anti-TROP2 Antibody Research Articles

EVOKE-02: A phase 2 study of sacituzumab govitecan (SG) plus pembrolizumab (pembro) with or without platinum chemotherapy in first-line metastatic non–small cell lung cancer (NSCLC).

TPS9146 Background: Most patients (pts) with advanced NSCLC do not harbor genomic alterations associated with approved first-line targeted therapies. The standard of care for these pts is a programmed death (ligand)-1 (PD-[L]1) inhibitor alone, if the tumor highly expresses PD-L1, or in combination with platinum doublet chemotherapy, independent of PD-L1 expression. However, most pts do not respond to these therapies or achieve only a transient response, highlighting an unmet need. SG is an antibody-drug conjugate composed of an anti–Trop-2 antibody coupled to the cytotoxic SN-38 payload via a proprietary, hydrolyzable linker. In the phase 1/2 IMMU-132-01 basket study (NCT01631552), SG demonstrated an objective response rate (ORR) of 17% and median overall survival (OS) of 9.5 mo, with a manageable safety profile in 54 pts with metastatic NSCLC after multiple prior therapies (Heist RS, et al. J Clin Oncol. 2017). We hypothesize that combining SG with pembro or with pembro + platinum chemotherapy will improve outcomes for pts with advanced NSCLC. Methods: EVOKE-02 (NCT05186974) is an open-label, multicenter, multicohort, global phase 2 study evaluating SG plus pembro with or without carboplatin (carbo) or cisplatin (cis) in advanced NSCLC. Key eligibility criteria include age ≥18 y, stage IV NSCLC at enrollment, measurable disease by RECIST v1.1, ECOG performance status of 0 or 1, and adequate organ function. Pts must not have actionable genomic alterations and must not have received prior systemic therapy for metastatic NSCLC. Up to 164 pts will be enrolled. SG plus pembro will be assessed in squamous/nonsquamous NSCLC with Tumor Proportion Score (TPS) ≥50% (cohort A, ̃30 pts) and TPS < 50% (cohort B, ̃30 pts), and SG plus pembro with carbo/cis in nonsquamous (cohort C, ̃40 pts) and squamous (cohort D, ̃40 pts) NSCLC regardless of PD-L1 expression. Pts are randomly assigned if cohorts enrolling concurrently have overlapping eligibility. SG will be administered intravenously (IV) at 10 mg/kg on d 1 and 8 until disease progression or unacceptable toxicity, pembro 200 mg IV on d 1 for up to 35 cycles, carbo AUC 5 or cis 75 mg/m2 on d 1 for up to 4 cycles in 21-d cycles. A safety run-in will be conducted for cohorts C and D (up to 24 pts each) to determine the optimal SG dose by dose de-escalation. Choice of platinum will be based on preliminary efficacy in safety run-in. The primary endpoints are ORR assessed by independent review per RECIST v1.1 and the incidence of dose-limiting toxicities per dose for the first 21 d of the safety run-in to determine the recommended phase 2 dose of SG in combination with pembro and a platinum. Key secondary endpoints include progression-free survival by independent review, OS, duration of response, disease control rate, and safety. This study is open for recruitment and is enrolling globally. Clinical trial information: NCT05186974.

Sacituzumab govitecan (SG) versus treatment of physician’s choice (TPC) in patients (pts) with previously treated, metastatic triple-negative breast cancer (mTNBC): Final results from the phase 3 ASCENT study.

1071 Background: Treatment goals for pts with metastatic breast cancer include extended survival and improved quality of life (QoL). SG is an antibody-drug conjugate composed of an anti–Trop-2 antibody coupled to the cytotoxic SN-38 payload via a proprietary, hydrolyzable linker. SG received FDA approval for pts with mTNBC who received ≥2 prior chemotherapies (at least 1 in the metastatic setting). In the pivotal phase 3 ASCENT study (NCT02574455), SG demonstrated a significant survival benefit over single-agent chemotherapy TPC in the primary analysis population of pts with second line or greater (2L+) mTNBC without known brain metastases at baseline (Bardia A et al. NEJM 2021) and QoL (Loibl S. et al. ESMO 2021). With additional follow up, we present the final data on efficacy, including overall survival (OS), safety, and QoL. Methods: Pts with mTNBC refractory or relapsing after ≥2 prior chemotherapies with at least 1 in the metastatic setting were randomized 1:1 to receive SG (10 mg/kg IV on days 1 and 8, every 21 days) or TPC (capecitabine, eribulin, vinorelbine, or gemcitabine) until disease progression or unacceptable toxicity. Primary endpoint was progression-free survival (PFS) per RECIST 1.1 by independent review in pts without known brain metastases at baseline. Key secondary endpoints included OS, safety, and health-related QoL. Safety was analyzed in pts who received ≥1 dose of study drug. Results: Of 529 pts enrolled, 468 did not have known brain metastases at baseline (median age: 54 y [range, 27-82]; median prior lines: 4 [range, 2-17]). As of Feb 25, 2021 (final database lock), SG (n = 235) vs TPC (n = 233) significantly improved median PFS (5.6 vs 1.7 mo; HR: 0.39; P< 0.0001) and median OS (12.1 vs 6.7 mo; HR: 0.48; P< 0.0001). The OS rate at 24 months was 22.4% (95% CI, 16.8-28.5) in the SG arm and 5.2% (95% CI, 2.5-9.4) in the TPC arm. In the safety population (n = 482), key treatment-related grade ≥3 adverse events with SG (n = 258) vs TPC (n = 224) were diarrhea (11% vs 0.4%), neutropenia (52% vs 33%), anemia (8% vs 5%), and febrile neutropenia (6% vs 2%). There was no grade ≥3 neuropathy and 1 case of grade 3 interstitial lung disease reported with SG. No patient experienced a treatment-related death with SG, and there was 1 treatment-related death with TPC due to neutropenic sepsis. Treatment discontinuations due to AEs were ≤3% in both arms. SG arm showed clinically meaningful and statistically significant improvements than the TPC arm in scores for all five primary focus health-related QoL domains. Conclusions: The analysis based on the final database lock of ASCENT confirms the superior survival outcomes of SG over single-agent chemotherapy, with a manageable safety profile and improvement in QoL for pts with mTNBC in the 2L+ setting. These findings reinforce SG as an effective treatment option for this pt population. Clinical trial information: NCT02574455.

