Christy Russell, MD, Medical Adviser for Imedex, is the editor for this month’s issue of OncoFacts. In this issue, Dr Russell reports on the latest findings from the 31st Annual San Antonio Breast Cancer Symposium (SABCS) conference held on December 10-14, 2008 in San Antonio, Texas.

In this issue:

• Adjuvant and Neoadjuvant Chemotherapy
• Neoadjuvant Chemotherapy
• Adjuvant Bevacizumab
• Molecular Profiling and Bisphosphonate Therapy
• Possible Anti-tumor Effects of Bisphosphonates
• HER2-positive Early Breast Cancer – Clinical Outcome with Small Tumor Size
• Assays for Predicting Recurrence for Early-Stage Breast Cancer
• Hormone Therapy in the Adjuvant and Metastatic Setting
• Adjuvant Hormone Therapy
• HER2-positive Early and Advanced Breast Cancer
• HER2-positive Advanced Breast Cancer
• Combination of HER2-directed and Anti-angiogenesis Therapy
• Metastatic Breast Cancer
• Quick Poll

Adjuvant and Neoadjuvant Chemotherapy

Two large US Cooperative Group trials and 1 European trial were presented comparing sequential versus concurrent chemotherapy with doxorubicin (A)/epirubicin (E), cyclophosphamide (C), and docetaxel (T).

Abstract 75: Dr Sandra Swain presented the results of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-30 trial after patients had been on study for a mean time of 79 months. In this study, 5351 women with stage I, II, or IIIA breast cancer were randomly assigned to 1 of 3 arms:

1. AC --> T: A (60 mg/m²) + C (600 mg/m²) every (q) 3 weeks x 4 --> T (100 mg/m²) q 3 weeks x 4
2. AT: A (50 mg/m²) + T (75 mg/m²) q 3 weeks x 4
3. TAC: A (50 mg/m²) + C (500 mg/m²) + T (75 mg/m²) q 3 weeks x 4

The primary aims of the trial were to compare sequential versus concurrent therapy with regards to its effect on disease-free survival (DFS) and overall survival (OS) as well as the utility of cyclophosphamide. The results showed that AC --> T was superior to TAC (P = .006) and AT (P = .001) for DFS, and that AC --> T was superior to AT (P = .034) and marginally better than TAC (P = .086) for OS. With regards to toxicity, AC --> T had significantly greater febrile neutropenia and stomatitis than either of the other two arms. There were no treatment interactions between outcome and nodal status, estrogen receptor (ER) or menopausal status. An interesting menstrual history sub-study was also presented assessing the relationship between the onset of amenorrhea and outcome. Of 2366 evaluable premenopausal women, 1868 developed amenorrhea for > 6 months. Patients who developed amenorrhea had a statistically significant improvement in OS (P = .038) and DFS (P = .00041), which was seen across all treatment arms and subgroups, analyzed.

Abstract 77: With a median follow-up of 65 months, the Breast Cancer International Research Group (BCIRG) 005 trial was presented comparing sequential versus concurrent chemotherapy with doxorubicin, cyclophosphamide, and docetaxel. In this trial, 3298 women with stage T1-3, N1, M0 invasive breast cancer were randomly assigned to 1 of 2 treatments arms as follows:

1. TAC: (75/50/500 mg/m²) q 3 weeks x 6
2. AC: (60/600 mg/m²) q 3 weeks x 4 --> T: (100 mg/m²) q 3 weeks x 4

The primary statistical endpoint was DFS and secondary endpoints were OS and safety. Results showed that for the primary endpoint of DFS, adjuvant TAC was equivalent to AC --> T in patients with node-positive, HER-2 normal breast cancer. With regards to toxicity, TAC was associated with more febrile neutropenia and use of granulocyte colony-stimulating factor (G-CSF), but less sensory neuropathy, nail changes, and myalgia.

Abstract 78: The West German Study Group and the AGO-Mamma Intergroup presented results of their phase III randomized trial in women with T1-3, invasive breast cancer with 1-3 positive lymph nodes. This trial randomized 1837 women to 1 of the following 2 arms:

1. Fludarabine, epirubicin, and cyclophosphamide (FEC [500/100/500 mg/m²]) q 3 weeks x 6
2. Epirubicin and cyclophosphamide (EC[90/600 mg/m2]) q 3 weeks x 4 --> T: (100 mg/m2) q 3 weeks x 4

The primary statistical endpoint was event-free survival (EFS) with secondary endpoints of OS, safety, and quality of life. After a 41-month median follow-up, both the estimated 5-year EFS (P = .009) and OS (P = .04) were significantly better for EC --> T versus FEC. Epirubicin and cyclophosphamide --> T was associated with more arthralgia, mucositis, and sensory neuropathy, and FEC was associated with greater anemia and thrombocytopenia, and vomiting. There was no difference in febrile neutropenia.

