Unlocking Latest Insights Into HR-Positive, HER2-Negative Treatment Strategies

Publication
Article
Targeted Therapies in OncologyJune 02, 2024
Volume 13
Issue 8
Pages: 26

Recent approvals herald novel strategies for addressing advanced or metastatic breast cancer with ESR1 mutations.

CDK4/6 inhibitors mark a substantial stride in the treatment of hormone receptor (HR)–positive, HER2-negative breast cancer. However, the focus on optimizing outcomes centers on their combination with aromatase inhibitors. Recent approvals herald novel strategies for addressing advanced or metastatic breast cancer with ESR1 mutations. These pivotal updates were shared by William J. Gradishar, MD, during the National Comprehensive Cancer Network 2024 Annual Conference.1

“I’m going to touch on different issues in advanced disease regarding CDK4/6 inhibitors and the nuances of where we can use these drugs [before] and after disease progression. We’ll look at some new therapies that have become available and those we anticipate will be available [mentioned below] and how we incorporate mutational status in our decision-making,” Gradishar said.

Gradishar is the Betsy Bramsen professor of breast oncology, professor of medicine, and chief in the Division of Hematology and Medical Oncology at the Feinberg School of Medicine at Northwestern University. He is also deputy director for the clinical network and director of the Maggie Daley Center for Women’s Cancer Care at the Robert H. Lurie Comprehensive Cancer Center in Chicago, Illinois.

CDK4/6 Inhibitors

There are 3 CDK4/6 inhibitors currently available for metastatic disease in the first- and second-line settings: abemaciclib (Verzenio), palbociclib (Ibrance), and ribociclib (Kisqali). “If you look at data across the PALOMA[-2] trial [NCT01740427], the MONALEESA trials [NCT01958021, NCT02278120, NCT02422615], and the MONARCH trials [NCT02246621, NCT02107703], there is a consistency in the results that is quite striking,” Gradishar began. These trial results were consistent across the board specifically regarding the progression-free survival rates (PFS) and overall response rate (ORR) in the f irst-line setting and again in the second-line setting, all improving overall outcomes. The ORR rates in the first line were primarily in the 50% range across agents and, for the second-line setting, in the 40% range for abemaciclib and ribociclib. The PFS rates in the first line were primarily in the 20% range (P = .0001).

As a result, these drugs are used in the first-line setting and 2 agents have emerged as producing the most survival benefit, ribociclib and abemaciclib, Gradishar explained.

Furthermore, patients do well for a longer duration and many of the therapies are impacting PFS.

Gradishar explained that a CDK4/6 inhibitor is often combined with an aromatase inhibitor (AI). However, there has been some debate about whether patients on adjuvant endocrine therapy with an AI, who later experience disease progression within a short time frame, might benefit more from a different combination. Investigators in the phase 2 PARSIFAL trial (NCT02491983) evaluated this by assessing whether fulvestrant (Faslodex) or letrozole (Femara) was the optimal endocrine partner for palbociclib in patients with untreated, endocrine-sensitive HR-positive/ HER2-negative advanced breast cancer.2 There is “completely overlapping outcome with respect to PFS; it made no difference whatsoever,” Gradishar stated.

Chemotherapy, when compared with palbociclib plus hormone therapy, was also addressed. As shown by the data from the PEARL study (NCT02028507), there was no difference reported in overall survival (OS): 31.1 months for chemotherapy vs 32.8 months for palbociclib plus hormone therapy.3 In the ESR1 wild-type population, the PFS was also overlapping and conveyed no difference with using the same regimens. The data are similar according to the phase 2 Young Pearl study (NCT02592746), suggesting “that you do not need to feel compelled to go forward with chemotherapy,” Gradishar said.1,4

Sequential Therapy

A question that remains unresolved is whether sequential CDK4/6 inhibitor therapy is effective. The phase 2 MAINTAIN trial (NCT02632045) data showed some improvement with ribociclib followed by endocrine therapy (n = 4) vs placebo followed by endocrine therapy (n=119). The median PFS was 5.29 months in the treatment arm vs 2.76 months with placebo (hazard ratio, 0.57; 95% CI, 0.39-0.95; P = .006).5 Included were patients with HR-positive, HER2-negative metastatic breast cancer who progressed during endocrine therapy and CDK4/6 inhibitor. It showed that there was a “signal suggesting that there may be a subset of patients where the use of sequential CDK4/6 inhibitors may offer some modest benefit,” Gradishar said.

“At the American Society of Clinical Oncology [ASCO] Annual Meeting 2024 we will hear results from the [phase 3] postMONARCH trial [NCT05169567], which is for patients who have progressed on a CDK4/6 inhibitor and are randomly assigned to fulvestrant plus or minus abemaciclib.… We’ll see what these results are, but the collective takeaway is that it is not routine to use sequential CDK4/6 inhibitors yet,” Gradishar said.

Pathways

Regarding targeting the PIK3CA, AKT, and mTOR pathway, Gradishar addressed the phase 3 SOLAR-1 trial (NCT02437318) data that showed there was no benefit adding alpelisib (Piqray) with wild-type PIK3CA; however, if the patient has a PIK3CA mutation, there was an additional benefit with adding alpelisib to endocrine therapy.6 The median PFS was approximately 2 months in wild-type populations, but for those with a PIK3CA mutation, it doubled from 5 to 11 months.

