A Review of Selected Presentations From the 2022 San Antonio Breast Cancer Symposium®
• December 6-11, 2022 • San Antonio, Texas
Sacituzumab Govitecan vs Treatment of Physician’s Choice: Efficacy by Trop-2 Expression in the TROPiCS-02 Study of Patients With HR+/HER2– Metastatic Breast Cancer
Metastatic breast cancer (mBC) continues to present treatment challenges in part because various subtypes express different markers, thus requiring different targeted drugs. Hormone receptor–positive/human epidermal growth factor 2–negative (HR+/HER2–) breast cancer is the most common type of this disease, accounting for approximately 70% of all cases.1,2 Resistance to endocrine therapy typically develops, and oncologists have vigorously sought alternatives.
Expression of trophoblast cell surface antigen 2 (Trop-2) has been observed across all breast cancer subtypes, and Trop-2 is an attractive target for the treatment of patients who have received multiple lines of therapy for HR+/HER2– mBC.3,4
Sacituzumab govitecan (SG) is a novel antibody-drug conjugate (ADC) that comprises a humanized anti–Trop-2 antibody with an SN-38 payload covalently attached by means of a pH-sensitive, hydrolyzable linker.5 The SN-38 moiety is a topoisomerase I inhibitor that is more potent than its predecessors. SG is approved for the treatment of patients with metastatic triple-negative breast cancer who have received 2 or more prior therapies, including 1 or more treatments for mBC.6
TROPiCS-02 Trial
The phase 3 TROPiCS-02 trial evaluated the safety and efficacy of SG vs that of the physician’s choice of therapy in patients with unresectable locally advanced or metastatic HR+/HER2– disease.7,8 Patients had had disease progression after treatment with 1 or more endocrine therapies, a taxane, and a CDK4/6 inhibitor. Enrolled patients had received 2, 3, or 4 prior lines of chemotherapy for metastatic disease and had measurable disease by Response Evaluation in Solid Tumors (RECIST) 1.1.9
Patients were stratified on the basis of visceral metastases, endocrine therapy in the metastatic setting, and number of prior lines of therapy. The study included 543 participants, who were randomly assigned to receive SG (10 mg/kg on days 1 and 8 of 21-day cycles) or the physician’s choice of therapy (capecitabine, vinorelbine, gemcitabine, or eribulin).
The primary endpoint was progression-free survival (PFS) by blinded independent central review. Patients in the TROPiCS-02 trial had received a median of 3 prior chemotherapy regimens for mBC, and 95% had visceral metastasis. After a median follow-up of 10.2 months, the trial met its primary endpoint, demonstrating a median PFS of 5.5 months (95% CI, 4.2-7.0 months) with SG vs 4.0 months (95% CI, 3.1-4.4 months) with the physician’s choice of treatment (hazard ratio [HR], 0.66; 95% CI, 0.53-0.83; P=.0003). The trial also showed superior overall survival (OS) with the ADC vs the comparator (14.4 vs 11.2 months, respectively; HR, 0.79; 95% CI, 0.65-0.96; P=.020).
Post Hoc Analysis
A post hoc analysis of the TROPiCS-02 study was conducted to evaluate efficacy outcomes with SG vs outcomes with the physician’s choice of treatment according to levels of expression of Trop-2.10 Tissue samples were collected from primary or metastatic tumors at study entry; however, levels of Trop-2 expression were not used to determine patient eligibility for the trial.
The median time from tumor tissue collection to study entry was 7.7 months (range, 0.03-177.9). Levels of Trop-2 expression were centrally determined by a validated research immunohistochemistry (IHC) assay. Samples were available from 238 patients (88%) in the ADC arm and 224 patients (83%) in the comparator arm. Trop-2 expression was observed in approximately 95% of tumors. Most patients (58%) had a histochemistry score (H-score) of 100 or greater.
Results from the retrospective analysis consistently suggested a trend of improved efficacy with SG vs the physician’s choice of treatment across all levels of Trop-2 expression examined (Table 1a, b; Figure 1). It is important to note the relatively small sizes of the patient groups and to interpret the results accordingly. Treatment with the ADC was associated with a manageable safety profile, and safety was not affected by levels of Trop-2 expression.
References
1. American Cancer Society. Key statistics for breast cancer. (Accessed December 30, 2022, at https://www” https://www.cancer.org/cancer/breast-cancer/about/how-common-is-breast-cancer.html.)
2. National Cancer Institute. Cancer stat facts: female breast cancer subtypes. (Accessed at https://seer” https://seer.cancer.gov/statfacts/html/breast-subtypes.html.)
