Sacituzumab Govitecan-hziy (Trodelvy)

Number: 0971

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses sacituzumab govitecan-hziy (Trodelvy) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

Note: Requires Precertification:

Precertification of sacituzumab govitecan-hziy (Trodelvy) is required of all Aetna participating providers and members in applicable plan designs.  For precertification of sacituzumab govitecan-hziy (Trodelvy), call (866) 752-7021 or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see Specialty Pharmacy Precertification.

1. Criteria for Initial Approval

   Aetna considers sacituzumab govitecan-hziy (Trodelvy) medically necessary for the following indications:

   1. Breast cancer - as a single agent for treatment of breast cancer when either of the following criteria are met:

      1. The disease is recurrent, unresectable, metastatic, or the member had no response to preoperative systemic therapy and all of the following criteria are met:

         1. The diagnosis of triple-negative breast cancer is confirmed by the cancer cells testing negative for all of the following receptors:
            
            
            1. Human epidermal growth factor receptor 2 (HER2); and
            2. Estrogen; and
            3. Progesterone; and

         2. The member has received at least two prior therapies, with at least one line for metastatic disease; or

      2. The disease is recurrent unresectable or metastatic, or the member had no response to preoperative systemic therapy and all of the following criteria are met:

         1. The cancer cells are hormone receptor positive and human epidermal growth factor receptor 2 (HER2)-negative; and
         2. The member has received prior treatment including all of the following:
            
            
            1. Endocrine therapy (e.g., anastrozole, letrozole, fulvestrant); and
            2. A CDK4/6 inhibitor (e.g., abemaciclib, palbociclib, ribociclib); and
            3. At least two lines of chemotherapy (including a taxane) at least one of which was in the metastatic setting;

         3. Member is not a candidate for fam-trastuzumab deruxtecan-nxki (Enhertu);

   2. Urothelial carcinoma - bladder cancer - as a single agent for subsequent treatment of locally advanced, recurrent, persistent, or metastatic bladder cancer in members who have received a platinum-containing chemotherapy and either a programmed death receptor-1 (PD-1) or a programmed death-ligand 1 (PD-L1) inhibitor;
   3. Urothelial carcinoma - primary carcinoma of the urethra - as a single agent for subsequent treatment of locally advanced, recurrent or metastatic primary carcinoma of the urethra in members who have received a platinum-containing chemotherapy and either a programmed death receptor-1 (PD-1) or a programmed death-ligand 1 (PD-L1) inhibitor;
   4. Urothelial carcinoma - upper genitourinary tract yumors or urothelial carcinoma of the prostate - as a single agent for subsequent treatment of locally advanced or metastatic upper genitourinary tract tumors or urothelial carcinoma (UC) of the prostate in members who have received a platinum-containing chemotherapy and either a programmed death receptor-1 (PD-1) or a programmed death-ligand 1 (PD-L1) inhibitor.

   Aetna considers all other indications as experimental and investigational.

2. Continuation of Therapy

   Aetna considers the continuation of sacituzumab govitecan-hziy (Trodelvy) therapy medically necessary for members requesting reauthorization for an indication listed in Section I when there is no evidence of unacceptable toxicity or disease progression while on the current regimen.

Dosage and Administration

Sacituzumab govitecan-hziy is available as Trodelvy for injection as 180 mg lyophilized powder in single-dose vials for reconstitution for intravenous infusion only. Do not administer as an intravenous push or bolus.

Breast Cancer and Urothelial Cancer

The recommended dose is 10 mg/kg once weekly on Days 1 and 8 of continuous 21-day treatment cycles until disease progression or unacceptable toxicity.

• First Infusion:

  Administer infusion over 3 hours. Observe individual during the infusion and for at least 30 minutes following the initial dose, for signs or symptoms of infusion-related reactions.

• Subsequent Infusions:

  Administer infusion over 1 to 2 hours if prior infusions were tolerated. Observe individual during the infusion and for at least 30 minutes after infusion.

Do not substitute Trodelvy for or use with other drugs containing irinotecan or its active metabolite SN-38.

Premedication for prevention of infusion reactions and prevention of chemotherapy-induced nausea and vomiting is recommended. Monitor individuals during the infusion and for at least 30 minutes after completion of infusion. Treatment interruption and/or dose reduction may be needed to manage adverse reactions.

