LETROZOLE IMPROVES PROGRESSION-FREE SURVIVAL OF POSTMENOPAUSAL PATIENTS WITH ADVANCED BREAST CANCER TREATED WITH PEGYLATED LIPOSOMAL DOXORUBICIN AND MAGNETOTHERMY.

CDK4/6 inhibitors as neoadjuvant treatment in breast cancer—what can we learn?

The phosphatidylinositol-3-kinase (PI3K) pathway is mutated and aberrantly activated in breast and other cancers and plays a key role in cancer cell proliferation and survival.1 2 The PI3K pathway is deregulated through a variety of mechanisms, including mutation or amplification of PI3K, loss or inactivation of the tumour suppressor phosphatase and tensin homolog deleted on chromosome 10 ( PTEN ), as well as activation of tyrosine kinase growth factor receptors or oncogenes upstream of PI3K.3 4 Activating mutations in PIK3CA , the gene encoding the alpha isoform (p110 α) catalytic subunit of PI3K, is present in up to 40% of patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancers5 6 and represents a molecular target to personalise therapy of selected patients with breast cancer.2 Standard of care therapy for advanced HR-positive/HER2-negative breast cancers consists on endocrine therapy with or without the use of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors.7 Therapy-resistance inevitably occurs in the majority of patients. The rationale of combining PI3K inhibitors and endocrine therapy is to synergistically inhibit both the PI3K and ER pathways.8 Initial trials of pan-PI3K inhibitors plus endocrine therapy for patients with advanced breast cancer showed modest benefit with high rates of toxicity limiting their clinical drug development.9–11 Selective isoform-specific PI3K inhibitors, such as an α-specific PI3K inhibitor, have subsequently revealed activity with less toxicity.12 13 The phase III SOLAR-1 (Clinical Studies of Alpelisib in Breast Cancer 1) trial investigated the efficacy and safety of alpelisib, a α-specific class-I PI3Kinhibitor, plus fulvestrant versus placebo plus fulvestrant in patients with metastatic HR-positive/HER2-negative breast cancer who had received endocrine therapy beforehand.14 About 85.6% of patients …

Apatinib combined with pegylated liposomal doxorubicin (PLD) versus PLD for platinum-resistant recurrent ovarian cancer (APPROVE): a multicenter, randomized, controlled, open-label, phase II trial

The aim of this study was to assess the clinical activity and toxicity of liposome-encapsulated doxorubicin citrate (Myocet) in a retrospective multicenter cohort of epithelial ovarian, primary peritoneal, and tubal cancer patients. Records of patients with recurrent epithelial ovarian, primary peritoneal, and tubal cancer treated with liposome-encapsulated doxorubicin citrate (60 mg/m on day 1 of a 21-day cycle) after failure of more than one previous regimen were reviewed. Fifty-three patients were evaluated for efficacy and toxicity. The median age of the patients was 59 (range 39-73). The median follow-up was 6 months (range 1-17). One patient (1.9%) showed a complete response and 13 patients (24.5%) showed a partial response, yielding an overall response rate of 26.4% (14/53 patients). Clinical benefit was achieved in 36 patients (67.9%). The median progression-free survival (PFS) for the entire study population was 4.0 months (range 1.0-14.8). The median PFS for platinum-sensitive and platinum-resistant patients was 4.0 months (ranges 1.0-14.8 and 1.0-9.4, respectively; P=0.652). The median overall survival from the start of liposome-encapsulated doxorubicin citrate was 10.0 months. Multivariate survival analysis showed no association between the liposome-encapsulated doxorubicin citrate line of treatment or platinum sensitivity to PFS in age and BRCA status-adjusted models. Only 11.3% of patients experienced grade 3-4 hematologic toxicities, 80% grade-2 alopecia, and 50% grade-1-2 fatigue. No other grade-4 toxicities, no significant cardiac events, or hand and foot syndromes were reported. Liposome-encapsulated doxorubicin citrate was well tolerated, with a good response and high clinical benefit rate. Further evaluation in a larger prospective cohort is warranted.