These trials seem to emphasize the benefit of adding a taxane to an anthracycline and cyclophosphamide, especially in women with a significant risk of recurrence from invasive breast cancer. Compared to AC --> T given every 3 weeks, TAC x 4, AT x 4, or FEC x 6 are inferior. With regards to DFS, TAC x 6 is equivalent to AC --> T, but a differing safety profile. Because most physicians in the US will choose either TAC x 6 or dose-dense AC -->paclitaxel for their patients with lymph node-positive breast cancer, the results of NSABP B-38 will have the potential to select among 1 of these 2 regimens.

Neoadjuvant Chemotherapy

Abstract 5102: The I-SPY trial evaluated tumor biomarker status at multiple time points in women with locally advanced breast cancer. The primary objective was to identify markers of response to neoadjuvant chemotherapy. In this trial, 221 women with tumors > 3 cm underwent neoadjuvant anthracycline-based chemotherapy, and treatment with AC --> T was the most common. Pathologic complete response (pCR) rates were statistically higher in women with tumors that were ER-negative, PR-negative, HER-2–positive, high Ki67, epidermal growth factor receptor (EGFR)–positive, and Bcl2–negaitive. Luminal A tumors defined by immunohistochemistry (IHC) proxy as being ER-positive or PR-positive/HER-2–negative had a very low pCR (9%) rate.

Adjuvant Bevacizumab

It is reported that the incidence of congestive heart failure (CHF) in anthracycline-based adjuvant trials that use 4 cycles of AC is up to 1%. There is concern, however, as to whether the addition of bevacizumab to doxorubicin may increase the risk of CHF. Thus, several trials were presented adding bevacizumab in the adjuvant setting with one of the primary endpoints being cardiac safety.

Abstract 4102: A multicenter group conducted 3 sequential safety studies using dose-dense doxorubicin-cyclophosphamide (ddAC) --> paclitaxel. One of these trials incorporated bevacizumab. This abstract evaluates the cardiac safety of ddAC alone or with bevacizumab. Left ventricular ejection fraction (LVEF) was evaluated at baseline and at completion of ddAC. Additional patients from 2 other trials using ddAC --> paclitaxel + trastuzumab and ddAC --> paclitaxel + trastuzumab + lapatinib were also used for comparison. At total of 236 women with a median age of 47 were enrolled in 1 of these 3 clinical trials. No patients developed symptomatic CHF. Two patients had an asymptomatic LVEF decline > 15%, of whom 1 patient had received bevacizumab.

Abstract 4104: The groups from Memorial-Sloan Kettering Cancer Center and University of California, San Francisco entered 80 patients into a clinical trial using the following regimen:

ddAC (60/600) + bevacizumab (10 mg/kg) q 2 weeks x 4 --> dose-dense nab-paclitaxel (dd nabP [260 mg/m2]) + bevacizumab (10 mg/kg) q 2 weeks x 4 --> bevacizumab (15 mg/kg) q 3 weeks for total of 1 year.

Left ventricular ejection fraction was evaluated at baseline and months 2, 6, 9, and 18. Fifty-one patients completed 1 year of therapy. There were no cases of symptomatic LV dysfunction in any of the patients. Three patients discontinued therapy because of an asymptomatic LVEF decline.

Abstract 4107: This third trial evaluated the feasibility of adding bevacizumab to 3 adjuvant docetaxel breast cancer regimens.

1. AC --> T: A (60 mg/m²) + C (600 mg/m²) q 3 weeks x 4 --> T (100 mg/m²) q 3 weeks x 4
2. TAC: (75/50/500 mg/m²) q 3 weeks x 6
3. Docetaxel, carboplatin, and trastuzumab (TCH [75/AUC6/6mg/kg]) for patients with HER2-positive breast cancer

Bevacizumab was administered at 15 mg/kg q 3 weeks x 52 weeks in all of the arms. Of the 225 planned patients in this phase IIb randomized, non-comparative trial, safety information was available for 138 who had received > 4 cycles of therapy. Documented CHF was reported in 3 patients (A = 1 patient, B = 2 patients). Accrual to the trial is ongoing, but the authors at this point felt that the safety profile was acceptable.

Molecular Profiling and Bisphosphonate

Therapy Denosumab is a fully human monoclonal antibody against RANK ligand. RANK ligand mediates osteoclastic bone resorption. Clinical trials using denosumab have been developed in the setting of bone metastases, as a treatment for osteoporosis, and as a preventive therapy for postmenopausal women undergoing aromatase inhibitor (AI) therapy.

