Chia C. Portera

Cardiac Toxicity and Efficacy of Trastuzumab Combined with Pertuzumab in Patients with Trastuzumab-Insensitive Human Epidermal Growth Factor Receptor 2–Positive Metastatic Breast Cancer

Purpose: To evaluate safety and efficacy of trastuzumab with pertuzumab in patients with human epidermal growth factor receptor 2 (HER2)–positive metastatic breast cancer who had progressive disease on trastuzumab-based therapy. Experimental Design: Patients with measurable HER2+ metastatic breast cancer, ≤3 trastuzumab-based regimens, and left ventricular ejection fraction (LVEF) ≥55% received 8 or 6 mg/kg trastuzumab and 840 mg pertuzumab i.v. followed by 6 mg/kg trastuzumab and 420 mg pertuzumab every 3 weeks. Cardiac evaluation and tumor response were assessed every 3 and 6 weeks, respectively. Results: Eleven patients received 64 cycles of trastuzumab plus pertuzumab. A total of 92 echocardiograms and 8 cardiac magnetic resonance imaging studies were done. With the lower limit of normal LVEF 55%, left ventricular systolic dysfunction was observed in six patients, three grade 1, two grade 2, and one grade 3 according to the National Cancer Institute Common Terminology Criteria for Adverse Events. The objective response rate was 18%. Two patients had partial responses, three had stable disease, and six had progressive disease. The median time to progression was 6 weeks. In baseline tumors from formalin-fixed paraffin-embedded primary and/or metastatic tumor biopsies, pHER2-Y1248 trended toward an increase in patients with partial response compared with those with stable disease/progressive disease (P = 0.095). Conclusion: Trastuzumab plus pertuzumab may have clinical benefit in selected patients who have previously been treated with trastuzumab. Cardiac toxicity, although asymptomatic in most cases, was associated with this treatment. Further evaluation of efficacy of this combination is required to define the overall risks and benefits.

Cardiac toxicity and efficacy of trastuzumab combined with pertuzumab in patients with [corrected] human epidermal growth factor receptor 2-positive metastatic breast cancer.

Purpose: To evaluate safety and efficacy of trastuzumab with pertuzumab in patients with human epidermal growth factor receptor 2 (HER2)–positive metastatic breast cancer who had progressive disease on trastuzumab-based therapy. Experimental Design: Patients with measurable HER2+ metastatic breast cancer, ≤3 trastuzumab-based regimens, and left ventricular ejection fraction (LVEF) ≥55% received 8 or 6 mg/kg trastuzumab and 840 mg pertuzumab i.v. followed by 6 mg/kg trastuzumab and 420 mg pertuzumab every 3 weeks. Cardiac evaluation and tumor response were assessed every 3 and 6 weeks, respectively. Results: Eleven patients received 64 cycles of trastuzumab plus pertuzumab. A total of 92 echocardiograms and 8 cardiac magnetic resonance imaging studies were done. With the lower limit of normal LVEF 55%, left ventricular systolic dysfunction was observed in six patients, three grade 1, two grade 2, and one grade 3 according to the National Cancer Institute Common Terminology Criteria for Adverse Events. The objective response rate was 18%. Two patients had partial responses, three had stable disease, and six had progressive disease. The median time to progression was 6 weeks. In baseline tumors from formalin-fixed paraffin-embedded primary and/or metastatic tumor biopsies, pHER2-Y1248 trended toward an increase in patients with partial response compared with those with stable disease/progressive disease (P = 0.095). Conclusion: Trastuzumab plus pertuzumab may have clinical benefit in selected patients who have previously been treated with trastuzumab. Cardiac toxicity, although asymptomatic in most cases, was associated with this treatment. Further evaluation of efficacy of this combination is required to define the overall risks and benefits.

Learning and confirming with preclinical studies: modeling and simulation in the discovery of GDC-0917, an inhibitor of apoptosis proteins antagonist.

