Prior Therapy For Metastatic Breast Cancer Research Articles

Abstract OT2-01-06: Phase II trial of palbociclib plus endocrine therapy followed by combination of pembrolizumab, palbociclib and endocrine therapy in patients with hormone receptor positive metastatic breast cancer

Abstract Background: The combination of CDK4/6 inhibitors (CDK4/6i) and endocrine therapy (ET) is standard-of-care for patients with hormone receptor positive (HR+) HER2- metastatic breast cancer (MBC). Immune modulatory effects of CDK4/6i are well documented preclinically but poorly understood in the clinical setting. Our previous study combining letrozole, palbociclib and pembrolizumab in patients with HR+ MBC (NCT02778685) showed a promising complete response rate of 31%. Dynamic changes in peripheral blood mononuclear cell (PBMC) subpopulations indicated that palbociclib may increase CD8+ TEMRA (terminally differentiated effector memory cells) and CD4+ TEM (effector memory cells) and enable immune activation. The current cohort 3 was designed to study the immune modulatory effect of palbociclib as an immune-priming agent with a biomarker enriched design. Methods: Women with ECOG 0-1, HR+ HER2- MBC, RECIST 1.1 measurable disease, no prior therapy for MBC were enrolled. Patients with endocrine therapy, including aromatase inhibitor +/- ovarian suppression or fulvestrant, were eligible. A palbociclib + ET lead-in design was used, starting on day -28 followed by combination therapy with pembrolizumab added on C1D1. Peripheral blood and tumor biopsy at baseline and on-treatment were collected to allow in-depth analysis of biomarkers predicting response to the combination. The primary endpoint was to evaluate if the palbociclib potentiated immune responses as a “priming” agent through PBMC analysis and on treatment tumor biopsy. Secondary endpoints included other immune cell subsets and changes that follow the combination with pembrolizumab. With 25 patients, assuming a standard deviation of 0.51 in the relative change in classic monocytes in PBMCs, there is 90% power to detect a relative change of log(C1D1/baseline) of 34.5% with a type I error (two-sided) of 0.05. Results: Between August 2020 and April 2022, 16 patients were enrolled in cohort 3. Currently 11 patients have adverse event (AEs) and 16 patients have response data. Median age was 57 years (39-72). 8/11 (73%) were non-Hispanic white, 1/11 (9%) Hispanic, 1/11 (9%) Asian, and 1/11 (9%) African American. 87% patients had grade 3 AEs, and 30% had grade 4 AEs. Grade 3 AEs were 9/11 (82%) neutropenia, 5/11 (45%) leukopenia, 1/11 (9%) elevated LFTs, and 1/11 (9%) each lymphopenia, hot flashes, febrile neutropenia, and pneumonitis. Grade 4 AEs were 1/11 (9%) lymphopenia. 8/16 (50%) patients achieved a partial response (PR), 5/16 (31%) had stable disease (SD), and 1/16 (6%) had progression of disease (PD) by RECIST 1.1. Additionally, 2/16 (13%) patients were too early to determine best overall response. Response rate (CR+PR) was 50%. PBMCs and tumor microenvironment profiling are ongoing. Conclusion: The combination of palbociclib, pembrolizumab and ET is well tolerated, and a response rate of 50% was identified in HR+ MBC patients who received this combination as front-line therapy. Dynamic changes in peripheral blood mononuclear cells and tumor microenvironment profiling are ongoing. Citation Format: Yuan Yuan, Colt A. Egelston, Weihua Guo, Susan E. Yost, Paul H. Frankel, Christopher Ruel, Mireya Murga, Aileen Tang, Norma Martinez, Daniel Schmolze, Daphne Stewart, James Waisman, Kelly Yap, Joanne Mortimer, Niki Tank. Phase II trial of palbociclib plus endocrine therapy followed by combination of pembrolizumab, palbociclib and endocrine therapy in patients with hormone receptor positive metastatic breast cancer [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 OT2-01-06.

Abstract P4-01-36: Real World Data for Trastuzumab Deruxtecan in HER2-Positive Metastatic Breast Cancer Patients with Brain Metastases

Abstract Background: Trastuzumab deruxtecan (T-DXd) improves outcomes in HER2-positive metastatic breast cancer (MBC) patients, including patients with previously treated stable brain metastases (BMs). Our objective was to examine the characteristics of HER2-positive MBC patients with BMs prior to T-DXd use. Methods: We performed a retrospective cross-sectional study of T-DXd prior authorization (PA) approvals by OncoHealth for HER2-positive MBC patients between 1/17/2020 – 6/21/2022. Using medical records and utilization management data, we assessed the characteristics of PA approvals for 145 patients requesting T-DXd in Stage 4, HER2-positive, female MBC with BMs. Results: Brain metastases were identified in 41/145 patients with HER2-positive MBC prior to T-DXd authorization. Among the 41 patients The mean age was within the range of 50-59 years, 72% were hormone receptor-positive, and all were HER2 positive. 19/41(46%) had symptomatic BMs, 5/41(12%) had asymptomatic BMs. Prior local therapies for the BMs included craniotomy in 19.5% and brain radiotherapy in 87.8% prior to T-DXd. The median number of prior MBC therapies was 2 (range: 0-8) and 73% (30/41) did not receive tucatinib-based therapy prior to T-DXd. Tucatinib-based therapy was the most common subsequent line of therapy among T-DXd patients with further therapy (5/8). For available data (13 metastatic patients), 8 metastatic patients received tucatinib for an average of 149 days before receiving T-DXd for an average of 238 days, compared to 5 metastatic patients who received T-DXd for an average of 295 days before receiving tucatinib for 240 days, implying improved disease management in the T-DXd-to-tucatinib sequence. Conclusions: In the real world, patients with symptomatic, progressing BMs are more likely to receive T-DXd prior to tucatinib or potential tucatinib-based therapy, with longer duration of stability and treatment. Appropriate sequencing of available treatments with activity on brain metastases such as T-DXd and tucatinib-based therapy needs to be further studied. Citation Format: Andrew Toler, Laura R. Bobolts, Mark Mangurian, Melissa Pozotrigo, Corey Wise, Hiywete Solomon, Nicole Hartung, Rory Makielski, Shika Marur, Meera Ravindranathan, Shanthi Marur. Real World Data for Trastuzumab Deruxtecan in HER2-Positive Metastatic Breast Cancer Patients with Brain Metastases. [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 P4-01-36.

Abstract PD13-07: 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 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.

Primary results from TROPiCS-02: A randomized phase 3 study of sacituzumab govitecan (SG) versus treatment of physician’s choice (TPC) in patients (Pts) with hormone receptor–positive/HER2-negative (HR+/HER2-) advanced breast cancer.

LBA1001 Background: HR+/HER2– disease is the most common subtype of metastatic breast cancer (MBC). Treatment includes sequential endocrine therapy combined with targeted agents followed by single-agent chemotherapy, with increasingly shorter durations of benefit. SG is an anti–Trop-2 antibody-drug conjugate approved for metastatic triple-negative breast cancer with ≥2 prior therapies (≥1 for MBC). The HR+/HER2– MBC cohort of the phase 1/2 IMMU-132-01 study (n = 54) had an objective response rate (ORR) of 31.5%, median progression-free survival (PFS) of 5.5 mo, median overall survival (OS) of 12 mo, and a manageable safety profile with SG. TROPiCS-02 is a phase 3 randomized study (NCT03901339) to confirm SG outcomes in HR+/HER2– advanced breast cancer. Methods: Adults with locally determined, HR+/HER2– unresectable locally advanced or MBC, ECOG performance status of 0 or 1, and 2-4 prior chemotherapy regimens for MBC were eligible; 1 prior therapy for MBC was allowed if disease progressed ≤12 mo after (neo)adjuvant therapy. Pts must have received ≥1 prior taxane, CDK4/6 inhibitor, and endocrine therapy in any setting. Pts were randomized 1:1 to receive SG (10 mg/kg IV on d1 and 8, every 21d) or TPC (capecitabine, eribulin, vinorelbine, or gemcitabine) until disease progression/unacceptable toxicity. Primary endpoint was PFS per RECIST v1.1 by blinded independent central review (final analysis) with key secondary endpoint of OS (1st planned interim analysis). Results: At data cutoff on Jan 3, 2022, 272 vs 271 pts were randomized to receive SG vs TPC, respectively. Pt characteristics in the SG vs TPC arms were similar (3 median prior chemotherapy regimens for MBC [range, 0-8]; 95% had visceral metastases, 86% had prior endocrine therapy for MBC for ≥6 mo, 60% and 38% received prior CDK4/6 inhibitors for ≤12 and > 12 mo, respectively). SG (vs TPC) improved median PFS (5.5 vs 4.0 mo; HR, 0.66; 95% CI, 0.53-0.83; P= 0.0003); PFS rates at 6 and 12 mo were 46% vs 30% and 21% vs 7%, respectively. SG vs TPC showed a numeric but nonsignificant difference in OS (13.9 vs 12.3 mo; HR, 0.84; P= 0.143); ORR (21% vs 14%) and clinical benefit rate (34% vs 22%) were higher with SG vs TPC and median duration of response was 7.4 vs 5.6 mo, respectively. Overall, 74% vs 60% of patients (SG vs TPC) had grade ≥3 treatment-emergent adverse events (AEs); neutropenia (51% vs 39%) and diarrhea (10% vs 1%) were most common. AEs leading to discontinuation of SG vs TPC were low (6% vs 4%). There was 1 treatment-related death in the SG arm; none in the TPC arm. Conclusions: SG had a statistically significant, clinically meaningful PFS benefit over single-agent chemotherapy and a manageable safety profile in pts with heavily pre-treated HR+/HER2– endocrine-resistant, unresectable locally advanced or MBC, who have limited treatment options. Clinical trial information: NCT03901339.

