Weise, Amy

Abstract Background LIV-1, a transmembrane protein and downstream target of STAT3, is highly expressed in breast cancer cells. It is associated with lymph node involvement and metastatic progression. SGN-LIV1A is an anti-LIV-1 antibody conjugated via a protease-cleavable linker to monomethyl auristatin E (MMAE). Upon binding to cell-surface LIV-1, SGN-LIV1A is internalized and releases MMAE, which disrupts microtubulin and induces apoptosis. Methods This ongoing, phase 1 study evaluates safety, tolerability, pharmacokinetics, and antitumor activity of SGN-LIV1A (q3wks IV) in women with LIV-1-positive, unresectable, locally advanced or metastatic breast cancer (LA/MBC) (NCT01969643). Patients (pts) with measurable disease and ≥2 prior cytotoxic regimens for LA/MBC are eligible. Pts with ≥ Grade 2 neuropathy are excluded. Response is assessed per RECIST v1.1; pts with stable disease (SD) or better can continue treatment until disease progression or intolerable toxicity. At completion of dose escalation in hormone receptor-positive/HER2-negative (HR+/HER2–) and triple-negative (TN) pts, expansion cohorts were opened to further evaluate safety and antitumor activity of monotherapy in TN pts. Tumor biopsies are evaluated for LIV-1 expression. Results To date, 69 pts (18 HR+/HER2–, 51 TN) have received a median of 3 cycles (range, 1–12) of SGN-LIV1A at doses of 0.5–2.8 mg/kg. Median age was 56 yrs. Pts had a median of 3 prior cytotoxic regimens for LA/MBC; 58 had visceral disease and 37 had bone metastases. No dose-limiting toxicities (DLTs) occurred in 19 DLT-evaluable pts; maximum tolerated dose was not exceeded at 2.8 mg/kg. Expansion cohorts of TN pts were opened at 2.0 and 2.5 mg/kg. Treatment-emergent adverse events (AEs) reported in ≥25% of pts were fatigue (59%), nausea (51%), peripheral neuropathy (44%), alopecia (36%), decreased appetite (33%), constipation (30%), abdominal pain, diarrhea, and neutropenia (25% each). Most AEs were Grade 1/2; AEs ≥ Grade 3 included neutropenia (25%) and anemia (15%). Febrile neutropenia occurred in 2 pts whose total dose exceeded 200 mg per cycle, including 1 treatment-related death due to sepsis. No other treatment-related deaths occurred on-study. Seven pts discontinued treatment due to AEs. In dose escalation, activity was observed in 17 efficacy evaluable (EE) HR+/HER2- pts, with a disease control rate (DCR= CR+PR+SD) of 59% (10 SD), including 1 pt with SD ≥24 wks. Among the 44 EE TN pts (dose escalation plus expansion cohorts), the objective response rate (ORR) was 32% (14 PR) with a confirmed PR rate of 21%, DCR was 64% (14 PR, 14 SD), and clinical benefit rate (CBR=CR+PR+SD ≥24 wks) was 36% (16 pts). For TN pts, median PFS was 11.3 wks (95% CI: 6.1, 17.1); 10 pts remain on treatment. Of 631 MBC tumor samples of all clinical subtypes evaluated for LIV-1, 91% were positive; 75% had moderate-to-high expression (H-score ≥100). Conclusions LIV-1 is expressed in almost all MBC tumors. SGN-LIV1A monotherapy was generally well tolerated and showed encouraging antitumor activity in heavily pretreated TN MBC, with a PR rate of 32%, confirmed PR rate of 21%, and CBR (≥24 wks) of 36%. Response duration data continue to evolve. Enrollment continues in the TN monotherapy expansion cohort. Citation Format: Modi S, Pusztai L, Forero A, Mita M, Miller KD, Weise A, Krop I, Burris III H, Kalinsky K, Tsai M, Liu MC, Hurvitz SA, Wilks S, Ademuyiwa F, Diab S, Han HS, Kato G, Nanda R, O'Shaughnessy J, Kostic A, Li M, Specht J. Phase 1 study of the antibody-drug conjugate SGN-LIV1A in patients with heavily pretreated triple-negative metastatic breast cancer [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 PD3-14.