Cyclin-dependent kinase (CDK) 4/6 inhibitors (CDK4/6is) are an important component of treatment for hormone receptor-positive/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC), but it is not known if patients might derive benefit from continuation of CDK4/6i with endocrine therapy beyond initial tumor progression or if the addition of checkpoint inhibitor therapy has value in this setting. The randomized multicenter phase II PACE trial enrolled patients with hormone receptor-positive/HER2- MBC whose disease had progressed on previous CDK4/6i and aromatase inhibitor (AI) therapy. Patients were randomly assigned 1:2:1 to receive fulvestrant (F), fulvestrant plus palbociclib (F + P), or fulvestrant plus palbociclib and avelumab (F + P + A). The primary end point was investigator-assessed progression-free survival (PFS) in patients treated with F versus F + P. Overall, 220 patients were randomly assigned between September 2017 and February 2022. The median age was 57 years (range, 25-83 years). Most patients were postmenopausal (80.9%), and 40% were originally diagnosed with de novo MBC. Palbociclib was the most common previous CDK4/6i (90.9%). The median PFS was 4.8 months on F and 4.6 months on F + P (hazard ratio [HR], 1.11 [90% CI, 0.79 to 1.55]; P = .62). The median PFS on F + P + A was 8.1 months (HR v F, 0.75 [90% CI, 0.50 to 1.12]; P = .23). The difference in PFS with F + P and F + P + A versus F was greater among patients with baseline ESR1 and PIK3CA alterations. The addition of palbociclib to fulvestrant did not improve PFS versus fulvestrant alone among patients with hormone receptor-positive/HER2- MBC whose disease had progressed on a previous CDK4/6i plus AI. The increased PFS seen with the addition of avelumab warrants further investigation in this patient population.

Background Approximately 15% of patients (pts) with hormone receptor (HR)+ human epidermal growth factor receptor 2 (HER2)- breast cancer will develop brain metastases (BM) (Kuksis et al, NeuroOnc 2021). Cyclin dependent kinase 4/6 inhibitors (CDK4/6i) with an endocrine therapy partner are recommended 1st line treatments in HR+HER2- metastatic breast cancer (MBC). Preclinical models show that CDK4/6i can cross the blood brain barrier (BBB). In vitro assays have shown that abemaciclib crosses the BBB more effectively than palbociclib or ribociclib (George et al, Front Oncol 2021). The efficacy of CDK4/6i in patients with breast cancer BM is not well described. Methods We examined prior treatment data for 368 pts with HR+HER2- BM who received a CDK4/6i between 2015 to 2021. The primary endpoint was overall survival (OS) from the time of starting CDK4/6i after BM development. CNS progression free survival (PFS) was assessed in pts who received CDK4/6i after BM development. We examined the relationship between OS, type and timing of CDK4/6i in multivariate analyses. Statistical analyses were conducted using R 4.1.2 software. Results Of the total cohort of 368 pts, 23% (n=86) had de novo MBC and 77% (n=282) had relapsed MBC. At initial presentation of MBC 79% (n=290) of pts had no BM, 19% (n=71) had BM and extracranial disease and 2% (n=7) had BM only. 56% (n=205) received a CDK4/6i before BM development, 37% (n=136) received a CDK4/6i after BM development and 7% (n=27) received a CDK 4/6i both before and after BM development. The most common CDK4/6i used first was palbociclib (85%, n=312) followed by abemaciclib (13%, n=47) and ribociclib (2%, n=9). At the time of data cutoff 277 pts were dead, 55 were alive and 36 were lost to follow up. The median follow-up of surviving pts from BM development was 32 months. 163 pts received a CDK4/6i post BM: palbociclib (66%, n=108), abemaciclib (31%, n=51) and ribociclib (3%, n=4). Of these 163 pts 83% (n=136) received a CDK4/6i as their 1st or 2nd systemic treatment post BM. In the cohort of 163 pts who received a CDK4/6i post BM, 9% did not receive local BM therapy, 40% had whole brain radiotherapy (WBRT), 34% had stereotactic surgery (SRS) alone and 17% had surgery +/- SRS. The median CNS PFS for pts who received a CDK4/6i after BM was 21 months with palbociclib and 14 months with abemaciclib (p value 0.11). Too few pts received ribociclib for analysis. CNS PFS was 21 months for pts receiving a CDK4/6i only after BM development and 10 months for those who received CDK4/6i both before and after BM diagnosis (p = 0.01). Pts who died prior to CNS progression were censored. Median OS from the time of starting CDK4/6i after BM development for pts receiving a CDK4/6i only after BM development was 25 months versus 12 months for those who received it both before and after BM development (p = 0.03). There was no statistically significant difference in OS when adjusting for the type of local BM treatment received, time from initial MBC diagnosis to BM, or the Breast Graded Prognostic Assessment (GPA) score (Sperduto et al, IJROBP 2020). Conclusions This observation suggests that there is a greater OS benefit from the time of starting CDK4/6i after BM development in pts who receive CDK4/6i solely after BM development compared to pts who received a CDK4/6i both before and after BM development. This is not unexpected given the known OS benefit associated with early use of these agents. Our unique observation of longer CNS PFS for patients who did not receive CDK4/6i prior to BM but who received it afterward suggests that CDK4/6i exposure prior to BM development may lead to development of resistance mechanisms that reduces CNS efficacy upon rechallenging with CDK4/6i after BM development. There was no statistically significant difference in post-BM CNS PFS by type of CDK4/6i received. This motivates investigation of biomarkers for patient selection and our ongoing work in collecting a matched comparison cohort of HR+HER2- pts with BM who never received CDK4/6i. Citation Format: Sonya Chew Minmin, Yuan Chen, Daniel Kelly, Mark E. Robson, Andrew D Seidman. Characterization of breast cancer brain metastases overall and progression-free survival and timing of cyclin-dependent kinase 4/6 inhibitor use: Retrospective single institution experience [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-09.

