A Review of Selected Presentations From SABCS 2023
December 5-9, 2023 • San Antonio, Texas
Clinical Outcomes by Age Subgroups in the Phase 3 TROPiCS-02 Study of Sacituzumab Govitecan vs Treatment of Physician’s Choice in HR+/HER2– Metastatic Breast Cancer
The open-label, phase 3 TROPiCS-02 trial evaluated sacituzumab govitecan vs the physician’s treatment of choice in patients with previously treated, endocrine-resistant, hormone receptor–positive/human epidermal growth factor–negative (HR+/HER2–) metastatic breast cancer.1-3 Enrolled patients had either inoperable locally recurrent breast cancer or metastatic breast cancer that had progressed after prior therapy with 1 or more regimens of endocrine therapy, a taxane, and a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, or with 2 to 4 lines of chemotherapy. Stratification factors included visceral metastasis, 6 or more months of endocrine therapy in the metastatic setting, and prior lines of chemotherapy. In the experimental arm, patients received sacituzumab govitecan (10 mg/kg, days 1 and 8, in 21-day cycles); patients in the control arm received the physician’s choice of chemotherapy agent from among capecitabine, vinorelbine, gemcitabine, and eribulin. The primary endpoint was progression-free survival (PFS) according to blinded independent review.
The TROPiCS-02 study randomized 272 patients to an experimental arm and 271 to a control arm. The study yielded a superior median PFS with sacituzumab govitecan vs physician’s treatment of choice (5.5 vs 4.0 months; hazard ratio [HR], 0.66; P=.003), as well as a significant improvement in median overall survival (OS; 14.4 vs 11.2 months; HR, 0.79; P=.020).1,2 A post hoc study evaluated the efficacy, safety, and quality of life of patients from the TROPiCS-02 study on the basis of age subgroups.3 Because the incidence of HR+/HER2– metastatic breast cancer increases with age, the study compared patients who were younger than 65 years vs patients who were 65 years old or older. Median PFS was superior with sacituzumab govitecan vs physician’s treatment of choice, both among patients who were younger than 65 years (5.5 vs 4.1 months; HR, 0.69; 95% CI, 0.53-0.89) and among patients who were 65 years old or older (6.7 vs 3.5 months; HR, 0.59; 95% CI, 0.38-0.93) (Figure 1). The median OS was also superior with sacituzumab govitecan vs chemotherapy, both in the younger patient subgroup (14.1 vs 11.5 months; HR, 0.81; 95% CI, 0.64-1.02) and in the older patient subgroup (14.9 vs 10.1 months; HR, 0.80; 95% CI, 0.54-1.19). In both the younger and older patient subgroups, treatment-emergent adverse events (AEs) of grade 3 or higher were more common with sacituzumab govitecan than with chemotherapy, as were treatment-emergent AEs leading to dose interruption. Sacituzumab govitecan was generally associated with a superior quality of life, and in the subgroup of patients younger than 65 years, the time to deterioration owing to fatigue was significantly longer with the antibody-drug conjugate (ADC) than with chemotherapy (P=.021).
References
1. Rugo HS, Bardia A, Marmé F, et al. Overall survival with sacituzumab govitecan in hormone receptor-positive and human epidermal growth factor receptor 2-negative metastatic breast cancer (TROPiCS-02): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2023;402(10411):1423-1433.
2. Rugo HS, Bardia A, Marmé F, et al. Sacituzumab govitecan in hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2022;40(29):3365-3376.
3. Bardia A, Schmid P, Tolaney SM, et al. Clinical outcomes by age subgroups in the phase 3 TROPiCS-02 study of sacituzumab govitecan vs treatment of physician’s choice in HR+/HER2– metastatic breast cancer. Abstract P05-21-09. Presented at: the 2023 San Antonio Breast Cancer Symposium; December 5-9, 2023; San Antonio, Texas.
