Chemotherapy For Advanced Disease Research Articles

Abstract PO2-20-02: A Phase 3 study of gedatolisib plus fulvestrant with and without palbociclib in patients with HR+/HER2- advanced breast cancer previously treated with a CDK4/6 inhibitor plus a non-steroidal aromatase inhibitor (VIKTORIA-1)

Abstract Patients who receive frontline CDK4/6 inhibitor (CDK4/6i) therapy eventually experience disease progression. Resistance to CDK4/6i is likely a transient adaptive mechanism that may be reversed by inhibition of the PI3K/mTOR pathway. Thus, combination of CDK4/6i and PI3K/mTORi after disease progression on CDK4/6i could restore sensitivity to CDK4/6i and prevent activation of the PI3K/mTOR pathway. This hypothesis was evaluated in a Phase 1b study (Layman SABCS 2021) of gedatolisib (geda), a potent inhibitor of PI3K and mTOR. Subjects with HR+/HER2- ABC treated with prior CDK4/6i received geda (180 mg IV weekly for 3 weeks, then one week off) with palbociclib (P) and fulvestrant (F). Median PFS was 12.9 months with 63% overall response rate. Efficacy was observed regardless of PIK3CA mutation status (Wesolowski SABCS 2022). Geda was well tolerated, with few discontinuations due to treatment-related adverse events (4%). The most common AE was stomatitis; hyperglycemia of any grade occurred in 26% of patients. This preliminary data, dosing schedule, and study population characteristics form the basis for the Phase 3 trial, VIKTORIA-1. This Phase 3 multinational clinical trial will evaluate geda and F with or without P in patients with HR+/HER2- ABC previously treated with any CDK4/6i in combination with a non-steroidal aromatase inhibitor (AI) therapy. Those without tumor PIK3CA mutations will be assigned to Study 1 (n=351) and randomized to Arm A (geda, P, and F), Arm B (geda and F), or Arm C (F). Those with PIK3CA mutations will be assigned to Study 2 (n=350) and randomized to Arm D (geda, P, and F), Arm E (alpelisib and F), or Arm F (geda and F). Key eligibility criteria include adults with confirmed metastatic or locally advanced breast cancer, any menopausal status, radiologically evaluable disease, and prior CDK4/6i treatment in combination with a non-steroidal AI. Prior hormonal therapy, including SERDs, is allowed. Key exclusion criteria include prior treatment with a PI3K, Akt, or mTOR inhibitor, prior treatment with chemotherapy for advanced disease, more than two lines of prior endocrine therapy, bone only disease with no soft tissue components, active CNS metastases, and type 1 diabetes or uncontrolled type 2 diabetes. The primary endpoint is PFS assessed by blinded independent central review per RECIST v1.1. Secondary endpoints included overall survival (OS), safety and tolerability, ORR, duration of response, time to response, CBR, quality of life, and pharmacokinetics. Enrollment is ongoing. This trial abstract was previously presented at the 2022 San Antonio Breast Cancer Symposium, December 6-10, 2022. Citation Format: Sara Hurvitz, Fabrice André, Massimo Cristofanilli, Giuseppe Curigliano, Antonio Giordano, Hyo Han, Miguel Martín, Barbara Pistilli, Hope Rugo, Robert Wesolowski, Igor Gorbatchevsky, Sibylle Loibl. A Phase 3 study of gedatolisib plus fulvestrant with and without palbociclib in patients with HR+/HER2- advanced breast cancer previously treated with a CDK4/6 inhibitor plus a non-steroidal aromatase inhibitor (VIKTORIA-1) [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 PO2-20-02.

A phase 3 study of gedatolisib plus fulvestrant with and without palbociclib in patients with HR+/ HER2- advanced breast cancer previously treated with a CDK4/6 inhibitor plus a nonsteroidal aromatase inhibitor (VIKTORIA-1).

TPS1118 Background: Patients who receive frontline CDK4/6 inhibitor (CDK4/6i) therapy eventually experience disease progression. Resistance to CDK4/6i is likely a transient adaptive mechanism that may be reversed by inhibition of the PI3K/mTOR pathway. Thus, combination of CDK4/6i and PI3K/mTORi after disease progression on CDK4/6i could restore sensitivity to CDK4/6i and prevent activation of the PI3K/mTOR pathway. This hypothesis was evaluated in a Phase 1b study (Layman SABCS 2021) of gedatolisib (geda), a potent inhibitor of PI3K and mTOR. Subjects with HR+/HER2- ABC with prior CDK4/6i received geda (180 mg IV weekly for 3 weeks, then one week off) with palbociclib (palbo) and fulvestrant (FUL). Median PFS was 12.9 months with 63% overall response rate. Efficacy was observed regardless of PIK3CA mutation status (Wesolowski SABCS 2022). Geda was well tolerated, with few discontinuations due to treatment-related adverse events (4%). The most common AE was stomatitis; hyperglycemia of any grade occurred in 26% of patients. This preliminary data, dosing schedule, and study population characteristics form the basis for the Phase 3 trial, VIKTORIA-1 (NCT05501886). Methods: This Phase 3 multinational clinical trial will evaluate geda and FULwith or without palboin patients with HR+/HER2- ABC previously treated with any CDK4/6i in combination with a non-steroidal aromatase inhibitor (AI) therapy. Those without tumor PIK3CA mutations will be assigned to Study 1 (n=351) and randomized to Arm A (geda, palbo, and FUL), Arm B (geda and FUL), or Arm C (FUL). Those with PIK3CA mutations will be assigned to Study 2 (n=350) and randomized to Arm D (geda, palbo, and FUL), Arm E (alpelisib and FUL), or Arm F (geda and FUL). Key eligibility criteria include adults with confirmed metastatic or locally advanced breast cancer, any menopausal status, radiologically evaluable disease, and prior CDK4/6i treatment in combination with a non-steroidal AI. Prior hormonal therapy, including SERDs, is allowed. Key exclusion criteria include prior treatment with a PI3K, Akt, or mTOR inhibitor, prior treatment with chemotherapy for advanced disease, more than two lines of prior endocrine therapy, bone only disease with no soft tissue components, active CNS metastases, and type 1 diabetes or uncontrolled type 2 diabetes. The primary endpoint is PFS assessed by blinded independent central review per RECIST v1.1. Secondary endpoints included overall survival, safety and tolerability, ORR, duration of response, time to response, CBR, quality of life, and pharmacokinetics. The trial is open for enrollment. Clinical trial information: NCT05501886 .