3. Coates JT, Sun S, Leshchiner I, et al. Parallel genomic alterations of antigen and payload targets mediate polyclonal acquired clinical resistance to sacituzumab govitecan in triple-negative breast cancer. Cancer Discov. 2021;11(10):2436-2445.
4. Vidula N, Yau C, Rugo H. Trophoblast cell surface antigen 2 gene (TACSTD2) expression in primary breast cancer. Breast Cancer Res Treat. 2022;194(3):569-575.
5. Goldenberg DM, Sharkey RM. Sacituzumab govitecan, a novel, third-generation, antibody-drug conjugate (ADC) for cancer therapy. Expert Opin Biol Ther. 2020;20(8):871-885.
6. Trodelvy [sacituzumab govitecan] prescribing information. Gilead Sciences, Inc.; Foster City, CA; 2022.
7. Bardia A, Tolaney SM, Punie K, et al. Biomarker analyses in the phase III ASCENT study of sacituzumab govitecan versus chemotherapy in patients with metastatic triple-negative breast cancer. Ann Oncol. 2021;32(9):1148-1156.
8. Rugo H, Bardia A, Marmé F, et al. Overall survival (OS) results from the phase III TROPiCS-02 study of sacituzumab govitecan (SG) vs treatment of physician’s choice (TPC) in patients (pts) with HR+/HER2- metastatic breast cancer (mBC) [ESMO abstract LBA76]. Ann Oncol. 2022;33(suppl 7).
9. 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.
10. Rugo H, Bardia A, Marmé F, et al. Sacituzumab govitecan (SG) vs treatment of physician’s choice (TPC): efficacy by Trop-2 expression in the TROPiCS-02 study of patients (pts) with HR+/HER2– metastatic breast cancer (mBC). Presented at the 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX. Abstract GS1-11.33
Effect of Sacituzumab Govitecan vs Chemotherapy in HR+/HER2– Metastatic Breast Cancer: Patient-Reported Outcomes From the TROPiCS-02 Trial
Although therapies may improve longevity for patients with HR+/HER2– mBC, their quality of life is also an important consideration. The TROPiCS-02 study assessed patient-reported outcomes (PROs) by means of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) health utility index and the EuroQol 5 Dimension 5 level (EQ-5D-5L) descriptive system and the EQ visual analogue pain scale (EQ VAS).1-3
The Patient Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) measurement system was used to capture patient-reported toxicity symptoms. The frequency of PROs in patients treated with SG was compared with the frequency in those who received the physician’s choice of treatment. Baseline demographics and characteristics were similar in the compared patient groups.
In all, 543 patients participated in the randomized TROPiCS-02 trial, and between 82% and 95% of patients were available for PRO analysis. In the primary domains of the EORTC QLQ-C30, the outcomes of role functioning (HR, 0.92; 95% CI, 0.75-1.14) and pain (HR, 0.92; 95% CI, 0.74–1.14) were similar; however, treatment with SG significantly prolonged the time to deterioration in comparison with the physician’s choice of treatment in terms of global health status/quality of life (HR, 0.74; 95% CI, 0.59-0.91), physical functioning (HR, 0.77; 95% CI, 0.62-0.96), and fatigue (HR, 0.76; 95% CI, 0.62-0.93) (Figure 2).
SG was also associated with a longer time to deterioration in comparison with the physician’s choice of treatment in terms of emotional functioning (HR, 0.67; 95% CI, 0.54-0.84), dyspnea (HR, 0.75; 95% CI, 0.61-0.94), insomnia (HR, 0.77; 95% CI, 0.62-0.97), and financial difficulties (HR, 0.79; 95% CI, 0.62-0.99).
On the EQ VAS, time to deterioration was also significantly longer with the ADC than with the physician’s choice of treatment (HR, 0.79; 95% CI, 0.64-0.98). Results from the PRO-CTCAE questionnaire showed that the proportions of patients with symptom worsening to a score of 3 or 4 were similar in the SG and the physician’s choice of treatment cohorts for decreased appetite, nausea, vomiting, constipation, abdominal pain, shortness of breath, and fatigue. However, study treatment with SG was superior to the physician’s choice of treatment in terms of the frequency of diarrhea (35% vs 11%) and hair loss (71% vs 24%).
References
1. Bardia A, Tolaney SM, Punie K, et al. Biomarker analyses in the phase III ASCENT study of sacituzumab govitecan versus chemotherapy in patients with metastatic triple-negative breast cancer. Ann Oncol. 2021;32(9):1148-1156.
