Beyond CDK4/6 Inhibitors in Metastatic Breast Cancer: What’s Next?

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Because of their well-established efficacy, inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) are the standard of care in the treatment of hormone receptor–positive, HER2-negative metastatic breast cancer. The question now is this: after disease progresses on a CDK4/6 inhibitor and endocrine therapy, what should be the next move?

Sara A. Hurvitz, MD

Sara A. Hurvitz, MD

The latest findings to inform this question were presented by Sara A. Hurvitz, MD, Professor of Medicine, University of California, Los Angeles, Jonsson Comprehensive Cancer Center, at Physicians’ Education Resource’s (PER) Miami Breast Cancer Conference, presented virtually this year.1

Though CDK4/6 inhibitors have significantly improved outcomes, patients invariably experience disease progression. Acquired resistance is an obstacle to treatment. When upregulated, the PI3K/AKT/mTOR pathway is a key factor in this process, Dr. Hurvitz said.

Targeting PIK3CA Mutations

In the SAFIR02 trial, 28% of patients with hormone receptor–positive, HER2-negative metastatic breast cancer harbored PIK3CA mutations in their primary tumors, most of them in exon 9 or 20.2 These patients had lower rates of response and stable disease, higher rates of disease progression, and worse overall survival (median = 19.6 vs 23.5 months for wild-type disease; P = .04). The data showed that PIK3CA mutation is prognostic, she said.

BOLERO-2 was the first randomized trial to validate the benefit of targeting the PI3K/AKT/mTOR pathway.3 It also led to the approval of a PI3K pathway inhibitor, specifically one targeting mTOR: everolimus. Analysis of tumor tissue or circulating tumor cell DNA (ctDNA) showed that everolimus plus exemestane was effective in both PIK3CA-mutated and wild-type tumors, with median progression-free survival times of around 7 months in each vs 3 months with placebo.4 It is important to note, however, that these samples were from patients naive to a CDK4/6 inhibitor, she said.

Assessing the benefit of everolimus in patients previously treated with a CDK4/6 inhibitor was one aim of the retrospective Italian EVERMET study.5 Patients received everolimus plus exemestane either as first-line treatment or in a subsequent line that either did or did not include a CDK4/6 inhibitor.

“It’s not unexpected that patients treated with this regimen in the first line had the best progression-free survival (median of almost 12 months), but what’s interesting is that progression-free survival was fairly similar whether patients’ prior treatment was CDK4/6 inhibitor–based or not (medians of approximately 5 and 7 months, respectively),” she reported. “These findings indicated support for using everolimus after disease progression on a CDK4/6 inhibitor, but, of course, these data are retrospective and hypothesis-generating only.”

The second PI3K pathway inhibitor to be approved was the alpha-selective inhibitor alpelisib. SOLAR-1, the pivotal trial that evaluated alpelisib, enrolled patients regardless of mutation status.6 In the subset of patients with PIK3CA mutations, median progression-free survival was 11.0 months with alpelisib plus fulvestrant vs 5.7 months with fulvestrant alone (hazard ratio [HR] = 0.56; P = .00065); no benefit was shown in patients with wild-type disease. “This finding was a little different from that of BOLERO-2, where the benefit of everolimus was seen regardless of PIK3CA mutation status,” she noted.

Overall survival was not improved, though an encouraging trend was shown. Most notably, in patients with visceral metastases, “an interesting separation of the curves” favored alpelisib,7 she added. “This generated support for using alpelisib in these high-risk patients.”

Testing for PIK3CA: Start With Plasma

It is important, therefore, to test for the PIK3CA mutation, first by ordering an assay on plasma, but then “reflex testing” the tumor if the results in plasma are negative, Dr. Hurvitz advised. This recommendation is based on a SOLAR-1 biomarker analysis finding discordance between PIK3CA detection in ctDNA vs tumor tissue.8 Of 188 patients with wild-type tumors by plasma ctDNA, 38% were subsequently found to have a mutation by tumor testing, and these patients benefited from alpelisib. “This means that up to 40% of patients could miss out on treatment with alpelisib if we relied only on ctDNA,” she emphasized.

It was important to evaluate the efficacy of alpelisib in patients with disease progression on a CDK4/6 inhibitor. Although only 6% of the SOLAR-1 population included such patients, the subsequent BYLieve trial did include a large proportion of patients with disease progression after a CDK4/6 inhibitor.9,10 If the endocrine partner was an aromatase inhibitor, the patients received alpelisib plus fulvestrant (cohort A); if it was fulvestrant, they received alpelisib plus letrozole (cohort B).

The primary endpoint—6-month progression-free survival—was met in both cohorts. The percentage of patients alive without progressive disease at 6 months was 50.4% in cohort A and 46.1% in cohort B; median progression-free survival was, respectively, 7.3 and 5.7 months. Cohort A met the primary endpoint, with more than 50% of patients alive without disease progression at 6 months.

