SABCS: Subgroup analysis of trastuzumab deruxtecan (T-DXd) shows 'encouraging' results in controlling stable brain metastases in HER2-positive metastatic breast cancer
UCLA Jonsson Comprehensive Cancer Center researchers present this and other important findings at the San Antonio Breast Cancer Symposium Dec. 7-10
A subgroup analysis of a phase III study led by researchers at the UCLA Jonsson Comprehensive Cancer Center found consistent progression-free survival (PFS) and objective response rate (ORR) benefit when women with HER2-positive metastatic breast cancer were treated with the HER2-targeting antibody-drug conjugate trastuzumab deruxtecan (T-DXd), compared to the current standard of treatment.
Although consistent PFS and ORR benefits were seen across various subgroups, the therapy appeared to be surprisingly effective in controlling intracranial tumors in patients who had stable brain metastases when they joined the study.
Confirmed objective response rate (for disease outside the brain) was more than three times higher in these patients with brain metastases who were treated with the study drug compared to those receiving standard treatment, according to the investigators, who are presenting their findings in a General Session presentation at the 2021 San Antonio Breast Cancer Symposium (SABCS). Median progression-free survival in patients with brain metastases was 15 months in the T-DXd treatment arm compared with three months in the standard treatment arm.
Moreover, the researchers said, confirmed responses and partial responses observed in the brain suggest the treatment is associated with substantial intracranial tumor response and reduction in central nervous system disease. Of 36 patients with brain metastases treated with T-DXd, 63.9% experienced a response in the brain, 10 of whom experienced a complete response. This compared favorably to the results in 36 patients with brain metastases treated with trastuzumab emtansine (T-DM1) (33.4% intracranial response and one complete response).
"The main goals in the treatment of HER2-positive metastatic breast cancer, including those with stable brain metastases, are to improve symptoms, stabilize or reduce the tumor size and improve overall survival," said first author Dr. Sara Hurvitz, director of the Breast Cancer Clinical Research Program at the UCLA Jonsson Comprehensive Cancer Center. "The greater efficacy seen in DESTINY-Breast 03 in the subgroup of patients with stable brain metastases at baseline in this study are encouraging and may provide another potential option for patients who have experienced disease progression on currently available therapies."
DESTINY-Breast03 is a phase III clinical trial evaluating T-DXd, a HER2-targeted monoclonal antibody that delivers high concentrations of chemotherapy directly to cancer cells that have the HER2 protein on their surface. Primary results from the study, reported in September, found that the treatment significantly prolonged progression-free survival when compared to standard treatment. "This data is nothing short of phenomenal and will be practice changing," Hurvitz said at the time.
Up to 20% of breast cancers are classified as HER2 positive, meaning the tumor has extra copies of the gene for HER2 and too much HER2 protein on the cell surface, which causes the cancer to behave more aggressively, leading to worse outcomes, including a higher chance of metastasizing. The development of HER2-targeted treatments, such as trastuzumab, pertuzumab, and T-DM1, has greatly improved outcomes, but most patients with advanced disease will experience disease resistance and progression despite having these targeted therapies.
The first-line standard of care for patients with HER2-positive metastatic breast cancer is HER2 antibody therapy with pertuzumab/trastuzumab, plus chemotherapy. If the cancer progresses, standard care since 2013 has been to switch therapy to T-DM1, which is an antibody-drug conjugate comprised of trastuzumab and chemotherapy.
Primary results of the DESTINY-Breast03 study showed that T-DXd is significantly better than T-DM1 when used after a patient's disease has progressed on trastuzumab and chemotherapy. Hurvitz said these data support T-DXd becoming the standard second-line therapy for metastatic disease, as recently recommended in new guidelines published by the National Comprehensive Cancer Network (NCCN). The U.S. Food and Drug Administration gave accelerated approval for the drug in 2019 for patients with unresectable or metastatic HER2-postive breast cancer who have received two or more prior HER2-based regimens in the metastatic setting.
Publication Number: GS3-01
General Session 3 – Hall 3 – Thursday, Dec. 9, 8:45-11:15 a.m. CT (embargoed until this time)
Trastuzumab deruxtecan (T-DXd; DS-8201a) vs. trastuzumab emtansine (T-DM1) in patients (pts) with HER2+ metastatic breast cancer (mBC): subgroup analyses from the randomized phase 3 study DESTINY-Breast03
Hurvitz disclosures in abstract: Ownership Interest (stock, stock options, or other ownership interest excluding diversified mutual funds); Author; Ambrx, Arvinas, Astra Zeneca, Bayer, Daiichi Sankyo, Dignitana, Genentech/Roche, Gilead, GSK, Lilly, Macrogenics, Novartis, OBI Pharma, Pfizer, Pieris, PUMA, Radius, Samumed, Sanofi, Seattle Genetics, Zymeworks. Other; Author; Lilly, Ambrx, Arvinas, Astra Zeneca, Bayer, Daiichi Sankyo, Dignitana, Genentech/Roche, Gilead, GSK, Macrogenics, Novartis, OBI Pharma, Pfizer, Pieris, PUMA, Radius, Samumed, Sanofi, Seattle Genetics, Zymeworks. (Other authors have additional disclosures.)