2. Marmé F, Bardia A, Rugo HS, et al. Effect of sacituzumab govitecan vs chemotherapy in HR+/HER2– metastatic breast cancer: patient-reported outcomes from the TROPiCS-02 trial (COMBINE). Presented at the 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX. Abstract GS1-11.
3. Rugo H, Bardia A, Marmé F, et al. Overall survival (OS) results from the phase III TROPiCS-02 study of sacituzumab govitecan (SG) vs treatment of physician’s choice (TPC) in patients (pts) with HR+/HER2– metastatic breast cancer (mBC) [ESMO abstract LBA76]. Ann Oncol. 2022;33(suppl 7).
Trastuzumab Deruxtecan vs Physician’s Choice in Patients With HER2+ Unresectable and/or Metastatic Breast Cancer Previously Treated With Trastuzumab Emtansine: Primary Results of the Randomized Phase 3 Study DESTINY-Breast02
Trastuzumab deruxtecan (T-DXd) is an ADC comprising a humanized anti-HER2 antibody covalently linked to a topoisomerase I inhibitor by a tetrapeptide-based cleavable linker.1-3 Destiny-Breast01, a previously conducted open-label, single-arm, multicenter phase 2 study, evaluated the efficacy of T-DXd in 184 patients with HER2+ mBC who had previously received a median of 6 treatments with trastuzumab emtansine.4,5 The median duration of response was 20.8 months and the median PFS was 19.4 months, results that led to regulatory approvals of the ADC in several countries.
DESTINY-Breast02
Destiny-Breast02 was an open-label, multicenter phase 3 trial designed to evaluate T-DXd vs the physician’s choice of treatment in patients with centrally confirmed HER2+ unresectable or metastatic breast cancer previously treated with trastuzumab emtansine.6 Eligible patients had radiographic evidence of progression after their most recent treatment.
Patients were stratified according to hormone receptor status, prior treatment with pertuzumab, and history of visceral disease. They were then randomly assigned in a 2:1 ratio to receive T-DXd (5.4 mg/kg every 3 weeks) or the physician’s choice of treatment (trastuzumab plus capecitabine or lapatinib plus capecitabine). The primary endpoint was PFS according to blinded independent central review.
In all, 406 patients were assigned to the T-DXd arm and 202 to the comparator arm. The median duration of follow-up was 21.5 months (range, 0.1-45.6) in the T-DXd arm vs 18.6 months (range, 0-45.7) in the physician’s choice of treatment arm. Treatment was ongoing in 94 patients (23.3%) in the T-DXd arm vs 5 patients (2.6%) in the physician’s choice of treatment arm.
In the T-DXd and comparator arms, the primary reasons for discontinuation were disease progression (43.1% vs 72.3%, respectively) and adverse events (AEs; 18.3% vs 7.2%, respectively). Baseline characteristics were well balanced: The patients’ median age was 54.2 to 54.7 years (range, 22.4-88.5). The HER2 status was IHC3+ in the majority of the patients (79%-80%), and 58.4% to 58.6% of the patients had HR+ disease. Visceral metastases were observed in 20.8% to 22.2% of the patients. Patients in both arms had received a median of 2 prior lines of therapy (range, 0-10).
Progression-Free Survival
The trial achieved its primary endpoint, demonstrating a median PFS of 17.8 months (range, 14.3-20.8) with T-DXd vs 6.9 months (range, 5.5-8.4) with the physician’s choice of treatment (HR, 0.3589; 95% CI, 0.2840-0.4535; P<.000001). T-DXd therapy was superior to the physician’s choice of treatment in all subgroups examined (age, hormone receptor status, prior pertuzumab exposure, visceral disease, brain metastases at baseline, number of prior lines of therapy, and performance status) (Figures 3 and 4). Treatment with T-DXd also yielded a superior median OS in comparison with the physician’s choice of treatment (39.2 vs 26.5 months; HR, 0.6575; 95% CI, 0.5023-0.8605; P=.0021). The confirmed objective response rate (ORR) was 69.7% with T-DXd vs 29.2% with the physician’s choice of treatment (P<.0001), with complete response (CR) rates of 14.0% vs 5.0%, respectively.