Analysis of patients without and with an initial triple-negative breast cancer diagnosis in the phase 3 randomized ASCENT study of sacituzumab govitecan in metastatic triple-negative breast cancer

PurposeSacituzumab govitecan (SG) is an antibody–drug conjugate composed of an anti–Trop-2 antibody coupled to SN-38 via a proprietary hydrolyzable linker. In the ASCENT study, SG improved survival versus single-agent treatment of physician’s choice (TPC) in pre-treated metastatic triple-negative breast cancer (mTNBC). Hormone/HER2 receptor changes are common, particularly at relapse/metastasis. This subanalysis assessed outcomes in patients who did/did not have TNBC at initial diagnosis, before enrollment.MethodsTNBC diagnosis was only required at study entry. Patients with mTNBC refractory/relapsing after ≥ 2 prior chemotherapies were randomized 1:1 to receive SG or TPC. Primary endpoint was progression-free survival (PFS) in patients without brain metastases.ResultsOverall, 70/235 (30%) and 76/233 (33%) patients who received SG and TPC, respectively, did not have TNBC at initial diagnosis. Clinical benefit with SG versus TPC was observed in this subset. Median PFS was 4.6 versus 2.3 months (HR 0.48; 95% CI 0.32–0.72), median overall survival was 12.4 versus 6.7 months (HR 0.44; 95% CI 0.30–0.64), and objective response rate (ORR) was 31% versus 4%; those who also received prior CDK4/6 inhibitors had ORRs of 21% versus 5%. Efficacy and safety for patients with TNBC at initial diagnosis were generally similar to those who did not present with TNBC at initial diagnosis.ConclusionPatients without TNBC at initial diagnosis had improved clinical outcomes and a manageable safety profile with SG, supporting SG as a treatment option for mTNBC regardless of subtype at initial diagnosis. Subtype reassessment in advanced breast cancer allows for optimal treatment.Clinical trial registration number NCT02574455, registered October 12, 2015.

168P Sacituzumab govitecan (SG) efficacy in patients with metastatic triple-negative breast cancer (mTNBC) by HER2 immunohistochemistry (IHC) status: Findings from the phase III ASCENT study

HER2 IHC1+ or IHC2+ and in situ hybridization (ISH)-negative results are sometimes referred to as HER2-Low. SG is a novel antibody-drug conjugate composed of an anti–Trop-2 antibody coupled to SN-38 via a proprietary, hydrolyzable linker. SG is approved in mTNBC for the second line (2L) onwards. In the ASCENT study, SG had significant progression-free survival (PFS) and overall survival (OS) benefit vs chemotherapy of physician’s choice (TPC). This ASCENT post hoc subgroup analysis evaluates SG efficacy in HER2 IHC0 and HER2-Low mTNBC.

189P Pharmacokinetics (PK) of sacituzumab govitecan (SG) in patients (Pts) with metastatic triple-negative breast cancer (mTNBC) and other solid tumors

SG is a novel antibody-drug conjugate (ADC) composed of an anti–Trop-2 antibody coupled to SN-38 via a proprietary, hydrolyzable linker. SG is approved for pts with mTNBC who received ≥2 prior chemotherapies (>1 in the metastatic setting) and has accelerated approval for pts with metastatic urothelial cancer who received prior platinum-containing chemotherapy and a PD-1/PD-L1 inhibitor. These analyses evaluated the PK of SG, Free SN-38, and Total Antibody (tAB) with SG administration. Population PK (PopPK) models were developed using data from 529 pts across 2 clinical studies, IMMU-132-01 (phase 1/2 in pts with advanced epithelial cancers including TNBC, UC, and lung cancer; PK n=276) and ASCENT (phase 3 in pts with mTNBC who received ≥2 prior therapies (>1 in the metastatic setting); PK n=253). Pts received SG at 8 to 18 mg/kg IV (IMMU-132-01) or 10 mg/kg IV (ASCENT) on d1 and d8, of every 21d cycle. Clinically relevant covariates were evaluated to assess their impact on exposure. The PopPK models of SG and tAB were developed independently. The model of Free SN-38 was developed in a sequential manner with a first-order release of Free SN-38 (payload) from SG (the ADC). The typical parameter estimates for clearance and steady-state volume of distribution were 0.133 L/hr and 3.68 L for SG and 0.0164 L/hr and 4.26 L for tAB. Bodyweight correlated with the clearance and volume parameters of all 3 analytes, but with limited impact on the exposure with the clinical regimen. There was no model-predicted accumulation of either SG or Free SN-38 with repeated dosing. Overall, mild to moderate renal impairment, mild hepatic impairment, age, sex, baseline albumin level, race, ECOG status, tumor type, UGT1A1 genotype or Trop-2 expression did not have a clinically relevant impact on exposure of any of the evaluated analytes. The PK of SG, Free SN-38, and Total Antibody were well characterized based on a robust dataset across two large trials. The analyses supported the approved 10 mg/kg clinical regimen and did not identify a need for dose-adjustment based on any of the evaluated patient demographics or disease characteristics.

