Adjuvant CDK4/6 inhibitors combined with endocrine therapy in HR-positive, HER2-negative early breast cancer: A meta-analysis of randomized clinical trials

 

Adjuvant CDK4/6 inhibitors combined with endocrine therapy in HR-positive, HER2-negative early breast cancer: A meta-analysis of randomized clinical trials

 

by Hong-Fei Gao, Ying-Yi Lin, Teng Zhu, Fei Ji, Liu-Lu Zhang, Ci-Qiu Yang, Mei Yang, Jie-Qing Li, Min-Yi Cheng, Kun Wang 

 

The Breast: VOLUME 59, P165-175, OCTOBER 01, 2021

 

Background

The benefit of adjuvant cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors with endocrine therapy (ET) in hormone receptor-positive, human epidermal growth factor 2 receptor-negative (HR+/HER2-) early breast cancer (EBC) is uncertain. Hence, we performed a meta-analysis to determine the efficacy and safety of adjuvant CDK4/6 inhibitors plus ET and to identify potential preferred subpopulations for this regimen.

Methods

A literature search was conducted in PubMed, Embase, Cochrane databases up to Jan 15, 2021. Hazard ratios (HRs) for invasive disease-free survival (IDFS) and risk ratios (RRs) for grade 3/4 adverse events (AEs) and treatment discontinuation were extracted. Analysis with predefined subgroup variables was done. Trial sequential analysis (TSA) was performed to assess the conclusiveness of survival outcomes.

Results

Three trials were eligible (N = 12647). Compared with ET, adjuvant CDK4/6 inhibitors with ET prolonged IDFS in patients with HR+/HER2- EBC (HR 0.87, 95% CI 0.76–0.98, p = 0.03, I2 = 19%), with positive therapeutic responses observed in patients with N2/N3 nodal status (HR 0.83, 95% CI 0.71–0.97, p = 0.02, I2 = 0%). None of the cumulative z-curves crossed the trial monitoring boundaries in TSA, and no reliable conclusion could be drawn. The combination treatment carried a higher risk of grade 3/4 AEs (RR 4.14, 95% CI 3.33–5.15, p < 0.00001) and an increase in treatment discontinuation due to AEs (RR 19.16, 95% CI 9.27–39.61, p < 0.00001).

Conclusions

Adjuvant CDK4/6 inhibitors with ET might provide survival benefit in HR+/HER2- EBC. A statistically significantly improved IDFS was only observed in N2/N3 subgroup. However, overall evidence favoring the use of this combination regimen was inadequate.

First- and second-line treatment strategies for hormone-receptor (HR)-positive HER2-negative metastatic breast cancer: a real-world study

 

First- and second-line treatment strategies for hormone-receptor (HR)-positive HER2-negative metastatic breast cancer: a real-world study

by Debora Basile, Lorenzo Gerratana, Carla Corvaja, Giacomo Pelizzari, Giorgia Franceschin, Elisa Bertoli, Lorenza Palmero, Diego Zara, Martina Alberti, Silvia Buriolla, Lucia Da Ros, Marta Bonotto, Mauro Mansutti, Simon Spazzapan, Marika Cinausero, Alessandro Marco Minisini, Gianpiero Fasola, Fabio Puglisi 

The Breast: VOLUME 57, P104-112, JUNE 01, 2021 (Published: March 11, 2021)

Background

Endocrine therapy (ET) plus cyclin-dependent-kinases 4/6 inhibitors (CDK4/6i) represents the standard treatment for luminal-metastatic breast cancer (MBC). However, prospective head-to-head comparisons are still lacking for 1st line (L) options, and it is still crucial to define the best strategy between 1st and 2nd L.

Materials and methods

717 consecutive luminal-MBC pts treated between 2008 and 2020 were analyzed at the Oncology Department of Aviano and Udine, Italy. Differences about survival outcomes (OS, PFS and PPS) were tested by log-rank test. The attrition rate (AR) between 1st and 2ndL was calculated.

Results

At 1stL, pts were treated with ET (49%), chemotherapy (CT) (31%) and ET-CDKi (20%) while, at 2ndL, 33% received ET, 33% CT and 8% ET-CDKi. Overall AR was 10%, 7% for CT, 8% for ET and 17% for ET-CDKi. By multivariate analysis, 1stL ET-CDK4/6i showed a better mPFS1 and OS. Moreover, 2ndL ET-CDK4/6i demonstrated better mPFS2 compared to ET and CT. Notably, 1stL ET-CDKi resulted in higher mPFS than 2ndL ET-CDKi. Intriguingly, 1stL ET-CDK4/6i was associated with worse mPPS compared to CT and ET. Secondarily, 1stL ET-CDK4/6i followed by CT had worse OS compared to 1stL ET-CDK4/6i followed by ET. Notably, none of baseline characteristics at 2ndL influenced 2ndL treatment choice (ET vs. CT) after ET-CDKi.

