Kisqali (ribociclib)

The PFS benefit was more pronounced in those individuals who received abemaciclib or ribociclib as second CDK4/6i. Continuation of CDK4/6 inhibition was associated with higher rates of grade 3 and 4 neutropenia (range: 25-40%) and anemia (range: 1.7-11%). In conclusion, switching CDK4/6i and ET conferred a statistically significant improvement of PFS in comparison to ET alone in patients with progression or recurrence on prior CDK4/6i-containing therapy.

P2, N=200, Recruiting, Oana Danciu | Trial completion date: Dec 2027 --> Aug 2029 | Trial primary completion date: Dec 2024 --> Aug 2028

P1/2, N=280, Not yet recruiting, Novartis Pharmaceuticals

Pseudo-Scr elevation appears to be a class effect of CDK4/6i, with similar rates of Scr elevation observed across the three agents currently FDA approved.

P2, N=169, Completed, Melissa K Accordino | Active, not recruiting --> Completed

Notably, the combined approach of ET and CDK4/6 inhibitor represents a novel intervention in managing DCBM in patients with LBC.

Cyclin D-dependent kinase 4/6 inhibitors palbociclib, ribociclib and abemaciclib, in combination with aromatase inhibitors anastrozole and letrozole or oestrogen receptor degrader fulvestrant, are being assessed as candidates for therapeutic drug monitoring. DLLME proved to be the most ecologically acceptable method due to the high degree of miniaturisation (AGREEprep score 0.44), PLR enabled very high sample throughput and cost-effectiveness (BAGI 72.5), while SPE showed the best analytical performance (redness score 100). All three methods are suitable for their designated purpose, and the choice of the ideal method can be made based on the scope of application, available funds and equipment and desired ecological footprint.

While some benefit, albeit modest, has been observed from switching to a different CDK4/6i after progression (e.g. ribociclib after palbociclib in the MAINTAIN trial and abemaciclib after both palbociclib and ribociclib in the postMONARCH trial), the current evidence (mainly with palbociclib) clearly argues against maintaining the same CDK4/6i. However, selected patients with indolent disease, prolonged exposure to previous CDK4/6i treatment (especially palbociclib) and without actionable molecular alterations, may be suitable for suchmaintenance strategy beyond progression. In this challenging and rapidly evolving treatment landscape, ongoing studies can refine the optimal approach and identify clinical and molecular factors to select the best treatment for the right patient.

Initially treated for early-stage disease with surgery, chemotherapy, radiotherapy, and ET, she progressed to metastatic disease and received ribociclib, letrozole, and goserelin, achieving a partial response. Managed with prednisolone and azathioprine, ribociclib was reintroduced at a reduced dose and later escalated to full dose. This case report highlights the importance of a multidisciplinary approach to balance oncologic efficacy with hepatologic safety.

This retrospective study included 193 patients who received either ribociclib or palbociclib in combination with first-line ET. Multivariate analysis identified the symptomatic disease and liver metastasis as independent predictors of shorter mPFS (HR; 1.835, 95% CI; 1.146-2.939 and HR; 2.433, 95% CI; 1.329-4.454, respectively). Our analysis revealed that although symptomatic individuals who underwent CDK4/6 inhibitor plus ET experienced a significant reduction in mPFS durations compared to asymptomatic patients, the 22-month mPFS indicated that CDK4/6 inhibitor plus ET is an effective treatment option.

P=N/A, N=435, Completed, Novartis

Concomitant use of PPIs with ribociclib or palbociclib did not affect the efficacy of either CDK4/6 inhibitor. PPIs can be administered alongside these medications when clinically indicated.

The relationship between DLBCL and glutathione-related genes was uncovered by our research, and six glutathione genes were linked to DLBCL. These genes might be used as diagnostic biomarkers or targets for treatment for DLBCL patients.

The combination of CDK4/6i and ET significantly improves PFS and OS compared to ET alone in both Asian and non-Asian patients with HR+/HER2-aBC. Although the magnitude of benefit appears to be independent of ethnicity, future clinical trials should devise a standardized method for stratifying patients by ethnicity to more effectively assess potential differences in treatment benefits.

P=N/A, N=286, Recruiting, Second Affiliated Hospital, School of Medicine, Zhejiang University | Trial completion date: Sep 2027 --> Jan 2027 | Initiation date: Sep 2024 --> Jan 2024 | Trial primary completion date: Sep 2026 --> Jan 2026

This study confirms first-line CDK 4/6i effectiveness, with abemaciclib and ribociclib showing prolonged PFS vs. palbociclib. This study could not confirm a ranking of the three CDK 4/6i.

