Two Drugs 'Graduate' From Novel I-SPY 2 Breast Cancer Trial

Alexander M. Castellino, PhD

July 06, 2016

Two studies from the novel clinical trial collaboration known as the Investigation of Serial Studies to Predict Your Therapeutic Response through Imaging and Molecular Analysis 2 (I-SPY 2) have provided evidence for the effectiveness of two new drugs in the neoadjuvant treatment of breast cancer.

The results predict that two investigational agents ― neratinib (HKI-272, Puma Biotechnology, Inc) and veliparib (ABT-888, AbbVie Inc) in combination with carboplatin ― will be successful in phase 3 clinical trials.

Both drugs are oral agents that have different mechanisms of action. Neratinib is an irreversible small molecule that inhibits ErbB, human epidermal growth factor receptor 2 (HER2) 2, and HER4; veliparib is a poly(ADP-ribose) polymerase (PARP) inhibitor.

The findings were published online July 6 in the New England Journal of Medicine. They are accompanied by a commentary and an editorial.

"The I-SPY 2 platform is a promising adaptive strategy for matching targeted therapies for breast cancer with the patients most likely to benefit from them," write David Harrington, PhD, and Giovanni Parmigiani, PhD, from the Dana-Farber Cancer Institute, Boston, Massachusetts, in a commentary.

"[T]he main benefit of the I-SPY 2 approach is in quickly providing data that can help investigators choose which of several promising new approaches to pursue in larger trials," write authors of an accompanying editorial. The editorialists are Lisa A. Carey, MD, of the Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, and Eric P. Winer, MD, of the Breast Oncology Program at the Dana-Farber Cancer Institute.

"These two multicenter trials may ultimately lead to changes in treatment in the years ahead," they write. But they also raise several questions about graduating the regimens to the phase 3 level and about extrapolating between endpoints used in this study and randomized studies.

For both of the studies, pathologic complete response (pCR) was an endpoint in the neoadjuvant treatment of breast cancer.

"[T]hese trials were not designed to predict the ultimate success of either neratinib or carboplatin-veliparib in improving disease-free or overall survival," they contend.

A breast cancer medical oncologist who was approached for comment agreed that there are questions over the use of pCR as an endpoint.

"The question to ask is whether one can use pCR as a useful marker to accelerate drug development," Clifford Hudis, MD, chief executive officer of the American Society of Clinical Oncology, told Medscape Medical News.

Its utility to screen for activity remains, but we must not overinterpret the results. Dr Clifford Hudis

In the realm of clinical studies designed to determine the efficacy of agents brought into clinical development, I-SPY 2 answers some questions quite well, but extrapolating its observations may be overstretching. "Its utility to screen for activity remains, but we must not overinterpret the results," Dr Hudis said.

What I-SPY 2 Does Well

I-SPY 2 is a platform trial that evaluates the efficacy of new agents against matched tumor signatures in a relatively short time and with a small number of patients in the neoadjuvant treatment of breast cancer. In neoadjuvant studies, pCR is an intermediate endpoint that is relevant because tumor eradication is desired before proceeding to surgery.

Patient selection and optimization of drug choices are important in breast cancer as viewed as a family of biologically distinct diseases, explain the editorialists. Adjuvant therapy trials are large, take years to complete, and are often associated with small improvements in outcomes, the editorialists point out. That is why there has been an explosion of neoadjuvant studies in systemic therapy for breast cancer, they explain.

The I-SPY 2 consortium was set up in 2009, with 16 centers testing neoadjuvant therapies for breast cancer. Women aged 18 years and older with clinical stage 2 or 3 breast cancer are enrolled into the study. Patients are required to have clinically or radiologically measurable disease in the breast (>2.5 cm in diameter). Another requirement is that the tumor be >2 cm in diameter, as assessed by imaging.

Biomarker assessment based on HER2 status, hormone-receptor status, and a 70-gene profile using MammaPrint (Agendia) was performed at baseline to classify patients according to prospectively defined breast cancer subtypes.

Set up as a standing platform trial, new drugs and regimens are continually evaluated against appropriate controls that circulate in the phase 2 study. On the basis of the molecular signature of the tumor, new drugs or combinations enter the trial through new experimental arms and are evaluated against standard therapy. The drugs or regimens being tested are removed from the trial once it is determined how they compare against standard therapy.

"These [adaptive] trials use a new approach to trial design; rather than creating a fixed framework of statistical assumptions that determines sample size and power, the trials react to results as they arrive. This adaptive approach potentially allows for faster and more flexible trial design," write the editorialists.

The trial uses a Bayesian statistical analysis, which measures success as a probability of being superior in a phase 3 study compared with the control. "Graduation" by signature (HER and hormone receptor status) and futility stopping — meaning how test drug(s) leave the trial — are also determined from a Bayesian analysis to predict an 85% probability of success in a future study with an accrual of 300 patients for testing the neoadjuvant combination in a phase 3 study. Therapies that reach prespecified thresholds of efficacy in one or more specific biomarker signatures "graduate" from the I-SPY 2 trial.

"Oncology has been slow to adopt Bayesian designs even though they are often well suited to settings in which inference and decisions benefit from adaptation based on accruing information," Dr Harrington and Dr Parmigiani write in their commentary. Some of the reluctance stems from a natural discomfort with replacing a familiar approach that has had some success in the past, they add.

Neratinib Results

In the neratinib study, 115 patients with HER2-positive, hormone-receptor-negative breast cancer received neratinib (12 weekly cycles) along with standard therapy (trastuzumab [Herceptin, Genentech, Inc], paclitaxel, doxorubicin, and cyclophosphamide given at standard doses and schedules), and 78 patients received standard therapy.

