Progression following CDK4/6 inhibitors remains a significant clinical challenge in patients with estrogen receptor-positive (ER+)/HER2-negative (HER2–) breast cancer—and questions about how to treat these patients persist.

At the 2025 San Antonio Breast Cancer Symposium in San Antonio, Texas, Shom Goel, MBBS, PhD, from the Peter MacCallum Cancer Centre, in Melbourne, Australia, discussed emerging agents designed to overcome CDK4/6 inhibitor resistance, with specific attention to CDK4, CDK2, and CDK7 overexpression and targeting the G1 cell cycle.

The G1 Cell Cycle and ER+/HER2– Metastatic Breast Cancer

G1 refers to the G1 phase of the cell cycle, which is exactly where CDK4/6 inhibitors and many of the emerging agents are acting. The G1 phase of the cell cycle is comprised of 4 main parts: G1 (Gap 1) involves initial cellular growth, signal sensing, and cell division; S (Synthesis) is responsible for DNA replication; and G2 (Gap 2) prepares cells for mitosis—the final phase in the cell-cycle.¹

In ER+/HER2– breast cancer, estrogen receptor (ER) signaling, cyclin D and CDK4/6 work together to phosphorylate the retinoblastoma protein (RB), causing the cell to advance past the G1 restriction point and enter the S phase. CDK4/6 inhibitors given with endocrine therapy (ET) block CDK4/6-mediated RB phosphorylation, keeping RB in its active, growth-suppressive state and arresting cells in G1 to prevent uncontrolled proliferation.¹

In resistant tumors, G1 control is bypassed by cyclin D upregulation, causing an overactivation of CDK4/6 even in the presence of an inhibitor. In conjunction, cyclin E upregulation activates CDK2, a powerful driver of the transition between the G1 and S cell-cycle phases., which phosphorylates RB. Upstream pathway changes, such as PI3K/AKT or growth factor signaling, also feed into cyclin D/E and G1 regulation.¹

“And so, our task trying to reverse this resistance is to think of new ways to prevent that phosphorylation again and pull RB back into this active state,” explained Goel. “Essentially, the cancer cells are in a tug of war and the battleground here is RB phosphorylation. Whether we win or lose will determine whether the cancer cell will stop or go.”¹

Most of the emerging agents designed to overcome CDK4/6 resistance are targeting proteins that control the G1 to S cell-cycle transition. These novel agents more selectively target CDK4, as well as other cyclins including CDK2 and CDK7.¹

CDK4 Inhibitors

CDK4 is a G1‑phase cell‑cycle kinase that partners with cyclin D to phosphorylate RB and inactivate its tumor‑suppressor function, allowing cells to pass the G1 to S checkpoint and replicate DNA. The antitumor benefit of current CDK4/6 inhibitors is believed to come from CDK4 inhibition; thereby, selective, deep CDK4 inhibition can deepen G1–S blockade while sparing CDK6 for more sustained CDK4 suppression.¹

Atirmociclib (PF-07220060; Pfizer) is an investigational oral agent with greater selectively for CDK4 over CDK6 to restore cell-cycle regulation. Because most of the antitumor effects in ER+ disease are believed to arise from CDK4 inhibition, strategies that achieve deeper and more sustained CDK4 blockade may offer greater therapeutic benefit. Additionally, targeting CDK4 more selectively and sparing CDK6 can also help reduce instances of neutropenia, allowing for higher dosing and more sustained inhibition of the truly relevant target.¹

Atirmociclib showed promising capabilities in a phase 1/2 trial (NCT04557449)² evaluating atirmociclib in combination with fulvestrant (Faslodex; AstraZeneca) and letrozole in heavily pretreated patients who progressed following CDK4/6 inhibitor.¹

The data showed that combining atirmociclib with fulvestrant and letrozole yielded a clinically meaningful objective response rate (ORR) of 32%. The safety profile was also favorable, with significantly lower instances of grade 3 neutropenia compared with conventional CDK4/6 inhibitors such as ribociclib (Kisqali; Novartis).¹

