Studies on Herceptin (Trastuzumab) and Kadcyla (T-DM1)

Fallleaves

Just wanted to put together a few studies I've found on Herceptin and Kadcycla. If anyone has any good studies, let me know and I'll add them!

"Trastuzumab regimens for early breast cancer"
"The review includes eight trials that involved 11,991 women with HER2-positive operable breast cancer who were assigned by chance to receive trastuzumab or not. Trastuzumab is always paired with a standard chemotherapy as starting treatment but it can also be continued alone or with hormone-blocking medications, such as an aromatase inhibitor or tamoxifen. Women were followed by clinicians for several years (three on average). The review found that trastuzumab significantly reduced recurrence and mortality. Some patients in treatment develop severe heart toxicity (i.e. congestive heart failure (CHF)). Breast cancer mortality is reduced by one-third but the risk of heart toxicity is five times more likely for women receiving trastuzumab than women receiving standard therapy alone. If 1000 women were given standard therapy alone (with no trastuzumab) then about 900 would survive and five would have experienced heart toxicities. If 1000 women were treated with standard chemotherapy and trastuzumab for one year, about 933 would survive (33 more women will have their lives prolonged), about 740 would be free of disease recurrence (95 more women will not experience the disease return), and 26 would have serious heart toxicity (21 more than the chemotherapy alone group) due to the drug. These heart toxicities are often reversible if the treatment is stopped straight away."
http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD006243.pub2/abstract;jsessionid=C20843598EE21E274BCDD68940758EC0.f01t04
(Mojas, 2012)

"Years after treatment for HER2-positive early stage breast, trastuzumab continues to show life-altering benefit"
"The study reports long term findings (8 years) from two randomized phase III studies that led to U.S. Food and Drug Administration approval of Herceptin use in early stage HER2-positive breast cancer."
"They found that the use of trastuzumab produced a 37 percent improvement in survival and a 40 percent reduction in risk of cancer occurrence, compared to patients treated with chemotherapy alone."
"The findings also confirmed long-term safety of trastuzumab, Dr. Perez says. Over eight years, there was no increase in the incidence of secondary cancers and only a minor increase in heart problems, she says."
http://www.sciencedaily.com/releases/2014/10/141020212339.htm
(Mayo Clinic, 10/20/14)

This is a good review of trastuzumab and similar drugs, and various combinations among them.

"Therapeutic considerations in treating HER2-positive metastatic breast cancer"
"The advent of trastuzumab, a monoclonal antibody to HER2, revolutionized the management of HER2-positive breast cancer (BC) in the metastatic and adjuvant settings. However, relapse despite adjuvant trastuzumab and resistance to trastuzumab in the metastatic setting remain substantial clinical problems for many patients with HER2-positive BC."
"There has been progress, with the approval of three additional HER2-targeted agents in the last six years: lapatinib, pertuzumab, and ado-trastuzumab emtansine (T-DM1). Other HER2-targeted therapies, including neratinib and afatinib, are in clinical development, and trials of novel agents such as heat shock protein-90 (HSP90) inhibitors, phosphatidylinositol-3-kinase (PI3K) inhibitors, and HER2-targeted vaccines are ongoing. In addition to developing new therapy, research is addressing several unique challenges in the management of HER2-positive MBC. In this article, we discuss advances in the treatment of HER2-positive MBC, with a focus on novel HER2-targeted therapy and HER2-targeted agents recently approved by the United States Food and Drug Administration (FDA). Additionally, we also address the management of brain metastases (BM) and hormone receptor (HR) - positive, HER2-positive MBC. "
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4180403/
(O'Sullivan, 2014)

