Research ArticleOriginal Article
Open Access

Clinical benefit and safety profile of cross-line therapy with CDK4/6 inhibitors: a retrospective study of HR+/HER2– advanced breast cancer

Qi Zhao, Mingxia Jiang, Jiaxuan Liu, Mengqi Zhang, Maiyue He, Shihan Zhou, Jiani Wang, Hongnan Mo, Bo Lan, Peng Yuan, Pin Zhang, Fei Ma, Qiao Li and Binghe Xu
Cancer Biology & Medicine September 2024, 20240204; DOI: https://doi.org/10.20892/j.issn.2095-3941.2024.0204

Abstract

Objective: CDK4/6 inhibitors (CDK4/6is) in combination with endocrine therapy have secured a central role in the treatment of hormone receptor (HR)-positive advanced breast cancer (ABC) and have transformed the therapeutic landscape. Cross-line CDK4/6i therapy in which another CDK4/6i is continued after progression on a prior CDK4/6i may still offer advantageous therapeutic effects. Cross-line CDK4/6i therapy is an area of active investigation in the ongoing pursuit to improve outcomes for patients with HR+/human epidermal growth factor receptor 2 (HER2)– ABC.

Methods: This retrospective study enrolled 82 patients with HR+/HER2– ABC who were treated with cross-line CDK4/6is (abemaciclib, palbociclib, ribociclib, and dalpiciclib) after progression with another CDK4/6i. The primary endpoint was progression-free survival (PFS) according to version 1.1 of the Response Evaluation Criteria in Solid Tumors. Secondary endpoints included toxicity, objective response rate, disease control rate, and overall survival. Adverse events (AEs) were graded according to version 5.0 of the Common Terminology Criteria for Adverse Events, as promulgated by the U.S. Department of Health and Human Services.

Results: Eighty-two HR+/HER2– ABC patients who received cross-line CDK4/6i therapy from January 2022 to February 2024 were enrolled. The median age of the patients was 60 years. The median PFS of all patients was 7.6 months (95% CI, 5.9-9.2). Cox regression analysis identified lung metastasis and a switch to endocrine therapy following prior CDK4/6i therapy as independent predictive factors for PFS. Notably, patients who previously received abemaciclib and switched to palbociclib upon disease progression had a median PFS of 10.7 months. The strategy of transitioning to chemotherapy after progression on a prior CDK4/6i, then to a subsequent CDK4/6i merits further investigation. Hematologic toxicity was the most common grade ≥ 3 AEs. No instances of fatal safety events were observed.

Conclusion: Cross-line CDK4/6i therapy is associated with significant clinical benefits and manageable safety profiles in patients with HR+/HER2– ABC, which underscores cross-line CDK4/6i therapy potential as an effective treatment strategy.

keywords

Introduction

According to the latest data released by the International Agency for Research on Cancer, an estimated 2.3 million new cases of breast cancer were diagnosed globally in 2022, making breast cancer the second most common cancer worldwide after lung cancer, which had 2.48 million cases. Breast cancer is the most common malignancy among women in China with 306,000 cases (16.7%) and the incidence is increasing and affecting younger women1,2. Among women with breast cancer, hormone receptor (HR)+ [estrogen and/or progesterone receptor]/human epidermal growth factor receptor 2 (HER2)– [HR+/HER2–] breast cancer accounts for 65%–75% of all breast cancers3. Patients with early-stage HR+/HER2– breast cancer can achieve a 5-year survival rate of > 90% with adjuvant endocrine therapy (ET). However, malignant cells can develop resistance to ET by acquiring new mutations and changing gene expression. The 5-year survival rate for patients with advanced breast cancer (ABC) within this subtype is only 30.6%4. Therefore, innovative therapeutic strategies are urgently needed to improve the prognosis of patients with ABC.

