Capivasertib plus fulvestrant in patients with HR-positive/HER2-negative advanced breast cancer: phase 3 CAPItello-291 study extended Chinese cohort

Background Abemaciclib is a selective CDK4 & 6 inhibitor approved on a continuous dosing schedule for HR+, HER2- advanced breast cancer (ABC) as monotherapy (MONARCH 1) and in combination with endocrine therapy (ET). A previous Phase 1b (NCT01394016) cohort of HR+ ABC patients (pts) demonstrated efficacy of abemaciclib monotherapy (150mg and 200mg Q12H starting dose); given the small sample size and nonrandomized design the impact of the starting dose was unclear. nextMONARCH 1 (NCT02747004) evaluated abemaciclib in 2 monotherapy arms, in a randomized setting. Abemaciclib has been associated with dose-dependent early onset diarrhea that is well managed with antidiarrheal therapy. nextMONARCH 1 also explored the 200mg Q12H abemaciclib dose in combination with prophylactic loperamide to reduce incidence/severity of diarrhea and dose adjustments. A third arm evaluated abemaciclib + tamoxifen as a strategy to overcome endocrine resistance. Methods nextMONARCH 1 is a multicenter, randomized, open-label, Phase 2 study of abemaciclib or abemaciclib + tamoxifen in women with HR+, HER2- ABC who have progressed on or after prior ET and previously received chemotherapy. Pts were stratified by presence of liver metastases and prior use of tamoxifen in the advanced setting. Randomization was 1:1:1 to abemaciclib 150mg Q12H + daily tamoxifen 20mg (Arm A) or abemaciclib 150mg Q12H (Arm B); or abemaciclib 200mg Q12H + prophylactic loperamide (Arm C). Key eligibilities were ≥2 chemotherapy regimens (1-2 administered in metastatic setting), measurable disease and no prior treatment with CDK4 & 6 inhibitors. Primary objective was progression free survival (PFS). Key secondary objectives included objective response rate (ORR), dclinical benefit rate (CBR), and safety. PFS analysis tested superiority of Arm A to C at ∼110 events across the 2 arms assuming a hazard ratio (HR) of 0.667 to achieve ∼80% power. Arm B would be considered non-inferior to Arm C if the observed PFS HR is <1.2. Results 234 pts were randomized to Arms A (n=78), B (n=79) and C (n=77). 166 PFS events have been observed (A: 57; B: 54; C: 55). Median PFS was 9.1 months in Arm A, 6.5 in Arm B and 7.4 in Arm C (A vs C: HR=.815, 95% CI, .556-1.193, p=.293; B vs C: HR=1.045, 95% CI, .711-1.535 p=.811). Investigator-assessed ORR was 34.6%, 24.1% and 32.5% (confirmed ORR: 25.6%, 19.0%, 28.6%) and CBR was 61.5%, 49.4% and 51.9% in Arms A, B and C, respectively. Prophylactic loperamide reduced the incidence and severity of diarrhea (C: 62.3%, Gr 3: 7.8%) compared to MONARCH 1 (90.2%, Gr 3: 19.7%, Dickler et al. 2017) resulting in similar rates of diarrhea with 150mg abemaciclib without prophylaxis (A: 53.8%, Gr 3: 1.3%; B: 67.1%, Gr 3: 3.8%). The adverse event profile across arms was generally consistent with other breast studies of abemaciclib. Conclusions nextMONARCH 1 confirmed single-agent activity of abemaciclib in heavily pretreated pts with HR+, HER2- ABC. Efficacy of abemaciclib monotherapy at 150mg was similar to 200mg. Combining tamoxifen with abemaciclib did not demonstrate a statistically significant improvement in PFS compared to abemaciclib monotherapy. Addition of prophylactic loperamide to abemaciclib 200mg resulted in diarrhea similar to 150mg without prophylaxis. Citation Format: Hamilton E, Cortes J, Dieras V, Ozyilkan O, Chen S-C, Petrakova K, Manikhas A, Jerusalem G, Hegg R, Lu Y, Bear MM, Johnston EL, Martin M. nextMONARCH 1: Phase 2 study of abemaciclib plus tamoxifen or abemaciclib alone in HR+, HER2- advanced breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD1-11.

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.

Background: In the Phase 3 randomized, double-blind CAPItello-291 trial, the addition of capivasertib (a potent, selective pan-AKT inhibitor) to fulvestrant in patients with aromatase inhibitor-resistant, hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative (HER2− defined as immunohistochemistry [IHC] 0, or 1-positive or IHC2-positive/in situ hybridization-negative) advanced breast cancer (ABC) significantly improved progression-free survival (PFS) versus placebo + fulvestrant (hazard ratio [HR] 0.60, 95% confidence interval [CI] 0.51–0.71; p< 0.001). PFS benefit was observed in patients with detectable AKT pathway alterations (HR 0.50, 95% CI 0.38–0.65; p< 0.001) and without (0.70; 95% CI; 0.56–0.88). Here, we report PFS by gene within the AKT pathway-altered population. Methods: Patients were randomized 1:1 to receive fulvestrant (500 mg intramuscularly on days 1 and 15 of cycle 1, and day 1 of each subsequent 28-day cycle) with either placebo or capivasertib (400 mg twice daily; 4 days on, 3 days off). AKT pathway-alteration status (at least one qualifying alteration in the genes PIK3CA, AKT1, or PTEN) was determined post-randomization, using next-generation sequencing in tumor tissue. HRs were calculated using Cox proportional hazards models. Data cut-off Aug 15, 2022. Results: Of the 708 patients randomized to treatment, 289 (41%) had AKT pathway-altered tumors (capivasertib-fulvestrant n=155; placebo-fulvestrant n=134). In the AKT pathway-altered population, 43% had liver metastases and 40% primary endocrine therapy resistance. Prior therapy for advanced disease included: 89% of patients with ≥1 line of prior treatment, 71% with a prior cyclin-dependent kinase 4 and 6 inhibitor, and 18% with prior chemotherapy. Baseline characteristics were broadly balanced between treatment groups. Most patients with an AKT pathway-altered tumor had only one detectable alteration (272/289, 94%). Thirteen patients (capivasertib-fulvestrant n=4; placebo-fulvestrant n=9) had co-occurring PIK3CA and PTEN alterations, and four patients (capivasertib-fulvestrant n=2; placebo-fulvestrant n=2) had co-occurring PIK3CA and AKT1 alterations. Consistent PFS benefit of capivasertib-fulvestrant over placebo-fulvestrant was observed across all alterations (Table). The safety profile of capivasertib-fulvestrant in the AKT pathway-altered population was consistent with the overall population. Conclusions: Compared with fulvestrant alone, the addition of capivasertib to fulvestrant provided a consistent PFS benefit across alterations in all three key genes within the AKT pathway in patients with HR-positive/HER2-negative ABC. https://clinicaltrials.gov/: NCT04305496 Funding: CAPItello-291 is sponsored by AstraZeneca. Editorial acknowledgment: AstraZeneca-funded medical writing support was provided by Suzanne Patel, Ph.D., from BOLDSCIENCE Inc. Capivasertib was discovered by AstraZeneca subsequent to a collaboration with Astex Therapeutics (and its collaboration with the Institute of Cancer Research and Cancer Research Technology Limited). Table. Citation Format: Sacha Howell, Hope Rugo, Mafalda Oliveira, Florence Dalenc, Javier Cortés, Henry Gómez, Xichun Hu, Komal Jhaveri, Petr Krivorotko, Sibylle Loibl, Serafin Morales Murillo, Meena Okera, Yeon Park, Joo Hyuk Sohn, Masakazu Toi, Eriko Tokunaga, Lyudmila Zhukova, Andrew Lloyd, Elza de Bruin, Coumaran Egile, Celina D’Cruz, Nicholas Turner. Capivasertib and fulvestrant for patients with aromatase inhibitor-resistant HR positive/HER2-negative advanced breast cancer: exploratory analysis of PFS by AKT pathway gene from the Phase 3 CAPItello-291 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 PS17-03.

