HER2/neu

Everolimus Improves Progression-Free Survival.

Posted by

0


Inhibition of the mammalian target of rapamycin (mTOR) is important for overcoming endocrine resistance in ER-positive breast cancer, and positive results from the BOLERO-2 trial (N Engl J Med 2012 Feb 9; 366:520) led to the approval of the mTOR inhibitor everolimus in combination with exemestane for patients who develop progressive disease after treatment with a nonsteroidal aromatase inhibitor. The importance of the mTOR signaling pathway is not restricted to endocrine-sensitive breast cancer. Preclinical data suggest that targeting human epidermal growth factor receptor-2 (HER2) and mTOR may overcome trastuzumab resistance.

Now, O’Regan and colleagues have conducted the multicenter, phase III, randomized, controlled, double-blind BOLERO-3 trial (Abstract 505) to evaluate the combination of the mTOR inhibitor everolimus, the chemotherapy agent vinorelbine, and the HER2 inhibitor trastuzumab versus vinorelbine and trastuzumab in 569 patients with HER2-positive advanced breast cancer; 84% of patients received trastuzumab in the metastatic disease setting and developed disease progression, whereas 16% developed disease progression while receiving adjuvant trastuzumab or within 12 months of receiving it. Patients could have received up to three treatment regimens for metastatic disease; 27% of patients received prior lapatinib.

The inclusion of everolimus conferred a significant improvement in progression-free survival (7.0 vs. 5.8 months; P=0.0067) but no improvement in rates of overall survival (at current follow-up), objective response, or clinical benefit. The addition of everolimus to chemotherapy (5 mg daily) was associated with toxicities similar to that seen when everolimus was combined with the AI exemestane: stomatitis, fatigue, rash, hyperglycemia, and rare pneumonitis.

The combination of everolimus, vinorelbine, and trastuzumab may provide yet another option for patients with HER2-positive metastatic breast cancer. But, if approved, it will likely be positioned after both first-line trastuzumab, pertuzumab, and a taxane and second-line trastuzumab emtansine (T-DM1; JW Oncol Hematol Feb 26 2013). Other treatment considerations in this space include lapatinib and capecitabine, alternative trastuzumab/chemotherapy combinations, and the combination of trastuzumab and lapatinib.

Source: Journal Watch Oncology and Hematology

 

 

Panitumumab Fails to Improve Outcome in Esophagogastric Cancer.

Posted by

1


Adding panitumumab to chemotherapy resulted in significantly shorter overall survival.

 

For patients with adenocarcinomas of the esophagus and stomach, conventional 5-fluorouracil (5-FU) plus platinum-based chemotherapy achieves an overall survival of only 9 to 11 months. The only targeted therapy approved for this disease is trastuzumab, which improves response and survival when combined with chemotherapy in human epidermal growth factor receptor 2 (HER2)-positive metastatic disease (JW Oncol Hematol Sep 14 2010).

Investigators from the U.K. now report the results of an industry-funded, open-label, multicenter, randomized, phase III trial of the epidermal growth factor receptor (EGFR)-targeted agent panitumumab plus chemotherapy for untreated metastatic esophagogastric cancer. Patients received either EOC: epirubicin (50 mg/m2), oxaliplatin (130 mg/m2), and capecitabine (1250 mg/m2/day for 21 days) cycled every 3 weeks; or modified EOC plus panitumumab: epirubicin (50 mg/m2), oxaliplatin (100 mg/m2), and capecitabine (1000 mg/m2/day for 21 days) plus panitumumab (9 mg/kg) cycled every 3 weeks.

Of 1000 planned patients, only 553 were treated due to early trial closure after an interim analysis showed inferior overall survival with modified EOC plus panitumumab. Most patients treated were male (82%–83%), were age 60 or older (60%–62%), and had performance status 1 (52%) and cancers of the esophagus (38%–40%) or gastroesophageal junction (27%–34%).

