Palbociclib Group Research Articles

A systematic review of health-related quality of life outcomes in patients with advanced breast cancer treated with palbociclib.

Aim: To evaluate the impact of palbociclib treatment on health-related quality of life (HRQoL) in patients with hormone receptor-positive, human epidermal growth factor 2-negative advanced breast cancer (HR+/HER2- aBC) or metastatic breast cancer (mBC) in both the clinical and real-world setting. Materials & methods: A systematic literature review was conducted to identify clinical trials and real-world evidence studies up to June 2023 that reported HRQoL outcomes in patients with HR+/HER2- aBC or mBC treated with Palbociclib. Results: 15 unique studies reported across 35 records were identified. Of these, seven were randomized controlled trials (RCTs), three were single-arm clinical trials and five were real-world evidence (RWE) studies. HRQoL was generally found to be maintained in patients with HR+/HER2- aBC or mBC across RCTs, single-arm clinical trials and RWE studies. HRQoL measures across instruments, study types and line of therapy, were largely reported to be at least maintained if not improved from baseline among patients treated with palbociclib and were observed to be comparable or better in the palbociclib group versus monotherapy control arm in RCTs. Similar results were seen for treatment-related outcomes (e.g., sexual functioning, upset by hair loss, systemic therapy side effects etc.), and important individual patient outcomes, including pain, fatigue and physical functioning. Findings were also consistent across key clinical characteristics (visceral metastases, neutropenia), as well as patient populations often underrepresented in clinical trials (Asian patients, older adults). Conclusion: Overall, current evidence suggests that HRQoL is largely preserved with the addition of palbociclib to endocrine therapy in patients with HR+/HER2- aBC or mBC across study types and populations.

Comparative effectiveness analysis of survival with first-line palbociclib or ribociclib plus AI in HR + /HER2- advanced breast cancer (CEPRA study): preliminary analysis of real-world data from Thailand

BackgroundThe current standard first-line treatment for hormone receptor-positive/human epidermal growth factor receptor 2 negative (HR + /HER2 −) advanced breast cancer (ABC) is a combination of aromatase inhibitor (AI) plus CDK4/6 inhibitors (CDK4/6i). Direct comparison trials of different CDK4/6i are scarce. This real-world study compared the effectiveness of first-line AI plus ribociclib versus palbociclib.MethodsThis multicenter retrospective cohort study, conducted in six cancer centers in Thailand, enrolled patients with HR + /HER2 − ABC treated with first-line AI, and either ribociclib or palbociclib. Propensity score matching (PSM) was performed. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), overall response rate (ORR), time to chemotherapy (TTC), and adverse events.ResultsOf the 250 patients enrolled, 134 patients with ribociclib and 49 patients with palbociclib were captured after PSM. Baseline characteristics were well-balanced between groups. Median PFS in patients receiving ribociclib and palbociclib were 27.9 and 31.8 months, respectively (hazard ratio: 0.87; 0.55–1.37). The median OS in the AI + ribociclib arm was 48.7 months compared to 59.1 months in the AI + palbociclib arm (hazard ratio: 0.55; 0.29–1.05). The median TTC in the AI + palbociclib group was 56 months, but not reached in the AI + ribociclib group (p = 0.42). The ORR of AI + ribociclib and AI + palbociclib were comparable (40.5% vs. 53.6%, p = 0.29). Patients receiving palbociclib demonstrated a higher proportion of neutropenia compared to those receiving ribociclib, despite a similar dose reduction rate (p = 0.28). Hepatitis rate was similar between the ribociclib (21%) and palbociclib groups (22%). Additionally, a low incidence of QT prolongation was observed in both the ribociclib (5%) and palbociclib groups (4%).ConclusionThis preliminary analysis of a real-world study demonstrated the comparable effectiveness of ribociclib and palbociclib with AI as an initial therapy for HR + /HER2 − ABC. No statistically significant difference in PFS, OS, and TTC was found in patients treated with AI combined with palbociclib or ribociclib. Longer follow-up and further prospective randomized head-to-head studies are warranted.

The analysis of prescribing CDK4/6 inhibitors for patients with breast cancer in real clinical practice.

e13082 Background: The analysis of prescribing CDK4/6 inhibitors for patients with HR+/Her2neu- breast cancer was conducted at the St. Petersburg City Clinical Oncology Dispensary from April 2020 to October 2023. Patients in group 1 (n=365) received Palbociclib, and patients in group 2 (n=450) received Ribociclib. Methods: 99.45% of participants in the 1 group were female. In the 2 group all patients female. The average age of patients in both groups was 66 years. Results: In the first line of therapy, the clinical oncologist's choice more often leaned towards Ribociclib (p=0.0293). In later lines, Palbociclib was more frequently prescribed (p=0.0086). Ribociclib was significantly more often prescribed compared to Palbociclib in cases of primary hormone resistance (19.8%vs.13.9% (p=0.0288)). A higher "tumor burden" was documented at the start of therapy in patients receiving Ribociclib - 9.32% (5 or more loci of metastatic involvement). The frequency of overall response was significantly higher with Palbociclib (24.3%vs.11.7% (p=0.00001)), which is likely related to the higher incidence of primary hormone resistance and prescription in cases with a higher "tumor burden" in the Ribociclib group. The presence of PIK3CA mutations in patients of the Palbociclib group signifies a significant difference in response to therapy. The mPFS is 26(95% CI 16-29) when the mutation is present and 11(95% CI 9-14) when it is absent (p=0.0016). In the presence of metastatic liver impairment, significant differences in the mPFS assessment were in favor of Ribociclib (12 (95% CI 10-19) vs 11.0 (95% CI 9-15) (p<0.0001)). For the presence of a BRCA mutation, age, presence of bone metastases, brain metastases, visceral metastases (excluding liver), hormonal partner, there were no statistically significant differences between the groups for progression-free survival. The mPFS in both groups was comparable, and we didn't obtain statistically significant differences. In the 1st line the mPFS is not yet reached (p=0.602). In the 2nd line - in the Ribociclib group - 20, Palbociclib -22 (p=0.253). In the 3rd and later lines - the mPFS in the Ribocilib group - 19 (6.9-31.1), Palbociclib -14 (7.3-20.7) (p=0.775). The hematologic toxicity occurred significantly more often with Palbociclib (p=0.00001). As for Ribociclib, an undesirable event such as asthenia was prominent. The influence of dose-limiting toxicity on mPFS has been noted. In the presence of dose-limiting toxicity in the Palbociclib group, the mPFS has not been reached and is significantly different from the mPFS in patients who did not have a dose reduction. Conclusions: The analysis showed that Ribociclib is more often prescribed in the 1 line for patients with a higher 'tumor burden' and with primary hormone resistance. In relation to this, we observe a decrease in such an indicator as the frequency of overall response in this group of patients compared to Palbociclib.