Background Tucatinib (TUC) is a highly selective oral tyrosine kinase inhibitor of HER2 with minimal inhibition of EGFR. It was recently approved by the FDA for patients (pts) with HER2+ metastatic breast cancer (MBC), including pts with brain metastases (BM) whose cancers have progressed on at least 1 prior anti-HER2 regimen in the metastatic setting. In the HER2CLIMB (NCT02614794) pivotal trial, pts with HER2+ MBC previously treated with trastuzumab (T), pertuzumab, and trastuzumab emtansine (T-DM1) were randomized to receive TUC or placebo in combination with T and capecitabine (C). The addition of TUC resulted in clinically meaningful and statistically significant improvements in overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) in HER2+ MBC pts. Primary methods and outcomes have been reported previously (Murthy, NEJM 2019). Here we present an exploratory analysis describing the outcomes in the HER2CLIMB trial based on hormone receptor (HR) status. Methods Pts were randomized 2:1 to receive TUC or placebo in combination with T and C. All pts had a baseline brain MRI and randomization was stratified by presence of BM, ECOG status, and geographic region. All pts with HER2+ MBC who were positive for either or both estrogen receptor and progesterone receptor (> 1%) were assigned to the HR “positive” subgroup. Pts not meeting the above criteria were assigned to the HR “negative” subgroup. For the exploratory HR+/HR- efficacy analysis presented here, PFS per RECIST 1.1 by blinded independent central review was evaluated in the first 480 pts enrolled. OS, PFS in pts with baseline BM, and confirmed ORR in pts with measurable disease were evaluated in the total study population. P values presented for PFS are nominal. Results Overall, 612 pts were enrolled to HER2CLIMB; 370 pts (60%) had HR+ and 242 (40%) had HR- tumors. Baseline demographics and disease characteristics in HR+/HR- subgroups were generally balanced between treatment arms. In the HR+ group, there was a 42% reduction in the risk of progression or death in the TUC arm (hazard ratio: 0.58; 95% CI: 0.42, 0.80; P=0.0008); median (95% CI) PFS was 7.6 mo (7.4, 9.5) in the TUC arm vs 5.6 mo (4.3, 7.4) in the control arm. In the HR- group, there was a 46% reduction in the risk of progression or death in the TUC arm (hazard ratio: 0.54; 95% CI: 0.34, 0.86; P=0.008); median (95% CI) PFS was 8.1 mo (7.0, 11.6) in the TUC arm vs 4.2 mo (3.1, 8.6) in the control arm. In the total population, median OS was 21.7 mo vs 18.2 mo in HR+ in the TUC arm vs control arm, respectively; median OS in HR- was 31.1 mo in the TUC arm vs 14.1 mo in the control arm. In pts with BM in the HR+ group (n=166 [45%]), there was a 52% reduction in the risk of progression or death (hazard ratio: 0.48; 95% CI: 0.31, 0.75; P=0.0008); median (95% CI) PFS was 7.5 mo (5.6, 9.5) in the TUC arm vs 5.1 mo (4.1, 5.7) in the control arm, and median OS was 18.1 mo vs 12.8 mo, respectively. In pts with BM in the HR- group (n=125 [52%]), there was a 50% reduction in the risk of progression or death (hazard ratio: 0.50; 95% CI: 0.27, 0.95; P=0.03); median (95% CI) PFS was 7.8 mo (6.1, 11.6) in the TUC arm vs 5.4 mo (2.9, 8.6) in the control arm, and median OS was 18.5 mo vs 11.5 mo, respectively. In the total population, ORR was numerically higher in the TUC arm vs the control arm regardless of HR status (HR+: 37.4% [95% CI: 30.8, 44.5] vs 27.1% [95% CI: 19.0, 36.6], respectively and HR-: 45.3% [95% CI: 36.7, 54.0] vs 15.6% [95% CI: 7.8, 26.9], respectively). Conclusions Among pts with HER2+ MBC previously treated with T, pertuzumab, and T-DM1, the addition of TUC to T and C showed clinically meaningful improvements of PFS, OS, and ORR independent of HR status. Furthermore, pts with HR+ and HR- MBC with BM derived similar benefit from the addition of TUC to T and C. Citation Format: Erika Hamilton, Mattea Reinisch, Sherene Loi, Alicia Okines, Paula R. Pohlmann, Eva Harder Brix, Hugues Bourgeois, Belinda Yeo, Cheryl Aylesworth, Melody Cobleigh, Anthony Goncalves, Rebecca Moroose, Katherine H.R. Tkaczuk, Michaela Tsai, Christine Simmons, Michael Andersson, Hatem Soliman, Michelina Cairo, Lisa A. Carey, David Cameron, Jorge Ramos, Wentao Feng, Mafalda Oliveira. Tucatinib vs placebo in combination with trastuzumab and capecitabine for patients with locally advanced unresectable or HER2-positive metastatic breast cancer (HER2CLIMB): Outcomes by hormone receptor status [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 PD3-08.