Abstract OT3-26-02: A Phase 3 study of gedatolisib plus fulvestrant with and without palbociclib in patients with HR+/HER2- advanced breast cancer previously treated with a CDK4/6 inhibitor plus a non-steroidal aromatase inhibitor (VIKTORIA-1)

Abstract Background: Gedatolisib is a potent reversible dual inhibitor that selectively targets all Class I isoforms of phosphoinositide 3-kinase (PI3K) and mechanistic target of rapamycin (mTOR). Two separate pivotal clinical trials demonstrated that PI3K and mTOR inhibitors are active in combination with endocrine therapy and prolong progression-free survival (PFS) among patients with hormone receptor positive (HR+)/HER2-negative (HER2-) advanced breast cancer (ABC) who had previously received endocrine therapy (SOLAR-1, BOLERO-2). CDK4/6 inhibitor (CDK4/6i) therapy has been approved in the front-line setting. However, patients eventually experience disease progression on CDK4/6i based therapy. Available data indicates that resistance to CDK4/6i is a transient adaptive mechanism that may be reversed by adding inhibitors of the PI3K/mTOR pathway (PI3K/mTORi). Thus, combination of PI3K/mTORi and CDK4/6i in patients whose disease progressed on prior CDK4/6i could potentially both restore sensitivity to CDK4/6i and prevent adaptive activation of the PI3K/mTOR pathway. This hypothesis was evaluated in a Phase 1b study (Layman SABCS 2021). Subjects with HR+/HER2- ABC who were CDK4/6i pretreated received gedatolisib (180 mg IV weekly for 3 weeks, then one week off) in combination with standard doses of palbociclib and fulvestrant. Median PFS was 12.9 months, and overall response rate was 63%. Grade 3-4 adverse events (AE) were observed at a low rate, and toxicity was overall easily managed with available standards of care, and few patients discontinued treatment due to treatment-related adverse events (4%). The most common AE was stomatitis; hyperglycemia of any grade occurred in 26% of patients. This preliminary data, dosing schedule, and study population characteristics form the basis for the Phase 3 trial, VIKTORIA-1. Trial design: This Phase 3, open-label, randomized, multinational two-part clinical trial will evaluate the efficacy and safety of gedatolisib and fulvestrant with or without palbociclib in patients with HR+/HER2- ABC previously treated with any CDK4/6i in combination with non-steroidal aromatase inhibitor therapy. Those without tumor PIK3CA mutations will be assigned to Study 1 and those with PIK3CA mutations will be assigned to Study 2. Study 1 will include up to 351 subjects randomized in a 1:1:1 ratio to Arm A (gedatolisib, palbociclib, and fulvestrant), Arm B (gedatolisib plus fulvestrant), or Arm C (fulvestrant). For subjects in Arm C whose disease progresses, crossover to Arm A or B is allowed. Study 2 will include up to 350 subjects randomized in a 3:3:1 ratio to Arm D (gedatolisib, palbociclib, and fulvestrant), Arm E (alpelisib plus fulvestrant), or Arm F (gedatolisib plus fulvestrant). Key eligibility criteria include adults with confirmed metastatic or locally advanced breast cancer, any menopausal status for females, radiologically evaluable disease, and prior CDK4/6i treatment with non-steroidal AI. Prior therapy with SERD, including fulvestrant is allowed. Key exclusion criteria include prior treatment with a PI3K, protein kinase B (Akt), or mTOR inhibitor, prior treatment with chemotherapy for advanced disease, more than two lines of prior endocrine therapy, bone only disease with no soft tissue components, active CNS metastases, and type 1 diabetes or uncontrolled type 2 diabetes. The primary endpoint is PFS assessed by blinded independent central review (BICR) per RECIST v1.1. Secondary endpoints included overall survival (OS), safety and tolerability, ORR, duration of response, time to response, CBR, quality of life, and pharmacokinetics. This trial is open for enrollment. Citation Format: Sara Hurvitz, Fabrice Andre, Massimo Cristofanilli, Giuseppe Curigliano, Antonio Giordano, Hyo S. Han, Miguel Martín, Barbara Pistilli, Hope Rugo, Robert Wesolowski, Samuel Suzuki, Sarah C. Mutka, Igor Gorbatchevsky, Sibylle Loibl. A Phase 3 study of gedatolisib plus fulvestrant with and without palbociclib in patients with HR+/HER2- advanced breast cancer previously treated with a CDK4/6 inhibitor plus a non-steroidal aromatase inhibitor (VIKTORIA-1) [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 OT3-26-02.

Lurbinectedin in patients with pretreated BRCA1/2-associated metastatic breast cancer: Results from a phase II basket study.

1092 Background: Lurbinectedin (L) is a selective inhibitor of oncogenic transcription that leads to cell apoptosis and shows antitumor activity against homologous recombination repair-deficient cell lines. A previous phase II study (Cruz et al. JCO 2018;36:3134-3143) demonstrated antitumor activity in patients (pts) with pretreated metastatic breast cancer (median of 1 prior advanced chemotherapy line) and BRCA1/2-mutated tumors with L 3.5 mg/m2 or 7.0 mg flat dose (equivalent to 4.0 mg/m2) every three weeks [q3wk]). This report focuses on the outcomes in the BRCA1/2-associated breast cancer cohort of a phase II Basket multitumor trial. Methods: This phase II study evaluated L 3.2 mg/m2 1-hour intravenous (i.v.) infusion q3wk in a cohort of 21 female pts with pretreated BRCA1/2-associated breast cancer. The primary efficacy endpoint was ORR according to RECIST v1.1. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), OS and safety. Results: Median age was 45 years (range, 29-73 years). Hormone receptor (HR)+ disease was observed in 76.2% of pts, triple negative disease in 19.0% and HER2+ in 9.5%. BRCA1 and BRCA2 were reported in 47.6% and 52.4% of pts, respectively. Median number of prior lines of chemotherapy for advanced disease was 2 (range, 0-3 lines). Prior poly(ADP-ribose) polymerase inhibitors and platinum compounds had been administered to 23.8% and 47.6% of pts, respectively. Confirmed partial response (PR) was observed in six pts (ORR = 28.6%; 95% CI, 11.3-52.2%). Lurbinectedin was active in both BRCA mutations: four PRs in 11 pts (36.4%) in BRCA2 and two PRs in 10 pts (20.0%) in BRCA1. Median DoR was 8.6 months, median PFS was 4.1 months and median OS was 16.1 months. Stable disease (SD) was observed in ten pts (47.6%), including three pts with unconfirmed response in a subsequent tumor assessment (ORR unconfirmed = 42.9% [95%CI, 21.8-66.0]). Clinical benefit rate (PR + SD≥4 months) was 76.2% (95% CI, 52.8-91.8%). The most common grade 3/4 toxicity was neutropenia (42.9%; grade 4, 23.8%; with no febrile neutropenia). Conclusions: This phase II study met its primary endpoint and confirmed the activity of L in pretreated BRCA1/2-associated breast cancer pts. L 3.2 mg/m2 1-hour i.v. infusion q3wk showed an acceptable, predictable and manageable safety profile. Considering the exploratory aim of this trial as well as previous results in other phase II study, further development of L in this indication is warranted. Clinical trial information: NCT02454972.

Results from plasmaMATCH trial cohort E: A phase II trial of olaparib and ceralasertib in patients with triple-negative advanced breast cancer (CRUK/15/010).