The application of modeling and simulation techniques is increasingly common in the preclinical stages of the drug development process. GDC-0917 [(S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-N-(2-(oxazol-2-yl)-4-phenylthiazol-5-yl)pyrrolidine-2-carboxamide] is a potent second-generation antagonist of inhibitor of apoptosis (IAP) proteins that is being developed for the treatment of various cancers. GDC-0917 has low to moderate clearance in the mouse (12.0 ml/min/kg), rat (27.0 ml/min/kg), and dog (15.3 ml/min/kg), and high clearance in the monkey (67.6 ml/min/kg). Accordingly, oral bioavailability was lowest in monkeys compared with other species. Based on our experience with a prototype molecule with similar structure, in vitro–in vivo extrapolation was used to predict a moderate clearance (11.5 ml/min/kg) in humans. The predicted human volume of distribution was estimated using simple allometry at 6.69 l/kg. Translational pharmacokinetic-pharmacodynamic (PK-PD) analysis using results from MDA-MB-231-X1.1 breast cancer xenograft studies and predicted human pharmacokinetics suggests that ED50 and ED90 targets can be achieved in humans using acceptable doses (72 mg and 660 mg, respectively) and under an acceptable time frame. The relationship between GDC-0917 concentrations and pharmacodynamic response (cIAP1 degradation) was characterized using an in vitro peripheral blood mononuclear cell immunoassay. Simulations of human GDC-0917 plasma concentration-time profile and cIAP1 degradation at the 5-mg starting dose in the phase 1 clinical trial agreed well with observations. This work shows the importance of leveraging information from prototype molecules and illustrates how modeling and simulation can be used to add value to preclinical studies in the early stages of the drug development process.

A phase 1B study of dulanermin in combination with modified FOLFOX6 plus bevacizumab in patients with metastatic colorectal cancer.

OBJECTIVES The study objectives were to evaluate the safety, tolerability, and preliminary efficacy of multiple doses of dulanermin in combination with modified FOLFOX6 and bevacizumab in previously untreated patients with locally advanced, recurrent, or metastatic colorectal cancer. PATIENTS AND METHODS A total of 23 patients received dulanermin at dosages of 4.5 or 9 mg/kg/d given on days 1 to 3 of each 14-day cycle along with standard dosing of modified FOLFOX6 plus bevacizumab. Dose-limiting toxicities, adverse events (AEs), maximum tolerated dose, and response according to Response Evaluation Criteria in Solid Tumors were assessed. RESULTS In the first cohort (3 patients given dulanermin at 4.5 mg/kg/d) and second cohort (6 patients given dulanermin at 9 mg/kg/day), no dose-limiting toxicities were observed. The subsequent 14 patients were treated with a dulanermin dosage of 9 mg/kg/d. Patients (N = 23) received 2 to 42 cycles of dulanermin (median 15). The most common grade 3 or 4 AEs were neutropenia (39%), hypertension (17%), peripheral neuropathy (17%), hand-foot syndrome (13%), and pulmonary embolism (13%). Three patients (13%) discontinued the study because of serious AEs. Overall, a best response of partial response was observed in 13 patients (57%) (9 confirmed, 4 unconfirmed), stable disease was observed in 7 patients (30%), and disease progression was observed in 3 patients (13%). The median progression-free survival was 9.9 months (95% confidence interval, 7.0-12.7). CONCLUSIONS Overall, the addition of dulanermin to first-line FOLFOX plus bevacizumab was well tolerated in patients with advanced colorectal cancer, with similar AEs that would be expected from FOLFOX plus bevacizumab. A randomized study is required to assess the clinical efficacy of dulanermin in this patient population.

Phase Ib study of drozitumab combined with first-line mFOLFOX6 plus bevacizumab in patients with metastatic colorectal cancer

In this multicenter phase Ib study, drozitumab was given in combination with the mFOLFOX6 regimen and bevacizumab in patients with previously untreated, locally advanced recurrent or metastatic colorectal cancer on day 1 of every 14-day cycle. Nine patients were treated at 2 different cohort dose levels of drozitumab. No dose-limiting toxicities occurred at either dose level and the maximum tolerated dose was not reached. Two patients had a partial response of 4.93 and 4.96 months duration. Cohort 2 dose level is the recommended starting dose level for future trials.

The heart of the matter.

