Taking a Look at Four Noteworthy Studies

Debu Tripathy, MD

The pace of discovery in breast cancer research has been brisk in the past year, leading not only to the approval of several new therapies but also to clinical trial results with the potential to change practice.

For an expert view on recent significant developments, OncologyLive sat down with Debu Tripathy, MD, coleader of the Women’s Cancer Program and a professor of Medicine at the Norris Comprehensive Cancer Center at the University of Southern California in Los Angeles.

Tripathy also is a program director for the 30th Annual Miami Breast Cancer Conference, scheduled for March 7-10, 2013, where practicing oncologists can learn about the details and nuances of research advances from leading oncology experts, and discuss ways of translating these advances into clinical practice. The conference is hosted by Physicians’ Education Resource (PER).

“Given the rapidity with which we are seeing new developments, just about every meeting has something new to report,” Tripathy noted.

Everolimus Evaluated in HER2-Positive Disease

Speaking in advance of the upcoming 2012 CTRC-AACR San Antonio Breast Cancer Symposium on December 4-8, Tripathy identified studies he is anticipating and discussed recently released research that he finds noteworthy. These studies include:In July, the FDA approved everolimus (Afinitor) in combination with exemestane (Aromasin) for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer after progression following letrozole or anastrozole.

BOLERO-1 seeks to evaluate everolimus in combination with trastuzumab (Herceptin) in patients with HER2-positive locally advanced or metastatic breast cancer with no prior systemic therapy except endocrine therapy (Figure).

Figure. BOLERO-1 Study Design¹

Eligibility

• HER2+
• Measurable disease/ bone lesions
• Trastuzumab-naïve or prior trastuzumab and/ or chemotherapy >12 months before trial
• Discontinue endocrine therapy before trial
• No prior mTOR inhibitor treatment

719

patients

Randomized

2:1

Treatment Arms

Everolimus+paclitaxel+ trastuzumab

Stratification by

• Visceral metastases

• Prior trastuzumab

Placebo+paclitaxel+ trastuzumab

Treatment until progression or intolerable toxicity

Follow-up

• Progression
• Safety
• Overall survival

Complete trial details are available at www.ClinicalTrials.gov, NCT00876395.

The trial, launched in September 2009, has enrolled 719 women, and the primary completion date had been forecasted for October 2012, researchers said at the American Society of Clinical Oncology annual meeting in June.¹

Although trastuzumab has demonstrated an objective response rate in up to 84% of patients in combination with paclitaxel in metastatic disease settings, the majority of patients develop resistance within one year, Hurvitz et al noted.

Tripathy said everolimus has proved effective in several settings through its ability to inhibit mammalian target of rapamycin (mTOR) and other growth factor receptor systems.

“In the area of hormonal therapy resistance, we have known for a long time that growth factor receptor pathways appear to be activated. So blocking them downstream from the receptor, for example at the level of PI3 kinase, or even further downstream, blocking mTOR, might be able to achieve benefits,” Tripathy said.

“Now mTOR also is involved in growth factor signaling through the HER2 pathway. So another logical question is, can it add to the benefit of trastuzumab?” he added.

GRN1005 Tackles Blood−Brain Barrier

Tripathy said a small phase II study suggested a benefit to the dual therapy in patients who had progressed on trastuzumab, setting the stage for the larger trial. Novartis Pharmaceuticals, which manufactures Afinitor, is seeking to further explore its potential.GRN1005 is a peptide-drug conjugate that targets low-density lipoprotein receptor-related proteins (LRPs) in order to deliver paclitaxel across the blood−brain barrier, according to the Geron Corporation, the California-based company developing the drug.

The drug is being evaluated in a phase II trial in patients with breast cancer whose disease has metastasized to the brain. The study, which seeks to enroll 100 participants, involves administering GRN1005 alone to patients with HER2-negative tumors or in combination with trastuzumab for those who are HER2-positive. The primary outcome is the intracranial objective response rate.

OncLive TV Exclusive

Dr Debu Tripathy Previews the Phase II GRN1005 Study

“The question here is whether we can see responses in CNS [central nervous system] disease in patients who have progressed after radiation or even in patients who have not received radiation,” Tripathy said. “Both cohorts are being tested. Also, the question is whether we might see responses in systemic disease.”

He said GRN1005, which is administered intravenously, might offer new options for certain patients. “This drug does have some of the same expected toxicities of paclitaxel, such as cytopenias and neuropathy,” he said. “Yet its penetration of the blood—brain barrier could be significant enough that it can treat diseases of both sites, or may be used in patients who do not have options for local therapy.”