“The findings lend support to using alpelisib after treatment with a CDK4/6 inhibitor,” she said. “It was reassuring to see that the results compare nicely with those of SOLAR-1 (44% alive without disease progression at 6 months), where most patients were CDK inhibitor–naive.”

Newer studies have combined PI3K inhibitors with CDK4/6 inhibitors and endocrine therapy, but toxicity has made these efforts challenging.

Other Targets

Other studies are evaluating ways to target AKT in this pathway. In the randomized phase II FAKTION trial, capivasertib plus fulvestrant was compared with fulvestrant alone in patients resistant to aromatase inhibitors.11 Median progression-free survival was 10.3 months vs 4.8 months (HR = 0.58; P = .0044), and median overall survival was 26.0 vs 20.0 months, respectively (HR = 0.59; P = .071). The phase III CAPItello-291 trial of this promising combination is now underway.

Other studies are showing that the results are not as good when the AKT inhibitor is combined with paclitaxel rather than an endocrine agent, including the phase I/II BEECH trial of capivasertib plus paclitaxel12 and the phase III IPATunity130 study of ipatasertib plus paclitaxel.13 In both studies, the combinations failed to improve progression-free survival over paclitaxel alone. “If we are going to hit AKT in hormone receptor–positive breast cancer, we should probably use an endocrine partner and not chemotherapy,” she commented.

HER2 Mutations

HER2 mutations may also prove to be a good target in estrogen receptor–positive breast cancer. An arm of the SUMMIT basket trial evaluated neratinib plus trastuzumab and fulvestrant mostly in patients who had received prior fulvestrant and a CDK4/6 inhibitor.14 The response rate was 46%, and median progression-free survival was 8.3 months, with some patients experiencing remissions beyond 144 weeks. The study provides support for using a tyrosine kinase inhibitor in patients with HER2 mutations, according to Dr. Hurvitz.

An ongoing phase II study is evaluating tucatinib plus trastuzumab (and fulvestrant if hormone receptor–positive) in HER2-mutated tumors, as a second-line or later treatment. If the combination is effective and causes less diarrhea than neratinib, the study will validate the strategy of targeting HER2 mutations with a drug that is better tolerated, she said.

ESR1 Mutations

ESR1 mutations also crop up during the course of therapy,” she continued. “In contrast to PIK3CA mutations, which do not appear to be acquired with treatment, we do see acquisition of ESR1 mutations after CDK inhibitor therapy.” According to data from several trials, ESR1 mutations are observed in more than one-quarter of patients with hormone receptor–positive, HER2-negative disease that progresses on inhibitors of CDK4/6, PI3K, or mTOR.

The phase III PRADA-1 study, which involved 1,017 patients treated in the first line with an aromatase inhibitor plus palbociclib, showed how these mutations can be acquired and how treatment, when it is effective, may clear them.15 Patients underwent cell-free DNA testing for ESR1 mutations upon enrollment and during treatment. At baseline, 3% of patients had an ESR1 mutation, but it did impact prognosis: their median progression-free survival was 11.0 months vs 26.7 months for patients without mutations (HR = 2.3; P < .001). Interestingly, for patients who cleared those mutations early in the course of treatment, median progression-free survival rose to 24.1 months, rivaling their wild-type counterparts. PRADA-1 is evaluating the impact of switching the endocrine agent to fulvestrant for patients who develop an ESR1 mutation but have not yet had disease progression.

Other Novel Approaches

Many different agents are being evaluated as oral selective estrogen receptor degraders. Additionally, there are many other “honorable mentions,” she said, including histone deacetylase (HDAC) inhibitors and BCL2 inhibitors.

Although the HDAC inhibitor entinostat has proved to be disappointing, positive results were recently reported for tucidinostat.16 Also encouraging are early results seen with the BCL2 inhibitor venetoclax, which is effective in certain blood cancers. BCL2 is an antiapoptotic protein that is overexpressed in more than 80% of primary estrogen receptor–positive tumors.

In a phase Ib trial, venetoclax plus tamoxifen led to clinical benefit rates of 62% to 100% in patients previously treated with tamoxifen, CDK4/6 inhibitors, or everolimus (plus endocrine therapy).17 The ongoing phase II VERONICA trial will evaluate venetoclax plus fulvestrant after CDK4/6 inhibitor therapy, stratifying patients by high vs low BCL2 expression.

Antibody-drug conjugates such as sacituzumab govitecan-hziy are also being evaluated in clinical trials, as are combinations that include immunotherapy and fibroblast growth factor inhibitors. 

DISCLOSURE: Dr. Hurvitz has an immediate family member who holds stock or other ownership interests in Ideal Implant and ROMTech; has received institutional research funding from Ambrx, Amgen, Astra Zeneca, Arvinas, Bayer, Cytomx, Daiichi-Sankyo, Genentech/Roche, Gilead, GSK, Immunomedics, Lilly, Macrogenics, Novartis, Pfizer, OBI Pharma, Pieris, PUMA, Radius, Sanofi, Seattle Genetics, Dignitana, Zymeworks, and Phoenix Molecular Designs, Ltd.; and has been reimbursed for travel accommodations by Lilly.


