Sacituzumab govitecan in heavily pretreated, platinum-resistant high grade serous ovarian cancer.

Background: Treatment of recurrent platinum-resistant high grade serous ovarian cancer (HGSOC) remains a challenge. Novel treatment options for recurrent disease are an unmet need. Case: A 69-year-old with recurrent, metastatic, platinum-resistant HGSOC overexpressing TROP2 experienced a significant response to the antibody-drug conjugate (ADC) sacituzumab govitecan after multiple failed lines of chemotherapy and targeted treatment. Following sacituzumab govitecan treatment she experienced a confirmed partial response as well as a return of CA-125 to baseline. Having now completed 8 cycles (ie, over 6 months of treatment), her disease continues to demonstrate a response to sacituzumab govitecan treatment. The ADC has been well tolerated at a dose of 10 mg/kg with no dose-limiting toxicity or need for dose reductions. Conclusion: Sacituzumab govitecan may represent a treatment option for platinum-resistant/recurrent HGSOC that have previously failed prior lines of chemotherapy. Clinical trials with sacituzumab govitecan in platinum-resistant ovarian cancer patients are currently ongoing (https://classic.clinicaltrials.gov/ct2/show/NCT06028932).

UGT1A1*28 polymorphism and the risk of toxicity and disease progression in patients with breast cancer receiving sacituzumab govitecan.

BACKGROUND: Sacituzumab govitecan (sacituzumab) emerged as an important agent in metastatic and locally recurrent HER2-negative breast cancer treatment. UGT1A1 polymorphisms have also been shown to predict sacituzumab toxicity. METHODS: In this retrospective study, we sought to evaluate the associations between UGT1A1 status, toxicity, and therapeutic outcomes in sacituzumab recipients with advanced breast cancer who underwent genotype testing for UGT1A1 alleles (N = 68). RESULTS: We found 17 (25%) of our patients to be homozygous for UGT1A1*28 and 24 (35.3%) were heterozygous. Of seven African American patients with triple-negative breast cancer, five were homozygous for UGT1A1*28 and two were heterozygous. Patients with a homozygous UGT1A1*28 genotype were significantly more likely to have treatment terminated because of adverse effects. However, the polymorphism was not associated with treatment discontinuation because of disease progression. CONCLUSION: This retrospective, real-world analysis suggests potential clinical utility in UGT1A1 testing for patients receiving sacituzumab, but future trials are needed to confirm the association between genotypes and treatment outcomes.

Efficacy of Antibody Drug Conjugates Alone and in Combination with other Agents in Metastatic Urothelial Carcinoma: A Scoping Review.

INTRODUCTION: Antibody drug conjugates represent a promising class of antineoplastic agents comprised of a monoclonal antibody linked to a potent cytotoxic payload for targeted delivery of chemotherapy to tumors. Various antibody drug conjugates have demonstrated impressive efficacy in patients with metastatic urothelial carcinoma in clinical trials, leading to two FDA approved therapies and several other agents and combinations in clinical development. MATERIALS AND METHODS: A comprehensive systematic review was undertaken utilizing the principles of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Queried databases included Ovid MEDLINE, Ovid Embase, Web of Science Core Collection and Cochrane CENTRAL Trials. The search sought to identify prospective therapeutic clinical trials in humans with metastatic urothelial carcinoma with a single-arm or randomized controlled trial design investigating antibody drug conjugate-containing regimens. RESULTS: The literature search yielded 4,929 non-duplicated articles, of which 30 manuscripts and conference abstracts were included, which derived from 15 clinical trials including 19 separate cohorts with efficacy outcome results. Eleven trials investigated ADC monotherapy, while two investigated combination regimens, and the remaining two studies were mixed. Five unique ADC targets were represented including Nectin-4, Trop-2, HER2, Tissue Factor, and SLITRK6. Twelve clinical trial cohorts required prior treatment (63%). Objective response rate was reported for all studies and ranged from 27-52% for ADC monotherapies and 34-75% for ADC plus anti-PD-1 agents. Time to event outcome reporting was highly variable. CONCLUSION: In addition to enfortumab vedotin and sacituzumab govitecan, various HER2-targeted antibody drug conjugates and ADC-anti-PD-1 combination regimens have demonstrated efficacy in clinical trials and are poised for clinical advancement.

Antibody-drug conjugates as a novel therapeutic modality to treat recurrent refractory germ cell tumors.

This review provides a rationale for using the Food and Drug Administration (FDA)-approved antibody-drug conjugates (ADCs) for implementing as therapy in recurrent refractory germ cell tumors similar to their position in the treatment of other types of chemoresistant solid tumors. Germ cell tumors (GCTs) originate from germ cells; they most frequently develop in ovaries or in the testes, while being the most common type of malignancy in young men. GCTs are very sensitive to cisplatin-based chemotherapy, but therapeutic resistance occurs in a considerable number of cases, which is associated with disease recurrence and poor patient prognosis. ADCs are a novel type of targeted antitumor agents that combine tumor antigen-specific monoclonal antibodies with chemically linked chemotherapeutic drugs (payload) exerting a cytotoxic effect. Several FDA-approved ADCs use as targeting moieties the antigens that are also detected in the GCTs, offering a benefit of this type of targeted therapy even for patients with relapsed/refractory testicular GCTs (rrTGCT) unresponsive to standard chemotherapy.

Preclinical evidence for the use of anti-Trop-2 antibody-drug conjugate Sacituzumab govitecan in cerebral metastasized castration-resistant prostate cancer.