Aberrant cell proliferation resulting from cell cycle dysregulation is a key mechanism driving tumor progression and represents a prominent target for anti-cancer drug development. Activation of cyclin-dependent kinases (CDKs) via interaction with cyclins is essential for the transition from one cell cycle phase to another cell cycle phase and is required for cell proliferation5. Therefore, the advent of CDK4/6 inhibitors (CDK4/6is) has made available new targeted treatment options for HR+/HER2– breast cancer6. Four CDK4/6is (dalpiciclib, palbociclib, ribociclib, and abemaciclib) have been widely approved for clinical use in combination with ET in patients with metastatic HR+/HER2− breast cancer. The phase III DAWNA-2 (dalpiciclib plus letrozole or anastrozole), phase III PALOMA-2 (palbociclib plus letrozole), phase III MONARCH-3 (abemaciclib plus letrozole), and phase III MONALEESA-2 trials (ribociclib plus letrozole) demonstrated that the median progression-free survival (mPFS) was significantly improved in combination with a CDK4/6i as first-line therapy for patients with ABC (dalpiciclib, 30.6 months vs. 18.2 months; palbociclib, 24.8 months vs. 14.5 months; abemaciclib, 28.2 months vs. 14.8 months, ribociclib, 25.3 months vs. 16.0 months)7–10.

Furthermore, the results of the phase III PALOMA-3 trial indicated that among patients who received palbociclib as second or later-line therapy, the PFS with palbociclib and fulvestrant combination therapy was superior to fulvestrant plus placebo (17.9 months vs. 8.8 months)11,12. Data from the phase III MONARCH-2 trial also showed that the objective response rate (ORR) in the abemaciclib plus fulvestrant cohort was much higher than the fulvestrant plus placebo cohort (48.1% vs. 21.3%)13. Based on the clinical trials described previously, a CDK4/6i plus ET is recommended as first-line therapy in HR+/HER2− ABC patients. However, appropriate treatment for patients who progress on a CDK4/6i has not been established. Single-agent ET, such as fulvestrant, has limited efficacy in patients with disease progression on CDK4/6i14. ET combined with a PI3K-AKT-mTOR signaling inhibitor has become increasingly acceptable in patients with CDK4/6i progression according to the SOLAR-1 trial and BYLieve trials15,16. There is no substantial clinical data to confirm whether cross-line CDK4/6i treatment (continued use of another CDK4/6i after progression while taking a previous CDK4/6i) confers benefits to patients with progression and whether the sequence of treatment is important. Although a prospective study, the phase III postMONARCH trial (NCT05169567), recruited patients who had disease progression on first-line ET plus a CDK4/6i then randomly allocated patients to abemaciclib plus fulvestrant versus fulvestrant alone, the results have not been published.

In addition to clinical efficacy, the four widely approved CDK4/6is exhibit significant clinical differences in toxicity. Neutropenia is the primary dose-limiting toxicity (DLT) of ribociclib, dalpiciclib, and palbociclib, while ribociclib also induces other DLTs, including QTc interval prolongation10,17,18. The most frequent abemaciclib are diarrhoea DLTs (high serum creatinine and increased risk of venous thromboembolism)19. Although the differences in toxicity profiles of these four inhibitors allow clinicians to tailor treatment for individual patients, the choice of CDK4/6i still reflects, in part, clinician preference. Furthermore, accessibility of other endocrine-based combination therapies, such as PI3K inhibitors, is limited. Therefore, cross-line CDK4/6i treatment also has clinical value in China.

In conclusion, there is an urgent need for evidence to support the efficacy of switching to another CDK4/6i after disease progression with a previous CDK4/6i in current clinical decision-making and to determine the optimal sequencing and administration methods for cross-line CDK4/6i treatment. The safety issues following the use of cross-line CDK4/6is also need to be a focus of attention. This study evaluated the efficacy and safety of cross-line CDK4/6i therapy for HR+/HER2− ABC.

Materials and methods

Patients

This retrospective study enrolled patients with HR+/HER2− ABC who were treated with a cross-line CDK4/6i (abemaciclib, palbociclib, ribociclib, and dalpiciclib) after progression with another CDK4/6i from January 2022 to February 2024. The inclusion criteria were as follows: (1) cytologic or histologically confirmed diagnosis of HR+/HER2− advanced or metastatic breast cancer; (2) age ≥ 18 years; (3) received cross-line CDK4/6i treatment (continuing or changing to a different CDK4/6i after progression on a previous CDK4/6i with the option to switch to other treatments between the two courses of CDK4/6i treatment) until disease progression, unacceptable toxicity, or patient death; (4) availability of data on response evaluation and survival; (5) availability of previous therapies [whether receiving anthracycline/taxane-based chemotherapy, ET, or chemotherapy was administered before CDK4/6i treatment in the advanced stage; whether chemotherapy, targeted therapy, or ET was administered between two courses of CDK4/6i treatment; whether receiving sequential CDK4/6i treatment (directly switching to another CDK4/6i after progression on a previous CDK4/6i without changing to other therapies in between the 2 CDK46is)]. ABC was characterized as de novo stage IV or recurrent breast cancer and validated by clinical, imaging, histologic, or cytologic criteria. The exclusion criteria were as follows: (1) patients receiving only one CDK4/6i treatment or switching to another CDK4/6i but not due to disease progression; (2) patients lacking information on previous or cross-line CDK4/6i treatment; (3) HER2 2+ with gene amplification or HER2 3+; and (4) a second primary malignant tumor. All data were retrospectively collected from medical records (Figure 1).