e13020 Background: Cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) in combination with an aromatase inhibitor (AI) has emerged as the standard first line treatment in patients with hormone receptor positive, human epidermal growth factor receptor-2 (HER-2) negative metastatic breast cancer (MBC). In this analysis, we describe population-based outcomes for first-line treatment with a CDK4/6i combined with an AI. Methods: All patients who were prescribed CDK4/6i + AI from January 2016 through June 2019 in a large Canadian province were included. Descriptive statistics were used to summarize patient demographics, tumor and treatment characteristics. Survival distributions were estimated using the Kaplan-Meier method. Multivariate analysis (MVA) using a Cox proportional hazards model was constructed to examine associations between potentially prognostic clinical variables and progression free survival (PFS). Results: A total of 316 patients were included. Median age was 61 years (interquartile range, 53-70 years), 82% were postmenopausal women, 39% had de novo MBC, and 48% had non-visceral disease. Palbociclib was prescribed in 94% of patients and the remaining patients received ribociclib. The CDK4/6i was dose-reduced upfront or during treatment in 47%. While 70% of the patients discontinued treatment due to progression, 30% stopped due to toxicity/patient preference/physician recommendation. With a median follow-up of 28.1 months, the median PFS was 37.9 months (95% CI, 26.7-NR). In the MVA, PR-negative tumour (HR, 2.37; 95% CI, 1.45-3.88; P = 0.001) and dose reduction of the CDK4/6i (HR, 1.51; 95% CI, 1.06-2.16; P = 0.022) predicted worse PFS. Median overall survival (OS) was not reached. The 30-month and 36-month OS rates were 74% and 68%, respectively. Of patients who progressed (n = 131), 89% received second-line treatment (chemotherapy in 46%, single agent hormonal therapy in 35%, hormonal therapy plus a targeted agent in 15%, and other in 4%). Median time to progression on second line chemotherapy was 9.0 (5.8-17.6) months and second line hormonal therapy +/- targeted agent was 4.0 (3.4-8.6) months (P = 0.012). Conclusions: The real-world outcomes of first-line use of CDK4/6i and AI are encouraging. PR negative tumors and dose reduction appear to be negative prognostic markers. CDK4/6i + AI as first-line treatment for HR-positive, HER2-negative MBC in Alberta is justified based on favorable PFS and early OS outcomes.

CDK4/6 inhibitor treatment for patients with hormone receptor-positive, HER2-negative, advanced or metastatic breast cancer: a US Food and Drug Administration pooled analysis.

