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Last updated: June 22, 2026
CDK4 and CDK6 (cyclin-dependent kinases 4 and 6) are serine/threonine kinases that, in complex with D-type cyclins (cyclin D1, D2, D3), phosphorylate the retinoblastoma (Rb) tumor suppressor protein. Phosphorylated Rb releases the E2F transcription factor, which drives the cell from G1 phase into S phase of the cell cycle. In hormone receptor-positive (ER+) breast cancer, estrogen receptor signaling upregulates cyclin D1 and creates a strong dependency on the cyclin D — CDK4/6 — Rb axis for proliferation.
A CDK4/6 inhibitor is a small-molecule oral drug that:
In ER+/HER2- breast cancer, CDK4/6 inhibitors combined with endocrine therapy (aromatase inhibitor or fulvestrant) approximately double progression-free survival vs endocrine therapy alone in the metastatic setting (PALOMA-2/-3, MONALEESA-2/-3/-7, MONARCH-2/-3). The adjuvant trials — monarchE (abemaciclib, FDA 2021) and NATALEE (ribociclib, FDA 2024) — extended this benefit into high-risk early-stage HR+/HER2- breast cancer, making CDK4/6 inhibitors part of curative-intent therapy for the first time.
| Drug | Sponsor | Class | Regulatory Status | Trials in Corpus |
|---|---|---|---|---|
| Palbociclib (Ibrance, PD-0332991) | Pfizer | CDK4/6i (first-in-class) | FDA Feb 2015: HR+/HER2- 1L metastatic breast (PALOMA-2/-3). | 97 trials (13 Phase 3) |
| Ribociclib (Kisqali, LEE011) | Novartis | CDK4/6i | FDA Mar 2017: HR+/HER2- 1L metastatic (MONALEESA-2/-3/-7). FDA Sep 2024: adjuvant high-risk early breast (NATALEE). | 88 trials (16 Phase 3) |
| Abemaciclib (Verzenio, LY2835219) | Eli Lilly | CDK4/6i (continuous dosing) | FDA Sep 2017: HR+/HER2- 2L+ metastatic (MONARCH-2/-3) + 3L+ monotherapy (MONARCH-1). FDA Oct 2021: adjuvant high-risk early breast (monarchE) — the first adjuvant CDK4/6i. | 109 trials (13 Phase 3) |
| Dalpiciclib (SHR6390) | Jiangsu Hengrui | CDK4/6i | NMPA-approved 2023 (China). China-led HR+/HER2- breast Phase 3 program. Not FDA-approved. | 33 trials (5 Phase 3) |
| Trilaciclib (Cosela, G1T28) | G1 Therapeutics | CDK4/6i (transient HSPC arrest for chemoprotection) | FDA Feb 2021: proactive myelopreservation prior to chemo in ES-SCLC. Distinct mechanism: protects bone marrow, not anti-tumor. | 21 trials (1 Phase 3) |
| PF-07220060 | Pfizer | Next-gen CDK4-selective | Investigational. CDK4-selective design intended to escape the CDK6-driven hematologic toxicity of pan-CDK4/6 inhibitors. | 3 trials (Phase 1/2) |
Other agents (lerociclib, birociclib) had zero RECRUITING trials in the June 2026 corpus and are listed for completeness only.
The first-in-class CDK4/6 inhibitor. FDA February 2015 for HR+/HER2- advanced/metastatic breast cancer in combination with an aromatase inhibitor (1L) or fulvestrant (2L), based on PALOMA-2 (palbociclib + letrozole 1L) and PALOMA-3 (palbociclib + fulvestrant post-endocrine progression). Dosed 125 mg daily on a 21-days-on / 7-days-off schedule. Dominant toxicity is neutropenia (frequently grade 3-4 but rarely febrile). Notably, palbociclib failed to meet its adjuvant primary endpoint (PALLAS, PENELOPE-B) and is the only one of the three breast CDK4/6 inhibitors without an adjuvant indication. Key Phase 3 trials in the corpus: NCT06377852 (The CDK4/6 Inhibitor Dosing Knowledge / CDK Study, optimizing CDK4/6i dosing in metastatic breast); NCT04966481 (palbociclib + cetuximab vs cetuximab monotherapy in CDKN2A-altered HPV-unrelated head and neck squamous cell carcinoma — the most advanced cross-cancer Phase 3 in the CDK4/6 class); NCT06748222 (E-Mindfulness adjunct quality-of-life Phase 3 in breast cancer patients).