BackgroundThe phase III MONALEESA-3 trial included first- (1L) and second-line (2L) patients and demonstrated a significant overall survival (OS) benefit for ribociclib + fulvestrant in patients with hormone receptor–positive, human epidermal growth factor receptor 2–negative (HR+/HER2−) advanced breast cancer (ABC) in the final protocol-specified and exploratory (longer follow-up) OS analyses. At the time of these analyses, the full OS benefit of 1L ribociclib was not completely characterized because the median OS (mOS) was not reached. As CDK4/6 inhibitor (CDK4/6i) + endocrine therapy (ET) is now a preferred option for 1L HR+/HER2− ABC, we report an exploratory analysis (median follow-up, 70.8 months; 14.5 months longer than the prior analysis) to fully elucidate the OS benefit in the MONALEESA-3 1L population.MethodsPostmenopausal patients with HR+/HER2− ABC were randomized 2:1 to 1L/2L fulvestrant + ribociclib or placebo. OS in 1L patients (de novo disease or relapse > 12 months from completion of [neo]adjuvant ET) was assessed by Cox proportional hazards model and Kaplan–Meier methods. Progression-free survival 2 (PFS2) and chemotherapy-free survival (CFS) were analyzed. MONALEESA-3 is registered with ClinicalTrials.gov (NCT02422615).ResultsAt data cutoff (January 12, 2022; median follow-up time, 70.8 months), mOS was 67.6 versus 51.8 months with 1L ribociclib versus placebo (hazard ratio (HR) 0.67; 95% CI 0.50–0.90); 16.5% and 8.6% of ribociclib and placebo patients, respectively, were still receiving treatment. PFS2 (HR 0.64) and CFS (HR 0.62) favored ribociclib versus placebo. Among those who discontinued treatment, 16.7% and 35.0% on ribociclib or placebo, respectively, received a subsequent CDK4/6i. No new safety signals were observed.ConclusionsThis analysis of MONALEESA-3 reports the longest mOS thus far (67.6 months) for 1L patients in a phase III ABC trial. These results in a 1L population show that the OS benefit of ribociclib was maintained through extended follow-up, further supporting its use in HR+/HER2− ABC.

Background: There are multiple therapeutic strategies for patients (pts) with hormone receptor positive (HR+), HER2 negative (HER2-) metastatic breast cancer (MBC) following progression on a first-line cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) and endocrine therapy (ET). There is an unmet need for predictive and prognostic biomarkers to identify HR+, HER2- MBC pts likely to benefit from continued CDK4/6i therapy beyond progression. Thymidine kinase (TK), an enzyme involved in DNA synthesis, represents a promising biomarker due to the association of elevated serum TK activity (sTKa) with greater tumor cell division and poorer clinical outcomes. We investigated sTKa as a potential biomarker of response to continued CDK4/6i therapy beyond progression in the MAINTAIN trial. Methods: MAINTAIN was the first randomized controlled trial to demonstrate a significant progression-free survival (PFS) benefit for HR+, HER2- MBC patients who switched ET (fulvestrant or exemestane) and received the CDK4/6i ribociclib compared to ET plus placebo after progressing on prior CDK4/6i and ET. We evaluated the association between sTKa and PFS. In this exploratory analysis, sTKa levels were analyzed from blood samples collected at baseline and cycle 2 day 1 (C2D1) by Biovica using the Divitum® TKa assay. Patients were categorized into low (<250 Divitum® unit of Activity [DuA]) and high (≥250 DuA) sTKa groups for PFS analysis. The cut-off point of 250 DuA is a clinically validated and FDA 510(k) cleared reference value for prognosis in HR+ MBC. Log-rank test and Cox regression models were used to assess the association between sTKa levels and PFS as well as calculate hazard ratios (HR) and 95% confidence intervals (CI). The database was locked on Jan 4, 2022. Results: Of the 119 MAINTAIN participants, 90 had samples available for analysis. Forty (44%) in the placebo+ET group and 50 (56%) in the ribociclib+ET group. Eighty-one pts had baseline sTKa, 73 had C2D1 sTKa, and 69 had sTKa at both timepoints. Fifty-three percent (43/81) of pts had high baseline TKa and 37% (27/73) of pts had high C2D1 TKa. Pts with low baseline sTKa exhibited a non-significant trend towards improved PFS compared to those with high baseline sTKa (median PFS [mPFS] 5.6 vs 3.0 mo; HR 0.73, 95% CI 0.45-1.18, p=0.198). In contrast, pts with low C2D1 sTKa demonstrated a statistically significant PFS benefit compared to those with high C2D1 sTKa (mPFS 5.7 vs 2.7 mo; HR 0.30, 95% CI 0.17-0.52, p<0.001). Notably, the mPFS in the ribociclib+ET group was 10.9 mo for pts with low C2D1 sTKa compared to 2.7 mo for those with high C2D1 sTKa (HR 0.15, 95% CI 0.06-0.37, p<0.001). The placebo+ET group did not show a statistically significant PFS benefit for those with low C2D1 sTKa versus high C2D1 sTKa (mPFS 4.8 vs 2.5 mo; HR 0.51, 95% CI 0.23-1.13, p=0.098). Among 69 pts evaluated for sTKa dynamics, the longest PFS was seen in 13 pts (19%) who transitioned from high baseline to low C2D1 sTKa (mPFS 8.2 mo; 95% CI 5.6-16.6). Twenty-one (30%) pts who maintained high sTka levels from baseline to C2D1 had the shortest PFS (mPFS 2.7 mo; 95% CI 2.1-3.0). Conclusions: In the phase II MAINTAIN trial, sTKa was a predictive biomarker for response to switching ET + continuing CDK4/6i in HR+, HER2- MBC pts following progression on CDK4/6i and ET. Low (<250 DuA) C2D1 sTKa levels predicted a positive treatment response, especially among those receiving ribociclib+ET. sTKa dynamics from baseline to C2D1 were prognostic, providing insights into PFS outcomes. Our analysis supports C2D1 as a critical timepoint for sTKa in assessing continued benefit of CDK4/6i and risk of progression. Further research in a larger trial evaluating sTKa dynamics and clinical outcomes is warranted. Citation Format: Ruth Sacks, Codruta Chiuzan, Melissa K. Accordino, Elizabeth Sakach, Amy Williams, Prabhjot S. Mundi, Claire Sathe, Meghna S. Trivedi, Naomi Sender, Yelena Novik, Amy Tiersten, George Raptis, Lea N. Baer, Sun Y. Oh, Amelia B. Zelnak, Kari B. Wisinski, Eleni Andreopoulou, Williams J. Gradishar, Erica Stringer-Reasor, Sonya A. Reid, Anne O'Dea, Ruth O'Regan, Katherine D. Crew, Dawn L. Hershman, Kevin Kalinsky. Serum Thymidine Kinase as a Biomarker for Response Beyond Progression in First-line CDK 4/6 Inhibitors: Insights from the Randomized Phase II MAINTAIN Trial [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 P4-01-22.