The results showed that the investigational agent, when added onto standard therapy, yielded higher pCR rates: 56% vs 33% for standard therapy (95% Bayesian probability interval, 37% - 73%). The analysis predicts a 79% success for the neratinib in combination with standard therapy in a phase 3 study.

Neratinib is expected to proceed in the successor I-SPY 3 program, which aims to provide data that would be the basis for accelerated approval. With a dual HER2 regimen (pertuzumab [Perjeta, Genentech, Inc] and trastuzumab) incorporated into the current standard of care, the experimental arm is expected to be modified to test the combination of neratinib, pertuzumab, trastuzumab, and taxane with two other combinations ― pertuzumab/trastuzumab/taxane, and neratinib/trastuzumab/taxane.

However, the editorialists question this strategy. They point out that nearly one third of patients who received neratinib had clinically significant diarrhea, resulting in a high rate of treatment discontinuation. They also note that the drug has graduated to a phase 3 trial in which it will be tested in an untried combination ― the planned combination of neratinib, pertuzumab, and trastuzumab was not tested in I-SPY 2. "It is difficult to know whether predictions of success based on a single-agent trial can be extrapolated when multiple agents are combined," the editorialists write.

"It is also possible, if not probable, that the three-drug regimen proposed would have considerable toxic effects when added to chemotherapy. This approach raises concerns and could result in substantial overtreatment of a large proportion of the patient population," they add.

Veliparib Results

In the veliparib study, 72 patients with triple-negative breast cancer received veliparib/carboplatin along with standard therapy (paclitaxel, doxorubicin, and cyclophosphamide given at standard doses and schedules), and 44 patients received standard therapy.

The results showed that this investigational agent, when used in combination with carboplatin and standard therapy, provided higher pCR rates: 51% vs 26% for standard therapy (95% Bayesian probability interval, 36% - 66%). The analysis predicted an 81% success for the veliparib combination in a phase 3 study.

In this case, the editorialists question whether the efficacy that was seen can be attributed to veliparib alone. They note that "in triple-negative disease, recent studies have consistently found a higher pathological complete response rate with the addition of platinum drugs." They suggest that it is possible that the results were driven partially or entirely by carboplatin, rather than by the new drug.

Other Questions

In their editorial, Dr Carey and Dr Winer caution about viewing pCR as a clinically meaningful endpoint: "Clinicians should remember that pathological complete response rate itself is not a clinically meaningful end point; its value is as a surrogate for outcome." They explain that although pCR is consistently associated with a decreased risk for relapse and death, even substantial improvements in pCR in neoadjuvant studies have not consistently translated into improvements in long-term outcomes.

Then there is the issue about extrapolating observations from a neoadjuvant study into settings involving other disease states. The fact that a drug graduates from I-SPY 2 does not necessarily imply that it will be as active in other settings, Dr Hudis explained.

For example, the NeoALLTO study tested whether lapatinib, a tyrosine kinase inhibitor against EGFR, would improve pCR when added to the combination of paclitaxel and trastuzumab. It did so dramatically: the pCR with the lapatinib combination was nearly twice that seen with paclitaxel and trastuzumab.

However, similar benefits were not seen in the adjuvant setting, as shown in the ALLTO study. In this trial, the combination of lapatinib, trastuzumab, and pacitaxel fared no better than that of trastuzumab and paclitaxel in the adjuvant setting with respect to longer-term outcomes.

"We cannot always take shortcuts," Dr Hudis said.

Another example is the combination of T-DM1 (Kadcyla, Genentech, Inc) and pertuzumab, which was not effective in metastatic breast cancer, as reported in the MARIANNE study. In MARIANNE, the graduation of the combination from I-SPY 2 did not reflect what was seen in the neoadjuvant setting, Dr Hudis pointed out.

Phenotypes and genotypes may change rapidly as the disease progresses, Dr Hudis noted. Asking a neoadjuvant therapy to perform in the same way in either the adjuvant or the metastatic setting may not be logical, he indicated. "The endpoint is meaningful in its context," Dr Hudis said. Data from the neoadjuvant setting cannot necessarily predict outcomes in other settings, he indicated.

The editorialists explain that pCR will correlate with survival outcomes only if the agents tested will also eradicate resistant tumor clones.

"At this time, improvements in pathological complete response rates as reported in neoadjuvant studies — whether the studies are exploratory, such as I-SPY 2, or more definitive — should not change clinical practice; rather, we should wait for the definitive clinical trials that result from them," Dr Carey and Dr Winer conclude.

However, Dr Harrington and Dr Parmigiani contend that the I-SPY 2 platform and model "are important first steps toward the efficient use of clinical resources" and urge continued innovation in trial design. "As more new targets and drugs are discovered, traditional statistical designs, at best cumbersome and inefficient today, will be wholly insufficient for matching patients with effective drugs," they conclude.

Initial support for the I-SPY 2 TRIAL was provided by the Safeway Foundation, the Bill Bowes Foundation, Quintiles Transnational Corporation, Johnson & Johnson, Genentech, Amgen, the San Francisco Foundation, Give Breast Cancer the Boot, Eli Lilly, Pfizer, Eisai Company, the Side Out Foundation, the Harlan Family, the Avon Foundation for Women, Alexandria Real Estate Equities, and private individuals and family foundations. Dr Hudis has disclosed no relevant financial relationships. He previously served on the I-SPY 2 Data Safety Monitoring Committee but has since resigned. Dr Harrington is statistical consultant for the New England Journal of Medicine. Dr Carey, Dr Parmigiani, and Dr Winer have disclosed no relevant financial relationships.

N Engl J Med. Published online July 6, 2016. Article abstract, Neratinib study, Veliparib study, Commentary, Editorial


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