Abstract P1-18-22: AKT inhibition in combination with endocrine therapy and a CDK4/6 inhibitor (CDK4/6i) in patients with hormone receptor positive (HR+)/HER2 negative metastatic breast cancer (MBC) and prior CDK4/6i exposure: A translational investigation

Abstract Background: The cyclin-dependent kinase 4/6 inhibitors, with endocrine therapy (ET), have become the standard of care for patients with HR+/HER2- MBC. Prior insight from tumor biopsies and preclinical analyses suggest that AKT1 activation can provoke CDK4/6i resistance, highlighting a potential therapeutic role for AKT inhibition (AKTi) in this setting. However, combinatorial inhibition can be associated with significant toxicity and identification of the optimal biological dose is often challenging. In this translational co-clinical study, we evaluated escalating doses of AKTi combination with CDK 4/6i in parallel patient-derived pre-clinical models as well as a phase 1b clinical trial. Methods: In an open-label phase Ib dose-escalation clinical trial (TAKTIC, NCT03959891), we evaluated the safety, tolerability and efficacy of escalating doses of the AKT1 inhibitor ipatasertib (ipat) in combination with palbociclib (palbo) and fulvestrant (fulv) for patients with HR+/HER2- MBC. Inclusion criteria include unresectable or metastatic disease, at least 1 prior therapy for MBC including any CDK4/6i, and up to 2 prior lines of chemotherapy for MBC (no limit on prior endocrine therapy). In addition, response to escalating doses of ipat and palbo (with fulv) were explored in vitro via an ATP-based viability assay in tumor cell lines derived from circulating tumor cells (CTC) isolated from patients with endocrine-refractory HR+ MBC. Results: In the dose-escalation portion of the phase 1b clinical trial, 23 patients received the triplet combination of ipat, palbo, and fulv (median number of prior lines = 4.3, range 1-7; 100% with prior CDK4/6i): 3 pts received ipat at 200mg + 125mg palbo, 15 pts received 300mg + 125mg palbo, and 5 pts received 400mg + 100mg palbo, all with fulv (500 mg). Among the 23 patients, 20 patients (86.9%) had disease control (4 partial response and 16 stable disease) as the best response, per RECIST. Grade 3/4 toxicities included neutropenia (n=20), lymphopenia (n=3), diarrhea (n=3), thrombocytopenia (n=2), transaminitis (n=2), and rash (n=2). Two DLTs were observed in the 300mg ipat + 125mg palbo cohort (grade 4 neutropenia ≥ 7 days), but none at 400mg + 100mg palbo. The combination of ipat and palbo demonstrated an additive effect in vitro, with increased sensitivity to lower doses of palbo in the presence of ipat. Based on the totality of data, 400mg ipat + 100mg palbo + fulv 500 mg was selected as the recommended phase II dose (RP2D) in the post-CDK4/6i setting. Conclusions: The triplet combination of endocrine therapy with AKTi and lower dose CDK4/6i appears to be well tolerated in heavily pre-treated pts, with preliminary evidence of clinical activity. Further study is needed to evaluate biomarkers associated with higher AKTi benefit in order to guide rational development of combination therapy for patients with HR+/HER2- MBC in the post-CDK4/6i setting. Overall, this translational study demonstrates how insight into the molecular mechanisms of CDK4/6i resistance and combinatorial modeling can be leveraged to develop actionable therapeutic regimens for patients with MBC. Citation Format: Seth A. Wander, Douglas S. Micalizzi, Taronish Dubash, Dejan Juric, Laura M. Spring, Neelima Vidula, Jennifer Keenan, Maureen Beeler, Elene Viscosi, Dante Che, Elizabeth L. Fisher, Rachel A. Hepp, Beverly Moy, Steven J. Isakoff, Leif W. Ellisen, Jeffrey G. Supko, Shyamala Maheswaran, Daniel A. Haber, Aditya Bardia. AKT inhibition in combination with endocrine therapy and a CDK4/6 inhibitor (CDK4/6i) in patients with hormone receptor positive (HR+)/HER2 negative metastatic breast cancer (MBC) and prior CDK4/6i exposure: A translational investigation [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 P1-18-22.

Abstract CT189: Characterization of ESR1 mutations at metastatic relapse and outcome under first line aromatase inhibitor and palbociclib in the PADA-1 trial

Abstract Background: Palbociclib (Pal) combined with an aromatase inhibitor (AI) is a standard of care as first line therapy in ER+ HER2- metastatic breast cancer (MBC). Cell-free DNA (cfDNA) ESR1 mutation (ESR1mut) status prior to treatment initiation may be associated with shorter progression-free survival (PFS) under first line Pal+AI; however, the impact of the exact type of ESR1mut, of their quantitative levels and clonality are unknown. In a subsidiary analysis of the first line PADA-1 phase 3 trial, cfDNA samples previously detected as positive by ddPCR were submitted to NGS; mutations types, level and clonality were correlated with patient outcomes under first line Pal+AI. Methods: PADA-1 (NCT03079011) is a phase III trial testing the clinical utility of real time ESR1mut detection in the blood of patients treated with AI-Pal. Main inclusion criteria are patients with ER+ HER2- MBC, who never received adjuvant AI or completed adjuvant AI for >12 months, with neither prior therapy for MBC nor visceral crisis. ESR1mut are tracked in cfDNA from up to 4ml of plasma by a single ddPCR assay targeting E380, L536, Y537 and D538 hotspots (i.e. >90% of known ESR1 activating mutations) with 0.1% sensitivity (Jeannot et al, Oncogene 2020). We sequenced the ddPCR positive cfDNA samples using a short amplicon-based NGS panel spanning 30 genes, including the full sequence of ESR1. We assessed for the correlation between PFS and ESR1mut type (NGS), absolute level (copy/ml, ddPCR) or variant allelic frequency (VAF, NGS & ddPCR), and clonality (NGS, pending the detection of other driver mutations). Results: Among the 1,017 included patients, N=33 (3.2%) had an ESR1mut detected by ddPCR at inclusion (median VAF= 2.5%, range (0.09-46.6%). 26/33 left-over cfDNA samples were available for NGS. ESR1mut VAFs retrieved by NGS and ddPCR showed an excellent intraclass correlation coefficient (ICC= 0.98; 95% CI [0.89;0.99]). In N=3 samples with low VAF by ddPCR (<1%), NGS was not able to detect ESR1mut. ESR1 codons 380, 536, 537 and 538 were mutated in N=5, 6, 10 and 7 patients, respectively (5 patients (19.2%) having polyclonal mutations). Among evaluable patients, ESR1mut were found clonal and subclonal in 11 (47.8%) and 12 (52.2%) patients, respectively. After a median follow-up of 24.8 months (range 0-41.9 months) (485 PFS events among the 1,017 included patients), ESR1mut detection at inclusion was found to be a prognostic factor for PFS (median PFS = 11.6 months 95% CI [8.3; NR] vs 28.5 months 95% CI [23.3;30.2]; HR= 2.2 95% CI = [1.4;3.4]). ESR1mut type, clonality and baseline levels had no significant additional impact on PFS. Conclusion: Presence of ESR1mut detected in cfDNA at metastatic relapse are associated with a shorter PFS under first line AI and palbociclib. ddPCR and NGS yielded similar quantitative results, while supplementary information obtained by NGS (mutation type and clonality) did not add further prognostic information. Funding: Pfizer, French National Cancer Institute (Grant PRT-K 2020-041) Citation Format: Anne Pradines, Céline Callens, Aurélia Doussine, Ivan Bièche, Jérôme Lemonnier, Marjorie Mauduit, Thomas Bachelot, Florence Dalenc, Alain Lortholary, Barbara Pistilli, Thibault De La Motte Rouge, Renaud Sabatier, Jean-Marc Ferrero, Sylvain Ladoire, Frédérique Berger, François-Clément Bidard. Characterization of ESR1 mutations at metastatic relapse and outcome under first line aromatase inhibitor and palbociclib in the PADA-1 trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT189.

