AMEERA-1: Phase 1/2 study of amcenestrant (SAR439859), an oral selective estrogen receptor (ER) degrader (SERD), with palbociclib (palbo) in postmenopausal women with ER+/ human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 1058-1058
Author(s):  
Sarat Chandarlapaty ◽  
Hannah M. Linden ◽  
Patrick Neven ◽  
Katarina Petrakova ◽  
Aditya Bardia ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Postmenopausal Women ◽  
Targeted Therapies ◽  
Phase 1 ◽  
Safety Data ◽  
Growth Factor Receptor ◽  
Metastatic Breast ◽  
Part D ◽  
Part C ◽  
Hot Flush

1058 Background: AMEERA-1 (NCT03284957) investigates amcenestrant, an oral SERD, as monotherapy and combined with targeted therapies in ER+/HER2– mBC. Here we report data from dose escalation (Part C) and dose expansion (Part D) of amcenestrant + palbo. Methods: Patients (pts) were postmenopausal women with ER+/HER2– mBC and ≥ 6 mos prior advanced endocrine therapy (ET) or adjuvant (adj) ET resistance (relapse on adj ET started ≥ 24 mos ago or < 12 mos after completing adj ET). Prior chemotherapy (≤ 1) for advanced disease was allowed; targeted therapies were not except ≤ 1 CDK4/6i in Part C. Part C assessed dose-limiting toxicities (DLTs) and aimed to establish the recommended phase 2 dose (RP2D) for amcenestrant (200 or 400 mg once daily [QD], in 28-day cycles) in combination with palbo (125 mg QD for 21 days on/ 7 days off). Safety (treatment-emergent adverse events [TEAEs] and lab abnormalities per CTCAE v4.03) and pharmacokinetics (PK) were evaluated. Antitumor activity at the RP2D for amcenestrant + palbo was evaluated in a subset of Part C pts and Part D, according to RECIST v1.1, determined locally by investigators. Results: Feb 8, 2021 data cutoff. In Part C (n = 15; 200 mg: 9; 400 mg: 6), no DLTs occurred and amcenestrant 200 mg QD was selected as the RP2D with palbo, based on PK and safety data. In the pooled safety population at the RP2D (n = 39; Part C: 9; Part D: 30), median (range) age was 59 y (33–86) with ECOG PS 0 (74.4%) or 1 (25.6%) and 2 (1–6) organs involved. Immediate prior therapy was neo/adj (41.0%, all ET resistant) or advanced (59.0%, range 1–4 lines). Median (range) exposure was 32 wks (1–66) with 59.0% pts on ongoing therapy. No amcenestrant dose reductions occurred; 25.6% had ≥ 1 palbo dose reduction. Most common non-hematological TEAEs related to amcenestrant were Grade 1–2 nausea and fatigue (17.9% each), asthenia and hot flush (10.3% each); to palbo were fatigue (30.8%), nausea (25.6%), asthenia and dysgeusia (10.3% each). Two pts discontinued due to AEs. The majority (94.9%) had neutrophil count decrease (53.8% Grade ≥ 3). Preliminary antitumor activity after at least 6 cycles of therapy (unless early treatment discontinuation) is reported in the table below. Conclusions: In pts with ER+/HER2– mBC, safety at the RP2D of amcenestrant + palbo was favorable, with no safety signals of bradycardia or eye disorders. Preliminary antitumor activity was observed (ORR: 31.4% and CBR: 74.3%). Clinical trial information: NCT03284957 .[Table: see text]

CheckMate 8KX: Phase 1/2 multitumor preliminary analyses of a subcutaneous formulation of nivolumab (± rHuPH20).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2575-2575
Author(s):  
Sara Lonardi ◽  
Iwona Lugowska ◽  
Christopher G. C. A. Jackson ◽  
Anne O'Donnell ◽  
Rastilav Bahleda ◽  
...  
Keyword(s):  
De Novo ◽  
Phase 1 ◽  
Geometric Mean ◽  
Primary Objective ◽  
Tumor Type ◽  
Part D ◽  
Part C ◽  
Local Site ◽  
Survival Expectations ◽  
Grade 3