1024 Background: The plasmaMATCH trial was an open label platform trial, consisting of circulating tumour DNA (ctDNA) testing in ̃1000 patients with advanced breast cancer (ABC) linked to parallel treatment cohorts with therapies matched to mutations identified in ctDNA. Cohorts A-D have already reported (Turner N et al, Lancet Oncol 2020). Cohort E recruited patients with triple negative breast cancer (TNBC) without a targetable mutation identified at ctDNA screening, treating with olaparib (PARP inhibitor) plus ceralasertib (ATR inhibitor). Methods: Patients with TNBC who had received 1 or 2 lines of chemotherapy for advanced disease or relapsed within 12 months of (neo)adjuvant chemotherapy were eligible. Treatment was olaparib 300mg b.i.d continuously and ceralasertib 160mg qd on days 1–7 on a 28 day cycle, until disease progression. The primary endpoint was confirmed objective response rate by RECIST v1.1. Secondary endpoints included clinical benefit rate, progression-free survival (PFS) and safety. Biomarker analysis included response according to BRCA and somatic DNA repair gene status and ATM loss. Using a two-stage design with a target response rate of 25%, unacceptable response rate of 10%, alpha=2% and power=90%, ≥13 responses out of 69 evaluable stage 2 patients were required to infer efficacy (5/37 stage 1). Results: Between 17/09/18 and 5/10/20 75 patients enrolled in Cohort E of whom 70 were evaluable for response. The median age was 55.6 years. 42 (56%) patients had 1 and 13 (17.3%) had 2 prior line(s) of chemotherapy for metastatic disease. Efficacy is shown in Table. The most common grade ≥3 adverse events were: hypertension 12 (17%) and anaemia 9 (13%). Dose reductions and interruptions occurred in 19 (26.4%) and 34 (47.2%) patients respectively. Conclusions: The response rate to olaparib and ceralasertib did not meet pre-specified criteria for efficacy in the overall evaluable population. Responses were observed in patients without germline or somatic BRCA1/2 mutations. Translational analyses are underway to identify potential biomarkers of response in this population and will be presented at the meeting. Clinical trial information: ISRCTN16945804. [Table: see text]

Multicenter phase II trial of Camrelizumab combined with Apatinib and Eribulin in heavily pretreated patients with advanced triple-negative breast cancer

In the later-line setting or for patients with PD-L1-negative tumors, immunotherapy-based regimens remain ineffective against advanced triple-negative breast cancer (TNBC). In this multicentered phase II trial (NCT04303741), 46 patients with pretreated advanced TNBC were enrolled to receive camrelizumab 200 mg (day 1), and apatinib 250 mg daily, plus eribulin 1.4 mg/m2 (day 1 and 8) on a 21-day cycle until progression, or unacceptable toxicity. Primary endpoint was objective response rate (ORR) according to RECIST 1.1. Secondary endpoints included toxicities, disease control rate (DCR), clinical benefit rate, progression-free survival (PFS), and 1-year overall survival. With a median of 3 lines of prior chemotherapy in the advanced setting, 17.4% had received PD-1/PD-L1 blockade plus chemotherapy for advanced disease. The ORR was 37.0% (17/46, 95% CI 23.2–52.5). The DCR was 87.0% (40/46, 95% CI 73.7–95.1). Median PFS was 8.1 (95% CI 4.6–10.3) months. Tertiary lymphoid structure was associated with higher ORR. Patients with lower tumor PML or PLOD3 expression had favorable ORR and PFS. PD-L1 status was not associated with ORR/PFS. Grade 3/4 treatment-related adverse events occurred in 19 (41.3%) of 46 patients. Camrelizumab plus apatinib and eribulin shows promising efficacy with a measurable safety profile in patients with heavily pretreated advanced TNBC.

Abstract OT2-11-03: AMEERA-1 : Phase 1/2 study of amcenestrant (SAR439859), an oral selective estrogen receptor (ER) degrader (SERD), with alpelisib in postmenopausal women with ER+/human epidermal growth factor receptor 2-negative (HER2-)PIK3CA-mutated advanced breast cancer

Abstract Background Amcenestrant is an optimized oral SERD with potent dual activity of ER antagonism and degradation resulting in inhibition of ER signaling. Amcenestrant monotherapy or combination with palbociclib showed antitumor activity and a favorable safety profile in postmenopausal women with heavily pretreated ER+/HER2- mBC. PIK3CA mutations are associated with endocrine resistance in ER+/HER2- patients (pts). Published data support the addition of the PI3Kα inhibitor alpelisib to SERD therapy for these pts. Methods AMEERA-1 (NCT03284957) is an open-label, non-comparative, dose escalation and dose expansion Phase 1/2 study of amcenestrant as monotherapy, then in combination with other anti-cancer targeted therapies. Parts F and G investigate safety run-in and dose expansion, respectively, of amcenestrant in combination with alpelisib. Postmenopausal women with ER+/HER2- advanced breast cancer, PIK3CA mutated in tumor tissue or cfDNA, ECOG performance status 0-1, and ≥ 6 months prior endocrine therapy are eligible. Pts must have progressed on an aromatase inhibitor plus CDK4/6 inhibitor as first-line therapy for advanced disease. Part F allows ≤ 1 prior chemotherapy for advanced disease; no prior chemotherapy is allowed in Part G. Exclusion criteria in Parts F and G include prior drugs targeting the PI3K axis, type 1 diabetes, uncontrolled type 2 diabetes, history of severe cutaneous reactions, and ongoing osteonecrosis of the jaw. Part F assesses dose-limiting toxicities and pharmacokinetics (PK) of a standard dose of amcenestrant plus the approved dose of alpelisib (300 mg once daily). Additional amcenestrant doses or a lower dose of alpelisib may be explored based on safety and PK. The primary objective in Part F is to confirm the recommended phase 2 dose (RP2D) of amcenestrant in combination with alpelisib, based on safety. In Part G, approximately 34 pts will be treated at the RP2D, the primary endpoint being safety and tolerability. Secondary endpoints include PK and antitumor activity. This study is currently recruiting participants. This abstract was previously submitted to the 2021 European Society for Medical Oncology Annual Congress. Funding: Sanofi. Citation Format: Mario Campone, Aditya Bardia, Peter Kabos, Sarat Chandarlapaty, Patrick Neven, Valentina Boni, Simon Lord, Sylvaine Cartot-Cotton, Marina Celanovic, Alice Gosselin, Vasiliki Pelekanou, Hannah M Linden. AMEERA-1 : Phase 1/2 study of amcenestrant (SAR439859), an oral selective estrogen receptor (ER) degrader (SERD), with alpelisib in postmenopausal women with ER+/human epidermal growth factor receptor 2-negative (HER2-)PIK3CA-mutated advanced breast cancer [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 OT2-11-03.