Real-world comparison of the efficacy of three CDK4/6 inhibitors (CDK4/6i) in the first-line treatment of endocrine-sensitive advanced breast cancer (aBC): Single institution experience.

e13080 Background: The combination of CDK4/6i and endocrine therapy (ET) is the standard of care in the first-line treatment of hormone receptor positive (HR+), HER2- aBC. In registrational studies, the progression-free survival (PFS) of all three CDK4/6i ranged from 23.8 to 28.12 months and overall survival (OS) from 53.9 to 66.8. In Croatia, both ribociclib and palbociclib were approved for clinical use in August 2018 and abemaciclib in November 2019. Methods: This retrospective study included patients with endocrine-sensitive HR+, HER2- aBC treated with aromatase inhibitor (AI) and CDK4/6i in the first-line setting between August 2018 and October 2023 at University Hospital Centre Zagreb. Ethics committee approval was obtained before the study was commenced. Patient demographics, clinical presentation, tumor characteristics and treatment data were collected. Real-world PFS (rwPFS) and OS analyses were done with the final data cut-off date of December 31, 2023, using type 1 right censoring. Data were analyzed using the Kaplan-Meier method. Results: Of the 274 patients treated with a combination of CDK4/6i and ET in the first-line setting, 172 with endocrine-sensitive tumors (98 de novo metastatic and 74 with treatment-free interval longer than 12 months) were eligible for the study, of which 41.86% (72/172) received ribociclib, 44.19% (76/172) palbociclib, and 13.95% (24/172) abemaciclib. Overall rwPFS was 48 months (95% CI:35-53). In the abemaciclib group, median rwPFS and OS were not reached in the follow-up period. The rwPFS was 48 (95% CI:27-53) for ribociclib and 47 (95% CI:30-49) for palbociclib. The overall OS was 62 months (95% CI:47-62). Median OS in the ribociclib group was 62 months (95% CI:40-62) and in the palbociclib group 52 (95% CI:42-54) months. Conclusions: The PFS and OS results for palbociclib and ribociclib in this retrospective real-world study correlate with results from randomized clinical trials, confirming some inferiority of palbociclib compared to ribociclib in the context of OS. Due to the later availability of the drug, larger sample size and longer follow-up will be needed to make definitive conclusions on the efficacy of abemaciclib.

Abstract PO4-05-04: Comparative effectiveness of Palbociclib plus Aromatase inhibitor versus fulvestrant alone as initial endocrine therapy for HR+/HER2- advanced breast cancer in Chinese clinical practice: a real-world study

Abstract Background: In the real world, there are still a large number of HR+/HER2- advanced breast cancer patients receiving initial endocrine therapy with fulvestrant monotherapy in China, especially patients with bone metastases only. It is due to lack of data comparing the effective between Palbociclib combined with AI and fulvestrant monotherapy as initial endocrine therapy. On the other hand, there are economic factors and access issues. According to the National Cancer Center's previous clinical experience, Palbociclib combined with AI is superior to fulvestrant monotherapy in HR+/HER2- advanced breast cancer patients receiving initial endocrine therapy. Therefore, we collected and summarized the previous clinical data in our center to compare the effective of Palbociclib combined with AI and fulvestrant monotherapy for HR+/HER2-advanced breast cancer patients receiving initial endocrine therapy in China. Patients and methods: This is a retrospective real-world study of multicenter studies. It aimed at verifying the effective of Palbociclib combined with AI and fulvestrant monotherapy for HR+/HER2-advanced breast cancer patients receiving initial endocrine therapy in China. A total of 392 patients with ≥3 months of follow-up received Palbociclib plus AI or fulvestrant alone in the first-line setting between April 1, 2015 and February 1, 2023. Stabilized inverse probability treatment weighting (sIPTW) was used to balance baseline demographic and clinical characteristics. Real-world progression-free survival (rwPFS) and overall survival (OS) were analyzed. Results: After sIPTW adjustment, a median follow-up of 37 months (range 34-40) in the Palbociclib group and 59 months (range 56-61) in those taking fulvestrant alone. Palbociclib combination regiment was associated with significantly longer median rwPFS compared to fulvestrant alone (22.0 vs 14.0 months; HR,0.469;95% CI 0.370–0.594, p< 0·0001). Median OS was not reached in the Palbociclib group and was 57 months (95% CI 54.0–66.0) in the fulvestrant group(HR,0.666; 95% CI 0.437–1.017, p< 0·94). Conclusion: In the real-world population of patients, palbociclib combined with AI endocrine therapy is superior to fulvestrant monotherapy in HR+/HER2- advanced breast cancer patients receiving initial endocrine therapy. PFS and OS before IPTW PFS and OS after IPTW Table patient characteristics Citation Format: Jian Yue, Xue Wang, Jie Ju, Zixiang Yang, Tong Wei, Peng Yuan, Min Gao, Ling Xu, Yin Guan. Comparative effectiveness of Palbociclib plus Aromatase inhibitor versus fulvestrant alone as initial endocrine therapy for HR+/HER2- advanced breast cancer in Chinese clinical practice: a real-world study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-05-04.