Abstract 1155: Forty-six women with metastatic breast cancer (MBC) and bone metastases demonstrated elevated urine-N-telopeptide (uNTx) that is a marker of bone resorption, despite the use of intravenous (IV) bisphosphonates. In this randomized phase II trial, the patients were randomly assigned to IV bisphosphonates every 4 weeks or to subcutaneous denosumab (180 mg) q 4 weeks or every 12 weeks. At week 13, 76% of denosumab and 33% of IV bisphosphonate-treated patients had uNTx levels < 50 nM/mM. The denosumab-induced suppression of uNTx was rapid, and sustained through 25 weeks. Phase III trials of denosumab in patients with cancer who have bone metastases are in progress.

Abstract 2106: Prior reports had shown that denosumab significantly increase the bone mineral density (BMD) at 12 months compared to placebo in women with early breast cancer undergoing AI therapy. This trial reports on 252 women with breast cancer who had an initial T-score ranging between -1.0 to -2.5. The women were randomly assigned to receive either placebo or denosumab. The objective of the trial was to evaluate the covariates influencing the effects of denosumab on BMD. The subgroups evaluated were as follows: AI duration, AI type, prior tamoxifen, age, time since menopause, BMD, and baseline T-score. The results showed that denosumab significantly improved the percentage change in BMD compared to placebo at all skeletal sites and all subgroups.

Abstract 44: This trial provided a 36-month update of the ZO-FAST trial which randomly assigned 1064 postmenopausal women with a BMD T-score > -2.0 to letrozole + zoledronic acid (upfront) or to letrozole followed by zoledronic acid for those women whose BMD drops < -2.0. The zoledronic acid was given as a 4 mg IV infusion every 6 months. The primary endpoint of the trial was percentage change in BMD at 12 months. As expected, at 36 months, the mean percentage change in lumbar BMD was +4.39 for upfront and -4.90 for delayed zoledronic acid. Similar findings were seen in the hip as well. There was no significant difference in fractures between the 2 groups. There were no cases of renal impairment, but there was one case of osteonecrosis of the jaw on the immediate zoledronic acid arm.

Possible Anti-tumor Effects of Bisphosphonates

It has been reported that the effects of bisphosphonates on tumor cells in vitro include a reduction in proliferation, an increase in tumor cell apoptosis, a decrease in cell adhesion, a decrease in tumor angiogenesis, and an increase in efficacy of other anti-cancer therapies. This effect was clinically demonstrated in the Austrian Breast and Colorectal Cancer Study Group (ABCSG)-12 trial, which was presented during the American Society of Clinical Oncology (ASCO) Annual meeting in June 2008. That trial found that premenopausal women with medical ovarian suppression and tamoxifen/AI +/- zoledronic acid had a significant improvement in DFS for those women receiving the zoledronic acid. The AZURE trial is an ongoing trial, which has randomized 3360 women with stage II/III breast cancer to standard neoadjuvant/adjuvant chemotherapy with or without zoledronic acid. Although the outcomes of the entire trial have not yet been reported, a retrospective analysis of patients who received neoadjuvant chemotherapy was performed to see if the addition of zoledronic acid to chemotherapy improves the pathologic response.

Abstract 5101: From the main AZURE trial, 205 patients received neoadjuvant chemotherapy. The mean residual tumor size was reduced from 42.4 mm to 28.2 mm when comparing chemotherapy alone to chemotherapy + zoledronic acid (P = .002). In addition, pCR was improved from 5.8% to 10.9% respectively. There was also a significant reduction in the percentage of patients requiring mastectomy when given zoledronic acid. The authors concluded that there was evidence of a possible antitumor effect for zoledronic acid in the neoadjuvant setting.

Abstract 44: One of the endpoints in the previously mentioned ZO-FAST trial was not only an improvement in BMD for immediate vs delayed zoledronic acid, but also a reduction in recurrence. There were 22 recurrences in the immediate group and 40 in the delayed group for a hazard ratio (HR) of 0.588 (P = .03). The authors concluded that these results added to the growing body of evidence that zoledronic acid can provide anti-tumor effects and may prolong DFS in patients with early breast cancer.

HER2-positive Early Breast Cancer – Clinical Outcome with Small Tumor Size

There has been a lack of prognostic outcome for women with early HER2-positive breast cancer with negative lymph nodes and small tumor size. Two abstracts were presented that attempted to address this clinical dilemma.

Abstract 701: Investigators from the M. D. Anderson Cancer Center reviewed 965 T1a, b N0M0 breast cancer tumors diagnosed between 1990 and 2002. Of these patients, 77% were HR-positive, 13% were triple negative, and 10% were HER2-positive. When compared to the women with small HER2–negaive tumors, patients with HER2-positive breast cancer were more likely to be premenopausal; the cancers were predominantly ductal in origin; were less likely to be HR-positive, and had a higher nuclear grade. The 5-year recurrence rate of the HER2-psotive tumors that were < 1 cm was 23%. HER2-positivity is a powerful negative prognostic factor for patients with tumors <1 cm (HR 2.7).