1. Hurvitz S: Metastatic ER+ breast cancer: Beyond CDK4/6 inhibition. 2021 Miami Breast Cancer Conference. Presented March 5, 2021.

2. Mosele F, Stefanovska B, Lusque A, et al: Outcome and molecular landscape of patients with PIK3CA-mutated metastatic breast cancer. Ann Oncol 31:377-386, 2020.

3. Hortobagyi GN, Chen D, Piccart M, et al:Correlative analysis of genetic alterations and everolimus benefit in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: Results from BOLERO-2. J Clin Oncol 34:419-426, 2016.

4. Moynahan ME, Chen D, He W, et al: Correlation between PIK3CA mutations in cell-free DNA and everolimus efficacy in HR+, HER2- advanced breast cancer: Results from BOLERO-2. Br J Cancer 116:726-730, 2017.

5. Nichetti F, Marra A, Giorgi CA, et al: Efficacy of everolimus plus exemestane in CDK 4/6 inhibitors-pretreated or naive HR-positive/HER2-negative breast cancer patients: A secondary analysis of the EVERMET study. ESMO Virtual Congress 2020. Abstract 337P. Presented September 17, 2020.

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 32:208-217, 2021.

7. Andre F, Ciruelos E, Rubovszky G, et al: Overall survival results from SOLAR-1, a phase III study of alpelisib plus fulvestrant for hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. ESMO Virtual Congress 2020. Abstract LBA18. Presented September 19, 2020.

8. Ciruelos EM, Loibl S, Mayer IA, et al: Clinical outcomes of alpelisib plus fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer with PIK3CA alterations detected in plasma ctDNA by next-generation sequencing: Biomarker analysis from the SOLAR-1 study. 2020 San Antonio Breast Cancer Symposium. Abstract PD2-06. Presented December 9, 2020.

9. Rugo HS, Lerebours F, Ciruelos E, et al: Alpelisib + fulvestrant in patients with PIK3CA-mutated hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer previously treated with cyclin-dependent kinase 4/6 inhibitor + aromatase inhibitor: BYLieve study results. ASCO20 Virtual Scientific Program. Abstract 1006. Presented May 29, 2020.

10. Rugo HS, Lerebours F, Juric D, et al: Alpelisib + letrozole in patients with PIK3CA-mutated, hormone-receptor positive, human epidermal growth factor receptor-2-negative advanced breast cancer previously treated with a cyclin-dependent kinase 4/6 inhibitor + fulvestrant: BYLieve study results. 2020 San Antonio Breast Cancer Symposium. Abstract PD2-07. Presented December 9, 2020.

11. 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, randomized, controlled, phase 2 trial. Lancet Oncol 21:345-357, 2020.

12. Turner NC, Alarcón E, Armstrong AC, et al: BEECH: A dose-finding run-in followed by a randomised phase II study assessing the efficacy of AKT inhibitor capivasertib (AZD5363) combined with paclitaxel in patients with estrogen receptor-positive advanced or metastatic breast cancer, and in a PIK3CA mutant sub-population. Ann Oncol 30:774-780, 2019.

13. Turner N, Dent R, O’Shaughnessy J, et al: Ipatasertib + paclitaxel for PIK3CA/AKT1/PTEN-altered hormone receptor-positive HER2-negative advanced breast cancer: Primary results from Cohort B of the IPATunity130 randomised phase III trial. ESMO Virtual Congress 2020. Abstract 283MO. Presented September 18, 2020.

14. Jhaveri K, Saura C, Guerrero-Zotano A, et al: Latest findings from the breast cancer cohort in SUMMIT: A phase 2 ‘basket’ trial of neratinib + trastuzumab + fulvestrant for HER2-mutant, hormone receptor-positive, metastatic breast cancer. 2020 San Antonio Breast Cancer Symposium. Abstract PD1-05. Presented December 9, 2020.

15. Bidard FC, Callens C, Dalenc F, et al: Prognostic impact of ESR1 mutations in ER+ HER2- MBC patients with prior treatment with first-line AI and palbociclib: An exploratory analysis of the PRADA-1 trial. ASCO20 Virtual Scientific Program. Abstract 1010. Presented May 30, 2020.

16. Jiang Z, Li W, Hu X, et al: Tucidinostat plus exemestane for postmenopausal patients with advanced, hormone receptor-positive breast cancer (ACE): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 20:806-815, 2019.

17. Lok SW, Whittle JR, Vaillant F, et al: A phase Ib dose-escalation and expansion study of the BCL2 inhibitor venetoclax combined with tamoxifen in ER and BCL2-positive metastatic breast cancer. Cancer Discov 9:354-369, 2019.