Multicenter Retrospective Cohort Study of the Sequential Use of the Antibody-Drug Conjugates (ADCs) Trastuzumab Deruxtecan (T-DXd) and Sacituzumab Govitecan (SG) in Patients With HER2-Low Metastatic Breast Cancer (MBC)
Trastuzumab deruxtecan (T-DXd) is an ADC comprising an anti-HER2 antibody that is chemically bound by a tumor-selective, cleavable linker to an agent that blocks the activity of topoisomerase I.1 T-DXd is approved for the treatment of unresectable or metastatic HER2-positive (HER2+) breast cancer in patients who have received a prior anti-HER2–based regimen and for the treatment of unresectable or metastatic HER2-low breast cancer.2,3 Sacituzumab govitecan is an ADC comprising an antibody against TROP2 and the SN-38 payload, which is an active metabolite of irinotecan; the antibody and payload are linked together by a pH-sensitive, cleavable linker. Sacituzumab govitecan is approved for the treatment of unresectable locally advanced or metastatic triple-negative breast cancer (TNBC) and for the treatment of unresectable locally advanced or metastatic HR+/HER2– breast cancer.4-6
A retrospective cohort study investigated the safety and efficacy as well as the effect of sequencing of these 2 ADCs in the real-world setting at 5 cancer treatment centers among patients with HER2-low metastatic breast cancer.7 The study included 84 patients with HER2-low metastatic breast cancer who had received therapy with both ADCs in either order or who had received monotherapy with 1 of the ADCs while participating in a clinical trial. Most of the 84 patients had visceral disease before receiving ADC therapy and were heavily pretreated. Among 56 patients with HR+/HER2-low disease, 24 had received sacituzumab govitecan followed by T-DXd and 32 had received T-DXd followed by sacituzumab govitecan.
Among 56 patients who received sacituzumab govitecan as their first ADC, the median PFS was 8.0 months with sacituzumab govitecan and 3.7 months with T-DXd. Among patients who received T-DXd as their first ADC, the median PFS was 5.5 months with T-DXd and 2.6 months with sacituzumab govitecan (Table). There were 28 patients who had HR–/HER2-low disease, including 25 who received sacituzumab govitecan as their first ADC. Among this group, the median PFS was 7.8 months with sacituzumab govitecan and 2.8 months with T-DXd. Among 3 patients who received T-DXd as their first ADC, the median PFS was undetermined for both ADCs. In all subgroups, the median objective response rate (ORR) was higher and the median PFS was longer with the first ADC treatment than with the second ADC treatment.
References
1. De Santis P, Sanna V, Perrone M, et al. Antibody-drug conjugates in HR+ breast cancer: where are we now and where are we heading? J Clin Med. 2023;12(23):7325.
2. Trastuzumab deruxtecan (Enhertu) prescribing information. 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761139s021lbl.pdf. Daiichi Sankyo, Inc. Accessed January 5, 2024.
3. Modi S, Jacot W, Yamashita T, et al; DESTINY-Breast04 Trial Investigators. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med. 2022;387(1):9-20.
4. Bardia A, Hurvitz SA, Tolaney SM, et al; ASCENT Clinical Trial Investigators. Sacituzumab govitecan in metastatic triple-negative breast cancer. N Engl J Med. 2021;384(16):1529-1541.
5. Rugo HS, Bardia A, Marmé F, et al. Sacituzumab govitecan in hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2022;40(29):3365-3376.
6. Sacituzumab govitecan (Trodelvy) prescribing information. Gilead Sciences, Inc.; 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761115s023lbl.pdf. Accessed January 5, 2024.
7. Huppert L, Mahtani R, Fisch S, et al. Multicenter retrospective cohort study of the sequential use of the antibody-drug conjugates (ADCs) trastuzumab deruxtecan (T-DXd) and sacituzumab govitecan (SG) in patients with HER2-low metastatic breast cancer (MBC). Abstract PS08-04. Presented at: the 2023 San Antonio Breast Cancer Symposium; December 5-9, 2023; San Antonio, Texas.
Efficacy of Sacituzumab-Govitecan (SG) Post Trastuzumab-Deruxtecan (T-DXd) and Vice Versa for HER2low Advanced or Metastatic Breast Cancer (MBC): A French Multicentre Retrospective Study
T-DXd and sacituzumab govitecan were approved for the treatment of HER2-low metastatic breast cancer on the basis of the ASCENT, TROPiCS-02, and DESTINY-Breast04 trials.1 The multicenter ADC Low study retrospectively evaluated the efficacy and safety of the 2 ADCs when administered sequentially as monotherapy in patients with HER2-low metastatic breast cancer.2 The primary endpoint was the PFS on the basis of treatment with the second ADC. The study included 179 patients, 115 of whom received sacituzumab govitecan as their first ADC and 64 of whom received T-DXd as their first ADC. The first ADC was the median third line of therapy, and the second ADC was the median fifth line of therapy. At the time of data analysis, 32% of patients were still receiving therapy with the second ADC.
After treatment with the first ADC, the median PFS was 2.7 months for the patients with HR+ disease and 4.9 months for the patients with HR– disease. (Table 2) The low median PFS among the patients with HR+ disease was considered to stem from the fact that T-DXd was the median fourth line of treatment in that patient group. After treatment with the second ADC, the median PFS was 2.7 months for the entire study population (95% CI, 2.4-3.3 months); the median PFS after treatment with the second ADC was short regardless of ADC sequencing (95% CI, 2.2-3.1 months). Multivariate analysis suggested a trend toward benefit with sacituzumab govitecan as the first ADC, but in the comparison with T-DXd as the first ADC, the difference did not reach statistical significance (P=.063).
