The use of endocrine therapy as single agents serves as the control arm for many clinical studies seeking to improve upon outcomes with combination regimens and newer agents for patients with HR-positive, HER2-negative advanced breast cancer.
Current reccomendations for the treatment of patients with hormone receptor (HR)–positive/HER2-negative (HR+/HER2–) advanced breast cancer have highlighted the use of endocrine therapy as a significant backbone of treatment in this disease setting.1
Frontline therapy usually consists of an aromatase inhibitor or fulvestrant (Faslodex) plus a CDK4/6 inhibitor, according to an upgraded guideline from the American Society of Clinical Oncology (ASCO). Then in the second and thirdline settings, treatment switches to targeted therapy or chemotherapy with a continued backbone of endocrine therapy (FIGURE2,3).
“If we look at patients after they’ve had a CDK4/6 inhibitor getting single-agent hormonal therapy, the median progression-free survival [PFS] [is approximately] 2.75 months or so…so single-agent activity with hormonal therapy is limited,” Kevin Kalinsky, MD, MS, the Louisa and Rand Glenn Family Chair in Breast Cancer Research and director of breast medical oncology and the Glenn Family Breast Center at the Winship Cancer Institute of Emory University in Atlanta, Georgia, said in an interview with Targeted Therapies in Oncology™ during the 2022 ASCO Annual Meeting.
The use of endocrine therapy as single agents serves as the control arm for many clinical studies seeking to improve upon outcomes with combination regimens and newer agents for patients with HR+/HER2– advanced breast cancer. Oral presentations from the ASCO meeting showed that clinical studies are continuing to show benefits for the use of targeted therapies and immunotherapies over treatment with standard endocrine therapy alone.
“[Over the past several years, we have learned] that the outcome for patients without PIK3CA mutations [who are] treated with single-agent endocrine therapy after disease progression on a CDK4/6 inhibitor is woefully inadequate, with a median PFS of [approximately] 2 to 3 months with fulvestrant alone. Given these findings there has been a focus on developing novel agents as well as interrogating the benefit of continuing CDK4/6 inhibitor upon progression on a prior CDK4/6 inhibitor,” said ASCO discussant Claudine Isaacs, MD, FRCPC, professor of medicine and oncology, associate director of clinical research and leader of the Clinical Breast Cancer Program at the Lombardi Comprehensive Cancer Center at Georgetown University in Washington, DC.
CDK4/6 Inhibitors Treatment with CDK4/6 inhibitors showed mixed survival results in 2 trials of patients with advanced HR+/HER2– breast cancer: PALOMA-2 (NCT01740427) and MAINTAIN (NCT02632045).
In the phase 2 MAINTAIN trial, patients with unresectable or metastatic HR+/HER2– breast cancer who had previously progressed on a prior CDK4/6 inhibitor were randomized to receive ribociclib (Kisqali) and an alternate endocrine therapy or placebo and endocrine therapy.4 Most patients had received palbociclib (Ibrance) as their first CDK4/6 inhibitor plus endocrine therapy and had received up to 1 line of chemotherapy for metastatic disease. In the study, patients in both arms received a different endocrine therapy—fulvestrant if the patient previously progressed on an aromatase inhibitor and exemestane if the patient previously progressed on fulvestrant.
At a median follow-up of 18.2 months, the median PFS in the ribociclib and endocrine therapy arm was 5.29 months (95% CI, 3.02-8.12) compared with 2.76 months (95% CI, 2.66-3.25) with placebo and endocrine therapy (HR, 0.57; 95% CI, 0.39-0.95; P = .006). Twenty percent of patients responded to treatment with ribociclib and endocrine therapy vs 11% on endocrine therapy and placebo (P = .51), and the clinical benefit rate was 43% vs 25%, respectively (P = .06). The median duration of response was 18.8 months (interquartile range [IQR], 11.4-50.2) with ribociclib and endocrine therapy and 14.8 months (IQR, 6.7-21.3) with endocrine therapy and placebo.