Source: Gilead Sciences, 2022

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Other CPT codes related to the CPB:
88360	Morphometric analysis, tumor immunohistochemistry (eg, Her-2/neu, estrogen receptor/progesterone receptor), quantitative or semiquantitative, per specimen, each single antibody stain procedure; manual
88361	using computer-assisted technology
96413 - 96416	Chemotherapy administration, intravenous infusion technique
HCPCS codes covered if selection criteria are met:
J9317	Injection, sacituzumab govitecan-hziy, 2.5 mg
Other HCPCS codes related to the CPB:
Letrozole, abemaciclib, palbociclib, ribociclib – no specific code
J9000	Injection, doxorubicin hydrochloride, 10 mg
J9196	Injection, gemcitabine hydrochloride (accord), not therapeutically equivalent to j9201, 200 mg
J9198	Injection, gemcitabine hydrochloride, (infugem), 100 mg
J9201	Injection, gemcitabine hydrochloride, not otherwise specified, 200 mg
J9267	Injection, paclitaxel, 1 mg
J9358	Injection, fam-trastuzumab deruxtecan-nxki, 1 mg
J9393	Injection, fulvestrant (teva) not therapeutically equivalent to J9395, 25 mg
J9394	Injection, fulvestrant (fresenius kabi) not therapeutically equivalent to J9395, 25 mg
J9395	Injection, fulvestrant, 25 mg
Q2049	Injection, doxorubicin hydrochloride, liposomal, imported lipodox, 10 mg
Q2050	Injection, doxorubicin hydrochloride, liposomal, not otherwise specified, 10 mg
S0170	Anastrozole, oral, 1 mg
ICD-10 codes covered if selection criteria are met:
C50.011 - C50.929	Malignant neoplasm of breast
C67.0 - C67.9	Malignant neoplasm of bladder [urothelial cancer]
C68.0 - C68.9	Malignant neoplasm of other and unspecified urinary organs [primary carcinoma of the urethra and upper genitourinary tract tumors]

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Background

U.S. Food and Drug Administration (FDA)-Approved Indications

• Trodelvy is indicated for the treatment of adult patients with unresectable locally advanced or metastatic triple-negative breast cancer (mTNBC) who have received two or more prior systemic therapies, at least one of them for metastatic disease.
• Trodelvy is indicated for the treatment of adult patients with unresectable locally advanced or metastatic hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative (IHC 0, IHC 1+ or IHC 2+/ISH-) breast cancer who have received endocrine based therapy and at least two additional systemic therapies in the metastatic setting.
• Trodelvy is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer (mUC) who have previously received a platinum-containing chemotherapy and either a programmed death receptor-1 (PD-1) or a programmed death-ligand 1 (PD-L1) inhibitor.

Compendial Uses

• Breast cancer
  
• Urothelial carcinoma
  
  
  • Bladder cancer
  • Primary carcinoma of the urethra
  • Upper genitourinary tract tumors
  • Urothelial carcinoma of the prostate

Sacituzumab govitecan-hziy is available as Trodelvy (Immunomedics, Inc.) and is an antibody-drug conjugate that combines a humanized monoclonal antibody, which targets the human trophoblast cell-surface antigen 2 (Trop-2), with SN-38 (an active metabolite of irinotecan, a topoisomerase I inhibitor), which is conjugated to the antibody by a cleavable linker (Bardia et al., 2019). TROP2, also known as epithelial glycoprotein-1 antigen (EGP-1), is a cell-surface receptor that is overexpressed by a variety of human epithelial carcinomas (e.g., breast, colon, and lung). This antigen is involved in the regulation of cell-cell adhesion and its expression is associated with increased cancer growth, aggressiveness and metastasis (NCI, 2020). Sacituzumab govitecan-hziy enables delivery of high concentrations of SN-38 to tumors.

Trodelvy (sacituzumab govitecan-hziy) carries the following black box warnings:

• Neutropenia - In clinical trial, neutropenia was noted in 62% of patients and Grade 3-4 neutropenia was noted in 47% of patients treated with Trodelvy. Febrile neutropenia was noted in 6% of patients.
• Diarrhea - In clinical trial, diarrhea was noted in 64% of all patients and Grade 3 diarrhea was noted in 12% of patients treated with Trodelvy.