Although rates of response were equivalent in the two treatment arms (42%–46%), modified EOC plus panitumumab resulted in inferior overall survival (the primary endpoint; 8.8 vs. 11.3 months; HR 1.37; P=0.013) and a trend toward inferior progression-free survival (6.0 vs. 7.4 months; HR 1.22; P=0.068). Modified EOC plus panitumumab resulted in more grade 3 or 4 diarrhea, mucositis, and skin rash, but less grade 3 or 4 neuropathy and hematologic toxicity, likely due to a shorter duration of therapy.

Comment: This large, randomized trial in unselected patients with advanced esophagogastric cancer indicates that the addition of panitumumab to chemotherapy has a deleterious effect on patient outcomes. These findings are consistent with those simultaneously reported for cetuximab (JW Oncol Hematol May 28 2013).Given these strikingly negative results, interest in further study of potential EGFR-targeted therapies for esophagogastric cancer will likely diminish, and the possibility of discovering a biomarker to identify patients who might benefit from such treatments is unlikely.

 

Source: Journal Watch Oncology and Hematology

 

 

 

Novartis drug Afinitor® significantly extended time without disease progression in women with HER2 positive advanced breast cancer.

Posted by

0


  • nova
  • Everolimus plus trastuzumab and vinorelbine met primary endpoint of extending PFS compared to placebo plus trastuzumab and vinorelbine after prior therapy[1]
  • Results of Phase III trial, BOLERO-3, first to show potential benefit of everolimus in HER2 positive advanced breast cancer, an aggressive form of the disease[1]
  • Detailed data will be presented at the upcoming ASCO Annual Meeting and shared with regulatory authorities worldwide

Results of a pivotal Phase III trial in women with HER2 positive (HER2+) advanced breast cancer showed that Afinitor® (everolimus) tablets in combination with trastuzumab (Herceptin®*) and vinorelbine significantly extended progression-free survival (PFS) after prior therapy when compared to treatment with placebo plus trastuzumab and vinorelbine,meeting the study’s primary endpoint[1].

Efficacy and safety data from the BOLERO-3 (Breast cancer trials of OraL EveROlimus-3) trial were assessed as part of a prospectively planned analysis. These results will be presented on June 2 at the American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois[2], as well as at future medical congresses, and shared with regulatory authorities worldwide.

“We are encouraged by the BOLERO-3 results and are committed to helping improve treatment options for the HER2 positive patient population where there remains an unmet need,” said Alessandro Riva, Global Head, Oncology Development & Medical Affairs, Novartis Oncology. “Everolimus works differently than any currently available treatment for HER2 positive breast cancer, and these results support its potential expanded role in advanced breast cancer.”

Everolimus targets the PI3K/AKT/mTOR pathway, which is hyperactivated in many types of cancers[3]. mTOR is a protein that acts as an important regulator of cell division, blood vessel growth and cell metabolism[4]. Data confirm that blocking mTOR is a proven approach to maximize the benefit of existing advanced breast cancer treatments[4].

Everolimus is approved as Afinitor in more than 65 countries including the United States and the countries of the European Union to treat postmenopausal women with hormone receptor-positive, HER2 negative (HR+/HER2 negative) advanced breast cancer in combination with exemestane, after recurrence or progression following a non-steroidal aromatase inhibitor[1]. The specific indications vary by country[1]. HR+/HER2 negative advanced breast cancer is the most common form of the disease[5]. Approximately 70% of all invasive breast cancers are positive for HR expression at the time of diagnosis[6].

*Herceptin® is a registered trademark of Genentech, Inc.

Study design

BOLERO-3 is a Phase III, randomized, double-blind study of everolimus plus trastuzumab and vinorelbine conducted at 159 clinical trial sites globally[1]. The trial included 569 women with HER2 positive locally advanced or metastatic breast cancer who were previously treated with a taxane and were resistant to trastuzumab[1]. Participants were randomized 1:1 to receive either everolimus 5 mg/day orally or placebo, plus weekly vinorelbine 25 mg/m2 IV and weekly trastuzumab 2 mg/kg IV following loading dose of 4 mg/kg[1].