The benefit of continuing CDK4/6 inhibition was even seen in a small group of patients who had previously received ribociclib (n= 14; HR, 0.50; 95% CI, 0.15-1.70) compared with those who had previously received palbociclib (n= 103; HR, 0.58; 95% CI, 0.38-0.90).
“In terms of CDK4/6 inhibitor after CDK4/6 inhibitor, it’s promising to see [with] all of those observational data [and] preclinical data [that we are now] seeing this in a randomized trial. This is the first proof-of-principle study demonstrating that there is benefit of CDK4/6 inhibition after CDK4/6 inhibition,” Kalinsky said. He also noted that several larger, randomized trials are continuing to explore this clinical question.
The double-blind phase 3 PALOMA-2 trial randomized patients with estrogen receptor (ER)– positive/HER2-negative (ER+/HER2–) advanced breast cancer to receive first-line therapy with either palbociclib and letrozole (Femara) or letrozole and placebo.5
The median overall survival (OS) in the palbociclib and letrozole arm was 53.9 months (95% CI, 49.8-60.8) compared with 51.2 months (95% CI, 43.7-58.9) for patients who received letrozole monotherapy (n = 222; HR, 0.956; 95% CI, 0.777-1.777; P = .3378). After adjusting for missing survival data, which was significant in both arms of the trial, the median OS for patients treated with the combination was 51.6 months (95% CI, 46.9- 57.1) compared with 44.6 months (95% CI, 37.0-52.3) in the control arm (HR, 0.869; 95% CI, 0.706-1.069).
“The OS is numerically longer with palbociclib and letrozole compared with the control arm, although these results were not statistically significant. However, the median OS of 50 months in this population represents a significant improvement in the natural history of HR-positive breast cancer. Interpretation of OS in PALOMA-2 is limited by the large and disproportionate percentage of patients with missing survival data between the treatment arms,” Richard S. Finn, MD, professor of medicine at the David Geffen School of Medicine at University of California Los Angeles, said in his presentation at the ASCO meeting.
At ASCO, 2 presentations focused on biomarker analyses from studies of targeted therapies in combination with endocrine therapy in previously treated patients with HR+/HER2– breast cancer.
The first was for capivasertib, an investigational inhibitor of 3 isoforms of the serine/threonine kinase AKT, plus fulvestrant compared with fulvestrant and placebo in patients with ER+/ HER2– metastatic or unresectable locally advanced disease in the phase 2 FAKTION trial (NCT01992952). All patients had progressed on an aromatase inhibitor for advanced disease or relapsed on adjuvant aromatase inhibition, had received up to 1 line of chemotherapy for metastatic disease, and had received up to 3 lines of endocrine therapy. However, there was no prior exposure to fulvestrant or PI3K/AKT/mTOR inhibition allowed.6,7
Primary findings from the study with a median follow-up of 4.9 months showed a median PFS of 10.3 months (95% CI, 5.0-13.2) with capivasertib and fulvestrant treatment compared with 4.8 months (95% CI, 3.1-7.7) with fulvestrant alone (unadjusted HR, 0.58; 95% CI, 0.39-0.84; 2-sided P = .0044). Objective responses were observed in 29% of patients in the capivasertib arm and in 8% of patients in the placebo arm (odds ratio [OR], 4.42; 95% CI, 1.65-11.84; 2-sided P = .0031).Clinical benefit was reported in 55% vs 41%, respectively (OR, 1.78; 95% CI, 0.91-3.47; 2-sided P = .093).6
As of the ASCO presentation, OS data were mature, showing a median OS of 29.3 months (95% CI, 23.7-39.0) with capivasertib and fulvestrant in comparison with 23.4 months (95% CI, 18.7-32.7) with fulvestrant and placebo (adjusted HR, 0.66; 95% CI, 0.45-0.97; P = .035).7
Next-generation sequencing was conducted to identify PI3K/AKT/PTEN pathway altered status in the study participants, and alterations were discovered in 25% of tumors that were originally considered to not have alterations in this pathway.
