TROPHY U-01 (NCT03547973) COHORT 1 is a phase 2 open-label study of sacituzumab govitecan (SG) in patients with metastatic urothelial cancer (mUC) and disease progression after both platinum-based regimens and checkpoint inhibitors (CPIs).

SG is a Trop-2–directed antibody-drug conjugate (ADC). It is a humanized anti–Trop-2 antibody, which is an epithelial antigen expressed on many solid tumors and is highly expressed in urothelial cancer. SG is distinct from other ADCs because there is a high drug-to-antibody ratio, and there is a bystander effect due to its hydrolysable linker. When SG’s SN-38 payload, which is a more potent parent compound than irinotecan, is released, the hydrolysable payload allows drugs to get into the tumor cells and the microenvironment around the tumor cells, making SG unique. This attribute has significant activity across several tumors, and SG has recently been approved for triple-negative breast cancer and received fast track designation for mUC. A phase 3 trial in urothelial cancer is under way.

Cohort 1 consisted of 100 patients with mUC who progressed after prior platinum-based and CPI-based therapy. Patients were given 10 mg/kg on days 1 and 8 of an every- 21-day cycle, and the primary objective was overall response rate (ORR) by central review. The cohort was conducted in 2 stages. Scott T. Tagawa, MD, MS, FACP, presented the first 35 patients at the European Society for Medical Oncology (ESMO) 2019 meeting, which led to a continued enrollment of cohort 1 up to the intention-to-treat analysis of 113 patients based on a blinded independent central assessment of data for RECIST v1. The data cutoff for the report was May 18, 2020.

Regarding patient disposition, 66% of patients in the trial stopped treatment because of progressive disease versus 14% who have continued treatment. Comparatively, there are still patients in follow-up for survival in 50% of the cases. The median treatment time was 3.7 months. Although the patient population was highly pretreated, 28% had liver metastases, and 48% had lung or pleural metastases. The median number of anticancer regimens was 3, and more than 50% of patients had more than 3 regimens. This treatment was a fourth line therapy, and 72% percent of patients had had cisplatin and 35% had carboplatin.

At the ESMO virtual meeting, Yohann Loriot, MD, PhD, presented a 27% ORR, which included a 5% conversion rate and a 22% partial remission rate. The median duration of response was 5.9 months. Reduction in tumor size was also observed in the study. Specifically, 76% of patients had reduction in their tumor size as it relates to primarily third- and fourth-line therapy.

Many of the patients from the study are still alive. Twenty-seven of 31 responders are alive, and 8 have an ongoing response and were still on treatment as of the data cutoff. Additionally, many of the patients by the May 20, 2020, cutoff were still on treatment.

The median progression-free survival (PFS) was 5.4 months. The median overall survival was 10.5 months. Comparatively, second-line therapy in this case has been historically 7 to 9 months in duration. Therefore, having a fourth-line therapy with a median overall survival of 10.5 months and a PFS of 5.4 months is excellent for that sick patient population with widely metastatic visceral disease.

Adverse effects included mostly neutropenia, leukopenia, and anemia. A portion of patients experienced diarrhea, but few reached grade 3 and 4. Other adverse effects included nausea and fatigue, but the majority of symptoms were not grade 3 or 4. These results may have been due to the drug irinotecan and UGT1A1 genotypes being homozygous; therefore, this population was most likely to have the neutropenia, which additionally was not associated with diarrhea in this study. Moreover, there was a 30% granulocyte colony-stimulating factor usage in the study.

In conclusion, the TROPHY U-01 cohort 1 results confirm the interim findings presented by Tagawa and prior phase 1 and 2 study results. SG has significant activity and is safe in patients with heavily pretreated mUC who progress on platinum, cisplatin, carboplatin, and a CPI. The results of SG were a 27% overall response rate, 5.9 months’ median duration of response, and 5.4 months’ median PFS. Additionally, the therapies compare favorably with single-agent chemotherapy that is typically given in the second or third line, such as the taxanes or vinflunine. SG has received fast track designation in this indication and may have the potential to change practice in this setting. A phase 3 confirmatory trial in mUC called TROPiCS-04 (NCT04527991) is under way.

The TROPiCS-04 study design is for patients with mUC on the upper tract or urothelial tract. Mixed histological types will be allowed, but if the urothelial cancer is predominant, patients will have progressed after platinum-based therapy and a CPI or platinum in the neoadjuvant adjuvant setting within 12 months and will be randomized, specifically 482 patients to SG and investigators’ choice of either docetaxel, paclitaxel, or vinflunine. Currently, the primary end point is overall survival.

Articles

TROPHY U-01 cohort 1 is a phase 2 open-label study of sacituzumab govitecan in patients with metastatic urothelial cancer and disease progression after both platinum-based regimens and checkpoint inhibitors.

ESMO 2020 Highlights With Cora Sternberg, MD, FACP

Hello, on behalf of my coauthors and me, it is my pleasure to present the first results of the phase 3 ASCENT trial (NCT02574455) on sacituzumab govitecan versus treatment of physician’s choice (TPC) in patients with previously treated metastatic triple-negative breast cancer (TNBC). Because of compelling evidence of efficacy and a unanimous recommendation from the Data and Safety Monitoring Committee, the ASCENT trial was halted early.