The median duration of treatment was 11.3 months in the patients who received T-DXd vs approximately 4.5 months in those who received the physician’s choice of treatment. Treatment-emergent AEs of grade 3 or higher were observed in 52.7% of the patients in the T-DXd arm vs 44.1% of those in the comparator arm and were considered drug-related in 41.3% vs 30.8% of patients, respectively. Treatment-emergent AEs were associated with discontinuation of study therapy in 19.8% of patients in the T-DXd arm vs 9.7% in the comparator arm. In the T-DXd arm, AEs of special interest included interstitial lung disease (ILD) and left ventricular dysfunction. Among 404 patients evaluable for safety in the T-DXd arm, 3 patients (0.7%) experienced grade 3 ILD and 2 patients (0.5%) experienced grade 5 ILD. Also in the T-DXd arm, 2 patients (0.5%) experienced a left ventricular dysfunction event of grade 3 or higher.
References
1. Nakada T, Sugihara K, Jikoh T, Abe Y, Agatsuma T. The latest research and development into the antibody-drug conjugate, [fam-] trastuzumab deruxtecan (DS-8201a), for HER2 cancer therapy. Chem Pharm Bull (Tokyo). 2019;67(3):173-185.
2. Ogitani Y, Aida T, Hagihara K, et al. DS-8201a, a novel HER2-targeting ADC with a novel DNA topoisomerase I inhibitor, demonstrates a promising antitumor efficacy with differentiation from T-DM1. Clin Cancer Res. 2016;22(20):5097-5108.
3. Perez J, Garrigós L, Gion M, et al. Trastuzumab deruxtecan in HER2-positive metastatic breast cancer and beyond. Expert Opin Biol Ther. 2021;21(7):811-824.
4. Manich CS, Modi S, Krop I, et al. Trastuzumab deruxtecan (T-DXd) in patients with HER2-positive metastatic breast cancer (MBC): updated survival results from a phase II trial (DESTINY-Breast01) [ESMO abstract 279P]. Ann Oncol. 2021;32(suppl 5).
5. Modi S, Saura C, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med. 2020;382(7):610-621.
6. Krop I, Park YH, Kim SB, et al. Trastuzumab deruxtecan vs physician’s choice in patients with HER2+ unresectable and/or metastatic breast cancer previously treated with trastuzumab emtansine: primary results of the randomized, phase 3 study DESTINY-Breast02. Presented at the 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX. Abstract GS2-01.
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
Breast tumors that express the estrogen receptor (ER) are dependent on estrogen-mediated signaling for growth. The standard first-line therapy for ER+/HER2– mBC is endocrine therapy plus a CDK4/6 inhibitor.1 However, it is common for such tumors to become resistant to this therapy, such as with estrogen receptor 1 (ESR1). Available alternative treatments for hormone-resistant tumors are limited by poor efficacy and significant toxicity.
Elacestrant
Elacestrant is a next-generation selective estrogen receptor disruptor (SERD) that causes degradation of the ER. The EMERALD trial, an open-label, international phase 3 trial, evaluated elacestrant vs standard of care (SOC) in patients with ER+/HER2– advanced breast cancer.2 Eligible patients were men or postmenopausal women who had received prior treatment with a CDK4/6 inhibitor within 1 year before initiation of the chemotherapy regimen. Prior treatment with fulvestrant was allowed.
Patients were randomly assigned to receive oral elacestrant (400 mg daily) or standard endocrine therapy (fulvestrant, anastrozole, letrozole, or exemestane). The researchers sought 2 primary endpoints: PFS in all patients and PFS in patients who had an ESR1 mutation.
Among the 478 randomized patients, 228 had tumors with an ESR1 mutation. Patient baseline characteristics were well balanced between the 2 arms.
Visceral metastasis was noted in 68.2% of patients in the elacestrant arm vs 71.1% of patients in the SOC arm. The percentages of patients who had received prior treatment with fulvestrant were 29.3% in the elacestrant arm vs 31.4% in the SOC arm. The percentages of patients who had received 2 prior lines of endocrine therapy were 46.0% in the elacestrant arm vs 40.6% in the SOC arm; 81% of patients in each arm had received prior treatment with an aromatase inhibitor.
Elacestrant Was Found to Be Significantly More Effective
The researchers found that treatment with elacestrant significantly improved median PFS in comparison with SOC (HR, 0.70; 95% CI, 0.55-0.88; P=.002). Updated results continued to demonstrate superior outcomes with elacestrant vs SOC.3
Median PFS, determined for patient groups based on the duration of prior CDK4/6 inhibitor therapy, showed consistent benefit regardless of the duration of prior CDK4/6 inhibitor therapy (Table 2a, b).
Updated safety data were consistent with prior findings. Most AEs were mild, with no grade-4 treatment-related AEs reported. Treatment discontinuation due to an AE was reported in 3.4% of patients in the elacestrant arm and 0.9% in the SOC arm. No treatment-related death occurred in either arm. No hematologic safety signals arose, and no patient in either arm experienced sinus bradycardia.