P1/2, N=74, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Jun 2025 --> Dec 2025 | Trial primary completion date: Apr 2025 --> Nov 2025

P3, N=1684, Active, not recruiting, West German Study Group | Recruiting --> Active, not recruiting

P3, N=500, Recruiting, American Society of Clinical Oncology | Not yet recruiting --> Recruiting

Dalpiciclib plus fulvestrant is effective and comparatively safe in postmenopausal women with hormone receptor-positive and HER2-negative breast cancers. Dalpiciclib, buparlisib, fulvestrant, and ribociclib cause neutropenia, severe depression, adverse gastroenterological effects, and adverse hepatological effects, respectively.

Mechanistically, inhibition of activin receptor-like kinase 1 signaling increased key restriction point mediators, and treatment with the CDK4/6 inhibitors palbociclib or ribociclib blocked increases in pRB1 and retinal AVMs in HHT mice. Endothelial cell-specific deletion of CDK6 was sufficient to protect HHT mice from AVM pathology. Thus, clinically approved CDK4/6 inhibitors might have the potential to be repurposed for HHT.

However, clinical trials have been predominantly carried out with selected populations and single drugs (Palbociclib, Ribociclib or Abemaciclib). At baseline, and considering the pre-defined criteria, ctDNA analysis detected PIK3CA mutations in 32.25% and 44.44% of patients by AVENIO and ddPCR, respectively. ESR1 mutations were detected in 3.22% and 9.37% by AVENIO and ddPCR, respectively. For PIK3CA mutations, the Kappa value was 0.62 (p-value: 0.0004) and 0.47 for ESR1 mutations (p-value: 0.0039).

Pts had either de-novo metastatic (53%) or secondary endocrine resistance (44%) and mainly received either ribociclib or abemaciclib in combination with an aromatase inhibitor; only 5% received a CDK4/6i + fulvestrant. ctDNA and sTKa determination give complementary information throughout the pts treatment journey. TC estimation may give useful information on the potential detectability of ctDNA variants in a given sample, potentially informing biomarker search strategies. sTKa is a reliable marker which gives a result in every patient.

PFS (p=0.003) and OS (p=0.03) differed significantly by logrank test between the four groups: Low-Low-Low (n=14) median PFS and OS not reached; High-Low-Low (n=26) PFS 23.8m (95%CI can't be calculated) and OS 51.8m (95%CI 15.4 to 88.1); High-Low-High (n=24) PFS 17.5m (95%CI 10.2 to 24.8) and OS 34.3m (95%CI15.1 to 53,7) High-High-High PFS 10.3m (95%CI 1.73 to 18.9) and OS 30.3m (95%CI 15.1 to 45.6) In exploratory analyses no significant differences between median TKa at C1D15 or C2D1, or early TKa dynamic patterns were observed between patients treated with palbociclib (n=48) vs ribociclib (n=29), p=0.33 to 1.0. TKa analysis at later time points is ongoing. TKa is an encouraging biomarker for personalized disease monitoring in MBC.

In this retrospective analysis DDFS, IDFS and BCSS were all numerically worse in a NATALEE eligible high risk pT2N0 population compared to a population with pT1-2N1 tumours of any grade or Ki67 index. These findings suggest that tumour biology may have a more important prognostic value than the tumour stage in HR-positive HER2 negative early stage breast cancer. Longer follow-up in the NATALEE-trial is needed to investigate the possible benefit of adding Ribociclib to adjuvant therapy based on clinicopathological features.

MAINTAIN was the first randomized controlled trial to demonstrate a significant progression-free survival (PFS) benefit for HR+, HER2- MBC patients who switched ET (fulvestrant or exemestane) and received the CDK4/6i ribociclib compared to ET plus placebo after progressing on prior CDK4/6i and ET. In the phase II MAINTAIN trial, sTKa was a predictive biomarker for response to switching ET + continuing CDK4/6i in HR+, HER2- MBC pts following progression on CDK4/6i and ET. Low (<250 DuA) C2D1 sTKa levels predicted a positive treatment response, especially among those receiving ribociclib+ET. sTKa dynamics from baseline to C2D1 were prognostic, providing insights into PFS outcomes.