Sacituzumab govitecan is a first-in-class antibody drug conjugate (ADC) directed toward Trop-2, which is expressed in all subtypes of breast cancer and is linked to poor prognosis. Sacituzumab govitecan has 3 components: the antibody against Trop-2, a hydrolysable linker for payload release, and the SN-38 payload, which is the active metabolite of irinotecan. Sacituzumab govitecan is distinct from other ADCs, with 3 unique properties. First, the antibody is highly specific for Trop-2. Second, the ADC has a high drug-to-antibody ratio; therefore, for every antibody, there are 7.6 molecules of SN- 38 attached to the ADC. Third, internalization and enzymatic cleavage by the tumor cell is not required for liberation of SN-38. Hydrolysis of the linker releases SN-38 extracellularly in the tumor microenvironment, providing the bystander effect.

Sacituzumab govitecan received accelerated approval from the FDA for treatment of patients with metastatic TNBC and fast track designation in metastatic urothelial cancer. The FDA was involved in the phase 1 and phase 2 trials with this agent. In patients with pretreated metastatic breast cancer, a response rate of 33% was seen, and this resulted in accelerated approval.

ASCENT was designed as a phase 3 confirmatory study of sacituzumab govitecan versus TPC for patients with refractory/relapsed metastatic TNBC. In terms of eligibility, patients with metastatic TNBC who had received at least 2 prior lines of chemotherapy for advanced disease were eligible. There was no upper limit. Prior therapies could include either neoadjuvant treatment that resulted in progression within 12 months of completion or adjuvant treatment completed as frontline.

The primary end point of the trial was progression-free survival (PFS), and the secondary end points included overall survival and objective response rate. The stratification factors were the number of prior chemotherapies, the geographic region, and the presence or absence of brain metastases. Here we present primary and secondary results, including PFS and overall survival. Additional secondary results, including biomarkers, efficacy in brain metastasis only, and the impact of the UGT1A1 genotype on safety and tolerability, will be presented in a future meeting.

Analysis of the primary end point of PFS was based on central assessment of a brain metastasis–negative patient population using a stratified log-rank test. A predefined maximum gap of 15% for patients with brain metastases was included in the trial. Assuming a hazard ratio of 0.667, a sample size of at least 488 patients would provide more than 90% power to detect statistically significant improvement in PFS, with 315 defined PFS events. The safety population included all patients with brain metastasis, positive and negative, who received at least 1 dose of treatment. The data cutoff for this analysis was March 11, 2020.

In the trial, 730 patients were screened, and 529 were randomized to receive sacituzumab govitecan or TPC, which was eribulin, capecitabine, gemcitabine, or vinorelbine; patients receiving TPC were considered the safety population. There were 235 patients without brain metastases in the sacituzumab govitecan arm and 233 in the TPC arm. This was the primary data set for efficacy analysis. The treatment discontinuation rate due to adverse events (AEs) was low. Within the TPC arm, most patients received eribulin followed by vinorelbine, gemcitabine, and capecitabine.

In terms of demographics and patient characteristics, most patients were female, with a median age of around 54 years. Most patients were White, but 12% were African American in both arms. Regarding BRCA mutation status, 7% of patients in the sacituzumab govitecan arm and 8% in the TPC arm were known to be BRCA positive. Previous lines of anticancer regimens received by the patients included all anticancer therapies, not only chemotherapy but also other targeted therapies. For patients who had hormone receptor–positive disease and became triple negative at the time of metastatic diagnosis, these also included endocrine therapy.

The median for the number of previous anticancer regimens was 4 in both arms. Regarding prior chemotherapy, 100% of patients had received taxanes, 81% had received an anthracycline, and about 66% had received prior platinum. About 25% of patients had received a prior checkpoint inhibitor. The most common sites of metastases were the lung and liver.

All subgroups derived benefit with sacituzumab govitecan, regardless of age, race, prior therapies, region, prior use of immunotherapy, liver metastases, and initial diagnosis of TNBC. A blinded independent central review analysis depicted the PFS observed in sacituzumab govitecan versus standard chemotherapy. The median PFS was 5.6 months with sacituzumab govitecan and 1.7 months with TPC. This corresponded to a hazard ratio of 0.41; therefore, there was a 59% lower risk of progression with sacituzumab govitecan than with TPC. This was highly statistically significant, with P < .0001. This was also seen by investigator-assessed PFS and across the full study population, including patients with brain metastases. Moreover, the hazard ratio was clinically meaningful and statistically significant.

Sacituzumab govitecan was associated with a significant improvement in overall survival, with a median overall survival of 12.1 months versus 6.7 months with TPC, which corresponds to a hazard ratio of 0.48. These results were both statistically significant and clinically meaningful. The objective response rate was 35% with sacituzumab govitecan and 5% with TPC. The clinical benefit rate (defined as having stable disease for more than 6 months, or objective response rate) was 45% with sacituzumab govitecan and 9% with TPC.

Regarding tolerability, sacituzumab govitecan was well tolerated, with a manageable safety profile consistent with that of previous reports. The key grade 3 or higher treatment-related AEs with sacituzumab govitecan included neutropenia, diarrhea, and anemia. In addition, 6% of patients who received sacituzumab govitecan had febrile neutropenia versus 2% of those who received TPC.