Introduction: Mutations in PIK3CA, which encodes the α-isoform of phosphatidylinositol 3-kinase (PI3Kα), occur in ~40% of patients (pts) with HR+, HER2- ABC and can contribute to endocrine resistance. Alpelisib (ALP), a PI3Kα-selective inhibitor and degrader, plus fulvestrant (FUL) demonstrated efficacy in the phase 3 SOLAR-1 trial, which included 20 pts who had prior CDK4/6i in the PIK3CA-mutant cohort. Limited clinical data are available in the post-CDK4/6i setting for PIK3CA-mutated, HR+, HER2- ABC. BYLieve (NCT03056755), an ongoing phase 2, multicenter, open-label, 3-cohort noncomparative study, is the first trial evaluating ALP + endocrine therapy (FUL or letrozole [LET]) in pts with PIK3CA-mutated, HR+, HER2- ABC who progressed on/after prior therapy, including CDK4/6i. In the prior CDK4/6i + aromatase inhibitor (AI) cohort (Cohort A), pts received ALP + FUL. With median follow-up of 11.7 months (mo), the primary endpoint in Cohort A was met—50.4% of pts were alive and without disease progression (PD) at 6 mo per local investigator assessment (n=61; 95% CI, 41.2%-59.6%). Median progression-free survival (mPFS) was 7.3 mo (n=72; 95% CI, 5.6-8.3 mo); AEs were consistent with prior observations. Now, we report on the cohort of pts who received a CDK4/6i + FUL as immediate prior therapy before enrollment (Cohort B). Methods: Daily oral treatment in Cohort B consisted of ALP 300 mg + LET 2.5 mg. Each cohort planned to enroll at least 112 pts with centrally confirmed PIK3CA mutation, based on immediate prior treatment of either a CDK4/6i + AI (Cohort A), a CDK4/6i + FUL (Cohort B), or systemic chemotherapy or endocrine therapy (which may also include prior CDK4/6i + FUL; Cohort C, follow-up ongoing). The primary endpoint, the proportion of pts with centrally confirmed PIK3CA mutation alive without PD at 6 mo per local investigator using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, is assessed for each cohort separately and is met if the lower bound of the 95% CI is >30%. Men and premenopausal women were allowed goserelin 3.6 mg subcutaneously or leuprolide 7.5 mg intramuscularly every 28 days. Results: 126 pts whose immediate prior treatment was CDK4/6i + FUL were enrolled into Cohort B: 115 had centrally confirmed PIK3CA mutations. Median follow-up was 15.0 mo (range, 1-31 mo); 58 (46.0%) had ≥2 lines of prior therapy in the metastatic setting, and 103 (81.7%) pts progressed on prior AI therapy. The primary endpoint was met with 46.1% (95% CI, 36.8%-55.6%) of pts alive without PD at 6 mo. mPFS was 5.7 mo (95% CI, 4.5-7.2 mo). The most frequent all-grade AEs (≥25%) were diarrhea (67.5%), hyperglycemia (63.5%), nausea (54.8%), decreased appetite (44.4%), stomatitis (34.1%), fatigue (31.0%), rash (31.0%), and vomiting (24.6%). Most frequent grade ≥3 AEs included hyperglycemia (25.4%), rash (9.5%), and rash maculopapular (7.9%). Incidence of AEs leading to treatment discontinuation was 14.3% (n=18); most frequent AEs leading to discontinuation were rash (4 pts, 3.2%, including rash maculopapular), fatigue, and diarrhea (3 pts, 2.4% each). Conclusion: Alpelisib in combination with LET following progression on FUL + CDK4/6i and prior AIs was effective in this noncomparative trial. Consistent with the known safety profile of alpelisib, manageable toxicities were observed. These data suggest that alpelisib in combination with LET may be an effective treatment option for pts with PIK3CA-mutated, HR+, HER2- ABC in the post-CDK4/6i setting. Citation Format: Hope S. Rugo, Florence Lerebours, Dejan Juric, Nicholas Turner, Stephen Chia, Pamela Drullinsky, Aleix Prat, Rafael Villanueva Vázquez, Murat Akdere, Christina Arce, Yu-Ming Shen, Eva Ciruelos. Alpelisib + letrozole in patients with PIK3CA-mutated, hormone-receptor positive (HR+), human epidermal growth factor receptor-2-negative (HER2-) advanced breast cancer (ABC) previously treated with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) + fulvestrant: BYLieve study results [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 PD2-07.