PFS was extended even further in the group of patients with expanded pathway alterations who were treated with capivasertib (median, 12.8 months; 95% CI, 6.6-18.8) vs those who received fulvestrant alone (median, 4.6 months; 95% CI, 2.8- 7.9) (adjusted HR, 0.44; 95% CI, 0.26-0.72; P = .0014). Comparatively, the HR in the nonaltered group was 0.70 (95% CI, 0.40-1.25; P = .23). Median OS in the altered pathway group was 38.9 months (95% CI, 23.3- 50.7) with capivasertib compared with 20.0 months (95% CI, 14.8-31.4) without (adjusted HR, 0.46; 95% CI, 0.27-0.79; P = .005). In the nonaltered pathway group, the HR was 0.86 (95% CI, 0.49-1.52; P = .60) (TABLE7).
In the randomized, double-blind phase 3 SOLAR-1 trial (NCT02437318), alpelisib (Piqray) plus fulvestrant was explored in comparison with fulvestrant and placebo in patients with HR+/HER2– advanced breast cancer who had previously received endocrine therapy.8,9
Primary findings from the study, with a median follow-up of 20 months, showed a median PFS of 11.0 months (95% CI, 7.5- 14.5) in those treated with alpelisib and fulvestrant compared with 5.7 months (95% CI, 3.7-7.4) with fulvestrant monotherapy in patients with PIK3CA mutations (HR, 0.65; 95% CI, 0.50-0.85; P< .001). For those without PIK3CA mutations, the HR was 0.85 (95% CI, 0.58-1.25).8
Exploratory biomarker analyses of the SOLAR-1 trial presented at ASCO showed hypothesis-generating clinical benefit for the alpelisib arm regardless of the presence of an altered MAPK pathway gene, genes implicated in endocrine therapy, or CDK4/6 inhibition resistance. In those with MAPK pathway alterations (ERBB2, NF1, ERBB3, KRAS, EGFR, BRAF, MAP2K1), the median PFS was 10.9 months (95% CI, 5.5-12.7) with alpelisib and fulvestrant compared with 3.6 months (95% CI, 2.1-5.7) with fulvestrant and placebo (HR, 0.43; 95% CI, 0.23-0.80). In the wild-type group, the median PFS was 11.6 months (95% CI, 8.1-19.2) with alpelisib vs 7.2 months (95% CI, 3.7-9.6) without (HR, 0.56; 95% CI, 0.40-0.79).9
Additionally, benefit from the addition of alpelisib was more pronounced in patients with low tumor mutational burden (18.5 months vs 3.2 months with fulvestrant monotherapy; HR, 0.38; 95% CI, 0.21-0.68).
Isaacs suggested that the findings from both studies need to be validated in a patient population with prior CDK4/6 inhibitor exposure. However, both studies did highlight the importance of biomarkers to identify patients who are appropriate candidates for targeted therapies.
Beyond and after the use of endocrine therapy, novel agents are hoping to improve upon the survival outcomes of the more heavily pretreated patients with HR+/ HER2– breast cancer.
In the phase 3 TROPiCS-02 trial (NCT03901339), treatment with the TROP-2–directed antibody-drug conjugate led to sacituzumab govitecan (Trodelvy) and was explored in comparison with investigator’s choice of standard chemotherapy in patients with HR+/HER2– breast cancer who have resistance to endocrine therapy. Patients had received a median of 3 prior lines of chemotherapy in the metastatic setting.10
The median PFS was 5.5 months (95% CI, 4.2-7.0) with sacituzumab govitecan vs 4.0 months (95% CI, 3.1-4.4) with chemotherapy (HR, 0.66; 95% CI, 0.53-0.83; P < .0003). At 12 months, the PFS rates were 21.3% vs 7.1%, respectively. Although OS data were not yet mature at the time of the analysis, a numeric trend was seen favoring the use of the antibody-drug conjugate (stratified HR, 0.84; 95% CI, 0.67-1.06; P = .14).
