The past year has seen an unprecedented number of practice-changing advances across all three major breast cancer subtypes. For patients with early-stage triple-negative breast cancer, neoadjuvant chemotherapy plus pembrolizumab firmly entered the standard of care based on improvements in event-free survival.
Guest Editors
Sarah L. Sammons, MD
Nancy U. Lin, MD
Dr. Sammons is a breast medical oncologist and Assistant Professor of Medicine and Assistant Director of Breast Oncology Research at Duke University. Dr. Lin is Associate Chief, Division of Breast Oncology at the Susan F. Smith Center for Women’s Cancers at Dana-Farber Cancer Institute; Director, Metastatic Breast Cancer Program at Dana-Farber Cancer Institute; and Associate Professor of Medicine at Harvard Medical School.
Olaparib led to an overall survival benefit in patients with early-stage HER2-negative, BRCA1/2-associated breast cancer. For patients with metastatic estrogen receptor–positive/HER2-negative breast cancer, overall survival benefits were reported with ribociclib. Furthermore, for endocrine-resistant patients, fam-trastuzumab deruxtecan-nkxi (T-DXd), sacituzumab govitecan-hziy, and elacestrant all showed activity in phase III clinical trials. In HER2-positive metastatic breast cancer, T-DXd showed superiority over ado-trastuzumab emtansine (T-DM1) in the second-line setting. Finally, for metastatic triple-negative breast cancer, T-DXd demonstrated activity in patients with estrogen receptor–negative, HER2-low tumors, opening up a new target in triple-negative breast cancer, and the novel antibody-drug conjugate datopotamab deruxtecan (Dato-DXd) demonstrated promising early results.
Advances in Neoadjuvant and Adjuvant Therapies
KEYNOTE-522 randomly assigned 1,174 patients with stage II or III triple-negative breast cancer to neoadjuvant pembrolizumab plus chemotherapy (followed by adjuvant pembrolizumab) vs placebo plus chemotherapy. At the fourth planned interim analysis, estimated event-free survival at 36 months was 84.5% vs 76.8%, favoring pembrolizumab.1 The hazard ratio (HR) for distant recurrence–free survival was 0.61 (95% confidence interval [CI] = 0.46–0.82). In July 2021, the U.S. Food and Drug Administration (FDA) granted approval to pembrolizumab for high-risk, early-stage triple-negative breast cancer.
OlympiA focused on HER2-negative, BRCA1/2-associated breast cancer. Patients received 1 year of the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib after completion of standard neoadjuvant/adjuvant therapy and local therapy. With 3.5 years of median follow-up, an overall survival benefit has now emerged (HR = 0.68, P = .009).2 On March 11, 2022, the FDA granted approval to olaparib for patients with germline BRCA-mutated, HER2-negative, high-risk early breast cancer who were treated with neoadjuvant or adjuvant therapy. Results of OlympiA highlight the importance of offering
germline testing to patients who would otherwise meet eligibility for olaparib, regardless of family or personal cancer history.
MonarchE randomly assigned 5,637 patients with high-risk, lymph node–positive hormone receptor–positive/HER2-negative breast cancer to adjuvant endocrine therapy with or without abemaciclib. Updated results were presented at the European Society for Medical Oncology (ESMO) Congress 2021 showing continued invasive disease–free survival (HR = 0.696, 95% CI = 0.588–0.823; P < .0001) and distant recurrence–free survival benefit (HR = 0.687, 95% CI = 0.571–0.826; P < .0001).3 Ki67 index was prognostic but not predictive of abemaciclib benefit.4 Overall survival data are immature. On October 12, 2021, the FDA approved abemaciclib for adjuvant treatment of adult patients with hormone receptor–positive, HER2-negative, node-positive, early-stage breast cancer at high risk of recurrence, and a Ki67 score ≥ 20%, as determined by an FDA-approved test. Conversely, ASCO and National Comprehensive Cancer Network (NCCN) guidelines recommend consideration of adjuvant abemaciclib in the monarchE population regardless of Ki67.
