Next Generation of CDK Inhibitors Are Breaking Ground in HER2– Breast Cancer

The next generation of CDK inhibitors have hit the ground running, with recent data in advanced solid tumors demonstrating the early efficacy of inhibitors such as BLU-222 targeting CDK2 as well as PF-07220060 targeting CDK4.^1,2

The first-in-class next-generation CDK4-selective inhibitor, PF-07220060, in combination with endocrine therapy (ET), showed encouraging clinical efficacy and a favorable safety profile in patients with hormone receptor (HR)–positive, HER2-negative metastatic breast cancer, according to data from a phase 1/2a trial (NCT04557449) presented at the 2024 European Society for Medical Oncology Breast Cancer Annual Congress. Treatment with the novel oral inhibitor, which has a significant sparing of CDK6, plus ET elicited a median progression-free survival of 8.1 months (95% CI, 5.3-10.9) in patients treated in parts 1B and 1C of the study (n = 33); patients in part 1B received PF-07220060 at 300 or 400 mg twice daily in combination with letrozole and in part 1C in combination with fulvestrant (Faslodex). The disease control rate was 81.8%, and 21.2% of patients experienced partial responses and 1 patient (3%) had a complete response.¹

“There’s a new generation of CDK4 and CDK6 inhibitors being developed that may have better antitumor activity and may be more selective for targeting CDK4, which is believed to be mediating most of the antitumor effect of CDK4/6 inhibitors,” Joseph A. Sparano, MD, said in an interview with OncologyLive. Sparano is the Ezra M. Greenspan, M.D. Professor in Clinical Cancer Therapeutics, chief of the Division of Hematology Oncology, and deputy director of the Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai in New York, New York. He is also the 2024 Giants of Cancer Care® recipient in the Breast Cancer category.

The data from the phase 1/2 study support an ongoing phase 3 trial (NCT06105632) evaluating PF-07220060 plus fulvestrant vs investigator’s choice of therapy in patients with HR-positive, HER2-negative advanced or metastatic breast cancer who experienced disease progression on prior CDK4/6 inhibitor–based therapy.

Findings from the trial also revealed that patients with ESR1 mutations (n = 15) experienced an objective response rate (ORR) of 26.7% (95% CI, 7.8%-55.1%) compared with 40.0% (95% CI, 12.2%-73.8%) among those without ESR1 mutations (n = 10) when treated with the CDK4 inhibitor plus ET. Patients with at least 1 PIK3CA, AKT1, or PTEN mutation (n = 10) achieved an ORR of 40.0% (95% CI, 12.2%-73.8%) compared with 26.7% (95% CI, 7.8%-55.1%) among those without one of the aforementioned mutations (n = 15). The treatment was well tolerated overall, with no grade 4 or higher treatment-related treatment-emergent adverse effects (TEAEs) observed. A serious treatment-related TEAE of nausea also occurred in 1 patient.

CDK2 Plus CDK4/6 Inhibition Shows Potential

As data suggest that the overexpression of cyclin A/E-CDK2 complex disrupts normal cell cycle regulation, which leads to uncontrolled proliferation of cancer cells, agents targeting CDK2 are of particular interest with the new wave of CDK inhibitors. Investigators have also noted that research should focus on the optimization of the selectivity, potency, and pharmacokinetics of CDK2 inhibitors as well as proteolysis-targeting chimeras (PROTACs).²

Findings from the phase 1/2 VELA trial (NCT05252416) presented at the 2024 American Society of Clinical Oncology Annual Meeting were the first to show the successful combination of a selective CDK2 inhibitor with an approved CDK4/6 inhibitor. Safety data revealed BLU-222—an oral, potent, highly selective CDK2 inhibitor—was well tolerated as monotherapy in patients with heavily pretreated advanced solid tumors as well as in combination with ribociclib (Kisqali) with fulvestrant in patients with HR-positive, HER2-negative breast cancer. No dose-limiting toxicities were seen with the combination in patients with breast cancer, and there were no BLU-222–related dose discontinuations in this patient population.³

An ongoing dose escalation and optimization portion of the trial is currently enrolling patients to receive BLU-222 in combination with 400 or 600 mg of ribociclib with fulvestrant. Dose confirmation cohorts for the regimen with ribociclib and letrozole are also planned (Figure).^1,3,4

Looking to the Future With PROTAC-Based Therapy

“Promising therapeutic strategies include a host of new antiestrogenic therapies based on different mechanisms of action such as PROTACs, estrogen receptor antagonists, and other agents that can more effectively target tumors that have developed acquired resistance to antiestrogen therapy,” Sparano explained.