Novartis's CDK4/6 inhibitor. FDA March 2017 for HR+/HER2- advanced/metastatic breast cancer in combination with an aromatase inhibitor (MONALEESA-2/-3 postmenopausal, MONALEESA-7 premenopausal). Dosed 600 mg daily on a 21-days-on / 7-days-off schedule. Distinct safety profile: QTc prolongation (ECG monitoring required at baseline, day 14 of cycle 1, and start of cycle 2) and hepatic-function monitoring. FDA September 2024: adjuvant treatment of HR+/HER2- node-positive high-risk early breast cancer in combination with an aromatase inhibitor, based on the NATALEE trial — the second adjuvant CDK4/6 inhibitor after monarchE. Key Phase 3 trials in the corpus: NCT07085767 (palazestrant + ribociclib as 1L treatment of ER+/HER2- advanced breast); NCT07647328 (camizestrant + ribociclib Phase IIIb in ER+/HER2- advanced breast); NCT05827081 (Phase IIIb ribociclib + endocrine therapy in early breast cancer); NCT07237256 (chemotherapy de-escalation in HR+/HER2- intermediate-risk early breast with adjuvant ribociclib); NCT05952557 (CAMBRIA-2, camizestrant adjuvant endocrine-based therapy in ER+/HER2- early breast); NCT07391774 (ribociclib monotherapy vs chemotherapy then ribociclib in stage II breast); NCT07340658 (Letrozole SIE vs Femara® combined with ribociclib in advanced metastatic breast); NCT07400523 (ribociclib in HR+/HER2- early breast with residual disease after neoadjuvant chemotherapy).
Eli Lilly's CDK4/6 inhibitor. FDA September 2017 for HR+/HER2- advanced/metastatic breast cancer in combination with fulvestrant (MONARCH-2) or as monotherapy after endocrine + chemo (MONARCH-1, 3L+). Differentiated by continuous dosing (no 7-day break), which reflects higher CDK4 vs CDK6 selectivity and a profile dominated by diarrhea (manageable with loperamide + dose adjustment) and venous thromboembolism rather than neutropenia. FDA October 2021: adjuvant treatment of HR+/HER2- node-positive high-risk early breast cancer based on the monarchE trial — the first adjuvant CDK4/6 inhibitor (preceded ribociclib's NATALEE adjuvant approval by ~3 years). Key Phase 3 trials in the corpus: NCT06341621 (chemotherapy omission with extended adjuvant abemaciclib in 1-3 positive lymph nodes); NCT07190443 (AURA / JCOG2313, adjuvant abemaciclib for locoregional recurrence of HR+/HER2- breast); NCT05696626 (lasofoxifene + abemaciclib vs fulvestrant + abemaciclib in metastatic ER+/HER2- post-CDK4/6i); NCT04862663 (CAPItello-292, capivasertib + CDK4/6i + fulvestrant in HR+/HER2- advanced/metastatic breast).
Jiangsu Hengrui's oral CDK4/6 inhibitor, NMPA-approved in China (2023) for HR+/HER2- advanced breast cancer in combination with endocrine therapy. Not FDA-approved. Dalpiciclib anchors a substantial China-led Phase 3 program with 33 trials in the corpus (5 Phase 3), positioned as a domestic alternative to palbociclib / ribociclib / abemaciclib in China and as a combination partner in HER2+ and resistant breast cancer settings. Key Phase 3 trials in the corpus: NCT07354022 (HRS-8080 + dalpiciclib in advanced/metastatic breast cancer resistant to prior endocrine + CDK4/6i); NCT07615751 (pyrotinib + trastuzumab + dalpiciclib vs pyrotinib + trastuzumab + docetaxel in advanced HER2-positive breast cancer — an unusual triple combination of HER2-targeted + HER2 monoclonal antibody + CDK4/6i).
G1 Therapeutics's CDK4/6 inhibitor with a fundamentally different clinical use case. FDA February 2021 for proactive myelopreservation in adults receiving chemotherapy for extensive-stage small cell lung cancer (ES-SCLC). Mechanism: trilaciclib is given before chemotherapy, transiently arresting hematopoietic stem and progenitor cells (HSPCs) in G1 phase so that cytotoxic chemotherapy (which preferentially kills cycling cells) spares them — reducing chemo-induced neutropenia, anemia, and thrombocytopenia. SCLC cells are Rb-null and therefore not affected by trilaciclib's CDK4/6 block, which preserves chemotherapy's anti-tumor activity. The current Phase 3 in the corpus: NCT07473128 (trilaciclib for the prevention of myelosuppression in limited-stage SCLC — extending Cosela's existing ES-SCLC label to LS-SCLC).
The 350 recruiting (and 108 not-yet-recruiting) CDK4/6 inhibitor trials are grouped below by clinical setting. By far the largest disease is HR+/HER2- breast cancer (45 of the 67 Phase 3 trials), but the class is now expanding into adjuvant disease, post-CDK4/6i salvage, biomarker-stratified non-breast indications (CDKN2A, PIK3CA), and the unique myelopreservation use case of trilaciclib.