Figure 1
Figure 1

Trial profile.

Study design and treatment

This study assessed the efficacy and safety of cross-line treatment with different CDK4/6is combined with ET in HR+/HER2− ABC. The study included patients registered at the Cancer Hospital Chinese Academy of Medical Science who underwent cross-line CDK4/6i treatment between January 2022 and February 2024. Eighty-two patients met the inclusion criteria for this study. Safety and efficacy outcomes from patient medical records were collected regardless of patient age or duration of CDK4/6i treatment. Additionally, data pertaining to treatment patterns were gathered.

The variables that were evaluated included PFS, overall survival (OS), ORR, disease control rate (DCR), and safety. The primary endpoint was PFS. Secondary endpoints included toxicity, ORR, DCR, and OS in patients with measurable lesions. Adverse events (AEs) were graded according to version 5.0 of the Common Terminology Criteria for Adverse Events, as promulgated by the U.S. Department of Health and Human Services. According to version 1.1 of the Response Evaluation Criteria in Solid Tumors, PFS was defined as the time from initiation of cross-line CDK4/6i treatment to disease progression or death from any cause. OS was defined as the time from initiation of cross-line CDK4/6i treatment to death from any cause or last follow-up evaluation. ORR was defined as the percentage of evaluable patients with a complete response (CR) or partial response (PR) as the best objective tumor response at baseline. DCR was defined as the percentage of evaluable patients with CR, PR, or stable disease (SD) at baseline for ≤ 24 weeks.

Patients received CDK4/6i combined with ET. CDK4/6i dosing [abemaciclib (150 mg po bid d1-28/q28d); palbociclib (125 mg po qd d1-21/q28d); dalpiciclib (150 mg po qd d1-21/q28d); and ribociclib (600 mg po qd d1-21/q28d)] was adjusted according to dose modification, as recommended by the FDA prescribing information, AEs, or physician judgment. All four CDK4/6is were administered in cycles of 28 days until disease progression or the occurrence of intolerable AEs.

Statistical analysis

Statistical analyses were performed utilizing SPSS (version 26.0). Additionally, R Studio (version 4.1.2) and Adobe Illustrator (2020) were used for the creation of graphical representations. The Kaplan-Meier survival estimate was used to analyze the correlation between the basic pathologic characteristics of the clinical patients and survival benefits (mPFS and mOS). The Cox proportional hazards model was used to investigate the correlation between the patient baseline characteristics and the risk associated with PFS. The Schoenfeld residual test with the R Studio was used to determine whether the PH assumption held (Table S1). Characteristics that demonstrated a strong association with survival outcomes in clinical contexts were subjected to both univariate and multivariate analyses. Covariates were utilized as categorical variables to simplify the statistical model, thereby making the model more comprehensible and interpretable. Continuous variables, such as age, were transformed into categorical variables (≤ 60 and > 60 years of age). A P < 0.05 was set as the threshold for statistical significance.

Results

Patients and treatment

The study included 82 HR+/HER2− ABC patients who received cross-line CDK4/6i therapy after progression with a previous CDK4/6i from January 2022 to February 2024. The median age of patients was 60 years (range, 30–83 years). The detailed characteristics of patients are shown in Table 1. There were 14 patients (17.1%) initially diagnosed as stage I, 21 patients (25.6%) as stage II, 22 patients (26.8%) as stage III, 13 patients (15.9%) as de novo IV stage, and 12 patients (14.6%) in whom the stage was not available. According to the Nottingham grade, which evaluates the differentiation of breast cancer, 10 patients (12.2%) were diagnosed as grade III, 39 patients (47.6%) as grade II, 1 patient (1.2%) as grade I, and 32 patients (39.0%) in whom a diagnosis was not available. Thirty-four patients (41.5%) had a Ki67 level < 25%, 30 patients (36.6%) had a Ki67 between 25% and 50%, 7 patients (8.5%) had a Ki67 > 50%, and 11 patients (13.4%) did not have Ki67 data available. Liver metastases were detected in 38 patients (46.3%), lung metastases in 33 patients (40.2%), bone metastases in 60 patients (73.2), brain metastases in 7 patients (8.5%), lymph node metastases in 36 patients (43.9%), and visceral metastases in 59 patients (72.0%). There were 18 patients (22.0%) who had 1 metastatic lesion, 32 patients (39.0%) had 2 lesions, and 32 (39.0%) patients had ≥ 3 lesions.