Additional warnings and precautions include the following:

• Hypersensitivity and infusion-related reactions - In clinical trial, hypersensitivity reactions within 24 hours of dosing were noted in 37% of patients and Grade 3-4 hypersensitivity was noted in 1% of patients treated with Trodelvy.
• Nausea and vomiting - In clinical trial, nausea was noted in 67% of all patients and Grade 3-4 nausea in 5% of patients treated with Trodelvy. In clinical trial, vomiting was noted in 40% of all patients and Grade 3-4 vomiting was noted in 3% of these patients treated with Trodelvy.
• Increased risk of adverse reactions in patients with reduced uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1) - Individuals who are homozygous for the UGT1A1*28 allele are at increased risk for neutropenia, febrile neutropenia, and anemia when treated with Trodelvy.
• Embryo-fetal toxicity.

Source: Immunomedics, 2021

A phase I/II study of sacituzumab govitecan-hziy (IMMU-132) evaluated patients with epithelial cancers. The primary objective was to evaluate the safety and tolerability of IMMU-132 as a single agent administered in 3-week treatment cycles until unacceptable progression or toxicity, in previously treated patients with advanced epithelial cancer. In Phase II, the primary objective was the evaluation of the safety and efficacy of IMMU-132 administered in 3-week treatment cycles at a dose selected in Phase I, while the secondary objectives include pharmacokinetics and immunogenicity. This open-label study enrolled patients who were at least 18 years of age and had one of the following epithelial cancer types: gastric adenocarcinoma, esophageal cancer, hepatocellular carcinoma (HCC), non-small-cell lung cancer (NSCLC), small-cell lung cancer (SCLC), epithelial ovarian cancer, cervical cancer, endometrial cancer, follicular thyroid cancer, glioblastoma multiforme (GBM), hormone-refractory prostate cancer, head and neck cancers- squamous cell, renal cell cancer (RCC), urothelial cancer, non-triple-negative breast cancer, and triple-negative breast cancer (TNBC, n=108). Eligibility also included stage IV (metastatic) disease (except for patients with GBM), refractory to or relapsed after at least one prior standard therapeutic regimen, adequate performance status (ECOG 0 or 1), expected survival 6 months or greater, measurable disease by CT or MRI, at least 2 weeks beyond high dose systemic corticosteroids (however, low dose corticosteroids < 20 mg prednisone or equivalent daily are permitted), adequate hematology without ongoing transfusional support (hemoglobin > 9 g/dL, ANC > 1,500 per mm³, platelets > 100,000 per mm³) and adequate renal and hepatic function. The overall safety population (N=420) consisted of all patients who entered the study up to a pre-defined enrollment cutoff date; patients in the overall safety population received sacituzumab govitecan doses of 8, 10, 12, and 18 mg/kg (Bardia et al., 2019, Immunomedics, 2019).

