WHITE OAK, MD—In a groundbreaking decision, the Oncologic Drugs Advisory Committee (ODAC) to the U.S. Food and Drug Administration voted yesterday for accelerated approval of the monoclonal antibody pertuzumab (Perjeta) in the neoadjuvant setting. If approved by the agency, the therapy would be the first neoadjuvant drug to treat breast cancer in the United States, and the first treatment approved based on pathological complete response (pCR) data.
Pertuzumab, which is already approved for HER2-positive metastatic breast cancer, would be used as part of combined therapy including trastuzumab in the neoadjuvant setting for high-risk women with early-stage HER2 positive breast cancer.
At issue is the fact that more than 6,000 Americans die of HER2-positive breast cancer annually. Pertuzumab's mechanism of action targets the HER2 receptor in a different, complementary way to that of trastuzumab; the two drugs together achieve a dual HER2 blockade.
The FDA does not have to take ODAC's advice, but often does. The agency is expected to make a decision on pertuzumab for the neoadjuvant indication by October 31.
“This is a historic moment,” said ODAC Chair Mikkael Sekeres, MD, MS, Director of the Cleveland Clinic Taussig Cancer Institute's Leukemia Program and Chair of the Hematology/Oncology Pharmacy and Therapeutics Committee, and OT's Clinical Advisory Editor for Hematology/Oncology. “This is a unique situation. ... It's the totality of the data” that is showing benefit.
He added, “It's a chance to get this drug to people quicker, and I'm pretty sure it won't impose harm on people.” He told OT he was very pleased by the vote: 13 of the 14 voting ODAC members voted for approval, with one member abstaining. “For the first time we've recommended approval of a drug for the neoadjuvant treatment of breast cancer,” Sekeres said, which would move the drug from the metastatic setting to early-stage breast cancer in hopes of preventing high-risk women from progressing to metastasis.
But, he had a stern word of warning for the drug's sponsor, Genentech, which is conducting a large Phase III confirmatory study of pertuzumab in the adjuvant setting called APHINITY: “All eyes will be on the confirmatory APHINITY trial,” he said. “If it's negative we urge you to avoid a repeat of Avastin and withdraw this drug from the neoadjuvant indication.”
Sandra Horning, MD, Genentech Senior Vice President and Global Head of Clinical Hematology/Oncology, a former ODAC member and former ASCO President, and a breast cancer survivor, said the company would withdraw the neoadjuvant indication for pertuzumab if the APHINITY trial has negative results.
Asked by OT if he was pleased by ODAC's vote, Richard Pazdur, MD, FDA's Director of the Office of Hematology & Oncology Products in the Office of New Drugs, said he was. For breast cancer patients, he said, using pertuzumab in the neoadjuvant setting might prevent some high-risk women from developing metastatic disease, which he said is too often “a death sentence.”
During the day-long ODAC meeting at FDA, Pazdur urged ODAC members to think about pertuzumab not only from the standpoint of individual breast cancer patients but also from a public health perspective: “availing therapies to a very high-risk patient population early.”
‘Sobering’ Testimony from a Breast Cancer Patient
Pazdur said he found the testimony of breast cancer patient Kelly Lange during the public hearing session of the ODAC meeting sobering. Lange has stage IV HER2-positive breast cancer. “Herceptin saved my life,” she said. But, she asked, “What might have been?” if pertuzumab had been available to her early in her course of therapy; if it had been, she said, her breast cancer might never have metastasized and she might be out working at a job and not testifying at an ODAC meeting.
“Early access is critical,” she said. “When these drugs work, they work really well.”
NEOSPHERE, TRYPHAENA, CLEOPATRA
The Committee members cast their votes for accelerated approval for the new indication of pertuzumab based primarily on a study called NEOSPHERE, a multicenter, randomized trial in 417 patients with operable locally advanced or inflammatory HER2-positive breast cancer.
In that study, patients were randomly allocated to receive one of four neoadjuvant regimens; the main comparison for the ODAC review was trastuzumab plus docetaxel (arm A) vs. pertuzumab plus trastuzumab plus docetaxel (arm B). The study's primary endpoint was pCR, defined by the FDA-preferred definition as the absence of invasive cancer in the breast and lymph nodes. Patients on arm B, the pertuzumab arm, showed a statistically significant improvement in pCR of 17.8 percent compared with patients on arm A.
NEOSPHERE, though, was not the only study of pertuzumab that ODAC members considered in casting their vote. Other studies with pertuzumab data presented by the drug's sponsor at the meeting included TRYPHAENA, a study whose primary endpoint was cardiac safety, and CLEOPATRA, which showed a significant improvement in progression-free survival and overall survival in study subjects taking pertuzumab.
Pazdur noted that for accelerated approval, FDA considers all the data available: “We're looking at the totality of the evidence in a disease setting. We look at this as a special situation,” he said. The APHINITY confirmatory trial was a factor in the ODAC vote. This trial is fully accrued with 4,805 patients and will provide data on efficacy, safety, and long-term outcomes; data are expected in 2016.
Comments from José Baselga
If approved by the FDA, the neoadjuvant use of pertuzumab would represent a new drug development paradigm in early HER2-breast cancer, said pertuzumab investigator José Baselga, MD, PhD, Physician-in-Chief of Memorial Sloan-Kettering Cancer Center.
Speaking on behalf of approval of the new neoadjuvant indication, he said, “Survival in HER2 early breast cancer has been transformed by trastuzumab; yet, a substantial number of patients are still dying. ... Dual HER2 blockade is superior.” He added that pCR is an acceptable endpoint in these studies: “In HER2 disease, pCR is associated with improved long-term outcomes.”
Side Effects Profile
Industry representatives and ODAC members discussed the side effects profile of pertuzumab in detail: In NEOSPHERE, the most common grade 3 or higher adverse events for the pertuzumab regimen were neutropenia, febrile neutropenia, and diarrhea. Potential cardiac adverse events were especially worrisome, said ODAC member Deborah K. Armstrong, MD, Associate Professor of Oncology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University School of Medicine.
In TRYPHAENA, which investigated the tolerability of pertuzumab, trastuzumab, and anthracycline neoadjuvant regimens, no new or unexpected cardiac adverse events were observed in any of the study arms, according to Genentech data.
Also of concern to ODAC members was how neoadjuvant pertuzumab regimens would be used in clinical practice: “How exactly am I going to give it to a patient?” said ODAC member James Liebmann, MD, Assistant Professor of Medicine in the Department of Medicine at the University of Massachusetts.
Baselga said there are multiple regimens that are used with HER2 therapies, with no single conventional approach. “Part of our task is to think about how we will actually use the drug,” noted Sekeres.
ODAC members agreed that information on the drug label for the new indication would be key. Pazdur said FDA is working on an internal initiative to make the label for drugs approved via the accelerated-approval pathway clearer and more understandable—free of what he called “code language” and “gibberish.” He said that if the agency approves pertuzumab for the new neoadjuvant indication, the label would most likely specify that it be used in patients who meet the criteria of those studied in the NEOSPHERE trial.
ODAC's Abstaining Member: Tito Fojo
The ODAC member who abstained from the vote, Tito Fojo, MD, PhD, Program Director for Medical Oncology at the National Cancer Institute, said he had problems with the study methodology of NEOSPHERE, including its small size, the fact that the majority of patients enrolled were outside the United States. and the use of an unproven surrogate endpoint.
Pazdur noted that there is no perfect new drug application. “Every application has its warts, folks,” he said. “This is what we have. Should we wait five years for more data? We're looking at an agent that may prevent metastatic disease.”
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