BackgroundWe performed a network meta-analysis of randomized controlled trials (RCTs) to indirectly compare the efficacy of different targeted agents with fulvestrant for patients with hormone-receptor-positive (HR+) and human epidermal growth factor receptor type 2-negative (HER2–) advanced breast cancer (ABC) following progression on prior endocrine therapy.MethodsThe titles/abstracts were searched from the PubMed, EMBASE, and the Cochrane Library databases for RCTs to evaluate the efficacy of palbociclib plus fulvestrant vs alternative targeted therapies plus fulvestrant for postmenopausal HR+/HER2– ABC following progression on prior endocrine therapy. In addition, the primary measured outcome was progression-free survival (PFS) and objective response rate. The surface under the cumulative ranking (SUCRA) value of each treatment was calculated to achieve the best ranking for each treatment.ResultsA total of 11 studies, including 4,178 patients in the network meta-analysis, were included and analyzed. In terms of the pooled hazard ratios (HRs) for PFS, palbociclib plus fulvestrant was superior to other target agents plus fulvestrant (HR=0.62, 95% credible interval [CrI]: 0.40–0.96; HR=0.62, 95% CrI: 0.47–0.96; for pictilisib plus fulvestrant and buparlisib plus fulvestrant, respectively). Ribociclib plus fulvestrant has no difference in abemaciclib plus fulvestrant and palbociclib plus fulvestrant (HR =1.02, 95% CrI =0.72–1.45; HR =1.22, 95% CrI =0.84–1.78). In terms of objective response rate, compared with placebo plus fulvestrant, abemaciclib plus fulvestrant, dovitinib plus fulvestrant, buparlisib plus fulvestrant, and palbociclib plus fulvestrant had a significant difference (odds ratio [OR] =2.84, 95% CrI =1.91– 4.31; OR =3.62, 95% CrI =1.21–12.48; OR =1.80, 95% CrI =1.25–2.60; and OR =2.52, 95% CrI =1.43– 4.72, respectively).ConclusionAccording to the present study, palbociclib plus fulvestrant may be the optimal treatment for HR+/HER2– postmenopausal women with ABC after disease progression following endocrine therapy.

Background: In the international Phase III COmparisoN of Faslodex In Recurrent or Metastatic breast cancer (CONFIRM) study, fulvestrant 500 mg was associated with significantly longer progression-free survival (PFS) over the 250 mg dose (hazard ratio [HR] 0.80; 95% confidence interval [CI] 0.68, 0.94; p=0.006) in postmenopausal women with advanced breast cancer (ABC) following failure on prior endocrine therapy. There were no clinically meaningful differences between the treatment groups in terms of the incidence or severity of adverse events. The present study was designed to compare the efficacy and safety of fulvestrant 500 mg versus 250 mg in a Chinese population for registration purposes. Methods: This was a Phase III randomized, double-blind study in a Chinese population (ClinicalTrials.gov: NCT01300351). Postmenopausal women with estrogen receptor positive (ER+) ABC following failure on prior endocrine (antiestrogen [AO] or aromatase inhibitor [AI]) therapy were randomized 1:1 to fulvestrant 500 mg or 250 mg. Patients (pts) were stratified by post-AO/post-AI status and enrollment of post-AI pts was capped at 45%. Primary study endpoint was PFS. Consistency with the global CONFIRM study was to be concluded if the HR for the treatment comparison of PFS was <1 (full analysis set; stratified log-rank test); the study was not powered to detect significant differences between treatment groups. Secondary endpoints included pharmacokinetics, ORR, CBR, DoR, DoCB, safety and tolerability. Results: 221 pts were randomized to fulvestrant 500 mg (n=111) or fulvestrant 250 mg (n=110). 121 pts were in the post-AO subgroup and 100 pts were in the post-AI subgroup. Demographic and baseline characteristics were balanced between fulvestrant 500 mg and fulvestrant 250 mg and comparable with those in the global CONFIRM study. 98% (119/121) in the post-AO subgroup and 92% (92/100) in the post-AI subgroup had adjuvant endocrine therapy, while only 12% (14/121) in the post-AO subgroup and 51% (51/100) in the post-AI subgroup used salvage endocrine therapy. At the time of the primary analysis, 152 progression events (69%) had occurred (post-AO 59% [71/121]; post-AI 81% [81/100]). Median PFS was 8.0 months (m) in the fulvestrant 500 mg group vs 4.0 m in the 250 mg group (HR 0.75; 95% CI 0.54, 1.03; p=0.078); the predefined criterion for consistency with the global CONFIRM study was met. In a predefined subgroup analysis of PFS, the HR for fulvestrant 500 mg vs 250 mg was <1 in both post-AO (median PFS 8.1 m vs 5.6 m; HR 0.86; 95% CI 0.54, 1.37) and post-AI (median PFS 5.8 m vs 2.9 m; HR 0.65; 95% CI 0.42, 1.03) subgroups. Secondary endpoints favored fulvestrant 500 mg over 250 mg, with the exception of median DoR. Safety and tolerability profiles were consistent with the known safety profile of fulvestrant. Conclusions: Data from the present study support the superior clinical benefit of fulvestrant 500 mg vs 250 mg demonstrated in the global CONFIRM study, in postmenopausal Chinese women with ER+ ABC. Hazard ratios favoring fulvestrant 500 mg were observed in both the post-AO and post-AI settings. Citation Format: Zefei Jiang, Qingyuan Zhang, Zhimin Shao, Kunwei Shen, Li Li, Jifeng Feng, Zhongseng Tong, Kangsheng Gu, Xiaojia Wang, Binghe Xu, Guofang Sun, Huifang Chen, Yuri Rukazenkov. A phase III study of fulvestrant 500 mg versus 250 mg in postmenopausal Chinese women with advanced breast cancer and disease progression following failure on prior antiestrogen or aromatase inhibitor therapy: Supporting superior clinical benefit for the [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-13-07.