Abstract OT2-11-02: Ameera-1 Arm 4: Phase 1/2 study of amcenestrant (SAR439859), an oral selective estrogen receptor (ER) degrader (SERD), with everolimus in postmenopausal women with ER+/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer

Abstract Background Amcenestrant (SAR439859) is an optimized oral SERD with potent dual activity that antagonizes and degrades the ER, resulting in inhibition of the ER signaling pathway. Amcenestrant, as monotherapy or in combination with palbociclib, has shown antitumor activity and a favorable safety profile in postmenopausal women with heavily pretreated ER+/HER2- advanced breast cancer. Published data support the addition of targeted therapy to endocrine therapy for patients with ER+/HER2- advanced breast cancer. The objective of Arm 4 of the AMEERA-1 study is to evaluate safety and antitumor activity of amcenestrant in combination with the mammalian target of rapamycin (mTOR) inhibitor everolimus for patients with ER+/HER2- advanced breast cancer. Methods AMEERA-1 (NCT03284957) is an open-label, non-comparative, dose escalation and dose expansion Phase 1/2 study of amcenestrant as monotherapy, then in combination with other anti-cancer targeted therapies. Arm 4 investigates dose escalation (Part H) and dose expansion (Part I), of amcenestrant in combination with everolimus. Postmenopausal women with ER+/HER2- advanced breast cancer, ECOG performance status 0-1, and ≥ 6 months prior endocrine therapy are eligible. In Arm 4 (Parts H and I), ≤ 1 prior line of a single endocrine therapy for advanced disease is allowed. Patients must have progressed on a non-steroidal aromatase inhibitor plus cyclin-dependent kinase 4/6 inhibitor as first-line therapy for advanced disease. Prior treatment with fulvestrant or any other SERD is not allowed. Part H allows ≤ 1 prior chemotherapy for advanced disease; no prior chemotherapy for advanced disease is allowed in Part I. Exclusion criteria in Arm 4 include prior drugs targeting the phosphoinositide 3-kinase axis; history of or concurrent pneumonitis; history of severe cutaneous reactions; type 1 diabetes; uncontrolled type 2 diabetes; uncontrolled hypercholesterolemia, hypertriglyceridemia, and hyperglycemia; any uncontrolled infection; uncontrolled stomatitis, angioedema due to angiotensin-converting enzyme inhibitors, and impaired wounds. Part H evaluates the selected amcenestrant dose for combination therapy plus everolimus 10 mg once daily (QD) (the approved standard dose) or everolimus 5 mg QD, taken in 28-day cycles. Additional amcenestrant doses may be explored based on safety and pharmacokinetics (PK). The objective of Part H is to determine the recommended dose (RD) of everolimus in combination with the selected amcenestrant dose for combination therapy, based on preliminary safety, PK, and antitumor activity data. The primary endpoint in Part H is the incidence of treatment-related dose-limiting toxicities (DLTs) at Cycle 1. Approximately up to 12 DLT-evaluable patients will be needed to establish the RD of everolimus in combination with amcenestrant in Part H. In Part I, approximately 12 patients will be treated at the RD of everolimus for combination therapy with amcenestrant, the primary endpoint being safety and tolerability. Secondary endpoints include PK and antitumor activity. Funding: Sanofi. Citation Format: Mario Campone, Patrick Neven, Katarina Petrakova, Sofia Braga, Marina Celanovic, Patrick Cohen, Alice Gosselin, Sylvaine Cartot-Cotton, Vasiliki Pelekanou, Valentina Boni. Ameera-1 Arm 4: Phase 1/2 study of amcenestrant (SAR439859), an oral selective estrogen receptor (ER) degrader (SERD), with everolimus in postmenopausal women with ER+/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer [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 OT2-11-02.

Abstract OT2-11-04: Ameera-1 Arm 5: Phase 1/2 study of amcenestrant (SAR439859), an oral selective estrogen receptor (ER) degrader (SERD), with abemaciclib in postmenopausal women with ER+/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer

Abstract Background Endocrine therapy in combination with a targeted cyclin-dependent kinase (CDK) 4/6 inhibitor is the clinical standard for treatment of ER+/HER2- advanced breast cancer. Amcenestrant (SAR439859) is an optimized oral SERD with potent dual activity that antagonizes and degrades the ER, resulting in inhibition of the ER signaling pathway. In previous arms of the AMEERA-1 study, amcenestrant, as monotherapy or in combination with the CDK4/6 inhibitor palbociclib, demonstrated antitumor activity and a favorable safety profile in postmenopausal women with heavily pretreated ER+/HER2- advanced breast cancer. The objective of Arm 5 of the AMEERA-1 study is to evaluate safety and antitumor activity of amcenestrant in combination with the CDK4/6 inhibitor abemaciclib for patients with ER+/HER2- advanced breast cancer. Methods AMEERA-1 (NCT03284957) is an open-label, non-comparative, dose escalation and dose expansion Phase 1/2 study of amcenestrant as monotherapy, then in combination with other anti-cancer targeted therapies. Arm 5 investigates dose escalation (Part J) and dose expansion (Part K), of amcenestrant in combination with abemaciclib. Postmenopausal women with ER+/HER2- advanced breast cancer, ECOG performance status 0-1, and ≥ 6 months prior endocrine therapy are eligible. In Arm 5 (Parts J and K), ≤ 1 prior line of a single endocrine therapy for advanced disease is allowed. Prior treatment with fulvestrant or any other SERD is not allowed; in addition, prior therapy with CDK4/6 inhibitors for advanced disease is not allowed. Part J allows ≤ 1 prior chemotherapy for advanced disease, while prior chemotherapy for advanced disease is not allowed in Part K. Additional exclusion criteria in Arm 5 are prior drugs targeting the phosphoinositide 3-kinase axis; history of or concurrent pneumonitis; and history of or concurrent venous thromboembolism (i.e., deep vein thrombosis, pulmonary embolism, or cerebral venous sinus thrombosis). Part J evaluates the selected amcenestrant dose for combination therapy plus abemaciclib 150 mg twice daily (BID) (the approved standard dose) or abemaciclib 100 mg BID, taken in 28-day cycles. Additional dose levels of amcenestrant may be explored based on safety and pharmacokinetics (PK). The objective of Part J is to determine the recommended dose (RD) of abemaciclib in combination with the selected amcenestrant dose for combination therapy, based on preliminary safety, PK, and antitumor activity data. The primary endpoint in Part J is the incidence of treatment-related dose-limiting toxicities (DLTs) at Cycle 1. Approximately up to 12 DLT-evaluable patients will be needed to establish the RD of abemaciclib in combination with amcenestrant in Part J. In Part K, approximately 20 patients will be treated at the RD of abemaciclib for combination therapy with amcenestrant, the primary endpoint being safety and tolerability. Secondary endpoints include PK and antitumor activity. Funding: Sanofi. Citation Format: Mario Campone, Sarat Chandarlapaty, Aditya Bardia, Patrick Neven, Katarina Petrakova, Peter Kabos, Valentina Boni, Sofia Braga, Marina Celanovic, Patrick Cohen, Alice Gosselin, Sylvaine Cartot-Cotton, Vasiliki Pelekanou, Hannah Linden. Ameera-1 Arm 5: Phase 1/2 study of amcenestrant (SAR439859), an oral selective estrogen receptor (ER) degrader (SERD), with abemaciclib in postmenopausal women with ER+/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer [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 OT2-11-04.