Abstract Background LIV-1, a transmembrane protein and downstream target of STAT3, is highly expressed in breast cancer cells. It is associated with lymph node involvement and metastatic progression. SGN-LIV1A is an anti-LIV-1 antibody conjugated via a protease-cleavable linker to monomethyl auristatin E (MMAE). Upon binding to cell-surface LIV-1, SGN-LIV1A is internalized and releases MMAE, which binds to tubulin and induces G2/M arrest and apoptosis. Methods This is an ongoing, phase 1 dose-escalation study evaluating safety, tolerability, pharmacokinetics, and antitumor activity of SGN-LIV1A (q3 wks IV) in women with LIV-1-positive, unresectable, locally advanced or metastatic breast cancer (LA/MBC) (NCT01969643). Patients (pts) with measurable disease and ≥2 prior cytotoxic regimens for LA/MBC were eligible. Pts with ≥Grade 2 neuropathy were excluded. Response was assessed per RECIST v1.1; pts with stable disease (SD) or better could continue treatment until disease progression or intolerable toxicity. At completion of dose escalation in hormone receptor-positive/HER2-negative (HR+/HER2–) and triple-negative (TN) pts, expansion cohorts were opened to further evaluate safety and antitumor activity of monotherapy in TN pts and combination therapy with trastuzumab (Tz) in HER2-positive (HER2+) pts. Pre- and post-treatment tumor biopsies were done to evaluate LIV-1 expression and other correlative endpoints. Results To date, 39 pts (18 HR+/HER2–, 21 TN) have received a median of 3 cycles (range, 1–10) of SGN-LIV1A monotherapy at doses of 0.5–2.8 mg/kg. Median age was 57 yrs (range, 33–79). At baseline, pts had a median of 4 prior cytotoxic regimens for LA/MBC (range, 2–8); 36 had visceral disease and 25 had bone involvement. No dose-limiting toxicities (DLT) occurred in 19 DLT-evaluable pts; maximum tolerated dose was not exceeded at 2.8 mg/kg. Treatment-emergent adverse events (AEs) reported in ≥30% of pts were: fatigue (64%), nausea (54%), alopecia (46%), decreased appetite (41%), constipation (39%), neutropenia (33%), and vomiting (31%). Peripheral neuropathy was reported in 9 pts (23%). Most AEs were Grade 1/2, except neutropenia (all ≥Grade 3). Four pts discontinued treatment due to AEs (acute respiratory distress syndrome, nausea, pneumonia, tachycardia). In dose escalation, modest activity was observed in 17 efficacy evaluable (EE) HR+/HER2- pts, with a disease control rate (DCR) of 59% (10 SD), including 1 pt with SD≥24 wks. Among the 17 EE TN pts (dose escalation plus cohort expansion), the overall response rate (ORR) was 41% (7 PR), DCR was 82% (7 PR, 7 SD) and clinical benefit rate (CBR=OR+SD≥24 wks) was 53% (9 pts). For TN pts, median PFS was 17.1 wks (95% CI: 6.0, 18.4); 6 pts remain on treatment. Of 281 MBC tumor samples evaluated for LIV-1, 93% were positive; 81% had moderate-to-high expression (H-score ≥100). Conclusions LIV-1 is expressed in almost all MBC tumors. SGN-LIV1A monotherapy has been generally well tolerated and shown encouraging antitumor activity in heavily pretreated TN MBC, with a PR rate of 41% and a CBR at ≥24 wks of 53%. Response duration data continue to evolve. Enrollment continues in the TN monotherapy expansion cohort and the HER2+ combination cohort with Tz. Citation Format: Forero-Torres A, Modi S, Specht J, Miller K, Weise A, Burris III H, Liu M, Krop I, Pusztai L, Kostic A, Li M, Mita M. Phase 1 study of the antibody-drug conjugate (ADC) SGN-LIV1A in patients with heavily pretreated metastatic breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-12-04.