Abstract PO1-04-10: Body Mass Index and Treatment Efficacy in advanced Luminal Breast Cancer: Insights from the GEICAM/2013-02 (PEARL) trial

Abstract Background: Endocrine therapy (ET) and treatment directed against molecular targets (CDK 4/6, PI3K, mTOR) constitute the basis of initial treatments for patients with advanced luminal breast cancer. Most of these treatments are oral and have been developed at a fixed dose, without weight adjusted dosing. There is little evidence on the influence that patients’ weight might have on clinical outcomes of these oral drugs in the context of a randomized clinical trial. The present study analyzes the potential impact of the weight of patients treated in the two cohorts of the PEARL trial (NCT02028507) on Progression-Free Survival (PFS), Overall Survival (OS) and the incidence of side effects in each treatment arm. Methods: GEICAM/2013-02 (PEARL) is a multicenter, phase III randomized clinical trial that enrolled patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer (MBC) who progressed to a prior aromatase inhibitor. Patients were randomized 1:1 to receive ET + palbociclib or capecitabine. Patient weight was assessed based on baseline body mass index (BMI) categories: normal (BMI ≤25 Kg/m2), overweight (BMI 25-29.9 Kg/m2) and obesity (BMI ≥30 Kg/m2). Cox's stratified proportional hazard model was used for survival analysis. Adverse events were assessed and graded according to National Cancer Institute common terminology criteria for adverse events (NCI-CTCAE) version 4.0. Results: A total of 600 patients were included in the study and all were evaluable for the weight-based analysis, including 301 in the ET +palbociclib arm and 299 in the capecitabine arm. The distribution of patient’s weights is shown in Table 1. For the Intention-to-treat (ITT) population, no significant difference in the median OS was found between the different weight categories (Normal: 32.8 months vs overweight: 31.9 months, [p=0.467]; obese: 32 months [p=0.407]). Specifically, for patients with normal weight, the median PFS was 9.3 months in the ET + palbociclib group compared to 9.0 months in the capecitabine group (hazard ratio (HR) 0.83, 95% confidence interval [CI]: 0.61-1.13; p=0.23). In the overweight group, the PFS was 7.5 months in the ET+palbociclib group and 11.1 months in the capecitabine group (HR 1.17, 95% CI: 0.87-1.58; p=0.30) while for the obese group, the PFS was 5.7 months vs 11.7 months (HR 1.14, 95% CI: 0.82-1.59; p=0.43), respectively. No substantial differences in the incidence of grade ≥ 3 events were observed when considering weight categories in the different treatment groups (capecitabine arm (Normal: 60%, Overweight: 70.4%, Obese: 61.6%) and ET+palbociclib arm (Normal: 74.5%, Overweight: 76.1%, Obese: 51.6%). Conclusions: Our findings, despite not finding statistically significant differences, suggest a potentially clinically relevant trend towards improved PFS with capecitabine in overweight and obese patients compared to those receiving palbociclib plus ET. The impact of weight on the outcomes with fixed-dose oral drugs warrants further investigation in future studies. Table 1. Citation Format: Manuel Alva, Sara López-Tarruella, Christoph Zielinski, Manuel Ruíz - Borrego, Nicholas Turner, Eva Ciruelos, Montserrat Muñoz, Begoña Bermejo, Mireia Margelí, Antonio Antón, Zsuzsanna Kahan, Tibor Csöszi, Maribel Casas, Laura Murillo, Serafin Morales Murillo, Emilio Alba, Einav Nili-Gal Yam, Angel Guerrero, Lourdes Calvo, Juan de la Haba-Rodríguez, Manuel Ramos, Isabel Álvarez, Andrés García-Palomo, María Koehler, José Ángel García-Sáenz, J. Ignacio Chacón, Claire Swift, Christiane Thallinger, Miguel Gil-Gil, Miguel Martín. Body Mass Index and Treatment Efficacy in advanced Luminal Breast Cancer: Insights from the GEICAM/2013-02 (PEARL) trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-04-10.

A comparison between the adverse event profiles of patients receiving palbociclib and abemaciclib: analysis of two real-world databases.

Palbociclib and abemaciclib are cyclin-dependent kinase (CDK) 4/6 inhibitors currently used to treat breast cancer. Although their therapeutic efficacies are considered comparable, differences in adverse event (AE) profiles of the two drugs remain unclear. We analysed two real-world databases, the World Health Organization's VigiBase and the Food and Drug Administration Adverse Event Reporting System (FAERS), to identify differences in AE profiles of palbociclib and abemaciclib. Data of patients with breast cancer receiving palbociclib or abemaciclib recorded until December 2022 were extracted from the VigiBase and FAERS databases. In total, 200 types of AEs were analysed. The reporting odds ratios were calculated using a disproportionality analysis. Cytopenia was frequently reported in patients receiving palbociclib, whereas interstitial lung disease and diarrhoea were frequently reported in those receiving abemaciclib. Moreover, psychiatric and nervous system disorders were more common in the palbociclib group, whereas renal and urinary disorders were more common in the abemaciclib group. This study is the first to show comprehensively the disparities in the AE profiles of palbociclib and abemaciclib. The findings highlight the importance of considering these differences when selecting a suitable CDK4/6 inhibitor to ensure safe and favourable outcomes for patients with breast cancer.

Clinical Impact of CDK4/6 Inhibitors in De Novo or PR- or Very Elderly Post-Menopausal ER+/HER2- Advanced Breast Cancers.