Abstract P157: Targeting Trop2 for treatment of prostate and breast cancer

Abstract Background: Prostate cancer and breast cancer are the most commonly diagnosed non-skin cancers and the second leading cause of cancer related mortalities in men and women respectively in the United States. Fifteen percent of breast cancer is TNBC characterized with lack of receptors for estrogen, progesterone, and HER-2/neu making it resistant to hormone therapies and therapies targeting estrogen, progesterone, and HER-2/neu signaling. The first line of treatment for men with advanced prostate cancer is androgen depravation therapy. While initial responses are observed, unfortunately, the disease frequently recurs as a lethal metastatic form referred to as castration-resistant prostate cancer (CRPC). We recently identified that the cell surface receptor, Trop2, is a new regulator of TNBC and CRPC. We demonstrated that Trop2 is highly expressed in CRPC and TNBC. In this study, we set out to test the therapeutic potential of new fully humanized human anti-Trop2 antibody fragments in CRPC and NEPC. Methods: We have generated new human anti-Trop2 antibody fragments. Lentiviral infection was used to generate prostate and breast cancer cell lines with over-expression of Trop2 and knock-down of Trop2. In vivo functional assays were performed including subcutaneous xenograft growth and metastasis. Results: High protein levels of Trop2 are observed in metastatic CRPC and TNBC. Furthermore, loss of Trop2 significantly delays growth, migration and invasion of prostate and breast cancer cells in vitro and delays tumor growth and metastasis of prostate and breast cancer in vivo. Overexpression of Trop2 enhances tumor growth and metastasis of prostate cancer cells and drives CRPC. We generated new fully humanized human anti-Trop2 antibody fragments that have therapeutic efficacy in preclinical models of prostate and breast cancers. Conclusions: In a previous study, we identified cell surface receptor, Trop2, as a novel driver of metastatic CRPC. Herein, our new findings reveal that Trop2 represents a promising therapeutic target for prostate, breast, and potentially other epithelial cancers. We identified lead antibody candidates that bind to human Trop2 protein with high affinity and stability. Furthermore, our lead anti-Trop2 Abs significantly delay the tumors growth in CRPC and TNBC without measurable toxicity and provide new therapeutic strategy for metastatic CRPC and TNBC. Citation Format: Tanya Stoyanova. Targeting Trop2 for treatment of prostate and breast cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P157.

In This Issue

In This Issue

Trophoblast cell-surface antigen 2 expression in lung cancer patients and the effects of anti-cancer treatments.

Trophoblast cell-surface antigen 2 (TROP2) is expressed on the surface of trophoblast cells and many malignant tumor cells. However, data on TROP2 expression in advanced lung cancer are insufficient, and its changes have not been fully evaluated. We assessed the prevalence and changes in TROP2 expression in patients with lung cancer who received anti-cancer treatments using immunohistochemical (IHC) analysis with an anti-TROP2 antibody (clone: SP295). IHC scores were graded from 0 to 3; grade ≥ 2 was considered positive for TROP2 expression. We defined a difference in IHC score, before and after anti-cancer treatments, as the change in TROP2 expression. Before anti-cancer treatment, TROP2 expression was observed in 89% (143/160) of the patients and was significantly more common in adenocarcinoma and squamous cell carcinoma than in neuroendocrine carcinoma (P < 0.001). After anti-cancer treatment, TROP2 expression was observed in 87% (139/160) of the patients. The distribution of TROP2 expression in post-treatment samples was analogous to that in pre-treatment samples when compared using the Wilcoxon signed-rank test (P = 0.509). However, an increase in TROP2 expression was seen in 19 (12%), and a decrease in 20 (13%) patients. Patients treated with targeted therapy showed significantly higher changes in TROP2 expression (P = 0.019) and thoracic radiotherapy was more likely to increase TROP2 expression than chemotherapy alone. Although some anti-cancer treatments might alter the TROP2 expression, TROP2 was expressed in most lung cancer specimens before and after anti-cancer treatments. These results support the development of TROP2-directed therapy against advanced lung cancer in various treatment lines.

257P Health-related quality of life (HRQoL) in the ASCENT study of sacituzumab govitecan (SG) in metastatic triple-negative breast cancer (mTNBC)

SG is an antibody-drug conjugate composed of an anti–Trop-2 antibody coupled to SN-38 via a proprietary hydrolyzable linker. In the ASCENT intention-to-treat analysis, SG significantly prolonged progression-free survival (PFS; median 4.8 vs 1.7 mo) and overall survival (OS; median 11.8 vs 6.9 mo) vs single-agent chemotherapy of physician’s choice (TPC) in the second line or greater (2L+) mTNBC setting. Here we assess the impact of SG on HRQoL in the ASCENT study.