In the phase 3 CAPItello-291 trial (NCT04305496), patients with HR-positive, HER2-negative disease were randomly assigned to receive capivasertib with fulvestrant or placebo with fulvestrant.7 The agent appeared to be only effective in patients with an altered pathway, Gradishar said. The median PFS for patients with AKT pathway–altered tumors receiving the experimental treatment was 7.3 months vs 3.1 months in those in the control arm of the study (hazard ratio, 0.50; 95% CI, 0.38-0.65; P =.001). The OR was trending positively but not yet statistically significant, Gradishar explained. In those with a PIK3CA alteration, the median PFS was 5.6 months vs 2.1 months, respectively, with an adjusted hazard ratio of 0.51 (95% CI, 0.37-0.70). For patients with a PTEN alteration, the median PFS was 9.1 months (range, 5.5-11.1) vs 3.6 (range, 1.8-6.7), respectively (hazard ratio, 0.43; 95% CI, 0.21-0.88).

In the phase 2/3 INAVO120 trial (NCT04191499), investigators evaluated a triplet combination that included inavolisib, palbociclib, and fulvestrant (n=161) vs placebo with palbociclib and fulvestrant (n=164).8 The patients included in the trial had PIK3CA- mutated, HR-positive, HER2- negative disease.

The ORR for the experimental treatment arm was 58.4% vs 25.0% in the control arm and the clinical benefit rate was 75.2% vs 47.0%, respectively. The median PFS was significantly improved from 7.3 months to 15 months with a stratified hazard ratio of 0.43 (P = .0001). T his suggests that for a patient who harbors a PIK3CA mutation, there may be some benefit with triplet therapy at the onset, then sequential treatment with a CDK4/6 inhibitor and following with a PIK3CA inhibitor, Gradishar said. However, the median OS is not yet reached.

ESR1 Mutations

The phase 3 EMERALD trial (NCT03778931), which included patients with estrogen receptor– positive HER2-negative metastatic breast cancer, evaluated elacestrant (Orserdu) vs investigator’s choice of AI or fulvestrant and showed an incremental PFS improvement with elacestrant.9 The longer the patient was taking a prior CDK4/6, the longer the PFS is with elacestrant compared with standard of care, Gradishar said.1

“Where the field is headed is toward a grouping of oral SERDs [selective estrogen receptor degraders],” Gradishar said, briefly addressing agents currently in development in the early stage setting as well as the metastatic setting, which include camizestrant, giredestrant, and imlunestrant.

“Many [of these agents] have shown activity in patients who harbor ESR mutations and are likely to be combined with other endocrine therapy. They are reflected in the National Comprehensive Cancer Network guidelines and ASCO guidelines detailing where we use these drugs and how we think about implementing and incorporating these drugs into treatment plans,” Gradishar concluded.

REFERENCES:
1. Gradishar W. Updates to the management of HR-positive, HER2-negative breast cancer. April 6, 2024. Accessed May 12, 2024. https://tinyurl.com/3bunmnut
2. Llombart-Cussac A, Pérez-García JM, Bellet M, et al. Fulvestrant-palbociclib vs letrozole-palbociclib as initial therapy for endocrine-sensitive, hormone receptor-positive, ERBB2-negative advanced breast cancer: a randomized clinical trial. JAMA Oncol. 2021;7(12):1791-1799. doi:10.1001/ jamaoncol.2021.4301
3. Martín M, Zielinski C, Ruiz-Borrego M, et al. Overall survival with palbociclib plus endocrine therapy versus capecitabine in postmenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer in the PEARL study. Eur J Cancer. 2022;168:12-24. doi:10.1016/j. ejca.2022.03.006
4. Lee S, Im SA, Kim GM, et al. Patient-reported outcomes of palbociclib plus exemestane with GnRH agonist versus capecitabine in premenopausal women with hormone receptor-positive metastatic breast cancer: a prospective, open-label, randomized phase II trial (KCSGBR 15-10). Cancers (Basel). 2020;12(11):3265. doi:10.3390/ cancers12113265
5. Kalinsky K, Accordino MK, Chiuzan C, et al. Randomized phase II trial of endocrine therapy with or without ribociclib after progression on cyclin-dependent kinase 4/6 inhibition in hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer: MAINTAIN trial. J Clin Oncol. 2023;41(24):4004-4013. doi:10.1200/ JCO.22.02392
6. André F, Ciruelos EM, Juric D, et al. Alpelisib plus fulvestrant for PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: final overall survival results from SOLAR-1. Ann Oncol. 2021;32(2):208-217. doi:10.1016/j. annonc.2020.11.011
7. Turner NC, Oliveira M, Howell SJ, et al. Capivasertib in hormone receptor-positive advanced breast cancer. N Engl J Med. 2023;388(22):2058-2070. doi:10.1056/NEJMoa2214131
8. Turner N, Jhaveri K, Kalinsky K, et al. 355TiP phase III study of GDC-0077 or placebo (pbo) with palbociclib (P) + fulvestrant (F) in patients (pts) with PIK3CA-mutant/ hormone receptor-positive/HER2-negative locally advanced or metastatic breast cancer (HR+/HER2– LA/MBC). Ann Oncol. 2020;31(suppl 4):S391-S392. doi:10.1016/j.annonc.2020.08.457
9. 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. doi:10.1200/ JCO.22.00338
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