Granulocyte colony-stimulating factor usage was 49% with sacituzumab govitecan and 23% with TPC. Patients receiving sacituzumab govitecan had no severe cardiovascular toxicity and no grade 2 or higher neuropathy or grade 3 or higher interstitial lung disease. Therefore, the AEs were hematological conditions, including neutropenia and anemia, or gastrointestinal conditions, with diarrhea being the most common gastrointestinal AE seen with this agent. This is consistent with expectations because AEs are not expected with the SN-38 payload of sacituzumab govitecan.

There were no treatment-related deaths with sacituzumab govitecan, and the rate of AEs resulting in treatment discontinuation was low in both arms: 4.7% for sacituzumab govitecan and 5.4% for TPC. Overall sacituzumab govitecan was well tolerated, and the AEs were managed with either a granulocyte colony-stimulating factor for neutropenia or an antidiarrheal for diarrhea. ASCENT is the first phase 3 trial to demonstrate an improvement in PFS and overall survival with an ADC over standard therapy for patients with metastatic TNBC. This confirms that sacituzumab govitecan should be the new standard of care for patients with pretreated metastatic TNBC. Looking forward, ongoing studies are evaluating sacituzumab govitecan in earlier lines of therapy. These therapies include neoadjuvants, adjuvants, and those in combination with other targeted agents such as PARP inhibitors.

Sacituzumab govitecan is also being looked at in other breast cancer subtypes such as hormone receptor–positive breast cancer. Additionally, the TROPiCS-02 trial (NCT03901339) is looking at sacituzumab govitecan versus standard chemotherapy for patients with hormone receptor-positive metastatic breast cancer. The TROPiCS-02 trial is currently open for enrollment. I would like to thank the patients and their caregivers for their valuable contribution and commitment. We thank the dedicated clinical trial investigators and the devoted team for participating in the ASCENT trial, as this would not have been possible without their commitment and dedication. Finally, thank you to the patients, as well as to the devoted team members. 

Aditya Bardia, MD, MPH, discusses the results of the ASCENT trial in triple-negative breast cancer. 

ESMO 2020 Highlights With Aditya Bardia, MD, MPH

Trophoblast cell surface antigen 2 (Trop-2) is a glycoprotein that spans the epithelial membrane surface and plays a role in cell self-renewal, proliferation, and transformation.

 Encoded by the TACSTD2 gene, Trop-2 is a 35-kDa protein composed of a large extracellular domain, a single transmembrane domain, and a short intracellular tail that is the functionally dominant part of the protein.

Under physiological conditions, Trop-2 plays an essential role in embryonic development, placental tissue formation, embryo implantation, stem cell proliferation, and organ development.

 A low basal expression level of Trop-2 is found on the surface of multiple normal epithelial tissues, including skin and oral mucosa.

 Trop-2 can promote tumor growth and its overexpression is common in many types of malignant epithelial tumors.

 is regulated by several pro-oncogenic transcription factors (eg, CREB1, nuclear factor [NF]–κB, and HOXA

 expression may be upregulated because of the inactivation of several transcription factors (eg, HNF4A, TP63/TP53L, ERG, HNF1A/TCF-1, and FOXP3).

Overexpression of Trop-2 accelerates the cancer cell cycle and drives cancer growth. Knocking out the 

 gene disturbs the proliferation of tumor cells, further validating the role of Trop-2 in tumorigenesis.

Trop-2 was first elucidated as a transducer of intracellular calcium signals; however, it is now known to function in a variety of cell signaling pathways associated with tumorigenesis (Figure 1).

 Expression of Trop-2, as a calcium signal transducer, causes calcium to be mobilized from internal stores. Increased intracellular calcium levels activate MAPK, which in turn increases levels of phosphorylated ERK1 and ERK2.

 ERK1 and ERK2 are important mediators of cell cycle progression, angiogenesis, cell proliferation, cell invasion, and metastasis.

 Intracellular calcium also activates the NF-κB pathway, which is involved in stimulation of cell growth, and the RAF pathway, which is essential for the upregulation of 

, one of the most commonly overexpressed genes in human solid tumors.

In addition to stimulating calcium release and MAPK signaling, Trop-2 is involved in several other pro-oncogenic signaling pathways, leading to tumor cell growth and proliferation. Activation of cyclin E and D further promotes cell cycle progression.

Alteration of the Notch, Hedgehog, and Wnt pathways may discourage appropriate stem cell proliferation and differentiation.

 Trop-2 signaling also appears to be dependent on β-catenin.

 Direct interaction between β-catenin and the intracellular domain of Trop-2, through β-catenin signaling, enhances stem cell–like properties (eg, self-renewal and transformation) of cancer cells.

 Attenuation of IGF-1 receptor signaling by Trop-2 encourages cancer growth and malignancy, particularly in lung cancers.

Figure 1. Involvement of Trop-2 in Tumorigenic Signaling Pathways

Trop-2 Overexpression as a Valuable Biomarker in Solid Tumors

Trop-2 is inextricably linked to cancer progression and metastasis because of its role as a key regulator of the hallmarks of cancer, including cell growth, proliferation, migration, invasion, and survival.

 A variety of human epithelial cancer cells are characterized by Trop-2 overexpression, including breast, lung, urothelial, gastric, colorectal, pancreatic, prostatic, cervical, head and neck, and ovarian carcinomas.

 In an analysis of 702 tissue samples from patients with breast cancer, Trop-2 expression was detected via immunohistochemistry (IHC) across a wide range of breast cancer subtypes.

 Trop-2 expression is substantially higher in hormone receptor–positive/HER2-negative (HR+/HER2-) disease and triple-negative breast cancer (TNBC) compared with other breast cancer subtypes, including HER2-positive disease.

