Targeted therapies continue to improve outcomes in HER-2–positive breast cancer

The FDA’s decision in February to approve ado-trastuzumab emtansine for the treatment of HER-2–positive breast cancer has been labeled a momentous day in oncology.

Ado-trastuzumab emtansine (Kadcyla, Genentech) is the fourth FDA-approved drug to join the armamentarium against metastatic HER-2–positive breast cancer, joining trastuzumab (Herceptin, Genentech), lapatinib (Tykerb, GlaxoSmithKline) and pertuzumab (Perjeta, Genentech).

Research has shown the drug — indicated for patients previously treated with trastuzumab and taxane-based chemotherapy — offers more benefit than previous standard therapies, delivering high doses of chemotherapy to the tumor while causing less toxicity to other areas of patients’ bodies.

“We have, in clinical practice, found the drug to be effective and very well tolerated,” Erica L. Mayer, MD, MPH, a medical oncologist at Dana-Farber Cancer Institute in Boston, who has worked with ado-trastuzumab emtansine for several years as part of early-stage clinical trials, told HemOnc Today. “We welcome the approval of Kadcyla. We feel this is a strong agent that will hopefully improve survival outcomes in our patients while helping them achieve a better quality of life.”

HemOnc Today spoke with several leading clinicians about the evolution of treatments for HER-2–positive breast cancer, the implications FDA approval of ado-trastuzumab emtansine will have on clinicians and patients, and the potential that other investigational agents may offer in the fight against the disease.

“Approval of Kadcyla means there is another option to help extend survival in these patients compared with the previously approved regimen,” Edith A. Perez, MD, director of the breast cancer program at Mayo Clinic in Jacksonville, Fla., and a HemOnc Today Editorial Board member, said in an interview. “It also provides confirmation that clinical research is helping to improve patient care.”

Evolution of agents

Increased amounts of HER-2 protein are found in certain types of cancer cells, including 15% to 20% of breast cancers. The increased amounts of protein contribute to cell aggressiveness, survival and growth.

Progress in the development of therapies began when the HER-2 gene was first recognized as a certain oncogene of breast cancer tumor types, according to Vered Stearns, MD, professor of oncology and co-director of the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center’s Breast Cancer Program.

“The reason for the success of therapies targeting HER-2 is because, when trastuzumab was initially developed, the studies concentrated on women with tumors that overexpressed or amplified HER-2. The therapy was targeted from the very beginning,” Stearns told HemOnc Today.

“In other types of investigations — when we knew that a drug or agent may be working but we didn’t know exactly what type of breast cancer it may be targeting — you might not see the same effect because it was diluted by including women with different types of breast cancer,” Stearns said. “We are smarter today than we may have been 10 years ago by including women with specific types of breast cancer in each new drug study.”

HER-2–positive breast cancer is unique in that there is a target that is biologically significant for the survival and growth of the cancer cell.

“It has been demonstrated for many years that specifically targeting the HER-2 receptor has a profound impact on cancer cell survival and subsequently can lead to cancer cell death,” Mayer said.

Work conducted in the laboratory of Dennis Slamon, MD, at UCLA’s Jonsson Comprehensive Cancer Center, as well as that of other investigators, originally led to this discovery.

Slamon and colleagues were partially responsible for the research that led to the FDA approval of trastuzumab in both the metastatic and adjuvant settings. That approval, granted in 1998, was followed by subsequent research that then led to the approvals for lapatinib, pertuzumab and ado-trastuzumab emtansine.

In his research, Slamon identified HER-2 as a cancer target after other investigators had determined that the HER-2 family of genes could be relevant to cancer growth. He found that normal quantities of HER-2 maintained the breast cell’s growth but, in excess, the HER-2 protein increased growth signals and divided more rapidly, creating a tumor.

“Historically, with the initial trials that assessed trastuzumab alone, there was a benefit in about 20% to 30% of women. When trastuzumab was combined with chemotherapy, this benefit of seeing a reduction in tumors went up to 60% to 70%,” Stearns said. “This is what led us to investigate trastuzumab mostly in combinations with a cytotoxic agent and also with hormonal agents.”

Trastuzumab can be used alone, but only in limited circumstances, Stearns said.

“Coming up with strategies when you try and provide women with the same benefit or better benefit while reducing the potential for side effects has been of great interest, and that is why this new approval of Kadcyla is so exciting,” Stearns said.

