Immunohistology expression of Trop-2 vs response

Serum concentration of intact sacituzumab govitecan and hRS7 IgG taken 30 min after injection for each of the 4 dose levels tested.

Trop-2 expression in archived tissue specimens from 6 patients enrolled in the clinical trial with sacituzumab govitecan.

Case Study 2: Response assessment by CT with Trop-2 expresssion by immunohistology

Time to progression in relation to the immunohistological score in 16 patients with diverse cancers enrolled in the sacituzumab govitecan trial who provided archival tissue specimens.

This file contains additional methods, including eligibility criteria, study design, pharmacokinetics and immunogenicity, and immunohistology, as well as additional results related to several notable patient narratives.

Evaluation of IHC staining vs best overall response in SCLC treated with 8 or 10 mg/kg starting dose of sacituzumab govitecan

Milatuzumab (hLL1) is a humanised IgG1κ antibody that reacts with a cell surface epitope of human CD74, the human leukocyte antigen (HLA) class-II associated invariant chain present on antigen-presenting cells (APCs), including B cells and dendritic cells.1 Although initially studied for oncologic malignancies,2–5 dysregulation of APCs may also occur in non-malignant disorders, and several preclinical studies showed that milatuzumab modestly inhibited B cell proliferation, enhanced spontaneous migration, alterations of adhesion molecule expression and chemotaxis important for lymphocyte recruitment,6 and also reduced production of interferon-α in stimulated peripheral blood mononuclear cells isolated from healthy donors and patients with systemic lupus erythematosus (SLE) (unpublished results). Migration inhibitory factor (MIF) is a cytokine that activates a multicomponent receptor comprising the CD74 ligand-binding …

6081 Background: Unselected pts with EC who progressed on prior chemotherapy have a poor prognosis with limited treatment options. SG is a novel antibody-drug conjugate that targets Trop-2, a cell surface glycoprotein highly expressed in many epithelial tumors. It is conjugated to deliver SN-38, the active metabolite of irinotecan, via a proprietary hydrolyzable linker. Preclinical studies show SG has activity against chemotherapy-resistant EC and significant bystander effect against EC with heterogenous Trop-2 expression (Perrone E. Mol Oncol. 2019). Methods: The phase I/II basket study (NCT01631552) evaluated pts unselected for Trop-2 with advanced solid tumors who received intravenous SG (days 1 and 8 of 21-day cycles), until progression or unacceptable toxicity. CT/MRI scans were obtained at 8-week intervals for response assessment by RECIST 1.1. We report results for mEC pts who progressed after ≥1 prior systemic therapy and were treated with SG 10 mg/kg. Endpoints include safety, objective response rate (ORR), clinical benefit rate (CBR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Results: 18 mEC pts (all women; 17 white and 1 black; median age 69 years [range, 41–76]) had a median 3.5 (range 2–6) prior lines of therapy. All pts received prior treatment with platinum therapies. At a median follow-up of 12.7 months, the ORR (95% CI) was 22.2% (6.4–47.6), with 4 partial responses. CBR (95% CI) was 44.4% (21.5–69.2), with 8 of 18 pts having either an objective response or stable disease ≥6 months. The DOR of responders ranged from 9.1 to 26.6 months, with 2 of 4 responders having a duration of ≥18 months. Median PFS (95% CI) was 3.2 months (1.9–9.4), and median OS (95% CI) was 11.9 months (4.7–not calculable). Key grade ≥3 TRAEs in the overall basket study safety population (n=495) included neutropenia (28%), neutrophil count decrease (14%), anemia (10%), diarrhea (8%), fatigue (6%), and febrile neutropenia (5%). A similar safety profile was seen in the mEC cohort. Conclusions: Median OS in unselected pts with mEC who progressed on prior platinum therapy is ~10 months with an ORR of ~10%. SG monotherapy showed clinical activity in pts with relapsed/refractory mEC, consistent with previous preclinical findings, and support further clinical investigation (NCT04251416). The phase II TROPiCS-03 (NCT03964727) study in pts with metastatic solid tumors selected based on elevated Trop-2 expression by a validated IHC assay will also provide further insights. Clinical trial information: NCT01631552.