View this table:
Table 1

Baseline characteristics of HR+/HER2− advanced breast cancer patients treated with cross-line CDK4/6i based therapy

Of the 82 patients, 13 (15.9%) received neoadjuvant therapy, 46 (56.1%) accepted radiotherapy, and 69 (84.1%) underwent surgery. Thirty-seven patients (45.1%) received previous CDK4/6i treatment with abemaciclib, 43 (52.4%) received palbociclib, and 2 patients (2.4%) received other CDK4/6is (clinical trial). The efficacy of CDK4/6i in the previous treatment was ≥ 6 months in 61 patients (74.4%) and < 6 months in 21 patients (25.6%). Forty-two patients were treated with abemaciclib (51.2%), 21 with palbociclib (25.6%), 10 (12.2%) with dalpiciclib, 5 (6.1%) with ribociclib, and 4 (4.9%) with other CDK4/6is (these 4 patients participated in a clinical trial involving new CDK4/6 inhibitors) as cross-line CDK4/6i treatment. Thirty-eight patients (46.3%) received sequential treatment with other CDK4/6is after progression on previous CDK4/6i treatment.

Among patients not receiving sequential treatment, 9 (11.0%) underwent ET and 39 (47.6%) received chemotherapy. There were 27 patients (32.9%) received 1-2 lines of treatment, 26 (31.7%) received 3–4 lines, and 29 patients (35.4%) received ≥ 5 lines (the cross-line CDK4/6i treatment was not included). Additionally, there were 58 patients (70.7%) who received taxane and 49 (59.8%) who received anthracycline treatment.

Efficacy

Disease progression occurred in 14 patients (17.1%) up to April 2024. Among the 82 patients, no patients achieved a CR, 19 (23.2%) had a PR, and 49 (59.8%) had SD. The ORR was 23.2% (19/82) and the DCR was 82.9% (67/82). The mPFS of patients who received cross-line CDK4/6i therapy was 7.6 months (95% CI: 5.9-9.2) and data for the OS are still being collected (Figure 2A, Figure S1A).

Figure 2
Figure 2

Kaplan-Meier plot for PFS in all patients and subgroups. (A) Kaplan-Meier plot for PFS in all patients who received cross-line CDK4/6i treatment. (B) Kaplan-Meier plot for liver metastases-associated PFS. (C) Kaplan-Meier plot for lung metastases-associated PFS. (D) Kaplan-Meier plot for visceral metastases-associated PFS. (E) Kaplan-Meier plot for metastatic number-associated PFS. (F) Kaplan-Meier plot for total treatment line-associated PFS.

Based on univariate analysis (Table 2), the number of metastases, liver metastases, lung metastases, visceral metastases, previous treatment lines, and chemotherapy treatment lines were significantly associated with PFS among patients who received cross-line CDK4/6i therapy. Variables that were shown to be significant based on univariate analysis and those variables that were clinically high-risk factors were selected for inclusion in a multivariate analysis model (Table 2). The findings demonstrated that lung metastases and switch to ET after previous CDK4/6i therapy were independent predictive factors for PFS with cross-line CDK4/6is.