To identify a subgroup of patients who were more likely to benefit from treatment with a second ADC, patients were categorized according to their response to ADC therapy. Those with primary resistance had progressive disease as their best response, and those with secondary resistance had an objective response or stable disease. On the basis of these concepts, 40.4% of the patients had primary resistance and 59.6% had secondary resistance to the first ADC. In the patients who were also resistant to the second ADC, payload cross-resistance may have developed at progression with the first ADC. Among the patients who exhibited primary resistance at progression with the first ADC, a short time of efficacy with the second ADC was noted in 39%. The study suggests that sequencing 2 ADCs with the same payload may limit efficacy, particularly in heavily pretreated patients.
References
1. Nicolò E, Boscolo Bielo L, Curigliano G, Tarantino P. The HER2-low revolution in breast oncology: steps forward and emerging challenges. Ther Adv Med Oncol. 2023;15:17588359231152842.
2. Poumeaud F, Morisseau M, Cabel L, et al. Efficacy of sacituzumab-govitecan (SG) post trastuzumab-deruxtecan (T-DXd) and vice versa for HER2low advanced or metastatic breast cancer (MBC): a French multicentre retrospective study. Abstract PS08-02. Presented at: the 2023 San Antonio Breast Cancer Symposium; December 5-9, 2023; San Antonio, Texas.
Randomized Phase 3 Study of Datopotamab Deruxtecan vs Chemotherapy for Patients With Previously-Treated Inoperable or Metastatic Hormone Receptor-Positive, HER2-Negative Breast Cancer: Results From TROPION-Breast01
Datopotamab deruxtecan (Dato-DXd) is an ADC comprising a TROP2-directed antibody linked to deruxtecan, a topoisomerase I inhibitor.1 The open-label, international, phase 3 TROPION-Breast01 trial evaluated Dato-DXd vs chemotherapy in patients with HR+/HER2– breast cancer.2-4 The study included patients who had previously received 1 or 2 lines of chemotherapy for inoperable or metastatic disease. Patients had experienced disease progression on endocrine therapy or for whom endocrine therapy was unsuitable. Stratification factors included the number of prior lines of chemotherapy, geographic location, and prior exposure to a CDK4/6 inhibitor. Patients were evenly randomized to receive Dato-DXd (6 mg/kg, day 1) or the investigator’s choice of chemotherapy on a 21-day schedule. The study’s 2 primary endpoints were PFS and OS according to a blinded independent review.
The TROPION-Breast01 study included 732 patients and showed a significant improvement in median PFS when Dato-DXd was compared with chemotherapy (6.9 vs 4.5 months; HR, 0.64; 95% CI, 0.53-0.76; P<.0001) (Figure 2), thus meeting the primary endpoint of PFS. Among 317 patients with more than 12 months of prior treatment with a CDK4/6 inhibitor, the median PFS was 7.1 months with Dato-DXd vs 5.0 months with chemotherapy (HR, 0.61; 95% CI, 0.45-0.82). Patients who received the ADC also had a longer time until the first subsequent therapy vs those who received chemotherapy (8.2 vs 5.0 months; HR, 0.53; 95% CI, 0.45-0.64). Therapy with Dato-DXd was also superior to the investigator’s choice of chemotherapy among patient subgroups, including patients with prior exposure to a CDK4/6 inhibitor (≤12 months or >12 months) and patients with or without brain metastasis at baseline.
Among the patients who received treatment with the ADC, the rate of treatment-related AEs of at least grade 3 was 21%, which was less than half the rate observed in the chemotherapy arm (45%). In the Dato-DXd arm, treatment-related AEs led to treatment discontinuation in 3% of patients, and serious treatment-related AEs were observed in 6% of patients. Grade 3 or higher AEs of clinical interest in the Dato-DXd arm included neutropenia (1%) and stomatitis (6%). On the basis of measures of time to deterioration in quality of life, overall quality of life was superior with Dato-DXd in comparison with chemotherapy, as were more specific measures of physical functioning and pain.
References
1. Okajima D, Yasuda S, Maejima T, et al. Datopotamab deruxtecan, a novel TROP2-directed antibody-drug conjugate, demonstrates potent antitumor activity by efficient drug delivery to tumor cells. Mol Cancer Ther. 2021;20(12):2329-2340.
2. Bardia A, Jhaveri K, Im SA, et al. Randomized phase 3 study of datopotamab deruxtecan vs chemotherapy for patients with previously-treated inoperable or metastatic hormone receptor-positive, HER2-negative breast cancer: results from TROPION-Breast01. Abstract GS02-01. Presented at: the 2023 San Antonio Breast Cancer Symposium; December 5-9, 2023; San Antonio, Texas.
