In Historic Vote, ODAC Suggests Approval of Neoadjuvant Pertuzumab Regimen

Mikkael Sekeres, MD, MS

The FDA’s Oncologic Drugs Advisory Committee (ODAC) voted 13-0 with one abstention in support of pertuzumab (Perjeta) in combination with trastuzumab and docetaxel for patients with HER2-positive breast cancer in the neoadjuvant setting. If the FDA follows the recommendation of ODAC, this pertuzumab regimen would be the first neoadjuvant regimen formally approved by the FDA for any type of cancer.

The favorable reaction by ODAC bodes well for the eventual accelerated approval of pertuzumab in this setting. While the FDA is not required to follow the recommendations of ODAC, historically, the federal agency often does. The FDA is scheduled to make a decision regarding the approval of the pertuzumab regimen in this setting on or before October 31, 2013.

Today’s ODAC meeting was the first in which the committee was asked to consider recommending an oncologic drug for approval on the basis of pathologic complete response (pCR) as the primary endpoint in the pivotal clinical trials. The committee was asked to consider the question of whether pertuzumab demonstrated “a favorable benefit to risk evaluation for the neoadjuvant treatment of early breast cancer.”

“It’s not every day that this committee gets to consider a new indication in breast cancer,” said Mikkael Sekeres, MD, MS, associate professor of Medicine in the department of Hematologic Oncology and Blood Disorders at the Cleveland Clinic Taussig Cancer Institute in Ohio and ODAC chairperson.

If this pertuzumab regimen receives FDA approval, the decision could be precedent-setting and result in much earlier approvals for drugs in earlier disease settings.

José Baselga, MD, PhD

“Early disease is the setting where we can have the biggest impact on long-term survival,” said Jose Baselga, MD, physician-in-chief at Memorial Sloan-Kettering Cancer Center in New York, in a presentation before ODAC today. Baselga served as primary investigator of the CLEOPATRA trial, which resulted in the FDA’s approval of this same pertuzumab regimen in the metastatic setting, and he is also a primary investigator in the APHINITY trial, which is evaluating the efficacy of this pertuzumab regimen in the adjuvant setting.

Baselga noted that, typically, the time between a drug’s approval in the metastatic setting and its subsequent approval in an earlier setting is “simply much too long.” He gave the examples of docetaxel and trastuzumab, where eight years passed between the approvals of each drug in the metastatic and adjuvant settings, respectively. In the case of pertuzumab, Baselga said that its efficacy has been well established in clinical trials and will continue to be assessed in the APHINITY trial in the adjuvant setting, with results expected to become available in late 2016.

However, Baselga indicated that an approval of pertuzumab in the neoadjuvant setting now, a full three years prior to when those results will become available, could have an immediate impact on patients.

“In terms of survival, even though trastuzumab has had a profound impact, a substantial number of patients are still dying from HER2-positive disease,” Baselga said. “I feel strongly that we should make this therapy available to [patients] now.”

Much of the discussion among members of ODAC concerned the potential precedents set by approving an oncologic drug in the neoadjuvant setting. The pivotal trials at the center of this supplemental biologics license application were relatively small compared with many of the clinical trials that have resulted in the approval of drugs for breast cancer in the metastatic setting, enrolling on the order of a couple of hundred patients as opposed to multiple thousands of patients. Therefore, these trials were not powered to determine survival information. Despite several meta-analyses showing an association between pCR and survival benefits, no definitive answer has been derived from these studies as of yet.

“We shouldn’t be assuming what the survival will be when the study is not powered to show that,” said Antonio Tito Fojo, MD, PhD, program director of Medical Oncology at the National Cancer Institute and one of the members of ODAC. Fojo abstained from today’s vote.

Among the concerns raised by other members of ODAC were the fact that the benefit may be more pronounced in hormone receptor-negative patients; whether docetaxel will be the chemotherapy that oncologists prefer to use with pertuzumab and trastuzumab should the regimen receive approval; and what long-term toxicities might be demonstrated when more data becomes available.

Richard Pazdur, MD

However, in addition to the way the regimen may affect individual patients, Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, asked ODAC to consider the potential benefits to society as a whole if the drug, once approved, did indeed reduce the disease burden in patients with early stage, HER2-positive breast cancer.

The results of two trials were at the center of much of the discussion: the NEOSPHERE trial and the supportive TRYPHAENA trial.

In the NEOSPHERE trial, a multicenter, open-label, phase II study, treatment-naïve patients with HER2-positive breast cancer were randomly assigned in a 1:1:1:1 ratio and stratified by operable, locally advanced, and inflammatory breast cancer as well as hormone receptor expression.¹ These patients received four neoadjuvant cycles of either trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg every 3 weeks) plus docetaxel (75 mg/m², escalating, if tolerated, to 100 mg/m² every 3 weeks; n = 107; group A); pertuzumab (loading dose 840 mg, followed by 420 mg every 3 weeks) in combination with the group A trastuzumab and docetaxel regimen (n = 107; group B); the pertuzumab and trastuzumab regimens without docetaxel (n = 107; group C); and pertuzumab plus docetaxel (n = 96; group D). The primary endpoint of the study was pathological complete response (pCR).