Breast Cancer

From the phase I/II trial (IMMU-132), Bardia and colleagues (2019) conducted a single-arm phase II study that found sacituzumab govitecan-hziy to be associated with durable objective responses in patients with heavily pretreated metastatic triple-negative breast cancer (TNBC). The phase II study consisted of a single-group, multicenter trial involving patients with advanced epithelial cancers who received sacituzumab govitecan-hziy intravenously on days 1 and 8 of each 21-day cycle until disease progression or unacceptable toxic effects. A total of 108 patients received sacituzumab govitecan-hziy at a dose of 10 mg per kilogram of body weight after receiving at least two previous anticancer therapies for metastatic TNBC. The end points included safety; the objective response rate (ORR; according to Response Evaluation Criteria in Solid Tumors, version 1.1); the duration of response (DoR); the clinical benefit rate (defined as a complete or partial response or stable disease for at least 6 months); progression-free survival (PFS); and overall survival (OS). Post hoc analyses determined the response rate and duration, which were assessed by blinded independent central review. The 108 patients with TNBC had received a median of 3 previous therapies. Four deaths occurred during treatment; 3 patients (2.8%) discontinued treatment because of adverse events. Grade 3 or 4 adverse events (in ≥10% of the patients) included anemia and neutropenia; 10 patients (9.3%) had febrile neutropenia. The response rate (3 complete and 33 partial responses) was 33.3% (95% confidence interval [CI], 24.6 to 43.1), and the median duration of response was 7.7 months (95% CI, 4.9 to 10.8); as assessed by independent central review, these values were 34.3% and 9.1 months, respectively. The clinical benefit rate was 45.4%. Median PFS was 5.5 months (95% CI, 4.1 to 6.3), and OS was 13.0 months (95% CI, 11.2 to 13.7). The investigators stated that sacituzumab govitecan-hziy is an antibody–drug conjugate with Trop-2 as the target of recognition; it can deliver cytotoxic chemotherapy to tumors, including adjacent cancer cells, in concentrations that are higher than those with standard chemotherapy and may reduce toxic effects in normal tissues that do not express the target. High expression of Trop-2 in TNBC and its association with a poor prognosis suggest that it is a rational therapeutic target in this patient population. The investigators concluded that, sacituzumab govitecan-hziy (IMMU-132) had efficacy with a 33% response rate in a heavily pretreated population of patients with metastatic TNBC. Diarrhea and myelosuppression were the primary adverse events, and discontinuation rates were low.

On April 22, 2020, the Food and Drug Administration (FDA) granted accelerated approval for Trodelvy (sacituzumab govitecan-hziy) (Immunomedics, Inc.) for the treatment of adult patients with metastatic TNBC who have received at least 2 prior therapies for metastatic disease.  Trodelvy, which was granted Breakthrough Therapy Designation and Priority Review, was approved based on the objective response rate (ORR) and duration of response (DOR) observed in the single-arm, multi-center phase II study (Bardia et al, 2019).  The ORR was 33.3 %, with a median duration of response of 7.7 months.  Of the patients with a response to Trodelvy, 55.6 % maintained their response for 6 or more months and 16.7 % maintained their response for 12 or more months.  Continued approval had been contingent upon verification of clinical benefit in the confirmatory Phase 3 ASCENT study, which was halted by the independent Data Safety Monitoring Committee (DSMC) for compelling evidence of efficacy across multiple endpoints.  The ASCENT trial was designed to validate the promising safety and efficacy data of sacituzumab govitecan observed in the phase II study of heavily pre-treated patients with metastatic TNBC (FDA, 2020; Immunomedics, 2020(a)(b)).

On April 07, 2021, the FDA granted full approval to Trodelvy (sacituzumab govitecan-hziy) for adult patients with unresectable locally advanced or metastatic triple-negative breast cancer (TNBC) who have received 2 or more prior systemic therapies, at least 1 of them for metastatic disease.  The FDA approval was based on the supporting data from the Phase 3 ASCENT study (Gilead, 2021a).

The Phase 3 ASCENT trial was a multicenter, open-label, randomized study in which Bardia and colleagues (2021) evaluated the efficacy of Trodelvy in patients with unresectable locally advanced or metastatic triple-negative breast cancer (mTNBC) who had relapsed after at least two prior chemotherapies for breast cancer (one of which could be in the neoadjuvant or adjuvant setting in which progression occurred in a 12 month period). The study consisted of 468 patients without brain metastases who were randomly assigned (1:1) to receive Trodelvy (235 patients) or single-agent chemotherapy (233 patients) of the physician's choice (eribulin, vinorelbine, capecitabine, or gemcitabine). Patients in the Trodelvy arm received 10 mg/kg as an intravenous infusion on days 1 and 8 of a 21-day treatment cycle. The major efficacy outcome was progression-free survival. The median progression-free survival was 5.6 months (95% confidence interval [CI], 4.3 to 6.3; 166 events) with Trodelvy and 1.7 months (95% CI, 1.5 to 2.6; 150 events) with chemotherapy. The median overall survival was 12.1 months (95% CI, 10.7 to 14.0) with Trodelvy and 6.7 months (95% CI, 5.8 to 7.7) with chemotherapy. Objective response in patients was noted as 35% with Trodelvy and 5% with chemotherapy. The occurrence of notable treatment-related adverse events of grade 3 or higher were neutropenia (51% with Trodelvy and 33% with chemotherapy), leukopenia (10% and 5%), diarrhea (10% and < 1%), anemia (8% and 5%), and febrile neutropenia (6% and 2%).