Prognostic impact of ESR1 mutations in ER+ HER2- MBC patients prior treated with first line AI and palbociclib: An exploratory analysis of the PADA-1 trial.

1010 Background: The question of which is the best endocrine partner to CDK4/6 inhibitors in first line for ER+ HER2- metastatic breast cancer (MBC) remains open. ESR1 mutations might be of paramount importance, as they confer resistance to AI but not to SERD. In pts treated with first line palbociclib-AI combination (PADA-1 trial, NCT03079011), we investigated ESR1mut detection rate at inclusion, prior to any therapy, and their prognostic impact. Methods: The PADA-1 phase 3 trial (NCT03079011, UCBG-GINECO) evaluates the utility of monitoring the onset of ESR1mut in cell-free DNA (with a ddPCR assay [Jeannot et al, Oncogene 2020]) of pts receiving AI-palbociclib in first line. Included pts had no prior therapy for MBC and no overt resistance to AI. Results: N = 1017 ER+ HER2- MBC pts were included in 22 months from 04/2017 and had their cfDNA tested for ESR1mut at inclusion and during therapy. N = 33/1017 pts had a detectable circulating ESR1mut at inclusion (3.2%, 95%CI [2.2;4.5]), ESR1mut positivity being associated with a prior exposure to AI in the adjuvant setting (p < 0.01). N = 1 pt died after 1 month on treatment. In N = 25/32 evaluable pts (78%), ESR1mut became undetectable in cfDNA (AF < 0.1%) within the first 5 months on treatment, with a median time to ESR1mut ‘clearance’ of 34 days. Among these 25 pts, 14 pts (56%) had ESR1mut detected again during therapy; 2 pts (8%) experienced a progression with no ESR1mut detected; the remaining 9 patients (36%) were still both ESR1mut -free and progression-free at time of analysis. With a median FU time of 12.4 months (range: 0-25.3m) under AI-palbociclib, the 33 ESR1mut-positive pts had a shorter PFS (median: 17.5mo, 95%CI[10.5-NR]) than the 984 ESR1mut-negative pts (median not reached), with an estimated HR = 2.8 [1.6;5.0]. Updated data will be presented at the meeting. Conclusions: ESR1mut are rarely detected in the cfDNA of ER+ HER2- MBC patients with no overt resistance to AI. The quick ‘clearance’ of ESR1mut under treatment and the observed 17.5 months-long median PFS both suggest that the AI-palbociclib combination retain a clinical activity in this population. ESR1mut-positivity prior was however associated with a significantly shorter PFS, suggesting that ESR1mut positivity at baseline could accelerate the onset of resistance to AI-palbociclib. These findings may put into perspective the incoming results of the PARSIFAL trial. Clinical trial information: NCT03079011 .

Phase Ib trial to evaluate safety and anti-tumor activity of the AKT inhibitor, ipatasertib, in combination with endocrine therapy and a CDK4/6 inhibitor for patients with hormone receptor positive (HR+)/HER2 negative metastatic breast cancer (MBC) (TAKTIC).

1066 Background: The cyclin-dependent kinase 4/6 inhibitors (CDK4/6i), with an anti-estrogen, are the standard of care for HR+/HER2- MBC. Insights from patient biopsies and preclinical analysis suggest that AKT1 activation can provoke CDK4/6i resistance. We hypothesized that targeting AKT1 following CDK4/6i progression may provide clinical benefit. Methods: TAKTIC is an open-label phase Ib trial exploring the combination of the AKT1 inhibitor, ipatasertib (ipat), with an aromatase inhibitor (Arm A), fulvestrant (Arm B), or the triplet combination (Arm C) of fulvestrant + ipat + palbociclib (palbo). The primary objective is to evaluate the safety and tolerability of ipat in combination with endocrine therapy +/- CDK4/6i. 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 interim analysis from the triplet combination (Arm C). Results: As of 1/31/2020, 25 pts have enrolled, including 12 on Arm C, all of whom received prior CDK4/6i (median no of prior lines = 5.5, range 2-7). Along with fulvestrant, 3 pts received ipat at 200mg + 125mg palbo, 7 pts received 300mg + 125mg palbo, and 2 pts received 400mg + 100mg palbo. To date, 8/12 pts remain on treatment including 2 with partial response, 3 with stable disease, 3 with restaging studies pending and 4 with progressive disease. The triplet combination was well tolerated. Grade 3 toxicities included reduced WBC (8/12), reduced neutrophil count (11/12), reduced lymphocyte count (2/12) and single instances of transaminitis, rash, and reduced platelet count. The only grade 4 toxicity was reduced neutrophil count (4/12). There were no DLTs observed and no discontinuations due to toxicity. Mean steady state pharmacokinetic parameters for ipat were similar to historical data from single agent trials suggesting that combined treatment with palbo + fulvestrant did not affect the pharmacokinetics of ipat. Updated analysis will be presented at the meeting. Conclusions: The triplet combination of endocrine therapy with CDK 4/6i and AKTi appears to be well tolerated in heavily pre-treated pts, with a subset demonstrating signs of clinical benefit. The trial demonstrates how insights into the molecular mechanisms of CDK4/6i resistance could be leveraged into actionable therapeutic regimens for HR+/HER2- MBC. Clinical trial information: NCT03959891 .

Abstract P5-11-22: Clinical and biological efficacy of first line AI and palbociclib in ER+ HER2- MBC with detectable circulating ESR1 mutation prior to treatment initiation