Publication Number: OT1-12-05
Ongoing Trials Poster Session 1 – Wednesday, Dec. 8, 5-6:30 p.m. CT (embargoed until this time)
Phase II neoadjuvant trial evaluating trastuzumab deruxtecan with or without anastrozole for HER2-low, HR+ early stage breast cancer
In addition to presenting the DESTINY-Breast03 subgroup data, Hurvitz will provide an update on a related trial in progress that is evaluating the benefits of T-DXd in patients with breast cancers expressing low levels of HER2. T-DXd has demonstrated promising clinical effectiveness in HER2-low breast cancer. This is believed to be the first and only ongoing study evaluating the experimental therapy as an early pre-surgical treatment with or without anti-estrogen therapy for hormone receptor-positive, HER2-low breast cancer. It is designed to "shed light on clinical activity and biomarkers, which may guide larger confirmatory studies" for patients with these breast cancers.
Hurvitz disclosures in abstract: Contracted Research; Author; Ambryx, Amgen, Arvinas, Bayer, Biomarin, Cascadian Therapeutics, Daiichi Sankyo, Dignitana, Genentech/Roche, Gilead Sciences, GlaxoSmithKline, Immunomedics, Lilly, Macrogenics, Merrimack, Novartis, OBI Pharma, Pfizer, Phoenix Molecular Designs, Pieris Pharmaceuticals, Puma Biotechnology, Radius Health, Sanofi, Seattle Genetics, Zymeworks. Ownership Interest (stock, stock options, or other ownership interest excluding diversified mutual funds); Spouse/Partner; Ideal Implant, ROM Tech. Other; Author; Pfizer, Roche, Lilly. (Other authors have additional disclosures.)
Here are other presentations of note.
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Publication Number: PD10-04
Spotlight Poster Discussion 10 – Thursday, Dec. 9, 5-6:30 p.m. CT (embargoed until this time)
Phase Ib/II open-label, randomized trial of atezolizumab (atezo) with ipatasertib (ipat) and fulvestrant (fulv) vs control in MORPHEUS-HR+ breast cancer (M-HR+ BC) and atezo with ipat vs control in MORPHEUS triple negative breast cancer (M-TNBC)
Hurvitz will provide updated data on survival, response rates, and adverse events from two MORPHEUS clinical trials. Morpheus is a platform that consists of multiple, global, phase Ib/II trials designed to gauge safety and identify early evidence of effectiveness in treatment combinations for various cancers.
Here, atezolizumab (atezo), an anti-PD-L1 checkpoint inhibitor, was evaluated in combination with ipatasertib (ipat), which inhibits a protein kinase (AKT) often involved in a hyperactivated signaling pathway that supports cancer growth. The combination therapy was studied in two separate randomized trials. In one, patients with hormone receptor-positive breast cancer received the combined therapies and the estrogen receptor antagonist fulvestrant. In the other, patients with triple-negative breast cancer received the combined therapies without fulvestrant. Both trials had control groups for comparison. Atezo plus ipat and fulvestrant was found to be tolerable and showed a preliminary efficacy signal in the hormone receptor-positive breast cancer study. Atezo plus ipat had only limited efficacy in the triple-negative breast cancer trial.
Hurvitz disclosures in abstract: Contracted Research; Author; Ambrx, Amgen, Astra Zeneca, Arvinas, Bayer, Cytomx, Daiichi-Sankyo, Genentech/Roche, Gilead, GSK, Immunomedics, Lilly, Macrogenics, Novartis, Pfizer, OBI Pharma, Pieris, PUMA, Radius, Sanofi,, Seattle Genetics, Dignitana, Zymeworks, Phoenix Molecular Designs. Other; Author; Travel: Lilly. (Other authors have additional disclosures.)
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Publication Number: PD13-06
Spotlight Poster Discussion 13 – Friday, Dec. 10, 7-8:30 a.m. CT (embargoed until this time)
Neoadjuvant giredestrant (GDC-9545) + palbociclib versus anastrozole + palbociclib in postmenopausal women with estrogen receptor-positive, HER2-negative, untreated early breast cancer: Primary analysis of the randomized, open-label, phase II coopERA breast cancer study
Hurvitz will present updated results from the phase II coopERA breast cancer study for postmenopausal women with estrogen receptor-positive, HER2-negative, untreated early breast cancer. Like results of a previous, interim analysis, treatment with giredestrant appears superior to that with anastrozole.