354 Background: Patients (pts) with mUC who progress after platinum (PLT)-based chemotherapy and immune checkpoint inhibitor (CPI) therapy have poor outcomes and limited treatment options. Sacituzumab govitecan (SG) is a novel antibody-drug conjugate. It consists of a monoclonal antibody targeting Trop-2, an epithelial cell surface antigen overexpressed in UC, conjugated to the active metabolite of irinotecan (SN38). Methods: We performed a phase I/II basket study in pts with advanced solid tumors receiving intravenous SG administered on day 1 and 8 of 21-day cycles, until progression or unacceptable toxicity. CT/MRI scans were obtained at 8-week intervals for response assessment. We evaluated pts with mUC who progressed after ≥1 prior systemic therapy and were treated with SG at the 10 mg/kg dose level. Endpoints included safety, objective response rate (ORR) by RECIST 1.1, clinical benefit rate (CBR; complete response [CR], partial response [PR], or else SD ≥6-mo), and Kaplan-Meier estimated duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Results: 45 pts (41M/4F; median age 67, range 49-90; ECOG 0/1: 31%/69%) received a median of 2 (range: 1-6) prior treatment lines, including PLT-based chemotherapy (95%) and CPI (38%). 33 had visceral metastases involving liver (n=15), lung (n=27), and other organs (n=5). The ORR was 31% (14/45), with 2 CR and 12 PR. In pts with visceral involvement, the ORR was 27% (9/33). The ORR in CPI-treated pts was 23% (4/17). The median DOR was 12.6 mo (2 pts continuing >2 y), and the CBR was 47% (21/45). Median PFS and OS were 7.3 mo and 18.9 mo, respectively. The AE profile was consistent with prior reports. Grade ≥3 AEs in ≥5% of pts were neutropenia/neutrophil count decreased (38%), anemia (11%), hypophosphatemia (11%), diarrhea (9%), fatigue (9%), and febrile neutropenia (7%). Conclusions: SG demonstrated clinical activity in pts with relapsed/refractory mUC, including CPI-treated pts and pts with visceral disease. A single-arm, open-label, global phase 2 trial is underway to evaluate antitumor activity and safety of SG in advanced UC.(TROPHY-U-01; NCT03547973). Clinical trial information: NCT03547973.

EMBODY 1 (ClinicalTrials.gov identifier: NCT01262365) and EMBODY 2 (ClinicalTrials.gov identifier: NCT01261793) investigated the efficacy and safety of epratuzumab, a CD22‐targeted humanized monoclonal IgG antibody, in patients with systemic lupus erythematosus (SLE). The studies showed no significant difference from placebo in primary or secondary clinical outcome measures but did demonstrate B cell–specific immunologic activity. The aim of this post hoc analysis was to determine whether epratuzumab had a different clinical efficacy profile in SLE patients with versus those without an associated diagnosis of Sjögren's syndrome (SS).

1004 Background: Sacituzumab govitecan is a novel antibody-drug conjugate consisting of SN-38, the active metabolite of irinotecan, conjugated to a humanized mAb targeting Trop-2 (trophoblastic antigen-2), which is highly expressed in many epithelial cancers. A phase I/II basket trial (NCT01631552) investigated its activity in patients (pts) with advanced cancers, and we previously reported on pts with triple-negative mBC. Results in HR+/ HER2 negative (as per ASCO/CAP guidelines) mBC pts who had ≥ 1 prior hormonal therapy are presented here. Methods: Pts received sacituzumab govitecan at a dose of 10 mg/kg on days 1 & 8 of a 21-day cycle until progression or unacceptable toxicity. Eligibility included ≥ 1 prior line of standard therapy for metastatic disease, measurable disease by CT or MRI. Efficacy was assessed locally by RECIST 1.1. Adverse events (AE) were evaluated according to CTCAE v4.0, Results: Fifty-four pts with HR+/HER2- mBC (all female; median age 54 yrs, range 33-79) were accrued between 2/2015 and 6/2017. For metastatic disease, all pts received at least 2 prior treatments, with a median of 3 prior hormonal agents and 2 prior chemotherapy regimens. Prior treatments in any setting included taxane (93%), anthracycline (69%) and CDK 4/6 inhibitors (69%). 16 pts have died, 27 are in long-term follow-up and 11 still on treatment. The median number of doses was 11 (range 1-74). Treatment was generally well tolerated, with no treatment-related deaths. Based on currently available AE data, grade ≥ 3 toxicity (≥10%) included neutropenia and leukopenia; there was 1 case each of grade ≥ 3 diarrhea and febrile neutropenia. As of 12/31/2017 data cutoff, the overall response rate (ORR) was 31% (17 PRs/54) by local assessment, and the clinical benefit rate (CBR: PR+SD > 6 months) was 48%. For pts who received CDK inhibitors, ORR was 24% (9 PRs/37). Maturing durability of response and progression-free survival to be presented at the meeting. Conclusions: Sacituzumab govitecan as a single agent induced objective responses in heavily pre-treated HR+/HER2neg mBC, and was well tolerated with a safety profile consistent with previous reports. Clinical trial information: NCT01631552.