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Table 2

Univariate and multivariate analyses of factors predicting progression-free survival in patients treated with cross-line CDK4/6i based treatment

The Kaplan-Meier survival estimate was further used to analyze the correlation between the basic pathologic characteristics of the clinical patients and their survival benefits. The mPFS in patients with liver and lung metastases were significantly shorter than the mPFS in patients without these metastases (liver, 11.4 vs. 6.1 months; P = 0.003; lung, 8.6 vs. 4.7 months; P = 0.044; Figure 2B and C) unlike other metastases, including bone, brain, and lymph nodes (Figure S1B-D). Visceral metastases had a significantly effect on mPFS (16.2 vs. 6.2 months; P = 0.008; Figure 2D). The number of metastases had a significant effect on the mPFS of cross-line CDK4/6i-treated patients (P = 0.006; Figure 2E). The mPFS of patients with 2 or 3 metastases was 6.1 and 6.4 months, respectively, while the mPFS of patients with 1 metastatic site was not reached. Among the patients, 12.2% of the patients had bone metastases only. In addition, patients who had varied total treatment lines before cross-line CDK4/6i therapy exhibited a significantly different mPFS duration. The patients who received 1–2 treatment lines had a longer mPFS than those patients who received 3–4 and ≥ 5 lines (11.4 vs. 8.5 vs. 5 months, respectively; P = 0.018; Figure 2F).

For patients in whom the previous CDK4/6i efficacy duration was ≥ 6 months, there was no significant difference in mPFS compared to those patients in whom efficacy was <6 months (10.7 vs. 7.3 months; P = 0.556; Figure 3A). Sequential treatment with another CDK4/6i after progression on previous CDK4/6i therapy did not impact the mPFS of patients (7.7 vs. 7.0 months; P = 0.919; Figure 3B). The difference between the mPFS of patients who received sequential treatment with another CDK4/6i or was switched to ET or chemotherapy after progression on a previous CDK4/6i was not significant (switch to chemotherapy, 8.5 vs. 5.9 months; P = 0.09; switch to ET, 7.3 vs. not reached; P = 0.083; Figure 3C and D). We also analyzed the impact of sequential abemaciclib and palbociclib treatment on PFS. There was no statistically significant difference in PFS between patients who received abemaciclib first followed by palbociclib upon progression versus those patients who received palbociclib first and were then switched to abemaciclib upon progression (10.7 vs. 8.0 months, P = 0.948; Figure 3E).

Figure 3
Figure 3

Kaplan-Meier plot for subgroup-associated PFS. (A) Kaplan-Meier plot for previous CDK4/6i efficacy duration-associated PFS. (B). Kaplan-Meier plot for sequential CDK4/6i treatment-associated PFS. (C) Kaplan-Meier plot for endocrine therapy (ETs) switch-associated PFS. (D) Kaplan-Meier plot for chemotherapy (CTx)-associated PFS (E) Kaplan-Meier plot for “Abe switch to Pal” subgroup- and “Pal switch to Abe” subgroup-associated PFS (Abe: abemaciclib, Pal: palbociclib).

Safety

All the AEs observed in patients receiving cross-line CDK4/6i are displayed in Table 3. The most common AEs were leukopenia (80.5%), neutropenia (78.0%), and anemia (69.5%), while only 6 patients (7.3%) had grade 1–2 rashes. The cross-line CDK4/6i treatment was associated with mild toxicity with most AEs grade 1–2 [anemia (67.1%), leukopenia (61.0%), and decreased appetite (57.3%)]. Hematologic toxicity [neutropenia (28.0%), leukopenia (19.5%), and thrombocytopenia (6.1%)] was the most common grade ≥ 3 AE. No patient discontinued CDK4/6i treatment due to AEs. Fifteen patients (18.3%) delayed treatment because of hematologic toxicity or COVID-19, while 11 patients (13.4%) reduced the CDK4/6i dose. Overall, the patients tolerated the cross-line CDK4/6i treatment well.

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Table 3

Treatment-emergent adverse events

Discussion

ET has always been the primary treatment for HR+/HER2− breast cancer and effectively inhibits the growth of hormone-dependent tumor cells by reducing the levels of estrogen or inhibiting estrogen synthesis. With advances in precision medicine, treatment strategies continue to be optimized20. It is worth noting that the introduction of CDK4/6is has provided a new strategy for overcoming resistance to ET. By blocking the tumor cell cycle, CDK4/6is help reverse or delay resistance to ET. Currently, CDK4/6is are recommended by authoritative guidelines domestically and internationally for adjuvant intensification and salvage therapy in high-risk patients, not only improving treatment outcomes but also providing patients with safer and more comfortable treatment options21,22. After undergoing chemotherapy and ET, HR+/HER2− breast cancer has smoothly transitioned into an era of targeted therapy represented by CDK4/6i.