CDK4/6i + aromatase inhibitor (letrozole or anastrozole) was the foundational 1L combination from PALOMA-2 / MONALEESA-2 / MONARCH-3. The current Phase 3 wave is replacing the AI partner with an oral selective estrogen receptor degrader (oral SERD), primarily palazestrant, camizestrant, and giredestrant, to improve depth and duration of ER blockade.
After 1L progression on CDK4/6i + AI, the landscape is biomarker-stratified: PIK3CA-mutant tumors get capivasertib (CAPItello-291) or inavolisib (INAVO120); ESR1-mutant tumors get elacestrant (Orserdu); and a major question is whether to continue CDK4/6i past progression with a different partner.
monarchE (abemaciclib, FDA Oct 2021) and NATALEE (ribociclib, FDA Sep 2024) established CDK4/6 inhibitors as part of curative-intent adjuvant therapy in HR+/HER2- node-positive high-risk early breast cancer. The current Phase 3 frontier is twofold: chemo de-escalation / omission using adjuvant CDK4/6i intensification, and oral SERD + CDK4/6i adjuvant (CAMBRIA-2).
Beyond HR+/HER2- breast, biomarker-driven CDK4/6 dependency is now being tested in Phase 3 in CDKN2A-altered head and neck cancer and via combination programs in mCRPC. These are some of the first true cross-cancer CDK4/6 inhibitor Phase 3 trials.
Trilaciclib is a CDK4/6 inhibitor by molecular class but a chemoprotectant by clinical use. Given before chemotherapy, it transiently arrests HSPCs in G1 so cytotoxic chemo spares them. Tumor cells with intact Rb pathway lose this protection; SCLC (Rb-null) is unaffected.
Showing curated Phase 3 highlights from 350 RECRUITING + 108 not-yet-recruiting CDK4/6 inhibitor interventional trials in the ClinTrialFinder corpus as of June 22, 2026 (67 Phase 3 across the class; per-disease Phase 3 breakdown: breast 45, prostate 1, head and neck 1, SCLC 1, other 2). For the latest searches: palbociclib, ribociclib, abemaciclib, dalpiciclib, trilaciclib.
Resistance to CDK4/6 inhibitors is now a major clinical problem — almost all 1L metastatic patients eventually progress on CDK4/6i + endocrine therapy. Known resistance mechanisms include:
Next-generation strategies in the corpus include:
An emerging area is CDK2/4/6 combination inhibition, on the rationale that CDK2 activation is a common bypass mechanism downstream of CDK4/6 inhibition.
What is a CDK4/6 inhibitor and how does it work?
CDK4 and CDK6 are kinases that, with D-type cyclins, phosphorylate the Rb tumor suppressor protein to drive the cell from G1 phase into S phase of the cell cycle. In ER+/HER2- breast cancer, estrogen receptor signaling upregulates cyclin D1 and creates strong dependency on the cyclin D–CDK4/6–Rb axis. A CDK4/6 inhibitor blocks the ATP-binding pocket of CDK4 and CDK6, holds Rb hypophosphorylated, and arrests the cancer cell in G1. CDK4/6 inhibitors require an intact Rb pathway (Rb-null tumors are resistant). Combined with endocrine therapy, they approximately double progression-free survival in HR+/HER2- metastatic breast cancer (PALOMA, MONALEESA, MONARCH), and monarchE + NATALEE extended this benefit into adjuvant high-risk early breast.
Which CDK4/6 inhibitors are FDA-approved?
Palbociclib (Ibrance, Pfizer): FDA Feb 2015 HR+/HER2- 1L metastatic (PALOMA-2/-3) — first-in-class. Ribociclib (Kisqali, Novartis): FDA Mar 2017 HR+/HER2- 1L metastatic (MONALEESA-2/-3/-7); FDA Sep 2024 adjuvant high-risk early breast (NATALEE) — second adjuvant CDK4/6i. Abemaciclib (Verzenio, Eli Lilly): FDA Sep 2017 HR+/HER2- 2L+ metastatic (MONARCH-2) + 3L+ monotherapy (MONARCH-1); FDA Oct 2021 adjuvant high-risk early breast (monarchE) — first adjuvant CDK4/6i. Trilaciclib (Cosela, G1 Therapeutics): FDA Feb 2021 myelopreservation during chemo in ES-SCLC (chemoprotectant, not anti-tumor). Dalpiciclib (SHR6390, Hengrui) is NMPA-approved (China) but not FDA-approved. Consult current FDA prescribing information.
What's the difference between Ibrance, Kisqali, and Verzenio?