3. Bardia A, Jhaveri K, Im SA, et al. Datopotamab deruxtecan (Dato-DXd) vs chemotherapy in previously-treated inoperable or metastatic hormone receptor-positive, HER2-negative (HR+/HER2–) breast cancer (BC): Primary results from the randomised phase III TROPION-Breast01 trial [ESMO abstract LBA11]. Ann Oncol. 2023;34(suppl 2).
4. Bardia A, Jhaveri K, Kalinsky K, et al. TROPION-Breast01: datopotamab deruxtecan vs chemotherapy in pre-treated inoperable or metastatic HR+/HER2- breast cancer. Future Oncol. 2023;fon-2023-0188.
HER2CLIMB-02: Randomized, Double-Blind Phase 3 Trial of Tucatinib and Trastuzumab Emtansine for Previously Treated HER2-Positive Metastatic Breast Cancer
Tucatinib is a HER2-directed tyrosine kinase inhibitor (TKI) that is approved for the treatment of patients with locally advanced or metastatic breast cancer, including those with brain metastasis.1,2 Trastuzumab emtansine (T-DM1) is a HER2-directed ADC that delivers a microtubule-disrupting agent, emtansine, to the targeted cell.3 The double-blind, phase 3 HER2CLIMB-02 study evaluated T-DM1 combined with tucatinib or placebo in patients with unresectable locally advanced or metastatic breast cancer.4 The study enrolled patients with HER2+ disease who had experienced disease progression after treatment with trastuzumab and a taxane in any setting. Patients with previously treated brain metastases that did not require immediate local therapy were allowed. Stratification factors included the number of prior lines of therapy for metastatic disease, HR status, brain metastasis, and Eastern Cooperative Oncology Group performance status. The primary endpoint was PFS by investigator assessment according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.5
The HER2CLIMB-02 study randomized 228 patients to T-DM1 plus tucatinib and 235 to T-DM1 plus placebo (Figure 3). Baseline characteristics were well balanced between the 2 arms. Patients had a median age of 53 to 55 years and 60% had HR+ disease. Current or prior brain metastases were noted in 43% to 45% of patients, including active (22%-24%) and treated stable (20%-21%) masses. Patients had received a median of 1 prior line of systemic therapy in the metastatic setting (range, 0-8), and nearly all the patients had received prior treatment with pertuzumab (89%-91%). The trial met its primary endpoint, demonstrating a median PFS of 9.5 months with T-DM1 plus tucatinib vs 7.4 months with T-DM1 plus placebo (HR, 0.76; 95% CI, 0.61-0.95; P=.0163). Analysis of prespecified subgroups showed a consistent improvement in median PFS with T-DM1 plus tucatinib vs T-DM1 plus placebo. Among patients with brain metastasis, the median PFS was again superior with T-DM1 plus tucatinib (n=99) vs T-DM1 plus placebo (n=105; 7.8 vs 5.7 months; HR, 0.64; 95% CI, 0.46-0.89); statistical significance was not evaluated because of the hierarchical testing strategy. Among evaluable patients in the overall study population, the confirmed ORR was 42.0% with the tucatinib combination vs 36.1% with the placebo combination, with a complete response rate of approximately 4% in both arms. After a median follow-up of 24.4 months, the median OS was similar for the 2 arms (HR, 1.23; 95% CI, 0.87-1.74). Interim OS results did not meet the prespecified crossing boundary of P≤.0041.
In the arm that received T-DM1 plus tucatinib, 68.8% of patients experienced a treatment-emergent AE of grade 3 or higher vs 41.2% in the placebo arm, and 1.3% of patients in the arm that received T-DM1 plus tucatinib had a fatal treatment-emergent AE vs 0.9% in the placebo arm. The most common treatment-emergent AEs of grade 3 or higher in the T-DM1-plus-tucatinib arm vs the T-DM1-plus-placebo arm were increased alanine transaminase (16.5% vs 2.6%), increased aspartate transaminase (16.5% vs 2.6%), and anemia (8.2% vs 4.7%). Hepatic events in the T-DM1-plus-tucatinib arm were generally transient, manageable, and reversible.
References
1. Kulukian A, Lee P, Taylor J, et al. Preclinical activity of HER2-selective tyrosine kinase inhibitor tucatinib as a single agent or in combination with trastuzumab or docetaxel in solid tumor models. Mol Cancer Ther. 2020;19(4):976-987.
2. Tucatinib (Tuksya) prescribing information. Seagen, Inc. April 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213411s000lbl.pdf. Accessed January 4, 2024.
3. Trastuzumab emtansine (Kadcyla) prescribing information. Genentech, Inc. 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/125427lbl.pdf. Accessed January 4, 2024.