Although anthracyclines have served as the mainstay of effective cytotoxic therapy for breast cancer during the last 30 years, the time has come to evaluate whether the benefits outweigh the significant risks of cardiac toxicity. In this issue of the Journal of Clinical Oncology, Pinder et al report an increased incidence of congestive heart failure (CHF) in older women who had more than 10 years follow-up and were treated with adjuvant anthracyclines for breast cancer. Women who received anthracyclines had higher rates of CHF, even though they were younger and had fewer comorbidities compared with women who received nonanthracycline regimens or no chemotherapy. For women aged 66 to 70 years at 10 years follow-up, a diagnosis of CHF was made in 38.4%, 32.5%, and 29% for anthracyclinetreated, nonanthracycline-treated, and no-chemotherapy groups, respectively. Age, African American race, hypertension, diabetes, and coronary artery disease were significant predictors of CHF. Although follow-up was shorter and with fewer patients, trastuzumab treatment was a significant predictor of CHF. These results further emphasize the magnitude of longterm risk for cardiovascular disease in older patients treated with anthracyclines, which has been previously reported by others. The observation of ethnicity as an independent risk factor for CHF highlights the importance of population studies, because these patients are under-represented in clinical trials. In this study, African American women had a relative 49% higher risk of developing CHF compared with white women, but they also had more advanced disease at diagnosis and were more likely to receive anthracycline-containing chemotherapy. Identification of at-risk populations will help to tailor therapies aimed specifically to reduce anthracycline-related cardiac toxicities. However, like all population-based studies, this study has inherent limitations and weaknesses. The database used in this study was compiled for reimbursement purposes on the basis of nonrandomly selected populations. The Surveillance, Epidemiology, and End Results (SEER)-Medicare captures only services covered by Medicare and does not include information on health maintenance organization enrollees, who account for a significant percentage of the Medicare population. In addition, records of certain conditions are inaccurate because of inadequate coding. Therefore, when one interprets population studies, limitations of the data and potential bias of data sampling should be taken into consideration. Some of the specific concerns are as follows, and most of them are pointed out by the authors. First, because no information was available to determine the severity and diagnostic criteria for CHF or to discriminate between systolic and diastolic dysfunction, the potential for misdiagnosis of patients with mild or nonclassic symptoms was substantial. Second, critical information, such as cumulative anthracycline dose, other toxicities, and hormonal treatment, was not captured in the database. It should be noted that, on the basis of a study in which left ventricular ejection fraction was obtained carefully and frequently, cardiotoxicity occurred at doxorubicin cumulative doses of 300 mg/m and lower. This is much lower than a previously recommended threshold dose of 500 mg/m. Third, the link between radiation and CHF may have been underestimated because of the lack of specific information on the techniques used and the dose of radiation to the heart. A recent report found that radiation to the internal mammary chain or a higher mean dose of radiation to the heart was associated with increased risk of CHF. This association was not apparent if radiation alone administered to the left or right side was independently considered. These limitations may have contributed to the surprising observation that anthracyclines did not significantly increase the risk of CHF in women ages 71 to 80 years. This finding directly contradicts the results from other studies suggesting that anthracycline-associated cardiac toxicity increases with increased age. In addition, by excluding other cardiac diseases and focusing on only CHF, this study may have missed an even broader scope of cardiovascular toxicity induced by anthracyclines, especially in this older population. Other factors that may have potential for causing long-term cardiac toxicity should also be considered. The rates of CHF reported in this study were high compared with CHF prevalence in the general population. It may have been useful to have a control group without breast cancer from the Medicare database. Increased long-term risk for CHF has been reported in patients who have received cyclophosphamide, methotrexate, and fluorouracil (CMF). Also, preliminary information from one trial with an aromatase inhibitor, letrozole, reported an increase in ischemia and CHF in the letrozole-treated group, although this was not statistically significant. Evidence of cardiac toxicity from other treatment modalities of breast cancer may emerge from longer follow-up. Despite its limitations, this study provides valuable information to the current debate on the role of adjuvant anthracyclines. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 25 NUMBER 25 SEPTEMBER 1 2007

Evaluation of lymphangiogenic factors, vascular endothelial growth factor D and E-cadherin in distinguishing inflammatory from locally advanced breast cancer

BACKGROUND Inflammatory breast cancer (IBC) is an aggressive form of breast cancer that on presentation resembles locally advanced breast cancer (LABC). This study identified molecular features of IBC and LABC to investigate pathogenesis. MATERIALS AND METHODS This study involved 100 IBC cases identified in a national IBC registry and 107 non-IBC LABC cases from the National Cancer Institutes Cooperative Breast Cancer Tissue Resource (CBCTR). Vascular endothelial growth factor D (VEGF-D) and E-cadherin levels and lymphatic vessel density (LVD) measured by podoplanin staining were examined by immunohistochemistry on paraffin-embedded tumor specimens. Intralymphatic tumor emboli (ILTE) were assessed in IBC and non-IBC tumors. IBC cases diagnosed by clinicians but not meeting the case definitions of the American Joint Committee on Cancer (AJCC) or the Surveillance, Epidemiology and End Results (SEER) Program of the National Cancer Institute (NCI)(designated atypical IBC) were compared with AJCC- and/or SEER-defined cases (designated classic IBC). RESULTS E-cadherin levels were significantly higher in classic IBC cases compared with non-IBC cases (P = .031), whereas compared with classic IBC, patients with non-IBC LABC had significantly higher LVD (P = .0017) and VEGF-D levels (P < .0001). ILTE was marginally greater in classic IBC than in non-IBC (P = .046). The profile of laboratory values in atypical IBC cases more closely resembled those fitting classic IBC than LABC. CONCLUSION E-cadherin levels, LVD, VEGF-D expression, and to a lesser extent, ILTE differed between classic IBC and non-IBC LABC. The similarity of laboratory results between atypical IBC and classic IBC vs. LABC suggests the need for broadening both the AJCC and SEER case definitions for this disease.