Abstract Background: In ER+ HER2- metastatic breast cancer (MBC), activating ESR1 mutations (ESR1mut) confer resistance to aromatase inhibitors (AI) when used as single agent. The impact of ESR1mut, when detected at baseline (prior to the initiation of therapy), on the efficacy of first line combined AI- CDK4/6 inhibitor therapy remains however unknown. Methods: The PADA-1 phase 3 trial (NCT03079011) aims at evaluating the utility of monitoring the onset of ESR1mut in cell-free DNA (cfDNA) from patients (pts) receiving AI-palbociclib, as a biomarker to trigger a switch from AI to fulvestrant. Main inclusion criteria were pts with no prior therapy for MBC and with no overt resistance to AI (i.e. no adjuvant AI or adjuvant AI completed >12 months prior to the metastatic relapse). The present exploratory analysis evaluated the biological and clinical outcome of patients who tested positive for ESR1mut at baseline (before any treatment). Results: From 04/2017 to 01/2019, N=1017 ER+ HER2- MBC pts were included and had their cfDNA tested for ESR1mut at inclusion and during therapy (at 1 month and then every 2 months). N=33/1017 pts had a detectable circulating ESR1mut at inclusion (3.2%, 95%CI [2.2;4.5]), with a median allelic frequency (AF) of 2.5% (range: 0.1- 46%). First, we evaluated the kinetics of ESR1mut in the 33 ESR1mut-positive pts at inclusion. N=1 pt died after 1 month on treatment. In N=25/32 pts (78%), ESR1mut became undetectable (AF<0.1%) within the first 5 months on treatment, with a median time to ESR1mut ‘clearance’ in cfDNA of 34 days 95%CI[29;91d]. Among these 25 pts, with a median follow-up of 10 months (range 0-25.1m): 14 pts (56%) had ESR1mut detected again in cfDNA during AI-palbociclib therapy; 2 pts (8%) experienced a disease progression with no ESR1mut detected; the remaining 9 patients (36%) are still both ESR1mut -free and disease progression-free at time of analysis. Secondly, we evaluated the prognostic impact of cfDNA ESR1mut status at inclusion on progression-free survival (PFS) under AI palbociclib treatment, with an overall median follow-up time of 12.4 months (range: 0-25.3m). The 33 ESR1mut-positive pts experienced a shorter PFS (median PFS: 17.5mo, 95%CI=[10.5-NR]) than the 984 ESR1mut-negative pts (median PFS not reached), with an estimated HR= 2.8, 95%CI=[1.6;5]. Conclusions: ESR1mut are rarely detected in the cfDNA of ER+ HER2- MBC patients with no overt resistance to AI. The quick ‘clearance’ of ESR1mut observed in most patients following treatment initiation and the observed 17.5 months-long median PFS both suggest that the AI palbociclib combination retain clinical activity in ESR1mut-positive MBC. However, in most patients, these mutations were eventually detected again later during therapy and ESR1mut- positivity was associated with a significantly shorter PFS, suggesting that ESR1mut positivity at baseline could accelerate the onset of resistance to AI-palbociclib. Funding: Pfizer Citation Format: François-Clément Bidard, Céline Callens, Florence Dalenc, Barbara Pistilli, Thibault de la Motte Rouge, Florian Clatot, Véronique D'Hondt, Luis Teixeira, Sibille Everhard, Hélène Vegas, Jérôme Lemonnier, Ivan Bieche, Anne Pradines, Jean-François Paitel, Dominique Spaeth, Jean-Luc Canon, Isabelle Moullet, Jean-Yves Pierga, Frédérique Berger, Thomas Bachelot, Suzette Delaloge. Clinical and biological efficacy of first line AI and palbociclib in ER+ HER2- MBC with detectable circulating ESR1 mutation prior to treatment initiation [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 P5-11-22.

Abstract P1-18-04: Phase 3 SOPHIA study of margetuximab + chemotherapy vs trastuzumab + chemotherapy in patients with HER2+ metastatic breast cancer after prior anti-HER2 therapies: Infusion time substudy results

Abstract Background: Margetuximab (M) is an investigational Fc-engineered anti-HER2 monoclonal antibody that targets the same epitope as trastuzumab (T) and exerts similar antiproliferative effects. Compared with T, M has higher affinity for both the 158V (high-binding) and 158F (low-binding) allotypes of the activating Fc receptor CD16A. M enhances innate immunity, including CD16A-mediated antibody-dependent cellular cytotoxicity, and does so more effectively than T in vitro. Based on ex vivo experiments with cells collected from patients (pts) before and after treatment, M induces adaptive immunity, including enhanced T-cell clonality and induction of HER2-specific T- and B-cell responses. The SOPHIA trial (NCT02492711) showed that in pts with pretreated HER2+ metastatic breast cancer (MBC), M+chemotherapy improved progression-free survival vs T+chemotherapy, with comparable safety. M is intended to be dosed at 15 mg/kg every 3 weeks, with infusions over 120 min at every cycle (C). A substudy of SOPHIA was conducted to evaluate the safety and tolerability of reduced infusion times from C2 onward. Methods: Eligible pts had HER2+ MBC after ≥4 lines of prior therapy for MBC, including prior T, pertuzumab, and ado-T emtansine. Enrolled pts received a 120-min M infusion, with or without chemotherapy, in C1, then either 60- or 30-min infusions in C2 and beyond. This single-arm substudy was unblinded, with no comparator. The primary objective was incidence of Grade 3 or greater infusion-related reactions (IRRs) by the end of C2. Incidence of all IRRs was a secondary objective. Results: Of 88 pts enrolled, 69 received M+chemotherapy and 19 received M alone. Mean age was 54.5 years; 99% were female and 71% white. The median number of cycles of M received was 3 (range 1-17). Overall, 7 pts were assigned to received 60-min M infusions starting at C2 (range 1-17 cycles), and 76 pts were assigned to received 30-min M infusions starting at C2 (range 1-14 cycles). Five pts did not receive C2 treatment due to non-radiologic progressive disease, unrelated adverse event (AE), patient or physician decision, or loss to follow-up. Eighty (91%) pts had premedication for IRRs. No pt had Grade ≥3 IRR. Overall, 18 (21%) had IRRs (2 Grade 1, 16 Grade 2), all but 1 of which occurred in C1 (120 min). Of the 18 pts with IRRs, 17 (94%) were premedicated and 10 (56%) were treated for IRRs. The overall rate of IRRs in premedicated pts was 21% (17/80) and in non-premedicated pts was 13% (1/8). One pt experienced IRRs in both C1 and C2 (Grade 2 in C1 and Grade 1 in C2); the same patient then received 6 additional cycles of M (30 min) with no IRRs after C2 (C3-8) and had no premedication after C1. No pt discontinued treatment due to an IRR. Of 88 pts enrolled, 85 (97%) pts experienced an AE, and 7 (8%) had Grade ≥3 AEs. Fifty (57%) pts had M-related AEs. The most common (>5% of pts) M-related AEs were IRRs in 17 (19%), fatigue in 9 (10%), diarrhea in 5 (6%), and aspartate aminotransferase increase in 5 (6%). Serious AEs occurred in 13/88 pts (15%), none of which were considered M-related by the investigator. Conclusions: In this heavily pretreated population, shorter M infusion times did not lead to an increase in IRRs. IRRs were most likely to occur during C1 when the infusion time was 120 min. No Grade ≥3 IRRs were observed. Of 18 pts with Grade 1-2 IRRs, only 1 had an IRR after C1. These results showed that the acceptable safety and tolerability profile of M was maintained even after infusion time is reduced to 30-min from C2 onward. Shorter infusion times may reduce the burden of chronic M therapy on pts, caregivers, and clinic staff. Citation Format: William J. Gradishar, Seock-Ah Im, Fatima Cardoso, Javier Cortes, Giuseppe Curigliano, Mark D. Pegram, Antonino Musolino, Rosanna Berardi, Michelino De Laurentiis, Shakeela W. Bahadur, Young-Hyuck Im, Cynthia Lynch, Yelena Novik, Sutton Edlich, Edwin Rock, Shengyan Hong, Hope S. Rugo, SOPHIA Study Group. Phase 3 SOPHIA study of margetuximab + chemotherapy vs trastuzumab + chemotherapy in patients with HER2+ metastatic breast cancer after prior anti-HER2 therapies: Infusion time substudy results [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 P1-18-04.

Abstract OT2-08-01: A phase 1b trial to evaluate safety and anti-tumor activity of the AKT inhibitor, ipatasertib, in combination with endocrine therapy with/without CDK 4/6 inhibitor for patients with hormone receptor positive (HR+)/HER2 negative metastatic breast cancer (MBC) (TAKTIC)