4. Hurvitz SA, Loi S, O’Shaughnessy J, et al. HER2CLIMB-02: randomized, double-blind phase 3 trial of tucatinib and trastuzumab emtansine for previously treated HER2-positive metastatic breast cancer. Abstract GS01-10. Presented at: the 2023 San Antonio Breast Cancer Symposium; December 5-9, 2023; San Antonio, Texas.
5. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247.
Sequencing Antibody-Drug Conjugate After Antibody-Drug Conjugate in Metastatic Breast Cancer (A3 Study): Multi-institution Experience and Biomarker Analysis
To provide insights regarding best practices for sequencing the administration of ADCs, a study conducted at 3 academic medical institutions evaluated outcomes in patients with metastatic HR+/HER2– breast cancer or TNBC who were treated with 2 or more ADCs in sequence.1 Clinical data were extracted by chart review. Cross-resistance to the second ADC was defined as disease progression at the first restaging assessment or progression within 60 days after initiating treatment. The study identified 68 patients with metastatic HR+/HER2– breast cancer or TNBC who received therapy with 2 ADCs between August 2014 and June 2023. The study included 30 patients (44%) with HR+/HER2– disease and 38 patients (56%) with TNBC. There were 50 patients (74%) who had HER2-low disease. At the time of initiation of treatment with the second ADC, the patients had a median age of 59.6 years (range, 29.9-88.6). Before the start of therapy with the second ADC, patients had received a median of 4 lines of prior therapy in the metastatic setting.
The median time to progression with the first ADC was 161 days (95% CI, 131-224) and with the second ADC was 77 days (95% CI, 51-112; P<.01). Of 47 patients who were treated with a second ADC that had a change in antibody target and a change in payload, cross-resistance was observed in 23 patients (49%) (Figure 4). Of 10 patients who were treated with a second ADC that had the same payload but a different antibody target, cross-resistance was observed in 3 (30%). Of 14 patients who were treated with a second ADC that had the same antibody target but a different payload, 8 (57%) exhibited cross-resistance. Only 3 patients were treated with a second ADC that had the same target and payload as the first ADC, and 2 of these patients (67%) showed cross-resistance. Tumor DNA sequencing data were available for 20 patients who had received therapy with more than 1 ADC. Mutations in genes associated with topoisomerase I, including TOP1, TOP2A, TOP3A, and TOP3B, were identified in 7 patients who exhibited cross-resistance to the second ADC, which carried a payload that inhibited topoisomerase I activity.
Reference
1. Abelman RO, Spring LM, Fell G, et al. Sequencing antibody-drug conjugate after antibody-drug conjugate in metastatic breast cancer (A3 study): multi-institution experience and biomarker analysis. Abstract PS08-03. Presented at: the 2023 San Antonio Breast Cancer Symposium; December 5-9, 2023; San Antonio, Texas.
Elacestrant vs Standard-of-Care in ER+/HER2– Advanced or Metastatic Breast Cancer (mBC) With ESR1 Mutation: Key Biomarkers and Clinical Subgroup Analyses From the Phase 3 EMERALD Trial
Endocrine therapy plus a CDK4/6 inhibitor is the preferred first-line therapy for patients with estrogen receptor–positive (ER+)/HER2– metastatic breast cancer.1 The open-label, phase 3 EMERALD trial compared elacestrant, a selective estrogen receptor degrader (SERD), vs standard-of-care therapy (SOC) in patients with ER+/HER2– metastatic breast cancer.2,3 Enrolled patients were required to have had 1 or 2 prior lines of endocrine therapy as well as prior therapy with a CDK4/6 inhibitor. Patients in the SOC arm were treated with an aromatase inhibitor or fulvestrant. The study included 239 patients who were randomized to elacestrant and 239 who were randomized to SOC. The trial led to the approval of elacestrant for patients with ER+/HER2– metastatic breast cancer harboring mutations in the ESR1 gene following 1 or more lines of endocrine therapy.4 Thus, elacestrant became the first SERD to be approved for the treatment of patients with ER+/HER2– breast cancer harboring an ESR1 mutation.