A Phase I Dose-Escalation Study Evaluating the Safety Tolerability and Pharmacokinetics of CUDC-427, a Potent, Oral, Monovalent IAP Antagonist, in Patients with Refractory Solid Tumors

Purpose: To determine the dose-limiting toxicities (DLT), adverse events (AE), pharmacokinetics, and preliminary evidence of antitumor activity of CUDC-427 (formerly GDC-0917), a selective antagonist of inhibitor of apoptosis (IAP) proteins. Experimental Design: Patients with advanced solid malignancies were treated with escalating doses of CUDC-427 orally on a daily 14-day on/7-day off schedule in 21-day cycles using a modified continuous reassessment method design. Blood samples were assayed to determine the pharmacokinetic properties, pharmacodynamic alterations of cellular IAP levels in peripheral blood mononuclear cells (PBMC), and monocyte chemoattractant protein-1 (MCP-1) levels. Results: Forty-two patients received 119 cycles of CUDC-427. Overall, the most common treatment-related toxicities were fatigue, nausea, vomiting, and rash. One DLT (grade 3 fatigue) occurred in a patient at 450 mg dose level during cycle 1, and 5 patients experienced AEs related to CUDC-427 that led to discontinuation and included grade 3 pruritus, and fatigue, and grade 2 drug hypersensitivity, pneumonitis, rash, and QT prolongation. The maximum planned dose of 600 mg orally daily for 2 weeks was reached, which allometrically scaled to exceed the IC90 in preclinical xenograft studies. Significant decreases in cIAP-1 levels in PBMCs were observed in all patients 6 hours after initial dosing. Responses included durable complete responses in one patient with ovarian cancer and one patient with MALT lymphoma. Conclusions: CUDC-427 can be administered safely at doses up to 600 mg daily for 14 days every 3 weeks. The absence of severe toxicities, inhibition of cIAP-1 in PBMC, and antitumor activity warrant further studies. Clin Cancer Res; 22(18); 4567–73. ©2016 AACR.

Cardiac toxicity and efficacy of trastuzumab combined with pertuzumab in patients with trastuzumab-insensitive HER2-positive metastatic breast cancer

Purpose: To evaluate safety and efficacy of trastuzumab with pertuzumab in patients with human epidermal growth factor receptor 2 (HER2)–positive metastatic breast cancer who had progressive disease on trastuzumab-based therapy. Experimental Design: Patients with measurable HER2+ metastatic breast cancer, ≤3 trastuzumab-based regimens, and left ventricular ejection fraction (LVEF) ≥55% received 8 or 6 mg/kg trastuzumab and 840 mg pertuzumab i.v. followed by 6 mg/kg trastuzumab and 420 mg pertuzumab every 3 weeks. Cardiac evaluation and tumor response were assessed every 3 and 6 weeks, respectively. Results: Eleven patients received 64 cycles of trastuzumab plus pertuzumab. A total of 92 echocardiograms and 8 cardiac magnetic resonance imaging studies were done. With the lower limit of normal LVEF 55%, left ventricular systolic dysfunction was observed in six patients, three grade 1, two grade 2, and one grade 3 according to the National Cancer Institute Common Terminology Criteria for Adverse Events. The objective response rate was 18%. Two patients had partial responses, three had stable disease, and six had progressive disease. The median time to progression was 6 weeks. In baseline tumors from formalin-fixed paraffin-embedded primary and/or metastatic tumor biopsies, pHER2-Y1248 trended toward an increase in patients with partial response compared with those with stable disease/progressive disease (P = 0.095). Conclusion: Trastuzumab plus pertuzumab may have clinical benefit in selected patients who have previously been treated with trastuzumab. Cardiac toxicity, although asymptomatic in most cases, was associated with this treatment. Further evaluation of efficacy of this combination is required to define the overall risks and benefits.