Citation for published version (Harvard): Gottenberg, J-E, Dörner, T, Bootsma, H, DevauchellePensec, V, Bowman, SJ, Mariette, X, Bartz, H, Oortgiesen, M, Shock, A, Koetse, W, Galateanu, C, Bongardt, S, Wegener, WA, Goldenberg, DM, MenoTetang, G, Kosutic, G & Gordon, C 2018, 'Efficacy of epratuzumab, an antiCD22 monoclonal igG antibody, in systemic lupus erythematosus patients with associated Sjögren's syndrome: posthoc analyses from the EMBODY trials', Arthritis and Rheumatology, vol. 70, no. 5, pp. 763-773. https://doi.org/10.1002/art.40425

Citation for published version (APA): Gottenberg, J-E., Doerner, T., Bootsma, H., Devauchelle-Pensec, V., Bowman, S. J., Mariette, X., ... Gordon, C. (2018). Efficacy of Epratuzumab, an Anti-CD22 Monoclonal IgG Antibody, in Systemic Lupus Erythematosus Patients With Associated Sjogren's Syndrome Post Hoc Analyses From the EMBODY Trials. Arthritis & Rheumatology, 70(5), 763-773. https://doi.org/10.1002/art.40425

Abstract Introduction: Sacituzumab govitecan (IMMU-132) is an antibody-drug conjugate (ADC) delivering SN-38, a topoisomerase-1 inhibitor, to mSCLC cells expressing Trop-2. We are studying the safety/tolerability and efficacy of IMMU-132 in patients with relapsed/refractory mSCLC who had received a platinum-containing first-line regimen. Experimental Procedure: Patients received 8 or 10 mg/kg IV IMMU-132 on days 1 and 8 of repeated 21-day cycles. Objective tumor response (ORR) was determined by RECISTv1.1 in patients receiving at least one treatment cycle, and progression-free survival (PFS) and overall survival (OS) in all patients by Kaplan-Meier methods. (ClinicalTrials.gov, NCT01631552) Summary of New Unpublished Data: A total of 53 patients (23/30 M/F, median 63 years old) with 1-7 (median 2) prior lines of therapy were enrolled between November, 2013 and June, 2016. Immunohistochemistry of evaluable archival tumor specimens for Trop-2 expression (N=26) showed 92% positivity (61% moderately to strongly positive). They received up to 32 treatment cycles (median 5); the most frequent Grade >3 adverse events were neutropenia (34%), fatigue (13%) and diarrhea (9%). Four patients did not complete one cycle of treatment. In the other 49 patients (14 at 8 mg/kg, 35 at 10 mg/kg), there were 7 confirmed PRs and 21 SDs as best response. The resulting ORR rate was 14% (7/49), with a median duration and time-to-progression of a response of 4.0 and 7.6 mos, respectively, and the clinical benefit rate (PR+SD >4 mos) was 35% (17/49). The ORR rate was similar in pts who were sensitive (>3 mos response) or resistant (<3 mos) to 1st-line therapy [13% (3/23) vs 15% (4/26), respectively]. In 2nd-line setting, IMMU-132 had a confirmed ORR rate of 14% (3/21), and a clinical benefit rate of 38% (8/21). This compares well to recent results with topotecan having an ORR of 13-16% in 2nd-line. Comparing dose levels, ORR was 17% (6/35) with 10 mg/kg vs 7% (1/14) with 8 mg/kg, with little difference in toxicity. Median PFS and OS in all 53 patients was 3.7 mos (95% CI, 2.0 - 4.3) and 7.0 mos (95% CI, 5.5 - 8.3), respectively, and included 6 long-term survivors (12.7 - 25.4 months). No antibody response to the ADC or antibody was detected despite multiple therapy cycles. Conclusion: These interim results demonstrate encouraging activity in patients with late-stage mSCLC having a high expression of Trop-2. Even after failing 1st-line platinum chemotherapy or 2nd-line topotecan therapy, IMMU-132 showed promising activity, and has a manageable toxicity profile. IMMU-132 given at 10 mg/kg on day 1 and 8 of a 3-week cycle was selected for further clinical evaluation in this population. Citation Format: Jhanelle E. Gray, Rebecca S. Heist, Alexander N. Starodub, D. Ross Camidge, Ebenezer Kio, Gregory Masters, W. Thomas Purcell, Michael J. Guarino, Jamal Misleh, Charles J. Schneider, Bryan J. Schneider, Allyson J. Ocean, Tirrell Johnson, Leena Gandhi, Kevin Kalinsky, Serengulam V. Govindan, Pius Maliakal, Boyd Mudenda, William A. Wegener, Robert M. Sharkey, David M. Goldenberg. Phase 2 study of sacituzumab govitecan (IMMU-132), an anti-Trop-2/SN-38 antibody-drug conjugate (ADC), in patients with pretreated metastatic small-cell lung cancer (mSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT155. doi:10.1158/1538-7445.AM2017-CT155

