News

Dual HER2 Blockade Defers Breast Cancer Progression

View on the News

Many HER2 Therapies in Development

The challenge to clinicians going forward will be how to best use the many HER2 therapies that are in development. On the basis of the data from the CLEOPATRA trial, pertuzumab would logically be used in combination with trastuzumab and chemotherapy as first-line therapy of HER2-positive metastatic breast cancer.


Dr. William Gradishar

Novel trastuzumab-maytansine (TDM1) is an immunoconjugate agent that combines trastuzumab with DM1, an antimicrotubule cytotoxic agent. TDM1 has significant antitumor activity in patients with HER2-positive metastatic breast cancer that progressed while they received anti-HER2 therapy and chemotherapy. A large, randomized, phase III clinical trial (EMILIA, NCT00829166) is comparing TDM1 with capecitabine-lapatinib in patients with HER2-positive metastatic breast cancer who have received pretreatment with trastuzumab. Smaller phase II trials have also shown the antitumor activity and acceptable side-effect profile of pertuzumab-TDM1 therapy (NCT00875979 and MARIANNE, NCT01120184).

Several oral, small-molecule tyrosine kinase inhibitors are also in development. Afatinib (BIBW 2992) is an oral, irreversible HER family inhibitor targeting EGFR (HER1), HER2, and HER4. Initial reports confirm the antitumor activity of afatinib alone or with chemotherapy in patients who have had disease progression while they were receiving other anti-HER2 therapy. Neratinib (HKI-272) is an oral, irreversible inhibitor of EGFR (HER1), HER2, and HER4 that has shown substantial single-agent activity in patients who have never received treatment with trastuzumab, as well as in patients who have already received trastuzumab therapy.

Dr. William J. Gradishar is with the Robert H. Lurie Comprehensive Cancer Center at Northwestern University, Chicago. He is also an associate editor of The Oncology Report. These comments were extracted from an editorial that appeared online in the New England Journal of Medicine on Dec. 7, 2011 (N. Engl. J. Med. 2011 Dec. 7 [Epub doi: 10.1056/NEJMe1113641]). Dr. Gradishar stated that he had no relevant financial disclosures to make.


 

FROM THE NEW ENGLAND JOURNAL OF MEDICINE

The addition of pertuzumab to a standard chemotherapy combination of trastuzumab and docetaxel led to an additional 6 months of progression-free survival in patients with HER2-positive metastatic breast cancer, CLEOPATRA trial investigators reported in the New England Journal of Medicine.

Adding pertuzumab drove median progression-free survival from 12.4 months in a control group treated with only the standard combination to 18.5 months in the pertuzumab group, they wrote. This is a statistically significant difference that corresponds to a 38% reduction in the risk for progression or death and an increase of 6.1 months in median progression-free survival.

The results support dual blockade of the HER2 growth factor, which is targeted in different locations by pertuzumab and trastuzumab (Herceptin). In a prepared statement, lead investigator Dr. José Baselga, chief of hematology/oncology at Massachusetts General Hospital in Boston, characterized the improvement as "huge."

"Most metastatic patients with HER2-positive breast cancer eventually stop responding to trastuzumab, so the fact that we now have an agent that can be added to current treatment to delay progression is very exciting," he said of the research, which was published online Dec. 7 and is being presented at the San Antonio Breast Cancer Symposium.

"With the advent of trastuzumab and now pertuzumab, we have come a very long way in treating a type of breast cancer that once had a very poor prognosis."

For the double-blind phase III trial, known as CLEOPATRA (Clinical Evaluation of Pertuzumab and Trastuzumab), 808 patients aged 18 years and older with centrally confirmed HER2-positive metastatic or locally recurrent, unresectable breast cancer were randomized from February 2008 through July 2010 either to a control group that received placebo plus trastuzumab and docetaxel (Taxotere) or the pertuzumab group, which received pertuzumab plus trastuzumab* and docetaxel.