Abstract 702: A retrospective cohort of 367, grade 1-2, node negative patients diagnosed between 1980 and 2002 was undertaken to assess the impact of HER2 status on survival. The events were significantly higher for the HER2-positive compared to HER2-negative with a HR of 6.78. The 5-year breast cancer specific survival rates were 96% HER2-negaitive and 68% HER2-positive. Events were higher not only for the whole cohort, but also were seen regardless of ER-status, age, or tumor size (either larger or smaller than 2 cm).

Assays for Predicting Recurrence for Early-Stage Breast Cancer

Oncotype DX has been available now for several years and has been validated as a molecular test that provides an assessment of distant recurrence for ER-positive patients who receive tamoxifen. However, because the use of aromatase inhibitors is fairly standard in postmenopausal women, Oncotype sought to understand the prognostic efficacy in this population of women.

Abstract 53: The goal of this trial was to determine whether Oncotype DX test is prognostic in the tamoxifen and anastrozole arms of the Arimidex, Tamoxifen Alone or in Combination (ATAC) trial. Of the 9366 women who were originally randomized to ATAC, only those women who did not receive chemotherapy, and were not on the combination arm of anastrozole + tamoxifen were considered. In all, there were 1231 women whose samples yielded a reportable recurrence score (RS).

Results:

The authors concluded that the primary analysis showed a highly statistically significant contribution by recurrence score to Cox proportional hazards model after adjustment for tumor size, grade, age, and treatment. The greater efficacy of anastrozole observed in the parent ATAC trial, and the similar hazard rations for RS in both treatment arms suggests a lower risk of distant recurrence for any RS in patients treated with an AI. The trial also demonstrated that the RS is an independent predictor of distant recurrence in node-negative and node-positive HR-positive patients treated with anastrozole. The established relationship between RS and distant recurrence for tamoxifen may now be applied for anastrozole with adjustment for the lower risk of distant recurrence with the AI.

Abstract 1063: The 70-gene prognostic signature assay was originally developed using stage I or II tumors from women < 55 years of age. This prognosis profile was developed to identify a group of women at very low risk of developing distant metastases. This study was performed to evaluate the prognostic value of the 70-gene prognosis profile in postmenopausal women. Tumor samples from 148 node-negative, postmenopausal women were selected. Although 18% of the patients had received adjuvant tamoxifen, none had received chemotherapy. In this trial, 91/148 (61%) were classified as have a good prognostic signature and 57/148 (39%) were classified as having a poor prognostic signature. The breast cancer-specific survival was 99%/90% at years 5/10 for the good prognosis signature, and were 80%/69% at years 5/10 for the poor prognostic signature. The authors concluded that although the 70-gene prognostic signature was originally designed for premenopausal women, it shows strong prognostic ability in postmenopausal patients as well.

Abstract 4171: Dr Knauer et al presented a study assessing the tumor samples from 169 women who had HER2-positive breast cancer from a larger dataset of 1280 patients. Samples were analyzed and then classified by the 70-gene signature as good or poor prognosis. Patients had a unilateral T1-3, N0-1, M0 tumor treated with either breast conserving therapy or mastectomy. The 70-gene signature classified 27 (16%) patients as good prognosis, with a 10-year distant disease-free survival of 89% (25/27), compared to 142 (84%) patients with a poor prognosis who had a distant disease-free survival (DDFS) of 64%. In addition, there was a subgroup of 90 patients who were not treated with either adjuvant chemotherapy or trastuzumab. The HR for good vs poor prognosis for the 10-year DDFS was 4.75. These data confirm that the 70-gene MammaPrint signature was a strong and independent prognostic indicator that can identify a subgroup with good clinical outcome in HER2–positive early breast cancer, even in the absence of chemotherapy and trastuzumab. In this genomic low-risk, highly endocrine responsive tumors (n = 11), no relapses or cancer-related deaths were observed. This subgroup will be further studied in the ongoing MINDACT trial.

Hormone Therapy in the Adjuvant and Metastatic Setting

Two trials were presented considering the use of hormone therapy in the metastatic setting, one of which was comparing high-dose versus low-dose estrogen, and other using high-dose fulvestrant compared to anastrozole.

Abstract 16: Dr Matt Ellis reported the results of a multicenter trial in women with HR-positive metastatic breast cancer who had an acquired aromatase inhibitor resistance. Women were randomly assigned to 30 mg estradiol (10 mg 3 times per day [tid]) daily or to 6 mg estradiol (2 mg tid) daily. In this trial, 66 women were enrolled. The clinical benefit rate (complete response [CR] + partial response [PR] + stable disease [SD] >24 weeks) were similar between the 2 arms 28.1% for the 30 mg dose and 29.4% for the 6 mg dose. As expected, there were greater adverse events in the high-dose arm including greater nausea and vomiting, hyponatremia, pleural effusion, and hypercalcemia. There was only 1 thromboembolic event per arm. The authors concluded that the use of estradiol 6 mg daily was beneficial and should be considered as a palliative therapy for women with HR-positive metastatic breast cancer.

