Background SERDs belong to a class of ER-targeted therapies that antagonize and degrade ERs, including in ER-dependent tumors resistant to other endocrine therapies (ET). This study (AMEERA-1; NCT03284957) investigates SAR439859, an oral SERD, as monotherapy and (in ongoing cohorts) in combination with targeted therapies in patients (pts) with ER+/HER2- mBC. Here we report updated safety and antitumor activity with SAR439859 monotherapy, including exploratory analyses by prior therapy and ESR1 status. Methods This open-label, phase 1/2, first-in-human study assessed SAR439859 as monotherapy in Parts A (dose escalation 20-600 mg once daily [QD]) and B (dose expansion with recommended dose at 400 mg QD). Eligible pts were heavily pre-treated, postmenopausal women with ER+/HER2- mBC and measurable disease who received ≥6 months of prior ET in the advanced setting. Prior chemotherapy, mammalian target of rapamycin inhibitors (mTORi) and cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) for advanced disease were allowed. This analysis pooled data from pts receiving SAR439859 ≥150 mg (Part A) and 400 mg (Part B), administered in 28-day cycles. Antitumor activity was assessed by the objective response rate and clinical benefit rate (CBR: complete response [CR], partial response [PR] and stable disease [SD] ≥24 weeks) per RECIST v1.1, determined by investigators. Analyses by prior therapy and baseline ESR1 mutation status were performed. Safety was also evaluated. Results Pts (n = 62; Part A: 13; Part B: 49) had a median age of 63 (range 37-88) years and ECOG PS 0 (59.7%) or 1 (40.3%); 93.5% had visceral metastases. Pts had a median of 2 (range 1-8) prior lines of therapy in the advanced setting (48.4% had ≥3 prior lines): all had prior ET and 72.6% had prior targeted therapy. SAR439859 monotherapy showed antitumor activity in the response-evaluable population (n = 59) and in subset populations with ≤3 prior lines (n = 33) or without prior mTORi, CDK4/6i, or SERD (n = 14) (Table 1). For pts with ESR1 status (n = 58), CBR with SAR439859 was comparable in ESR1 wild-type (36.7%) and mutant mBC (32.1%), with similar results in subpopulations. Treatment-related adverse events (TRAEs) occurred in 62.9% of pts (all grade 1-2); none resulted in SAR439859 discontinuation. Most frequent TRAEs were hot flush (16.1%); constipation and arthralgia (each 9.7%); decreased appetite, vomiting, diarrhea and nausea (each 8.1%); and fatigue (6.5%). Conclusions Among heavily pre-treated pts, SAR439859 demonstrated antitumor activity, similar to historical single-agent fulvestrant activity in less heavily pre-treated pts with advanced/mBC (2L+ setting; no prior targeted agents) (indirect comparison). In both subsets of pts with fewer prior advanced lines of therapy, SAR439859 showed trends of greater clinical activity versus historical fulvestrant activity. SAR439859 had a favorable safety profile with limited TRAEs. No safety signals of cardiac or ocular toxicities were observed. Ongoing parts of the study are investigating SAR439859 in combination with targeted therapies. Based on the monotherapy results, a randomized phase 2 study is investigating SAR439859 compared with physician’s choice in a 2L+ setting (AMEERA-3; NCT04059484). Funding: Sanofi. Antitumor activity overall and in subpopulations by prior lines of therapy (Parts A+B)Overall population (A+B)≤3 Prior advanced linesWithout prior targeted therapy(n = 59)a(n = 33)b(n = 14)cBOR, n (%)–CR000–PR5 (8.5)5 (15.2)3 (21.4)–SD24 (40.7)15 (45.5)8 (57.1)–PD30 (50.8)13 (39.4)3 (21.4)ORR, n (%)5 (8.5)5 (15.2)3 (21.4)CBR, n (%)20 (33.9)14 (42.4)9 (64.3)aPooled cohort (A ≥150 mg QD + B);bSubset of pooled cohort with ≤3 prior lines in the metastatic setting, including ≤1 of either prior chemotherapy or CDK4/6i and no prior mTORi; cSubset of pooled cohort with no prior mTORi, CDK4/6i, or fulvestrant.BOR, best overall response; CBR, clinical benefit rate; CR, complete response; ORR, objective response rate; PD, progressive disease; PR, partial response; SD, stable disease. Citation Format: Hannah M Linden, Mario Campone, Aditya Bardia, Gary A Ulaner, Alice Gosselin, Séverine Doroumian, Vasiliki Pelekanou, Marina Celanovic, Sarat Chandarlapaty. A phase 1/2 study of SAR439859, an oral selective estrogen receptor (ER) degrader (SERD), as monotherapy and in combination with other anti-cancer therapies in postmenopausal women with ER-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC): AMEERA-1 [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD8-08.