The primary endpoint of the trial is PFS[1]. Secondary endpoints include overall survival, objective response rate, time to deterioration of performance status, changes in quality-of-life scores over time, clinical benefit rate, duration of response, time to response, safety and pharmacokinetics[1].

About advanced breast cancer

Advanced breast cancer comprises metastatic breast cancer (stage IV) and locally advanced breast cancer (stage III)[7]. Metastatic breast cancer is the most serious form of the disease and occurs when the cancer has spread to other parts of the body, such as the brain, bones or liver[7]. Locally advanced breast cancer occurs when the cancer has spread to lymph nodes and/or other tissue in the area of the breast, but not to distant sites in the body[7].

Overactivation of the PI3K/AKT/mTOR pathway has been associated with disease progression in women with advanced breast cancer[4]. Eighty percent of advanced breast cancer is either hormone receptor-positive (HR+) and/or human epidermal growth factor receptor-2 positive (HER2 positive)[1],[8].

HR+ advanced breast cancer is the most common type of advanced breast cancer, with an estimated 220,000 women diagnosed globally each year[1]. HR+ advanced breast cancer is characterized by hormone receptor-positive tumors, a group of cancers that express receptors for certain hormones such as estrogen and progesterone. Cancer cell growth can be driven by these hormones[9].

In HER2 positive advanced breast cancer, overexpression of the HER2 gene activates signaling pathways, such as the mTOR pathway, leading to the uncontrolled growth and division of cancer cells[1],[10]. Globally, an estimated 140,000 women are living with HER2 positive advanced breast cancer[1].

About Afinitor® (everolimus)

Everolimus is approved as Afinitor® in the European Union for the treatment of hormone receptor-positive,HER2 negative (HR+/HER2 negative) advanced breast cancer, in combination with exemestane, in postmenopausal women without symptomatic visceral disease after recurrence or progression following a non-steroidal aromatase inhibitor. In the United States, Afinitor is approved for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2 negative breast cancer (advanced HR+/HER2 negative breast cancer) in combination with exemestane after failure of treatment with letrozole or anastrozole.

Afinitor (everolimus) tablets is approved in more than 95 countries, including the United States and throughout the European Union, in the oncology settings of advanced renal cell carcinoma following progression on or after vascular endothelial growth factor (VEGF)-targeted therapy, and in the United States and European Union for locally advanced, metastatic or unresectable progressive neuroendocrine tumors of pancreatic origin.

Everolimus is also available from Novartis for use in certain non-oncology patient populations under the brand names Afinitor® or Votubia®, Certican® and Zortress® and is exclusively licensed to Abbott and sublicensed to Boston Scientific for use in drug-eluting stents.

Indications vary by country and not all indications are available in every country. The safety and efficacy profile of everolimus has not yet been established outside the approved indications. Because of the uncertainty of clinical trials, there is no guarantee that everolimus will become commercially available for additional indications anywhere else in the world.

Important Safety Information about Afinitor (everolimus) tablets

Afinitor/Votubia can cause serious side effects including lung or breathing problems, infections (including sepsis), and kidney failure, which can lead to death. Mouth ulcers and mouth sores are common side effects. Afinitor/Votubia can affect blood cell counts, kidney and liver function, and blood sugar, cholesterol, and triglyceride levels. Afinitor/Votubia may cause fetal harm in pregnant women. Highly effective contraception is recommended for women of child-bearing potential while receiving Afinitor/Votubia and for up to eight weeks after ending treatment. Women taking Afinitor/Votubia should not breast feed. Fertility in women and men may be affected by treatment with Afinitor/Votubia.

The most common adverse drug reactions (incidence >=10 percent) are mouth ulcers, skin rash, feeling tired or weak, diarrhea, nausea, decreased appetite, infections (including upper respiratory tract infection), low level of red blood cells, abnormal taste, inflammation of lung tissue, weight loss, swelling of extremities or other parts of the body, nose bleeds, itching, vomiting, high level of blood cholesterol, headache, high level of blood sugar, cough, spontaneous bleeding or bruising, and breathlessness. The most common Grade 3-4 adverse drug reactions (incidence >=2 percent) are mouth ulcers, feeling tired or weak, infections, inflammation of lung tissue, diarrhea, spontaneous bleeding or bruising, low white blood cells (a type of blood cell that fights infection), and breathlessness. Cases of hepatitis B reactivation, blood clots in the lung or legs, and menstruation disorders such as absence of periods have been reported. Abnormalities were observed in hematology and clinical chemistry laboratory tests.