Dosing schedule: palbociclib + ribociclib 21-days-on / 7-days-off; abemaciclib continuous (higher CDK4-selectivity, lower hematologic toxicity). Adverse-event profile: palbociclib dominant neutropenia (grade 3-4 frequent, febrile rare); ribociclib neutropenia + QTc prolongation (ECG monitoring required) + hepatic function monitoring; abemaciclib diarrhea + VTE + less neutropenia. Adjuvant approval: only abemaciclib (Oct 2021, monarchE) and ribociclib (Sep 2024, NATALEE) are FDA-approved in high-risk early-breast-cancer adjuvant — palbociclib's adjuvant trials (PALLAS, PENELOPE-B) failed their primary endpoints. For 1L metastatic HR+/HER2-, all three are appropriate choices in combination with an aromatase inhibitor; tolerability and AE preference often guide selection.
What new combinations are entering Phase 3 with CDK4/6 inhibitors?
Oral SERD + CDK4/6i 1L metastatic: palazestrant + ribociclib (NCT07085767), camizestrant + ribociclib (NCT07647328 CAMBRIA Phase IIIb; NCT05952557 CAMBRIA-2 adjuvant), palazestrant vs SoC + CDK4/6i (NCT06016738), giredestrant vs fulvestrant + CDK4/6i (NCT06065748). PI3K/AKT + CDK4/6i: inavolisib + CDK4/6i + letrozole PIK3CA-mutant (NCT06790693); tersolisib + CDK4/6i (NCT07174336); CAPItello-292 capivasertib + CDK4/6i + fulvestrant (NCT04862663). Adjuvant chemo de-escalation: extended adjuvant abemaciclib 1-3 nodes (NCT06341621); ribociclib chemo de-escalation (NCT07237256); Cinnamon chemo-omission (NCT07432178).
What happens after CDK4/6i progression? What are the post-CDK4/6i options?
After 1L CDK4/6i + AI/fulvestrant progression in HR+/HER2- metastatic, options are biomarker-stratified. ESR1-mutant: elacestrant (Orserdu) monotherapy is FDA-approved; elacestrant + everolimus in Phase 3. PIK3CA-mutant: capivasertib + fulvestrant (FDA CAPItello-291) and inavolisib + palbociclib + fulvestrant (FDA INAVO120); mutant-selective tersolisib in Phase 3. Continuing CDK4/6i past progression: lasofoxifene + abemaciclib and CAPItello-292 capivasertib + CDK4/6i + fulvestrant. ADC options: sacituzumab govitecan (Trodelvy) and datopotamab deruxtecan (Datroway) are FDA-approved in 2L+/3L+ HR+/HER2- after endocrine + chemo, and Sac-TMT is in Phase 3 — see /mechanisms/trop2-adcs for the TROP2 ADC hub.
Are CDK4/6 inhibitors being studied in cancers outside HR+/HER2- breast?
Yes. The most advanced cross-cancer Phase 3 is NCT04966481 — palbociclib + cetuximab vs cetuximab in CDKN2A-altered HPV-unrelated head and neck squamous cell carcinoma, using CDKN2A (p16) loss as a molecular biomarker for CDK4/6 dependence. In mCRPC, Pfizer is running NCT06629779 for mevrometostat (PF-06821497, EZH2 inhibitor) which is co-developed alongside CDK4/6i partner strategies. Trilaciclib (Cosela) is FDA-approved for myelopreservation during chemo in ES-SCLC and is in Phase 3 (NCT07473128) to extend that label to LS-SCLC — this is a fundamentally different mechanism (chemoprotection of bone marrow, not anti-tumor). Beyond these, Phase 1/2 work continues in mantle cell lymphoma, liposarcoma (CDK4-amplified), low-grade glioma, and combination with KRAS G12C inhibitors — see /mechanisms/kras-inhibitors.
Find Matching CDK4/6 Inhibitor Trials
Use ClinTrialFinder's AI-powered matching to find palbociclib (Ibrance), ribociclib (Kisqali), abemaciclib (Verzenio), dalpiciclib, trilaciclib (Cosela), and next-generation CDK4/6 inhibitor trials based on your cancer type, HR/HER2 status, biomarker profile (PIK3CA, ESR1, CDKN2A), prior CDK4/6i exposure, and country.
Find Matching CDK4/6 Inhibitor TrialsThis page is for information only and is not medical advice. ClinTrialFinder helps you find clinical trials that may match your situation, but enrollment decisions and treatment choices should always be made with your medical oncologist. Trial eligibility, recruitment status, and treatment details can change — verify directly with the trial sponsor or on ClinicalTrials.gov before acting on any information here. FDA approval dates and indications are summarized for context only; consult the current FDA prescribing information for each drug for authoritative regulatory status.