Background. Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in combination with endocrine therapy represent the gold standard for treating patients with HR-positive/HER2-negative advanced breast cancer. However, endocrine resistance poses a risk factor for early disease progression. Escalating therapy strategies may lead to increased toxicity, resulting in dose reductions and treatment discontinuation. Notably, previous chemotherapy and concurrent radiotherapy are associated with myelotoxicity, which constitutes the primary adverse event in the majority of patients treated with CDK4/6i. In this study, we aimed to assess the rates of CDK4/6i dose reductions in patients experiencing early disease progression, considering the context of endocrine resistance, prior chemotherapy, and concurrent radiotherapy. Methods. We conducted a retrospective analysis of patients diagnosed with advanced breast cancer who received CDK4/6 inhibitor (CDK4/6i) treatment at our cancer center between 2018 and 2024. Results. A total of 491 patients received treatment with CDK4/6 inhibitors (CDK4/6i). Among these patients, 242 required dose reduction due to toxicity. Patients without CDK4/6i dose reduction had a median progression-free survival (PFS) of 23.8 months, compared to 31.6 months for patients with dose reduction (difference not significant, p = 0.19). The 24-month PFS for patients without CDK4/6i dose reduction was 49.8% (95% CI 42.3-57.2%) versus 60.0% (52.8-66.5%) for patients with dose reduction. The median overall survival (OS) in patients without CDK4/6i dose reduction was 39.5 months, compared to 46.5 months for patients with dose reduction (difference not significant, p = 0.77). The 36-month OS for patients without CDK4/6i dose reduction was 56.5% (95% CI 47.2-64.7%) versus 62.7% (54.3-69.9%) for patients with dose reduction. However, in the group of patients diagnosed with early disease progression, defined as progression within 12 months from CDK4/6i commencement, dose reduction rates were significantly lower than in patients with longer response (41% compared to 55.1%, p=0.03). No significant differences in the rates of previous chemotherapy and concurrent radiotherapy were observed between these two groups. Higher rates of endocrine resistance were observed in patients experiencing early disease progression (66.7% of patients compared to 40.2% of patients, p<0.001). Conclusions. Cyclin-dependent kinase 4/6 inhibitors dose reduction is safe, and treatment with a reduced dose remains efficacious in patients with advanced breast cancer. Lower dose reduction rates were observed in endocrine-resistant patients experiencing early disease progression. Therefore, considering treatment escalation in this population with a worse prognosis may be a feasible approach. However, further studies are necessary to address this specific patient group. Citation Format: Marcin Kubeczko, Anna Polakiewicz-Gilowska, Konstanty Chomik, Katarzyna Świderska, Marta Mianowska-Malec, Aleksandra Leśniak, Barbarba Łanoszka, Barbara Grandys, Natalya Lisovska, Michał Jarząb. Cyclin-dependent kinase 4/6 inhibitors dose reduction in patients with endocrine resistant advanced breast cancer experiencing early disease progression [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P4-12-07.