Methods Pre/perimenopausal pts with no prior systemic therapy for aggressive HR+/HER2− ABC were randomized 1:1 to RIB + letrozole/anastrozole + goserelin or physician's choice of combo CT. Contrary results in the CT arm suggest that these signatures warrant further studies on their potential predictive value. These data are hypothesis generating and should be interpreted with caution due to small sample sizes.

Overall, CDKi+ET had been administered in 1st, 2nd and ≥3rd line in 65.1%, 14.8% and 20.1% cases, with 54.0% patients progressing to ribociclib as CDKi and 57.1% progressing to letrozole as ET. Subtype switching towards less ET-sensitive IS, especially the HER2E, occurs under CDKi+ET and has prognostic value. Post-CDKi LumA disease showed the best outcomes, regardless of treatment type. This group of patients might be the ideal group to be treated with ET-based therapies.

Therapies targeting mutations in this pathway approved in conjunction with endocrine therapy include alpelisib, everolimus and capivasertib...She received nab-paclitaxel/atezolizumab for 4 months, letrozole and abemaciclib for 2 months, letrozole alone for 6 months, and letrozole and ribociclib for 6 weeks. Given presence of PIK3CA mutation, 4th line treatment with fulvestrant and alpelisib was planned...After progressing on capecitabine after 2 months, alpelisib with exemestane was initiated...Due to a low ejection fraction despite work with cardiooncology, she was not a candidate for trastuzumab deruxtecan. She progressed on oral cyclophosphamide and methotrexate after 2 months and Sacituzumab govitecan after 3 months...Comprehensive biomarker assessment is needed to identify patients who may benefit from sequential therapies. There is a need for trials comparing therapies that target the PI3K pathway at distinct points, potential sequencing of these therapies, and the optimal sequence strategy.

In this study, we analyzed a subset of patients from the Dallas Metastatic Breast Cancer Study comprised of patients with HR+, HER2 non-amplified, mBC who underwent treatment with a CDK4/6 inhibitor (palbociclib, ribociclib, abemaciclib) and ET, became resistant to therapy, and had ctDNA testing (n=102). There is an urgent need to develop predictive biomarkers that capture real-time changes in tumor biology. Tissue analyses from patients resistant to CDK4/6 inhibitors have demonstrated a 14%-28% expression of CCNE1, 16% of MYC mutations, and 9%-10% expression of RB mutations. In our study, we observe a lower rate of detection in ctDNA of each gene.

P1, N=34, Recruiting, University of Utah | Trial primary completion date: Aug 2024 --> Apr 2024

P2, N=200, Recruiting, Oana Danciu | Active, not recruiting --> Recruiting

This study highlights that patients with MCV delta > 10 had longer median progression-free survival compared to those with MCV delta ≤ 10.

P2, N=190, Recruiting, The First Affiliated Hospital with Nanjing Medical University

P1, N=45, Active, not recruiting, Dana-Farber Cancer Institute | Trial completion date: Sep 2024 --> Apr 2025

With longer follow-up and most patients off ribociclib, NATALEE continues to demonstrate iDFS benefit with ribociclib plus NSAI over NSAI alone in the overall population and across key subgroups. Observed adverse events remained stable.

The findings of this paper demonstrate a significant improvement in iDFS when ET is combined with CDK4/6i, compared to ET alone. Specifically, treatments with abemaciclib and ribociclib showed notable enhancements in dRFS.

Significantly higher eligibility rates were observed in patients who underwent a mastectomy, >70 years and ≤40 years for adjuvant abemaciclib and ribociclib, and in patients >80 years for ribociclib. A higher discontinuation rate for abemaciclib was reported in patients aged ≥65 years and it can be assumed that discontinuation rates may increase in even older patients. If the results of the NataLEE trial translate into clinical practice, the number of patients potentially eligible for adjuvant CDK4/6 inhibitors may increase, especially in the elderly population.

P2, N=376, Completed, Novartis Pharmaceuticals | Active, not recruiting --> Completed

P4, N=137, Recruiting, Novartis Pharmaceuticals | Trial completion date: Mar 2030 --> Feb 2028 | Trial primary completion date: Feb 2030 --> Jan 2028

P1/2, N=37, Recruiting, Kari Wisinski | Trial completion date: Sep 2024 --> Sep 2025 | Trial primary completion date: Sep 2024 --> Sep 2025

Differences in specific cell infiltration can lead to increased sensitivity of the immune-inflamed subgroup to anti-tumor drugs. The proposed lncRNA model holds great promise to assess the immune landscapes and therapeutic reactions of TNBC patients.