FDA spotlight: Recent decisions in HER2-positive breast cancer
Despite the burden placed on the FDA by the COVID-19 pandemic, the agency has made several notable decisions on cancer therapies during the past year.
Healio has compiled a list of the agency’s recent decisions on treatment for HER2-positive breast cancer to highlight some of the new and emerging therapies in this field.
ARX788
In January 2021, the FDA granted fast track designation to ARX788 (Ambrx) as monotherapy for patients with advanced or metastatic HER2-positive breast cancer who received at least one prior anti-HER2-based regimen in the metastatic setting. The antibody drug conjugate targets the HER2 receptor and consists of two cytotoxic payloads conjugated to a trastuzumab-based antibody.
Phase 1 studies evaluating the safety, tolerability and pharmacokinetic and preliminary efficacy of the treatment formed the basis for the fast-track designation.
Margetuximab
In December 2020, the FDA approved margetuximab-cmkb (Margenza, MacroGenics) — a HER2-targeted monoclonal antibody — for use in combination with chemotherapy for adults with metastatic HER2-positive breast cancer. The treatment is indicated for patients who received at least two prior anti-HER2 regimens, including one for metastatic disease.
The agency based its approval on results from the phase 3 SOPHIA trial, which were presented at the 2019 San Antonio Breast Cancer Symposium.
“The availability of more effective treatments for patients with metastatic, heavily treated HER2-positive breast cancer is important,” Hope S. Rugo, MD, professor of medicine and director of Breast Oncology and Clinical Trials Education at University of California, San Francisco Comprehensive Cancer Center told Healio in April 2020 prior to margetuximab’s approval. “While it is difficult to know how this drug fits into the rapidly expanding treatment paradigm for this disease, despite the data presented at the [2019 San Antonio Breast Cancer Symposium], patients are still progressing on their disease and dying from HER2-positive metastatic breast cancer,”
In a press release accompanying the FDA’s decision, Rugo said, “As the only HER2-targeted agent to have shown a PFS improvement vs. trastuzumab (Herceptin, Genentech) in a head-to-head phase 3 clinical trial, Margenza with chemotherapy represents the newest treatment option for patients who have progressed on available HER2-directed therapies.”
CT-0508
In July 2020, the FDA cleared an investigational new drug application for CT-0508 (Carisma Therapeutics), an autologous chimeric antigen receptor macrophage therapy that targets the HER2 protein on the surface of solid tumor cells, for treatment of solid tumors that overexpress HER2.
As a result of the agency’s decision, the drug’s manufacturer can start a phase 1, first-in-human, multicenter clinical trial for patients with recurrent or metastatic HER2 overexpressing solid tumors who were previously treated with HER2-targeted regimens.
Phesgo
In June 2020, the FDA approved Phesgo (Genentech), the first at-home therapeutic regimen for breast cancer, for treatment of adults with HER2-positive breast cancer.
The treatment, which is a combination of pertuzumab (Perjeta, Genentech), trastuzumab and hyaluronidase-zzxf, is indicated for those with early-stage or metastatic disease, is initially used in combination with chemotherapy but can then be administered subcutaneously at home by a health care professional after completion of chemotherapy.
The FDA based its decision on positive results from a noninferiority trial in which patients with operable or locally advanced HER2-positive breast cancer were randomly assigned neoadjuvant chemotherapy with concurrent administration of Phesgo or IV pertuzumab and trastuzumab in the neoadjuvant and adjuvant settings.
In an agency press release, Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research, emphasized that such treatments are being prioritized in light of the COVID-19 pandemic and its effects on vulnerable populations, such as those with cancer.
“At this critical time, we continue to expedite oncology product development. This application was approved about 4 months ahead of the FDA goal date,” Pazdur said.
Tucatinib
In April 2020, the FDA approved tucatinib (Tukysa, Seattle Genetics), an oral tyrosine kinase inhibitor that had previously received priority review, in combination with trastuzumab and capecitabine for patients with HER2-positive breast cancer that cannot be removed surgically or has metastasized and who have received at least one prior anti-HER2-based regimen in the metastatic setting.
The approval came on the heels of the presentation of the phase 3 HER2LCIMB data at the 2019 San Antonio Breast Cancer Symposium.
“I hope it’s going to be the next standard of care,” Rashmi K. Murthy, MD, assistant professor of breast medical oncology at The University of Texas MD Anderson Cancer Center, told Healio after presentation of the data. “No clinical trial has shown an overall survival benefit for patients who are this heavily pretreated, and also for a patient population that included those with untreated and progressing brain metastases, so I would say these are unprecedented results.”
Neratinib
In February 2020, neratinib (Nerlynx, Puma Biotechnology) won FDA approval in combination with capecitabine for treatment of adults with advanced or metastatic HER2-positive breast cancer who received at least two prior anti-HER2-based regimens in the metastatic setting.
The treatment, which is an irreversible pan-HER tyrosine kinase inhibitor, had already been approved for single-agent extended adjuvant treatment of adults with early-stage HER2-positive metastatic breast cancer after adjuvant trastuzumab-based therapy.
Data from the phase 3 NALA trial, which showed a significant improvement in PFS in patients with metastatic HER2-positive breast cancer and prior treatment with at least two anti-HER2-based regimens with neratinib-capecitabine, formed the basis for the agency’s approval.