Trop-2 overexpression is also common in non–small cell lung cancer (NSCLC).

 Using IHC on tissues collected from the tumors of 68 patients with NSCLC, Trop-2 expression was significantly higher in NSCLC tissues compared with matched healthy tissues (

 < .05). Moreover, its overexpression was associated with worse tumor, node, metastasis stage (

Bladder cancer, the most common urothelial cancer, is also marked by elevated Trop-2 expression.

 In a study of 102 transitional cell bladder cancer samples, IHC staining for Trop-2 demonstrated increased Trop-2 expression compared with noncancerous samples, and this expression pattern was significantly associated with worsened tumor grade (

 < .0 01), and bladder cancer recurrence (

Molecular markers that influence the biological progress of tumors often serve as important prognostic indicators. Overexpression of Trop-2 has been associated with more aggressive disease, poorer overall survival (OS), and worse disease-free survival in patients with solid tumors.

 A meta-analysis conducted in 2016 explored the association of Trop-2 expression and prognosis in patients with a variety of solid tumors (N = 2569). Results from the study showed that high Trop-2 expression negatively affected OS (hazard ratio, 1.896; 95% CI, 1.599-2.247; 

 < .001) and disease-free survival (pooled hazard ratio, 2.336; 95% CI, 1.596-3.419; 

Specific to breast cancers, increased Trop-2 mRNA is a strong predictor of lymph node involvement, distant metastasis, and poor OS.

Trop-2 is expressed across all breast cancer subtypes; however, overexpression appears more common in aggressive disease subtypes, including HR+/HER2- disease and TNBC.

Trop-2 overexpression is also associated with poor outcomes in patients with urothelial cancer. In an analysis of 102 tissue samples collected from patients with noninvasive bladder cancer, Trop-2 expression was higher in samples from patients who experienced disease recurrence compared with those who did not have recurrent disease (

 = .0 3). Additionally, patients with Trop-2 overexpression had significantly lower rates of recurrence-free survival (

 In a separate study, high Trop-2 expression analyzed by IHC was strongly correlated with bladder cancer severity and worsened disease prognosis, with particularly strong Trop-2 expression in muscle-invasive bladder cancer tissues compared with normal bladder tissues (

Taken together, the data indicate that Trop-2 is a potentially valuable therapeutic target, given the connection between its overexpression and poor prognosis in various solid tumors.

 Its value as a prognostic indicator and potential target for therapeutic development is particularly evident in advanced cancers that have limited or few treatment options available, such as TNBC and metastatic urothelial cancers.

Addressing Unmet Needs in Select Solid Tumors

TNBC is an aggressive form of invasive breast cancer that accounts for 15% to 20% of all breast cancers and a disproportionate number of deaths due to breast cancer.

 Its prevalence is particularly high in premenopausal women and those of African American and Hispanic descents.

 TNBC is characterized by a lack of estrogen and progesterone receptors and a low expression of HER2; therefore, TNBC cannot be effectively treated with standard hormone-based therapies and HER2-targeted agents.

Although chemotherapy has shown promising results in early TNBC, the majority of patients relapse and progress to metastatic TNBC within the first 3 to 5 years after initial treatment.

 The treatment of metastatic TNBC remains a clinical challenge, as no standard-of-care chemotherapy exists for previously treated patients.

 There is an urgent unmet need for effective treatment options in patients with metastatic TNBC.

In the United States, an estimated 81,400 new cases of urothelial cancer will be diagnosed in 2020, and approximately 18,000 Americans will die from the disease.

 The majority of urothelial cancers arise in the bladder, and established risk factors for bladder cancer include older age, male gender, Caucasian race, family history, and smoking.

 Muscle-invasive and meta-static urothelial cancers represent 25% of urothelial carcinoma cases and are characterized by substantially worse prognostic outcomes.

 Current chemotherapeutic options for metastatic disease offer a modest median OS of 15 months and a 5-year survival of less than 5%.

 Long-term survival is infrequent, and newer treatment modalities that target distinct molecular biomarkers are warranted.

As Trop-2 is a clinically relevant cell surface antigen among several solid tumor types, its overexpression on cancer cells makes it an ideal candidate for targeting by specific therapies.26 One targeted approach involves the use of antibody-drug conjugates (ADCs), a technology that has revolutionized the approach to cancer chemo-therapy over the past 2 decades.

An ADC is designed to contain 3 components: a monoclonal antibody (mAb), a cytotoxic drug called a payload, and a linker that connects the mAb to the cytotoxin. The mAb binds specifically to its tumor-associated antigen (eg, Trop-2), thereby delivering the cytotoxin to the surface of the tumor cell. Once bound, the ADC is internalized through receptor-mediated endocytosis. Lysosomal degradation of the ADC ensues, facilitating the release of the cytotoxin and enabling it to bind to its intracellular target and induce apoptotic cell death (Figure 2).

 The targeted nature of ADCs allows potent therapy to be delivered to the cancer cell itself, limiting systemic exposure. The result is fewer adverse effects (AEs), a wider therapeutic window, and reduced exposure of the drug to efflux mechanisms that can increase drug resistance.

Sacituzumab govitecan-hziy is the only FDA-approved Trop-2–targeted ADC, and several other agents are under preclinical and clinical development.

