Alexander M. Castellino, PhD

April 25, 2016

NEW ORLEANS — Results from the I-SPY 2 trial show that a new presurgery (neoadjuvant) combination of trastuzumab emtansine (T-DM1; Kadcyla, Genentech, Inc) and pertuzumab (Perjeta, Genentech, Inc) — both targeting HER2 — was significantly better at achieving a pathologic complete response (pCR) compared with the standard therapy of paclitaxel (multiple brands) and trastuzumab (Herceptin, Genentech, Inc) in women with HER2+ invasive breast cancer.

Data presented here at the American Association for Cancer Research (AACR) 2016 Annual Meeting showed that the new neoadjuvant combination achieved a pCR of 52% vs 22% with standard therapy.

In addition, an analysis based on hormone receptor (HR) status showed that the new combination was significantly better, regardless of HR status.

"Utilizing a different HER2-targeted treatment combination, we were able to demonstrate a significant improvement in pathological complete response in women with HER2+ invasive breast cancer," presenter Angela DeMichele, MD, MSCE, professor of medicine and epidemiology at the Perelman School of Medicine, University of Pennsylvania, in Philadelphia, told Medscape Medical News.

"Getting a greater proportion of patients to achieve a pCR is the underlying goal of neoadjuvant therapy," she said. Achieving a pCR is an excellent surrogate marker for long-term outcomes for patients, she explained.

"The significantly higher pCR achieved could translate into fewer women developing recurrent, metastatic breast cancer," she added.

Dr Angela DeMichele

However, a breast cancer expert who was approached for comment urged caution. There has been some debate about how useful pCR is as a marker for long-term survival, especially after the ALLTO results in 2014.

"The question to ask is whether one can use pCR as a useful marker to accelerate drug development," Clifford Hudis, MD, chief, Breast Medicine Service, Memorial Sloan Kettering Cancer Center, New York City, told Medscape Medical News.

"Its utility to screen for activity remains, but we must not overinterpret the results," he added.

I-SPY 2: An Adaptive Study

The I-SPY 2 study is an ongoing, adaptive trial with an innovative design.

"The idea of an adaptive study is to rapidly screen drugs to determine if they should be taken into randomized phase 3 trials," Dr DeMichele said.

The adaptive trial is designed as a standing platform trial. New drugs or combinations enter into the trial through new experimental arms. They are evaluated against the gold standard (control), which is standard therapy, and leave the trial once it is determined how they compare against standard therapy.

"New drugs and combinations are continually evaluated in the trial," Dr DeMichele said.

The study was not designed to compare experimental arms. Companies need assurance that their drugs will not be compared to competitor drugs, she explained.

Set as a formal consortium in 2010, I-SPY 2 has 16 centers testing neoadjuvant therapies. The platform also tests drugs for HER2- and triple-negative invasive breast cancer. For each, there is a different control that acts as the gold standard, she explained.

"This trial approach gets an answer with a smaller number of patients than is normally needed, and in a shorter time," Dr DeMichele told Medscape Medical News.

For the current dataset, the trial enrolled patients with invasive breast cancer measuring ≥2.5 cm and HER2+ disease. Patients were adaptively randomly assigned to four cycles of T-DM1 and pertuzumab (given every 3 weeks) or paclitaxel and trastuzumab (control) given weekly for 12 weeks, followed by doxorubicin and cyclophosphamide for four cycles.

All patients in the control arm during the course of the trial were considered for the analysis. At the time of analysis, 52 patients had been assigned to the experimental arm of the study, and 31 patients had been assigned to the control arm.

The trial uses a Bayesian statistical analysis, which measures success as a probability of being superior in a phase 3 study.

Adaptive assignment to the experimental arm was determined adaptively to test for superiority against the control. "Graduation" by signature (HER and HR status) and futility stopping — meaning how test drug(s) leave the trial — were also determined from a Bayesian analysis, which predicted the probability of success in a future study with an accrual of 300 patients for testing the neoadjuvant combination in a phase 3 study.