Conclusion

Our real-world data demonstrated that ET-CDKi represents the best option for 1stL luminal-MBC compared to ET and CT. Also, the present study pointed out that 2ndL ET, potentially combined with other molecules, could be a feasible option after CDK4/6i failure, postponing CT on later lines.

CDK 4/6 inhibitors mired in uncertainty in HR positive and HER2 negative early breast cancer

 

CDK 4/6 inhibitors mired in uncertainty in HR positive and HER2 negative early breast cancer

The Breast:  VOLUME  55, P75-78, FEBRUARY 01, 2021

by Serena Di Cosimo, Luca Porcu, Fatima Cardoso 

Highlights

•HR+/HER2-early BC patients have continuous risk of relapse and need new therapies

•Current short follow-up precludes any final conclusion re. adjuvant CDK4/6 inhibitors

•The proportional hazard assumption was hampered by the low number of events

•Wide point estimate 95%CI translated into imprecise number needed to treat (NNT)

•Besides efficacy, toxicity, compliance and cost are issues to consider in decision-making

•Research efforts need to continue to establish CDK4/6 inhibitor predictive biomarkers

Abstract

Cell-cycle abnormalities are common in estrogen receptor- and/or progesterone receptor-positive, and HER2-non-overexpressing (HR+/HER2-) breast cancer, and have long been considered potential therapeutic targets. Cyclin-dependent kinase (CDK) 4/6 inhibitors have dramatically changed the therapeutic management of HR+/HER2-advanced breast cancer by prolonging progression-free and overall survival when given in combination with endocrine therapy. In this article, available data from PALLAS and monarchE trials regarding the efficacy and toxicity of adjuvant combined therapy with CDK 4/6 inhibitors and endocine therapy in HR+/HER2-early breast cancer are reviewed, and relevant issues including study hypothesis, patient selection, and duration of follow-up are discussed.

Palbociclib combined with endocrine therapy in heavily pretreated HR+/HER2- advanced breast cancer patients: results from the Compassionate Use Program in Spain (PALBOCOMP)

 

Palbociclib combined with endocrine therapy in heavily pretreated HR+/HER2- advanced breast cancer patients: results from the Compassionate Use Program in Spain (PALBOCOMP)

 

The Breast:  VOLUME 54, P286-292, DECEMBER 01, 2020

 

Highlights

• CDK4/6 inhibitors combined with endocrine therapy have been widely accepted as a new standard therapy for hormone receptor-positive metastatic breast cancer patients in first or second line.

• Palbociclib alone or in combination with aromatase inhibitors, fulvestrant, or tamoxifen was effective and safe in heavily pretreated HR+/HER2- metastatic breast cancer patients.

• Palbociclib could be of higher benefit to patients with endocrine-sensitive disease that had a long duration of response to previous endocrine therapy.

• Real-world evidence of effectiveness and safety of use of palbociclib in heavily pretreated advanced breast cancer patients complements data from randomized clinical trials.

Abstract

Background

This study evaluated efficacy and safety of palbociclib, a CDK4/6 inhibitor, in heavily-pretreated hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer (mBC) patients during the compassionate use program in Spain from February 2015 to November 2017.

Patients and methods

Patient data were collected retrospectively from 35 hospitals in Spain. Patients with HR+/HER2- mBC who had progressed on ≥4 treatments for advanced disease were eligible.

Results

A total of 219 patients received palbociclib in combination with aromatase inhibitors (110; 50.2%), fulvestrant (87; 39.7%), tamoxifen (8; 3.6%) or as single agent (10; 4.6%). Mean age of the patients was 58 years; 31 patients (16.1%) were premenopausal and 162 (83.9%) were postmenopausal at the beginning of treatment with palbociclib. Patients had received a median of 3 previous lines of endocrine therapy (ET) for advanced disease. Real-world tumor response (rwTR) and clinical benefit rate were 5.9% (n = 13) and 46.2% (n = 101), respectively. The median real world progression-free survival (rwPFS) was 6.0 months (95% CI 5.7–7.0) and the median overall survival was 19.0 months (95% CI 16.4–21.7). Subgroup analysis revealed a significant difference in median rwPFS in patients treated with palbociclib plus fulvestrant depending on the duration of prior treatment with fulvestrant monotherapy (>6 versus ≤6 months; HR 1.93, 95% CI 1.37–2.73, p < 0.001). The most frequently reported toxicities were neutropenia, asthenia, thrombopenia and anemia.

Conclusions

Palbociclib can be an effective and safe treatment option in patients with heavily pretreated endocrine-sensitive mBC, especially in those with longer PFS to previous ET.