Figure 2. Mechanism of Action for Trop-2–Directed Antibody-Drug Conjugates

Sacituzumab govitecan-hziy is an ADC that binds to Trop-2 and delivers a potent cytotoxic drug into tumor cells.

 The FDA recently granted it accelerated approval for the treatment of metastatic TNBC, and it has also received fast track designation for metastatic urothelial carcinoma, NSCLC, and small cell lung cancer.

The composition of sacituzumab govitecan-hziy has been optimized to effectively target tumors expressing Trop-2. A humanized monoclonal antibody (hRS7) binds to Trop-2 and delivers govitecan (SN-38) to the cell surface. SN-38 is the active metabolite of irinotecan and functions as a DNA topoisomerase I inhibitor. A hydrolysable CL2a linker covalently binds SN-38 to h R S 7.

 When released intracellularly, SN-38 causes double-stranded DNA breaks that lead to apoptosis.

 Additionally, the hydrolysable linker allows a portion of the SN-38 payload to be released into the tumor microenvironment, leading adjacent tumor cells to be killed via a bystander effect.

Sacituzumab govitecan-hziy delivers SN-38 in its most active nonglucuronidated form. Because of its moderate toxicity profile, SN-38 is conjugated to hRS7 at a high drug-to-antibody ratio of up to 8 SN-38 molecules per antibody, allowing for greater drug delivery than systemic irinotecan can achieve.

 Irinotecan causes grade 3 to 4 diarrhea in approximately one-third of patients, whereas the lower toxicity of SN-38 may confer an improved therapeutic index.

 This high level of drug delivery may overcome the ability of Trop-2–expressing tumors to repair DNA breaks.

Therapeutic Development of Sacituzumab Govitecan-hziy in Breast Cancer

On April 22, 2020, sacituzumab govitecan-hziy received accelerated approval from the FDA for the treatment of adult patients with metastatic TNBC who have received at least 2 prior therapies for metastatic disease.

 Approval was based on findings of the phase 1/2, single-arm, multicenter IM-T-IMMU-132-01 trial (NCT01631552), in which sacituzumab govitecan-hziy produced durable responses in a subset of patients with heavily pretreated metastatic TNBC.

The IM-T-IMMU-132-01 trial enrolled 108 patients with metastatic TNBC who had received at least 2 prior treatments for metastatic disease. In the study population, the median number of prior systemic therapies in the metastatic setting was 3, and the majority of patients received prior taxanes (98%) and anthracyclines (86%) in the neoadjuvant or metastatic setting. The median age of study patients was 55 years (range 31-80); 99% were female, and 76% were Caucasian.31Brain metastases were present in 23% of patients, and visceral metastases were present in 77% of patients; these included metastases in the lung/pleura (57%), the liver (42%), and other visceral organs (adrenal glands, pancreas, and kidney; 7%).

Patients received sacituzumab govitecan-hziy 10 mg/kg administered intravenously on days 1 and 8 of 21-day cycles. Treatment continued until disease progression or unacceptable toxicity. The primary efficacy end point was objective response rate (ORR) assessed according to RECIST 1.1 tumor criteria. The secondary efficacy end points included time to response, duration of response, clinical benefit rate (defined as a complete or partial response or stable disease for ≥ 6 months), progression-free survival (PFS), and OS.

After a median follow-up duration of 9.7 months, an objective response occurred in 36 of 108 patients (ORR, 33.3%; 95% CI, 24.6%-43.1%), including a complete response in 3 patients.31 The median time to response was 2 months (range 1.6-13.5). The median response duration was 7.7 months (95% CI, 4.9-10.8), with 55.6% of patients responding at 6 months and 16.7% of patients still responding at 12 months.

An independent central review of the data found a similar ORR and median response duration (34.3% and 9.1 months, respectively).

 The clinical benefit rate, including stable disease for at least 6 months, was 45.4%. Median PFS was 5.5 months; the estimated probability of PFS at 6 and 12 months was 41.9% and 15.1%, respectively. Median OS was 13 months (95% CI, 11.2-13.7); the estimated probability of survival at 6 and 12 months was 78.5% and 51.3%, respectively.

The most common AEs of any grade were nausea (67%), neutropenia (64%), diarrhea (62%, predominantly grade 1), and fatigue (55%). Of grade 3 or 4 AEs, the most common were neutropenia, decreased white cell count, and anemia (occurring in 42%, 11%, and 11% of patients, respectively).

 Serious AEs occurred in 32% of patients, with the most common being febrile neutropenia (7%), vomiting (6%), nausea (4%), diarrhea (3%), and dyspnea (3%). Occurrence of AEs led to treatment interruption in 44% of patients, dose reductions in 34%, and discontinuation of treatment in 3%.

IM-T-IMMU-132-01 Trial HR+/HER2- Subpopulation Analysis

Treatment with sacituzumab govitecan-hziy showed encouraging results in a prespecified subpopulation of patients with histologically confirmed HR+/HER2- metastatic breast cancer from the IM-T-IMMU-132-01 trial.

A total of 54 patients with histologically confirmed HR+/HER2- metastatic breast cancer were enrolled. Eligible patients had received at least 1 line of hormone-based therapy and at least 1 prior chemotherapy in the metastatic setting. The median age of enrollees was 54 years (range, 33-79); aside from required prior hormone-based therapy, previous chemotherapies included a taxane (85%), an anthracycline (67%), capecitabine (65%), a CDK4/6 inhibitor (61%), an mTOR inhibitor (44%), and an immune checkpoint inhibitor (1.9%). After a washout period of at least 2 weeks since prior treatment, sacituzumab govitecan-hziy was dosed at 10 mg/kg via intravenous infusion on days 1 and 8 of 21-day cycles.