Abstract 6126: The Fulvestrant First-Line Study Comparing Endocrine Treatments (FIRST) trial is a randomized phase II trial comparing fulvestrant high-dose (HD [500 mg/month + 500 mg day 14 of month 1]) vs anastrozole 1 mg daily in women with HR-positive metastatic breast cancer. Women were eligible if they had not received prior hormone therapy in the metastatic setting. In this study, 117/204 patients entered were evaluable for response. The overall response rate (ORR [36% vs 35%]) and clinical benefit rate (72% vs 67%) were similar when comparing HD fulvestrant to anastrozole. Median time to progression was superior in the HD fulvestrant arm (not reached vs 12.5 months). Confirmation of these findings is awaited from an ongoing phase III comparison of HD fulvestrant and anastrozole (CONFIRM trial).

Adjuvant Hormone Therapy

Abstract 12: Dr James Ingle presented a meta-analysis on behalf of the Aromatase Inhibitors Overview Group of randomized trials of monotherapy and switching strategies incorporating tamoxifen and aromatase inhibitors. Information was sought on all trials started by 2000 in which 2 arms were compared with 1 arm containing tamoxifen and the other an aromatase inhibitor (cohort 1) versus trials were 1 arm contained tamoxifen and the other 2-3 years of tamoxifen and an aromatase inhibitor (cohort 2). Cohort 1 included 9856 women who had a direct comparison of tamoxifen and an aromatase inhibitor (ATAC and BIG 1-98). Cohort 2 included 9015 women. The authors concluded that aromatase inhibitors produced significantly lower recurrence rates compared with tamoxifen in both cohorts. Cohort 1 revealed a 23% proportional reduction in recurrence with the absolute gains being 2.9% at 5 years, and 3.9% at 8 years. Cohort 2 revealed a 29% proportional reduction in recurrence with the absolute gains being 3.1% at 3 years, and 3.5% at 6 years. With regards to mortality, no significant difference in breast cancer mortality was seen between the 2 groups. However, a significant reduction was seen in cohort 2 with an absolute reduction in breast cancer mortality for AI’s of 0.7% at 3 years and 1.6% at 6 years from treatment divergence. This difference in mortality may be an artifact of the trial design, however. By excluding the early relapses in the switching strategy, the patient population is depleted of the endocrine non-responsive tumors, so the effect of the superior endocrine treatment is more pronounced in the remaining patients.

Abstract 13: BIG 1-98 data was presented on behalf of the International Breast Cancer Study Group (BIG). This trial initially started as a 2-arm trial comparing 5 years of tamoxifen to 5 years of letrozole. In this trial, 1828 postmenopausal women with HR-positive early breast cancer were enrolled. Subsequently, the trial was amended to include 2 additional arms. For the amended trial, 6182 women were enrolled and were randomized to 1 of 4 arms:

1. Tamoxifen x 5 years
2. Letrozole x 5 years
3. Tamoxifen x 2 years --> Letrozole x 3 years
4. Letrozole x 2 years --> Tamoxifen x 3 years

The first analysis compared the outcome of the women randomized to 5 years of tamoxifen versus 5 years of letrozole adding the patients from the original and amended trial. Thus 4922 women with a median of 76 months follow-up were presented. The trial was complicated by the fact that 25% of the women randomized to 5 years of tamoxifen selectively crossed over to letrozole, mostly in years 3-5. The comparison of tamoxifen vs letrozole was thus done by intent to treat (ITT) and also by censoring treatment of those women at the time of crossover. Disease-free survival was improved by 12% in the ITT patients and by 16% in the censored patients with the use of letrozole versus tamoxifen and time to distant recurrence was improved by 15% in the ITT and 19% in the censored patients.

With a median follow-up of 71 months, the 4-arm option trial with 6182 patients was presented. The analysis presented only included 3 of the blinded arms (2, 3, and 4). The results showed that when comparing 5 years of letrozole to the sequence of tam --> letrozole, there is clear superiority for the use of letrozole alone. This finding was most pronounced in the node positive patients. In contrast, there was no difference in outcome for those patients who were initiated on letrozole for 2 years and then crossed over to tamoxifen versus those who received 5 years of letrozole.

The authors concluded that adjuvant endocrine therapy should start with letrozole, especially for patients at higher risk for early recurrence. In addition, they stated that if necessary patients could be switched to tamoxifen after 2 years of letrozole.