2575 Background: Immunotherapy has transformed cancer survival expectations. Nivolumab (NIVO), a programmed death-1 inhibitor, is approved for intravenous (IV) administration across multiple cancers. BMS is developing a subcutaneous (SC) NIVO formulation with a permeation enhancer, recombinant human hyaluronidase PH20 enzyme (rHuPH20), to allow for more rapid delivery and the potential to decrease treatment burden. We report the first data on pharmacokinetics (PK), pharmacodynamics, safety, and immunogenicity for SC NIVO + rHuPH20. Methods: CheckMate 8KX is a phase 1/2 study in checkpoint inhibitor-naïve patients (pts) who were ≥ 18 years of age, ECOG PS 0–1, with metastatic/unresectable solid tumors and measurable disease. The primary objective was to describe SC NIVO PK; secondary objectives were safety and immunogenicity. Additional analyses compared exposures to historical IV NIVO (Zhao X, et al. J Clin Oncol 2020;31:302–309). In cycle 1, pts in Part A received SC NIVO 720 mg + rHuPH20, and pts in Part B received SC NIVO 720 mg, SC NIVO 960 mg + rHuPH20, or SC NIVO 960 mg. For cycles 2+, pts in Parts A and B received IV NIVO 480 mg every 4 weeks (Q4W). Pts still on study switched to Part C, SC NIVO 1200 mg + rHuPH20 until end of therapy. In Part D, pts received de novo SC NIVO 1200 mg + rHuPH20 Q4W. Results: Patient characteristics varied by age, weight, tumor type, and prior treatment. NIVO exposures increased with increasing SC dose (Table). For 960 mg and 1200 mg NIVO + rHuPH20, Cavg and Ctau were above geometric mean exposures for IV NIVO 3 mg/kg every 2 weeks (Q2W), and Cmax was below IV NIVO 10 mg/kg Q2W. In Part C (n = 28), 13 (46.4%) pts experienced any-grade TRAEs with no new/worsening grade 3+ TRAEs or TRAEs leading to discontinuation/death; 7 (25.0%) reported grade 1 local site reactions. In Part D (n = 36), 27 (75.0%) pts experienced any-grade TRAEs, 4 (11.1%) grade 3/4 TRAEs, 2 (5.6%) serious grade 3/4 TRAEs with 1 leading to discontinuation, and no treatment-related deaths; 10 (27.8%) reported grade 1 local site reactions. Anti-NIVO antibodies (Ab) were observed with SC NIVO but not associated with altered PK/safety, or neutralizing Ab. Exploratory biomarker data found increased CD8+ tumor-infiltrating lymphocytes and PD-L1 tumor expression in post-treatment biopsies, similar to IV NIVO. Conclusions: Exposures associated with SC NIVO + rHuPH20 doses investigated in CheckMate 8KX were well tolerated, with a safety profile consistent with IV NIVO. Data support evaluation of SC NIVO + rHuPH20 in a phase 3 study. Clinical trial information: NCT03656718. [Table: see text]

scholarly journals Targeted Therapies in Triple-Negative Breast Cancer

Breast Care ◽  
2015 ◽  
Vol 10 (3) ◽  
pp. 159-166 ◽  
Author(s):  
Frederik Marmé ◽  
Andreas Schneeweiss
Keyword(s):  
Breast Cancer ◽  
Growth Factor ◽  
Triple Negative Breast Cancer ◽  
Targeted Therapies ◽  
Triple Negative ◽  
Checkpoint Inhibitors ◽  
Chemotherapy Resistance ◽  
Growth Factor Receptor ◽  
Metastatic Breast ◽  
Receptor Subtype

Triple-negative breast cancer (TNBC) is a heterogeneous disease comprised of several biologically distinct subtypes. However, treatment is currently mainly relying on chemotherapy as there are no targeted therapies specifically approved for TNBC. Despite initial responses to chemotherapy, resistance frequently and rapidly develops and metastatic TNBC has a poor prognosis. New targeted approaches are, therefore, urgently needed. Currently, bevacizumab, a monoclonal anti-vascular endothelial growth factor (VEGF)-A antibody, is the only targeted agent with an approval for the therapy of metastatic breast cancer, but does not provide a specific benefit in the TNBC subtype. This review discusses the current clinical developments in targeted approaches for TNBC, including anti-angiogenic therapies, epidermal growth factor receptor (EGFR)-targeted therapies, poly(ADP-ribose) polymerase (PARP) inhibitors and platinum salts, as well as novel strategies using immune-checkpoint inhibitors, which have recently demonstrated first promising results. Strategies focusing on specific subtypes of TNBC like anti-androgenic therapies for the luminal androgen receptor subtype (LAR) and others are also discussed.