The primary efficacy end point was ORR. Of the 54 patients enrolled, 17 patients achieved partial responses during a median follow-up duration of 11.5 months (ORR, 31.5%; 95% CI, 19.5%-45.6%). In the key secondary outcomes, patients experienced a median PFS of 5.5 months (95% CI, 3.6-7.6) and a median OS of 12.0 months (95% CI, 9.0-18.2). The median time to response was 2.1 months (95% CI, 1.4-7.8), and median duration of response was 8.7 months (95% CI, 3.7-12.7). Of the 17 responders, 4 achieved a response lasting more than 12 months (24%). The clinical benefit rate was 44.4% (95% CI, 30.9%-58.6%), with 7 patients showing stable disease for at least 6 months.

Safety analyses showed a manageable AE profile for sacituzumab govitecan-hziy. There were no reports of cardiac toxicity or severe peripheral neuropathy. The most common grade 3 or higher treatment-related AE was neutropenia, which occurred in 50% of patients. The incidence of diarrhea was 46% and was mild overall. Grade 3 diarrhea was reported in 4 patients, with no reports of grade 4.

 Serious AEs occurred in 2 patients, who experienced febrile neutropenia and 1 case each of neutropenia, viral pneumonia, sepsis, diarrhea, nausea, vomiting, dehydration, and acute respiratory failure.

ESMO 2020 Data: ASCENTTrial in Metastatic TNBC (NCT02574455)

Final results of the international, multicenter, open-label ASCENT trial (NCT02574455) were presented at the European Society for Medical Oncology (ESMO) Virtual Congress 2020. ASCENT was the first phase 3 study of an ADC to show improvement in PFS and OS compared with standard-of-care chemotherapy in patients with previously treated metastatic TNBC.

A total of 529 patients with metastatic TNBC were randomized 1:1 to receive either sacituzumab govitecan-hziy or physician’s choice of single-agent chemotherapy (capecitabine, eribulin, vinorelbine, or gemcitabine). The dose of sacituzumab govitecan-hziy was 10 mg/kg intravenously on days 1 and 8 of 21-day cycles. All patients had histologically or cytologically confirmed TNBC 

refractory to or relapsed after at least 2 prior chemotherapies including a taxane. The median age of the study population was 54 years, and the median number of prior chemotherapies received was 4.

In the primary end point, sacituzumab govitecan-hziy significantly improved median PFS (hazard ratio, 0.41; 

< .0001) compared with chemotherapy. The sacituzumab govitecan-hziy treatment group achieved a median PFS of 5.6 months compared with 1.7 months in the chemotherapy treatment group. Compared with chemotherapy, sacituzumab govitecan-hziy treatment also significantly improved key secondary end points of OS (12.1 vs 6.7 months; hazard ratio, 0.48;

The most common treatment-related grade 3 or higher AEs with sacituzumab govitecan-hziy compared with chemotherapy were neutropenia (51% vs 33%, respectively), diarrhea (10.5% vs < 1.0%), anemia (8% vs 5%), and febrile neutropenia (6% vs 2%). No treatment-related deaths were reported, and no cases of neuropathy or interstitial lung disease greater than grade 3 occurred with sacituzumab govitecan-hziy.

ESMO 2020 Data: Sacituzumab Govitecan-hziy in Combination with Talazoparib for Patients with Metastatic TNBC (NCT04039230)

At the ESMO Virtual Congress 2020, investigators presented the trial design, objectives, and status of a phase 1/2, open-label study that will investigate the efficacy and safety of sacituzumab govitecan-hziy in combination with the PARP inhibitor talazoparib for patients with metastatic TNBC.

 PARP is involved in repairing damaged DNA and is required for clearance of Trop-2 cleavage complexes; thus, PARP inhibitors may be complementary therapeutic partners with sacituzumab govitecan-hziy.

This study will include a dose escalation in phase 1b followed by a dose expansion in phase 2. Patients will receive sacituzumab govitecan-hziy on days 1 and 8 of 21-day cycles and talazoparib daily on days 15 to 21 of each cycle.

 The primary objective of phase 1b is to assess the dose-limiting toxicity rate and maximum tolerated dose of sacituzumab govitecan-hziy when given in combination with talazoparib. From these data, investigators will determine the recommended phase 2 dose. During phase 2, investigators will assess the ORR, PFS, OS, and clinical benefit rate. As of August 30, 2020, the trial was undergoing active recruitment, and a total of 20 patients were enrolled.

ESMO 2020 Data: Sacituzumab Govitecan-hziy for Breast Cancer Brain Metastases (NCT03995706)

SN-38, the cytotoxic payload delivered by sacituzumab govitecan-hziy, crosses the blood-brain barrier and is often included in central nervous system (CNS) cancer regimens.

 Investigators hypothesized that sacituzumab govitecan-hziy would yield therapeutically relevant SN-38 concentrations within the CNS of patients under-going craniotomy for breast cancer brain metastases or recurrent glioblastoma.