Abstract Background: The cyclin-dependent 4/6 inhibitors (CDK4/6i), in combination with an anti-estrogen, have emerged as the standard of care for patients with HR+/HER2- MBC. While only limited insight exists into the molecular factors that drive progression, emerging evidence suggests that activation of AKT1 may provoke resistance in a subset of patients. Overexpression of AKT1 also conveys resistance in HR+/HER2- breast cancer cells in vitro. AKT1 plays a well-established role in promoting tumor progression and metastasis. Targeting AKT1 following progression on CDK4/6i may provide durable clinical benefit in HR+/HER2- MBC. Trial Design: This is an open-label phase Ib trial with three arms - Arm A includes fulvestrant + ipatasertib and Arm B includes an aromatase inhibitor (AI) + ipatasertib. Arm C includes fulvestrant + ipatasertib + palbociclib. Arm A and B are dose-expansion cohorts while Arm C is a dose-escalation (standard 3+3 design) followed by subsequent dose-expansion. Eligibility Criteria: Key inclusion criteria include the presence of locally advanced/unresectable and metastatic HR+/HER2- breast cancer; postmenopausal status or pre/peri-menopausal status s/p oophrectomy or GNRH agonist; at least one prior therapy for MBC including any CDK4/6i; adequate performance status (ECOG 0-2); and adequate bone marrow and hepatic function. Stable CNS metastatic disease and up to two prior lines of chemotherapy for MBC are allowed (no limit on number of prior lines of endocrine therapy). Key exclusion criteria include prior use of fulvestrant (for Arm A); any prior intolerable toxicity with CDK4/6i (for Arm C); prior exposure to an AKT inhibitor in any setting; active CNS disease; concurrent use of specific CYP3A4 inhibitors or inducers; poorly controlled intercurrent illness; and pregnancy or active child-bearing potential. Specific Aims: The primary objective of this study is to evaluate the safety and tolerability of ipatasertib in combination with endocrine therapy (aromatase inhibitor or fulvestrant) with or without CDK4/6i in patients with HR+/HER2- MBC who have received prior CDK 4/6i. Secondary objectives include assessment of objective response rate (ORR), clinical benefit rate (CBR), and progression free survival (PFS). Exploratory objectives include next generation sequencing of solid tumor biopsies and cfDNA along with immunohistochemical analysis of tumor biopsies to identify genomic and protein-based predictors of response and resistance. Statistical Methods: Arms A and B constitute dose-expansion cohorts to confirm the safety/tolerability of ipatasertib use with anti-estrogens and evaluate preliminary efficacy. A dose-limiting toxicity (DLT) rate of <33% will constitute success for future doublet development. There will be an initial enrollment phase (n=6); if ≤ 2 DLTs occur, total enrollment will be pursued (n=15 for each arm). Arm C is a standard 3+3 phase I trial design to establish a recommended phase II dose (RP2D) and maximum tolerated dose (MTD). Once the doses are established, an expansion cohort will be pursued (n=15) to confirm safety of the triplet and evaluate preliminary evidence of efficacy. Present and Target Accrual: Anticipated accrual for Arms A+B will be n=15 (each). Arm C enrollment will be n=15-30 pending establishment of RP2D/MTD prior to dose expansion. Current enrollment n=4, since study activation in May 2019. Citation Format: Seth A. Wander, Dejan Juric, Laura M. Spring, Neelima Vidula, Maureen Beeler, Karleen Habin, Elene Viscosi, Lauren Scarpetti, Elizabeth Tripp, Rachel Hepp, Beverly Moy, Steven J. Isakoff, Leif W. Ellisen, Aditya Bardia. A phase 1b trial to evaluate safety and anti-tumor activity of the AKT inhibitor, ipatasertib, in combination with endocrine therapy with/without CDK 4/6 inhibitor for patients with hormone receptor positive (HR+)/HER2 negative metastatic breast cancer (MBC) (TAKTIC) [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 OT2-08-01.

307PD - Emergence of ESR1 mutation in cell-free DNA during first line aromatase inhibitor and palbociclib: An exploratory analysis of the PADA-1 trial

BackgroundIn ER+ HER2- metastatic breast cancer (MBC), resistance to estrogen deprivation by Aromatase Inhibitors (AI) can stem from activating ESR1 mutations (ESR1mut) or from other less characterized, mutually exclusive mechanisms. In this study, we report on factors associated with the onset of ESR1mut during therapy (vs other mechanisms of resistance). MethodsPADA-1 (NCT03079011) is a phase III trial testing the clinical utility of real time ESR1mut detection (on cell-free DNA, every 2 months) in ER+ HER2- MBC pts treated first line with AI and palbociclib. Main inclusion criteria are pts with no overt resistance to adjuvant AI and no prior therapy for MBC. This analysis compared pts who experienced a progressive disease with no ESR1mut detected (ESR1wt-PD) with those with a rising ESR1mut detected during therapy. Results1017 MBC pts were included in PADA-1 from 04/2017 to 01/2019 and are being followed-up. As of 01/31/2019, 242 pts presented either with an ESR1wt-PD (n=139, 57.4%) or a detectable ESR1mut (n=103, 42.6% (either prior to PD or at time of PD) at any time during AI-palbociclib therapy. During the first 6 months on treatment, ESR1mut (n=17, 18.7%) was less frequent than ESR1wt-PD (n=74, 81.3%); after 6 months, the opposite was true (ESR1mut: n=80, 53.0% vs ESR1wt-PD n=71, 47.0%); this change was highly significant (Chi2 test, p<0.001). Based to a Fine-Gray model adjusted for the number of metastases, a higher risk of ESR1mut during therapy was observed in pts with bone (HR=2.5 [1.1; 5.6]) or skin (HR=1.9 [1.1; 3.7]) metastases while liver metastases were associated with a lower risk of ESR1mut (HR=0.5 [0.3; 0.8]). No other characteristic (including exposure to AI in the adjuvant setting) was associated with the onset of ESR1mut. ConclusionsctDNA analysis in PADA-1 suggests that ESR1mut are rarely involved in primary resistance to AI-palbociclib therapy (i.e. PD within 6 months) but may represent the most prevalent mechanism of acquired resistance. The observed association between ESR1mut and metastatic sites might underlie the reported higher efficacy of selective estrogen receptor degraders (such as fulvestrant) in pts with bone metastases. Clinical trial identificationNCT: 03079011; EudraCT: 2016-004360-18. Legal entity responsible for the studyUNICANCER. FundingPfizer. DisclosureF. Bidard: Advisory / Consultancy, lectures fees: Pfizer; Advisory / Consultancy, lectures fees: AstraZeneca. B. Pistilli: Honoraria (self): AstraZeneca; Honoraria (self): MSD; Honoraria (self), Advisory / Consultancy: Pfizer; Advisory / Consultancy: Puma; Advisory / Consultancy: Merus. T. de La Motte Rouge: Advisory / Consultancy: Pfizer; Advisory / Consultancy: Novartis; Advisory / Consultancy: Roche; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Eisai; Advisory / Consultancy: MSD. R. Sabatier: Licensing / Royalties: Novartis; Research grant / Funding (self), Travel / Accommodation / Expenses, Licensing / Royalties: AstraZeneca; Licensing / Royalties: Tesaro; Research grant / Funding (institution): EISAI; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: Amgen; Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer. F. Clatot: Research grant / Funding (institution): AstraZeneca; Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Lilly; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Merck; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: BMS. T. Bachelot: Honoraria (self), Non-remunerated activity/ies: Roche; Honoraria (self), Research grant / Funding (institution), Non-remunerated activity/ies: Novartis; Honoraria (self), Research grant / Funding (institution), Non-remunerated activity/ies: AstraZeneca; Honoraria (self), Research grant / Funding (institution), Non-remunerated activity/ies: Pfizer. S. Delaloge: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Lilly; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Puma; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche. All other authors have declared no conflicts of interest.

Abstract PD2-06: Circulating ESR1 mutation detection rate and early decrease under first line aromatase inhibitor and palbociclib in the PADA-1 trial (UCBG-GINECO)