Network meta-analysis of eribulin versus other chemotherapies used as second- or later-line treatment in locally advanced or metastatic breast cancer

BackgroundEribulin mesylate (ERI; Halaven®) is a microtubule inhibitor approved in the United States for metastatic breast cancer patients with at least two prior chemotherapy regimens for metastatic breast cancer, and in the European Union in locally advanced breast cancer or metastatic breast cancer patients who progressed after at least one chemotherapy for advanced disease. This network meta-analysis compared the efficacy and safety of ERI versus other chemotherapies in this setting.MethodsSystematic searches conducted in MEDLINE, Embase, and the Cochrane Central Register of Clinical Trials identified randomized controlled trials of locally advanced breast cancer/metastatic breast cancer chemotherapies in second- or later-line settings. Efficacy assessment included pre-specified subgroup analysis of breast cancer subtypes. Included studies were assessed for quality using the Centre for Reviews and Dissemination tool. Bayesian network meta-analysis estimated primary outcomes of overall survival and progression-free survival using fixed-effect models. Comparators included: capecitabine (CAP), gemcitabine (GEM), ixabepilone (IXA), utidelone (UTI), treatment by physician’s choice (TPC), and vinorelbine (VIN).ResultsThe network meta-analysis included seven trials. Results showed that second- or later-line patients treated with ERI had statistically longer overall survival versus TPC (hazard ratio [HR]: 0.81; credible interval [CrI]: 0.66–0.99) or GEM+VIN (0.62; 0.42–0.90) and statistically longer progression-free survival versus TPC (0.76; 0.64–0.90), but statistically shorter progression-free survival versus CAP+IXA (1.40; 1.17–1.67) and CAP+UTI (1.61; 1.23–2.12). In triple negative breast cancer, ERI had statistically longer overall survival versus CAP (0.70; 0.54–0.90); no statistical differences in progression-free survival were observed in triple negative breast cancer.ConclusionsThis network meta-analysis suggests that ERI may provide an overall survival benefit in the overall locally advanced breast cancer/metastatic breast cancer populations and triple negative breast cancer subgroup compared to standard treatments. These findings support the use of ERI in second- or later-line treatment of patients with locally advanced breast cancer/metastatic breast cancer.

Single center observational study of the efficacy of chemotherapy in breast cancer patients treated before and after the widespread use age of CD4/6 inhibitors: Is there evidence that chemotherapy response is impacted by prior use of CD4/6 inhibitors?

e13019 Background: Recently CD4/6 inhibitors have radically changed treatment pathways, leading to a deferment of chemotherapy for advanced disease. Patients still relapse following this treatment; we wish to share our experience of chemotherapy both before and after this change and explore whether there is a change in efficacy. In England CD4/6 inhibitors are prescribed according to the guidelines set out by NHS England (NICE), and are generally utilised in the first line setting unless there is visceral crisis. Methods: This is a retrospective double cohort observational single centre study comparing the efficacy of a chemotherapy regimen (vinorelbine and capecitabine vin cap) before and after the incorporation of CD4/6 inhibitors into breast cancer treatment (Jan 2017- Nov 20). The doublet chemotherapy is widely used at our centre providing a well tolerated and effective alternative to intravenous treatments such as taxanes or single agent capecitabine. Data was collected contemporaneously using e prescribing software and audited retrospectively Results: In the audit period n=19 treated with cap, n= 97 with vin cap, n= 24 treated with CD4/6, (of whom 5 relapsed). 5 patients received abemaciclib first line, as initial therapy, all G3, stage 11A or above, median number of cycles 4.2, I received ribociclib, G2, stage 111A, 7 cycles and 17 received palbociclib, 10 first line, 4 following 1 course chemo, 2 after 2 courses and 1 and after 3 courses, 30% G3 and 70% G2, mean number of cycles 11.06. Patients who received first line cap progressed after a median of 3.5 cycles, with a range of 0-22 months (RR= 47%), for cape vin a median of 8.6, a range of 0-60 months (RR=77%), post CD4/6 mean of 8, median of 9, a range of 0-17 (RR=80%). Conclusions: Those post CD4/6 requiring chemo relapsed far short of the median TTP of around 26months and may have specific characteristics predicting poor response to CD4/6. Despite small numbers salvage chemotherapy remains effective with similar responses. First line vin cap is more efficacious and better tolerated than Cap.[Table: see text]

Small bowel adenocarcinoma: revisited

Small bowel malignancies are rare despite it representing 75% of the gastro intestinal (GI) length and 90% of the mucosal surface area. Even then small bowel adenocarcinoma (SBA) accounts for only 30-40% of all small intestine malignancies. Etiology is multifactorial and risk factors include hereditary mutations, inflammatory bowel diseases, coeliac disease. Presenting symptoms are vague and nonspecific and cannot usually be diagnosed by conventional upper and lower GI endoscopy as it is in an inaccessible location. This leads to delayed diagnosis and hence poor prognosis. Mainstay of treatment is surgical resection with adjuvant chemotherapy in advanced disease. We present a case study of a 74 years old woman who presented to the emergency department with small bowel obstruction and radiological features suggestive of underlying small bowel malignancy. She underwent urgent laparotomy with segmental small bowel resection and had intraoperative evidence of wide spread metastasis which was confirmed on subsequent tumor staging scans. She received adjuvant chemotherapy with complete metabolic response at one year post resection. SBA is generally diagnosed at advanced stage due to its anatomical location. Complete surgical resections should always be targeted. However, adjuvant chemotherapy plays a role in advanced disease even though clinical data of evidence is scarce.

A multicenter, retrospective study on impact of immunotherapy in urothelial carcinoma with bone metastases (Meet-Uro01 Study).

401 Background: Considerable numbers of patients (pts) with metastatic urothelial carcinoma (mUC) (approximately 25-47%) develop bone metastases (BoM). Their impact on the efficacy of immunotherapy (IO) is not yet sufficiently investigated. We developed a national collaboration on this issue, with the aim to assess the effect of BoM on survival outcomes of immunotherapy-treated pts in a large retrospective cohort. Methods: Data on pts diagnosed with mUC and treated between 07/14 and 08/20 with single-agent immunotherapy (IO) after failure of at least 1 previous line of chemotherapy (CT) for advanced disease, or (neo-)adjuvant CT within 12 months were retrospectively collected across 14 centers. PFS and OS were analyzed using the Kaplan-Meier method. Cox regression analysis was performed evaluating potential prognostic factors for OS and PFS. Each factor was evaluated in univariable (UV) and multivariable (MVA) analysis. Results: A total of 208 evaluable pts treated with single-agent immunotherapy (anti PD-1 n=42; anti PD-L1 n=166) were identified, including 122 without BoM (59% BoM-) and 86 (41%) BoM+. 13% of pts had progressed within 12 months after (neo-)adjuvant CT and 79% after a previous line of platinum-based CT for advanced disease (cisplatin 42.8%; carboplatin 36.5%). The presence of BoM negatively affected performance status (PS) of patients at baseline (ECOG PS 0/1/2 in 58% / 37% / 5% in BoM- vs 38% / 52% / 9% in BoM+; p=0.017). Other baseline characteristics were comparable. BoM+ showed shorter PFS (median 2.0 vs 2.6 months, HR 1.76 [95%CI, 1.31-2.37], p<0.001) and OS (median 3.9 vs 7.8 months, HR 1.59 [95%CI, 1.15-2.20], p=0.005) than BoM-. Probability of being alive was 62% vs 40% after 6 months, 38% vs 23% after 1 year and 24% vs 13% after 2 years, in BoM- and BoM+ respectively. Within each Bellmunt score, PFS and OS of BoM+ pts were shorter compared to BoM-. Both BoM and higher Bellmunt risk score were significantly associated with shorter PFS and OS in UV and MV analyses (Table). Conclusions: Patients with mUC treated with single-agent immunotherapy for BoM+ advanced disease have a dismal prognosis compared with BoM-. Further research is needed to understand the mechanism behind these clinical outcomes. [Table: see text]

NRG-GI004/SWOG-S1610: Colorectal Cancer Metastatic dMMR Immuno-Therapy (COMMIT) Study—A randomized phase III study of atezolizumab (atezo) monotherapy versus mFOLFOX6/bevacizumab/atezo in the first-line treatment of patients (pts) with deficient DNA mismatch repair (dMMR) or microsatellite instability high (MSI-H) metastatic colorectal cancer (mCRC).