Abstract 57: Tamoxifen is activated by CYP2D6 to a more potent SERM Endoxifen and the literature has suggested that those patients with impaired CYP2D6 metabolism have a higher risk of recurrence when given tamoxifen compared to women with no impairment of this metabolic pathway. The purpose of this study was to determine the role of CYP2D6 genetic variation as a predictive marker in women from a large prospective trial (ABCSG 8) that randomized women to 5 years of tamoxifen or 2 years of tamoxifen followed by 3 years of anastrozole. The authors designed a case control study in which tamoxifen treated patients were matched to 2 controls. Sixty-seven cases of women on 5 years of tamoxifen were genotyped for CYP2D6. When compared to the relative risk of women extensively metabolized CYP2D6, those women who metabolized CYP2D6 poorly had a 3.83 relative risk (P = .017) of a breast cancer event. There was no difference for patients women who metabolized CYP2D6 intermediately. This data continues to add to the body of findings that the metabolic activity of CYP2D6 may be important in influencing the eventual breast cancer outcome in women with early breast cancer who receive tamoxifen as their primary hormonal therapy.

HER2-positive Early and Advanced Breast Cancer

With the clear DFS and OS survival advantage afforded to women with HER2-positive breast cancer with the incorporation of trastuzumab, several large phase III trials have been initiated to see if this advantage can be improved upon with the incorporation of lapatinib. One such trial is the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (ALTTO) trial that randomized women with HER2-positive breast cancer who have been given adjuvant anthracycline-based therapy to 1 of 4 arms:

1. Paclitaxel + trastuzumab
2. Paclitaxel + lapatinib
3. Paclitaxel + trastuzumab + lapatinib
4. Paclitaxel + trastuzumab (12 weeks) --> lapatinib x 34 weeks

The concurrent use of paclitaxel, lapatinib and trastuzumab was investigated in 2 separate phase II clinical trials to assess safety of this regimen.

Abstract 2108: This adjuvant trial enrolled 95 women to receive received ddAC --> weekly paclitaxel at 80 mg/m2 with concurrent trastuzumab and lapatinib (1000 mg daily). Of the patients enrolled, 90 were evaluable. Of the patients, 37% (34) of the patients withdrew during paclitaxel/trastuzumab/lapatinib (PTL) phase, mostly due to grade 3 diarrhea.

Abstract 2109: In this trial, 122 patients with HER2-positive early breast cancer were placed on a similar study of AC (given q 2 or q 3 weeks) x 4 --> paclitaxel (80 mg/m2) weekly x 12 with concurrent trastuzumab and lapatinib (1000 mg daily). The trial was done to assess the incidence of CHF. Among the first 53 patients on trial, 45% developed grade 3/4 diarrhea. The trial was subsequently amended to reduce the lapatinib dose to 750 mg when given concurrently with paclitaxel and trastuzumab.

In addition to the standard use of anthracyclines and taxanes in the adjuvant setting for lymph node-positive breast cancer, the use of the regimen TC (docetaxel/cyclophosphamide) has become popular for women with lymph node-negative breast cancer. For women with lower-risk HER2-positive breast cancer, physicians have begun to combine this regimen with trastuzumab with a lack of safety of efficacy data.

Abstract 2111: The US Oncology Research group reported on a phase II clinical trial of 263 patients with HER2-positive and node-negative or T1/T2 with 1-3 positive lymph nodes. Women received docetaxel/cyclophosphamide (75/600) q 3 weeks x 4 with concurrent trastuzumab, and then trastuzumab for a total of 1 year. The safety and tolerability of this regimen were presented as part of this abstract. Sixteen patients discontinued participation in the trial due to adverse events, 4 of which were due to cardiac toxicity. No cases of CHF were observed.

HER2-positive Advanced Breast Cancer

Tyrosine Kinase Inhibitors:
Abstract 46: HER2 overexpression is correlated with reduced responsiveness to hormonal therapy in women with breast cancer. It is postulated that the blockage of HER2 might reverse this resistance. Thus, a phase III trial was undertaken randomizing 1286 postmenopausal HR-positive, HER2-positive, negative or unknown, previously untreated patients with metastatic or locally advanced breast cancer. Women were randomly assigned to letrozole + placebo or to letrozole + lapatinib with the primary statistical endpoint being progression-free survival (PFS). For the 219 women with HER2-positive breast cancer, PFS was improved from 3.0 months to 8.2 months with the addition of lapatinib to letrozole. In addition, ORR was improved from 15% to 28% and the clinical benefit rate from 29% to 48%. The safety profile of the combination was predictable and manageable.