The trial also assessed atirmociclib and letrozole in the first‑line for patients with endocrine‑sensitive metastatic ER+/HER2– disease in a separate cohort. These outcomes were also promising. Patients treated with the triplet showed an approximate 70% ORR and 91% of patients had no progression, no relapse, no treatment-ending toxicity, and were still alive at 1 year. Again, lower rates of grade 3 neutropenia than expected with some existing CDK4/6 inhibitors.¹

When to Use CDK4 Inhibitors

Beyond the availability of such drugs, understanding when to use agents is even more critical to encourage optimal patient outcomes. In his presentation, Goel outlined 3 main theoretical positions for atirmociclib in first-, second-, and later-line settings.¹

In the first line, it may be more beneficial to target CDK4 more aggressively upfront to reduce cell-cycle expression and address tumor heterogeneity. However, currently approved CDK4/6 inhibitors ribociclib, abemaciclib (Verzenio; Eli Lilly), and palbociclib (Ibrance; Pfizer) demonstrate similar progression-free survival benefits in large phase 3 trials, suggesting that we may already be reaching the maximal therapeutic impact of G1–S blockade in that treatment line.¹

In the second‑line following standard CDK4/6 resistance, Goel proposes more potent CDK4 inhibition if resistance is due to incomplete CDK4 inhibition to regain cell-cycle control.¹

“The first are the so‑called selective CDK4 inhibitors. And I call this sort of approach ‘pushing the brake pedal to the floor,’ because really what we’re saying here is—with our existing drugs—we’re not inhibiting CDK4 enough. Let’s hit it harder.”¹

This approach may incur some risk as many resistant tumors bypass via CDK2/cyclin E or other mechanisms unrelated to CDK4. Thereby, focusing in on CDK4 may not help—as Goel explained, “doubling down on that same target may not be very helpful, and it may be, like sharpening the wrong tool.”¹

In later line settings, tumors may epigenetically “reset” and become CDK4‑dependent again, resensitizing them to a CDK4‑focused drug. However, the heterogeneity and genomic instability of late‑line tumors mean resistant clones may still dominate.¹

CDK2 Inhibitors

Because CDK2 is a major bypass route in CDK4/6 resistance, it is a high‑priority target. The rationale is that blocking CDK2 could restore RB control and re‑establish a G1 arrest in CDK4/6‑resistant tumors. Further, combining s CDK2 with a CDK4/6 inhibitor may delay or prevent therapy resistance due to deeper suppression of RB phosphorylation and restoration of tumor control in CDK4/6‑resistant xenografts.¹

Goel highlighted 2 trials assessing the efficacy and safety of 2 investigational CDK2 inhibitors: INX-315-01 (Incyclix Bio, LLC) and tegtociclib (PF-07104091; Pfizer).

INX‑315 is an oral, small molecule CDK2 kinase inhibitor used in laboratory models to study CDK2’s role in CDK4/6 inhibitor resistance. Currently, it is not a clinically available agent; rather, it’s a research compound used to test the concept of dual CDK4 plus CDK2 blockade. Animal models show that adding INX‑315 to a CDK4/6 inhibitor, such as abemaciclib, reduces RB phosphorylation and reveals CDK2 as the major escape kinase in CDK4/6 resistance.¹

According to preclinical findings, an up‑front combination of CDK4/6 inhibitor and INX‑315 delays emergence of resistance in untreated tumors and offers deeper suppression of cell‑cycle gene expression.¹

INX‑315 is to be investigated in its first in-human, phase 1/2, open-label, dose escalation and dose-expansion trial (NCT05735080)³ in patients with advanced solid tumors, including those with hormone receptor-positive/HER2– breast cancer who progressed on a prior CDK4/6 inhibitor regimen. Part C of the study will investigate INX-315 as a combination therapy with abemaciclib and fulvestrant in advanced or metastatic breast cancer.¹

Tegtociclib (PF-07104091; Pfizer) is an early-phase CDK7-targeting inhibitor being evaluated in combination with atirmociclib for treatment of patients with ER+/HER2– metastatic breast cancer in a phase 1b/2, open-label, multicenter trial (NCT05262400).⁴ Data from this study are expected to clarify optimal dosing strategies when pairing 2 CDK-targeting agents, an approach that raises both mechanistic promise and tolerability challenges.