TPS158 Background: Despite activity of programmed cell death-1 (PD-1) pathway inhibition in dMMR/MSI-H mCRC, approximately one-third of patients demonstrate progressive disease as best response to anti-PD1 monotherapy. Preclinical models have demonstrated synergistic interactions between FOLFOX, anti-VEGF, and anti-PD-1. We hypothesize that the dMMR/MSI-H mCRC subset may be more effectively targeted by the combination of PD-1 pathway blockade and mFOLFOX6/bevacizumab (bev) rather than with anti-PD-1 therapy (atezo) alone. Methods: Initially a three-arm study, the mFOLFOX6/bev arm was closed to new enrollment on 6-4-20 due to emerging data; the redesigned COMMIT is a prospective phase III open-label trial that will randomize (1:1) mCRC dMMR/MSI-H pts (N=211) to either atezo monotherapy or mFOLFOX6/bev+atezo combination. Stratification factors include BRAFV600E status, metastatic site, and prior adjuvant CRC therapy. Primary endpoint is progression-free survival (PFS) as assessed by site investigator. Secondary endpoints include OS, objective response rate, safety profile, disease control rate, duration of response, and centrally-reviewed PFS. Health-related quality of life is an exploratory objective. Archived tumor tissue and blood samples will be collected for correlative studies. Key inclusion criteria are: mCRC without prior chemotherapy for advanced disease; dMMR tumor determined by local CLIA-certified IHC assay (MLH1/MSH2/MSH6/PMS2) or MSI-H by local CLIA-certified PCR or NGS panel; and measurable disease per RECIST. Support: U10CA180868, -180822, -180888, -180819, UG1CA189867, U24CA196067; Genentech, Inc. Clinical trial information: NCT02997228.

CONTESSA TRIO: A multinational, multicenter, phase (P) II study of tesetaxel (T) plus three different PD-(L)1 inhibitors in patients (Pts) with metastatic triple-negative breast cancer (TNBC) and tesetaxel monotherapy in elderly pts with HER2-metastatic breast cancer (MBC).

TPS1111 Background: Chemotherapy treatments with robust efficacy that preserve quality of life are needed. T is a novel, oral taxane that has potential advantages over currently available taxanes, including: oral administration with a low pill burden and once every 3 week (Q3W) dosing; no observed hypersensitivity reactions; preclinical evidence of central nervous system (CNS) penetration; and improved activity against chemotherapy-resistant tumors. More than 600 pts have been treated with T in clinical studies. T had robust monotherapy activity in a P2 study in 38 pts with HER2-, HR+ MBC, with a confirmed objective response rate (ORR) per RECIST 1.1 of 45%. Methods: CONTESSA TRIO is a 2-cohort, multinational, multicenter, P2 study. In Cohort 1, 90 pts (potential expansion to up to 150 pts) with metastatic TNBC who have not received prior chemotherapy for advanced disease will be randomized 1:1:1 to receive T at 27 mg/m2 Q3W plus either: (1) nivolumab at 360 mg Q3W; (2) pembrolizumab at 200 mg Q3W; or (3) atezolizumab at 1,200 mg Q3W. Nivolumab and pembrolizumab (PD-1 inhibitors) and atezolizumab (a PD-L1 inhibitor) are approved for the treatment of multiple types of cancer; atezolizumab, in combination with nab-paclitaxel, was recently approved in the US for the treatment of metastatic TNBC. The dual primary endpoints for Cohort 1 are ORR and progression-free survival (PFS). A sample size of 30 pts in each PD-(L)1 inhibitor treatment group has approximately 70% power to detect an ORR difference of ≥ 35% between the treatment group with the highest ORR and the treatment group with the lowest ORR. Secondary endpoints include duration of response (DoR) and overall survival (OS). Efficacy results for each of the 3 PD-(L)1 inhibitor combinations will be assessed for correlation with the results of each of the 3 approved PD-L1 diagnostic assays. CONTESSA TRIO is the first randomized clinical study to compare 3 approved PD-(L)1 inhibitors. In Cohort 2, 40 elderly pts (potential expansion to up to 60 pts) with HER2- MBC who have not received prior chemotherapy for advanced disease will receive T monotherapy at 27 mg/m2 Q3W. The primary endpoint for Cohort 2 is ORR. A sample size of 40 will allow the ORR to be estimated with a maximum standard error of < 8%. Secondary endpoints include PFS, DoR and OS. Pts with CNS metastases are eligible for both cohorts. The study was initiated in March 2019. Clinical trial information: NCT03952325 .

Abstract OT1-08-08: CONTESSA TRIO: A multinational, multicenter, phase 2 study of tesetaxel plus 3 different PD-(L)1 inhibitors in patients with metastatic triple-negative breast cancer (TNBC) and tesetaxel monotherapy in elderly patients with HER2- metastatic breast cancer (MBC)