In this single-center, nonrandomized, phase 0 study (NCT03995706), patients receive a single 10-mg/kg intravenous dose of sacituzumab govitecan-hziy the day prior to craniotomy and then resume therapy (on days 1 and 8 of 21-day cycles) after recovery. To date, 14 patients have been treated. For patients with recurrent glioblastoma (n = 7), the mean SN-38 concentration was 420 nM; for patients with breast cancer brain metastases (n = 7), the mean SN-38 concentration was 626 nM. Among those patients with residual measurable disease, 2 partial intracranial responses have been observed in each group after 12 weeks of treatment (ORR, 28% and 50% for glioblastoma and breast cancer brain metastases, respectively). As of September 2020, recruitment for this trial was ongoing.

Therapeutic Development of Sacituzumab Govitecan-hziy in Metastatic Urothelial Cancer

The metastatic urothelial cancer cohort of the IM-T-IMMU-132-01 trial reported encouraging activity with sacituzumab govitecan-hziy monotherapy (ORR, 31%; median PFS, 7.3 months; and median OS, 18.9 months).

Sacituzumab govitecan-hziy has FDA fast track desig-nation for metastatic urothelial cancer and is currently under further investigation in the phase 2 TROPHY U-01 trial (NCT03547973) and the upcoming phase 3 TROPiCS-04 trial (NCT04527991).

ESMO 2020 Data: TROPHY U-01 (NCT03547973)

Final data for cohort 1 and the trial design for cohort 3 were presented at the ESMO Virtual Congress 2020 for the pivotal phase 2, open-label, multicohort TROPHY U-01trial. The TROPHY U-01trial is investigating the safety and efficacy of sacituzumab govitecan-hziy in patients with heavily pretreated metastatic urothelial cancer across several cohorts. The study population across the TROPHY U-01 trial includes patients with disease progression despite treatment with platinum (PLT)-based chemotherapy, checkpoint inhibitors, or both. For all cohorts, the primary efficacy end point is ORR, and key secondary end points include PFS, OS, duration of response, and safety analyses.

Cohort 1 included a total of 113 patients who were treated with sacituzumab govitecan-hziy. The study population included patients who experienced disease progression after both PLT-based chemotherapy and checkpoint inhibitor therapy.

Overall, patients in cohort 1 were previously treated with a median of 3 therapies and were a median of 66 years of age. In the results presented at ESMO 2020, a total of 31 patients had achieved an objective response (ORR, 27%; 95% CI, 19%-37%), of which 6 were complete responses and 25 were partial responses. The median duration of response was 5.9 months (95% CI, 4.7-8.6); median PFS and OS were 5.4 months (95% CI, 3.5-6.9) and 10.5 months (95% CI, 8.2-12.3), respectively. Sacituzumab govitecan-hziy demonstrated manageable toxicity. Key grade 3 or higher AEs were neutropenia (35%), anemia (14%), febrile neutropenia (10%), and diarrhea (10%).

As of March 2020, cohort 3 had started enrollment and is ongoing. The study plans to enroll a total of 61 patients with metastatic urothelial cancer who are naïve to checkpoint inhibitor agents and have experienced disease progression or recurrence after PLT-based chemotherapy.

 As checkpoint inhibitors are the stan-dard-of-care therapy for patients who have failed on PLT-based chemotherapy, this study will investigate combination therapy with sacituzumab govitecan-hziy and the checkpoint inhibitor pembrolizumab. Exclusion criteria include active autoimmune disease or a history of interstitial lung disease, given the coadministration of pembrolizumab. A 10-patient lead-in cohort will determine standard the recommended phase 2 dose of sacituzumab govitecan-hziy (given on days 1 and 8 of 21-day cycles), to be given along with pembrolizumab 200 mg on day 1 of each cycle. The primary end point of ORR and secondary end points of PFS, OS, clinical benefit rate, duration of response, and safety will be assessed.

The phase 3, global, open-label TROPiCS-04trial aims to enroll 482 patients to investigate the efficacy and safety of sacituzumab govitecan-hziy in patients with metastatic or locally advanced unresectable urothelial cancer who have progressed despite prior therapy with PLT-based chemotherapy and a PD-1 or PD-L1 checkpoint inhibitor. Sacituzumab govitecan-hziy will be compared with physician’s choice of chemotherapy (paclitaxel, docetaxel, or vinflunine). The primary outcome measure will be OS; secondary outcomes will include PFS, ORR, safety, and quality of life. As of August 2020, the trial was not yet recruiting patients.

Additional Trop-2–Targeted Agents in Development

Evaluation of novel and existing ADCs has revealed that success is not based on the use of any one particular cytotoxic compound or conjugate platform. Factors such as the consistency and level of target-antigen expression, tumor progression, and specific properties of the cancer and stage of disease also play important roles.

 Several additional Trop-2–targeted ADCs are currently being investigated in solid tumors (Table).

Table. Clinical Investigations of Trop-2–Targeted Antibody-Drug Conjugates in Solid Tumors

DS-1062a is a Trop-2–directed ADC that contains the cytotoxic compound DXd, a derivative of exatecan that acts as a DNA topoisomerase I inhibitor.

 It is currently being investigated for the treatment of advanced NSCLC in an ongoing phase 1, multicenter, open-label study (NC T 03 401385).

The study involves a dose-escalation phase and a dose-expansion phase. Dose-limiting toxicity, maximum tolerated dose, and AEs will be explored in both phases.47 Eligible patients have experienced disease progression or recurrence despite previous treatments, have measurable disease per RECIST 1.1 criteria, and are able to provide a sufficient tumor tissue sample for Trop-2 measurement. Patients with multiple primary malignancies or untreated brain metastases are ineligible for the study.