On February 3, 2023, the FDA approved sacituzumab govitecan-hziy (Trodelvy) for the treatment of patients with unresectable locally advanced or metastatic hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer who have received endocrine-based therapy and at least two additional systemic therapies in the metastatic setting. The FDA approval was based on supporting data from the TROPiCS-02 study. This multicenter, open label, randomized study evaluated the efficacy of sacituzumab govitecan-hziy (Trodelvy) in 543 patients with unresectable locally advanced or metastatic hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer whose disease progressed after the following in any setting: a CDK 4/6 inhibitor, endocrine therapy, and a taxane. Patients received at least two prior chemotherapies in the metastatic setting (one of which could be in the neoadjuvant or adjuvant setting if recurrence occurred within 12 months). Patients were randomized (1:1) to sacituzumab govitecan-hziy, 10 mg/kg as an intravenous infusion, on Days 1 and 8 of a 21-day cycle (n=272) or single agent chemotherapy (n=271). Single agent chemotherapy was determined by the investigator before randomization from one of the following choices: eribulin (n=130), vinorelbine (n=63), gemcitabine (n=56), or capecitabine (n=22). Randomization was stratified by the following factors: prior chemotherapy regimens for metastatic disease (2 vs. 3-4), visceral metastasis (Yes or No), and endocrine therapy in the metastatic setting for at least 6 months (Yes or No). Patients were treated until disease progression or unacceptable toxicity. The primary efficacy outcome measure was progression-free survival (PFS) determined by blinded independent central review per RECIST v1.1. A key secondary efficacy outcome measure was overall survival (OS). Median PFS was 5.5 months (95% CI: 4.2, 7.0) in the sacituzumab govitecan-hziy arm and 4 months (95% CI: 3.1, 4.4) in the single agent chemotherapy arm (hazard ratio [HR] of 0.661 [95% CI: 0.529, 0.826]; p=0.0003). Median OS was 14.4 months for those receiving sacituzumab govitecan-hziy (95% CI: 13.0, 15.7) and 11.2 months (95% CI: 10.1, 12.7) for those receiving single agent chemotherapy (HR of 0.789 [95% CI: 0.646, 0.964]; p=0.0200) (FDA, 2023; Gilead Sciences, 2023).

Other Cancers

Cardillo et al (2015) state that as the clinical utility of sacituzumab govitecan (IMMU-132) expands to an ever-widening range of Trop-2-expressing solid tumor types, its efficacy in new disease models needs to be explored in a nonclinical setting. "Unlike most ADCs that use ultratoxic drugs and stable linkers, IMMU-132 uses a moderately toxic drug with a moderately stable carbonate bond between SN-38 and the linker. Flow cytometry and immunohistochemistry disclosed that Trop-2 is expressed in a wide range of tumor types, including gastric, pancreatic, triple-negative breast (TNBC), colonic, prostate, and lung. While cell-binding experiments reveal no significant differences between IMMU-132 and parental hRS7 antibody, surface plasmon resonance analysis using a Trop-2 CM5 chip shows a significant binding advantage for IMMU-132 over hRS7. The conjugate retained binding to the neonatal receptor, but it lost greater than 60% of the antibody-dependent cell-mediated cytotoxicity activity compared to that of hRS7. Exposure of tumor cells to either free SN-38 or IMMU-132 demonstrated the same signaling pathways, with pJNK1/2 and p21(WAF1/Cip1) upregulation followed by cleavage of caspases 9, 7, and 3, ultimately leading to poly-ADP-ribose polymerase cleavage and double-stranded DNA breaks. Pharmacokinetics of the intact ADC in mice reveals a mean residence time (MRT) of 15.4 h, while the carrier hRS7 antibody cleared at a similar rate as that of the unconjugated antibody (MRT ∼ 300 h). IMMU-132 treatment of mice bearing human gastric cancer xenografts (17.5 mg/kg; twice weekly × 4 weeks) resulted in significant antitumor effects compared to that of mice treated with a nonspecific control. Clinically relevant dosing schemes of IMMU-132 administered either every other week, weekly, or twice weekly in mice bearing human pancreatic or gastric cancer xenografts demonstrate similar, significant antitumor effects in both models".  The authors report that "phase I/II clinical trials (ClinicalTrials.gov, NCT01631552) confirm anticancer activity of IMMU-132 in cancers expressing Trop-2, including gastric and pancreatic cancer patients".