Background: More effective treatments for patients (pts) with endocrine-resistant, PIK3CA-mutated, hormone receptor-positive, HER2-negative breast cancer (HR+, HER2– BC) that prevent or overcome resistance are needed. Previous phosphatidylinositol-4,5-bisphosphate 3-kinase alpha (PI3Kα) inhibitors have a limited therapeutic window. Inavolisib is a highly potent and selective inhibitor of the PI3K catalytic subunit α isoform protein (p110α; encoded by the PIK3CA gene). In addition, inavolisib promotes the degradation of mutated p110α, which may limit toxicity. Prior preclinical data suggested substantial synergy between PI3K and cyclin-dependent kinase 4/6 inhibition plus endocrine therapy. The inavolisib first-in-human study (NCT03006172) showed that the triplet had a manageable safety profile, lack of drug–drug interactions, and promising preliminary antitumor activity. Methods: The Phase III, randomized, double-blind INAVO120 trial (NCT04191499) recruited 325 pts with PIK3CA-mutated, HR+, HER2– locally advanced/metastatic BC (LA/mBC) who relapsed during or within 12 months of adjuvant endocrine therapy completion, and who had no prior therapy for advanced BC. PIK3CA mutations were identified by central circulating tumor DNA (ctDNA) or local tissue/ctDNA analysis. Pts were randomized to inavolisib (9 mg orally once a day [PO QD] on Days 1–28 of each cycle) or placebo (PO QD) in combination with palbociclib (125 mg PO QD on Days 1–21 of each cycle) and fulvestrant (500 mg intramuscularly on Cycle 1 Days 1 and 15, and on Day 1 of each subsequent cycle). This is the first study to assess the triplet combination at maximum dose (inavolisib) or per-label dose/schedule (palbociclib/fulvestrant). The primary endpoint was investigator-assessed progression-free survival (INV-PFS). Secondary endpoints included overall survival (OS) and confirmed objective response rate (ORR). Adverse events (AEs) were graded per NCI-CTCAE v5. Results: After 21.3 months median follow-up, median INV-PFS was 15.0 months (95% confidence interval [CI] = 11.3, 20.5) with inavolisib + palbociclib + fulvestrant, and 7.3 months (95% CI = 5.6, 9.3) with placebo + palbociclib + fulvestrant (hazard ratio 0.43; 95% CI = 0.32, 0.59). Landmark INV-PFS event-free rates at 6, 12, and 18 months were 82.9%, 55.9%, and 46.2% with inavolisib, and 55.9%, 32.6%, and 21.1% with placebo. OS showed a trend in favor of inavolisib (hazard ratio 0.64; 95% CI = 0.43, 0.97; p = 0.0338 [boundary 0.0098 or hazard ratio 0.592]), with follow-up ongoing. Landmark OS event-free rates at 12 and 18 months were 85.9% and 73.7% with inavolisib, and 74.9% and 67.5% with placebo. Confirmed ORRs were 58.4% with inavolisib and 25.0% with placebo. Rates of selected Grade 3–4 AEs with inavolisib and placebo were: neutropenia at 80.2% and 78.4%; hyperglycemia at 5.6% and 0%; diarrhea at 3.7% and 0%; stomatitis and mucosal inflammation at 5.6% and 0%; and rash at 0% and 0%. The rate of discontinuation due to AEs was 6.2% for inavolisib and 0.6% for placebo. There were no treatment-related Grade 5 AEs. Conclusions: Inavolisib + palbociclib + fulvestrant demonstrated a statistically significant and clinically meaningful improvement in INV-PFS vs. placebo + palbociclib + fulvestrant in this high-risk population, and a favorable OS trend in favor of the inavolisib combination at the first interim analysis. Inavolisib + palbociclib + fulvestrant had a manageable safety profile consistent with the known safety profiles of the individual drugs (reflective of α isoform selectivity of inavolisib), and no new safety signal was identified. Inavolisib + palbociclib + fulvestrant could represent a new standard of care for pts with PIK3CA-mutated, HR+, HER2– LA/mBC. Citation Format: Komal L. Jhaveri, Seock-Ah Im, Cristina Saura, Dejan Juric, Sibylle Loibl, Kevin Kalinsky, Peter Schmid, Sherene Loi, Eirini Thanopoulou, Noopur Shankar, Guiyuan Lei, Thomas Stout, Katherine E. Hutchinson, Jennifer Schutzman, Chunyan Song, Nicholas C. Turner. Inavolisib or placebo in combination with palbociclib and fulvestrant in patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer: Phase III INAVO120 primary analysis [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 GS03-13.