Background: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET) provide significant clinical benefit in patients with HR+/HER2- metastatic breast cancer (MBC) and have become a standard of care treatment. Prior insights from tumor profiling and preclinical analyses suggest that AKT1 activation can induce CDK4/6i resistance. We hypothesized that targeting AKT1 following CDK4/6i progression may be an effective therapeutic strategy and conducted a clinical trial to evaluate both doublet (ET+AKTi) and triplet (ET+AKTIi+CDK 4/6i) therapy in the ≥ 2nd line MBC setting. Methods: TAKTIC is an open-label phase Ib clinical trial (clinicaltrials.gov NCT03959891) evaluating the combination of the AKT inhibitor ipatasertib (ipat) with fulvestrant (Arm A), an aromatase inhibitor (Arm B), or the triplet combination (Arm C) with fulvestrant + palbociclib (palbo). The primary objective is to evaluate the safety (NCI CTCAE 5.0) and tolerability of ipat in combination with endocrine therapy +/- CDK4/6i. Secondary objectives include clinical efficacy, as determined by objective response rate (RECIST v1.1), clinical benefit rate (CBR), progression-free survival (PFS), and overall survival (OS). Key inclusion criteria include unresectable HR+/HER2- MBC; at least 1 prior therapy for MBC including any CDK4/6i; up to 2 prior lines of chemotherapy for MBC (no limit on prior endocrine therapy). Here, we present an updated interim analysis from all study arms. Results: The trial completed accrual with 77 pts enrolled from June 2019 – February 2022, including 19 on Arm A, 16 on Arm B, and 42 on Arm C. Median age was 62 (range 32-88) and 65/77 pts (84%) received prior CDK4/6i (median no. of prior lines = 3, range 1-13). 56/77 pts (73%) had measurable disease at baseline and 50/77 pts (65%) had visceral metastases in the liver/lung (68% Arm A, 44% Arm B, 71% Arm C). Pts enrolled on Arms A and B received ipat at 400mg in combination with fulvestrant or an aromatase inhibitor, respectively. In Arm C, 27/42 pts enrolled into the dose escalation phase and received ipat + palbo at varying doses in combination with fulvestrant. Two DLTs were observed in the 300mg ipat + 125mg palbo cohort (grade 4 neutropenia ≥ 7 days). ET+400mg ipat + 100mg palbo was determined to be the recommended phase 2 dose (R2PD), and the remaining 15/42 pts on Arm C were treated at this dose level in the expansion phase. Treatment was well tolerated in all arms. Grade 3 and 4 toxicities included neutropenia (39/77, 50.6%), leukopenia (15/77, 19.5%), diarrhea (11/77, 14/3%), transaminitis (7/77, 9.1%), lymphopenia (6/77, 7.8%), rash (6/77, 7.8%), and thrombocytopenia (3/77, 3.9%). As of 6/28/2022, 16/77 pts remain on treatment. The median treatment duration for all pts is estimated at 6 months (range 0.5-39). Among the 56 pts with measurable disease, 11 had partial response (PR) and 32 had stable disease (SD) as the best response. CBR, defined as percentage of pts who achieved PR or SD > 6 months, was 48% across the study (53% Arm A, 31% Arm B, 57% Arm C). The median PFS was 5.5 months (95% confidence interval [CI]: 3.8 – 7.4) and the median OS was 24.5 months (95% CI: 17.1 – 33.9). Conclusions: The combination of ipat with endocrine therapy +/- palbo is well tolerated in heavily pre-treated pts, with preliminary evidence of clinical activity. This trial demonstrates how molecular insights related to CDK4/6i resistance inform potential therapy combinations. Further studies are needed to evaluate AKTi-based combinations in pts with HR+ MBC. Citation Format: Seth A. Wander, Jennifer C. Keenan, Andrzej Niemierko, Dejan Juric, Laura M. Spring, Jeffrey Supko, Neelima Vidula, Steven J. Isakoff, Lianne Ryan, Sarah Padden, Elizabeth Fisher, Amber Newton, Beverly Moy, Leif Ellisen, Douglas S. Micalizzi, Aditya Bardia. PD13-07 Combination therapy with the AKT inhibitor, ipatasertib, endocrine therapy, and a CDK4/6 inhibitor for hormone receptor positive (HR+)/HER2 negative metastatic breast cancer (MBC): results from the phase I TAKTIC trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD13-07.

Avelumab in platinum-resistant/refractory ovarian cancer (PRROC): phase 3 results from JAVELIN Ovarian 200

TPS1109 Background: Endocrine therapy (ET) + CDK4/6i is standard of care for HR+, HER2− ABC; however, CDK4/6i resistance, in which the phosphatidylinositol-3-kinase (PI3K) pathway has a key role, remains challenging. Progression-free survival (PFS) for ≥ 2nd-line ET monotherapy post CDK4/6i is poor; prognosis may be worse in patients with a PI3KCA mutation. ALP (PI3K-α selective inhibitor and degrader) + FUL is approved by the European Medicines Agency (EMA) for HR+, HER2–, PIK3CA-mutated ABC after ET monotherapy. Outside the EMA, ALP + FUL approval includes post-CDK4/6i use. ALP + FUL has shown clinical activity and consistent safety in a small subpopulation in SOLAR-1 with prior CDK4/6i treatment (n = 9) and in BYLieve Cohort A (CDK4/6i + AI as immediate prior treatment; n = 121). The EPIK-B5 study aims to confirm the efficacy and safety of ALP + FUL in a larger population with HR+, HER2–, PIK3CA-mutated ABC with prior CDK4/6i + AI treatment. Methods: EPIK-B5 is a Phase III, randomized (1:1), double-blind, placebo-controlled study assessing the efficacy and safety of ALP (300 mg/d orally starting Cycle 1 Day 1 [C1D1]) + FUL (500 mg intramuscularly on C1D1 and C1D15, and D1 of subsequent cycles) in patients (N ≈ 234) with HR+, HER2–, PIK3CA-mutated ABC progressing on/after CDK4/6i + AI. Patients randomized to placebo + FUL can cross over to ALP + FUL after progression. Randomization is stratified by presence of lung and/or liver metastasis and prior CDK4/6i setting. Adult men or postmenopausal women with confirmed HR+, HER2–, PIK3CA-mutated ABC and ≥ 1 measurable lesion are eligible. The primary endpoint is PFS per blinded independent review committee assessment. Secondary endpoints include overall survival, overall response and clinical benefit rates, duration of and time to response, PFS by PIK3CA-mutation status in circulating tumor DNA, PFS on next-line treatment, time to definitive deterioration of ECOG status, quality of life (QoL), and safety and tolerability. Exploratory endpoints include biomarker analyses, additional QoL endpoints, and time to subsequent chemotherapy. Recruitment is ongoing, with enrollment planned over 2 years in 18 countries; completion of primary data collection is anticipated in 2026. Clinical trial information: NCT05038735; EUDRACT2021-001966-39.

