduction in the risk of disease progression. For both the entire population and the ER–subgroup, ORR was greater with combination therapy than with capecitabine monotherapy.
Grade 3-4 treatment-related sensory neuropathy (21%), fatigue (9%), and neutropenia (68%) were more frequent with combination therapy in the total population.
Dr. Pivot concluded that ixabepilone plus capecitabine was superior to capecitabine alone in patients with metastatic breast cancer progressing after anthracycline/taxane treatment, and this benefit is achieved independent of ER status.
In June 2007, the US FDA accepted the filing of a New Drug Application for ixabepilone for the treatment of metastatic breast cancer, and is undergoing priority review. The target action date is in late October.
Adjuvant Trastuzumab in Early Breast Cancer A Meta-Analysis of 9,117 Patients
Dr. Gustavo A. Viani, Faculdade de Medicina de Marilia, Sao Paulo, Brazil, presented the results of a meta-analysis of 9,117 patients enrolled in five large, randomized, controlled trials, performed to evaluate whether trastuzumab (Herceptin) is an effective treatment for HER2- positive breast cancer if used after the completion of primary therapy. Dr. Viani was the lead researcher of the meta-analysis.
Pooled results from the five randomized trials of adjuvant trastuzumab showed a signifi- cant reduction of mortality
(P < 0.00001), recurrence (P < 0.00001), metastasis rate (P < 0.00001) and second tumors other than breast cancer
( P = 0.007) as compared with no adjuvant trastuzumab patients with early breast cancer. There was more grade 3-4 cardiac toxicity after trastuzumab (4.5%) than after regimens without trastuzumab (1.8%).
The likelihood of cardiac toxicity was 2.45-fold greater in trastuzumab arms than in study arms without trastuzumab. The likelihood of brain metastasis was 1.82-fold greater in patients who received trastuzumab than in those who did not receive trastuzumab.
Dr. Viani stated that “this meta-analysis strongly indicates that adjuvant trastuzumab must be considered a standard option on completion of locoregional therapy and neoadjuvant or adjuvant chemotherapy for women with early breast cancer. Adequate assessment of HER2-neu status is critical, and careful cardiac monitoring is warranted because of cardiac toxicity. Our data suggest that brain metastases will become increasingly prevalent due to greater control over systemic metastases in women who received trastuzumab.” He added, “Trials should be designed to determine the optimal timing of initiation of trastuzumab.”
In ERα Tumors, Up-Regulated Growth Factor Signaling Is Directly Involved in the Generation of the ERα— Phenotype by Repression of ERα Expression This Reversible Down-Regulation May be Targeted Clinically
Breast cancer presents as estrogen receptor alpha (ERα) positive (ERα ) or negative (ERα—). ERα– tumors have a poor prognosis and are resistant to antihormonal therapy. ERα– tumors frequently show overexpression, amplification, and/or hyperactivation of growth factor signaling, particularly of the erb-B family, resulting in hyperactivation of mitogen-activated protein kinase (MAPK) pathway. Previous investigations have shown that hyperactive MAPK causes reversible down regulation of ERα.
In a poster session, Prakash Vishnu, MD, Wayne State University, Farmington Hills, MI, presented the results of an in vitro study performed to determine whether the inhibition of MAPK activity in ERα— breast cancer cell lines and tumor specimens could restore ERα expression and antiestrogen response. Dr. Vishnu was lead investigator of the study.
Three established ERα— cell lines—SUM229 (ERα–/PR–/H2N–/EGFR ), SUM190 (ERα–/PR–/ H2N /EGFR ), and SUM149 (ERα–/PR–/H2N–/ EGFR )—and three tumor cell cultures derived from dissociation of ERα– breast tumors—DT5 (ERα–/PR–/H2N–), DT13 (ERα–/PR–/H2N ) and DT16 (ERα–/PR–/H2N–)—were used in the study.
Inhibition of MAPK was achieved by using U0126, an inhibitor of both MAPK/extracellular signal-regulated kinase (ERK) kinase 1 (MEK1) and MEK2. Western blotting was performed to visualize the re-expression of ERα. A colorimetric growth assay for cell proliferation and viability was performed using WST-1 to assess anti-estrogen sensitivity in these cells by treating them with 4-hydroxy-tamoxifen (a selective estrogen receptor modulator) and fulvestrant (an estrogen receptor antagonist) in combination with U0126.
Inhibition of MAPK resulted in re-expression of ERα protein in all three established ERα— cell lines and all three ERα– tumor cell cultures. U0126, while having no growth inhibitory effects on its own, restored the growth inhibitory effects of both 4-hydroxy-tamoxifen and fulvestrant.
Dr. Vishnu explained that these results support his research team’s hypothesis that there exists a population of ERα— tumors in which up-regulated growth factor signaling is directly involved in the generation of ERα– phenotype by repressing ERα expression. Furthermore, he added, this reversible down-regulation may be targeted clinically such that this repression can be reversed by inhibiting MAPK, resulting in re-expression of ERα and restoration of tamoxifen sensitivity.