EMILIA study

Ado-trastuzumab emtansine, formerly known as T-DM1, is an antibody drug conjugate that incorporates antitumor activities of trastuzumab with the potent cytotoxic agent emtansine.

The drug demonstrates how to exploit cell surface receptors to more specifically deliver chemotherapy to the tumor, Douglas Yee, MD, a 
HemOnc Today Editorial Board member, said in an interview.

“This concept has existed for a long time and there have been other examples of targeted therapies and antibodies, but certainly ado-trastuzumab emtansine represents an advance in our ability to utilize the strategy of a targeted fusion toxin,” said Yee, director of the Masonic Cancer Center, professor in the department of medicine and John H. Kersey Chair in Cancer Research at the University of Minnesota.

The FDA based its approval of ado-trastuzumab emtansine in part on data from the EMILIA study, which were presented at the ASCO Annual Meeting in 2012 in Chicago.

Kimberly L. Blackwell, MD, professor of medicine and assistant professor of radiation oncology at Duke Cancer Institute at Duke University, presented results of the phase 3 study, which showed women with HER-2–positive breast cancer experienced significantly improved PFS when treated with ado-trastuzumab emtansine compared with standard therapy of capecitabine (Xeloda, Hoffmann-La Roche) and lapatinib.

The data, later published in The New England Journal of Medicine, showed median PFS among patients assigned to ado-trastuzumab emtansine was 9.6 months vs. 6.4 months for patients assigned to standard therapy regimen (HR=0.65; 95% CI, 0.55-0.77). Results of an interim analysis showed ado-trastuzumab emtansine increased 2-year survival (64.7% vs. 51.8%) and produced a higher objective response (43.6% vs. 30.8%).

During a press conference at ASCO in 2012, Blackwell called the results a breakthrough for patients with metastatic breast cancer.

“It is the first of many antibody drug conjugates to follow that will link a potent anticancer agent to a targeted delivery system of an antibody,” Blackwell said.

The most common adverse effects reported in the ado-trastuzumab emtansine arm were thrombocytopenia (12.9%) and elevations in liver function tests (aspartate transaminase, 4.3%; and alanine transaminase, 2.9%). Adverse effects subsided when treatment stopped.

“Results of the EMILIA study demonstrated that ado-trastuzumab emtansine led to improvements in both PFS and OS, and examination of the toxicity profile of both arms of this study suggested ado-trastuzumab emtansine was well tolerated without the side effects of rash and diarrhea observed in the standard therapy arm,” Mayer said. “The favorable results observed in the EMILIA study supported the recent FDA approval of ado-trastuzumab emtansine in patients previously treated with [trastuzumab].”

Beyond clinical trials

John Glaspy, MD, MPH, the Estelle, Abe and Marjorie Sanders endowed chair in cancer research at UCLA’s Jonsson Comprehensive Cancer Center, was instrumental in the clinical trials of ado-trastuzumab emtansine and treated the first patient with the drug outside of the trial setting.

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The patient underwent treatment for HER-2–positive breast cancer for 14 years. Trastuzumab controlled her disease for a long time, but that treatment eventually stopped working and the cancer spread to other areas of her body.

“Her body couldn’t handle much more chemotherapy,” Glaspy said in an interview. “Once Kadcyla was approved, we asked it be provided to her very quickly.”

The FDA approved ado-trastuzumab emtansine just days after the patient entered hospice care. Glaspy ordered the new drug, and the patient began treatment via IV infusion the next day, making her the first patient outside of a clinical trial to receive the drug in the United States.

“We are now close to 9 weeks on treatment and you couldn’t pair her together with the person she was before we placed her on Kadcyla. For her, the word ‘game-changer’ under-dramatizes what happened to her,” Glaspy said. “Because she was off chemotherapy and on effective treatment, her functional status improved quickly and she essentially went from a chair-bound hospice patient whose quality of life had expired on this planet to being a fully functional person who is returning to a very normal level of activity. This certainly isn’t expected for every patient with HER-2–positive breast cancer who receives Kadcyla, but it shows you what can happen. You never know unless you try.”

First-line treatment

Ado-trastuzumab emtansine currently is approved as second-line treatment. However, there are ongoing studies designed to evaluate the compound as first-line treatment in HER-2–positive metastatic breast cancer.

In a recent randomized phase 2 study, Perez and colleagues reported that first-line treatment with ado-trastuzumab emtansine led to significant improvements in PFS and had a favorable safety profile in patients with HER-2–positive metastatic disease.