Source: Novartis newsletter

The 2012 San Antonio Breast Cancer Symposium.

Posted by

0


Highlights include sentinel lymph node surgery, eribulin, a cyclin-dependent kinase inhibitor, and chemotherapy for completely excised local recurrence.

Presentations at the 2012 San Antonio Breast Cancer Symposium (SABCS; December 4–8, 2012) addressed the role of sentinel lymph node surgery, eribulin versus capecitabine for heavily pretreated breast cancer, development of a new cyclin-dependent kinase inhibitor, and chemotherapy for completely resected local recurrence. Key findings are summarized below; for more information, please visit the SABCS website.

Averting Axillary Lymph Node Dissection
Previous guidelines have suggested that axillary dissection should still be performed in those patients who present with positive axillary nodes before preoperative systemic therapy. Randomized trials designed to compare preoperative versus postoperative adjuvant therapy in axillary node–positive breast cancer patients have shown that as many as 40% of patients who receive preoperative therapy will have negative axilla at the time of axillary lymph node dissection (ALND). This finding indicates that preoperative chemotherapy could allow a substantial proportion of patients with axillary node–positive disease to avoid axillary dissection. Now, investigators have sought to determine if sentinel lymph node (SLN) surgery after neoadjuvant chemotherapy permits identification of a group of patients in whom ALND can be averted (Abstract S2-1).

A total of 756 participants with axillary node–positive breast cancer received neoadjuvant chemotherapy followed by surgery; of these, 637 underwent both SLN surgery and ALND. SLN surgery correctly identified nodal status in 91% of patients, including 255 patients with node-negative disease and 326 with residual node positivity. The false-negative rate was 12.6%, but the success rate for identifying the SLN was highest when both blue-dye and radioactive colloid tracer were used (false-negative rate, 10.8%). Removing more sentinel nodes, placement of a surgical clip near the positive node, and nodal pathologic evidence of chemotherapeutic effectiveness all predicted greater success in identifying the SLN. These data require confirmation, but suggest that certain women with axillary node–positive disease can be spared ALND following neoadjuvant chemotherapy.

Eribulin versus Capecitabine for Heavily Pretreated Breast Cancer
As is true with any anticancer drug’s development, the goal is to administer the drug as early as possible during disease course. When eribulin was approved for metastatic breast cancer, the agent was determined to be active in patients with heavily pretreated metastatic disease: Those who received eribulin achieved a statistically significant survival benefit (2.5 months). Now, investigators report the results of an industry-sponsored, phase III trial (Abstract S6-6) of eribulin versus capecitabine in 1102 patients with locally advanced or metastatic disease who had received 3 prior chemotherapy regimens (2 for advanced disease). Progression-free survival (PFS), overall survival, and response rates were not statistically different between the two treatment groups; however, eribulin may have offered greater therapeutic benefit in certain prespecified subgroups (i.e., triple-negative, estrogen receptor–negative, or human epidermal growth factor receptor 2 [HER2]–negative). The overall results are disappointing in that earlier use of eribulin did not translate into an advantage for all patients with metastatic disease; however, further work should be focused on these specific patient groups.

Promising New Cyclin-Dependent Kinase Inhibitor
Cyclin-dependent kinases (CDKs) regulate cell-cycle progression by interacting with specific cyclin proteins. PD0332991 is an oral, highly selective inhibitor of CDK 4/6 kinase that prevents tumor cell-cycle progression from G1 to S phase. Preclinical studies have shown that ER-positive breast cancer (luminal subtype) is particularly sensitive to PD0332991. In a two-part, phase II study (Abstract S1-6), patients with ER+ metastatic breast cancer were randomized to letrozole alone or with PD0332991 as first-line therapy. The first part of the study included only ER+ patients, while the second part enriched for patients having ER+ tumors with loss of p16 and/or amplification of CCND1 (markers of sensitivity to PD0332991). The study’s first phase previously showed that PD332991 significantly improved PFS. Now, data from the second phase continue to show a statistically significant improvement in median PFS (7.5 months to 26.1 months) that favors the doublet over letrozole alone. Manageable neutropenia was the most common adverse event. Based on these encouraging results, a randomized, phase III trial of similar design is planned.