Abstract Background: Chemotherapy treatments with robust efficacy that preserve quality of life are needed. Tesetaxel is a novel, oral taxane that has potential advantages over currently available taxanes, including: oral administration with a low pill burden and once every 3 week (Q3W) dosing; no observed hypersensitivity reactions; preclinical evidence of central nervous system (CNS) penetration; and improved activity against chemotherapy-resistant tumors. More than 600 patients have been treated with tesetaxel in clinical studies. Tesetaxel had robust monotherapy activity in a Phase 2 study in 38 patients with HER2-, HR+ MBC, with a confirmed objective response rate (ORR) per RECIST 1.1 of 45%. CONTESSA TRIO investigates tesetaxel plus 3 different PD-(L)1 inhibitors in patients with TNBC and tesetaxel monotherapy in elderly patients with HER2- MBC. Trial design: CONTESSA TRIO is a 2-cohort, multinational, multicenter, Phase 2 study. In Cohort 1, 90 patients (with potential expansion to up to 150 patients) with metastatic TNBC who have not received prior chemotherapy for advanced disease will be randomized 1:1:1 to receive tesetaxel at 27 mg/m2 Q3W plus either: (1) nivolumab at 360 mg Q3W; (2) pembrolizumab at 200 mg Q3W; or (3) atezolizumab at 1,200 mg Q3W. Nivolumab and pembrolizumab (PD-1 inhibitors) and atezolizumab (a PD-L1 inhibitor) are approved for the treatment of multiple types of cancer; atezolizumab, in combination with nab-paclitaxel, was recently approved in the U.S. for the treatment of metastatic TNBC. The dual primary endpoints for Cohort 1 are ORR and progression-free survival (PFS). A sample size of 30 patients in each PD-(L)1 inhibitor treatment group has approximately 70% power to detect an ORR difference of 35% or greater between the treatment group with the highest ORR and the treatment group with the lowest ORR. An increase in the sample size to 50 patients in each treatment group will increase the power to approximately 85%. Secondary endpoints include duration of response (DoR) and overall survival (OS). Efficacy results for each of the 3 PD-(L)1 inhibitor combinations will be assessed for correlation with the results of each of the 3 approved PD-L1 diagnostic assays. CONTESSA TRIO is the first randomized clinical study to compare 3 approved PD-(L)1 inhibitors. In Cohort 2, 40 elderly patients (with potential expansion to up to 60 patients) with HER2- MBC who have not received prior chemotherapy for advanced disease will receive tesetaxel monotherapy at 27 mg/m2 Q3W. The primary endpoint for Cohort 2 is ORR. A sample size of 40 will allow the ORR to be estimated with a maximum standard error of < 8%. An increase in the sample size to 60 patients will decrease the maximum standard error to < 6.5%. Secondary endpoints include PFS, DoR and OS. Patients with CNS metastases are eligible for both cohorts. The Study was initiated in March 2019. For further information on this trial, email joconnell@odonate.com or visit clinicaltrials.gov (NCT03952325). Citation Format: Sara Tolaney, Joanne Blum, Igor Bondarenko, Arlene Chan, Noshir DaCosta, Yin-Hsun Feng, Yann Izarzugaza, Sung-Bae Kim, Mei-Ching Liu, Maria Eva Peréz Lopéz, Mafalda Oliveira, Samuel Guan Wei Ow, Michel Pavic, Hope Rugo, Lee Schwartzberg, Agostina Stradella, Stew Kroll, Joseph O'Connell, Thomas Wei, Elizabeth Mittendorf. CONTESSA TRIO: A multinational, multicenter, phase 2 study of tesetaxel plus 3 different PD-(L)1 inhibitors in patients with metastatic triple-negative breast cancer (TNBC) and tesetaxel monotherapy in elderly patients with HER2- metastatic breast cancer (MBC) [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 OT1-08-08.

Biliary tract cancer (BTC) in the elderly: A real-world tertiary cancer center experience.

492 Background: Although BTC is mostly a disease of the elderly, only limited data ara available on the optimal management of this patient (pt) population. In fact, older pts are underepresented in clinical trials and results are seldom reported by age group. In this study, we aimed at evaluating pattern of care and treatment outcome in BTC aged ≥ 70 years and comparing them with their younger counterparts. Methods: Medical records of BTC followed at the Modena Cancer Centre from 2007 and 2019 were retrospectively reviewed.. Overall survival (OS) was estimated with the Kaplan-Meier curves and compared by log-rank test. Differences between categorical variables were assessed using the chi square test. Univariate and multivariate analyses were performed to assess the impact of covariates on survival. Results: A total of 120 BTC patients (49%) ≥ 70 were included in the analysis. 54% (64) were female, 47% (56) had iCCA, 41% (49) GBC, and 12% (15) eCCA. 68% (81) had unresectable locally advanced or metastatic disease. 32% (39) underwent surgical resection, 60% (72) were treated with first-line chemotherapy (1L), while 29% (21) of them went on to receive second-line (2L). No differences in terms of both chance to receive surgery (p=0.59) and survival (p=0.25) were recorded compared to youngers. In the advanced-disease setting, median OS was 8 months and was significantly worse than that of the younger counterparts (p<0.001). Older patients were less likely to receive 1L (p<0.001) and 2L (p<0.001) chemotherapy and doublet regimens (p<0.001). Female gender (p=0.031), ECOG PS 0 (p<0.001), stage III (p<0.001) and NLR>3 (p<0.001) were independently associated with a better prognosis in older BTC receiving 1L, with 1-year OS of 82% (95%CI 68-91, p=0.031). Conclusions: In this real-world study, no survival difference was found between older and non-older surgically-treated patients. Contrariwise, elderly BTC were less frequently treated with chemotherapy for advanced disease and their outcome is poorer than youngers. However, clinical and biochemical prognostic have been identified that may assist in selecting older pts more likely to benefit from systemic treatment, both in clinical trials and daily practice.

Abstract PD2-12: Palbociclib in combination with fulvestrant or tamoxifen as treatment for hormone receptor positive (HR+) metastatic breast cancer (MBC) with prior chemotherapy for advanced disease (TBCRC 035) A phase II study with pharmacodynamics markers

Abstract Background Addition of the cyclin dependent kinase 4/6 inhibitor (CDK4/6i) palbociclib to endocrine therapy in the first and later line settings significantly improves progression free survival (PFS) in patients with HR+ MBC. The primary toxicity is neutropenia without an increase in febrile neutropenia. TBCRC035 explored rates of neutropenia in patients who had received prior chemotherapy for MBC with 2 dose levels of palbociclib, and correlated changes in retinoblastoma protein phosphorylation (pRB) and Ki67 expression in proliferating keratinocytes and tumor with response. Methods TBCRC035 is a 1:1 randomized multicenter phase II study evaluating palbociclib at either 125 or 100 mg in combination with physician choice fulvestrant or tamoxifen. Eligible patients (pts) with HR+ MBC had received >1 but <3 lines of chemotherapy for MBC, any number of prior hormone therapies, and were naïve to CDK4/6i. The primary endpoint was grade 3/4 neutropenia; secondary endpoints included response, safety/tolerability, inhibition of pRB and change in Ki67 in skin and tumor at day 14-21 of treatment compared to baseline. FFPE sections of skin punch and tumor biopsies obtained before and on treatment were stained using antibodies to Ki67, total RB, and phospho-RB-S780 using BOND polymer red detection. Stained slides were scanned into the Aperio image analysis platform; the percentage of marker positive cells and H-score was determined. Results 70 pts were enrolled (fully accrued); 35 randomized to 100 vs 125 mg of palbociclib respectively; data for the last 3 pts on the 125 mg arm is pending. Grade 3/4 neutropenia was more common in the 125 mg vs the 100 mg arm (56 vs 34%); dose adjustments for adverse events (AEs) occurred in 47 vs 43%, 4 vs 0 pts discontinued treatment due to AEs. Grade 3 febrile neutropenia was rare (1 patient each arm). Median duration of treatment was 5.2 vs 7.2 months. Response data and correlation with changes in pRB and Ki67 expression in skin and tumor by treatment arm will be reported. Conclusion In pts with prior chemotherapy for HR+ MBC, treatment with 100 mg of palbociclib in patients is associated with a lower rate of > grade 3 neutropenia compared to 125 mg. Correlation of response by dose with pRB and Ki67 has the potential to inform palbociclib dosing and reduce toxicity for pts with HR+ MBC. Citation Format: Rugo HS, Mayer EL, Storniolo AM, Isaacs C, Mayer I, Stearns V, Nanda R, Nangia J, Wabl C, Deluca A, Kochupurakkal B, Wolff AC, Shapiro GI. Palbociclib in combination with fulvestrant or tamoxifen as treatment for hormone receptor positive (HR+) metastatic breast cancer (MBC) with prior chemotherapy for advanced disease (TBCRC 035) A phase II study with pharmacodynamics markers [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 PD2-12.