The novel PROTAC protein degrader vepdegestrant (ARV-471) received fast track designation in February 2024 from the FDA for the treatment of patients with ER-positive, HER2-negative locally advanced or metastatic breast cancer previously treated with endocrine-based therapy, and the ongoing phase 3 VERITAC-2 trial (NCT05654623) will examine the agent vs fulvestrant in patients who previously received ET-based therapy.⁵

The oral PROTAC agent has a unique mechanism of action that harnesses the ubiquitin-proteasome system to induce degradation of the ER.4 In the phase 1b portion of a phase 1/2 study (NCT04072952), treatment with vepdegestrant plus the CDK4/6 inhibitor palbociclib (Ibrance) resulted in a 63.0% (95% CI, 47.5%-76.8%) clinical benefit rate for patients (n = 46) with ER-positive, HER2-negative advanced breast cancer who had previously received ET with or without a CDK4/6 inhibitor. Patients (n = 31) achieved an ORR of 41.9% (95% CI, 24.5%-60.9%).⁶

Vepdegestrant will be combined with the investigational CDK4-selective inhibitor PF-07220060 in the phase 1b/2 TACTIVE-K study (NCT06206837), which is currently enrolling patients. Preclinical models examining the combination showed it effectively suppressed tumor growth at a greater extent than either agent did as monotherapy.⁴

Another novel development surrounding biomarkers centers on prognostic tools, according to Sparano. “We’re now beginning to see prognostic tools developed that integrate both the prognostic and predictive information provided by biomarkers, with clinical pathologic features that provide prognostic information for distant recurrence,” he explained. “[This] can help [us] make more informed decisions regarding adjuvant therapy recommendations.”

Examining What’s New but Focusing on What’s Available Now

As therapies such as novel CDK inhibitors are generating excitement, “Predictive Biomarker Testing,” “Biology of Breast Pathogenesis and Key Molecular Pathways,” and “Germline Mutations and Management Issues” will be sessions of interest at the upcoming 22nd Annual School of Breast Oncology meeting held by Physicians’ Education Resource from November 6 to 9, 2024, in Atlanta, Georgia.⁷

Physicians including Sparano will gather to discuss not only exciting agents under development but also treatment approaches for available therapies and best practices.

In his presentation “The Art and Science of Managing Metastatic Breast Cancer,” Sparano will review the mechanistic basis for the efficacy of agents that have established clinical activity so that “clinicians have a much better understanding of why these drugs are benefiting patients and are associated with their [particular] clinical benefits and AEs.” He also noted that he will focus on the evolving evidence supporting the use of immunotherapy for the treatment of patients with localized triple-negative breast cancer in his second presentation “Considerations in Systemic Therapy for Early-Stage Triple-Negative Breast Cancer.”

Sparano added that this is especially relevant now as there are “emerging [data] from the phase 3 KEYNOTE-522 trial [NCT03036488] that pembrolizumab [Keytruda] added to chemotherapy can improve not only event-free survival but overall survival. The key challenge for the use of these agents in early-stage localized disease is the spectrum of immune-related AEs that develop, some of which can occur early and be potentially life-threatening, others of which can occur later and be chronic and require lifelong therapeutic interventions to address.”

In addition to immunotherapy in triple-negative disease, in the breast cancer treatment landscape, he’s keeping his eye on “broadly, the next generation of CDK4/6 inhibitors, antiestrogenic agents, and agents targeting the PI3K/AKT/mTOR pathway as well as antibody-drug conjugates targeting a variety of therapeutic targets.”

References

1. Yap TA, Sharma MR, Hamilton EP, et al. First-in-human phase I/IIa study of the first-in-class, next-generation CDK4-selective inhibitor PF-07220060 in combination with endocrine therapy (ET) in patients (pts) with HR+/HER2- metastatic breast cancer (mBC) who progressed on prior CDK4/6 inhibitors (CDK4/6i): safety and efficacy update. Abstract presented at: 2024 European Society for Medical Oncology Breast Cancer Annual Congress; May 15-17, 2024; Berlin, Germany. Abstract 184MO.
2. Zeng Y, Ren X, Jin P, et al. Inhibitors and PROTACs of CDK2: challenges and opportunities. Expert Opin Drug Discov. Published online July 12, 2024. doi:10.1080/17460441.2024.2376655
3. Juric D, Patel MR, Duska LR, et al. BLU-222, an investigational, oral, potent, and highly selective CDK2 inhibitor (CDK2i), as monotherapy in patients (pts) with advanced solid tumors and in combination with ribociclib (RIBO) and fulvestrant (FUL) in HR+/HER2− breast cancer (BC). J Clin Oncol. 2024;42(suppl 16):1056. doi:10.1200/JCO.2024.42.16_suppl.1056
4. Telli ML, Gawryletz CD, Wei M, et al. TACTIVE-K: phase 1b/2 study of vepdegestrant, a proteolysis targeting chimera (PROTAC) estrogen receptor (ER) degrader, in combination with PF-07220060, a cyclin-dependent kinase (CDK)4 inhibitor, in ER+/human epidermal growth factor receptor 2 (HER2)- advanced breast cancer. J Clin Oncol. 2024;42(suppl 16):TPS1131. doi:10.1200/JCO.2024.42.16_suppl.TPS1131
5. Arvinas and Pfizer’s vepdegestrant (ARV-471) receives FDA fast track designation for the treatment of patients with ER+/HER2- metastatic breast cancer. News release. Arvinas Inc. February 6, 2024. Accessed August 2, 2024.
6. Hamilton E, Hurvitz SA, McAndrew NP, et al. Vepdegestrant, a proteolysis targeting chimera (PROTAC) estrogen receptor (ER) degrader, plus palbociclib (palbo) in ER+/human epidermal growth factor receptor 2 (HER2)- advanced breast cancer: updated phase Ib cohort results. Abstract presented at: 2024 European Society for Medical Oncology Breast Cancer Annual Congress; May 15-17, 2024; Berlin, Germany. Abstract 218P.
7. Twenty-Second Annual School of Breast Oncology. Physicians’ Education Resource. Accessed August 2, 2024. bit.ly/4fvHoml