Expanding Indications for Antibody-Drug Conjugates Across All Subtypes
Until 2022, the efficacy of systemic therapies targeting HER2 has been limited to patients with breast cancer whose tumors overexpress HER2 (IHC 3+) or have evidence of ERBB2 amplification. T-DXd is an antibody-drug conjugate consisting of trastuzumab linked to a potent cytotoxic topoisomerase I inhibitor payload, approved in 2019 for use in HER2-positive metastatic breast cancer.5 Notably, T-DXd exhibits a bystander effect to neighboring tumor cells heterogeneously expressing HER2, raising the hypothesis that it may be active in the over 60% of HER2-negative tumors that express low levels of HER2 (defined as IHC 1+ or IHC 2+/ISH negative, newly termed HER2-low).6
DESTINY-Breast04 was a phase III clinical trial that randomly assigned 557 patients with HER2-low metastatic breast cancer and one to two prior lines of chemotherapy to receive T-DXd or the physician’s choice of chemotherapy. In patients with hormone receptor–positive, HER2-low metastatic breast cancer (n = 494), the median progression-free survival was 10.1 months for T-DXd vs 5.4 months in the physician’s choice group (HR = 0.51; P < .001).7 Overall survival was also improved with T-DXd: 23.9 months vs 17.5 months (HR = 0.64; P = .003). The triple-negative subgroup, though small (n = 63), also derived significant progression-free and overall survival benefits. This trial led to a standing ovation from the breast cancer community when presented at the 2022 ASCO Annual Meeting. Subsequently, on August 5, 2022, the FDA approved T-DXd for patients with HER2-low metastatic breast cancer who had received prior chemotherapy in the metastatic setting or developed disease recurrence within 6 months of completing adjuvant chemotherapy.
Of note, the optimal cutoff and correct diagnostic tests for HER2 predicting T-DXd efficacy are evolving. T-DXd has been studied in 36 patients with HER2 0 metastatic breast cancer, yielding a response rate of 30.6% in a heavily pretreated population and duration of response of 6.8 months.8 Finally, the efficacy of T-DXd following sacituzumab govitecan (or vice versa) is unknown. We have much to learn about how to sequence antibody-drug conjugates in metastatic breast cancer, but more options are a win for our patients.
The past year has also seen expanding indications for sacituzumab govitecan, a TROP2-targeted antibody-drug conjugate previously approved in metastatic triple-negative breast cancer.TROPiCS-02 was a phase III clinical trial that enrolled 543 patients with hormone receptor–positive/HER2-negative metastatic breast cancer who had received at least one endocrine therapy and a cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor and two to four lines of chemotherapy for metastatic breast cancer. Patients were randomly assigned to receive sacituzumab govitecan or treatment of physician’s choice. At ASCO 2022, Rugo et al presented the first results: median progression-free survival was 5.5 months with sacituzumab govitecan vs 4.0 months with physician’s choice (HR = 0.66; P = .0003).9 Positive overall survival data will be presented at ESMO 2022. While the FDA has not yet issued a decision on the use of sacituzumab govitecan for hormone receptor–positive/HER2-negative metastatic breast cancer, it has already been added as a category 2A preferred recommendation in the latest NCCN Clinical Practice Guidelines in Oncology.
Finally, there are a multitude of novel antibody-drug conjugates jockeying for position across breast cancer subtypes. One to watch is Dato-DXd, a TROP2-targeted antibody-drug conjugate with a deruxtecan payload.10 In the phase 1 TROPION-PanTumor01, 34% of all patients achieved an objective response, including 52% of patients who had not previously received sacituzumab govitecan, and responses were also observed in patients previously treated with sacituzumab govitecan.11
A New Second Line for HER2-Positive Metastatic Breast Cancer
For the past decade, the recommended sequence of therapy for patients with HER2-positive metastatic breast cancer has been first-line taxane/trastuzumab/pertuzumab, followed by second-line T-DM1. The DESTINY-Breast03 study challenged this precedent by randomly assigning 524 patients with HER2-positive metastatic breast cancer (previously treated with a taxane and trastuzumab) to T-DXd vs T-DM1. T-DXd led to unprecedented efficacy. The median progression-free survival by independent radiology review was not reached, with a lower bound of the 95% CI of 22.1 months, and median investigator-assessed progression-free survival was 25.1 months12; overall survival data are not yet mature. On May 4, 2022, the FDA granted regular approval to T-DXd to patients who have received a prior anti-HER2–based regimen either in the metastatic setting, or those who had disease recurrence during or within 6 months of completing (neo)adjuvant HER2-directed therapy.