Systemic Therapy for Completely Resected Local Recurrence
A troubling clinical dilemma arises when a patient who has previously received adjuvant systemic therapy develops a local recurrence that is completely resected. Clinicians recognize that such patients are at excess risk for systemic relapse, yet little data support using additional, nonendocrine, systemic therapy. Now, results of the Chemotherapy as Adjuvant for Locally Recurrent Breast Cancer (CALOR) trial provide guidance (Abstract S3-2). A total of 162 patients who developed first ipsilateral local and/or regional recurrences (in the absence of supraclavicular nodes or evidence of metastatic disease) that had been completely excised were randomized to 3 to 6 months of chemotherapy or no chemotherapy, with endocrine therapy or anti-HER2 therapy as appropriate. Radiation therapy was recommended for all patients. Most patients had developed ipsilateral recurrence in a conserved breast; one third had recurrence on the chest wall or in the mastectomy scar. Fewer than 10% of patients received anti-HER2 therapy, and >90% of patients eligible for endocrine therapy received some form of it. More than two thirds of chemotherapy patients received polychemotherapy. Five-year disease-free survival improved with the addition of chemotherapy (69% vs. 57%, P=0.045) and was most striking in the patients with ER-negative recurrences (67% vs. 35%, P=0.007). Overall survival also improved with the addition of chemotherapy. Although this study was substantially smaller than planned (original accrual goal, 974), another such trial is unlikely. As such, chemotherapy should be strongly considered in this clinical situation, particularly for patients with ER-negative recurrences.

Source: Journal Watch Oncology and Hematology

T-DM1 Prolongs Survival in Advanced HER2-Positive Breast Cancer.

Posted by

0


The drug-antibody conjugate was more effective and less toxic than lapatinib plus capecitabine in patients previously treated with trastuzumab and a taxane.

We can expect that the next breast cancer drug soon to be approved by the FDA will be trastuzumab emtansine (T-DM1), an antibody-drug conjugate combining trastuzumab with a derivative of the cytotoxic maytansine via a stable linker molecule (JW Oncol Hematol Oct 2 2012). T-DM1 is more than just another new agent. It represents vindication for those who have worked on fusion molecules for the last 2 decades. Previous efforts with such molecules were often derailed because the linker was either unstable (resulting in systemic exposure to the toxin) or cytotoxic (resulting in prohibitive adverse effects). With T-DM1, intracellular drug delivery only to human epidermal growth factor receptor 2 (HER2)–overexpressing tumor cells has been observed.

Now, investigators report the results of the EMILIA study, an industry-sponsored, phase III, randomized, open-label trial involving 991 patients with HER2-positive, unresectable, locally advanced or metastatic breast cancer who were previously treated with trastuzumab and a taxane. Patients received either T-DM1 or lapatinib plus capecitabine (LC) and were stratified by world region, number of prior chemotherapy regimens for advanced disease, and presence or absence of visceral disease. Primary endpoints were progression-free survival (PFS), overall survival (OS), and safety; secondary endpoints included objective response rate, duration of response, and time to symptom progression.

Median PFS was significantly longer with T-DM1 versus LC (9.6 vs. 6.4 months; hazard ratio, 0.65; P<0.001), as was median OS (30.9 vs. 25.1 months; HR, 0.68; P<0.001). Overall response rate was also superior with T-DM1 versus LC (43.6% vs. 30.8%; P<0.001), as were results for all secondary endpoints. Rates of grade 3 or 4 adverse events were 40.8% with T-DM1 and 57.0% with LC.