Starodub and colleagues (2015) conducted the first-in-human trial of a novel anti-Trop-2 antibody-SN38 conjugate, sacituzumab govitecan, for the treatment of various metastatic solid tumors. The phase I trial evaluated this antibody-drug conjugate (ADC) as a potential therapeutic agent for 25 pretreated patients (52-60 years old, 3 median prior chemotherapy regimens). Sacituzumab govitecan was administered on days 1 and 8 of 21-day cycles, with cycles repeated until dose-limiting toxicity or progression. Dose escalation followed a standard 3 + 3 scheme with 4 planned dose levels and dose delay or reduction allowed. Neutropenia was dose limiting, with 12 mg/kg the maximum tolerated dose for cycle 1, but too toxic with repeated cycles. Lower doses were acceptable for extended treatment with no treatment-related grade 4 toxicities and grade 3 toxicities limited to fatigue (n = 3), neutropenia (n = 2), diarrhea (n = 1), and leukopenia (n = 1). Using CT-based RECIST 1.1, two patients achieved partial responses (triple-negative breast cancer, colon cancer) and 16 others had stable disease as best response. Twelve patients maintained disease control with continued treatment for 16 to 36 weeks; 6 survived 15 to 20+ months. No preselection of patients based on tumor Trop-2 expression was done. The authors concluded this phase I experience has indicated that sacituzumab govitecan is tolerated with moderate and manageable toxicity, all related to the activity of SN-38, with no evidence of damage to normal tissues known to contain Trop-2. Importantly, sacituzumab govitecan is active in patients with diverse metastatic solid tumors, possibly even after failing prior therapy with topoisomerase-I inhibitors, which needs to be studied further. This 8 and 10 mg/kg doses were selected for the phase II studies for patients with TNBC, SCLC, NSCLC and other cancers.

Faltas and colleagues (2016) state that patients with metastatic, platinum-resistant urothelial carcinoma (PRUC) have had no FDA approved therapies. The response rates to second-line chemotherapy have generally been < 20%, with a median overall survival of < 1 year. The authors report on their experience with 6 heavily pretreated patients with advanced PRUC with the novel antibody-drug conjugate, sacituzumab govitecan (IMMU-132), which is comprised of the active metabolite of irinotecan, SN-38, conjugated to an anti-Trop-2 antibody. The authors note that Trop-2 is widely expressed in 83% or less of urothelial carcinomas. Patients (range, 42-80 years) were eligible for the trial if they had advanced PRUC (primary UC site: n=3 bladder, n= 2 renal pelvis, n=1 ureter). Sacituzumab govitecan was administered intravenously on days 1 and 8 of 21-day cycles that were repeated until dose-limiting toxicity or progression developed. Response was assessed using the Response Evaluation Criteria in Solid Tumors, version 1.1. When available, immunohistochemical staining of archival tumor biopsy specimens obtained from treated patients was performed. The authors found that of the 6 patients, 3 had a clinically significant response (progression-free survival, 6.7 to 8.2 months; overall survival, 7.5+ to 11.4+ months). Sacituzumab govitecan was well tolerated. Because of these results, the phase II trial was initiated. The authors concluded that their report highlights the promise of antibodyedrug conjugates, such as sacituzumab govitecan, as a novel therapeutic strategy for the treatment of PRUC.

Urothelial Cancer

On April 13, 2021, the FDA granted accelerated approval of Trodelvy (sacituzumab govitecan-hziy) for use in adult patients with locally advanced or metastatic urothelial cancer (UC) who previously received a platinum-containing chemotherapy and either a programmed death receptor-1 (PD-1) or a programmed death-ligand 1 (PD-L1) inhibitor.  The FDA approval was based on supporting data from the Phase 2 TROPHY study (Gilead, 2021b).  The Phase 2 TROPHY study was a single-arm, multicenter trial that consisted of 112 patients with locally advanced or metastatic urothelial cancer (mUC) who had received prior treatment with a platinum-containing chemotherapy and either PD-1 or PD-L1 inhibitor.  Patients received Trodelvy 10 mg/kg as an intravenous infusion on days 1 and 8 of a 21-day treatment cycle.  The major efficacy outcome measures included ORR and DOR.  ORR was noted in 27.7 % (95 % CI: 19.6 to 36.9) of patients with a complete response of 5.4% and a partial response of 22.3%. Thirty-one patients responded to Trodelvy therapy with a mediation DOR of 7.2 months (95 % CI: 4.7 to 8.6 months) (Immunomedics, 2021).

