Dealing With Progression in HR+/HER2– mBC: Could a CDK4/6 Inhibitor Swap be the Solution?

Sarah Sammons, MDeft

As the treatment arsenal for patients with hormone receptor (HR)–positive, HER2-negative metastatic breast cancer expands, data surrounding switching the CDK4/6 inhibitor and endocrine therapy backbone as well as novel PI3K agents under development, are helping to clarify how to best treat patients, according to Sarah Sammons, MD.

Data aiding in the decision of whether to switch the CDK4/6 inhibitor and endocrine therapy backbone first came from the phase 2 MAINTAIN trial (NCT02632045). Findings revealed that patients who switched endocrine therapy and received ribociclib (Kisqali) vs placebo following previous treatment with a CDK4/6 inhibitor and different endocrine therapy experienced a statistically significant progression-free survival (PFS) benefit (HR, 0.57; 95% CI, 0.39-0.85; P = .006).¹

Further, data from the phase 3 postMONARCH trial (NCT05169567) presented at the 2024 ASCO Annual Meeting were the first to show the benefit of continued CDK4/6 inhibition beyond progression with abemaciclib (Verzenio) plus fulvestrant (Faslodex) in a phase 3, randomized, placebo-controlled setting. Findings from the trial’s primary analysis showed that patients treated with the combination (n = 182) achieved a median investigator-assessed PFS of 6.0 months (95% CI, 5.6-8.6) vs 5.3 months (95% CI, 3.7-5.6) for patients treated with placebo plus fulvestrant (n = 186; HR, 0.73; 95% CI, 0.57-0.95; nominal P =.02).²

Additional data from the phase 2 PACE trial (NCT03147287) showed that adding palbociclib (Ibrance) to fulvestrant did not improve PFS vs fulvestrant alone in patients who experienced disease progression on a previous CDK4/6 inhibitor plus an aromatase inhibitor (AI). However, triplet therapy with the addition of avelumab (Bavencio) did improve PFS vs fulvestrant alone.³

In an interview with OncLive®, Sammons, a medical oncologist and associate director of the Metastatic Breast Cancer Program at Dana-Farber Cancer Institute in Boston, Massachusetts, detailed her interpretation of the data and additional research on PI3K inhibitors in HR-positive, HER2-negative metastatic breast cancer.

In a concurrent interview, Sammons highlighted how she treats patients who experienced disease progression on CDK4/6 inhibitors in this setting; she dove into her rationale for treatment selection when treating patients with and without genetic alterations.

OncLive: What are considerations for switching the CDK4/6 inhibitor and endocrine therapy backbone during treatment?

Sammons: The question of changing the CDK4/6 inhibitor and endocrine therapy backbone has now been answered in 3 [recent] studies. The studies that have looked at moving from an AI plus a CDK4/6 inhibitor to fulvestrant plus a CDK4/6 inhibitor are 2 smaller phase 2 studies—PACE and MAINTAIN.

PACE was a negative trial. Going from an AI [plus] palbociclib to fulvestrant and continuing the palbociclib was not effective. That’s not a strategy that we should take. The MAINTAIN trial looked at going from an AI plus palbociclib to fulvestrant plus ribociclib. It was a small phase 2 study of approximately 100 patients, but there was some advantage to switching from palbociclib to ribociclib. That could be an option for some patients, but now we have phase 3 data that are positive, which trump the phase 2 data.

postMONARCH looked at fulvestrant plus abemaciclib vs fulvestrant alone in patients who mostly had prior [treatment with] palbociclib or ribociclib. There was a statistically significant improvement in PFS that was a bit smaller than we would have hoped for. But intriguingly benefits were seen regardless of subtype [as well as] genomic status, and a blinded independent central review of PFS [showed] the benefit [also] seemed to be a bit larger [with the combination compared with fulvestrant alone].

The body of data with postMONARCH shows that abemaciclib plus fulvestrant could be an option for patients who experience progression after palbociclib, ribociclib, and an AI. But this space is getting very complex, we have a lot of options, and we need to be rigorous with evaluating the data and talking to our patients about the options.

What new research or agents will help to advance care for patients with HR-positive, HER2-negative metastatic breast cancer?

One of the main challenges with targeting the PI3K/AKT/mTOR pathway has been the adverse effects [AEs] that our patients experience. We’re always trying to do better with targeted therapies, both in terms of their efficacy and tolerability. There are a variety of mutation-specific PI3K inhibitors out there. The main toxicities experienced from PI3K inhibitors are due to inhibition of the wild-type receptor, which causes hyperglycemia, rash, and renal issues. There are some companies out there that are developing drugs that can specifically target the [mutation] pocket.

One drug that I’m excited about, and in full disclosure I’m helping develop it in clinical trials, is RLY-2608. It’s an allosteric inhibitor that is mutation-specific and it’s supposed to spare more of the wild-type receptor. The published results have shown good efficacy and favorable safety. I don’t believe we’re ever going to find a PI3K inhibitor that has no AEs, but minimizing them as much as possible is in line with our goals and patients’ goals.

There’s also LOXO-783 which is a PI3Kα H1047R inhibitor and STX-478, which is a mutant and PI3Kα isoform-selective inhibitor. I’m excited about these selective inhibitors, mostly because I’m hopeful for the day when these drugs will be a bit more tolerable for our patients [and] have either similar or improved efficacy.

References

1. 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
2. Kalinsky K, Bianchini G, Hamilton EP, et al. Abemaciclib plus fulvestrant vs fulvestrant alone for HR+, HER2- advanced breast cancer following progression on a prior CDK4/6 inhibitor plus endocrine therapy: primary outcome of the phase 3 postMONARCH trial.J Clin Oncol. 2024;42(suppl 17):LBA1001. doi:10.1200/JCO.2024.42.17_suppl.LBA1001
3. Mayer EL, Ren Y, Wagle N, et al. PACE: a randomized phase II study of fulvestrant, palbociclib, and avelumab after progression on cyclin-dependent kinase 4/6 inhibitor and aromatase inhibitor for hormone receptor–positive/human epidermal growth factor receptor–negative metastatic breast cancer. J Clin Oncol. 2024;42(17):2050-2060. doi:10.1200/JCO.23.01940