Hope S. Rugo, MD, FASCO, professor of medicine in the Division of Hematology and Oncology and director of breast oncology and clinical trials education at the University of California San Francisco Helen Diller Family Comprehensive Cancer Center, explained in an interview with Targeted Therapies in Oncology™ that there was a subset of patients with rapid progression in both arms before there was a separation of the curves. In the sacituzumab arm, there was also an improvement in quality-of-life metrics seen compared with the chemotherapy arm.
Overall, she said, the data suggest “sacituzumab has a role in the treatment of heavily pretreated patients with HR+/HER2– metastatic disease.”
1. Pistilli B, Lohrisch C, Sheade J, Fleming GF. Personalizing adjuvant endocrine therapy for early-stage hormone receptor–positive breast cancer. Am Soc Clin Oncol Educ Book. 2022;42:1-13. doi:10.1200/EDBK_350358
2. Burstein HJ, Somerfield MR, Barton DL, et al. Endocrine treatment and targeted therapy for hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer: ASCO guideline update. J Clin Oncol. 2021;39(35):3959-3977. doi:10.1200/JCO.21.01392
3. Isaacs C. Advanced hormone receptor–positive breast cancer: updates and emerging data. Presented at: 2022 ASCO Annual Meeting; June 4-7, 2022; Chicago, IL.
4. Kalinsky K, Accordino MK, Chiuzan C, et al. A randomized, phase II trial of fulvestrant or exemestane with or without ribociclib after progression on anti-estrogen therapy plus cyclin-dependent kinase 4/6 inhibition (CDK 4/6i) in patients (pts) with unresectable or hormone receptor–positive (HR+), HER2-negative metastatic breast cancer (MBC): MAINTAIN trial. J Clin Oncol. 2022;40(suppl 17):LBA1004. doi:10.1200/JCO.2022.40.17_suppl.LBA1004
5. Finn RS, Rugo HS, Dieras VC, et al. Overall survival (OS) with firstline palbociclib plus letrozole (PAL+LET) versus placebo plus letrozole (PBO+LET) in women with estrogen receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer (ER+/ HER2− ABC): analyses from PALOMA-2. J Clin Oncol. 2022;40(suppl 17):LBA1003. doi:10.1200/JCO.2022.40.17_suppl.LBA1003
6. Jones RH, Casbard A, Carucci M, et al. Fulvestrant plus capivasertib versus placebo after relapse or progression on an aromatase inhibitor in metastatic, oestrogen receptor-positive breast cancer (FAKTION): a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol. 2020;21(3):345-357. doi:10.1016/S1470-2045(19)30817-4
7. Jones RH, Casbard AC, Carucci M, et al. Fulvestrant plus capivasertib versus fulvestrant plus placebo after relapse or progression on an aromatase inhibitor in metastatic, estrogen receptor–positive breast cancer (FAKTION): overall survival and updated progression-free survival data with enhanced biomarker analysis. J Clin Oncol. 2022;40(suppl 16):1005. doi:10.1200/JCO.2022.40.16_suppl.1005
8. André F, Ciruelos E, Rubovszky G, et al; SOLAR-1 Study Group. Alpelisib for PIK3CA-mutated, hormone receptor–positive advanced breast cancer. N Engl J Med. 2019;380(20):1929-1940. doi:10.1056/ NEJMoa1813904
9. Juric D, Rugo HS, Reising A, et al. Alpelisib (ALP) + fulvestrant (FUL) in patients (pts) with hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2−) advanced breast cancer (ABC): biomarker (BM) analyses by next-generation sequencing (NGS) from the SOLAR-1 study. J Clin Oncol. 2022;40(suppl 6):1006. doi:10.1200/JCO.2022.40.16_suppl.1006
10. Rugo HS, Bardia A, Marmé F, et al. Primary results from TROPiCS-02: a randomized phase 3 study of sacituzumab govitecan (SG) versus treatment of physician’s choice (TPC) in patients (Pts) with hormone receptor–positive/HER2-negative (HR+/HER2-) advanced breast cancer. J Clin Oncol. 2022;40(suppl 17):LBA1001. doi:10.1200/JCO.2022.40.17_suppl.LBA1001