In the EMERALD trial, the duration of prior therapy with a CDK4/6 inhibitor correlated with elacestrant efficacy. Among all patients with an ESR1 mutation who had at least 12 months of prior exposure to a CDK4/6 inhibitor (n=159), the median PFS was 8.61 months with elacestrant vs 1.91 months with SOC (HR, 0.410; 95% CI, 0.262-0.634) (Table 3). Subgroup analysis was performed to evaluate the efficacy of elacestrant vs SOC in subgroups of patients with important biomarkers and clinical characteristics, such as resistance mutations and bone or visceral metastasis. The analysis showed a consistent benefit with elacestrant vs SOC among subgroups of patients with ESR1 mutation who had received at least 12 months of prior CDK4/6 inhibitor therapy, including those with bone metastasis (HR, 0.381; 95% CI, 0.230-0.623), liver and/or lung metastasis (HR, 0.354; 95% CI, 0.209-0.589), PIK3CA mutation (HR, 0.423; 95% CI, 0.176-0.941), HER2-low expression (HR, 0.301; 95% CI, 0.142-0.604), or TP53 mutation (HR, 0.300; 95% CI, 0.132-0.643).3 Safety analysis showed that the toxicity profile for each subgroup was similar to that of the overall population of patients with ESR1 mutation and at least 12 months of prior CDK4/6 inhibitor therapy.
References
1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Breast Cancer (v.5.2023). https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Updated December 5, 2023. Accessed January 4, 2024.
2. Bardia A, Bidard FC, Neven P, et al. EMERALD phase 3 trial of elacestrant vs standard of care endocrine therapy in patients with ER+/HER2– metastatic breast cancer: updated results by duration of prior CDK4/6i in metastatic setting [AACR abstract GS3-01]. Cancer Res. 2023;83(suppl).
3. Bardia A, O’Shaughnessy J, Bidard FC, et al. Elacestrant vs standard-of-care in ER+/HER2– advanced or metastatic breast cancer (mBC) with ESR1 mutation: key biomarkers and clinical subgroup analyses from the phase 3 EMERALD trial. Abstract PS17-02. Presented at: the 2023 San Antonio Breast Cancer Symposium; December 5-9, 2023; San Antonio, Texas.
4. Elacestrant (Orserdu) prescribing information. Stemline Therapeutics, Inc; January 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/217639s000lbl.pdf. Updated January 2023. Accessed December 20, 2023.
Highlights in Metastatic Breast Cancer from the 2023 San Antonio Breast Cancer Symposium: Commentary
Aditya Bardia, MD • Medical Oncologist, Massachusetts General Hospital • Boston, Massachusetts
The San Antonio Breast Cancer Symposium (SABCS), which was held in San Antonio, Texas, in December 2023, provided valuable insights into the management of metastatic breast cancer. Data focused on the efficacy, safety, and utilization as treatment options of several single-agent and combination therapies, including sacituzumab govitecan, datopotamab deruxtecan, elacestrant, and trastuzumab emtansine plus tucatinib.
Sacituzumab Govitecan
The phase 3 TROPiCS-02 study demonstrated a similar efficacy benefit with sacituzumab govitecan vs treatment of physician’s choice in patients with pretreated, endocrine-resistant, hormone receptor-positive/human epidermal growth factor receptor 2–negative (HR+/HER2–) metastatic breast cancer, regardless of age subgroup, with manageable safety.1 As expected, the older patients had higher Eastern Cooperative Oncology Group performance status scores and more preexisting comorbidities. Similar rates of treatment-emergent adverse events (AEs) were observed regardless of age subgroup, and efficacy was improved at higher vs lower relative dose intensity in patients older than 65 years. Time to deterioration owing to fatigue was significantly longer with sacituzumab govitecan vs physician’s choice in patients older than 65 years. Sacituzumab govitecan also demonstrated a favorable benefit-to-risk profile in older patients, a finding that supports its use vs physician’s choice in this patient population, which is known for experiencing increased toxicity and decreased efficacy with chemotherapy.
Antibody-Drug Conjugate Sequencing
Several abstracts looking at the sequential use of antibody-drug conjugates (ADCs) were presented at the poster spotlight session, including institutional experience from the University of California San Francisco, MD Anderson, French sites, and the Massachusetts General Cancer Center.2-6
Remarkably, all studies reported somewhat similar results, indicating that progression-free survival (PFS) was longer in patients who received a first ADC (ADC1) than in those who received a second ADC (ADC2) after ADC1. Regardless of which agent was used as ADC2, the PFS was shorter. It appears that cross-resistance between ADC1 and ADC2 developed in a subset of patients. However, other patients still derived benefit from the sequential use of ADC1 followed by ADC2. This finding raises pertinent questions for the field: How can we identify patients who continue to benefit from ADC2 after receiving ADC1? Can we identify biomarkers of resistance to avoid the use of ADC2 after ADC1?
Digging deeper into the specifics of ADC1 and ADC2, the abstracts looked at the question of trastuzumab deruxtecan after sacituzumab govitecan or vice versa. The group from MD Anderson demonstrated that using trastuzumab deruxtecan first, followed by sacituzumab govitecan, resulted in an overall survival benefit. Of note, this was not a randomized trial, so the results need to be viewed with caution. However, the findings are consistent with the current practice of considering trastuzumab deruxtecan for patients with HER2-low metastatic breast cancer, followed by the potential consideration of sacituzumab govitecan, the other ADC approved in this space.