Phase I/II study of SAR439859, an oral selective estrogen receptor degrader (SERD), in estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 1070-1070
Author(s):  
Mario Campone ◽  
Aditya Bardia ◽  
Gary A. Ulaner ◽  
Sarat Chandarlapaty ◽  
Alice Gosselin ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Targeted Therapy ◽  
Objective Response ◽  
Growth Factor Receptor ◽  
Metastatic Breast ◽  
Mtor Inhibitors ◽  
Hot Flush ◽  
Estrogen Receptor Positive ◽  
Esr1 Mutation ◽  
Ecog Ps

1070 Background: SERDs competitively antagonize and degrade the ER and can block signaling in ER-dependent tumors resistant to standard endocrine therapy (ET). This study (NCT03284957) investigates SAR439859, a potent oral SERD, in ER+/HER2- mBC. We present pooled dose escalation/expansion (Part A/B) data for SAR439859. Methods: Postmenopausal patients (pts) with ER+/HER2- mBC treated for ≥ 6 mos with prior ET received SAR439859 ≥ 150 mg QD (Part A) or 400 mg QD (Part B). Chemotherapy and targeted therapy in the advanced setting were allowed. Objective response rate (ORR; RECIST v1.1), clinical benefit rate (CBR; complete or partial response [PR] or stable disease [SD] ≥ 24 weeks), safety, and pharmacokinetics (PK) were assessed. Results: Pts (n = 62; Part A, 13; Part B, 49) had a median age of 63 yrs (range 37–88) and ECOG PS 0 (59.7%) or 1 (40.3%); 93.5% had visceral disease. All had prior ET, 74.2% had prior targeted therapy and 48.4% had ≥ 3 prior lines in the advanced setting. 61.3% of pts had treatment-related adverse events (TRAEs), all grade 1–2. Most frequent: hot flush (16.1%), constipation, arthralgia (both 9.7%), decreased appetite, vomiting, diarrhea, nausea (all 8.1%), fatigue (6.5%). No pts discontinued due to AEs. CBR was 35.6% overall, with antitumor activity irrespective of ESR1 mutation status (Table). In pts with no prior SERD, CDK4/6 or mTOR inhibitors (n = 14), ORR was 21.4% and CBR 64.3%. PK data for Part B and ESR1 mutation data will be provided. Conclusions: SAR439859 had a favorable safety profile with limited TRAEs. In these heavily pre-treated pts (prior targeted therapy in 74.2%), ORR and CBR were similar to historical fulvestrant performance in pts with no prior targeted therapy. Encouraging ORR and CBR in pts with no prior SERD, CDK4/6 or mTOR inhibitors (n = 14; ORR 21.4%; CBR 64.3%) supports SAR439859 development in earlier lines of therapy. Clinical trial information: NCT03284957 . [Table: see text]

A phase 1 multicenter, dose expansion study of ARX788 as monotherapy in patients with HER2-positive advanced gastric and gastroesophageal junction adenocarcinoma (ACE-Gastric-01).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16059-e16059
Author(s):  
Yang Zhang ◽  
Miaozhen Qiu ◽  
Jufeng Wang ◽  
Yanqiao Zhang ◽  
Xianglin Yuan ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Objective Response Rate ◽  
Response Rate ◽  
Phase 1 ◽  
Gastroesophageal Junction ◽  
Objective Response ◽  
Growth Factor Receptor ◽  
Maximum Tolerated Dose ◽  
Antibody Drug Conjugate ◽  
Her2 Positive

e16059 Background: ARX788 is a novel antibody drug conjugate (ADC) that consists of human epidermal growth factor receptor 2 (HER2) targeted monoclonal antibody (mAb) linked to a cytotoxic payload, AS269, a highly potent tubulin inhibitor. In a phase 1 study of ARX788 in HER2-positive advanced breast cancer (CTR20171162/ACE-Breast-01), the objective response rate (ORR) was 74 % (14/19) at 1.5 mg/kg Q3W. Here we present the safety, tolerability, and antitumor activity of ARX788 in HER2-positive advanced gastric and gastroesophageal junction (GEJ) cancer in the phase 1 (ACE-Gastric-01) study. Methods: participants with HER2+ gastric/GEJ cancer were administrated with ARX788 intravenously at dose levels of 1.3, 1.5, and 1.7 mg/kg Q3W to determine the maximum tolerated dose and recommended phase 2 dose; and to evaluate the antitumor activity. Efficacy endpoints included objective response rate (ORR) and disease control rate (DCR) per RECIST v1.1. Results: As of Jan 29, 2021, a total of 23 participants including 9 at the 1.3 mg/kg and 14 at the 1.5 mg/kg received at least one dose of ARX788. All patients were heavily treated previously. The confirmed ORR was 42.9% and 46.2% at the 1.3 and 1.5 mg/kg, respectively. As of the cut-off date, six participants were still under treatment with two of them were treated for longer than 12 months. Most AEs were grade 1 or 2 and were manageable. There were 2 drug-related grade 3 AEs and no grade 4 or 5 AEs occurred. No DLT was observed and the MTD was not reached. The dose expansion at the 1.7 mg/kg Q3W cohort is still ongoing and the mature data will be presented later. Conclusions: ARX788 was well tolerated with promising antitumor activity in patients with HER2-positive advanced gastric and GEJ adenocarcinoma. Clinical trial information: CTR20190639. [Table: see text]