Colon Cancer

Guerra and colleagues (2021) noted that they recently reported that activation of Trop2 via its cleavage at R87-T88 by ADAM10 underlies Trop2-driven progression of colon cancer; however, the mechanism of action and pathological impact of Trop-2 in metastatic diffusion remain unexplored.  Through searches for molecular determinants of cancer metastasis, these researchers identified Trop2 as unique in its up-regulation across independent colon cancer metastasis models.  Over-expression of wild-type Trop2 in KM12SM human colon cancer cells increased liver metastasis rates in-vivo in immunosuppressed mice.  Metastatic growth was further enhanced by a tail-less, activated ΔcytoTrop2 mutant, indicating the Trop2 tail as a pivotal inhibitory signaling element.  In primary tumors and metastases, transcriptome analysis showed no down-regulation of CDH1 by transcription factors for epithelial-to-mesenchymal transition; thus, suggesting that the pro-metastatic activity of Trop2 is through alternative mechanisms.  Trop2 can tightly interact with ADAM10.  Trop2 bound E-cadherin and stimulated ADAM10-mediated proteolytic cleavage of E-cadherin intracellular domain.  This induced detachment of E-cadherin from β-actin, and loss of cell-cell adhesion, acquisition of invasive capability, and membrane-driven activation of β-catenin signaling, which were further enhanced by the ΔcytoTrop2 mutant.  This Trop2/E-cadherin/β-catenin program led to anti-apoptotic signaling, increased cell migration, and enhanced cancer-cell survival.  In patients with colon cancer, activation of this Trop2-centered program led to significantly reduced relapse-free survival (RFS) and OS, indicating a major impact on progression to metastatic disease.  Recently, the anti-Trop2 mAb sacituzumab govitecan-hziy was shown to be active against metastatic breast cancer; these findings provided ground for potential major relevance of Trop2 as a target in metastatic colon cancer.

Extra-Mammary Paget's Disease

Ito and colleagues (2021) noted that extra-mammary Paget's disease (EMPD) is a rare skin cancer arising in the apocrine gland-rich areas.  Most EMPD tumors are dormant, but metastatic lesions are associated with poor outcomes owing to the lack of effective systemic therapies.  Trop2, a surface glycoprotein, has drawn attention as a potential therapeutic target for solid tumors.  Sacituzumab govitecan, an antibody-drug conjugate of Trop2, has recently entered clinical use for the treatment of various solid cancers; however, little is known regarding the role of Trop2 in EMPD.  In a retrospective study, these researchers immunohistochemically examined Trop2 expression in 116 EMPD tissue samples and 10 normal skin tissues.  In normal skin, Trop2 was expressed in the epidermal keratinocytes, inner root sheaths, and infundibulum/isthmus epithelium of hair follicles, eccrine/apocrine glands, and sebaceous glands.  Most EMPD tissues exhibited homogeneous and strong Trop2 expression, and high Trop2 expression was significantly associated with worse disease-free survival (DFS; p = 0.0343).  The authors concluded that the findings of this study suggested the potential use of Trop2-targeted therapy for EMPD and improved the understanding of the skin-related adverse effects of current Trop2-targeted therapies such as sacituzumab govitecan.

These researchers stated that besides the potential biases inherent in the retrospective design, one drawback of this study was that these investigators did not address the molecular mechanisms of Trop2, and the roles of Trop2 in EMPD are still unknown because no cell line of EMPD has been established.