For the study, researchers randomly assigned 137 patients to first-line treatment with either trastuzumab plus docetaxel (n=70) or ado-trastuzumab emtansine (n=67).

Median PFS was 14.2 months among patients assigned to ado-trastuzumab emtansine compared with 9.2 months for those assigned to trastuzumab plus docetaxel (HR=0.59; 95% CI, 0.36-0.97). Researchers reported a higher overall response rate (64.2% vs. 58%) and fewer adverse events among patients assigned to ado-trastuzumab emtansine. The researchers reported preliminary results suggesting similar OS rates between the two arms, but further follow-up is needed.

Looking ahead, researchers await the results from the MARIANNE trial, which includes patients with HER-2–positive progressive or recurrent locally advanced or previously untreated metastatic breast cancer.

The multicenter phase 3 trial is designed to evaluate the efficacy and safety of ado-trastuzumab emtansine plus pertuzumab or ado-trastuzumab emtansine with pertuzumab-placebo compared with trastuzumab plus docetaxel or paclitaxel.

PFS based upon tumor assessments up to 48 months and incidence of adverse events will serve as primary endpoints. Secondary endpoints will include the survival rate at 1 year and OS up to about 78 months. Final results are expected within the next couple of years.

“I am excited with the new set of studies that are ongoing or planned to look at Kadcyla as first-line treatment for metastatic breast cancer and also in the adjuvant setting. It has great potential,” Stearns said. “Having watched women receive this treatment in clinical trials for 1 or 2 years, it provides excellent quality of life while maintaining antitumor activity. This is an exciting approval and additional ammunition in our clinic.”

Cost concerns

Some clinicians have speculated there may be backlash due to the price of ado-trastuzumab emtansine.

The monthly cost of the drug in the United States is about $9,800. Based on median PFS of 9.6 months, that translates to $94,080 for a full course of treatment.

“Right now, we understand that we want to maximize the quantity and quality of patients’ lives,” Yee said. “There is a cost to any drug we use, but cost could be an important aspect when prescribing this drug.”

Genentech announced it will launch patient assistance programs intended to help patients who otherwise may not be able to afford ado-trastuzumab emtansine. Uninsured patients, as well as those who may have reached the lifetime limit allowed by their insurance companies, may qualify to receive the drug for free.

The cost of treating patients with cancer is a global concern, Mayer said.

“The oncology community is focused on improving the quality of care that we can offer patients, but has also become increasingly aware of the economic burden that newer forms of treatment can create. In this specific situation, this treatment appears to be highly effective and well tolerated, and is certainly something we look forward to offering our patients in clinic,” Mayer said. “We hope that negotiations over prices and reimbursement will help ensure drug availability to those who may benefit from it, while not bankrupting our population of breast cancer patients.”

Hope for the future

Other investigational compounds hold tremendous promise for patients with HER-2–positive breast cancer, Perez said.

“Continued improvements in patient outcomes, including cures, might be within reach with continued understanding of the biology of HER-2–positive disease and utilization of targeted therapeutic strategies,” Perez said.

Several new therapies are being tested in clinical trials. They include MM-111, which targets HER-2 and HER-3, and MM121, which targets HER-3. Both drugs are manufactured by Merrimack Pharmaceuticals.

MM-111 is a bispecific antibody designed to target cancer cells characterized by overexpression of HER-2. Merrimack is currently conducting multiple phase 1 clinical trials of MM-111 alone and in combination therapy settings. The company plans to initiate phase 2 studies later this year to further examine the role of MM-111 in treating various tumor types.

Results from the BOLERO-1 trial, which is assessing whether the addition of the mTOR inhibitor everolimus (Afinitor, Zortress; Novartis) to trastuzumab and chemotherapy is beneficial in patients with HER-2–positive breast cancer, were scheduled to be presented at the ASCO Annual Meeting earlier this month.

“This trial will tell us if there is a benefit to targeting further down the stream in the pathway,” Yee said. “If we think HER-2 and HER-3 activate the enterokinase signaling — which ultimately results in mTOR activation — then maybe it’s a good idea to target mTOR as well as the cell service receptors.”

Although the HER-2 treatment arena holds promise, there are unanswered questions that require further investigation, Stearns said.

“We know that there is a group of women who do not derive the same benefit from anti-HER–2 treatment,” she said. “One candidate that is predicted resistant is mutation in the phosphatidylinositide 3-kinases (PI3K). There are many agents now targeting this gene, and researchers are looking at combinations of anti-HER–2 agents with the PI3K inhibitors. This is something that can lead to further improvements in this 
population.”