258P Analysis of patients (pts) without an initial triple-negative breast cancer (TNBC) diagnosis (Dx) in the phase III ASCENT study of sacituzumab govitecan (SG) in brain metastases-negative (BMNeg) metastatic TNBC (mTNBC)

SG is an antibody-drug conjugate composed of an anti–Trop-2 antibody coupled to SN-38 via a unique hydrolyzable linker. In the ASCENT study, SG significantly prolonged survival vs chemotherapy of physician’s choice (TPC) in the second line or greater mTNBC setting (median progression-free survival [PFS], 5.6 vs 1.7 mo; median overall survival [OS], 12.1 vs 6.7 mo). Changes in hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status can occur during the temporal course of metastatic disease.

Datopotamab Deruxtecan, a Novel TROP2-directed Antibody-drug Conjugate, Demonstrates Potent Antitumor Activity by Efficient Drug Delivery to Tumor Cells.

Trophoblast cell surface antigen 2 (TROP2) is highly expressed on various epithelial tumors and correlates with poor prognosis. We developed the novel TROP2-directed antibody-drug conjugate (ADC), datopotamab deruxtecan (Dato-DXd, DS-1062a), with a potent DNA topoisomerase I inhibitor (DXd), and evaluated its antitumor activity and safety profiles in preclinical models.The pharmacologic activity and mechanism of action of Dato-DXd were investigated in several human cancer cell lines and xenograft mouse models including patient-derived xenograft (PDX) models. Safety profiles were also assessed in rats and cynomolgus monkeys.Dato-DXd bound specifically to TROP2 and was internalized into tumor cells followed by intracellular trafficking to lysosome and DXd release, which induced DNA damage and apoptosis in TROP2-expressing tumor cells in vitro. Dato-DXd exhibited in vivo antitumor activity with DNA damage induced by the accumulated DXd in TROP2-expressing xenograft tumors, but neither isotype control IgG-ADC nor anti-TROP2 antibody had this effect. Dato-DXd also showed potent antitumor activity with tumor regression in several TROP2-expressing xenograft tumors including NSCLC PDX models. Safety profiles of Dato-DXd in rats and cynomolgus monkeys were acceptable.Dato-DXd demonstrated potent antitumor activity against TROP2-expressing tumors by efficient payload delivery into tumors and acceptable safety profiles in preclinical models. These results suggest Dato-DXd could be a valuable treatment option for patients with TROP2-expressing tumors in the clinical setting.

Parallel Genomic Alterations of Antigen and Payload Targets Mediate Polyclonal Acquired Clinical Resistance to Sacituzumab Govitecan in Triple-Negative Breast Cancer.

Sacituzumab govitecan (SG), the first antibody-drug conjugate (ADC) approved for triple-negative breast cancer, incorporates the anti-TROP2 antibody hRS7 conjugated to a topoisomerase-1 (TOP1) inhibitor payload. We sought to identify mechanisms of SG resistance through RNA and whole-exome sequencing of pretreatment and postprogression specimens. One patient exhibiting de novo progression lacked TROP2 expression, in contrast to robust TROP2 expression and focal genomic amplification of TACSTD2/TROP2 observed in a patient with a deep, prolonged response to SG. Analysis of acquired genomic resistance in this case revealed one phylogenetic branch harboring a canonical TOP1 E418K resistance mutation and subsequent frameshift TOP1 mutation, whereas a distinct branch exhibited a novel TACSTD2/TROP2 T256R missense mutation. Reconstitution experiments demonstrated that TROP2T256R confers SG resistance via defective plasma membrane localization and reduced cell-surface binding by hRS7. These findings highlight parallel genomic alterations in both antibody and payload targets associated with resistance to SG. SIGNIFICANCE: These findings underscore TROP2 as a response determinant and reveal acquired SG resistance mechanisms involving the direct antibody and drug payload targets in distinct metastatic subclones of an individual patient. This study highlights the specificity of SG and illustrates how such mechanisms will inform therapeutic strategies to overcome ADC resistance.This article is highlighted in the In This Issue feature, p. 2355.

Assessment of sacituzumab govitecan (SG) versus treatment of physician’s choice (TPC) cohort by agent in the phase 3 ASCENT study of patients (pts) with metastatic triple-negative breast cancer (mTNBC).