Giredestrant is a new, experimental selective estrogen receptor degrader (SERD) that has shown promise against metastatic breast cancer, both alone and in combination with palbociclib. Here, it is being studied as a first therapy for women with untreated early breast cancer, with results measured by reduction of Ki67, a cancer antigen that serves as a biomarker of cancer cell proliferation.
Hurvitz will report the results of the primary analysis, which shows greater Ki67 suppression in patients receiving giredestrant than in those receiving anastrozole as part of their treatment.
Hurvitz disclosures in abstract: Contracted Research; Author; Ambrx, AstraZeneca, Amgen, Arvinas, Bayer, Daiichi Sankyo, Genentech/Roche, Gilead, GlaxoSmithKline, Immunomedics, Lilly, Macrogenics, Novartis, Pfizer, OBI Pharma, Pieris, PUMA, Radius, Sanofi, Seattle Genetics, Dignitana, Zymeworks, Phoenix Molecular Designs, Ltd, Support for third-party writing assistance for this abstract, furnished by Bonnie Jordan, BSc of Health Interactions, was provided by F. Hoffmann-La Roche Ltd, Basel, Switzerland. Ownership Interest (stock, stock options, or other ownership interest excluding diversified mutual funds); Author; NKMax. Ownership Interest (stock, stock options, or other ownership interest excluding diversified mutual funds); Spouse/Partner; Ideal Implant. Other; Author; Travel reimbursement from Lilly. (Other authors have additional disclosures.)
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Publication Number: PD13-08
Spotlight Poster Discussion 13 – Friday, Dec. 10, 7-8:30 a.m. CT (embargoed until this time)
First-in-human safety and activity of ARV-471, a novel PROTAC® estrogen receptor degrader, in ER+/HER2- locally advanced or metastatic breast cancer
Hurvitz is senior author of this presentation by first author Dr. Erika Hamilton, of the Sarah Cannon Research Institute in Nashville, Tennessee.
The authors report on this multicenter, first-in-human, open-label study assessing ARV-471, a selective PROteolysis-TArgeting Chimera (PROTAC) small molecule that induces degradation of estrogen receptors. The phase I dose escalation study – for locally advanced or metastatic estrogen receptor-positive, HER2-negative breast cancer – includes pre- and postmenopausal women to assess safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity.
Compared with fulvestrant, a well-established estrogen receptor degrader that requires intramuscular injection, the orally administered ARV-471 demonstrated superior ER degradation and antitumor activity in preclinical models. In this human trial, the drug was well tolerated, and it demonstrated robust ER degradation and encouraging clinical activity. It is now being evaluated in the VERITAC phase II monotherapy expansion at 200 mg. and 500 mg. once daily.
Hamilton disclosures from abstract: Consulting Fees (e.g. advisory boards); Author; payments to institution: Arcus Arvinas AstraZeneca Boehringer Ingelheim CytomX Daiichi Sankyo Dantari Deciphera Pharmaceuticals Eisai H3 Biomedicine Lilly Merck Mersana Novartis Pfizer, payments to institution: Puma Biotechnology Roche/Genentech Seattle Genetics Silverback Therapeutics. Contracted Research; Author; payments to institution: Abbvie Acerta Pharma AKESOBIO Australia Amgen ArQule Arvinas AstraZeneca Black Diamond Boehringer Ingelheim Cascadian Therapeutics Clovis Compugen Curis Daiichi Sankyo, payments to institution: Dana Farber Cancer Inst Deciphera eFFECTOR Therapeutics EMD Serono Fochon FujiFilm G1 Therapeutics H3 Biomedicine Harpoon Hutchinson MediPharma Immunogen Immunomedics, payments to institution: Infinity Pharmaceuticals InvestisBio Kadmon Krayopharm Leap Therapeutics Lilly Lycera Macrogenics Mallinckrodt MedImmune Meharry CCOP Mersana Merus Millennium, payments to institution: Molecular Templates Novartis Nucana Olema OncoMed Onconova Therapeutics Oncothyreon Orinove Pfizer PharmaMar Plexxikon Radius Health Regeneron Rgenix Roche/Genentech, payments to institution: Seattle Genetics Sermonix Pharmaceuticals Shattuck Labs Silverback StemCentRx Sutro Syndax Syros Taiho TapImmune Tesaro Torque Therapeutics Verastem Zenith Epigenetics, payments to institution: Zymeworks.
Hurvitz disclosures from abstract: Contracted Research; Author; Ambrx, Amgen, Astra Zeneca, Arvinas, Bayer, Cytomx, Daiichi-Sankyo, Genentech/Roche, Gilead, GSK, Immunomedics, Lilly, Macrogenics, Novartis, Pfizer, OBI Pharma, Pieris, PUMA, Radius, Samumed, Sanofi,. Other; Author; Travel: Lilly (2019). (Other authors have additional disclosures.)
The San Antonio Breast Cancer Symposium will be Dec. 7-10, livestreamed and in person at the Henry B. Gonzalez Convention Center, 900 Market Street, San Antonio, Texas.