The CDK4/6 inhibitors significantly increase progression-free survival (PFS) in ER+/HER2- advanced breast cancer patients. In clinical trials, overall survival (OS) improvement has been demonstrated for ribociclib and abemaciclib but not for palbociclib. We undertook a real-world evaluation of PFS and OS in 227 post-menopausal patients who received first-line CDK4/6 inhibitors. There is no significant difference in median PFS (27.5 months vs. 25.7 months, p = 0.3) or median OS (49.5 months vs. 50.2 months, p = 0.67) in patients who received either palbociclib or ribociclib, respectively. De novo disease is significantly associated with prolonged median PFS and median OS compared with recurrence disease (47.1 months vs. 20.3 months (p = 0.0002) and 77.4 months vs. 37.3 months (p = 0.0003), respectively). PR- tumours have significantly reduced median PFS and OS compared with PR+ disease (19.2 months vs. 38 months (p = 0.003) and 34.3 months vs. 62.6 months (p = 0.02), respectively). In the very elderly (>80 years), median PFS and OS are significantly shorter compared with patients who are 65 years or below (14.5 months vs. 30.2 months (p = 0.01), and 77.4 months vs. 29.6 months (p = 0.009), respectively) in the palbociclib group. Our data suggest that the benefit in the very elderly is limited, and PR+/de novo disease obtains the maximum survival benefit.

Neoadjuvant palbociclib plus either giredestrant or anastrozole in oestrogen receptor-positive, HER2-negative, early breast cancer (coopERA Breast Cancer): an open-label, randomised, controlled, phase 2 study

The development of more potent selective oestrogen receptor antagonists and degraders (SERDs) that can be orally administered could help to address the limitations of current endocrine therapies. We report the primary and final analyses of the coopERA Breast Cancer study, designed to test whether giredestrant, a highly potent, non-steroidal, oral SERD, would show a stronger anti-proliferative effect than anastrozole after 2 weeks for oestrogen receptor-positive, HER2-negative, untreated early breast cancer. In this open-label, randomised, controlled, phase 2 study, postmenopausal women were eligible if they were aged 18 years or older; had clinical T stage (cT)1c to cT4a-c (≥1·5 cm within cT1c) oestrogen receptor-positive, HER2-negative, untreated early breast cancer; an Eastern Cooperative Oncology Group performance status of 0-1; and baseline Ki67 score of at least 5%. The study was conducted at 59 hospital or clinic sites in 11 countries globally. Participants were randomly assigned (1:1) to giredestrant 30 mg oral daily or anastrozole 1 mg oral daily on days 1-14 (window-of-opportunity phase) via an interactive web-based system with permuted-block randomisation with block size of four. Randomisation was stratified by cT stage, baseline Ki67 score, and progesterone receptor status. A 16-week neoadjuvant phase comprised the same regimen plus palbociclib 125 mg oral daily on days 1-21 of a 28-day cycle, for four cycles. The primary endpoint was geometric mean relative Ki67 score change from baseline to week 2 in patients with complete central Ki67 scores at baseline and week 2 (window-of-opportunity phase). Safety was assessed in all patients who received at least one dose of study drug. The study is registered with ClinicalTrials.gov (NCT04436744) and is complete. Between Sept 4, 2020, and June 22, 2021, 221 patients were enrolled and randomly assigned to the giredestrant plus palbociclib group (n=112; median age 62·0 years [IQR 57·0-68·5]) or anastrozole plus palbociclib group (n=109; median age 62·0 [57·0-67·0] years). 15 (7%) of 221 patients were Asian, three (1%) were Black or African American, 194 (88%) were White, and nine (4%) were unknown races. At data cutoff for the primary analysis (July 19, 2021), the geometric mean relative reduction of Ki67 from baseline to week 2 was -75% (95% CI -80 to -70) with giredestrant and -67% (-73 to -59) with anastrozole (p=0·043), meeting the primary endpoint. At the final analysis (data cutoff Nov 24, 2021), the most common grade 3-4 adverse events were neutropenia (29 [26%] of 112 in the giredestrant plus palbociclib group vs 29 [27%] of 109 in the anastrozole plus palbociclib group) and decreased neutrophil count (17 [15%] vs 16 [15%]). Serious adverse events occurred in five (4%) patients in the giredestrant plus palbociclib group and in two (2%) patients in the anastrozole plus palbociclib group. There were no treatment-related deaths. One patient died due to an adverse event in the giredestrant plus palbociclib group (myocardial infarction). Giredestrant offers encouraging anti-proliferative and anti-tumour activity and was well tolerated, both as a single agent and in combination with palbociclib. Results justify further investigation in ongoing trials. F Hoffmann-La Roche.

Time to treatment failure (TTF) and overall survival (OS) with palbociclib (PAL) plus endocrine therapy (ET) versus ET in HR+/HER2- advanced breast cancer (ABC) patients: A real-world multicenter study from China.