References
1. National Comprehensive Cancer Network. NCCN Guidelines: Invasive Breast Cancer. Version 4.2022.
2. Bidard FC, Kaklamani VG, Neven P, et al. Elacestrant (oral selective estrogen receptor degrader) versus standard endocrine therapy for estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: results from the randomized phase III EMERALD trial. J Clin Oncol. 2022;40(28):3246-3256.
3. Bardia A, Bidard FC, Neven P, et al. EMERALD phase 3 trial of elacestrant versus standard of care endocrine therapy in patients with ER+/HER2- metastatic breast cancer: updated results by duration of prior CDK4/6i in metastatic setting. Presented at the 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX. Abstract GS3-01.
Capivasertib and Fulvestrant for Patients With Aromatase Inhibitor–Resistant, Hormone Receptor–Positive/Human Epidermal Growth Factor Receptor 2–Negative Advanced Breast Cancer: Results From the Phase III CAPItello-291 Trial
Tumors with alterations in the phosphatidylinositol-3-kinase (PI3K)/AKT/PTEN pathway are common in patients with advanced HR+/HER2– breast cancer.1 Mutations in this pathway can promote cell proliferation, prevent apoptosis, and confer resistance to treatment.
CAPItello-291 Phase 2
Mutations in AKT are associated with resistance to endocrine therapy. Capivasertib is a potent, selective inhibitor of the 3 AKT isoforms: AKT1, AKT2, and AKT3. CAPItello-291, a double-blind phase 2 trial, evaluated fulvestrant plus capivasertib vs fulvestrant plus placebo in 140 postmenopausal women with HR+/HER2– metastatic or inoperable locally advanced breast cancer that was resistant to aromatase inhibitor therapy.2
Prior therapy with a CDK4/6 inhibitor was not allowed. Median PFS with fulvestrant plus capivasertib was superior to median PFS with fulvestrant plus placebo (10.3 vs 4.8 months; HR, 0.56; 95% CI, 0.38-0.81; P=.0023).3 Median OS was also superior with the capivasertib combination (29.3 vs 23.4 months; HR, 0.66; 95% CI, 0.45-0.97; P=.035). The superiority of the capivasertib combination was more pronounced among patients with alterations in the PI3K/AKT/PTEN pathway.
CAPItello-291 Phase 3
The double-blind phase 3 CAPItello-291 study evaluated fulvestrant plus capivasertib vs fulvestrant plus placebo in patients with HR+/HER2– advanced breast cancer.4 Eligible patients had experienced recurrence during or within 12 months after treatment with an aromatase inhibitor. Participants were allowed to have had 2 or fewer prior lines of endocrine therapy and no or 1 prior line of chemotherapy for advanced breast cancer. Prior treatment with a CDK4/6 inhibitor was allowed. No prior treatment with a SERD, mTOR inhibitor, PI3K inhibitor, or AKT inhibitor was allowed. Patients were stratified on the basis of liver metastases, prior exposure to a CDK4/6 inhibitor, and geographic location, then randomized in a 1:1 ratio.
Patients in both arms received fulvestrant (500 mg on days 1 and 15 of cycle 15, then every 4 weeks). Patients in the experimental arm received capivasertib (400 mg twice daily, 4 days on then 3 days off), and patients in the control arm received matching placebo. Alterations in the PI3K/AKT1/PTEN pathway were determined by next-generation sequencing. The 2 primary endpoints were PFS by investigator assessment in the overall study population and in the subpopulation of patients with at least 1 alteration in PI3K, AKT1, or PTEN.
The CAPItello-291 trial randomly assigned 355 patients to capivasertib plus fulvestrant and 353 patients to placebo plus fulvestrant. The median age of patients the 2 arms was 58 to 59 years (range, 26-90), 99% were female, and the majority (74%-81%) were postmenopausal.
Approximately two-thirds of the patients in each arm had visceral metastases (liver metastases in 43%-44%), and 69% had received prior CDK4/6 inhibitor therapy for advanced or metastatic breast cancer. Alterations in the PI3K/AKT1/PTEN pathway were detected in 43.7% of patients in the capivasertib combination arm vs 38.0% in the placebo control arm.