Phase 1 study of the liposomal formulation of eribulin (E7389-LF): Results from the advanced gastric cancer expansion cohort.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4025-4025
Author(s):  
Kensei Yamaguchi ◽  
Satoru Iwasa ◽  
Motohiro Hirao ◽  
Takashi Oshima ◽  
Kazuaki Harada ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Febrile Neutropenia ◽  
Safety Profile ◽  
Phase 1 ◽  
Objective Response ◽  
Safety Data ◽  
Metastatic Breast ◽  
Prior Treatment ◽  
Phase 1 Study ◽  
Expansion Cohort

4025 Background: Eribulin has proven efficacy in previously treated metastatic breast cancer and liposarcoma. E7389-LF is a new formulation that uses liposomes to encapsulate eribulin, which is anticipated to improve eribulin concentration in tumor tissues. In the dose-expansion part of a phase 1 study of E7389-LF, the safety profile was acceptable and 2 patients (pts) out of 10 with gastric cancer (GC) had an objective response. Thus, the GC cohort was expanded for further evaluation. Here, we report efficacy and safety data from the phase 1 expansion cohort of pts with advanced GC who were treated with E7389-LF. Methods: Eligible pts were those with GC who had no alternative standard or effective therapy options after ≥2 prior chemotherapy regimens. Target total enrollment was 32 pts (10 pts in the initial GC cohort plus an additional 22 pts in the expanded cohort). E7389-LF 2.0 mg/m2 was administered intravenously once every 3 weeks. Tumor responses were assessed every 6 weeks (± 1 week) by RECIST v1.1. Results: At data cutoff (Oct 16, 2020), 34 pts with GC were enrolled (10 pts in the initial GC cohort; 24 pts in the expanded GC cohort) with a median of 5 prior therapies (range, 2–11). Previous immune checkpoint inhibitor (ICI) therapy was reported for 26 (76.5%) pts. All pts were evaluable for objective response rate (ORR) and progression-free survival (PFS), and 30 pts were evaluable for overall survival (OS). Among all pts with GC, the ORR was 17.6% (95% CI 6.8–34.5) and the disease control rate was 79.4% (95% CI 62.1–91.3). Median PFS was 3.7 months (95% CI 2.7–4.3) and median OS was 7.6 months (95% CI 6.7–15.4). The ORRs were 19.2% (95% CI 6.6–39.4) in ICI-pretreated pts and 12.5% (95% CI 0.3–52.7) in pts without prior ICI therapy. Median PFS was similar regardless of prior treatment with ICIs (3.7 months [95% CI 2.7–5.6] in ICI-pretreated pts vs 3.4 months [95% CI 1.0–4.3] in pts without prior ICI therapy); however, the PFS rate at 6 months in ICI-pretreated pts was higher vs the rate in pts without prior ICI therapy (35.9% [95% CI 17.2–55.1] vs 0%, respectively). Median OS was also longer in ICI-pretreated pts (evaluable pts, n = 23) vs pts without prior ICI therapy (evaluable pts, n = 7) (10.0 months [95% CI 6.7–not estimable] vs 6.7 months [95% CI 3.1–8.5], respectively). Common grade ≥3 adverse events included neutropenia (41.2%), leukopenia (29.4%), and anemia (26.5%). In cycle 1, there were no cases of febrile neutropenia among the 22 pts treated with prophylactic peg-GCSF; among pts who did not receive prophylactic peg-GCSF, 16.7% of pts had febrile neutropenia. Conclusions: E7389-LF had a manageable safety profile and encouraging activity in pts with heavily treated GC. In pts with GC, prior treatment with ICIs might enhance the potential efficacy of E7389-LF. These results support further development of E7389-LF for advanced GC. Clinical trial information: NCT03207672.

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