Introduction: PIK3CA (encoding phosphatidylinositol 3-kinase alpha [PI3Kα]) is a driver oncogene mutated (mut) in ~40% of HR+, HER2- ABCs, leading to endocrine therapy (ET) resistance and poor prognosis. Alpelisib (ALP) is the first oral α-selective PI3K inhibitor and degrader approved in this patient (pt) population. Primary analyses of Cohorts A and B from BYLieve, an ongoing Phase II noncomparative study, demonstrated efficacy and a consistent safety profile of ALP + ET (fulvestrant [FUL] or letrozole [LET]) in pts with PIK3CA-mut, HR+, HER2- ABC in the post CDK4/6i setting. Post hoc analyses of ALP benefit in pts with centrally confirmed PIK3CA mut, based on median duration of prior CDK4/6i, supported the efficacy of ALP + ET in CDK4/6i-resistant, HR+, HER2- ABC. Here we assessed whether those who achieved a short duration of disease control (6-month [mo] cutoff), with prior CDK4/6i + ET received clinical benefit with ALP + ET. Methods: In Cohorts A and B, pts with PIK3CA-mut, HR+, HER2- ABC had received CDK4/6i + aromatase inhibitor (AI) or FUL, respectively, as immediate prior therapy (majority in first line). Pts in Cohort A received ALP 300 mg PO QD + FUL 500 mg IM Q28D + C1D15; pts in Cohort B received ALP 300 mg PO QD + LET 2.5 mg PO QD. Within each cohort, pts were divided based on duration of prior CDK4/6i therapy (≤6 mo or >6 mo), and the association of progression-free survival (PFS) with this covariate was analyzed using a stratified log-rank test and Cox Proportional Hazards model. A 6-mo cutoff was selected based on the ESO-ESMO ABC5 cutoff for primary ET resistance, as current guidelines do not specify cutoffs for CDK4/6i resistance. This analysis is based on the PFS endpoint and included pts for whom duration of prior CDK4/6i therapy was known. Results: Of the 121 pts in Cohort A with centrally confirmed PIK3CA-mut disease (modified full analysis set, mFAS), 120 had duration of prior CDK4/6i available; 26 had CDK4/6i for ≤6 mo and 94 for >6 mo, with similar demographics/disease characteristics between subgroups. The hazard ratio (HR) of median PFS (mPFS) between the ≤6-mo group and >6-mo group was 0.50 (95% confidence interval [CI], 0.27-0.94), indicating a lower risk of progression in the ≤6-mo group, with mPFS 10.0 mo (95% CI, 5.55-not estimable) and 6.0 mo (95% CI, 5.16-8.31), respectively. Grade ≥3 adverse events (AEs) were experienced by 67.5% (n=85) of all pts (safety set) in Cohort A and by 76.9% (n=20)/65.0% (n=65) in the ≤6-mo/>6-mo subgroups, respectively. Of the 115 pts in Cohort B with centrally confirmed PIK3CA-mut disease (mFAS), 113 had duration of prior CDK4/6i available; 31 had CDK4/6i for ≤6 mo and 82 for >6 mo, with similar demographics/disease characteristics between subgroups. The HR of mPFS between the ≤6-mo and >6-mo groups was 0.76 (95% CI, 0.47-1.23), with the wide CI indicating no difference in risk of progression between subgroups, and mPFS was 5.9 mo (95% CI, 3.55-10.97) and 5.6 mo (95% CI, 3.68-7.10), respectively. Grade ≥3 AEs were experienced by 69.9% (n=86) of all pts (safety set) in Cohort B and by 63.6% (n=21)/72.2% (n=65) in the ≤6-mo/>6-mo subgroups, respectively. Conclusions: This demonstrates that pts with PIK3CA-mut, HR+, HER2- ABC who achieved ≤6-mo duration of disease control with prior CDK4/6i had a numerically longer PFS in Cohort A, and almost the same clinical efficacy in Cohort B, to ALP + ET vs pts with >6-mo duration of disease control, with a comparable safety profile. This confirms targeting PI3Kα with ALP provides clinical benefit in pts with CDK4/6i-resistant ABC, including early progressors, and supports consideration of ALP + ET as an immediate next-line option in this setting, possibly delaying chemotherapy. Citation Format: Stephen Chia, Eva M Ciruelos, Hope S Rugo, Florence Lerebours, Manuel Ruiz-Borrego, Pamela Drullinsky, Aleix Prat, Thomas Bachelot, Nicholas Turner, Ennan Gu, Christina Arce, Murat Akdere, Dejan Juric. Effect of duration of prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) therapy (≤6 mo or >6 mo) on alpelisib benefit in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA-mutated advanced breast cancer (ABC) from BYLieve [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 P1-18-08.