Multiple dosing schemes—including “high-low” and “low-high” combinations in which one agent is escalated while the other is reduced—are being tested to identify a regimen that is both tolerable and biologically active. Preliminary efficacy data from a small, heavily pretreated cohort showed an ORR of approximately 28%, suggesting a potential signal of activity in a post-CDK4/6 inhibitor population.¹

However, toxicity remains a central constraint as combining 2 CDK inhibitors increases the risk of overlapping adverse events (AE). Additionally, the toxicity profile of CDK2 inhibitors is not yet fully defined. Some early signals observed include gastrointestinal (GI) toxicities, cytopenias, and visual disturbances.¹

CDK7 Inhibitors

CDK7 is a very attractive target for emerging agents due to its substantial role in cell division and ER-driven transcription.¹

“So, what does CDK7 actually do? The first thing it does is boost the activity of other cell cycle CDKs—CDK2, CDK4, CDK6 and CDK1—by phosphorylating them, serving as a sort of master regulator of cell cycle CDK activity,” said Goel.¹

CDK7 also directly phosphorylates the ER, enhancing its activity, and phosphorylates RNA polymerase II to drive transcription of ER-regulated genes and other key oncogenes. Inhibiting CDK7 therefore offers a way to target multiple oncogenic pathways simultaneously.¹

Samuraciclib (CT7001; Carrick Therapeutics) is an investigational, first-in-class oral CDK7 inhibitor being evaluated in the open-label, interventional, multicenter, randomized, phase 2 SUMIT-BC trial (NCT05963984)⁵ in combination with fulvestrant for patients with HR+/HER2– advanced or metastatic breast cancer. ¹

There are limited data from the trial so far, but early observations suggest meaningful activity, particularly in tumors without TP53 mutations, indicating that TP53-wild-type disease may derive greater benefit from samuraciclib.¹

GI toxicities, such as diarrhea and nausea, are the primary AEs being reported in these early stages of the trial, which are significant enough that investigators are exploring formulation and dosing adjustments to improve tolerability.¹

Refining the Future of Post-CDK4/6 Therapy

As new CDK4-, CDK2-, and CDK7-targeting agents advance through early-phase trials, their potential to reshape post-CDK4/6 inhibitor treatment is becoming clearer—but so are the challenges. The path forward will require balancing biologic rationale with real-world tolerability as investigators refine dosing, combinations, and patient selection.

“As much as the biology is critical and drug discovery is critical, we may also find that we have to be guided simply by thoughtful empiricism and by the toxicity data as much as the efficacy data, and every trial,” concluded Goel, “we have to be looking at both sides of that coin to work out whether the balance truly does make sense.”¹

REFERENCES

1. Waks A, Loibl S, Mahtani R, et al. Educational session 6: ADCs in the clinic. Presented at: SABCS 2025. December 9-12, 2025. San Antonio, TX.

2. Study to Test the Safety and Tolerability of PF-07220060 in Participants With Advance Solid Tumors (CDK4i). Clinicaltrials.gov. Updated October 1, 2025. Accessed December 10, 2025. https://clinicaltrials.gov/study/NCT04557449#study-plan

3. Open-label study to evaluate the safety, tolerability, PK, and efficacy of INX-315 in patients with advanced cancer (INX-315-01). Clinicaltrials.gov. Updated September 19, 2025. Accessed December 10, 2025. https://clinicaltrials.gov/study/NCT05735080

4. A study to learn about the study medicine (called PF-07220060 in combination with PF-07104091) in participants with breast cancer and solid tumors. Clinicaltrials.gov. Updated November 18, 2024. Accessed December 10, 2025. https://clinicaltrials.gov/study/NCT05262400

5. A study of samuraciclib in combination with fulvestrant in metastatic or locally advanced breast cancer in adult participants (SUMIT-BC). Clinicaltrials.gov. Updated December 3, 2025. Accessed December 10, 2025. https://www.clinicaltrials.gov/study/NCT05963984