1077 Background: In pts with pretreated mTNBC, standard-of-care chemotherapy is associated with low objective response rates (ORRs) and short median progression-free survival (PFS). SG is an antibody-drug conjugate composed of an anti–Trop-2 antibody coupled to the cytotoxic SN-38 payload via a proprietary, hydrolyzable linker. SG received accelerated FDA approval for treatment of pts with mTNBC who have received ≥2 prior therapies for metastatic disease. The confirmatory phase 3 ASCENT study (NCT02574455) in pts with relapsed/refractory mTNBC demonstrated a significant survival benefit of SG over TPC (median PFS: 5.6 vs 1.7 mo, HR 0.41, P&lt; 0.0001; median overall survival [OS]: 12.1 vs 6.7 mo, HR 0.48, P&lt; 0.0001) with a tolerable safety profile. Here we summarize efficacy results for SG vs each TPC agent in ASCENT to examine how each TPC agent performed individually. Methods: Pts had mTNBC refractory to or progressing after ≥2 prior standard chemotherapy regimens. Pts were randomized 1:1 to receive SG (10 mg/kg intravenously on days 1 and 8, every 21 days) or single-agent TPC (eribulin, vinorelbine, capecitabine, or gemcitabine). Primary endpoint was PFS per RECIST 1.1 by independent review in brain metastases-negative (BMNeg) pts. Secondary endpoints were ORR per RECIST 1.1, duration of response, OS, and safety. Outcomes for each of the agents in the TPC arm were analyzed and compared with SG. Results: Of 529 pts enrolled, 468 were BMNeg. Among pts in the TPC cohort (n = 233), eribulin was the most commonly chosen chemotherapy (n = 126), followed by vinorelbine (n = 47), capecitabine (n = 31), and gemcitabine (n = 29). Treatment with eribulin, vinorelbine, capecitabine, and gemcitabine resulted in shorter median PFS vs SG (2.1, 1.6, 1.6, and 2.7 vs 5.6 mo, respectively); similar results were observed for median OS (6.9, 5.9, 5.2, and 8.4 vs 12.1 mo), ORR (5%, 4%, 6%, and 3% vs 35%), and clinical benefit rate (CBR; 8%, 6%, 10%, and 14% vs 45%). Key grade ≥3 treatment-related adverse events (TRAEs) with TPC overall vs SG included neutropenia (33% vs 51%), leukopenia (5% vs 10%), fatigue (5% vs 3%), and anemia (5% vs 8%). Key grade ≥3 TRAEs with eribulin vs SG included neutropenia (30% vs 51%), leukopenia (5% vs 10%), fatigue (5% vs 3%), anemia (2% vs 8%), and peripheral neuropathy (2% vs none), respectively. The safety profiles of vinorelbine, capecitabine, and gemcitabine combined were consistent with that of TPC overall and with eribulin. One treatment-related death was reported for the TPC arm (eribulin) and none with SG. Conclusions: The efficacy benefit observed with SG vs TPC in pts with mTNBC was retained when evaluating each TPC chemotherapy agent individually. These results confirm that SG should be considered as a new standard of care in pts with pretreated mTNBC. Clinical trial information: NCT02574455 .

Assessment of sacituzumab govitecan (SG) in patients with prior neoadjuvant/adjuvant chemotherapy in the phase 3 ASCENT study in metastatic triple-negative breast cancer (mTNBC).

1080 Background: mTNBC is a heterogenous disease with few treatment options and poor outcomes. Pts who recur ≤ 12 mo after completing (neo)adjuvant chemotherapy may represent a subset with more aggressive disease. SG is an antibody-drug conjugate composed of an anti–Trop-2 antibody coupled to the cytotoxic SN-38 payload via a proprietary, hydrolyzable linker. SG received accelerated approval for pts with mTNBC who received ≥ 2 prior therapies for metastatic disease; clinical benefit for SG over treatment of physician's choice (TPC) was confirmed in the phase 3 ASCENT study (NCT02574455) for median progression-free survival (PFS; 5.6 vs 1.7 mo), median overall survival (OS; 12.1 vs 6.7 mo), objective response rate (ORR; 35% vs 5%), clinical benefit rate (CBR; 45% vs 9%), and median duration of response (6.3 vs 3.6 mo). This ASCENT subanalysis of pts with mTNBC who recurred ≤ 12 mo after (neo)adjuvant chemotherapy and then only received 1 line of therapy in the metastatic setting assessed the benefit of SG in this subgroup vs the overall trial population. Methods: In ASCENT, pts with mTNBC refractory/relapsing after ≥ 2 prior chemotherapies were randomized 1:1 to receive SG (10 mg/kg IV on days 1 and 8, every 21 days) or TPC (capecitabine, eribulin, vinorelbine, or gemcitabine). Per protocol, a pt was eligible after only 1 prior regimen in the metastatic setting if their disease recurred within 12 months of completing (neo)adjuvant therapy. Primary endpoint was PFS per RECIST 1.1 by independent review in brain metastases-negative (BMNeg) pts. Efficacy and safety was assessed in a subset of pts who recurred ≤ 12 mo after (neo)adjuvant chemotherapy and then received 1 line of therapy in the metastatic setting. Results: In total, 33 and 32 BMNeg pts with a median age of 49 and 51 yrs received SG and TPC in this subgroup, respectively. In this subgroup, treatment with SG (vs TPC) improved PFS (median 5.7 vs 1.5 mo; HR, 0.41; 95% CI, 0.22-0.76; P = 0.0049) and OS (median 10.9 vs 4.9 mo; HR, 0.51; 95% CI, 0.28-0.91; P = 0.0227). We also observed higher ORR (30% vs 3%) and CBR (42% vs 6%) with a median response duration of 6.7 mo with SG vs not calculable with TPC. The efficacy results from this subgroup are similar to those for SG vs TPC in the overall BMNeg population. The safety profile of SG in pts in this subgroup was consistent with prior reports. There were no treatment-related deaths with SG. Conclusions: Pts with mTNBC who recurred ≤ 12 mo after (neo)adjuvant therapy and then had 1 line of prior therapy in the metastatic setting may represent a subset with more aggressive disease. In this subgroup, pts had superior outcomes with SG vs TPC in the second-line metastatic setting, consistent with the benefit seen in the overall BMNeg population. Studies are ongoing (NeoSTAR, NCT04230109; SASCIA, NCT04595565) to evaluate SG as an earlier-line treatment option for TNBC. Clinical trial information: NCT02574455 .