Abstract 37: Neratinib (HKI-272) is an irreversible ErbB1/2 receptor tyrosine kinase inhibitor. A phase II trial was undertaken in patients with stage IIIB, IIIC or IV HER2-positive advanced breast cancer. Patients were stratified based on their prior exposure to trastuzumab. In this study, 66 women with prior trastuzumab were accrued, and 70 women with no prior trastuzumab were accrued. The most common toxicity requiring dose adjustment was diarrhea. For the patients with prior trastuzumab, the ORR was 26%, the clinical benefit response (CBR) was 36% and the 16-week PFS was 60%. For women with no prior trastuzumab, the ORR was 56%, the CBR was 68% and the 16-week PFS was 77%. There are multiple ongoing trials with neratinib in combination with other biologics and chemotherapy drugs in breast cancer and other solid tumors.

Novel Agents:
Abstract 33: T-DM1 is an antibody drug conjugate designed to combine trastuzumab with a highly potent and toxic anti-microtubule agent DM1. The conjugate was developed to preferentially deliver DM1 to HER2-positive tumor cells. The objective of the trial was to assess the safety and efficacy of T-DM1 in patients with HER2-positive metastatic breast cancer who had progressed on prior HER2 targeted therapy. T-DM1 was delivered at a dose of 3.6 mg/kg intravenously (IV) q 3 weeks. The median number of prior chemotherapy regimens for MBC was 3 and 55% of patients had received prior lapatinib. Of 107 evaluable patients, the ORR was 39%. Of the 60 lapatinib-pretreated patients, the ORR was 38% and the ORR for 64 patients with centrally confirmed HER2-positive disease was 50%. The authors concluded that T-DM1 was an active agent in patients with HER2-postitive breast cancer previously treated with both trastuzumab and lapatinib.

Abstract 3136: A phase I trial of weekly T-DM1 was undertaken in 28 women with pretreated HER2-positive metastatic breast cancer. The median number of prior chemotherapy agents for women in this trial was 5. The maximum tolerated dose (MTD) was found to be 2.4 mg/kg weekly with no cardiac toxicity observed. The ORR was 46% in 26 evaluable patients, all of whom had received trastuzumab, paclitaxel, docetaxel and/or vinorelbine.

Combination of HER2-directed and Anti-angiogenesis Therapy

Abstract 3133: In this trial, 52 women with locally advanced or metastatic breast cancer with or without trastuzumab pretreatment were placed on a phase II trial of lapatinib (1500 mg daily) and bevacizumab (10 mg/kg q 2 weeks). The dose limiting toxicities (DLT) were rash and hypersensitivity reactions. Of the patients, 96% had received prior chemotherapy, 91% had received prior trastuzumab, and 21% received prior lapatinib. The ORR was 13% and the CBR was 31%. The 12-week PFS rate was 69%. The authors concluded that the combination of lapatinib + bevacizumab is well tolerated, with low rates of grade 3 diarrhea or rash and had an encouraging activity in this heavily pretreated group of patients.

Metastatic Breast Cancer

Trials Incorporating Bevacizumab:
Abstract 6121: The breast cancer team from Memorial Sloan-Kettering Cancer Center has previously reported on the use of capecitabine in a schedule different from the US Food and Drug Administration (FDA) approved dose and schedule. Their phase I trial showed that a flat dose of 2000 mg 2 times per day (BID) 7 days on and 7 days off was feasible with manageable hand foot syndrome (HFS) and diarrhea. Based on the previously reported trial of capecitabine +/- bevacizumab with improvement in response, if not TTP, the group at Memorial-Sloan Kettering Cancer Center sought to investigate the combination of flat-dosing every-other week capecitabine in combination with bevacizumab. This phase II trial incorporated 36 women with measurable MBC with any number of prior chemotherapy regimens permitted. Patients were excluded if they had received prior treatment with fluoropyrimidine or bevacizumab. Patients received capecitabine 2000 mg BID 7 - 7, and bevacizumab (10 mg/kg IV) q 2 weeks. Of the 36 patients accrued, 42% had received no prior therapy for MBC, 14% had received chemotherapy, and 53% had received hormone therapy. The response rate was seen in 31% of patients with a CBR of 65%. The regimen was well tolerated.

Abstract 1035: The AVADO trial is a double-blind, placebo-controlled trial randomizing 705 women with recurrent of MBC receiving front-line therapy. Women were randomized to 1 of 3 arms:

1. Docetaxel 100 mg/m2 q 3 weeks
2. Docetaxel 100 mg/m2 + bevacizumab 7.5 mg/kg q 3 weeks
3. Docetaxel 100 mg/m2 + bevacizumab 15 mg/kg q 3 weeks

Several studies were reported on from the database of this trial. Because thromboses and bleeding are among the potential side effects of bevacizumab, patients on anti-coagulation have been historically excluded for entry into bevacizumab trials. However, the AVADO trial did enroll patients receiving full-dose anticoagulation provided that their use was stable for > 2 weeks prior to study entry. This study was to investigate the incidence of bleeding and arterial and venous TE’s in patients receiving concomitant anticoagulation while on AVADO. The conclusions of the study were that aortic thromboembolism (ATE’s), venous thromboembolism (VTE’s), and bleeding events were relatively low throughout the entire study and did not appear to increase with bevacizumab use.