"Breast cancer with high TIL Levels: Skip the Trastuzumab?"
"Intriguing new findings from a study of stromal tumor infiltrating lymphocytes (Str-TILs) in breast cancer patients with HER2 tumors suggest that there is a small subgroup of patients (about 10%) who may not benefit from the addition of trastuzumab (Herceptin, Genentech, Inc) to chemotherapy."
"This small proportion of patients who had high levels of Str-TILs in the tumor specimens did well whether they were treated with chemotherapy alone or with chemotherapy plus trastuzumab, suggesting that these patients may not need trastuzumab, sparing them side effects and reducing costs. However, this research is too early yet to influence clinical decisions..."
http://www.medscape.com/viewarticle/836326
(Chusteka, 12/10/14)

"Systemic targeted therapy for her2+ early female breast cancer: a systematic review of the evidence for the 2014 Cancer Care Ontario Systemic therapy guideline."
"In four major trials (hera, National Surgical Adjuvant Breast and Bowel Project B-31, North Central Cancer Treatment Group N9831, and Breast Cancer International Research Group 006), adjuvant trastuzumab for 1 year was superior in disease-free survival (dfs) and overall survival (os) to no trastuzumab; trastuzumab showed no benefit in one trial (pacs 04). A shorter duration of trastuzumab (less than 1 year compared with 1 year) was evaluated, with mixed results for dfs: one trial showed superiority (finher), one trial could not demonstrate noninferiority (phare), another trial showed equivalent results (E 2198)"
"Longer trastuzumab duration (hera: 2 years vs. 1 year) showed no improvement in dfs or os and a higher rate of cardiac events."
"In the neoadjuvant setting (neoaltto, GeparQuinto, Neosphere), trastuzumab alone or in combination with another anti-her2 agent (lapatinib, pertuzumab) was compared with either lapatinib or pertuzumab alone and showed superior or equivalent rates of pathologic complete response. In the adjuvant setting, lapatinib alone or in combination with trastuzumab, compared with trastuzumab alone (altto) or with placebo (teach), was not superior in dfs."
"Taking into consideration disease characteristics and patient preference, 1 year of trastuzumab should be offered to all patients with her2-positive breast cancer who are receiving adjuvant chemotherapy. Cardiac function should be regularly assessed in this patient population."
http://www.ncbi.nlm.nih.gov/pubmed/25848335
(Mates, 2015)

Here's a recent Medscape article on Herceptin, but it doesn't indicate how long treatment was (1 or 2 years).

"Study Finds Trastuzumab Benefit-Risk Ratio Favorable in Long Term"
"The results of this analysis confirm that the incidence of trastuzumab-induced cardiac dysfunction is relatively low (approximately 3%) and the late development of cardiac toxicity is infrequent," Dr. Pooja P. Advani, of the Mayo Clinic in Jacksonville, Florida, told Reuters Health by email.
"Older age (60 or older), hypertension, and lower baseline heart function (ejection fraction) are associated with an increased risk of trastuzumab-induced cardiac dysfunction. In summary, trastuzumab continues to have a favorable benefit-to-risk ratio," she added.
Mayo researchers previously reported on short-term (3.75 years) cardiac safety in the NCCTG N9831 trial (http://bit.ly/1OLQyeo). In this new analysis, Dr. Advani and colleagues reported on cardiac safety during a median follow-up of 9.2 years.
"There has been some concern regarding the risks of long-term cardiac effects from trastuzumab and whether the cardiac dysfunction is truly reversible," Dr. Advani told Reuters Health. "Our results are fairly consistent with other pivotal studies and demonstrate a small but stable rate of cardiac events after post-operative anthracycline-based chemotherapy plus trastuzumab, with recovery of the ejection fraction in over half the patients who developed heart failure. Overall these results are reassuring and support that trastuzumab is the cornerstone for treatment of HER2-positive breast cancer."
http://www.medscape.com/viewarticle/852108
(Hand, 10/6/15)

Recommendations on what drug combinations should be first and second line treatment for advanced HER2 positive BC.