Comment: The excitement surrounding the anticipated FDA approval of T-DM1 is justified given that the drug successfully targets HER2-overexpressing disease with potent antitumor activity minus the full complement of adverse effects associated with typical chemotherapy partnered with trastuzumab. Of course, the stage is set for exploring T-DM1 in combination with other anti-HER2 agents, including pertuzumab (JW Oncol Hematol Jan 24 2012). Because the toxicity of T-DM1 is quite modest, adjuvant trials are under way to compare the use of this compound with standard trastuzumab-based regimens.

Source: Journal Watch Oncology and Hematology

 

The Next Big Thing for Metastatic Breast Cancer.

Posted by

0


The drug-antibody conjugate trastuzumab emtansine demonstrated single-agent activity in patients with previously treated HER2-positive disease.

Even with the recent approval of pertuzumab as a component (along with trastuzumab and docetaxel) of a first-line regimen for patients with human epidermal growth factor receptor 2 (HER2)–positive, metastatic breast cancer, the anticipated approval of trastuzumab emtansine (T-DM1) is eagerly awaited by oncologists as a treatment for patients with progressive HER2-positive breast cancer following treatment with trastuzumab. Indeed, clinical experience with T-DM1 — a fusion molecule combining trastuzumab with a cytotoxic (maytansine) utilizing a stable linker (see illustration) — has shown robust clinical activity following prior anti-HER2 therapy with relatively modest toxicity (J Clin Oncol 2011 Feb; 29:398).

Now, investigators have conducted an industry-supported, single-arm, phase II clinical trial to evaluate the effectiveness of T-DM1 (3.6 mg/kg intravenously, every 3 weeks) in 110 patients with metastatic HER-2-positive breast cancer who were previously treated with trastuzumab, lapatinib, an anthracycline, a taxane, and capecitabine. Patients had previously received a median of seven prior nonendocrine agents.

At median follow-up of 17.4 months, the objective response rate (the primary objective) was 34.5%, the clinical benefit rate (inclusive of stable disease) was 48.2%, and median progression-free survival (PFS) was 6.9 months. T-DM1 was well tolerated. Most adverse events were grade 1 or 2. The most common events of any grade were fatigue, nausea, and thrombocytopenia. Grade 3 or 4 thrombocytopenia occurred in 9.1% of patients, and grade 3 fatigue occurred in 4.5%.

Comment: T-DM1 was recently shown to be superior to combination capecitabine and lapatinib in metastatic breast cancer patients who were not as heavily pretreated as those in the current study (JW Oncol Hematol Jul 3 2012). T-DM1 will be rapidly embraced by clinical oncologists once it is approved, and the future development of this agent will likely move to earlier-stage breast cancer and be used in combination with other HER2-targeted agents such as pertuzumab.

Source:Journal Watch Oncology and Hematology

 

PREDICT Plus: development and validation of a prognostic model for early breast cancer that includes HER2.

Posted by

0


Predict (www.predict.nhs.uk) is an online, breast cancer prognostication and treatment benefit tool. The aim of this study was to incorporate the prognostic effect of HER2 status in a new version (Predict+), and to compare its performance with the original Predict and Adjuvant!.

Methods:

The prognostic effect of HER2 status was based on an analysis of data from 10 179 breast cancer patients from 14 studies in the Breast Cancer Association Consortium. The hazard ratio estimates were incorporated into Predict. The validation study was based on 1653 patients with early-stage invasive breast cancer identified from the British Columbia Breast Cancer Outcomes Unit. Predicted overall survival (OS) and breast cancer-specific survival (BCSS) for Predict+, Predict and Adjuvant! were compared with observed outcomes.

Results:

All three models performed well for both OS and BCSS. Both Predict models provided better BCSS estimates than Adjuvant!. In the subset of patients with HER2-positive tumours, Predict+ performed substantially better than the other two models for both OS and BCSS.

Conclusion:

Predict+ is the first clinical breast cancer prognostication tool that includes tumour HER2 status. Use of the model might lead to more accurate absolute treatment benefit predictions for individual patients.

Source: British journal of oncology