Abstract Background: Palbociclib (Pal) combined with an aromatase inhibitor (AI) is a standard of care as first line therapy in ER+ HER2- metastatic breast cancer (MBC). While ESR1 mutations (ESR1mut) are a characterized mechanism of resistance to AI as single agent, it remains unknown how these mutations, when detected prior to treatment initiation, may affect the efficacy of Pal+AI. In a subsidiary analysis of the first line PADA-1 trial, we report the ESR1mut detection rate at baseline and, in patients with ESR1mut detected at baseline, how ESR1 circulating tumor DNA levels changed after the first cycle of AI-Pal therapy. Methods: PADA-1 (NCT03079011) is a randomized phase III trial testing the clinical utility of real time ESR1mut detection (baseline, at 1 month and then every 2 months) in the blood of patients treated with AI-Pal (first step). Patients with rising ESR1mut in circulating tumor DNA (i.e. increasing or appearing mutations during first line AI-Pal therapy) are randomized in a second step between keeping AI-Pal or switching to Fulvestrant-Pal. Main inclusion criteria are patients with ER+ HER2- MBC, who never received adjuvant AI or completed adjuvant AI for &amp;gt;12 months, with neither prior therapy for MBC nor visceral crisis. ESR1mut are tracked in circulating DNA from up to 4ml of plasma by a ddPCR-based assay targeting E380, L536, Y537 and D538 hotspots (i.e. #90% of known ESR1 activating mutations) with #0.1% sensitivity (Bidard et al, AACR 2018 #3867). Results: From 04/2017 to 05/2018, 803 MBC patients have been included in 80 centers. Among these patients, ESR1mut were detected at baseline, prior to any systemic therapy, in 17 patients (2.1%, 95%CI=[1.3;3.3%]). ESR1mut levels ranged from 6 to 3959 copies/ml of plasma (median: 30 copies/ml); allelic frequency ranged from 0.3% to 47% (median=3.5%). ESR1mut were not associated with any of the tumor pathological characteristics (including PR status, primary TNM stage, number and type of metastatic sites); a non-significant association was observed with primary tumor grade (1.7% vs 4.1% in grade I-II vs III, Fisher: p=0.15). Among patients who received a prior adjuvant endocrine therapy, ESR1mut detection rate was lower in patients treated with tamoxifen (0.9% with any tamoxifen exposure vs 5.7% with no tamoxifen exposure; Yates Chi2: p=0.01) and observed only in patients treated with AI (4.9% with any AI exposure vs 0% with no AI exposure, Yates Chi2: p=0.009). Among the 17 patients with ESR1mut detected at baseline, only 4 patients had residual detectable ESR1mut detected after 1 month of AI-Pal therapy (3 of these 4 had decreased levels of ESR1 mutation). Conclusion: ESR1mut is a rare event in untreated AI-sensitive, ER+ HER2- MBC patients. Such detection is primarily associated with prior use of AI in the adjuvant setting. Interestingly, in most MBC patients with ESR1mut detected at baseline, ESR1mut became undetectable after 1 month of AI-Pal therapy, suggesting that this combination may retain early antitumor efficacy. Funding: Pfizer Citation Format: Bidard F-C, Pistilli B, Dalenc F, De la Motte Rouge T, Sabatier R, Frenel J-S, Ladoire S, Dubot C, Ferrero J-M, Levy C, Lortholary A, Stefani L, Mouret-Reynier M-A, Hardy A-C, Jacquin J-P, Grenier J, Chakiba C, Teixeira L, Soulie P, Everhard S, Lemonnier J, Jeannot E, Bieche I, Berger F, Pierga J-Y, Bachelot T, Delaloge S. Circulating ESR1 mutation detection rate and early decrease under first line aromatase inhibitor and palbociclib in the PADA-1 trial (UCBG-GINECO) [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 PD2-06.

Abstract P2-02-18: Higher mutation burden and mutant allele fraction of circulating tumor DNA corresponds to worse progression free survival in metastatic breast cancer patients

Abstract Introduction: Genomic profiling of circulating tumor DNA (ctDNA) allows non-invasive monitoring of tumor genetic changes and molecular heterogeneity. In addition to actionable mutations, mutational landscape derived from ctDNA could provide a better representation of overall tumor burden and tumor heterogeneity, as well as potentially impact clinical outcomes. To evaluate this hypothesis, this study assessed the association of mutation burden and average mutant allele fraction (MAF) with tumor subtype, therapeutic response, and survival in patients with metastatic breast cancer. Methods: Whole blood samples from patients with metastatic breast cancer were collected during clinic visits before start of a new therapy. Plasma-derived cell-free DNA underwent complete next-generation sequencing of 73 cancer-related genes with the Guardant360 test. Mutation burden was defined as the number of genes with mutations, and average MAF was calculated as the sum of the highest MAF for each mutated gene divided by the number of genes with mutations. Time to progression was measured from the date of new treatment initiation after circulating tumor DNA collection to the date of progression. Multivariate cox proportional hazard models assessed the association of mutation burden and average MAF with progression free survival (PFS), adjusted for age, receptor subtype (hormone receptor positive, HR+; human epidermal growth factor 2 positive, HER2+; triple negative breast cancer, TNBC), treatment subtype (chemotherapy vs. targeted therapy), and number of prior metastatic breast cancer therapies. A p value of 0.05 was considered statistically significant. Results: The study population consisted of 158 women with metastatic breast cancer (108 HR+, 14 HER2+, 19 TNBC) with a median age of 59 years and a median of 2 prior metastatic breast cancer therapies. Median follow up time was 4.0 months, and median PFS was 15.7 months. Mutation burden was greater in triple negative compared to hormone receptor positive breast cancer (7.5 vs. 4.8, p = 0.02) but no different in patients with &amp;gt; 2 prior metastatic therapies vs. not (5.1 vs. 4.7, p = 0.60) and age &amp;gt;45 vs. not (5.0 vs. 3.9; p = 0.26). In univariate models, high mutation burden (&amp;gt; median of 2) and high MAF (&amp;gt; median of 1.4) were significantly associated with worse PFS (Table). These results were similar in effect size and significance when adjusted for age, receptor subtype, treatment subtype, and number of prior metastatic breast cancer therapies. Impact of mutation burden on response to specific therapies will be presented at the meeting. VariableHazard Ratio95% Confidence Intervalp valueHigh mutation burden1.991.12-3.540.02High mutant allele fraction1.881.06-3.330.03 Conclusions: Higher ctDNA mutation burden and average MAF is associated with worse progression free survival and possibly reflects a more treatment refractory phenotype. Whether immunotherapy, alone or in combination, could influence the clinical outcomes in metastatic breast cancer patients with high ctDNA mutation burden is unclear and warrants additional research. Citation Format: Keenan T, Juric D, Niemierko A, Spring L, Park H, Malvarosa G, Beeler M, Moy B, Ellisen L, Isakoff S, Bardia A. Higher mutation burden and mutant allele fraction of circulating tumor DNA corresponds to worse progression free survival in metastatic breast cancer patients [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-02-18.

Safety and efficacy of the BCL2 inhibitor venetoclax in estrogen receptor (ER) and BCL2-positive metastatic breast cancer: The mBEP study.

1044 Background: The anti-apoptotic protein BCL2 is overexpressed in ~85% of ER+ breast cancer (BC). Venetoclax (ABT-199), a BCL2 inhibitor approved for CLL (400 mg/day), synergizes with tamoxifen in preclinical patient derived xenograft models by increasing apoptosis. In the first study to evaluate venetoclax in solid tumors, we tested the safety and efficacy of this combination in ER+BCL2+ metastatic BC. Methods: A ‘3+3 design’ dose escalation phase 1b study enrolled women with ER+ ( &gt; 1%), BCL2+ ( &gt; 10%, mod-high) and HER2 non-amplified metastatic BC. Patients received escalating doses of venetoclax 200, 400, 600 or 800 mg/day with tamoxifen 20 mg/day. The primary objective was to determine dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) over 4 weeks. There was no limit to the number of prior lines of therapy. Results: Fifteen patients were enrolled (mean age 62 years, range 44-78; previous tamoxifen, 10 pts). Mean lines of prior therapy for metastatic BC was 2.5 (median 2, range 0-6) and included tamoxifen (6 pts). ESR1 mutations were present in ctDNA of 4 patients. Treatment was well tolerated, with no DLT observed. MTD was not reached; 6 patients received the maximal planned dose (800 mg). The most common adverse event (AE) was lymphopenia (67% Grade 1-2; 13% Grade 3; No Grade 4), followed by nausea (46%, Grade 1-2), which was readily managed. Of 13 women with measurable disease (RECIST v1.1), 4 (31%) had a partial response and 5 (38%) had stable disease (clinical benefit rate, 69%). For patients with a partial response, tumor regression was rapid (evident at first restaging) and occurred in the 400-800 mg dose levels. Two patients with non-measurable bone-only disease had clinically stable disease (1 ongoing &gt; 64 weeks). The median duration of response has not yet been reached (range, 12 to &gt; 64 weeks). Conclusions: We demonstrated the safety of tamoxifen and venetoclax in ER+BCL2+ metastatic BC, with preliminary evidence of clinically relevant activity. A dose expansion study including serial biopsy, ctDNA and PET scans is ongoing at the 800 mg/day recommended phase 2 dose. Sponsor: Royal Melbourne Hospital Clinical trial information: ISRCTN98335443 , ACTRN12615000702516.