The optimal combination of different cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) with endocrine therapy (ET) for HR+/HER2- metastatic breast cancer (MBC) remains undefined due to a lack of head-to-head comparisons. This real-world study aimed to evaluate the effectiveness and safety of three CDK4/6 inhibitors combined with aromatase inhibitors (AI) or fulvestrant in the MBC setting. This study was a retrospective, observational, single-center analysis conducted in Tianjin Medical University Cancer Institute and Hospital, China between 1 January 2019 and 1 November 2023. The eligibility criteria were as follows: age ≥18years; histologically confirmed hormone receptor-positive, HER2-negative breast cancer; recurrent or metastatic disease; at least one measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1; and no prior systemic endocrine therapy for advanced disease. However, up to one line of prior chemotherapy in the metastatic setting was allowed. Statistical analyses were conducted using R software. Effective endpoints included progression-free survival (PFS), objective response rate (ORR), and clinical benefit rate (CBR). This study enrolled 341 patients with HR+/HER2- MBC who received first-line CDK4/6i-based therapy consisting of palbociclib (n = 138), abemaciclib (n = 119), or dalpiciclib (n = 84) in combination with either an AI or fulvestrant. The median follow-up durations for PFS were 15.6months, 10.9months, and 18.2months in the palbociclib, abemaciclib, and dalpiciclib groups, respectively. The maximum follow-up durations were 58.0months for the palbociclib group, 53.7months for the abemaciclib group, and 49.3months for the dalpiciclib group. Regarding clinical benefit rate (CBR), the values for palbociclib, abemaciclib, and dalpiciclib combined with an AI versus fulvestrant were 93.8% (95% CI: 86.2%, 97.3%) versus 93.1% (83.6%, 97.3%), 97.7% (92.1%, 99.4%) versus 96.8% (83.8%, 99.4%), and 93.3% (84.1%, 97.4%) versus 87.5% (69.0%, 95.7%), respectively. For objective response rate (ORR), the corresponding rates were 37.5% (95% CI: 27.7%, 48.5%) versus 60.3% (47.5%, 71.9%), 48.9% (38.7%, 59.1%) versus 67.7% (50.1%, 81.4%), and 45.0% (33.1%, 57.5%) versus 54.2% (35.1%, 72.1%), respectively. Median PFS was 25.3months for the palbociclib group, not reached (NR) for the abemaciclib group, and 36.0months for the dalpiciclib group. Statistical analysis showed that both abemaciclib and dalpiciclib combinations were associated with longer PFS compared with palbociclib (both P < 0.05); however, due to the shorter median PFS follow-up duration and the lower number of PFS events in the abemaciclib group, the data for this group remain immature and warrant further follow-up. The PFS following CDK4/6i plus ET treatment was not significantly related to the status of key molecular biomarkers. The type of ET (AIs vs. fulvestrant) did not significantly affect PFS, although a consistent trend toward PFS benefit was observed in the fulvestrant-based combination group, without reaching statistical significance. Liver and bone metastases were associated with shorter PFS. Safety profiles were consistent with known spectra of each CDK4/6i, with no new signals identified. In this real-world analysis, dalpiciclib was associated with superior PFS compared to palbociclib as first-line CDK4/6i-based therapy for HR+/HER2- MBC. ET partner did not significantly impact effectiveness, supporting tailored CDK4/6i selection based on patient and disease characteristics.