Background: Sorafenib (SOR) is an oral multikinase inhibitor with antiangiogenic and antiproliferative activity. We previously reported data from the primary analysis of SOLTI-0701 demonstrating a progressionfree survival (PFS) benefit with the oral regimen of SOR + capecitabine (CAP) vs placebo (PL)+CAP in patients with advanced breast cancer (BC). Here we describe overall survival (OS), a secondary endpoint of SOLTI-0701. Methods: SOLTI-0701 is a multinational (Brazil, France, Spain) phase 2b study in HER2-negative patients with locally advanced or metastatic BC and ≥1 prior chemo regimen for advanced BC. Patients were randomized (1:1) to receive CAP (1000 mg/m2 po, twice daily [BID], 14 of every 21 days) with PL or SOR (400 mg po, BID). The primary endpoint was PFS. The sample size was estimated at 220 patients based on patient accrual projections and the estimated rate of PFS events. OS analysis was planned after 120 events. Results: A total of 229 patients were enrolled (115 SOR+CAP and 114 PL+CAP) from August 2007 to December 2008. Treatment arms were balanced for age (mean 55.2 y), ECOG status 0 (68%) and 1 (30%), stage IV disease (91%), and visceral metastases (75%). In the primary analysis, median PFS was 6.4 mo for the SOR arm vs 4.1 mo for the PL arm (hazard ratio 0.58; 95% CI, 0.41-0.81; 1-sided P=0.0006); the most common Grade 3/4 toxicity was hand-foot skin reaction/syndrome (45% vs 13%, respectively); discontinuation of treatment due to adverse events was infrequent (15% vs 7%, respectively). OS data are expected by the 3rd quarter of this year and will be presented, as well as updated safety data. Conclusions: The oral combination of SOR+CAP significantly improved PFS in patients with advanced BC. The regimen was tolerable with a manageable toxicity profile. An ongoing phase 3 registration trial is evaluating the combination of SOR+CAP for advanced BC. The secondary endpoint of OS will better characterize the potential role of SOR in advanced BC as randomized controlled trials thus far have yet to demonstrate any survival benefit with antiangiogenic agents. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-16-01.

Introduction: Hyperactivation of the phosphoinositide-3-kinase (PI3K) pathway is a frequent event in human cancers and can be a result of phosphatase and tensin homolog (PTEN) loss, activation of receptor tyrosine kinases, or alterations in PI3K isoforms. About 40% of hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2-) breast cancers harbor alterations in the PIK3CA gene, which encodes the alpha subunit of PI3K (p110α). Mutations in PIK3CA can cause PI3K pathway hyperactivation, which may contribute to endocrine resistance. Alpelisib (ALP) is an α-selective PI3K inhibitor that, in combination with fulvestrant (FUL), demonstrated improved median progression-free survival (PFS) vs placebo (PBO) + FUL (11.0 vs 5.7 mo, respectively; hazard ratio [HR] 0.65; 95% confidence interval [CI], 0.50-0.85; P Methods: SOLAR-1 is a phase 3, randomized, double-blind study of ALP 300 mg (or PBO) once daily + FUL 500 mg every 28 days + Cycle 1 Day 15 in men and postmenopausal women with HR+, HER2- ABC. Retrospectively, PIK3CA alterations (mutations and amplifications) were assessed by NGS and PTEN levels were assessed by immunohistochemistry. PTEN loss was defined based on an H-score Results: Of 572 pts in SOLAR-1, 341 (60%) had a PIK3CA mutation in tumor tissue by PCR, valid NGS results were available for 404 (71%), and PTEN levels were available for 401 (70%). Of the pts with available PTEN results, 34 (8%) had PTEN loss. PFS results and HRs, by PIK3CA alteration status as detected by NGS and PTEN status, are shown in the Table. In pts whose tumors had any PIK3CA alteration (n=239), which included a small group of pts with alterations not detectable by the PCR-based test used for screening in SOLAR-1 (n=31), mPFS was improved in the ALP + FUL vs PBO + FUL arms. In the small group of pts (n=19) whose tumors had PTEN loss but no PIK3CA alteration, ALP showed an improved mPFS and favorable HR vs the placebo arm. In pts whose tumors had multiple alterations (n=44), HR and mPFS benefits of ALP were observed, albeit with wide 95% CIs. Conclusions: These data demonstrate the efficacy of ALP in pts whose tumors harbor PIK3CA alterations as detected by NGS, including alterations that were not detectable by the PCR-based test used in SOLAR-1. Additional analyses suggest that ALP is also effective in pts with single and multiple PIK3CA mutations and in those whose tumors do not harbor a PIK3CA alteration but do have PTEN loss; however, low patient numbers in the PTEN loss subgroups may limit conclusions. Citation Format: Dejan Juric, Fabrice Andre, Christian F. Singer, Joohyuk Sohn, Mario Campone, Sibylle Loibl, Pierfranco Conte, Hiroji Iwata, Eva Ciruelos, Ingrid A. Mayer, Albert Reising, Chong Ma, Michelle Miller, Naveen Babbar, Hope S. Rugo. Clinical outcomes of alpelisib in hormone receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer by next-generation sequencing-detected PIK3CA alteration status and phosphatase and tensin homolog loss: Biomarker analysis from the SOLAR-1 study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-10-04.