Abstract Background LIV-1, a multispan transmembrane protein and downstream target of STAT3, is highly expressed in breast cancer cells (Sussman 2014). It has been associated with lymph node involvement and linked with malignant progression to metastasis (Manning 1994). SGN-LIV1A is an anti-LIV-1 antibody conjugated via a protease-cleavable linker to monomethyl auristatin E (MMAE). Upon binding to cell-surface LIV-1, SGN-LIV1A is internalized and releases MMAE, which binds to tubulin and induces G2/M arrest and apoptosis. Methods A phase 1, open-label, dose-escalation study is ongoing to evaluate the safety, tolerability, antitumor activity, pharmacokinetics (PK), and the maximum tolerated dose (MTD) of SGN-LIV1A monotherapy (q3 wks IV) in women with LIV-1-positive, metastatic breast cancer (MBC) (NCT01969643). Patients (pts) with either hormone receptor-positive/HER2-negative (HR+/HER2–) or triple-negative (TN) disease were eligible if they had measurable disease and received ≥2 prior cytotoxic regimens in the metastatic setting. Pts with ≥ Grade 2 neuropathy were excluded. Response was assessed per RECIST v1.1, and pts with stable disease (SD) or better were eligible to continue treatment until disease progression or intolerable toxicity. Fresh tumor biopsies were obtained pre- and post-treatment to evaluate the LIV-1 expression-response relationship, mechanism of action, and tumor sensitivity to SGN-LIV1A. Results To date, 21 pts (17 HR+/HER2–, 4 TN) have received a median of 3 cycles (range, 1–7) of SGN-LIV1A at doses of 0.5–2.8 mg/kg. Median age was 58 yrs (range, 34–73), and pts had a median of 8 prior systemic metastatic therapies (range, 2–15). At baseline, 19 pts had visceral disease and 15 had bone involvement. No dose-limiting toxicities (DLTs) in Cycle 1 were observed in the 18 DLT-evaluable pts; MTD has not yet been identified. Treatment-emergent adverse events (AEs) reported in ≥30% of pts were primarily Grade 1/2 in severity and were: nausea (57%), fatigue and peripheral neuropathy (43% each), alopecia (38%), and vomiting (33%). Two pts discontinued treatment due to AEs (1 nausea, 1 tachycardia). Preliminary PK data suggest a linear increase in antibody-drug conjugate (ADC) exposure with increasing dose. In the 19 efficacy-evaluable pts, the overall response rate (ORR) was 11% (2 partial responses [PRs]) with clinical benefit of SD or better achieved in 63% (2 PR, 10 SD) of pts. Of note, all 4 pts with TN MBC achieved clinical benefit: 2 PR and 2 SD. Currently, the median duration of clinical benefit is 12.7 wks (range, 6.1–26.3). Four pts remain on treatment. To date, of the 179 MBC tumor specimens evaluated for LIV-1, 156 (87%) were LIV-1-positive; moderate-to-high LIV-1 expression (H-score ≥100) was present in 91% (94 of 103) of HR+/HER2– and 81% (47 of 58) of TN samples. Conclusions LIV-1 is expressed in the majority of metastatic breast cancer tissue samples, with moderate-to-high expression in both HR+/HER2- and TN disease. To date, SGN-LIV1A monotherapy has been generally well tolerated and resulted in a clinical benefit of SD or better in 63% of these heavily pre-treated pts, including 2 PRs in the 4 TN MBC pts. Response duration data continue to evolve. Clinical subtype-specific expansion cohorts are planned. Citation Format: Forero A, Burris III H, Mita M, Specht J, Weise A, Liu MC, Modi S, Pusztai L, Kostic A, Yang J, Li M, Hengel S, Miller K. Interim analysis of a phase 1 study of the antibody-drug conjugate SGN-LIV1A in patients with metastatic breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-14-05.