BACKGROUNDSacituzumab govitecan (IMMU‐132), an antitrophoblastic cell‐surface antigen (anti‐Trop‐2) humanized antibody‐SN‐38 conjugate, had encouraging efficacy in the phase 1 clinical trial. This report further examines the pharmacokinetics and safety of multiple cycles of IMMU‐132 at doses of 8 or 10 mg/kg in patients with diverse advanced epithelial cancers.METHODSPatients who had multiple prior therapies received IMMU‐132 on days 1 and 8 of 21‐day treatment cycles. Trop‐2 staining of archived tumor specimens, clearance of IMMU‐132 and its constituents (ie, immunoglobulin G [IgG], SN‐38 [a camptothecin, the active component of irinotecan], and glucuronidated SN‐38 [SN‐38G]), antibody responses, and uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) levels were determined. Safety was assessed according to Common Terminology Criteria for Adverse Events version 4.0, and responses were assessed using Response Evaluation Criteria in Solid Tumors, version 1.1.RESULTSPatients with diverse metastatic cancers who received IMMU‐132 at 8 mg/kg (n = 81) and 10 mg/kg (n = 97) were examined. Trop‐2 was positive in 93% of the available specimens. IMMU‐132 cleared with a half‐life of approximately 11 to 14 hours, reflecting the release of SN‐38 from the conjugate; IgG cleared more slowly (half‐life, approximately 103‐114 hours). Most SN‐38 in the serum (>95%) was bound to IgG. SN‐38G concentrations were lower than SN‐38 concentrations. Dose‐limiting neutropenia after the first cycle was not correlated with SN‐38 in serum or with UGT1A1 genotype. No antibody responses were detected. Objective responses were observed in several indications, including metastatic triple‐negative breast cancer, confirming that 10 mg/kg produced an encouraging overall response.CONCLUSIONSSacituzumab govitecan has a predictable pharmacokinetic profile and manageable toxicity at doses of 8 and 10 mg/kg. With objective responses and a good therapeutic index at 10 mg/kg, this dose was chosen for future development. Cancer 2017;123:3843–3854. © 2017 American Cancer Society

Purpose Trop-2, expressed in most triple-negative breast cancers (TNBCs), may be a potential target for antibody-drug conjugates. Sacituzumab govitecan, an antibody-drug conjugate, targets Trop-2 for the selective delivery of SN-38, the active metabolite of irinotecan. Patients and Methods We evaluated sacituzumab govitecan in a single-arm, multicenter trial in patients with relapsed/refractory metastatic TNBC who received a 10 mg/kg starting dose on days 1 and 8 of 21-day repeated cycles. The primary end points were safety and objective response rate; secondary end points were progression-free survival and overall survival. Results In 69 patients who received a median of five prior therapies (range, one to 12) since diagnosis, the confirmed objective response rate was 30% (partial response, n = 19; complete response, n = 2), the median response duration was 8.9 (95% CI, 6.1 to 11.3) months, and the clinical benefit rate (complete response + partial response + stable disease ≥ 6 months) was 46%. These responses occurred early, with a median onset of 1.9 months. Median progression-free survival was 6.0 (95% CI, 5.0 to 7.3) months, and median overall survival was 16.6 (95% CI, 11.1 to 20.6) months. Grade ≥ 3 adverse events included neutropenia (39%), leukopenia (16%), anemia (14%), and diarrhea (13%); the incidence of febrile neutropenia was 7%. The majority of archival tumor specimens (88%) were moderately to strongly positive for Trop-2 by immunohistochemistry. No neutralizing antibodies to the ADC or antibody were detected, despite repeated cycles developed. Conclusion Sacituzumab govitecan was well tolerated and induced early and durable responses in heavily pretreated patients with metastatic TNBC. As a therapeutic target and predictive biomarker, Trop-2 warrants further research.