Another key point is that women with HER-2–positive breast cancer tend to develop brain metastases early in their course of treatment.

“While we have many treatments to treat the cancer throughout the body, the treatments to the brain are more limited because many of our drugs do not cross the blood-brain barrier,” Stearns said. “Women, therefore, need surgery, radiation or radiosurgery. However, there may be some agents that do cross the blood-brain barrier, so we may want to use those preferentially in women who are at risk or in women who have developed brain metastases from HER-2 breast cancer. This is another area that needs a bit of research.”

The bottom line is that the addition of another agent to trastuzumab when targeting HER-2 is better than trastuzumab alone, Yee said.

“This isn’t to say that trastuzumab isn’t still a very valuable agent, but it has weakened enhance responses to trastuzumab by adding additional drugs targeting against HER-2,” he said. “There is still a lot of room for further improvements in the HER-2 strategy.”

Glaspy said he is optimistic.

“The past is usually the best predictor of the future and, in the past 20 years, we have seen nothing but increasing progress in this area,” Glaspy said. “I am very hopeful for the future of HER-2–positive breast cancer treatment.” – by Jennifer R. Southall

References:

Blackwell KL. Abstract #LBA1. Presented at: the 2012 American Society of Clinical Oncology Annual Meeting; June 1-5, 2012; Chicago.

Hurvitz SA. J Clin Oncol. 2013;31:1157-1163.

Verma S. N Engl J Med. 2012;367:1783-1791.

For more information:

John Glaspy, MD, MPH, can be reached at UCLA Hematology Oncology, 100 UCLA Medical Plaza, Suite 550, Los Angeles, CA 90095; email: jglaspy@mednet.ucla.edu.

Erica L. Mayer, MD, MPH, can be reached at Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA 02215; email: erica_mayer@dfci.harvard.edu.

Edith A. Perez, MD, can be reached at Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224; email: perez.edith@mayo.edu.

Vered Stearns, MD, can be reached at Sidney Kimmel Comprehensive Cancer Center, 401 N. Broadway, Baltimore, MD 21231; email: vstearn1@jhmi.edu.

Douglas Yee, MD, can be reached at Medicine — Hematology, Oncology and Transplantation Office, MMC 806 Mayo, 420 Delaware St. SE, Minneapolis, MN 55455; email: yeexx006@umn.edu.

Disclosure: Glaspy, Mayer, Perez, Stearns and Yee report no relevant financial disclosures.

 

Will ado-trastuzumab emtansine eventually eliminate untargeted chemotherapy in all patients with HER-2–positive breast cancer?

There is a good chance that it may.

This is likely the first of a series of antibody drug conjugates targeting the HER-2 receptor.

Although cells may become resistant to the underlying chemotherapy, it is hoped that other antibody drug conjugates based on different small-molecule or chemotherapy partners could be developed.

Although downregulation of HER-2 could be a definite mechanism of resistance to these targeted agents, it is still somewhat controversial whether this downregulation is clinically significant.

Adam M. Brufsky, MD, PhD, FACP, is a professor of medicine at the University of Pittsburgh School of Medicine. He can be reached at UPMC Cancer Center, Magee-Womens Hospital, 300 Halket St., Pittsburgh, PA 15213. Disclosure: Brufsky reports no relevant financial disclosures.

It is unlikely.

It is unlikely it will in all HER-positive tumors based upon what we know about their heterogeneity.

Some of these cancers are heterogeneous — that is, some cells within the tumor  have a lot of HER-2 in them but some do not.

Potentially, the cells that do not have a lot of HER-2 in them will be able to resist ado-trastuzumab emtansine and eventually grow a resistant tumor. It is something that has to be tested, but this is a logical assumption based upon current knowledge.

When one looks at some of these heterogeneous HER-2–positive tumors under the microscope, not all cells have high levels of HER-2, so presumably those “low HER-2” cells will bypass ado-trastuzumab emtansine and not be sensitive to it.

Carlos L. Arteaga, MD, is the president-elect of the American Association for Cancer Research as well as the Donna S. Hall chair in breast cancer, professor of medicine and cancer biology, associate director for clinical research and director of the VICC Breast Cancer Research Program at Vanderbilt-Ingram Cancer Center. He can be reached at Vanderbilt-Ingram Cancer Center, 691 Preston Building, Nashville, TN 37232-6838. Disclosure: Arteaga reports no relevant financial disclosures.