e13048 Background: Randomized controlled trials (RCTs) found that PAL plus ET had a considerable survival advantage in patients with HR+/HER2- ABC compared to ET. This real-world study aimed to complement the existing RCTs in addition to accounting for patient characteristics, adherence to treatment, and socioeconomic factors. Methods: Data of patients who had HR+HER2- ABC and received PAL plus ET (N=216) and ET (N=215) from September 2007 to May 2020 were retrospectively retrieved from the electronic medical record system of seven cancer centers across China. Stabilized inverse probability of treatment weighting (SIPTW) was applied to strictly balance the variables between the two cohorts. Results: A total of 400 patients were eligible for the study analysis. PAL plus ET was administered to 204 (51%) patients, and 196 (49%) patients received ET only. At the end of the observation, treatment failure occurred in 162 (79%) patients and 183 (93%) patients in both cohorts, due to disease progression (93.2% vs. 96.8%), financial inability (4.9% vs. 0%), intolerable adverse reactions (1.9% vs. 0.5%), and unknown reasons (0% vs. 2.7%). Most patients were postmenopausal (71.8%) and had visceral metastasis (65.2%). De-novo metastatic disease was seen in 13.0% of patients, and 45.2% of patients received first-line ET. More than half of the patients (57.8%) received aromatase inhibitors, and 38.5% received estrogen receptor degrader fulvestrant. With a median follow-up period of 39.5 and 40.5 months, the median TTF in PAL plus ET vs. ET was 11.8 vs. 9.47 months (HR=0.69, 95% CI: 0.56-0.86, p=0.00057), and OS analysis showed a median OS not reached (NR) vs. 40.7 months (HR=0.84, 95% CI: 0.62-1.13, p=0.25). Upon SIPTW, the standardized differences (-0.117 to 0.096) showed a good balance between the cohorts. Weighted median TTF was significantly longer in the PAL plus ET group than the ET group (11.8 vs. 7.07 months, HR=0.63, 95% CI: 0.49-0.80, p=0.000139). However, the results of weighted median OS were not statistically significant (NR vs. 38 months, HR=0.80, 95% CI: 0.53-1.21, p=0.29). In the balanced subgroup analysis, TTF showed a similar trend to that in the overall population, and in patients with de-novo metastatic disease and non-central nervous system (CNS) metastasis, OS was significantly longer in the PAL plus ET group than ET (HR=0.256, 95% CI: 0.112-0.586, p for interaction=0.013; HR=0.657, 95% CI: 0.443-0.973, p for interaction=0.013, respectively). Conclusions: Comparatively, PAL plus ET had significantly longer TTF than ET, supporting the use of PAL plus ET in HR+/HER2– ABC patients in real-world settings. In patients with de-novo metastatic disease and non-CNS metastasis, PAL plus ET showed significant OS benefit compared to ET, however, follow-up time needs to be increased in further studies.

Clinical features of CDK4/6 inhibitor-related interstitial lung disease in patients with breast cancer: a case series study.

Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are the standard treatment for advanced hormone receptor-positive breast cancer. Although interstitial lung disease is a rare (1-3.3%) but serious adverse event associated with CDK4/6 inhibitors, the incidence of interstitial lung disease in Japanese patients in the real world and the risk factors of interstitial lung disease are not clear. We retrospectively investigated the incidence of interstitial lung disease in 224 patients with advanced breast cancer who received CDK4/6 inhibitors at our hospital between 31 January 2017 and 31 January 2021. The correlation of age (>50 vs ≤50years), presence or absence of previous history of interstitial lung disease, lung metastasis, smoking history and chest radiation with the development of interstitial lung disease was evaluated. In total, 177 cases received palbociclib, 39 cases received abemaciclib and 8 cases received both palbociclib and abemaciclib, constituting a palbociclib group (n=185) and an abemaciclib group (n=47). At a median observation period of 607days, 8.0% (18/224) cases (13 definite and 5 probable cases) had interstitial lung disease; 6.5% (12/185) of palbociclib-treated and 13% (6/47) of abemaciclib-treated cases. The median time to interstitial lung disease onset was 178 (range, 14-750) days. There was no significant correlation between the background factors studied and the development of interstitial lung disease. The frequency of CDK4/6 inhibitor-induced interstitial lung disease was higher than that reported in clinical trials. We did not identify any risk factors for the development of interstitial lung disease in this study, and thus, larger studies that include patient predisposition are required.

Palbociclib plus letrozole versus placebo plus letrozole in Asian postmenopausal women with oestrogen receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer: Primary results from PALOMA-4

BackgroundThe cyclin-dependent kinase 4/6 inhibitor palbociclib has demonstrated efficacy and a manageable safety profile in combination with endocrine therapy in women with oestrogen receptor–positive (ER+)/human epidermal growth factor receptor 2–negative (HER2–) advanced breast cancer (ABC) in international phase 3 trials. The phase 3 PALOMA-4 trial evaluated the efficacy and safety of palbociclib plus letrozole versus placebo plus letrozole in Asian women with ER+/HER2– ABC. MethodsPostmenopausal women (n = 340) with no prior systemic treatment for advanced disease were randomised 1:1 to palbociclib (125 mg/d orally; 3 weeks on, 1 week off) plus letrozole (2.5 mg/d orally; continuously) or placebo plus letrozole. The primary end-point was investigator-assessed progression-free survival (PFS). Secondary end-points included tumour response and safety. ResultsMedian (95% CI) PFS was 21.5 (16.6–24.9) months with palbociclib plus letrozole and 13.9 (13.7–16.6) months with placebo plus letrozole (hazard ratio, 0.68 [95% CI, 0.53–0.87]; P = 0.0012). Consistent with the established safety profile, the most common adverse events (AEs) with palbociclib plus letrozole were neutropenia, leukopenia, thrombocytopaenia, and anaemia. Grade 3/4 neutropenia was reported in 84.5% of patients in the palbociclib arm versus 1.2% in the placebo arm. One serious AE of febrile neutropenia in the palbociclib group was reported. ConclusionsFindings from PALOMA-4 support the efficacy and safety of first-line palbociclib plus letrozole in postmenopausal Asian women with ER+/HER2– ABC. No new safety concerns of palbociclib plus letrozole were identified. Trial registrationClinicaltrials. gov, NCT02297438.