Background . mTNBC has an aggressive course with limited effective therapy options and a median progression-free survival (PFS) of 2-4 months (mos) with standard therapy. Sacituzumab govitecan (IMMU-132) is an ADC targeting Trop-2, an antigen present in many epithelial cancers, including TNBC, and delivering SN-38, a topoisomerase I inhibitor as its therapeutic moiety. IMMU-132 was awarded Breakthrough Therapy designation by FDA based on its previously reported activity in relapsed/refractory mTNBC patients. Here we present updated results from the mTNBC cohort of an ongoing phase I/II study (ClinicalTrials.gov, NCT01631552). Methods . mTNBC patients (pts) received IMMU-132 10 mg/kg on days 1 and 8 every 21 days. Trop-2 expression was not required for enrollment, but available tumor specimens underwent immunohistological (IHC) testing. Efficacy was assessed locally by RECIST 1.1; ORR, PFS and overall survival (OS) were determined for all pts. Pharmacokinetic parameters were estimated in select pts with adequate blood sampling. Immunogenicity to IMMU-132 was examined in all pts. Results . We previously reported preliminary efficacy results in 51 mTNBC patients. Here we present data on 69 patients with data cutoff June 5, 2016. Median age was 56 years (31-81) and a median of 5 prior therapies (range 1-12), with 66 evaluable for response; ORR was 29% (19/66) 2 confirmed complete (CR) and 17 confirmed partial responses (PR). The median intention-to-treat PFS is 5.6 mos (95% CI, 3.6-7.1 mos) and median OS is 14.3 mos (95% CI, 10.5-18.8 mos). PRs included 2 pts whose tumors did not respond to anti-PD-L1 therapy. The duration of response in the 19 confirmed responders (8 continuing therapy) is 11.5 mos (95% CI = 7.6 to 12.7). The clinical benefit rate (CR+PR+SDu003e6 mos) for the 66 assessable patients is currently 45.5%. The majority (88%) of archival tumor specimens were moderately (2+) to strongly (3+) positive by IHC for Trop-2, precluding using Trop-2 expression as a selection criterion. Among current adverse events, grade u003e3 drug-related toxicities included neutropenia (35%), leukopenia (16%), anemia (13%), vomiting (9%), diarrhea (10%), and febrile neutropenia (4%). Clearance kinetics in 8 pts showed IMMU-132 and IgG had a terminal half-life of 15.3 ± 2.7 h and 86.5 ± 40.5 h, respectively, with area under the curve for free SN-38 (unbound) only 3% of the total amount of SN-38 (e.g., IgG bound). Thus, most SN-38 remains bound to the conjugate, and is released at a rate predicted from in vitro serum stability studies. No pt developed anti-IMMU-132 antibodies. Conclusion The Trop-2-targeting ADC, IMMU-132, delivering cytotoxic doses of SN-38, shows high objective and durable tumor responses with manageable toxicity in heavily-pretreated pts with mTNBC in this updated cohort, supporting further development in this population with an unmet medical need. Citation Format: Bardia A, Diamond JR, Mayer IA, Isakoff SJ, Abramson V, Starodub AN, O9Shaughnessy J, Kalinsky K, Moroose R, Shah N, Juric D, Shapiro GI, Guarino M, Ocean AJ, Messersmith WA, Berlin JD, Wegener WA, Sharkey RM, Goldenberg DM, Vahdat LT. Sacituzumab govitecan (IMMU-132), an anti-Trop-2-SN-38 antibody-drug conjugate (ADC) for the treatment of relapsed/refractory, metastatic triple-negative breast cancer (mTNBC): Updated results [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 P4-22-15.