Datopotamab Deruxtecan
TROPION-Breast01 is a global, randomized, phase 3 trial that looked at datopotamab deruxtecan vs investigator’s choice of chemotherapy for patients with metastatic HR+ breast cancer who had received at least 1 prior line of chemotherapy.7 Patients were randomized 1:1 to datopotamab deruxtecan, given every 3 weeks, or the investigator’s choice of chemotherapy: eribulin, mesylate, vinorelbine, gemcitabine, or capecitabine. The primary endpoint of the trial was PFS by independent review. In addition, several secondary endpoints included PFS by investigator assessment, quality-of-life results, and safety.
The first results from TROPION-Breast01 were presented at the European Society for Medical Oncology (ESMO) Congress 2023. The study met its primary endpoint, demonstrating improvement in PFS with datopotamab deruxtecan vs physician’s choice of chemotherapy (hazard ratio, 0.63).8 At SABCS 2023, we saw results by subgroups, investigator-assessed PFS, quality of life, and safety.9 Per investigator assessment, an improvement in PFS was noted; the median PFS was approximately 7 months with datopotamab deruxtecan vs 4.5 months with standard chemotherapy. The benefit was maintained in patients who had baseline brain metastases vs those who did not, as well as in patients who had a prior duration of cyclin-dependent kinase 4/6 (CDK4/6) inhibitor treatment of more than 12 months vs those who did not.
In terms of safety, the patients who received datopotamab deruxtecan had fewer grade 3 AEs in comparison with those who received the investigator’s choice of chemotherapy. The most common AEs with chemotherapy were side effects like myelosuppression and neutropenia. Neutropenic fever was the cause of death in 1 patient. With datopotamab deruxtecan, common AEs included mucositis, although generally grade 1 or 2. The rate of grade 3 mucositis was low, and the rate of discontinuation because of mucositis was also low. Finally, in terms of quality of life, the patients who received datopotamab deruxtecan had a delayed time to deterioration in quality of life, global health-related quality of life, pain domain, and physical functioning domain. Generally, the patients receiving datopotamab deruxtecan had a delayed time to deterioration or a better quality of life in comparison with those receiving standard chemotherapy.
After all these factors of efficacy, safety, and quality of life were considered, datopotamab deruxtecan was superior to standard chemotherapy, and if approved, it would be the third ADC approved for patients with HR+ metastatic breast cancer.
Elacestrant
The EMERALD trial looked at elacestrant vs fulvestrant or endocrine monotherapy with an aromatase inhibitor for patients with estrogen receptor–positive (ER+) metastatic breast cancer after second-line or higher CDK4/6 inhibitor treatment. We saw improvement in PFS with elacestrant, particularly in patients who had detectable estrogen receptor 1 (ESR1) mutations and had received CDK4/6 inhibitors for more than 12 months.10 In that setting, PFS was about 8.5 months with elacestrant vs about 2 months with standard endocrine therapy. At SABCS 2023, we saw biomarker results from the EMERALD trial, which included patients with coexisting ESR1 and PIK3C mutations, with ESR1 and TP53 mutations, and with HER2-low breast cancer. 11 In all these subgroups, the benefit with elacestrant was maintained in comparison with standard-of-care endocrine therapy. The drug can be used regardless of these coexisting alterations so long as a patient has a detectable ESR1 mutation, which is consistent with the US Food and Drug Administration label for elacestrant in patients with metastatic ER+ breast cancer.12
Trastuzumab Emtansine Plus Tucatinib
The HER2CLIMB-02 study investigated trastuzumab emtansine plus tucatinib and found a notably improved PFS for this combination in comparison with a single agent.13 On average, the median enhancement in PFS was approximately 2 months. However, further data and extended follow-up, particularly evaluating the effect on overall survival, are necessary before integration of this approach into routine clinical practice can be considered. The study provided encouraging results supporting the concept that a combination therapy regimen involving an antibody-based treatment and a tyrosine kinase inhibitor can yield outcomes superior to those of single-agent treatment.
Disclosures
Dr Bardia is a consultant/serves on the advisory board for Pfizer, Novartis, Genentech, Merck, Radius Health, Immunomedics/Gilead, Sanofi, Daiichi Pharma/AstraZeneca, Phillips, Eli Lilly, and Foundation Medicine; and has received research/grants (to institution) from Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health, Immunomedics/Gilead, Daiichi Pharma/AstraZeneca, and Eli Lilly.