Outcomes in patients (pts) aged ≥65 years in the phase 3 ASCENT study of sacituzumab govitecan (SG) in metastatic triple-negative breast cancer (mTNBC).

1011 Background: Approximately 20% of pts diagnosed with TNBC are aged ≥65 y. Often, older pts are less fit for chemotherapy due to a greater rate of comorbidities, increased use of medications, and pre-existing frailty or functional loss. SG is an antibody-drug conjugate composed of an anti–Trop-2 antibody coupled to the cytotoxic SN-38 payload via a proprietary, hydrolyzable linker. The landmark phase 3 ASCENT study (NCT02574455) showed improved outcomes with SG vs single-agent chemotherapy of physician’s choice (TPC) in pts with relapsed/refractory mTNBC (median progression-free survival [PFS], 5.6 vs 1.7 mo; median overall survival [OS], 12.1 vs 6.7 mo). Here we assess the impact of age on the efficacy and safety of SG in ASCENT. Methods: Pts with mTNBC refractory/relapsing after ≥2 prior chemotherapies were randomized 1:1 to receive SG (10 mg/kg IV on days 1 and 8, every 21 days) or TPC (capecitabine, eribulin, vinorelbine, or gemcitabine) until disease progression/unacceptable toxicity. Primary endpoint was PFS per RECIST 1.1 by independent review in brain metastases-negative (BMNeg) pts. Safety outcomes were assessed in all treated pts. This prespecified subgroup analysis assessed the impact of age (pts ≥65 y) on PFS, OS, and safety. Results: Of 529 pts enrolled, 468 were BMNeg (median age, 54 y); of these, 44/235 pts (19%) who received SG and 46/233 pts (20%) who received TPC were aged ≥65 y. SG treatment improved median PFS vs TPC in pts ≥65 y (7.1 vs 2.4 mo; HR, 0.22; 95% CI, 0.12-0.40). SG vs TPC treatment also improved median OS in pts ≥65 y (15.3 vs 8.2 mo; HR, 0.37; 95% CI, 0.22-0.64). Treatment with SG vs TPC resulted in higher ORR (50% vs 0%) and clinical benefit rate (CBR, 61% vs 9%) in pts ≥65 y. Of the 7 pts ≥75 y who received SG, 2 had partial response, 4 had stable disease [SD], and 1 had SD &gt; 6 mo as best response. In pts &lt; 65 y, median PFS for SG vs TPC was 4.6 vs 1.7 mo (HR, 0.46; 95% CI, 0.35-0.59), and median OS was 11.2 vs 6.6 mo (HR, 0.50; 95% CI, 0.40-0.64), respectively; the ORR and CBR were 31% vs 6% and 41% vs 9%, respectively. Pts ≥65 y treated with SG vs TPC had similar rates of all grade and grade ≥3 treatment-emergent adverse events (TEAEs). TEAEs leading to dose reduction were similar in pts ≥65 y in the SG vs TPC arms (35% vs 33%) and were lower in pts &lt; 65 y (19% vs 24%). Key treatment-related TEAEs leading to dose reduction in pts ≥65 y in the SG vs TPC arms were neutropenia (including febrile neutropenia; 14% vs 25%), fatigue (10% vs 4%), diarrhea (6% vs 0%), and nausea (4% vs 0%). TEAEs leading to treatment discontinuation with SG vs TPC were low in pts ≥65 y (2% vs 2%) and &lt; 65 y (5% vs 6%). There were no treatment-related AEs leading to death in any SG-treated age group. Conclusions: Irrespective of age, pts who received SG had a significant survival benefit vs TPC, with a tolerable safety profile. Proactive AE monitoring and management will allow optimal therapeutic exposure to SG in older pts. Clinical trial information: NCT02574455 .

Abstract PS18-37: Loss of Trop2 protein in metaplastic carcinoma of breast by IHC