Most patients with HR+/HER2− patients with ABC will eventually develop resistance to CDK4/6is. The mechanisms of resistance are complex with strong heterogeneity6. Patients who are insensitive to CDK4/6i (those whose duration of first-line treatment control is < 1 y) remain a particularly challenging population to treat clinically, posing a major challenge in ABC therapy23. There is currently no standard follow-up treatment plan for patients with HR+/HER2− ABC who have failed CDK4/6i therapy. The main diagnostic and therapeutic approach in clinical practice is to continue targeted therapy combined with endocrine drugs. Treatment options include estrogen receptor degraders, such as elacestrant24, PI3K inhibitors, such as alpelisib16, AKT inhibitors, such as capivasertib14, mTOR inhibitors, such as everolimus25, histone deacetylase inhibitors, such as chidamide26, and cross-line CDK4/6i treatment (MAINTAIN study27). However, patients typically achieve a PFS benefit of up to 7 months.

In recent years, the emergence of antibody-drug conjugates, such as DS-820128, has provided a new approach for the treatment after resistance to a CDK4/6i. In the cohort of patients enrolled in the DESTINY-Breast 04 (DB04) study, 70% had HR+/HER2− ABC and were previously treated with a CDK4/6i. The DESTINY-Breast 04 (DB04) study demonstrated that compared to treatment of physician’s choice (TPC), the use of DS-8201 in this subgroup had a significantly prolonged mPFS (10.0 vs. 5.4 months; HR: 0.55). DS-8201 resulted in a mPFS of 9.5 months (TPC: 5.3 months) after treatment among patients resistant to CDK4/6i29. The TROPiCS-02 study also showed that patients who received 2nd–4th-line chemotherapy and patients who received CDK4/6i, trastuzumab deruxtecan (SG) similarly achieved significant improvement in PFS21. Subgroup analysis revealed that among patients who had rapid progression on a CDK4/6i (defined as CDK4/6i use ≤ 12 months), patients treated with SG had a mPFS of 6 months30. However, the inherent structure complexity of ABC and the process of targeting tumor cells may affect therapeutic efficacy, safety, and drug availability.

Therefore, even though patients have multiple treatment options, current treatment strategies for patients with HR+/HER2– ABC still face challenges in achieving long-term efficacy similar to CDK4/6i in first-line therapy in terms of PFS and safety31. For patients treated with CDK4/6i, determining the subsequent treatment strategy is a key focus of clinical attention. Currently, for patients with HR+/HER2− ABC, re-use of a CDK4/6i (cross-line CDK4/6i treatment) after progression on a previous CDK4/6i therapy is an active area of research. Several prospective studies have explored the value of cross-line CDK4/6i treatment but the conclusions were not consistent. The phase II MAINTAIN study showed that ABC patients who progressed after treatment with palbociclib, ribociclib and abemaciclib, continuing ribociclib in combination with ET compared to endocrine monotherapy improve the PFS (5.29 vs. 2.76 months; HR = 0.57; P = 0.006). However, the PACE study failed to demonstrate an improved PFS (4.6 vs. 4.8 months) or OS (24.6 vs. 27.5 months) compared to palbociclib in combination with fulvestrant versus fulvestrant monotherapy after progression on a previous CDK4/6i combined with aromatase inhibitor (AI) therapy.

This study was a retrospective analysis of 82 patients with HR+/HER2− ABC who underwent cross-line CDK4/6i treatment after disease progression by continuing or switching to a different CDK4/6i after at the Cancer Hospital Chinese Academy of Medical Science from January 2022 to February 2024. The aim of the study was to evaluate the efficacy and safety of this approach and determine the feasibility of cross-line CDK4/6i treatment strategies in clinical practice. We excluded patients who discontinued a previous CDK4/6i because of toxicity. For the overall group of 82 patients who received a cross-line CDK4/6i, the mPFS was 7.6 months (95% CI: 5.9–9.2 months) and the the data for OS are still being collected. The mPFS of this study was relatively longer compared to similar studies (phase II MAINTAIN study, 5.29 months and PACE study, 4.6 months). This retrospective study had the potential for information bias. No patients achieved a CR, 19 (23.2%) had a PR, 49 (59.8%) had SD, and 14 (17.1%) had disease progression. The ORR was 23.2% (19/82) and the DCR was 82.9% (67/82). Differences in the efficacy of cross-line CDK4/6i treatment observed in the aforementioned phase II clinical studies may be attributed to the following factors: different racial backgrounds; tumor burden at baseline [in this study, 10 patients (12.2%) had bone metastases alone, while 59 patients had visceral metastases (72.0%); and the proportion of patients previously treated with each CDK4/6i (initial palbociclib treatment > 80% vs. 52.4%).