Evidence for Capivasertib
In the overall population, the median PFS was 7.2 months (95% CI, 5.5-7.4) in the capivasertib-plus-fulvestrant arm vs 3.6 months (95% CI, 2.8-3.7) in the placebo-plus-fulvestrant arm (HR, 0.60; 95% CI, 0.51-0.71; P<.001). Among the patients with alteration in the PI3K/AKT1/PTEN pathway, the median PFS was 7.3 months (95% CI, 5.5-9.0) in the capivasertib-plus-fulvestrant arm vs 3.1 months (95% CI, 2.0-3.7) in the placebo-plus-fulvestrant arm (HR, 0.50; 95% CI, 0.38-0.65; P<.001).
The vast majority of subgroups benefited more from the addition of capivasertib than of placebo to fulvestrant, including patients with liver metastasis (HR, 0.61; 95% CI, 0.48-0.78) and patients with prior exposure to a CDK4/6 inhibitor (HR, 0.62; 95% CI, 0.51-0.75). According to investigator assessment, the ORR in the overall population was 22.9% with capivasertib plus fulvestrant vs 12.2% with placebo plus fulvestrant, with partial responses predominant in both arms (19.2% vs 10.8%, respectively). At 28% maturity overall, the median OS was superior with capivasertib in the overall study population (HR, 0.74; 95% CI, 0.56-0.98) as well as in the population of patients with alteration in the PI3K/AKT1/PTEN pathway (HR, 0.69; 95% CI, 0.45-1.05).
In the capivasertib-plus-fulvestrant arm vs the placebo-plus-fulvestrant arm, serious AEs occurred in 16.1% vs 8.0% of patients, AEs leading to death occurred in 1.1% vs 0.3% of patients, and AEs leading to discontinuation of the study treatment occurred in 13.0% vs 2.3% of patients, respectively. No grade 4 AEs were reported. The most common grade 3 AEs in the capivasertib-plus-fulvestrant arm were diarrhea, rash, and hyperglycemia.
References
1. Toss A, Piacentini F, Cortesi L, et al. Genomic alterations at the basis of treatment resistance in metastatic breast cancer: clinical applications. Oncotarget. 2018;9(60):31606-31619.
2. https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(22)00284-4/fulltex
3. Howell SJ, Casbard A, Carucci M, et al. Fulvestrant plus capivasertib versus placebo after relapse or progression on an aromatase inhibitor in metastatic, oestrogen receptor-positive, HER2-negative breast cancer (FAKTION): overall survival, updated progression-free survival, and expanded biomarker analysis from a randomised, phase 2 trial. Lancet Oncol. 2022;23(7):851-864.
4. Turner NC, Oliveira M, Howell S, et al. Capivasertib and fulvestrant for patients with aromatase inhibitor-resistant hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: results from the Phase III CAPItello-291 trial. Presented at the 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX. Abstract GS3-04.
Trastuzumab Deruxtecan vs Treatment of Physician’s Choice in Patients With HER2-Low Unresectable and/or Metastatic Breast Cancer: Subgroup Analyses From DESTINY-Breast04
Breast cancer tumors with low expression of HER2 by immunohistochemistry (IHC1+), as well as those that are both IHC2+ and HER2– by in situ hybridization, are classified as HER2-low and may respond to HER2-targeted therapy.
DESTINY-Breast04
Destiny-Breast04, an open-label, multicenter phase 3 trial, evaluated the safety and efficacy of T-DXd in patients with unresectable and/or metastatic breast cancer.1,2 Eligible patients had previously received 1 or 2 prior lines of chemotherapy for metastatic disease.
Patients were stratified according to HER2 status, number of prior lines of chemotherapy, and hormone receptor status. Patients with HR+ tumors were stratified on the basis of prior treatment with a CDK4/6 inhibitor, then randomized to receive T-DXd or the physician’s choice of chemotherapy.
Progression-Free Survival Advantage
The trial met its primary endpoint, demonstrating superior median PFS with T-DXd vs chemotherapy in the HR+ cohort of 494 patients (10.1 vs 5.4 months; HR, 0.51; P<.001). Median OS also was superior with T-DXd vs chemotherapy among patients with HR+ disease (23.9 vs 17.5 months; HR, 0.64; P=.003). In the overall study population, treatment with T-DXd was superior to chemotherapy in terms of median PFS (P<.001) and median OS (P=.001).
Subgroup Analyses
The efficacy and safety of T-DXd therapy were further elucidated by the analysis of subgroups based on demographics and disease characteristics.1 The results showed a consistent benefit across subgroups based on prior CDK4/6 exposure (among HR+ patients), disease burden, HER2 IHC status, number of prior lines of chemotherapy, age, presence of central nervous system metastases at baseline, and prior exposure to anthracycline.