3'-[18F]fluoro-3'-deoxythymidine ([18F]FLT) Positron Emission Tomography as an In Vivo Biomarker of inhibition of CDK 4/6-Rb pathway by Palbociclib in a patient derived bladder tumor

BackgroundSeveral new generation CDK4/6 inhibitors have been developed and approved for breast cancer therapy in combination with endocrine therapeutics. Application of these inhibitors either alone or in combination in other solid tumors has been proposed, but no imaging biomarkers of response have been reported in non-breast cancer animal models. The purpose of this study was to evaluate 3'-[18F]fluoro-3'-deoxythymidine ([18F]FLT) Positron Emission Tomography (PET) as in vivo biomarker of response to palbociclib in a non-breast cancer model.MethodsTwenty-four NSG mice bearing patient derived xenografts (PDX) of a well-characterized bladder tumor were randomized into 4 treatment groups: vehicle (n = 6); palbociclib (n = 6); temozolomide (n = 6); and palbociclib plus temozolomide (n = 6) and treated with two cycles of therapy or vehicle. Tumor uptake of [18F]FLT was determined by micro-PET/CT at baseline, 3 days, and 9 days post initiation of therapy. Following the second cycle of therapy, the mice were maintained until their tumors reached a size requiring humane termination.Results[18F]FLT uptake decreased significantly in the palbociclib and combination arms (p = 0.0423 and 0.0106 respectively at day 3 and 0.0012 and 0.0031 at day 9) with stable tumor volume. In the temozolomide arm [18F]FLT uptake increased with day 9 uptake significantly different than baseline (p = 0.0418) and progressive tumor growth was observed during the treatment phase. All groups exhibited progressive disease after day 22, 10 days following cessation of therapy.ConclusionSignificant decreases in [18F]FLT uptake as early as three days post initiation of therapy with palbociclib, alone or in combination with temozolomide, in this bladder cancer model correlates with an absence of tumor growth during therapy that persists until day 18 for the palbociclib group and day 22 for the combination group (6 days and 10 days) following cessation of therapy. These results support early modulation of [18F]FLT as an in vivo biomarker predictive of palbociclib therapy response in a non-breast cancer model.

Proton pump inhibitors may reduce the efficacy of ribociclib and palbociclib in metastatic breast cancer patients based on an observational study

IntroductionApproximately 20–33% of all cancer patients are treated with acid-reducing agents (ARAs), most commonly proton pump inhibitors (PPIs), to reduce gastroesophageal reflux disease symptoms. Palbociclib and ribociclib are weak bases so their solubility depends on different pH. The solubility of palbociclib dramatically decreases to < 0.5 mg/ml when pH is above 4,5 but ribociclibs’ solubility decreases when pH increases above 6,5. In the current study, we aimed to investigate the effects of concurrent PPIs on palbociclib and ribociclib efficacy in terms of progression-free survival in metastatic breast cancer (mBC) patients.Patients and methodsWe enrolled hormone receptor-positive, HER2-negative mBC patients treated with endocrine treatment (letrozole or fulvestrant) combined palbociclib or ribociclib alone or with PPI accompanying our observational study. During palbociclib/ribociclib therapy, patients should be treated with "concurrent PPIs" defined as all or more than half of treatment with palbociclib/ribociclib, If no PPI was applied, it was defined as ‘no concurrent PPI’, those who used PPI but less than half were excluded from the study. All data was collected from real-life retrospectively.ResultsOur study included 217 patients, 105 of whom received palbociclib and 112 received ribociclib treatment. In the study population CDK inhibitor treatment was added to fulvestrant 102 patients ( 47%), to letrozole 115 patients (53%). In the Palbociclib arm fulvestrant/letrozole ratio was 53.3/46.7%, in the ribociclib arm it was 41.07/58.93%. Of 105 patients who received palbociclib, 65 were on concomitant PPI therapy, 40 were not. Of the 112 patients who received ribociclib, 61 were on concomitant PPI therapy, 51 were not. In the palbociclib group, the PFS of the patients using PPIs was shorter than the PFS of the patients not using (13.04 months vs. unreachable, p < 0.001). It was determined that taking PPIs was an independent predictor of shortening PFS (p < 0.001) in the multivariate analysis, In the ribociclib group, the PFS of the patients using PPIs was shorter than the PFS of the patients not using (12.64 months vs. unreachable, p = 0.003). It was determined that taking PPIs was single statistically independent predictor of shortening PFS (p = 0.003, univariate analysis).ConclusionsOur study demonstrated that concomitant usage of PPIs was associated with shorter PFS in mBC treated with both ribociclib and especially palbociclib. If it needs to be used, PPI selection should be made carefully and low-strength PPI or other ARAs (eg H2 antagonists, antacids) should be preferred.

Palbociclib plus endocrine therapy significantly enhances overall survival of HR+/HER2- metastatic breast cancer patients compared to endocrine therapy alone in the second-line setting: A large institutional study.

Cyclin-dependent-kinase-4/6 inhibitor (CDK4/6i) plus endocrine therapy (ET) is standard of care for patients with advanced hormone receptor (HR)-positive, HER2-negative breast cancer (BC). The Breast Medical Oncology database at MD Anderson Cancer Center (MDACC) was analyzed to assess effectiveness of the CDK4/6i palbociclib plus ET compared to ET alone. From a total of 5402 advanced HR+ HER2- BC patients referred to MDACC between 1997 and 2020, we identified eligible patients who received palbociclib in combination with first-line (n=778) and second-line (n=410) ET. We further identified "control" patients who received ET alone in the first-line (n=2452) and second-line (n=1183) settings. Propensity score matching analysis was conducted to balance baseline demographic and clinical characteristics between palbociclib and control cohorts to assess the effect of palbociclib treatment on progression-free survival (PFS) and overall survival (OS). For propensity-matched-cohort in the first-line setting (n=708), palbociclib group had significantly longer median PFS (17.4 vs 11.1months; P < .0001) compared to controls. Median OS (44.3 vs 40.2months) did not show a statistically significant benefit in the first line setting. However, in the second-line setting, with 380 propensity-matched-cohort, the palbociclib group had significantly longer PFS (10 vs 5months, P < .0001) as well as OS (33 vs 24 months; P < .022), compared to controls. We conclude that in this single center analysis of a large cohort of metastatic HR+ HER2- BC patients, palbociclib in combination with ET was associated with improved PFS in both first-line and second-line settings and OS in the second-line setting compared to ET alone cohort.