With respect to safety, known CDK4/6i toxicity includes bone marrow suppression, gastrointestinal reactions, and fatigue. Long-term or repeated use of a CDK4/6i may increase the risk of cumulative dose toxicity. Therefore, the tolerability of cross-line CDK4/6i treatment is an important consideration. In this study, patients primarily received abemaciclib (37 patients) and palbociclib (43 patients) as previous CDK4/6i inhibitor before switching to other CDK4/6is upon tumor progression. There were fewer patients who received ribociclib (5 patients) and dalpiciclib (10 patients) as cross-line CDK4/6i treatment, with the majority receiving abemaciclib (42 patients) and palbociclib (21 patients). The results of this study indicated that the cross-line CDK4/6i AEs were primarily associated with hematologic toxicity. Compared to previous CDK4/6i treatment-associated AEs, the type and severity of toxicities were relatively unchanged. Hematologic toxicity [neutropenia (28.0%), leukopenia (19.5%), and thrombocytopenia (6.1%)] was the most common grade ≥ 3 AE. However, treatment was delayed in 15 patients (18.3%) due to AEs and the CDK4/6i dosewas reduced in 11 patients (13.4%). Overall, patients tolerated cross-line CDK4/6i treatment well. In the real-world clinical treatment, cross-line CDK4/6i treatment may be an effective treatment option for patients with HR+/HER2− ABC.

Due to the similar mechanisms underlying the anti-cancer effect and resistance among different CDK4/6is, the timing of cross-line CDK4/6i treatment is also an important clinical decision point. Navarro-Yepes et al.32 performed a retrospective analysis of HR+/HER2− ABC patients who received abemaciclib treatment after progressing on previous CDK4/6i therapy. The results showed that patients in the sequential abemaciclib treatment group (n = 18 pts) had a significantly longer median OS (42.7 vs. 17.3 months). Corollary molecular experiments confirmed that patients enriched in the G2/M pathway after prior palbociclib treatment might benefit from abemaciclib therapy, while those enriched in the OXPHOS pathway might be refractory. Thus, we analyzed the efficacy of sequential or non-sequential CDK4/6i treatment using the Kaplan-Meier method. The results showed that although there was no significant difference in efficacy between the two groups (7.7 vs. 7.0 months; P = 0.919) but the cross-line CDK4/6i treatment still conferred a PFS benefit. Interestingly, unlike previous studies related to cross-line CDK4/6i treatment, the current study included 20 patients (24.4%) who received previous treatment with abemaciclib followed by post-palbociclib. The mPFS of the subgroup previously treated with abemaciclib followed by post-palbociclib was better than the subgroup prior treated with palbociclib followed by post-abemaciclib (10.7 vs. 8.0 months; P = 0.948). However, due to the small overall sample size and the difference in the number of patients between the two groups, there was no statistical difference between the two groups. With the widespread use of CDK4/6is, larger-scale studies targeting patients who previously received abemaciclin followed by post-palbociclib in the future are expected to further advance clinical progress in this field.

For ABC patients, treatment in the advanced stage should not only focus on PFS but also consider the factors associated with the choice of subsequent treatments influenced by previous therapies. The primary goal of treatment remains to achieve OS benefits for patients. It is known that RB loss-function is associated with CDK4/6i resistance. A case report showed that a patient with HR+/HER2− breast cancer who had developed resistance to CDK4/6i regained sensitivity (abemaciclib combined with anastrozole, PFS = 4 months) after receiving chemotherapy (eribulin, which restored RB gene expression)33. Hence, we boldly speculate that chemotherapy may potentially eliminate resistance due to gene dysfunction and restore the efficacy of CDK4/6i. We conducted a Kaplan-Meier analysis on the non-sequential treatment subgroup within the cross-line CDK4/6i treatment population. The results indicated that patients who received chemotherapy following progression on the previous CDK4/6i had a shorter PFS compared to patients who did not undergo chemotherapy. Although there was no statistical difference between the two groups, the P-value was close to 0.05 (P = 0.09). This finding may reflect the later treatment line of the subgroup “switch to chemotherapy between cross-line CDK4/6i”. Due to the small sample size of this study, specific analysis targeting this subgroup with matched baseline patient characteristics could not be performed. However, following resistance to a previous CDK4/6i, receiving chemotherapy to eliminate resistance gene abnormalities before cross-line CDK4/6i might be a more effective treatment strategy. In the future, conducting larger-scale prospective studies to validate this hypothesis could provide valuable guidance for clinical treatment. Additionally, the PFS of patients who switched to ET was insufficient because of the limited sample size (n = 9).