Abstract 1027: Dr Chan et al looked at t2different endpoints from the AVADO trial. They attempted to see if there were any correlates between the development of hypertension from bevacizumab and DFS outcome. In addition, they hypothesized that the use of colony-stimulating factor (CSF) may adversely affect response.

Hypertension: Reported grade3-4 hypertension (HTN) was low in AVADO with 1 patient in the 7.5 mg/kg arm, and 8 in the 15 mg/kg arm experiencing HTN, so the correlation of HTN to outcome was undertaken for all grades of HTN.

Conclusions: The conclusions of the authors were that the efficacy of bevacizumab + docetaxel did not correlate with incidence of all grade HTN or G-CSF use.

Novel Agents:
The PI3K/akt/mTOR pathway is often activated in breast cancer, which subsequently increases gene transcription, cell growth, and vascular endothelial growth factor (VEGF) production. Inhibition of this pathway is an attractive target for advanced breast cancer. Several abstracts were presented using 1 of 2 mTOR inhibitors temsirolimus and everolimus (RAD001).

Abstract 406: It has been noted that resistance to trastuzumab is associated with Akt/mTOR activation. Preclinical studies have suggested that everolimus enhances the efficacy of trastuzumab, suggesting that it may be able to reverse resistance of trastuzumab. Dr Fasolo and colleagues initiated a multicenter phase I trial of daily and weekly everolimus (RAD001) in combination with vinorelbine and trastuzumab in patients with HER-2 overexpressing MBC with prior resistance to trastuzumab. Three different dose and schedules were investigated for RAD001. In this trial, 37 patients had been accrued, of which 17 received everolimus 5 mg daily, 6 received everolimus 20 mg weekly, and 14 received 30 mg weekly. All patients received vinorelbine 25 mg/m2 days 1 and 8 of a 21-day cycle along with weekly trastuzumab. The clinical benefit rate was 50% with a 15% PR rate and 3% CR rate. The authors concluded that this was an active regimen and both daily doing and weekly dosing were feasible.

Abstract 3119: Dr O’Regan and colleagues explored the use of paclitaxel + trastuzumab with everolimus. Paclitaxel was delivered at 80 mg/m2 on days 1, 8, and 15 every 4 weeks, with weekly trastuzumab. Everolimus was given daily at either a 5 mg or 10 mg dose, or weekly at a 30 mg, 50 mg, or 70 mg dose. Treatment was given until progression. As with the previous study, all patients were heavily pretreated and were trastuzumab resistant. Almost all patients had been previously exposed to taxanes and 44% were resistant. Among the first 9 evaluable patients for response, there was a 67% response rate and a 100% CBR. More patients will continue to be accrued to this trial.

Abstract 407: Dr Hahn and colleagues presented data from a phase II trial of temsirolimus in order to determine its single agent activity in MBC and to correlate its activity with PIK3CA mutations. In this study, 31 patients were enrolled and received TEM at 25 mg IV weekly. The median number of prior therapies was 4. Of the 31 patients, 3 experienced SD at 9 months. In addition, there was no correlation between mutations of PIK3CA and sensitivity to temsirolimus.

Many other abstracts were presented using novel agents such as the SRC-inhibitor dasatinib, and the PARP inhibitor BSI-201. These agents are promising, but the trials are early in their reporting.

Abstract 6117: Dr Linda Vahdat, et al presented a pooled analysis from 2 phase III studies comparing capecitabine alone to ixabepilone + capecitabine, examining the outcome for patients being treated in the first-line setting. This is a pooled analysis of 1973 women with MBC previously treated with an anthracycline and taxane and were randomized in an open-label fashion to receive either capecitabine alone (1250 mg/m2) PO BID x 14 days q 3 weeks, or ixabepilone (40 mg/m2 IV q 3 weeks) + capecitabine (1000 mg/m2) PO BID x 14 days q 3 weeks. In this analysis, 293 women who had relapsed < 12 months from adjuvant or neoadjuvant therapy received their randomized therapy in the front-line. Of these patients, 123 received the combination and demonstrated on ORR of 46%, with a median PFS of 5.6 months. For the 111 patients randomized to receive capecitabine alone, there was an 24% ORR with a median PFS of 2.8 months. The conclusions were that this pooled analysis demonstrated a significant ORR and PFS benefit when comparing ixabepilone + capecitabine to capecitabine alone in patients whose disease had relapsed within 12 months of adjuvant therapy.

OncoFacts™ Editor:

Christy Russell, MD

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