Abstract P6-18-14: Patient-reported outcomes with ribociclib-based therapy in hormone receptor-positive, HER2-negative advanced breast cancer: results from the phase III MONALEESA-2, -3, and -7 trials

Abstract Background: In the Phase III MONALEESA (ML) trials, ribociclib (RIB; cyclin-dependent kinase 4/6 inhibitor) + endocrine therapy (ET) significantly improved progression-free survival (PFS) vs placebo (PBO) + ET in patients (pts) with hormone receptor-positive (HR+), HER2-negative (HER2–) advanced breast cancer (ABC). Here we report key patient-reported outcomes (PROs) for pts treated with RIB-based regimens of interest (i.e. with a non-steroidal aromatase inhibitor [NSAI] or fulvestrant [FUL]) in the ML-2, -3, and -7 trials. Methods: Postmenopausal pts with HR+, HER2– ABC and no prior ET for advanced disease received RIB (600 mg/day; 3-weeks-on/1-week-off) + letrozole (2.5 mg/day; ML-2 [NCT01958021]), or FUL (500 mg every 28 days, with an additional dose on Day 15 of Cycle [C] 1; ML-3 [no prior ET for ABC subgroup only; NCT02422615]). Premenopausal pts with no prior ET and ≤1 line of chemotherapy for advanced disease received RIB + NSAI (anastrozole [1 mg/day]/letrozole [2.5 mg/day]) + goserelin (3.6 mg every 28 days; ML-7 [NCT02278120]). The primary endpoint for all trials was PFS. PROs were a secondary endpoint of all trials and were evaluated using EORTC QLQ-C30, QLQ-BR23 (ML-2 and ML-7), EQ-5D-5L, WPAI-GH (ML-7 only), and BPI-SF (ML-3 only) questionnaires. Changes from baseline and time to 10% deterioration (TTD) in health-related quality of life (HRQoL) were analyzed using linear mixed-effect and stratified Cox regression models, respectively. Results: A total of 1530 pts were included in this analysis. Questionnaire compliance was high across trials (ML-2/ML-3: >90%; ML-7: >80%). On-treatment HRQoL (EORTC QLQ-C30 global health status/quality of life [QoL] score) was maintained from baseline up to C34, C28, and C17 in both treatment arms for ML-2, ML-3, and ML-7, respectively. In ML-7, mean overall HRQoL scores continued to improve in the RIB arm from C18 to C28, but scores decreased in the PBO arm. At end of treatment, mean overall HRQoL scores decreased in both arms across trials. Median TTD (RIB vs PBO) was similar between arms, favoring the RIB arms (ML-2: 27.7 vs 27.6 months; hazard ratio 0.944; 95% confidence interval [CI] 0.720–1.237; ML-3: not reached [NR] vs 22.4 months; hazard ratio 0.721; 95% CI 0.484–1.074; ML-7: 24.0 vs 19.4 months; hazard ratio 0.759; 95% CI 0.561–1.028). Clinically meaningful reductions in EORTC QLQ-C30 pain score (>5 points from baseline) were observed in the RIB arm of ML-2 from as early as C3 and were sustained vs only at C7 and C13 in the PBO arm. Clinically meaningful reductions in pain were observed from C22 to C28 in the RIB arm of ML-7 vs only at C28 in the PBO arm. In ML-3, clinically meaningful reductions in pain were observed from C3 to C5, C11–17, and at C22 and C28 in the RIB arm vs C17–C25 in the PBO arm. Furthermore, median TTD of the BPI-SF pain severity index score was NR in either arm of ML-3 (hazard ratio 0.858; 95% CI 0.554–1.330). Conclusions: In addition to significantly prolonging PFS, RIB consistently maintains QoL regardless of ET combination partner. RIB + ET is also associated with clinically meaningful reductions in pain vs PBO + ET across a broad population of pts with HR+, HER2– ABC. Citation Format: Beck JT, Neven P, Esteva FJ, Bardia A, Harbeck N, Hurvitz S, O'Shaughnessy J, Verma S, Lanoue B, Alam J, Kong O, Chandiwana D, Chia S. Patient-reported outcomes with ribociclib-based therapy in hormone receptor-positive, HER2-negative advanced breast cancer: results from the phase III MONALEESA-2, -3, and -7 trials [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 P6-18-14.

Ixazomib in combination with carboplatin in pretreated women with advanced triple-negative breast cancer, a phase I/II trial of the AGMT (AGMT MBC-10 trial)

BackgroundTriple-negative breast cancer (TNBC) comprises a heterogeneous group of diseases which are generally associated with poor prognosis. Up to now, no targeted treatment beyond anti-VEGF therapy has been approved for TNBC and cytotoxic agents remain the mainstay of treatment. Ixazomib is a selective and reversible inhibitor of the proteasome, which has been mainly investigated in the treatment of multiple myeloma. In a preclinical study TNBC cells were treated with the first-generation proteasome inhibitor bortezomib in combination with cisplatin and synergistic efficacy was demonstrated. Clinical data are available for carboplatin plus bortezomib in metastatic ovarian and lung cancers showing remarkable antitumor activity and good tolerability (Mol Cancer 11:26 2012, J Thorac Oncol 4:87–92 2009, J Thorac Oncol 7:1032–1040, 2012). Based on this evidence, the phase I/II MBC-10 trial will evaluate the toxicity profile and efficacy of the second-generation proteasome inhibitor ixazomib in combination with carboplatin in patients with advanced TNBC.MethodsPatients with metastatic TNBC pretreated with at least one prior line of chemotherapy for advanced disease with a confirmed disease progression and measurable disease according to RECIST criteria 1.1 are eligible for this study. Patients will receive ixazomib in combination with carboplatin on days 1, 8, and 15 in a 28-day cycle. The phase I part of this study utilizes an alternate dose escalation accelerated titration design. After establishing the maximum tolerated dose (MTD), the efficacy and safety of the combination will be further evaluated (phase II, including 41 evaluable patients). All patients will continue on study drugs until disease progression, unacceptable toxicity or discontinuation for any other reason. Primary endpoint of the phase II is overall response rate, secondary endpoints include progression-free survival, safety, and quality of life. This trial is open for patient enrollment since November 2016 in six Austrian cancer centers. Accrual is planned to be completed within 2 years.DiscussionBased on preclinical and clinical findings an ixazomib and carboplatin combination is thought to be effective in metastatic TNBC patients. The MBC-10 trial is accompanied by a broad biomarker program investigating predictive biomarkers for treatment response and potential resistance mechanisms to the investigational drug combination.Trial registrationEudraCT Number: 2016–001421-13 received on March 31, 2016, ClinicalTrials.gov Identifier: NCT02993094 first posted on December 15, 2016. This trial was registered prospectively.