But how does T-DXd perform relative to tucatinib/capecitabine/trastuzumab in patients with stable and active HER2-positive brain metastases? In a subset analyses of DESTINY-Breast03, progression-free survival benefit was observed in patients with stable brain metastases (HR = 0.25, 95% CI = 0.13–0.45) in favor of T-DXd over T-DM1. Hurvitz et al at the 2021 San Antonio Breast Cancer Symposium reported that central nervous system (CNS) objective response rates were also higher with T-DXd (63.9% vs 32.8%),13 though this analysis included only 36 patients and did not report time from most recent CNS-directed radiotherapy. Several small studies have reported high intracranial response rates in patients with active or untreated HER2-positive brain metastases to T-DXd. TUXEDO-1 included 15 patients with HER2-positive metastatic breast cancer and active brain metastases (newly diagnosed or progressed after local therapy). Objective CNS response was 73.3%, which is unprecedented for an antibody-drug conjugate.14 DESTINY BREAST-12 is an ongoing phase IIIb/IV study evaluating T-DXd in patients with active or stable brain metastases and should shed some light on true intracranial activity.
Overall Survival Differences Emerge Among CDK4/6 Inhibitors
Abemaciclib, palbociclib and ribociclib are all FDA approved in addition to aromatase inhibitors in first-line hormone receptor–positive/HER2-negative metastatic breast cancer. Pivotal trials in the first line had nearly identical progression-free survival hazard ratios, and until now side effect profile differences and patient-physician preferences have led therapy choice. The final overall survival data from PALOMA-2 were presented at ASCO 2022 by Finn et al, showing no improvement to overall survival with the addition of palbociblib to letrozole, after a median follow-up of 90 months (medians 53.9 months with palbociclib/letrozole vs 51.2 months with letrozole alone; HR = 0.956, 95% CI = 0.777–1.177).15 These results contrast the overall survival data from MONALEESA-2 presented by Hortobagyi et al at ESMO 2021. Ribociclib added to letrozole improved median overall survival to 63.9 months (95% CI = 52.4–71.0 months) vs 51.4 months (95% CI = 47.2–59.7 months) with placebo plus letrozole (HR = 0.76; 95% CI = 0.63–0.93 months; two-sided P = .008).16 Ribociclib improved overall survival independent of metastatic site, number of sites, or prior systemic therapy.17
How do we reconcile these differences? The patient populations were nearly identical. PALOMA-2 investigators pointed to missing data as a potential cause for lack of demonstrated overall survival benefit with palbociclib, but these data beg the question: are all three CDK4/6 inhibitors created equal? Ribociclib and abemaciclib are four and five times more selective toward CDK4 over CDK6, and abemaciclib has diverse cyclin-CDK complex inhibition. Toxicity profiles also vary significantly. We await overall data for first-line abemaciclib from MONARCH-3 which will be presented at ESMO 2022, after this issue goes to press. For now, patient shared decision-making, including a discussion regarding overall survival data and side effect profiles with patients individually, is recommended.
Beyond CDK4/6 Inhibitors for Hormone Receptor–Positive/HER2-Negative Metastatic Breast Cancer
The industry race for an oral alternative with superior bioavailability and activity to the only FDA-approved selective estrogen downregulator (SERD), fulvestrant, is ongoing. The EMERALD trial randomly assigned 477 postmenopausal women with estrogen receptor–positive/HER2-negative metastatic breast cancer treated with one or two prior lines of endocrine therapy including a CDK4/6 inhibitor to receive either elacestrant or standard-of-care endocrine monotherapy, fulvestrant, or aromatase inhibitor. Patients with ESR1 mutations were nearly half of the trial population and were evenly distributed between arms. Progression-free survival assessed by blind independent central review was prolonged in the elacestrant arm vs the standard-of-care arm in all patients (HR = 0.70; 95% CI = 0.55–0.88; P = .002). Progression-free survival prolongation was more dramatic in patients with ESR1 mutations (HR = 0.55; 95% CI = 0.39–0.77, P = .0005).18 A new drug application for elacestrant has been accepted for Priority Review by the FDA, with a Prescription Drug User Fee Act date of February 17, 2023.