References
1. Bardia A, Schmid P, Tolaney S, et al. Clinical outcomes by age subgroups in the phase 3 TROPiCS-02 study of sacituzumab govitecan vs treatment of physician’s choice in HR+/HER2‒ metastatic breast cancer. Abstract P05-21-09. Presented at: the 2023 San Antonio Breast Cancer Symposium; December 5-9, 2023; San Antonio, Texas.
2. Rugo H, Cortés J, Curigliano G, et al. ASCENT-07: a phase 3, randomized, open-label study of sacituzumab govitecan versus treatment of physician’s choice in patients with HR+/HER2– inoperable, locally advanced, or metastatic breast cancer post-endocrine therapy. Abstract PO1-05-09. Presented at: the 2023 San Antonio Breast Cancer Symposium; December 5-9, 2023; San Antonio, Texas.
3. Huppert L, Mahtani R, Fisch S, et al. Multicenter retrospective cohort study of the sequential use of the antibody-drug conjugates (ADCs) trastuzumab deruxtecan (T-DXd) and sacituzumab govitecan (SG) in patients with HER2-low metastatic breast cancer (MBC). Abstract PS08-04. Presented at: the 2023 San Antonio Breast Cancer Symposium; December 5-9, 2023; San Antonio, Texas.
4. Poumeaud F, Morisseau M, Cabel L, et al. Efficacy of sacituzumab-govitecan (SG) post trastuzumab-deruxtecan (T-DXd) and vice versa for HER2low advanced or metastatic breast cancer (MBC): a French multicentre retrospective study. Abstract PS08-02. Presented at: the 2023 San Antonio Breast Cancer Symposium; December 5-9, 2023; San Antonio, Texas.
5. Abelman RO, Spring L, Fell G, et al. Sequencing antibody-drug conjugate after antibody-drug conjugate in metastatic breast cancer (A3 study): multi-institution experience and biomarker analysis. Abstract PS08-03. Presented at: the 2023 San Antonio Breast Cancer Symposium; December 5-9, 2023; San Antonio, Texas.
6. Raghavendra S, Wang Z, Basset R, Tripathy D. Antibody-drug conjugates (ADCs) in breast cancer: real world analysis of outcomes. Abstract PS08-01. Presented at: the 2023 San Antonio Breast Cancer Symposium; December 5-9, 2023; San Antonio, Texas.
7. ClinicalTrials.gov. A phase-3, open-label, randomized study of dato-DXd versus investigator’s choice of chemotherapy (ICC) in participants with inoperable or metastatic HR-positive, HER2-negative breast cancer who have been treated with one or two prior lines of systemic chemotherapy (TROPION-Breast01). https://clinicaltrials.gov/study/NCT05104866. NCT05104866. Updated October 11, 2023. Accessed December 19, 2023.
8. Bardia A, Jhaveri K, Im S, et al. Datopotamab deruxtecan (Dato-DXd) vs chemotherapy in previously-treated inoperable or metastatic hormone receptor-positive, HER2-negative (HR+/HER2–) breast cancer (BC): primary results from the randomised phase III TROPION-Breast01 trial [ESMO abstract LBA11]. Ann Oncol. 2023;34(2)(suppl):S1264-S1265.
9. Bardia A, Jhaveri K, Im SA, et al. Randomized phase 3 study of datopotamab deruxtecan vs chemotherapy for patients with previously-treated inoperable or metastatic hormone receptor-positive, HER2-negative breast cancer: results from TROPION-Breast01. Abstract GS02-01. Presented at: the 2023 San Antonio Breast Cancer Symposium; December 5-9, 2023; San Antonio, Texas.
10. Bardia A, Aftimos P, Bihani T, et al. EMERALD: phase III trial of elacestrant (RAD1901) vs endocrine therapy for previously treated ER+ advanced breast cancer. Future Oncol. 2019;15(28):3209-3218.
11. Bardia A, O’Shaughnessy J, Bidard FC, et al. Elacestrant vs standard-of-care in ER+/HER2- advanced or metastatic breast cancer (mBC) with ESR1 mutation: key biomarkers and clinical subgroup analyses from the phase 3 EMERALD trial. Abstract PS17-02. Presented at: the 2023 San Antonio Breast Cancer Symposium; December 5-9, 2023; San Antonio, Texas.
12. Elacestrant (Orserdu) prescribing information. Stemline Therapeutics, Inc; January 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/217639s000lbl.pdf. Updated January 2023. Accessed December 20, 2023.
13. Hurvitz S, Loi S, O’Shaughnessy J, et al. HER2CLIMB-02: randomized, double-blind phase 3 trial of tucatinib and trastuzumab emtansine for previously treated HER2-positive metastatic breast cancer. Abstract GS01-10. Presented at: the 2023 San Antonio Breast Cancer Symposium; December 5-9, 2023; San Antonio, Texas.