Establishing Optimal Duration of Trastuzumab

Tripathy said several other drugs, including capecitabine and lapatinib, have shown the ability to cross the blood−brain barrier but to “a somewhat limited extent.”Although trastuzumab has become a cornerstone of treatment regimens in women with invasive HER2- positive early breast cancer, researchers have been divided on the question of how long patients should receive the drug. Two studies presented at the European Society for Medical Oncology (ESMO) 2012 Congress support the standard-of-care use of trastuzumab in the adjuvant setting at one year, Tripathy said.

In the HERA trial, 5102 women with HER2-positive disease were randomized either to trastuzumab every three weeks for one year or two years, or to observation. Patients had received surgery, chemotherapy, and radiation as prior therapy.²

After a median eight years’ follow-up, the patients who had received one-year of trastuzumab demonstrated a 24% reduction in the risk of disease recurrence (HR = 0.76; P <.0001) and in the risk of death (HR = 0.76; P <.0005) compared with those in the observation arm, even though half the patients in the observation arm had been allowed to cross over. The results of two years of trastuzumab did not provide a statistically significant benefit over one year.

“This is an important study because we know that patients with HER2-positive breast cancer can continue to have recurrences even two, three, or four years out,” Tripathy said. “All of the major trials that have been done so far have been with one-year of therapy. This is really the only one to look at two years. And without a difference being seen now with this mature analysis, we have to conclude that one year is sufficient.

“There always is the possibility that there may be a subset of patients where longer treatment might be better, but this trial was not designed to look at subsets and only has the power to look at the whole group,” he said.

In the PHARE trial, researchers sought to determine whether a shorter duration of trastuzumab would be sufficient.³ More than 3380 patients were randomized to receive either six or 12 months of trastuzumab after prior therapy.

At a median follow-up of 47.5 months, the noninferiority of the six-month regimen could not be demonstrated. The disease-free hazard ratio of the six-month arm was 1.28 (95% CI, 1.05-1.56), suggesting a trend favoring the 12-month regimen, but crossed the significance threshold of 1.15, researchers said at ESMO.

Tripathy said the matter of a shorter duration was important because the cost and inconvenience of continued therapy can become factors in treatment, and because some patients develop cardiac dysfunction, even at the subclinical level.

He said the PHARE study had several limits, including varying treatment regimens in which only half of the patients received chemotherapy that overlapped with trastuzumab and a lower-than-expected number of events for analysis.

“This preliminary result is still a little bit underpowered and leaves open the possibility that perhaps the two are equivalent, but the suggestion from this trial at the current time still suggests that one year is the optimal duration of therapy,” Tripathy said. “So based on both the HERA and the PHARE studies, we have to conclude that one year is still optimal. Whether or not that holds for different subsets and how to handle toxicities that arise early on are still areas of controversy.”

While clinical investigations of these matters continue, Genentech, which developed trastuzumab, is working on the immunoconjugate TDM-1, the next generation of trastuzumab-based therapy. TDM-1 has shown improvements in progression-free and overall survival in the second line compared with the FDA-approved standard of lapatinib and capecitabine.⁴

References

1. Hurvitz SA, Andre F, Burris HA, et al. BOLERO-1: a randomized, phase III, double-blind, placebo-controlled multicenter trial of everolimus in combination with trastuzumab and paclitaxel as first-line therapy in women with HER2- positive (HER2+), locally advanced or metastatic breast cancer (BC). Presented at: 2012 ASCO Annual Meeting; June 1-5, 2012; Chicago, IL. Abstract TPS648.
2. Goldhirsch A, Piccart M, Procter M, et al. HERA trial: 2 years versus 1 year of trastuzumab after adjuvant chemotherapy in women with HER2-positive early breast cancer at 8 years of median follow up. Presented at: European Society for Medical Oncology 2012 Congress; September 28 — October 2, 2012; Vienna, Austria. Abstract LBA 6.
3. Pivot X, Romieu G, Bonnefoi H, et al. PHARE Trial results comparing 6 to 12 months of trastuzumab in adjuvant early breast cancer. Presented at: European Society for Medical Oncology 2012 Congress; September 28 — October 2, 2012; Vienna, Austria. Abstract LBA 5.
4. Verma S, Miles D, Gianni L. Updated overall survival results from EMILIA, a phase 3 study of trastuzumab emtansine (T-DM1) vs capecitabine (X) and lapatinib (L) in HER2-positive locally advanced or metastatic breast cancer (MBC). Paper presented at: European Society for Medical Oncology 2012 Congress; September 28-October 2, 2012; Vienna, Austria. Abstract LBA12.