Background: The Phase 2 PARSIFAL study assessed whether fulvestrant (FUL) or letrozole (LET) was the optimal endocrine partner for the cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) palbociclib (PAL) in patients (pts) with untreated, endocrine-sensitive, hormone receptor-positive (HR+)/HER2-negative (HER2-) advanced breast cancer (ABC) in the first-line setting. This trial failed to demonstrate an improvement in progression-free survival (PFS) of PAL+FUL over PAL+LET (Llombart-Cussac et al. Jama Oncol 2021). Following progression on CDK4/6i-based regimens in the metastatic setting, the EMERALD study (Bardia et al, SABCS 2022 GS3-01) identified early progressions (< 12 months [mo]) as a strong predictor of resistance to subsequent endocrine therapies. Here, we report updated PFS and overall survival (OS) from PARSIFAL, exploring a PFS <12 mo threshold as a prognostic factor for poor outcomes. Methods: This was an observational, international, multicenter study that included pts from the prospective PARSIFAL study, in which pts were randomly assigned (1:1) to receive PAL (oral 125 mg/day, 28-day cycles; 3 weeks on, 1 week off) plus FUL or LET at conventional doses. The primary objective was to extend the assessment of OS of PARSIFAL study with a longer median follow-up. Secondary objectives included extended PFS, other post-progression efficacy data, and the identification of new prognostic and predictive markers. The design had a planned recruitment of at least 388 pts with 195 deaths. The 2-sided stratified log-rank test (α = 0.05) had a 70% power to detect a hazard ratio ≤0.70 in favor of FUL + PAL arm. Results: A total of 389 pts (80.5%) from the PARSIFAL study were included in this analysis, involving 32 of the 47 original sites. Pts signed a new informed consent form according to local regulations. Demographic and baseline disease characteristics were similar between the PARSIFAL-LONG and the overall PARISFAL intention-to-treat populations. At the time of analysis, after a median follow up of 5.0 years (range, 0.1-7.3), 241 and 213 events were reported for PFS and OS, respectively. No differences in efficacy were observed between treatment arms whether for PFS (hazard ratio, 1.0, p=0.985) or OS (hazard ratio, 0.94, p=0.635). In accordance with the protocol for PARSIFAL-LONG, both arms were combined for subsequent analysis. The median PFS (mPFS) for the first-line PAL-based regimen population was 33.2 mo (95%CI, 27.7-39.5), with a median OS (mOS) of 65.4 mo (95%CI, 57.8-72.0). A total of 86 pts (22.1% of the population) had a mPFS time <12 mo (early progressors). mOS and mPFS for this early progressor subgroup were 24.0 mo (95%CI, 17.3-30.1) and 7.0 mo (95%CI, 5.6-8.3), respectively, and only 11 pts (12.8%) were still alive at the time of analysis. The remaining 303 pts (77.9%) were progression-free on PAL-based regimens at 12 mo (PFS≥12). The number of events for PFS and OS at this time were 165 (54.5%) and 138 (45.5%), respectively. mOS from randomization for the PFS≥12 subgroup was 81.5 mo (95%CI, 70.2-not achieved) and the mPFS was 49.8 mo (95%CI, 40.9-59.8). Following progression on PAL-based regimens, the PFS≥12 criteria was a strong predictor for mOS, with 27.0 vs 18.0 mo (hazard ratio, 0.67, 95%CI, 0.51-0.90, p=0.007) for PFS≥12 and early progressors, respectively. These differences may increase in the future, as 54.5% of pts with PFS≥12 are still alive compared to 12.8% of pts with an early progression. Conclusions: Extended follow-up analysis from PARSIFAL study confirms no major differences between LET or FUL when combined with PAL. mPFS and mOS results are consistent with those reported in other first-line trials involving different CDK4/6i. Progression within the first year of first-line CDK4/6i-based regimen for HR+/HER2- ABC pts may be prognostic of less favorable outcomes. Citation Format: Antonio Llombart-Cussac, José Manuel Pérez-García, Meritxell Bellet- Ezquerra, Florence Dalenc, Miguel Gil-Gil, Manuel Ruíz - Borrego, Joaquín Gavilá, Peter Schmid, Pilar Zamora, Duncan Wheatley, Eduardo Martínez-de Dueñas, Kepa Amillano, Antonio Antón, Paul Cottu, Gemma Viñas, Thierry Petit, Petra Tesarová, Juan Cueva, Marco Colleoni, Maria Purificación Martínez del Prado, Raquel Andrés, Marta Díaz Cabo, Susana Victorino, Miguel Sampayo-Cordero, Javier Cortés. PARSIFAL-LONG: Extended follow-up of hormone receptor-positive/HER2-negative advanced breast cancer patients treated with fulvestrant and palbociclib vs. letrozole and palbociclib in the PARSIFAL 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 RF01-03.

Background: The standard of care treatment for patients (pts) with hormone receptor-positive (HR+), HER2-negative metastatic breast cancer is a CDK 4/6 inhibitor (CDKI, abemaciclib, palbociclib, ribociclib) added to endocrine therapy (ET). Patients with liver or lung metastases may have a worse prognosis and derive different amounts of benefit from the addition of a CDKI. This pooled analysis examines whether patients with only lung (LuOM) or liver (LiOM) metastases may respond differently to CDKI-based treatment. Methodology: We pooled individual patient data from 7 randomized trials of CDKI+ET for patients with HR+, HER2-negative MBC submitted to the FDA before January 1, 2024, in support of marketing applications. The primary endpoint was investigator-assessed progression-free survival (PFS), and overall survival (OS) was a key secondary endpoint in all 7 trials. The analyses included all pts who received at least 1 dose of CDKI/placebo (PBO) with ET (aromatase inhibitor [AI] anastrozole or letrozole, or fulvestrant [F]). Using descriptive statistics, we performed a prespecified exploratory subgroup analyses in patients with LiOM or LuOM. Pts with bone-only disease, pleural lesions/effusion, ascites, other visceral metastasis, only nodal disease, and both lung and liver metastases were excluded. Analyses were performed in subgroups of pts treated with CDKI+AI only and pts with CDKI+F only. OS analyses were only performed on pts treated with CDKI+F based on data available at the time of this analysis. Median (med) PFS and OS were estimated using Kaplan-Meier (K-M) methods. Hazard ratios (HR) with 95% confidence intervals (CIs) for PFS and OS were estimated using Cox regression models. for PFS and OS were estimated using Cox regression models. Findings: Seven trials were used for PFS analyses (n=4200) and 1582 pts met inclusion criteria for the LiOM (n=651) and LuOM (n=931). Key baseline demographic and prognostic factors appeared similar between the subgroups. Accuracy of site of metastases and treatment allocation were limited to information captured in trials and datasets. LuOM PFS: 389 pts received CDKI+AI, 248 pts received PBO+AI, 197 pts received CDKI+F, and 97 pts received PBO+F. Med PFS was 25.3 mo (21.6-28.1) for CDKI+ET vs 15.2 mo (13.5-19.2) for PBO+ET (HR 0.64, 95% CI 0.53-0.78). Med PFS for CDKI+AI was 27.8 mo (23.1-31.1) vs 16.7 mo (13.8-24.2) for PBO+AI (HR 0.60, 95% CI 0.47-0.76). Med PFS for CDKI+F was 19.6 mo (13.8-not estimable [NE]) vs 14 mo (11.1-8.7) for PBO+F (HR 0.72, 95% CI 0.51-1.00). LiOM PFS: 142 pts received CDKI+AI, 141 pts received PBO+AI, 234 pts received CDKI+F, and 134 pts received PBO+F. Med PFS was 11.2 mo (9.4-13.1) for CDKI+ET vs 5.6 mo (3.6-7.0) for PBO+ET (HR 0.59, 95% CI 0.49-0.72). Med PFS for CDKI+AI was 13.1 mo (10.4-14.9) vs 9.4 mo (5.6-11.2) for PBO+AI (HR 0.63, 95% CI 0.47-0.84). Med PFS for CDKI+F was 9.4 mo (7.6 -12.9) vs 3.4 mo (2.0-5.4) for PBO+F (HR 0.51, 95% CI 0.40-0.65). Three trials were used for OS analyses (n=1948). CDKI+F OS (n=662): 431 pts received CDKI+F (197 LuOM and 234 LiOM) and 231 pts received PBO+F (97 LuOM and 134 LiOM). In LiOM, med OS was 31.8 mo (28.0-36.5) for CDKI+F vs 25.3 mo (21.9-31.8) for PBO+F (HR 0.77, 95% CI 0.59-1.01). In LuOM, med OS was 48.2 mo (41.5- NE) for CDKI+F vs 51.6 mo (36.3-NE) for PBO+F (HR 0.90, 95% CI 0.61-1.31), although these results should be interpreted with caution due to the high level of censoring after 3 years and limited follow up. KM curve of LuOM suggested non-proportional hazards; a restricted mean survival time analysis showed a difference at 54.4 mo of 0.98 mo (SE 2.2). Conclusion: Prior results show that pts with liver/lung metastases benefit from the addition of CDKI to ET. This pooled analysis suggests there may be differences in amount of benefit with adding CDKI to ET based on the site of the metastasis and the choice of ET. Further research is needed to understand which subgroup of pts with lung metastases may benefit more or less from adding CDKI to ET. Citation Format: Raissa Kentsa, Hee-Koung Joeng, Melanie Royce, Suparna Wedam, Mirat Shah, Preeti Narayan, Xin Gao, Joyce Cheng, Mallorie Fiero, Shenghui Tang, Christy Osgood, Richard Pazdur, Paul Kluetz, Jennifer Gao, Laleh Amiri-Kordestani. Efficacy of cyclin-dependent kinase 4/6 inhibitor + endocrine therapy in patients w/ hormone receptor-positive, HER2-negative advanced or metastatic breast cancer w/ liver or lung only metastases: a US Food & Drug Administration pooled analysis [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 P2-09-19.