Feasibility and kinetics of CD34+hematopoietic progenitor cell mobilization in response to a single administration of docetaxel chemotherapy and pegfilgrastim in a contemporary cohort of patients with metastatic breast cancer

Autologous hematopoietic stem cell transplantation (auto-HSCT) remains an experimental therapy for metastatic breast cancer (MBC) and there is no established protocol for cluster of differentiation 34+ (CD34+ ) hematopoietic progenitor cell (HPC) mobilization with historic studies using growth factors with or without chemotherapy. This study describes the feasibility and kinetics of CD34+ HPC mobilization following a single administration of docetaxel and the pegylated form of recombinant human granulocyte colony-stimulating factor analogue filgrastim (pegfilgrastim). The study design was serial measurement of peripheral blood CD34+ HPC in patients with MBC following a single administration of intravenous (IV) docetaxel 100 mg/m2 on day 1 and subcutaneous (SC) pegfilgrastim 6 mg on day 2. Eight patients with MBC were enrolled. The median age was 56 years (range 51-75 years). All patients had human epidermal growth factor receptor 2 (HER2) negative disease and either hormone refractory or negative disease. Three patients had bone only disease, four had visceral organ disease with or without bone involvement and one had locally unresectable disease only. All patients had prior therapy for early-advanced stage disease and prior therapy for MBC included seven patients receiving at least one line of hormone therapy and three having palliative chemotherapy. Six patients recorded a rise in the CD34+ count greater than 20 cells/μL. The median peak level was 40.2 cells/μL (standard deviation = 28.7) occurring on day 9 and with an average duration of 4 days. Overall, treatment was well tolerated with manageable side-effects. The single administration of docetaxel and pegfilgrastim was effective in mobilization of CD34+ HPC and peak levels followed a predictable course. This approach needs validation in prospective studies by preparation of auto-HSCT by leukapheresis and quantification of total CD34+ HPC yields.

Abstract CT330: Phase I study of PI3Kα inhibitor BYL719 + aromatase inhibitor (AI) in patients (pts) with hormone receptor-positive (HR+) metastatic breast cancer (MBC)

Abstract Background: Phosphatidylinositol 3-kinase (PI3K) hyperactivation contributes to endocrine therapy resistance. An α-selective PI3K inhibitor (BYL719) added to hormonal therapy may overcome this resistance. We conducted a phase I study to evaluate the safety and determine preliminary efficacy of BYL719 and an AI in pts with HR+ MBC. Methods: This 3+3 dose-escalation trial added oral BYL719 to letrozole (L) or exemestane (E) at standard doses using daily (Arm A: L; Arm B: E) and then intermittent dosing (Arm C: L + BYL719 every other week; Arm D: E + BYL719 on 5 of 7 days weekly). Pts with HR+ MBC, any or no PIK3CA mutation, and already on L/E were eligible. Endpoints were dose-limiting toxicity (DLT), tolerability (CTCAE 4.0), and efficacy. Paired tumor biopsies and serial plasma collection facilitated genomic, proteomic, and cell-free (cfDNA) correlatives. Results: 32 patients (Arm A/B: n = 7/7; Arm C/D: n = 9/9) received a mean of 99 days (range: 6-473d) of BYL719 + L or E. All were evaluable for toxicity; 25 (Arm A/B: 5/5; Arm C/D: 7/8) were evaluable for response. Median (M) age was 58.5 (30-83). M number of prior MBC therapies was 3 (1-12). PIK3CA status was mutant(MT)/wild-type(WT)/unknown in 8/5/1 pts on Arms A+B and 17/1/0 on Arms C+D. During dose escalation on Arms A+B, 14 pts received BYL719 doses up to 300mg/d, where 4 pts had 5 distinct DLTs: maculopapular rash (N = 3), hyperglycemia (N = 1), abdominal pain (N = 1). 8 week (w) best response on continuous dosing arms (n = 10 evaluable pts) was 1 PR (pt heavily pre-treated, including prior L, MBC to liver, Arm A, completed 10C); 7 SD (included -29.9%, -19%, -12%), and 2 POD. Due to toxicity, enrollment to these arms was halted prior to MTD determination. The protocol was amended to include 2 intermittent dosing arms. 3 DLTs were seen: Arm C, grade (G)3 rash, G1 fever and hypotension with &amp;gt;7d therapy hold; Arm D, G3 rash. Toxicities (Arms C+D, all cohorts, n = 18) included G≥4: hyperglycemia (n = 1, while pt on corticosteroids); G3: rash (n = 4); G1/2: mucositis (n = 9), hyperglycemia (n = 8), and anorexia (n = 5). MTD determinations are pending with evaluation of 350mg BYL719 5d on, 2d off ongoing on Arm D. On Arm C, of 7 evaluable pts, best response was SD in 3 pts (28w, 12w, 8+w in 1 pt each) and POD in 4 pts. On Arm D, of 8 evaluable pts, best response is SD in 6 pts (28+w, 16+w in 1 pt each; 20w, 8+w in 2 pts each), and POD in 2 pts. Using serial cfDNA analysis, PIK3CA mutant allele fraction declined with SD and PR and increased in pts with POD. Correlative studies including genomics and proteomics are ongoing. Conclusions: BYL719 with L or E is an active combination. Skin toxicity warranted evaluation of alternate schedules. A 5d on, 2d off schedule of BYL719 + exemestane appears tolerable and may allow for higher doses than daily administration, with MTD determination pending. Further safety, efficacy, and correlative data will be presented. Citation Format: Payal D. Shah, Mary E. Moynahan, Shanu Modi, Nicola Hamilton, Betty Ann Caravella, Stephen Zamora, Chau Dang, Theresa Gilewski, Tiffany Traina, Elizabeth Comen, Steven M. Sugarman, Gabriella D'Andrea, Diana Lake, Shari Goldfarb, Sujata Patil, Anne Covey, Michael Berger, Mario Lacouture, Larry Norton, Clifford A. Hudis, Jose Baselga, Sarat Chandarlapaty, Maura Dickler. Phase I study of PI3Kα inhibitor BYL719 + aromatase inhibitor (AI) in patients (pts) with hormone receptor-positive (HR+) metastatic breast cancer (MBC). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT330. doi:10.1158/1538-7445.AM2015-CT330

Abstract PD5-3: Phase I trial: PI3Kα inhibitor BYL719 plus aromatase inhibitor (AI) for patients with hormone receptor-positive (HR+) metastatic breast cancer (MBC)

Abstract Background: Phosphatidylinositol 3-kinase (PI3K) hyperactivation plays a role in endocrine therapy resistance. Adding an α-selective PI3K inhibitor (BYL719) to hormonal therapy may therefore overcome resistance in HR+ MBC. We report results from a phase I study to evaluate the safety and preliminary efficacy of BYL719 plus an AI in patients (pts) with HR+ MBC. Methods: This 3+3 dose-escalation trial studied daily oral BYL719 added to standard dose letrozole (L, Arm A) or exemestane (E, Arm B), and later examined intermittent dosing (Arm C, L + BYL719 every other week; Arm D, E + BYL719 on 5 of 7 days weekly). Pts with HR+ MBC, any/no PIK3CA mutation, and on L/E were eligible. A cycle (C) was 28 days (d). Endpoints were dose-limiting toxicity (DLT), tolerability (CTCAE 4.0), and efficacy (RECIST v1.1). Paired tumor biopsies were performed for genomic and proteomic correlatives. Serial plasma was collected to quantify cell-free (cf) DNA and mutant allele fraction. Results: 14 pts (median (M) age: 55 (30-69) yrs), 7 each on Arms A and B, received a M of 76d (6-312+) of BYL719 + L or E. All were evaluable for toxicity, 10 for response. PIK3CA status was mutant(MT)/wild-type(WT)/unknown in 8/5/1 pts. M number of prior MBC therapies was 2 (1-12) in Arm A, 6 (2-14) in Arm B. Arms had similar toxicities. On Arm A, BYL719 was given at 300mg daily (DL0) to 3 pts who completed the 28d DLT period. 2 pts had 3 distinct DLTs: maculopapular rash (N=1), hyperglycemia (N=1), abdominal pain (N=1). Dose was de-escalated (DL-1=250mg) with no DLT in 3 enrolled pts. On Arm B, DL0, 1 pt experienced DLT (maculopapular rash) of 3 initially enrolled pts. Arm B expansion at DL0 had 1 additional pt with DLT (rash). Clinically significant, treatment-related toxicities included grade (G)≥4: none; G3: maculopapular rash (N=8, including 1 pt treated at DL-1), hyperglycemia (N=1) and G1/2: fatigue (N=7), nausea (N=7), and hyperglycemia (N=6). Toxicity required 6 dose reductions in 4pts and discontinuation in 2 pts. M duration on study for PIK3CA MT vs. WT was 169.5d vs. 69.5d, respectively. In pts with PIK3CA–MT MBC evaluable for response (n=7), 6 had clinical benefit: 1 PR (pt heavily pre-treated, including prior L, MBC to liver, Arm A, now C10+ after DLT); SD (n=5, included -29.9%, -19%, -12%), and POD (n=1). In pts with PIK3CA-WT MBC evaluable for response (n=3), 2 had SD (no changes ≥+/-5%) and 1 had POD. Serial cfDNA analysis in 4 pts with SD or PR demonstrated a decrease of &amp;gt;90% in the PIK3CA mutant allele fraction on treatment. Due to toxicity seen with continuous BYL719, the study was amended to explore intermittent dosing schedules (Arm C, L; Arm D, E; DL0=250mg), with 5 pts enrolled, 3 of whom have completed the DLT period with no DLTs, and 1 pt with G3 rash. Correlative studies including serial cf DNA collection from these pts is ongoing. Conclusions: Continuously dosed BYL719 with L or E shows promising antitumor activity. Skin toxicity warranted evaluation of alternative schedules. Mutant allele fraction may be an early predictor of response and may serve as a pharmacodynamic marker during intermittent treatment. Safety, efficacy, and correlative data from study Arm C and Arm D will also be presented. Citation Format: Payal D Shah, Mary Ellen Moynahan, Shanu Modi, Betty Ann Caravella, Farrah M Datko, Stephen Zamora, Elizabeth Comen, Theresa Gilewski, Steven M Sugarman, Gabriella D'Andrea, Diana E Lake, Shari B Goldfarb, Sujata Patil, Anne Covey, Michael F Berger, Mario E Lacouture, Larry Norton, Clifford A Hudis, Jose Baselga, Sarat Chandarlapaty, Maura N Dickler. Phase I trial: PI3Kα inhibitor BYL719 plus aromatase inhibitor (AI) for patients with hormone receptor-positive (HR+) metastatic breast cancer (MBC) [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 PD5-3.