Among 348 patients with HR+ disease, median PFS with T-DXd was superior to median PFS with chemotherapy (10.0 vs 5.4 months; HR, 0.55; 95% CI, 0.42-0.74); rapid disease progression, defined as progression within 6 months after completion of a prior course of chemotherapy in early breast cancer, occurred in 22 patients. Among these patients, the proportion with a response was greater in those treated with T-DXd (7/14; 50%) than with chemotherapy (0/8). ORRs were consistently higher across all subgroups with T-DXd vs chemotherapy. Safety analysis revealed similar outcomes in the subgroups of patients who did vs those who did not have prior exposure to a CDK4/6 inhibitor, as well as in the subgroups of patients with a low vs a high burden of disease.
References
1. Harbeck N, Modi S, Jacot W, et al. Trastuzumab deruxtecan vs treatment of physician’s choice in patients with HER2-low unresectable and/or metastatic breast cancer: subgroup analyses from DESTINY-Breast04. Presented at the 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX. Abstract PS-11-01.
2. Modi S, Jacot W, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med. 2022;387(1):9-20
Progress in the Treatment and of Breast Cancer: Increased Survival, Improved Patient Experience, and Advances in Drug Formulation
Data presented at this year’s San Antonio Breast Cancer Symposium® (SABCS) have already started to excite our practice community. The positive results of very large ongoing trials were updated, as were the results of studies of promising new therapies, and various researchers reported on their efforts to improve patient experience and outcomes.
The research findings presented at the SABCS will improve both our clinical practice and the quality of care we deliver to our patients. It was another rich and inspiring meeting.
SABCS 2022
At this year’s meeting, the most significant findings fell into three broad categories:
1) Researchers provided significant updates on ongoing trials, including DESTINY-Breast03, EMERALD, and monarch-E, among others.
2) Findings were presented that challenge existing dogmas. The results of the POSITIVE and RIGHT Choice trials are likely to change the culture of oncology.
3) Significant findings presented on newer agents and targeted therapy options, including camizestrant and capivasertib, demonstrated that patients and clinicians can expect to see improvements in treatment efficacy and the overall patient experience.
Updates
The DESTINY-Breast03 Trial
At last year’s SABCS, preliminary results from this randomized phase 3 trial suggested significantly better progression-free survival (PFS) in patients who received trastuzumab deruxtecan (T-DXd) than in those who received trastuzumab emtansine (T-DM1). Both drug combinations were administered as second-line therapy to patients with metastatic breast cancer (mBC).
At SABCS 2022, we were able to see the significant advantage in overall survival (OS) provided by T-DXd. OS was shown to be significantly extended when this combination was compared with T-DM1 (hazard ratio [HR], 0.64; P=0.0037a,b).
These findings further cement the position of T-DXd as the most effective second-line therapy for patients with mBC. This is very encouraging news.
The EMERALD Trial
Fulvestrant is currently the only selective estrogen-receptor degrader (SERD) approved by the US Food and Drug Administration for patients with hormone receptor–positive mBC. However, the drug is administered as an intramuscular injection, which can be inconvenient for patients and so reduce compliance. Furthermore, fulvestrant is less effective when used as a second-line therapy. As a result, considerable interest has been shown in developing an oral SERD.
The randomized phase 3 EMERALD trial was designed to examine the safety and efficacy of an oral SERD, elacestrant, with that of standard-of-care (SOC) endocrine therapy in the second- and third-line treatment of hormone receptor–positive/human epidermal growth factor receptor 2–negative (HR+/HER2–) mBC. Preliminary results were presented at SACBS 2021. It was clear that elacestrant was associated with improved PFS in comparison with SOC.
Further examination of the PFS curves revealed an initial drop in the curves for both arms followed by separation in the curves in favor of elacestrant, highlighting activity in an “endocrine-sensitive” setting. At SABCS 2022, the team reported trial results by prior duration of CDK 4/6 inhibitor treatment as a surrogate marker of endocrine-sensitive disease. Elacestrant demonstrated longer PFS vs SOC that was positively associated with duration of prior treatment with a CDK4/6 inhibitor, which was more pronounced in ESR1-mutant mBC. (Median PFS was 7.2 months with capivasertib plus fulvestrant and 3.6 months with placebo plus fulvestrant (HR, 0.60; 95% CI, 0.51-0.71; P<0.001), highlighting a potential therapeutic role in this setting. Another oral SERD in advanced development is camizestrant, reviewed later in this summary.