Abstract Background: Trop2 (trophoblast cell surface antigen) is a transmembrane calcium transducer which has been associated with tumor growth, aggressiveness and metastasis. Compared to normal tissue, Trop2 is expressed at much higher levels in many epithelial tumors, which makes it an excellent target for ADCs (antibody-drug conjugates). Sacituzumab govitecan-hziy, an ADC that combines Trop-2 antibody with a SN-38 payload has been recently approved for treatment of refractory metastatic triple-negative breast cancer, and several other TROP2 targeted therapies are in development. To better understand Trop 2 expression in breast tumor that may help to identify patients who could benefit most from Trop2-targeted therapy, we aimed to screen Trop2 protein in multiple types of breast tumor. Design: Using chromogenic immunohistochemistry (IHC), Trop2 protein was examined in 42 formalin fixed paraffin embedded (FFPE) specimens from surgically resected breast tumors, including 21 TNBC, 16 HR+, 4 HER2+ (3 HR+/HER2+ and 1 HR-/HER2+), and 1 sarcoma. Sections were stained on an automated staining system (BOND-MAX; Leica Microsystems) using anti-TROP2 antibody (clone ERP20043, Abcam, cat# 214488). Membrane staining was assessed. The percentage of positivity (0% to 100%) and the staining intensity (0 = no staining, 1+ = weak staining, 2+ = moderate staining, and 3+ = strong staining) were evaluated and multiplied to generate H-score (0-300). Results: Among of 41 breast carcinoma cases, 38 (92.6%) cases expressed Trop2 protein in tumor cells, with a median H-score of 162.5, including 18/21 TNBC, 16/16 HR+, 4/4 HER2+ cases. Trop2 was expressed in several breast cancer histopathology subtypes, including 32 invasive ductal carcinomas (H score ranged from 29 - 290), 2 invasive lobular carcinomas (H score 140 and 145), 1 invasive papillary carcinoma (H score 70), 1 invasive micropapillary carcinoma (H score 210), 1 invasive squamous cell carcinoma (H score 245) and 1 metaplastic carcinoma with mesenchymal differentiation (cartilaginous sarcomatoid type) (H score 17). Three breast carcinomas were negative for Trop2 (H score 0). All three cases are metaplastic carcinomas, including two spindle cell carcinomas and one with mesenchymal differentiation, which are TNBC. Only two of 5 (40%) metaplastic carcinomas tested expressed Trop2 (p = 0.0034). One breast sarcoma was tested and had no TROP2 expression. Conclusion: Trop2 is commonly expressed in breast cancer. However, metaplastic carcinoma of breast has shown a trend of Trop2 protein loss. Further validation on Trop2 loss in metaplastic carcinoma might help with identifying breast cancer patients less likely to benefit from Trop2-targeted therapy. Citation Format: Fei Yang, Yasmeen Rizvi, Erkan Yuca, Ming Zhao, Kurt Evans, Xiaofeng Zheng, Aysegul Sahin, Funda Meric-Bernstam. Loss of Trop2 protein in metaplastic carcinoma of breast by IHC [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 PS18-37.

547P Rucaparib + sacituzumab govitecan (SG): Initial data from the phase Ib/II SEASTAR study (NCT03992131)

Preclinically, PARP inhibitors (PARPi) + TOP1 inhibitors have shown highly synergistic antitumour effects, but clinical development has been hampered by overlapping toxicities. Tumour-targeted delivery of a TOP1 inhibitor may reduce systemic toxicity of the combination; thus, we evaluated the PARPi rucaparib + SG, an antibody-drug conjugate composed of an anti-Trop2 antibody coupled to the active metabolite of irinotecan (SN-38) via a unique hydrolyzable linker.

Early results of TROPHY-U-01 Cohort 2: Sacituzumab govitecan (SG) in platinum-ineligible patients (pts) with metastatic urothelial cancer (mUC) who progressed after prior checkpoint inhibitor (CPI) therapy.

5027 Background: SG is an antibody-drug conjugate consisting of a humanized monoclonal anti–Trop-2 antibody coupled to the cytotoxic agent, SN-38, via a unique hydrolyzable linker. The epithelial cell surface antigen, Trop-2, demonstrates greater expression between UC vs normal tissue, and is a promising target. In a phase 1/2 basket study (IMMU-132-01), SG showed an overall response rate (ORR) of 31% and manageable toxicity in 45 pts with mUC who had a median of 2 (range 1–6) prior therapy lines (Tagawa 2019 ASCO GU). Recent interim results for cohort 1 of the TROPHY-U-01 study in 35 pts with mUC who progressed on platinum and CPI therapy demonstrated an ORR of 29% in pts with a median of 3 prior treatment lines (range 2–6) (Tagawa 2019 ESMO). The most common grade ≥3 treatment-related AE (TRAE) was neutropenia. Methods: TROPHY-U-01 (NCT03547973) is a global, open-label, phase 2 trial evaluating the antitumor activity of SG (10 mg/kg, days 1 and 8 of 21-day cycles) in pts with advanced UC with measurable disease and ECOG PS 0 or 1. Cohort 2 includes platinum-ineligible pts who progressed after CPI therapy in the first-line metastatic setting. The primary objective is ORR evaluated with RECISTv1.1 by central review. Secondary objectives include progression-free survival, overall survival, and duration of response. Results: 18 pts with baseline tumor assessment (50% male; median age 79 y [range 57–87], 67% visceral metastases; 28% liver metastases) received a median of 2 (range 1–5) prior therapies. At a median follow-up of 6 months, ORR was 28% (5/18) with 4 confirmed PRs, and 1 PR pending confirmation. The majority of pts (61% [11/18]) had target lesion reduction. The safety profile was consistent with prior reports. Key grade ≥3 TRAEs were neutropenia (39%), fatigue (33%), diarrhea (28%), leukopenia (22%), anemia (17%), and febrile neutropenia (11%). No events of interstitial lung disease, ocular toxicities, or grade &gt; 2 neuropathy were reported. There were no treatment-related deaths. Conclusions: In cisplatin-ineligible pts, the ORR for currently approved first-line CPI treatments is ~23–29% (Balar 2017 Lancet; Vuky 2018 ASCO). These preliminary data with SG show a manageable safety profile with an encouraging ORR of 28% and support the development of SG in platinum-ineligible pts with mUC who have progressed after CPI therapy. Clinical trial information: NCT03547973 .