Introduction. Сombination of alpelisib plus fulvestrant is approved in patients with hormone receptor positive, HER2-negative, PIK3CA-mutated advanced breast cancer (ABC) after progression on hormonotherapy. Efficacy data of alpelisib in heavily pretreated patients with HR+/HER-2-, PIK3CA-mutated advanced breast cancer are limited, only results from phase I trial are available. Here we report our results of alpelisib efficacy in 19 heavily pretreated patients.Object: to evaluate efficacy and safety of combination alpelisib plus fulvestrant in patients with HR+/HER2-, PIK3CA-mutated advanced breast cancer in initial and later lines of therapy in real clinical practice.Materials and methods. Combination of alpelisib plus fulvestrant was investigated in 19 patients with HR+/HER2-, PIK3CAmutated ABC, alpelisib at a dose of 300 mg per day plus fulvestrant at a dose of 500 mg i.m. every 28 days and once on day 15. Treatment continued until disease progression or unacceptable toxicity.Results. From February 2021 19 patients with HR+/HER2-, PIK3CA-mutated advanced breast cancer were treated with alpelisib plus fulvestrant. The data cut off is October 2021. Median lines of treatment in advanced disease was five, including 19 (100%) patients received CDK4/6, 14 (74%) – fulvestrant and/or everolimus and 15 (79%) – chemotherapy. 4 (21%) received alpelisib in a second line, 15 (79%) – in subsequent lines. Median progression-free survival was 7 months. The response was evaluated in 18 patients: partial response was achieved in 5 (28%) patients, stable disease – in 9 (50%), disease progression – 4 (22%). The most frequent adverse events were hyperglycemia – 74% (grade 3 – 22%), creatinine increased – 42% and rash – 37% (grade 3 – 22%). Only one patient has discontinued the treatment due to Quincke`s edema.Conclusions. Combination of alpelisib with fulvestrant is an effective option both in initial and later lines of therapy in patients with HR+/HER2-, PIK3CA-mutated advanced breast cancer including fulvestrant, CDK4/6 inhibitors and/or everolimus – pretreated patients.

Gedatolisib potently targets all four class I PI3K isoforms and mTORC1 and mTORC2 to comprehensively block the PI3K/AKT/mTOR pathway and has shown compelling activity in early clinical trials with palbociclib and fulvestrant. This phase III randomized trial (VIKTORIA-1; ClinicalTrials.gov identifier: NCT05501886) evaluated the efficacy of gedatolisib-based therapy, comparing gedatolisib, palbociclib, and fulvestrant (gedatolisib triplet) and gedatolisib plus fulvestrant (gedatolisib doublet) with fulvestrant monotherapy in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative (HER2-), PIK3CA wild-type (WT) advanced breast cancer. Eligible patients had disease progression during or after CDK4/6 inhibitor and aromatase inhibitor treatment. Comparison of progression-free survival as assessed by blinded independent central review for gedatolisib triplet versus fulvestrant and gedatolisib doublet versus fulvestrant was the primary objective. A total of 392 patients were randomly assigned 1:1:1. The median study follow-up was 10.1 months. The median progression-free survival was 9.3 months in the gedatolisib-triplet group, 2.0 months in the fulvestrant group (hazard ratio [HR] for progression or death, 0.24 [95% CI, 0.17 to 0.35]; P < .001), and 7.4 months in the gedatolisib-doublet group (HR, 0.33 [95% CI, 0.24 to 0.48]; P < .001 v fulvestrant). Grade ≥3 treatment-related adverse events (TRAEs) reported in the gedatolisib-triplet and gedatolisib-doublet groups, respectively, included neutropenia (62.3%, 0.8%), stomatitis (19.2%, 12.3%), rash (4.6%, 5.4%), hyperglycemia (2.3%, 2.3%), and diarrhea (1.5%, 0.8%). Study treatment discontinuation because of TRAEs was reported in 2.3% (triplet) and 3.1% (doublet) of patients. The addition of gedatolisib to fulvestrant, with or without palbociclib, significantly reduced the risk of disease progression or death in patients with hormone receptor-positive/HER2-, PIK3CA WT advanced breast cancer.