These are the types of advancements that will change the way we practice oncology, and the ways in which patients experience treatment. Instead of having to come to the office or hospital for an intramuscular injection, they will have the convenience of taking an oral medication at home. In addition, these medications appear to be more effective than fulvestrant.
The monarch-E Trial
The randomized phase 3 monarch-E trial had previously demonstrated higher rates of event-free survival (EFS) with adjuvant endocrine therapy plus abemaciclib than with endocrine therapy (ET) in patients with high-risk localized HR+ breast cancer. However, there was some concern regarding whether the EFS curves would continue to remain separate or converge.
At SABCS 2022, the monarch-E researchers reported continued positive results in their 4-year update of the phase 3 trial (PFS, 8.9 vs 1.9 months; HR, 0.41; 95% CI, 0.26-0.63). They demonstrated persistent benefit with abemaciclib plus ET over ET alone as adjuvant treatment for patients with high-risk early breast cancer.
Challenging Traditional Dogmas
Breast Conservation
Traditionally, mastectomy is considered for patients with multiple tumors, but it can be associated with significant morbidity. Researchers examined whether patients with multiple tumors in the breast could be safely treated with lumpectomy rather than mastectomy. They found that lumpectomy was safe and effective. The risk of recurrence proved to be low. Patient satisfaction was significantly improved.
Patients and clinicians can continue to become comfortable with less-radical surgeries, especially when effective adjuvant therapies are used.
The POSITIVE Trial
This study addressed an important question related to pregnancy among breast cancer survivors.
Findings from the POSITIVE study, an international single-arm trial, showed that stopping and restarting ET was safe and effective, and that patients were able to become pregnant.
Safety in the POSITIVE trial was defined as the risk of distant metastases in women who stopped therapy to conceive. The researchers found that from the perspective of distant recurrence, it was safe for these patients to cease ET for as long as 2 years, then restart ET and complete the duration of therapy.
The researchers continue to find that the following strategy is safe, at the proper time and for the proper duration: cease ET, attempt to become pregnant, become pregnant, carry a baby to term, safely deliver the baby, and then resume ET.
The researchers included nearly 10,000 women in their analysis, all of whom were being treated for stage I, II, or III breast cancer. Patients were eligible to pause ET at between month 18 and month 30. Those who chose to pause therapy were able to conceive, deliver a live birth, and resume ET without any increase in the rate of distant recurrence or decrease in survival.
This finding, of course, will come as a great relief to our patients who want to have children. They had previously been discouraged from attempting pregnancy during and after treatment. It gives clinicians greater confidence about holding adjuvant ET in the right patient.
The RIGHT Choice Trial
Traditionally, chemotherapy is recommended for patients with metastatic disease who are in visceral crisis. The RIGHT Choice trial compared ET with ribociclib vs standard chemotherapy as first-line therapy for patients with HR+ mBC having a “visceral crisis” or symptomatic disease. The primary finding was that ET with ribociclib was superior to chemotherapy plus ET for the treatment of patients with metastatic disease. In addition, rates of toxicity were lower in patients who received ET with ribociclib than in those who received chemotherapy.
New Agents
Considerable new data were presented on advances in drug development at SABCS 2022. Here are a few of the standouts.
CAPItello-291 Trial
The randomized phase 3 CAPItello-291 trial evaluated capivasertib plus fulvestrant vs fulvestrant plus placebo as second-line therapy for patients with HR+/HER2– mBC. The study demonstrated significant improvement in PFS with combination therapy (median PFS, 7 60 months; 95% CI, 0.51-0.71; P=0.001.). Diarrhea was the most common adverse effect with capivasertib, and the incidence of hyperglycemia was low.
This is a promising finding from the registration trial and likely will result in regulatory approval of the agent. If approved, another option for endocrine-based combination therapy, besides alpelisib and everolimus, will be available.
Camizestrant
Camizestrant is another oral SERD in clinical development. At SABCS, we saw the results of SERENA-2, a phase 2 randomized clinical trial that compared camizestrant vs fulvestrant as second-line therapy for patients with HR+/HER2– mBC. PFS was significantly better in patients treated with camizestrant than in those who received fulvestrant (median PFS, 17.4 vs 18.6 months; HR, 0.58 [95% CI, 0.41-0.81] and 0.67 [95% CI, 0.48-0.92]; P=0.01), supporting further the efficacy of SERDs.
In All …
It was another year of important news from SABCS 2022. Cancer treatment continues to become more effective for patients, and outcomes continue to improve.
Newer therapies offer more hope for improved clinical outcomes. Oncologists must maintain their efforts to accelerate meaningful research on the treatment of patients with breast cancer.