Although CDK4/6is are widely used in first-line treatment for patients with HR+/HER2− ABC, previous clinical studies have shown that some patients have a PFS < 6 months after first-line CDK4/6i combined with ET34. Therefore, the population experiencing rapid progression on a CDK4/6i should be given special attention in clinical diagnosis and treatment. EMERALD is a phase III clinical study evaluating the efficacy and safety of elacestrant in patients previously treated with a CDK4/6i35. The EMERALD phase III clinical study showed that in patients experiencing rapid progression on a CDK4/6i (PFS ≤ 6 months; 6 months < PFS ≤ 12 months), the shorter the duration of a frontline CDK4/6i, the worse the efficacy of subsequent treatment. Therefore, there is a significant unmet clinical need for patients experiencing rapid progression on a first-line CDK4/6i in clinical practice. In this study we divided patients into 2 groups based on the duration of prior CDK4/6i treatment (prior CDK4/6i efficacy duration ≥ 6 m). We observed that the longer the duration of prior CDK4/6i maintenance, the shorter the PFS benefit from the cross-line CDK4/6i treatment (10.7 vs. 7.3 months; P = 0.556). This finding may be due to the higher proportion of heavily pretreated patients (≥ 5 lines: 23.8% vs. 34.4%) in the subgroup with a previous CDK4/6i efficacy duration ≥ 6 months. In the future, expanding the sample size and conducting matched prospective studies may address the current clinical needs.

Additionally, we conducted survival analysis based on the disease characteristics of enrolled patients. The results revealed that patients with liver (11.4 vs. 6.1 months; P = 0.003), lung (8.6 vs. 4.7 months; P = 0.044), and visceral metastases (16.2 vs. 6.2 months; P = 0.008) notably lacked mPFS benefits. Multivariable Cox regression analysis was performed in this study by including variables that were significantly correlated in univariate analysis as well as factors that had important clinical implications. We found that lung metastases and non-sequential CDK4/6i treatment (endocrine switch therapy) were predictors of patient prognosis. These findings provide valuable information for future clinical decision-making and may influence treatment choices for patients. However, this study also has some limitations. Due to the limited sample size, survival outcome analysis of the four drugs (abemaciclib, palbociclib, ribociclib, and dalpiciclib) used in cross-line CDK4/6i treatment cannot be conducted. Being a single-center retrospective study, we observed the correlation between cross-line CDK4/6i treatment patterns and survival but could not establish a direct causal relationship between treatment and improvement in survival rates. Additionally, as retrospective studies rely on historical medical records, there may be some information bias in this study (for example, AEs). In the future this research needs to be conducted with larger samples to improve the reliability of the study and the generalizability of the conclusions.

In conclusion, patients with HR+/HER2− ABC receiving cross-line CDK4/6i therapy demonstrate good efficacy and safety. It is crucial to consider multiple factors, such as disease characteristics, patient preferences, drug resistance, and economic conditions to determine the possibility and timing of cross-line CDK4/6i therapy. Future research should explore biomarkers predicting treatment response and optimize cross-line CDK4/6i treatment strategies to improve patient quality of life, survival outcomes, and advance the development of personalized and precision treatment strategies.

Conflict of interest statement

No potential conflicts of interest are disclosed.

Author contributions

Conceived and designed the analysis: Binghe Xu and Qiao Li.

Collected the data: Qi Zhao, Mingxia Jiang, Jiaxuan Liu, Mengqi Zhang, Maiyue He, and Shihan Zhou.

Contributed data or analysis tools: Jiani Wang, Hongnan Mo, Bo Lan, Peng Yuan, Ping Zhang, and Fei Ma.

Performed the analysis: Mingxia Jiang.

Wrote the paper: Qi Zhao and Mingxia Jiang.

Data availability statement

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Acknowledgements

We deeply appreciate all authors who were involved in this study and patients who participated in this study.

Footnotes

  • ↵*These authors contributed equally to this work.

  • Received June 5, 2024.
  • Accepted August 15, 2024.

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