Single-arm, phase II study to evaluate the safety and efficacy of sacituzumab govitecan in patients with metastatic castration-resistant prostate cancer who have progressed on second generation AR-directed therapy.

TPS251 Background: In patients with mCRPC, androgen receptor (AR) pathway inhibitors such as enzalutamide or abiraterone acetate are often used as first-line systemic therapy. After progression on either of these inhibitors, the likelihood of response to the other is significantly lower than in the first-line setting. Multiple resistance mechanisms have been identified, including the emergence of AR splice variants. Trop2 is a cell-surface antigen that is expressed in &gt; 70% of prostate cancers and is enriched in mCRPC expressing AR splice variants. Sacituzumab govitecan (SG; IMMU-132) is a novel antibody drug conjugate composed of humanized anti-Trop2 antibody conjugated to SN-38 payload by hydrolyzable linker. SG has potential to be an effective therapy after progression on initial AR pathway inhibitors to meet this significant unmet clinical need. Methods: This is a single-arm, open-label, multicenter phase 2 trial (NCT03725761) to determine the efficacy and safety of SG. The primary endpoint is PSA response rate (≥50% PSA decline at or within 9 weeks of starting treatment); secondary endpoints include rPFS and overall survival. 55 subjects with mCRPC who have progressed on second-generation AR-directed therapy in either the hormone sensitive or CRPC setting will be included. Fresh or archived metastatic site biopsy is required. Subjects will be treated with SG IV at 10 mg/kg on Day 1 and Day 8 of 21-day cycles until disease progression. Subjects who receive ≥1 SG dose and have ≥1 PSA post-dose assessment will be included in final efficacy analysis. Circulating tumor cell biomarker studies will be performed throughout treatment and at progression to investigate potential mechanisms of response/resistance to SG. Tumor biopsies at baseline and after 3 therapy cycles will evaluate genomic alterations that predict treatment response. Subjects who remain progression free will undergo repeated evaluations of extent of disease every 9 weeks. The trial is actively accruing. Managed by: Prostate Cancer Clinical Trials Consortium; Funding: Immunomedics; Support: Prostate Cancer Foundation. Clinical trial information: NCT03725761.

Abstract 2386: TROP2-targeted photoimmunotherapy in experimental human pancreatic cancer

Abstract Background: Near-infrared photoimmunotherapy (NIR-PIT) is a newly developed cancer therapy that employs a selective monoclonal antibody (mAb) conjugated to a photosensitizer phthalocyanine dye, IR700. The complex mAb-IR700 binds to the specific antigen on the cellular membrane, and then NIR light is delivered, leading to rapid and target-selective cell death. The type I trans-membrane protein, TROP2, is found to be expressed at high levels in many epithelial cancers, including pancreatic carcinoma. Further, TROP2 overexpression correlates with poor prognosis and tumor aggressiveness. In this study, we investigated the antitumor effect of TROP2-targeted PIT in an experimental human pancreatic cancer model using anti-TROP2 mAb-IR700 conjugate. Methods: The experiments were performed on TROP2-overexpressing human pancreatic cancer cells (PK-59 and KP-3L) and 3T3/HER2 cells were used as the negative control. Anti-TROP2 antibody (Chiome Bioscience, Tokyo, Japan) was conjugated with IR700 and purified (TROP2-IR700). The expression and localization of TROP2 were determined by fluorescence microscopy and flow cytometry. LIVE/DEAD assay was performed to determine cytotoxicity exerted by NIR light irradiation in vitro. Subsequently, for in vivo studies, PIT was tested on a mouse tumor xenograft model (PK-59 cells). Specifically, tumor-bearing mice were intravenously injected with TROP2-IR700 and tumors were irradiated with NIR laser light, 1 day after the injection. Distribution of TROP2-IR700 was then monitored with small animal imaging system and the antitumor effects were determined by measuring the tumor diameter using a caliper. Additionally, the expression patterns of TROP2 and EGFR in human pancreatic cancer were analyzed by immunohistochemistry, using tissue microarray samples. Results: We found that TROP2-IR700 specifically localized on the cellular membrane as well as on lysosomes, in TROP2-overexpressing PK-59 and KP-3L cells, whereas no specific signals were observed in TROP2-negative 3T3/HER2 cells. Moreover, TROP2-IR700-mediated PIT was able to induce a strong cytotoxic effect in PK-59 and KP-3L cells, which was NIR-light dose dependent. The localization of TROP2-selective IR700 fluorescence was observed in the mouse xenograft, 1 day after intravenous injection with TROP2-IR700, and the tumor growth was significantly inhibited by NIR light irradiation compared to the control groups. Moreover, pancreatic cancer tissue microarray analysis revealed that 80% of the tumors were positive for TROP2 and 50% were positive for EGFR and the expression patterns were independent from each other. Conclusions: We demonstrated that TROP2-IR700-targeted PIT exerts an antitumor effect against TROP2 positive pancreatic cancer, both in vitro and in vivo, and could be a promising therapeutic option for human pancreatic cancer. Citation Format: Takashi Nishimura, Makoto Mitsunaga. TROP2-targeted photoimmunotherapy in experimental human pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2386.