"Treatment of HER2 positive advanced breast cancer with T-DM1: A review of the literature"
"T-DM1 is characterized by an innovative and selective mechanism of action on the HER2-positive tumor cells. Through this mechanism, T-DM1 leads to a double antitumor effect, an anti-HER2 effect mediated by the trastuzumab activity and a selective transport of a powerful antimitotic agent DM1 to the intracytoplasmic area. This particular mechanism of action increases the effectiveness while it reduces the toxicity."
"Regarding the results of the MARIANNE trial, T-DM1 is non-inferior and less toxic than trastuzumab + taxane in first line. However, taking into account the substantial improvement in OS obtained in the CLEOPATRA trial (Swain et al., 2015), in which the combination of docetaxel + trastuzumab + pertuzumab increased OS in 15.7 months vs docetaxel + trastuzumab + placebo, the dual combination of trastuzumab + taxane cannot be considered as the standard first line anymore. Thus MARIANNE results are insufficient neither T-DM1 or T-DM1 + pertuzumab were superior to trastuzumab + taxane. In this context, the CLEOPATRA study arm, docetaxel + trastuzumab + pertuzumab, remains the preferred first-line in metastatic HER2+ breast cancer, being T-DM1 an apparently less effective alternative. Thus T-DM1 in first line could be an option reserved for patients not suitable for pertuzumab because of high risk of cardiac adverse events."
"After the EMILIA results T-DM1 has shown superiority vs lapatinib and capecitabine, which was the standard second line in many centers. Considering the significant improvement in survival and better toxicity profile T-DM1 can be considered as the preferred second-line after previous treatment with trastuzumab + taxane. Finally, taking into account the data from the THERESA trial in those patients not previously treated with T-DM1 in second line, the administration of this compound in third or later lines should be recommended."
"T-DM1 in second line and later, after progression on trastuzumab and taxane based therapies or in an early relapse within 6 months after the completion of the adjuvant treatment, is associated with a better outcomes (significant increases in terms of duration of response, PFS and OS), safety profile and favorable clinical tolerabilityfor patients with advanced HER2-positive breast cancer compared with other available therapeutic options—T-DM1 3.6 mg/kg every 3 weeks is well tolerated and safe without cardiotoxicity, and no dose adjustments appear necessary in heavily pretreated patients."
http://www.croh-online.com/article/S1040-8428%2815%2930026-3/fulltext
(Martinez, 2015)

Edit 10/12/15 to add:

Was given a really interesting article on how Herceptin may keep micrometasteses on bone from growing, even in HER2 negative patients.

"University of Michigan study challenges notion of using Herceptin only for HER2 positive breast cancer"

"A recent study based on new analyses of old data found some tumors were incorrectly categorized as HER2-positive and as a result those women received adjuvant Herceptin. It turns out, they benefited as much from the treatment as woman with actual HER2-positive cancer."

"The researchers had previously shown HER2 plays an important role in cancer stem cells, the small number of cells in a tumor that fuel its growth and spread. These cells represent 1 percent to 5 percent of all the cells in a tumor. They are resistant to current chemotherapy and radiation treatments but since they express HER2, they are effectively targeted by Herceptin."

"Further, the researchers in this new study found that for tumors classified as HER2-negative, HER2 levels were higher in bone metastases compared to the primary breast tumor. Bone is the most frequent site to which breast cancer spreads.The researchers administered Herceptin to mice with these bone lesions and found that it was most effective when given early, when tumors were small or mere "micrometastases." In these cases, Herceptin almost completely blocked the tumors from growing. When the drug was given later, after tumors were established, it had little effect."

http://www.mcancer.org/news/archive/university-mic...

(University of Michigan Comprehensive Cancer Center, 2/26/13)

Edit on 10/13/15 to add:

This is a small restrospective study, but showed a strong benefit from vitamin D.

"Improved Clinical Outcomes Associated with Vitamin D supplementation During Adjuvant Therapy in Patients with Nonmetastatic HER2 Positive Breast Cancer" "In our final multivariate model, VD (vitamin D supplementation) was associated with improved disease free survival ([HR], .36)"

http://www.clinical-breast-cancer.com/article/S152... (Zeichner, 2015)