Plerixafor + granulocyte-colony stimulating factor (G-CSF) is administered to patients with lymphoma who are poor mobilizers of hematopoietic stem cells (HSCs) in Europe. This international, multicenter, non-interventional registry study (NCT01362972) evaluated long-term follow-up of patients with lymphoma who received plerixafor for HSC mobilization versus other mobilization methods. Propensity score matching was conducted to balance baseline characteristics between comparison groups. The following mobilization regimens were compared: G-CSF + plerixafor (G + P) versus G-CSF alone; G + P versus G-CSF + chemotherapy (G + C); and G-CSF + plerixafor + chemotherapy (G + P + C) versus G + C. The primary outcomes were progression-free survival (PFS), overall survival (OS), and cumulative incidence of relapse (CIR). Overall, 313/3749 (8.3%) eligible patients were mobilized with plerixafor-containing regimens. After propensity score matching, 70 versus 36 patients were matched in the G + P versus G-CSF alone cohort, 124 versus 124 in the G + P versus G + C cohort, and 130 versus 130 in the G + P + C versus G + C cohort. For both PFS and OS, the upper bound of confidence interval for the hazard ratio was >1.3 for all comparisons, implying that non-inferiority was not demonstrated. No major differences in PFS, OS, and CIR were observed between the plerixafor and comparison groups.
AMEERA-1 is a Phase 1/2 open-label single-arm study evaluating once-daily (QD) amcenestrant, an orally bioavailable selective estrogen receptor (ER) degrader, in postmenopausal women with ER+/HER2− advanced breast cancer (NCT03284957), who were mostly heavily pretreated (including targeted therapies and fulvestrant). In the dose escalation phase (Part A: n = 16), patients received amcenestrant 20-600 mg QD. Based on absence of dose-limiting toxicities, paired functional 18F-fluoroestradiol positron emission tomography, and pharmacokinetics, 400 mg QD was selected as recommended Phase 2 dose (RP2D) for the dose expansion phase (Part B: n = 49). No Grade ≥3 treatment-related adverse events or clinically significant cardiac/eye toxicities were reported. The Part B primary endpoint, confirmed objective response rate (ORR) was 3/45 at the interim analysis and 5/46 (10.9%) at the final analysis. The overall clinical benefit rate (CBR) was 13/46 (28.3%). CBRs among patients with baseline wild-type and mutated ESR1 were 9/26 (34.6%) and 4/19 (21.1%), respectively. Paired tumor biopsy and cell-free DNA analyses revealed ER inhibition and degradation, and a reduction in detectable ESR1 mutations, including Y537S. In conclusion, amcenestrant at RP2D of 400 mg QD for monotherapy is well-tolerated with no dose-limiting toxicities, and demonstrates preliminary antitumor activity irrespective of baseline ESR1 mutation status.
For patients with metastatic colorectal cancer (mCRC) that have failed a first-line oxaliplatin-based regimen, the preferred treatment option is an irinotecan-based regimen. This prospective, observational, noncomparative, post-authorization safety study (OZONE) evaluated the safety and effectiveness of aflibercept plus fluorouracil, leucovorin, and irinotecan (FOLFIRI) in patients with mCRC treated in daily practice after failure of an oxaliplatin-based regimen. Patients were grouped by age, renal impairment, hepatic impairment, race, number, and type of prior anticancer therapy. Of 766 treated patients enrolled, 59.5% were male, 94.8% had an Eastern Cooperative Oncology Group performance status of 0-1, all received previous chemotherapy (97.8% including oxaliplatin), and 58.6% had prior exposure to bevacizumab. At least one grade ≥ 3 treatment-emergent adverse event (TEAE) was reported in 68.3% of patients. Neutropenia, hypertension, diarrhea, and asthenia were the most frequently occurring grade ≥ 3 TEAEs. Antivascular endothelial growth factor class events were infrequent. Subgroup analyses did not reveal major differences in the safety profile according to age, renal and hepatic status, race, or prior anticancer therapy. For the total population, median overall survival was 12.5 months, median progression-free survival was 6.1 months, and overall response rate was 16.3%. Aflibercept in combination with FOLFIRI is a safe and efficacious regimen administered in current clinical practice to patients with mCRC previously treated with oxaliplatin. The study results, conducted in real-world clinical practice with a less selected patient population, are aligned with the VELOUR (NCT00561470) trial and no new safety issues were identified.
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]
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