Notably, several other oral SERDs have yielded negative trials in recent weeks including amcenestrant (AMEERA-3, AMEERA-5) and giredestrant (acelERA). There were differences in patient populations and trial designs compared to EMERALD, and whether these explain differences in trial results, or whether elacestrant is truly a superior SERD, is unknown at this time.
The PADA-1 trial represents yet another approach to treatment selection and sequencing in patients with hormone receptor–positive/HER2-negative metastatic breast cancer.19 Patients on an aromatase inhibitor and palbociclib were prospectively followed with liquid biopsies to detect emergent ESR1 mutations. Patients with a mutation in the absence of radiographic disease progression were randomly assigned to continue therapy or an early switch to fulvestrant plus palbociclib. Early switching was associated with prolonged progression-free survival (median of 5.7 vs 11.9 months; HR = 0.61, P = .005). Beyond the novel treatment assignment approach utilized in PADA-1, and the beginning exploration of the clinical utility of serial ESR1 mutation tracking, the study contributes to our understanding of the potential role of continuation of CDK4/6 inhibitors through multiple lines of therapy, a concept formally tested in the MAINTAIN trial.20 The ongoing PACE (ClinicalTrials.gov identifier NCT03147287) and postMONARCH (NCT05169567) trials should further clarify whether there is a role for the use of CDK4/6 inhibitors after disease progression on a prior CDK4/6 inhibitor.
Identifying Additional Patient Subsets That Could Benefit From Immunotherapy
NIMBUS was a single-arm, nonrandomized phase II trial that tested the combination of nivolumab and ipilimumab in patients with HER2-negative metastatic breast cancer and high tumor mutation burden (TMB), prospectively defined as ≥ 9 mutations per megabase (mut/Mb).21 The objective response rate was 16.7%; in the small number of patients with TMB ≥ 14 mut/Mb, objective response rate was 60.0%. The prior phase II TAPUR study reported a 21% objective response rate to single-agent pembrolizumab in patients with ≥ 9 mut/Mb. Due to differences in patient populations between NIMBUS and TAPUR, cross-trial comparisons are not valid. Whether nivolumab adds to ipilumumab activity is also not answered by NIMBUS. However, NIMBUS provides further evidence that benefits of PD-1 inhibition in patients with metastatic breast cancer extend beyond PD-L1–positive triple-negative breast cancer and further supports the use of next-generation sequencing testing in patients with HER2-negative metastatic breast cancer to identify actionable targets.
Summary
The past year has seen notable advances across both early-stage and metastatic breast cancer. Over the coming year, we expect to see further progress in the endocrine therapy and CDK4/6 inhibitor spaces; updated data on T-DXd and sacituzumab govitecan, as well as novel antibody-drug conjugates; and additional insights into patient selection and treatment optimization with immunotherapy-based approaches.
DISCLOSURE: Dr. Sammons has served as an advisor or consultant for AstraZeneca, Daiichi Sankyo, Foundation Medicine, Novartis, Pfizer, and Sermonix Pharmaceuticals; and has received research funding from Abbvie, AstraZeneca/MedImmune, Bristol Myers Squibb, Eli Lilly, and Sermonix Pharmaceuticals. Dr. Lin has received institutional research support from Genentech, Merck, Pfizer, Seattle Genetics, AstraZeneca, Zion Pharmaceuticals, and Olema Pharmaceuticals; has served as an advisor or consultant to Artera, Pfizer, Puma, Seattle Genetics, Daiichi Sankyo, AstraZeneca, Prelude Therapeutics, Denali Therapeutics, Olema Pharmaceuticals, Aleta BioPharma, Affinia Therapeutics, and Voyager Therapeutics; and has received royalties from UpToDate.
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15. Finn RS, Rugo HS, Dieras VC, et al: Overall survival with first-line palbociclib plus letrozole versus placebo plus letrozole in women with estrogen receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer: Analyses from PALOMA-2. 2022 ASCO Annual Meeting. Abstract LBA1003. Presented June 4, 2022.
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17. O’Shaughnessy J, Stemmer SM, Burris HA, et al: Overall survival subgroup analysis by metastatic site from the phase 3 MONALEESA-2 study of first-line ribociclib + letrozole in postmenopausal patients with HR+/HER2– advanced breast cancer. 2021 San Antonio Breast Cancer Symposium. Abstract GS2-01. Presented December 8, 2021.
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