Abstract P5-20-07: Phase II Trial of Dasatinib in Combination With Weekly Paclitaxel for Patients with Metastatic Breast Carcinoma

Abstract Background: Src kinase plays an important role in proliferation, survival, angiogenesis and metastasis in several malignancies including breast cancer. Therefore, inhibition of Src and other tyrosine kinases (TKs) represents a novel therapeutic approach. Dasatinib is a potent inhibitor of 5 oncogenic TKs, inhibits VEGF-stimulated proliferation, has potent bone anti-resorptive activity and selectively inhibits basal-type breast cancer growth. Preclinically, the combination of dasatinib and paclitaxel had superior antitumor activity to either agent alone. In a previous phase I study, we determined that, in combination with weekly paclitaxel, the optimum dose of dasatinib was 120mg. Of note, 4/9 (44%) patients treated at or above this dasatinib dose level had objective tumor response. We now present results from the phase II trial of this combination. Methods: Patients with MBC, ECOG PS 0–1, normal hepatic, renal, marrow function were eligible. Patients had measurable, HER2-negative metastatic breast cancer (MBC), ≤2 prior therapies for MBC. Treatment consisted of weekly paclitaxel 80 mg/m2 IV 3/4 weeks + Dasatinib 120mg orally daily. Response was assessed by RECIST after every 8 weeks of therapy. Simon's two-stage optimal design was used to test the null hypothesis of a 15% response rate (RR) against the alternative of a 30% RR. In stage I, planned enrollment was 23 patients based on Type I and Type II errors of 10%. If 4 or more responses are observed, enrollment will be extended to 55 patients. Exploratory correlative biomarkers of clinical benefit include Src phosphorylation (p-Src) in peripheral blood mononuclear cells, plasma levels of VEGFR2 and collagen Type IV, circulating tumor cells (CTCs) and tumor gene expression profiling. Results: 21 patients (19 females, 2 male) have enrolled; median age 48 (range 30–79). Patients received a median of 1 prior therapy for MBC (range 0–2). 6 patients are not assessable for response: 1 has received &amp;lt;8 weeks treatment, 5 came off study for toxicity (2 hypersensitivity reaction to paclitaxel, 1 infection, 1 diarrhea/nausea, 1 bleeding likely related to anticoagulation). Among the 15 patients assessable for response, best response to date is as follows: 2 (13%) patients partial response, 11 (73%) patients stable disease (SD) and 2 (13%) patients progression of disease. Of patients with SD, 6/11 (55%) continue on treatment after median of 2 months (range 2–10) and 5/11 (45%) patients have come off study after median of 10 months (range 3–21). Most toxicities have been hematological and low grade. Diarrhea and neuropathy have generally been low grade and no new toxicities related to the combination have occurred since expansion into the phase II. Potential biomarkers of clinical benefit including, p-Src, VEGFR2, collagen Type IV, and CTCs will be presented. Conclusion: Data from this phase II has demonstrated preliminary evidence of activity for weekly paclitaxel and dasatinib 120mg in patients with MBC. These findings are consistent with data from this dose level in the earlier phase I study. Predictive biomarkers of clinical benefit are under investigation. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-20-07.

Abstract P5-18-12: Comparison of treatment patterns and outcomes in metastatic breast cancer patients initiated on trastuzumab vs. lapatinib; a retrospective analysis

Abstract Background: Trastuzumab-or lapatinib-based therapies are recommended by the National Comprehensive Cancer Network (NCCN) guidelines as preferred agents for metastatic HER2-positive breast cancer. Few studies have compared treatment patterns, healthcare resource utilization (HRU), and costs in metastatic breast cancer (MBC) patients receiving trastuzumab vs. lapatinib. The objective of this study was to compare discontinuation rates, HRU, and costs in MBC patients (pts) initiated on trastuzumab vs. lapatinib. Methods: MBC adult women initiated on trastuzumab or lapatinib on/after 03/13/2007 (lapatinib FDA-approval date) were selected from the US-based PharMetrics® Integrated Database (2000–2011). Selected pts were required to be continuously eligible in their healthcare plan ≥6 months prior to and ≥30 days following trastuzumab or lapatinib initiation date. Pts were observed over the period spanning from trastuzumab or lapatinib initiation date (without restriction on line of therapy) up to the end of continuous health plan enrollment or data availability, whichever occurred first. Trastuzumab or lapatinib discontinuation rates (gap ≥45 consecutive days) were compared using multivariate Cox proportional-hazards models and reported as hazard ratios (HRs). Incremental HRU was estimated using negative binomial regression models and reported as incidence rate ratios (IRRs). Monthly cost difference (2010 USD; measured from a payer perspective) were estimated using multivariate generalized linear or two-part models. Since a large proportion of lapatinib users were previously treated with trastuzumab, a sensitivity analysis was conducted to control for the impact of prior trastuzumab use. Results: Among the 643 pts selected, 381 and 262 pts were initiated on trastuzumab and lapatinib, respectively. Of the 262 pts initiated on lapatinib, 171 (65%) were previously treated with trastuzumab. After adjustment for confounders (demographics, index year, prior MBC therapies, comorbidities, baseline HRU, and MBC duration), compared to trastuzumab users, lapatinib users had a higher rate of treatment discontinuation (HR = 1.57; p &amp;lt; .001). While lapatinib users had a higher rate of outpatient visits (not treatment administration related) compared to trastuzumab users (HR = 1.19; p &amp;lt; 0.004), there were no observed significant differences of other HRU and total monthly healthcare costs between the two groups ($11,138±8,751 vs. $11,159 ±8,674, respectively; adjusted difference=$637 p = .397). Sensitivity analyses showed that pts who were initiated on lapatinib without prior trastuzumab use had a higher incidence of inpatient admissions (IRR = 1.74; p = .002) and greater overall medical service costs compared to pts who were initiated on trastuzumab (adjusted difference=$3,059; p &amp;lt; .001). Conclusion: Overall, while MBC pts initiated on trastuzumab or lapatinib had similar healthcare costs, pts initiated on lapatinib had higher rates of treatment discontinuation and outpatient visits (not treatment administration related). Medical costs were significantly higher among pts initiated on lapatinib without prior trastuzumab use. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-18-12.