In this analysis, the I-SPY 2 study showed that for women with invasive disease, neoadjuvant therapy with T-DM1 and pertuzumab was superior to paclitaxel and trastuzumab for HER2+ tumors overall, as well as for HER+/HR+ and HER2+/HR- breast cancer.

With estimated pCRs of 46% (vs 17% for the control) for HER2+/HR+ disease and 64% (vs 33% for the control) for HER2+/HR- disease, the new HER2-targeted combination was superior to the control of paclitaxel and trastuzumab.

Statistically, the new neoadjuvant combination was 99.5% and 99.1% more likely to be superior for HER2+ overall and HER+/HR+, respectively; for HER2+/HR- disease, the likelihood of superiority was 98%.

Additionally, the combination of T-DM1 and pertuzumab had higher than 90% odds of being successful in a phase 3 study, with the odds being highest for HER2+ disease (94% vs 93% for HER+/HR+ and 90% for HER+/HR- disease). The threshold for predicting success in a phase 3 study was 85%.

"The combination of T-DM1 and pertuzumab was also less toxic," Dr DeMichele said. The degree of neuropathy and hair loss associated with paclitaxel was significantly higher than with the new combination, she explained.

"The ability to offer patients a more effective and less toxic treatment option is important to patients' quality of life," she said.

This new neoadjuvant combination now needs to be confirmed in a phase 3 study, Dr DeMichele indicated.

Another HER-2-targeted therapy, pertuzumab, has became a standard of care when added to paclitaxel and trastuzumab in this setting. Pertuzumab was granted accelerated approval by the US Food and Drug Administraiton for neoadjuvant use in October 2013.

In clinical practice in the United States, many patients now receive a taxane (paclitaxel) with both trastuzumab and pertuzumab. This combination was also superior to the standard combination of paclitaxel and trastuzumab, as shown by another presentation from the I-SPY 2 trial.

Although I-SPY 2 was not designed to compare the combination of T-DM1 and pertuzumab with that of paclitaxel, trastuzumab, and pertuzumab, the results from the different arms of the trial show that the combination of T-DM1 and pertuzumab was the least toxic combination, Dr DeMichele said.

Lessons to Be Learned

If a drug graduates from the I-SPY 2 trial, this does not imply that its activity will translate to other settings.

In an interview with Medscape Medical News, Dr Hudis pointed to the story of lapatinib (Tykerb, GlaxoSmithKline) in the neoadjuvant setting. In the NeoALLTO trial, results showed that adding lapatinib — a tyrosine kinase inhibitor against EGFR — to the combination of paclitaxel and trastuzumab nearly doubled the pCR in comparison with the standard of paclitaxel and trastuzumab. However, in the ALLTO study, the combination of lapatinib, trastuzumab, and paclitaxel fared no better than that of trastuzumab and paclitaxel in the adjuvant setting for longer-term outcomes.

"We cannot take shortcuts," Dr Hudis said.

Another example was given by the discussant for the paper, Mark Pegram, MD, Susy Yuan-Huey Hung Professor of Oncology and director of the Breast Cancer Oncology Program at Stanford Women's Cancer Center, Stanford University. He noted that the combination of T-DM1 and pertuzumab was not effective in metastatic breast cancer in the MARIANNE study. "In MARIANNE, the graduation of the combination from I-SPY 2 did not reflect what we see in the neoadjuvant setting," Dr Pegram said.

With phenotypes and genotypes changing rapidly, expecting a neoadjuvant therapy to reflect what will happen in the adjuvant or metastatic setting may not be logical, he explained. "Data from the neoadjuvant setting cannot predict metastatic outcomes," Dr Pegram said.

Echoing similar sentiments, Dr Hudis said: "The endpoint is meaningful in its context."

Dr DeMichele has received institutional research support from Pfizer, Novartis, Johnson & Johnson, Calithera, Incyte, and Genentech and has participated in scientific advisory boards for Pfizer and Novartis. Dr Pegram is a consultant for and is on the advisory boards of several companies and receives honoraria and research funding from industry. Dr Hudis previously served on the I-SPY 2 Data Safety Monitoring Committee but recently resigned from that position.

American Association for Cancer Research (AACR) 2016 Annual Meeting: Abstract CT042, presented April 18, 2016.

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