To be eligible for the trial, patients had to have a baseline left ventricular ejection fraction of 50% or greater and no history of declines to less than 50% during or after prior trastuzumab therapy (N. Engl. J. Med. 2011 Dec. 7 [doi: 10.1056/NEJMoa1113216]). Patients could have received one prior hormonal treatment for metastatic breast cancer and/or prior systemic neoadjuvant or adjuvant therapy, including prior trastuzumab and docetaxel. The median age of patients was 54 years, and 59% were white.

Study medication consisted of an 840-mg loading dose of pertuzumab followed by 420-mg three times weekly; an 8-mg/kg loading dose of trastuzumab followed by 6 mg/kg three times weekly, and a 75 mg/m2 dose of docetaxel every three weeks with subsequent dose escalation to 100 mg/m2 if 75 mg/m2 was well tolerated. At least six cycles of docetaxel were recommended. The primary study end point was progression-free survival as determined by independent review.

The researchers noted that the survival data are not complete, "since the interim analysis of overall survival was performed after 165 events had occurred (43% of the prespecified total number of events for the final analysis). Although there is a strong trend toward prolonged survival with pertuzumab plus trastuzumab plus docetaxel, the result is exploratory ... The final analysis of overall survival is event-driven and is estimated to be performed in 2013," they wrote.

The objective response rate was 69.3% in the control group vs. 80.2% in the pertuzumab group. While the difference favored the pertuzumab group statistically, the researchers consider the finding exploratory until the final analysis is conducted.

No increased rates of symptomatic or asymptomatic cardiac dysfunction were observed in the pertuzumab group, compared with the control group. However, diarrhea, rash, mucosal inflammation, febrile neutropenia, and dry skin were reported more frequently in the pertuzumab group, compared with the control group.

"The events were mostly grade 1 or 2 and occurred during the period of concomitant docetaxel administration," the researchers wrote. "Grade 3 or higher febrile neutropenia and diarrhea were also increased in the pertuzumab group."

Dr. Baselga and his associates went on to state that the study findings "suggest that targeting HER2-positive tumors with two anti-HER2 monoclonal antibodies that have complementary mechanisms of action results in a more comprehensive blockade of HER2 and highlights the clinical importance of preventing the ligand-dependent formation of HER2 dimers in order to silence HER2 signaling to the greatest extent possible."

The study was funded by F. Hoffmann-LaRoche and Genentech. Dr. Baselga disclosed that he is a member of the scientific advisory board for F. Hoffmann-LaRoche and for numerous other pharmaceutical companies. He is also a paid consultant for F. Hoffmann-LaRoche, Genentech, and for numerous other pharmaceutical companies.

* Correction 12/8/11: An earlier version of this story incorrectly described the regimen in the pertuzumab group. The error has been corrected.

Recommended Reading

Discussing End-of-Life Planning with Patients
MDedge Hematology and Oncology
Study Supports HBV Screening, Prophylaxis in Chemotherapy Patients
MDedge Hematology and Oncology
Coronary Disease, Stroke to Drop Below Cancer as Top Killer
MDedge Hematology and Oncology
Practice Changers Expected at San Antonio Breast Cancer Symposium
MDedge Hematology and Oncology
Long-Term Risk of GI Cancers Not Elevated in Celiac Patients
MDedge Hematology and Oncology
BOLERO-2: Everolimus Plus Exemestane Delays Breast Cancer Progression
MDedge Hematology and Oncology
Breast Cancer Gene Profile Identifies Early vs. Late Recurrences
MDedge Hematology and Oncology
Zoledronic Acid's Breast Cancer Benefit Extends 7 Years
MDedge Hematology and Oncology
FDA Drops Restrictions for Thrombocytopenia Treatments
MDedge Hematology and Oncology
IOM Dissects Environmental Risk Factors for Breast Cancer
MDedge Hematology and Oncology