New Trial Models Aim to Accelerate Pace of Neoadjuvant Approvals

New models have emerged for examining novel breast cancer treatments in the neoadjuvant setting that avoid the lengthy process of standard, large adjuvant trials.

Kathy Albain, MD

pCR and Pertuzumab

In recent years, new models have emerged for examining novel breast cancer treatments in the neoadjuvant setting that avoid the lengthy process of standard, large adjuvant trials. In a talk at MBCC, Kathy Albain, MD, a professor of Medicine at the Loyola University Chicago Stritch School of Medicine, reviewed several of these models, including the use of pathologic complete response (pCR) as a surrogate endpoint and the adaptive I-SPY 2 trial.In May 2012, the FDA released draft guidance for industry on the use of pCR (absence of invasive cancer in the breast and lymph nodes) as an endpoint to support accelerated approval of neoadjuvant therapies for early-stage breast cancer.

The guidance emphasizes that “A pathologic complete response is a surrogate endpoint that is reasonably likely to predict clinical benefit in breast cancer, but its use is restricted in the regulatory setting to high-risk tumors since limited safety data are available [with this accelerated approach]…unlike our older paradigm with years and years of work in the classical adjuvant setting,” said Albain, who is also director of the Breast Clinical Research Program and Thoracic Oncology Program at Cardinal Bernardin Cancer Center.

Albain added that the guidance stipulates, “A change in pCR, if robust, can result in accelerated drug approval in small, confirmatory phase III trials in homogeneous subsets.”

In September 2013, pertuzumab (Perjeta) became the first drug approved by the FDA under these guidelines. Pertuzumab received accelerated approval for use in combination with trastuzumab (Herceptin) and chemotherapy to treat patients with early-stage breast cancer in the neoadjuvant setting.

The pertuzumab-based regimen was specifically approved to treat patients at high risk for metastases or death with HER2-positive, locally advanced, inflammatory, or early-stage breast cancer. Following surgery, patients might still be eligible to receive additional chemotherapy and should continue to receive trastuzumab for 1 year, according to the FDA.

The approval was primarily based on pCR data from the NeoSphere and TRYPHAENA trials. The FDA also considered data from the phase III CLEOPATRA trial, which formed the basis for the initial approval of pertuzumab for patients with advanced, HER2-positive breast cancer.


“We [now] await the results of the APHINITY trial, which is the confirmatory adjuvant trial [for the presurgical pertuzumab regimen],” said Albain.In 2010, the Foundation for the National Institutes of Health and its Biomarkers Consortium launched the I-SPY 2 breast cancer clinical trial, a novel study designed to accelerate the development of neoadjuvant treatments. “Trials like I-SPY 2 will be critical to bringing our novel pipeline drugs to our patients more efficiently and effectively,” Albain said.

The innovative, multidrug, phase II trial uses an adaptive design, based on biomarker subtypes, to evaluate a series of novel agents and combinations added to standard neoadjuvant therapy. The approach involves evaluating drugs in small study populations, using advanced statistical techniques that will promptly identify potentially successful cohorts. Successful drugs, labeled “graduates,” are moved into phase III testing, known as “I-SPY 3.”

Data for the first two graduates, veliparib (ABT-888) and neratinib (PB272), were announced in December at the San Antonio Breast Cancer Symposium.

Combining the oral PARP inhibitor veliparib with carboplatin improved pCR rates in women with triple-negative breast cancer, thus qualifying the drug to move to the next round of clinical testing. In January, AbbVie launched a phase III trial in which 620 patients with early-stage, triple-negative breast cancer will be randomized to one of three arms: veliparib in combination with carboplatin and paclitaxel; placebo plus carboplatin/paclitaxel; or placebo plus paclitaxel (NCT02032277). Patients in all arms would follow these regimens with doxorubicin/cyclophosphamide.

Neratinib, an irreversible tyrosine kinase inhibitor that blocks EGFR signaling, graduated after showing a probability of superiority as part of a combination regimen with paclitaxel followed by doxorubicin/cyclophosphamide in patients who are HER2-positive and hormone receptornegative, according to Puma Biotechnology, Inc. The company announced that full results would be presented at a future scientific meeting.

In her concluding remarks, Albain reemphasized that a new paradigm has emerged in neoadjuvant breast cancer research with a focus on smaller, expeditious trials. “There’s a rapidly changing landscape away from larger adjuvant trials—a new day is here.”


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