Prostate Cancer

Shen and colleagues (2021) noted that prostate cancer remains the 2nd leading cause of cancer-associated deaths among men in the U.S.  Trop2 correlates with poor clinical outcome and is highly expressed in metastatic, treatment-resistant prostate cancer.  High levels of Trop2 are prognostic for biochemical recurrence.  Trop2 regulates tumor growth and metastatic ability of prostate cancer.  Moreover, over-expression of Trop2 drives the trans-differentiation to neuroendocrine phenotype in prostate cancer.  Furthermore, Trop2 is over-expressed across epithelial cancers and has emerged as a promising therapeutic target in various solid epithelial cancers.  The FDA recently approved the use of a Trop2-targeting ADC (antibody-drug conjugate), sacituzumab govitecan for the treatment of metastatic, TNBC with at least 2 prior therapies.  The authors reviewed the role of Trop2 in prostate cancer tumorigenesis and its potential as a promising biomarker and therapeutic target for prostate cancer.

Salivary Gland Carcinomas

Wolber and colleagues (2021) stated that therapeutic options for unresectable, recurrent or metastatic salivary gland carcinomas (SGC) are scarce.  Trop-2 is involved in a variety of oncogenic cell signaling pathways.  Its potential as a target for the antibody-drug conjugate sacituzumab govitecan has already been demonstrated in different tumor entities.  The FDA approved this antibody-drug conjugate for the treatment of metastatic TNBC.  These investigators examined Trop-2 protein expression in different entities of SGCs.  They retrospectively reviewed the medical records of all patients that underwent surgery for a primary SGC in a tertiary referral center between 1990 and 2014.  Immunohistochemical (IHC) staining for Trop-2 was carried out and rated as negative, weak, moderate or high using a semi-quantitative score.  Furthermore, representative cases were analyzed using MALDI-mass spectrometry (MS) imaging to confirm the IHC results.  The cohort consisted of 114 tumors of the parotid gland (90.4 %) and submandibular gland (9.6 %).  It mainly included mucoepidermoid, salivary duct and adenoid cystic carcinomas.  In IHC samples, 44 % showed high, 38 % moderate and 10 % weak expression rates of Trop-2.  MALDI-MS imaging confirmed the presence of Trop-2 protein in 80 % of the tested tumor samples.  The authors concluded that this was the 1st study to demonstrate that several types of SGC express Trop-2 with variable intensity.  Since there are currently few systemic therapeutic options for advanced SGCs, Trop-2 represents a promising target for further clinical studies, such as with sacituzumab govitecan.

The authors concluded that drawbacks of this trial included the retrospective design of the analyses.  The limited number of cases among each individual tumor type made it difficult to establish correlations with clinical parameters or outcome.  However, due to the low incidence of certain SGC subtypes, desirable prospective studies with sufficient subjects are especially challenging.  Nevertheless, despite these shortcomings these investigators are convinced that the findings of this exploratory study can be followed-up in clinical studies with Trop-2 as a target in SGC.

Esophageal Adenocarcinoma

Hoppe et al (2022) noted that the trophoblast cell surface antigen 2 (TROP2) is expressed in many carcinomas and may represent a target for treatment.  Sacituzumab govitecan (SG) is a TROP2-directed ADC.  Nearly nothing is known regarding the biological effectiveness of SG in esophageal adenocarcinoma (EAC).  These researchers examined the TROP2 expression in nearly 600 human EAC.  Furthermore, they used the EAC cell lines (ESO-26, OACM5.1C, and FLO-1) and a xenograft mouse model to examine this relationship.  Of 598 human EACs analyzed, 88 % showed varying degrees of TROP2 positivity.  High TROP2 positive ESO-26 and low TROP2 positive OACM5.1C showed high sensitivity to SG in contrast to negative FLO-1.  In-vivo, the ESO-26 tumor showed a significantly better response to SG than the TROP2-negative FLO-1 tumor.  ESO-26 vital tumor cells showed similar TROP2 expression on all carcinoma cells as before therapy initiation, FLO-1 was persistently negative.  The authors concluded that the findings of this study data suggested that is a new therapeutic option in esophageal adenocarcinoma and the TROP2 expression in irinotecan-naïve EAC correlated with the extent of treatment response by sacituzumab govitecan.  These researchers stated that TROP2 is emerging as a predictive biomarker in completely TROP2-negative tumors’ and this should be considered in future clinical trials.

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