Patients who received the combination of pertuzumab, trastuzumab, and docetaxel had a pCR rate of 45.8% (95% CI, 36.1-55.7), a significant improvement over patients who received trastuzumab and docetaxel without pertuzumab, who had a pCR rate of 29% (95% CI, 20.6 -38.5; P = .014). The pCR rates for the remaining two groups were 24% in those who received pertuzumab and docetaxel without trastuzumab (95% CI, 15.8-33.7), and 16.8% in patients who received pertuzumab and trastuzumab (95% CI, 10.3-25.3).

The most common grade 3 or higher side effects observed in the four groups were neutropenia (61, 48, 1, and 52 patients in the four groups, respectively), febrile neutropenia (8, 9, 0, and 7, respectively), and leukopenia (13, 5, 0, and 7, respectively). The number of adverse events was similar in the three groups (A, B, and D) that received chemotherapy as part of their treatment regimen, with 15 to 20 serious adverse events per group in 10% to 17% of patients, but was much lower in group C, which did not receive chemotherapy (four serious adverse events in 4% of patients).

The results of the TRYPHAENA trial were presented at the 2011 CTRC-AACR San Antonio Breast Cancer Symposium,² and updated safety results were recently published in the journal Annals of Oncology. This study was a phase II, multicenter, open-label study that enrolled 225 patients with operable, locally advanced, or inflammatory breast cancer. Patients were randomized in a 1:1:1 ratio to receive six neoadjuvant cycles every 3 weeks. The first group, Arm A, received a regimen of 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) followed by docetaxel, with trastuzumab and pertuzumab given concurrently throughout the treatment. Arm B received FEC followed by docetaxel plus trastuzumab and pertuzumab. Arm C received docetaxel and carboplatin plus trastuzumab and pertuzumab. After patients were treated with neoadjuvant therapy, they underwent surgery and continued on trastuzumab until they completed 1 year of treatment. The study was not powered to compare the three study arms.

The study found that the pCR rates were 61.6% in the concurrent group (A), 57.3% in the sequential group (B), and 66.2% in the anthracycline-free arm (C). The most common severe adverse events (AEs) observed in the three arms were neutropenia (47.2%, 42.7%, and 46.1%, in the three arms, respectively), leukopenia (19.4%, 12.0%, and 11.8%), and febrile neutropenia (18.1%, 9.3%, and 17.1%). Additional high AE rates observed with the anthracycline-free arm included anemia (17.1%), thrombocytopenia (11.8%), and diarrhea (11.8%).

Gary Lyman, MD, MPH

While these studies served as the primary basis for today’s ODAC vote, a combination of other studies, including the results of the CLEOPATRA trial in the metastatic setting as well as evidence supporting the use of pCR as an endpoint, served as the basis for the overwhelmingly positive vote.

“We need to look at the totality of the evidence…and not just one study,” said Gary Lyman, MD, MPH, professor of Medicine and director of Comparative Effectiveness and Outcomes Research at Duke University School of Medicine and the Duke Comprehensive Cancer Center, and a temporary voting member of ODAC.

The ODAC members stressed to Genentech, the drug’s manufacturer, that they are very interested in the results of the APHINITY trial. If the pertuzumab regimen is approved by the FDA but the results of the APHINITY trial are negative, ODAC recommended that the company voluntarily withdraw pertuzumab from the market for use in this neoadjuvant setting.

With many members of the public commenting on the life-changing experiences they had with pertuzumab, and others commenting on the need for earlier treatment options, the company is viewing today’s decision as a positive step in the future of this drug.

“More than 6,000 people in the United States die of HER2-positive breast cancer each year,” said Hal Barron, MD, chief medical officer and head, Global Product Development. “The ODAC’s recommendation is a step toward bringing Perjeta to people with HER2-positive, early-stage breast cancer, where treatment can potentially prevent the disease from returning and spreading.”

1. Gianni L, Pienkowski T, Im Y-H, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomized, multicenter, open-label, phase 2 trial. Lancet Oncol. 2012;13(1):25-32.
2. Schneeweiss A, Chia S, Hickish T, et al. Neoadjuvant pertuzumab and trastuzumab concurrent or sequential with an anthracycline-containing or concurrent with an anthracycline-free standard regimen: a randomized phase II study (TRYPHAENA). 2011 CTRC-AACR San Antonio Breast Cancer Symposium; December 6-10, 2011; San Antonio, Texas. Abstract S5-6.