Abstract P5-13-33: Longitudinal transcriptional profiling of CTCs in metastatic breast cancer patients receiving the CDK4/6 inhibitor Palbociclib to predict therapy response

Abstract Background: CDK4/6 inhibitors represent a new treatment option for metastatic (M), hormone receptor-positive/HER2-negative (HR+/HER2-) breast cancer (BC) patients. However, predictive markers have not been defined to decide who will benefit from CDK4/6 inhibitors. Circulating tumor cells (CTCs) represent the tumoral heterogeneity in real time and are available for molecular characterization via minimal-invasive sequential blood sampling. Here, we aim to identify biomarkers of resistance to Palbociclib by conducting transcriptional profiling of CTCs before therapy initiation (baseline) and after six months under treatment. Methods: Blood of 50 HR+/HER2-MBC patients drawn at baseline of Palbociclib plus endocrine treatment and blood of 20 HR+/HER2-MBC patients drawn before initiation of endocrine monotherapy, as well as blood samples of these 70 patients after six months under treatment will be analyzed. Patients with progressive disease within the first six months of treatment were defined as non-responders. Isolation of CTCs was conducted using positive immunomagnetic selection targeting EpCAM, EGFR and HER2 (AdnaTest EMT2/StemCell Select). cDNA was analyzed by a new multimarker qPCR panel utilizing QuantiNova LNA Probe assays targeting 25 genes. qPCR data was normalized to CD45 to substract the effect of contaminating leukocytes. Additionally, data was normalized to 20 healthy female donor controls to identify BC specific overexpression signals with a specificity of &amp;gt;90% for all targets. Consumables: QIAGEN, Germany. Results: We successfully established the multimarker qPCR according to the MIQE guidelines. Up to now, the binary mRNA overexpression signals of 25 targets in CTCs isolated at baseline were analyzed in 40 of the total 70 planned MBC patients. In detail, 24 of those 40 patients were treated with Palbociclib plus endocrine therapy, including seven responders and 15 non-resonders, while the 16 other patients were treated with endocrine therapy alone (seven non-responders and nine responders). In the entire cohort, STAT1 signals were significantly related to a decreased overall survival (p=0.0034) and NFKB1 signals correlated significantly with an increased progression free survival (PFS; p=0.027). In the Palbociclib group, CDK2, WWTR1 and YAP1 overexpression signals were more common in non-responders compared with responders. MLH1 and NFKB1 signals were more common in responders than in non-responders. In this cohort, MLH3 overexpression at baseline was significantly correlated with prolonged PFS (p=0.047) and the patient with the longest PFS (35 months) was the only patient with detectable ERBB4, JUN, CETN2 and TEAD2 signals. In the control group treated with endocrine therapy alone, signal prevalence of CXCR4 and STAT1 were increased in the non-responders versus responders and ABCC2, ESR1, FAT4 and FGFR1 signals were more frequently detected in the responders. Conclusion: Transcriptional profiling of CTCs represents a real-time snapshot of the disease complexity. Characterization of the CTCs isolated from blood drawn at baseline is promising for the identification of urgently needed predictive markers (here MLH3 overexpression), while characterization of CTCs isolated under treatment can elucidate the transcriptional dynamics and might be used as monitoring marker by differentiation of non-responders and responders. We will finalize CTC analysis of the entire cohort and will continue blood sampling of additional Palbociclib treated patients, also in the follow-up of the disease, to validate CTC MLH3 overexpression as predictive biomarker for CDK4/6 inhibitor treatment and moreover, to find further overexpression signals in CTCs relevant for MBC therapy management. Citation Format: Sabine Kasimir-Bauer, Charlotte Gruber, Oliver Hoffmann, Rainer Kimmig, Corinna Keup. Longitudinal transcriptional profiling of CTCs in metastatic breast cancer patients receiving the CDK4/6 inhibitor Palbociclib to predict therapy response [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-13-33.

Safety of adjuvant CDK4/6 inhibitors during the COVID-19 pandemic.

Safety of adjuvant CDK4/6 inhibitors during the COVID-19 pandemic.

Comparative effectiveness of first-line palbociclib plus letrozole versus letrozole alone for HR+/HER2\u2212 metastatic breast cancer in US real-world clinical practice

BackgroundFindings from randomized clinical trials may have limited generalizability to patients treated in routine clinical practice. This study examined the effectiveness of first-line palbociclib plus letrozole versus letrozole alone on survival outcomes in patients with hormone receptor–positive (HR+)/human epidermal growth factor receptor–negative (HER2−) metastatic breast cancer (MBC) treated in routine clinical practice in the USA.Patients and methodsThis was a retrospective observational analysis of electronic health records within the Flatiron Health Analytic Database. A total of 1430 patients with ≥ 3 months of follow-up received palbociclib plus letrozole or letrozole alone in the first-line setting between February 3, 2015, and February 28, 2019. Stabilized inverse probability treatment weighting (sIPTW) was used to balance baseline demographic and clinical characteristics. Real-world progression-free survival (rwPFS) and overall survival (OS) were analyzed.ResultsAfter sIPTW adjustment, median follow-up was 24.2 months (interquartile range [IQR], 14.2–34.9) in the palbociclib group and 23.3 months (IQR, 12.7–34.3) in those taking letrozole alone. Palbociclib combination treatment was associated with significantly longer median rwPFS compared to letrozole alone (20.0 vs 11.9 months; hazard ratio [HR], 0.58; 95% CI, 0.49–0.69; P < 0.0001). Median OS was not reached in the palbociclib group and was 43.1 months with letrozole alone (HR, 0.66; 95% CI, 0.53–0.82; P = 0.0002). The 2-year OS rate was 78.3% in the palbociclib group and 68.0% with letrozole alone. A propensity score matching analysis showed similar results.ConclusionsIn this “real-world” population of patients with HR+/HER2− MBC, palbociclib in combination with endocrine therapy was associated with improved survival outcomes compared with patients treated with letrozole alone in the first-line setting.Trial registrationClinicaltrials.gov; NCT04176354