As of November 2018, a total of 22 patients had been treated with 1 of 3 escalating doses of DS-1062a. Nearly 82% of patients experienced at least 1 treatment-emergent AE, with fatigue being the most common complaint. Fatigue was the only reported grade 3 or higher AE and was reported by 1 patient. Of 18 tumor-evaluable patients, 1 showed a partial response and 8 showed stable disease. Maximum-tolerated dose has not been achieved, and investigators will continue to monitor for safety and disease progression.

RN927C, also known as PF-06664178, is an ADC composed of a Trop-2–directed antibody conjugated with the cytotoxic microtubule inhibitor PF-06380101. Release of PF-06380101 leads to mitotic arrest, apoptosis, and cell death.3 Preclinical studies demonstrated the ability of RN927C to induce cell death among various tumor cell lines, including those from the skin, lung, head and neck, breast, ovary, and colon.

RN927C was investigated in a phase 1, open-label, nonrandomized dose-escalation study (NCT02122146)of patients with advanced or metastatic solid tumors that were unresponsive to current therapies or for whom no standard therapy was available. The primary objective of the study was to determine the maximum tolerated dose and recommended phase 2 dose. Secondary outcomes included safety and preliminary evidence of antitumor activity. A total of 31 patients were enrolled and received treatment with escalating doses of RN927C. Stable disease was noted in 11 patients (39%), but no partial or complete responses were seen. Doses of 3.6 mg/kg, 4.2 mg/kg, and 4.8 mg/kg were considered intolerable, primarily because of skin reactions and development of neutropenia. The next-lower dose of 2.4 mg/kg was well tolerated, but the study was terminated early because of minimal anti-tumor activity and excessive toxicities.

BAT8003 is an ADC composed of a Trop-2–directed antibody conjugated to a potent cytotoxic maytansine derivative. The ADC has been optimized to facilitate site-specific conjugation, which allows for a more controllable drug-antibody ratio. In addition, a fucosylation of the Fc region of the antibody enhances its antibody-dependent cell-mediated cytotoxicity effect. In preclinical xenograft and primate models, BAT8003 demonstrated strong inhibition of tumor growth at doses of 5 mg/kg and 15 mg/kg, with a highest non–severely toxic dose of 20 mg/kg given once every 3 weeks.

Given the promising preclinical data, a phase 1 dose-escalation study (NCT03884517) is currently investigating the safety, tolerability, and pharmacokinetics of BAT8003 in patients with advanced epithelial cancer who are either ineligible for standard therapy or have disease refractory to standard therapy.Eligible patients will receive escalating doses of BAT8003 (0.2-10.0 mg/kg) on day 1 of each 21-day cycle. The study will be divided into 3 periods: (1) the first 21-day cycle, which will examine the safety of a single BAT8003 administration, observe for dose-limiting toxicities, and establish preliminary pharmacokinetic parameters; (2) cycles 2 through 8, which will examine safety, immunogenicity, and preliminary efficacy of escalating doses of BAT8003; and (3) an expansion period, which could include an additional 10 to 30 cases to further assess safety and efficacy once a safe and effective dose has been established. As of the last update on March 21, 2019, the trial was actively recruiting patients.

Trop-2 has established itself as a clinically meaningful 

biomarker among several types of solid malignancies. Its ability to promote self-renewal, proliferation, and cell invasion makes it an ideal candidate for targeted anti-tumor therapies, including ADCs.

Sacituzumab govitecan-hziy is the first Trop-2–directed ADC to receive FDA approval for the treatment of metastatic TNBC. In the pivotal IM-T-IMMU-132-01 trial, sacituzumab govitecan-hziy showed encouraging results in patients with multiple difficult-to-treat solid tumor types, including TNBC, HR+/HER2- metastatic breast cancer, and metastatic urothelial cancer.

 Sacituzumab govitecan-hziy and other Trop-2–directed ADCs represent a novel strategy to improve outcomes among these populations of patients with few therapeutic options. Data from additional trials of sacituzumab govitecan-hziy were presented at the ESMO Virtual Congress 2020. In the ASCENT trial, sacituzumab govitecan improved response rates and survival outcomes in patients with metastatic TNBC compared with standard-of-care therapy.

 Data from a cohort of patients with metastatic urothelial cancer in the TROPHY U-01 trial indicated positive survival impacts with manageable toxicity.

 Additional trials of sacituzumab-govitecan-hziy (as monotherapy or in combination with PARP inhibitors or checkpoint inhibitors) are under way in patients with metastatic TNBC, breast cancer brain metastases, and metastatic or locally advanced urothelial cancer.

Other Trop-2–directed ADCs are under investigation in NSCLC and advanced epithelial cancers.

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Zeng P, Chen MB, Zhou LN, Tang M, Liu CY, Lu PH. Impact of TROP2 expression on prognosis in solid tumors: a systematic review and meta-analysis. 

Lin H, Huang JF, Qiu JR, et al. Significantly upregulated TACSTD2 and cyclin D1 correlate with poor prognosis of invasive ductal breast cancer. 

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Trophoblast cell surface antigen 2 is a glycoprotein that spans the epithelial membrane surface and plays a role in cell self-renewal, proliferation, and transformation.

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