Abstract PS5-19: Exploratory biomarker analysis of Young-PEARL [palbociclib plus exemestane with GnRH agonist versus capecitabine in premenopausal women with HR (hormone receptor)-positive, HER2-negative metastatic breast cancer (MBC)] study

Abstract Background: Young-PEARL study showed median progression-free survival (PFS) of 20·1 months in the palbociclib plus endocrine therapy group versus 14·4 months in the capecitabine group (hazard ratio 0·659 [95% CI 0·437-0·994], log-rank p=0·0235). We conducted exploratory biomarker analysis to predict the efficacy of the trial. Methods: This was a phase II trial that randomized 184 patients with HR+ MBC in premenopausal women to palbociclib plus exemestane with GNRH agonist (Arm A, n=79) versus capecitabine (Arm B, n=62). We performed targeted sequencing (CancerSCANTM) containing 375 cancer-related genes (141 patients) and whole transcriptome sequencing (165 patients) using baseline tumor samples to examine genomic alteration in relation to drug response in terms of PFS. Result: By research-based PAM50 subtyping, 73% of patients classified as Luminal (Luminal A and Luminal B), and showed better prognosis in all patients and Arm A (p&amp;lt;0.05) in compared to no survival difference in Arm B (p=0.284). PFS difference between LumA and LumB was not statistically significant in Arm A (p=0.196). PIK3CA mutation (41%), TP53 mutation (33%), GATA3 mutation (25%), CCDN1 CNV (29%), BRCA2 mutation (14%) were the most frequently detected in this population. High TMB, TP53 mutation, ClinVar pathogenic somatic BRCA2 mutation (3.5%) showed worse prognosis in Arm A (p&amp;lt;0.05). Non-luminal patients with TP53 or BRCA2 mutations were poor prognosis in Arm A. Patients with BRCA2 pathogenic mutations showed worse prognosis regardless PAM50 subtypes, and luminal patients showed longer PFS compared to non-luminal patients among patients without BRCA2 pathogenic mutations in Arm A. RB1 loss, known as a resistant biomarker of CDK4/6 inhibitor was found in 4% of Arm A, and was associated with shorter PFS (log2 HR=2.26, 95% CI 0.51 to 4.01, p=0.011). AURKA mutation/amplification and RAD51C amplification were significantly associated to the patients with PFS less than 6 month. ESR1 mutations were found in 3.5% of patients, which was less than PEARL (29.4%) and PALOMA-3 (25.1%) trials. ESR1 mutations and ESR1/2 expression were not associated with shorter PFS. Notch 2/3/4 pathway expression was lower in patients with longer PFS (PFS more than 20month). ETIMATE ImmuneScore was higher in non-luminal compared to luminal patients, and didn’t show survival difference in Arm A, but luminal patients with low ImmuneScore showed better prognosis. The relative proportion of 22 immune cell types was deconvoluted by CIBERSORT, and T cell CD4 memory resting, Macrophage M0 and M2 were abundant. NK cell activated was higher proportion in patients with longer PFS. Low TIL patients with low interferon and high T cell regulation expression showed worse prognosis. Germline BRCA mutation and integrated analyses of genomic and transcriptomic profiles will be reported. Conclusions: The alteration of a few genes including Rb1 loss may be associated with resistance of palbociclib in HR-positive premenopausal population with MBC. Luminal type showed better prognosis, and BRCA2 pathogenic mutation showed worse prognosis regardless luminal/non-luminal type. ESR1 mutation was found in low population frequency because all patients didn’t received AI therapy. Further exploration of molecular variables is warranted to determine and validate biomarkers of efficacy. Clinical trial information: NCT02592746. Citation Format: Kyunghee Park, Gun Min Kim, Kyung Hae Jung, Seok Yun Kang, In Hae Park, Jee Hyun Kim, Hee Kyung Ahn, Woong-Yang Park, Seock-Ah Im, Yeon Hee Park. Exploratory biomarker analysis of Young-PEARL [palbociclib plus exemestane with GnRH agonist versus capecitabine in premenopausal women with HR (hormone receptor)-positive, HER2-negative metastatic breast cancer (MBC)] study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS5-19.

Palbociclib Plus Fulvestrant in Korean Patients from PALOMA-3 With Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer.

In the PALOMA-3 trial, the median progression-free survival (PFS) was longer among patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) advanced breast cancer (ABC) treated with palbociclib plus fulvestrant than those treated with placebo plus fulvestrant. This subgroup analysis examined the efficacy and safety of palbociclib among Korean patients enrolled in PALOMA-3 (n = 43 [palbociclib group, n = 24; placebo group, n = 19]). In both groups, > 40% of patients were pre/perimenopausal at enrollment. The median PFS was significantly prolonged with palbociclib vs. placebo (12.3 [95% confidence interval (CI), 9.1–not estimable] vs. 5.4 months [95% CI, 1.9–9.2]; hazard ratio, 0.40 [95% CI, 0.19–0.83]; one-sided p = 0.005), and the confirmed objective response was 21.1% and 11.8%, respectively (odds ratio, 2.0 [95% CI, 0.24–24.8]). Neutropenia was the most common adverse event associated with palbociclib. Overall, palbociclib plus fulvestrant was effective and generally safe among Korean patients with HR+/HER2− ABC, regardless of menopausal status.