PURPOSE: Improved survival rates have been observed in castration-resistant prostate cancer (CRPC) due to advancements in treatment options. However, individuals with brain metastases still have limited therapeutic options and an unfavorable prognosis. Therefore, there is an urgent need to explore new therapeutic avenues, such as antibody-drug conjugates (ADCs), which have demonstrated significant clinical activity against active brain metastases in solid tumors. Our objective was to determine the expression levels of the ADC targets Trop-2 and NECTIN-4 in cerebral metastasized CRPC (mCRPC). METHODS: Immunohistochemical staining of Trop-2 and NECTIN-4 with evaluation of H-score was performed in CRPC brain metastases (n = 31). Additionally, we examined Trop-2 protein expression in prostate cancer cell lines and studied their responsiveness to the anti-Trop-2 ADC Sacituzumab govitecan (SG) in vitro. RESULTS: Our analysis revealed that most patients exhibited moderate to strong Trop-2 expression [n = 27/31 with H-score ≥100, median H-score 220 (IQR 180-280)], while NECTIN-4 was absent in all cerebral metastases. Mechanistically, we demonstrated that the efficacy of SG depends on Trop-2 expression levels in vitro. Overexpression of Trop-2 in Trop-2-negative PC-3 cells led to sensitization to SG, whereas CRISPR-Cas9-mediated knockdown of Trop-2 in Trop-2-expressing DU-145 cells conferred resistance to SG. CONCLUSION: The substantial expression of Trop-2 in cerebral metastases, along with our preclinical in vitro results, supports the efficacy of SG in treating cerebral mCRPC. Thus, our results extend the understanding of the potential of ADCs in prostate cancer treatment and provide an additional treatment strategy for the challenging subset of patients with cerebral metastases.

Sacituzumab govitecan vs. chemotherapy for metastatic breast cancer: a meta-analysis on safety outcomes.

Aim: There is limited data available regarding the comparison of Sacituzumab govitecan (SG) vs. chemotherapy in metastatic breast cancer patients. Materials & methods: We performed a systematic review and meta-analysis aimed to assess the safety profile of SG vs. chemotherapy for metastatic breast cancer (mBC) clinical trials. Results: The pooled odds ratio for outcomes such as grade 3-4 and all grade neutropenia, leukopenia, anemia and other non-hematological adverse events showed a higher risk for patients receiving SG. No statistically significant differences were reported in terms of grade 3-4 fatigue, all grade nausea, febrile neutropenia and treatment discontinuation due to adverse events. Conclusion: Our data, coupled with a statistically and clinically meaningful survival benefit, support the use of SG for mBC.

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Use of Antibody-Drug Conjugates in the Early Setting of Breast Cancer.

Antibody-drug conjugates (ADCs) are anticancer agents with the capacity to selectively deliver their payloads to cancer cells. Antibody-drug conjugates consist of a monoclonal antibody backbone connected by a linker to cytotoxic payloads. Antibody-drug conjugate effect occurs either by directly targeting cancer cells via membrane antigen or through "bystander effect." Antibody-drug conjugates have demonstrated efficacy against various types of tumors, including breast cancer. Ado-trastuzumab emtansine is presently the only approved ADC for the treatment of breast cancer in the early setting, while several ADCs are now approved for metastatic breast cancer. Due to the transformative impact that several ADCs have reported in the setting of advanced breast cancer, researchers are now testing more of such compounds in the early setting, to portend benefits to patients through highly potent anticancer drugs. Ongoing trials hold the potential to transform treatment protocols for early breast cancer in the near future. These trials are aiming at evaluating different treatment modulation approaches, as informed by breast cancer risk of recurrence, including toward treatment de-escalation. Efforts are provided in ongoing clinical trials to identify the patients who will benefit most, to pursue paradigms of precision medicine with the novel ADCs. This review focuses on the potential role of ADCs in early breast cancer, providing an overview of the latest progress in their development and how they are implemented in ongoing clinical trials.

OptimICE-RD: sacituzumab govitecan + pembrolizumab vs pembrolizumab (± capecitabine) for residual triple-negative breast cancer.

Patients with early-stage triple-negative breast cancer (TNBC) with residual invasive disease after neoadjuvant therapy have a high risk of recurrence even with neoadjuvant and adjuvant treatment with pembrolizumab. Sacituzumab govitecan, a Trop-2-directed antibody-drug conjugate with a topoisomerase I inhibitor payload, improved progression-free survival (PFS) and overall survival (OS) versus chemotherapy in patients with pre-treated metastatic TNBC. Moreover, preclinical data suggest that topoisomerase I inhibitors may enhance the effects of immune checkpoint inhibitors through activation of the cGAS-STING pathway. Here we describe the international randomized phase III AFT-65/ASCENT-05/OptimICE-RD trial, which evaluates the efficacy and safety of sacituzumab govitecan plus pembrolizumab versus treatment of physician's choice (pembrolizumab ± capecitabine) among patients with early-stage TNBC with residual invasive disease after neoadjuvant therapy.Clinical Trial Registration: NCT05633654 (ClinicalTrials.gov)Other Study ID Number(s): Gilead Study ID: GS-US-595-6184Registration date: 1 December 2022Study start date: 12 December 2022Recruitment status: Recruiting.

AFT-65/ASCENT-05/OptimICE-RD is an ongoing clinical trial that is testing a new treatment combination for patients with stage II or III triple-negative breast cancer (TNBC). Stage II­III means the cancer is confined to the breast and/or nearby lymph nodes and can be surgically removed. However, there remains a risk that the cancer could recur after surgery. To reduce this risk, patients with stage II­III TNBC receive anti-cancer medication before and after surgery. For some patients, receipt of anti-cancer medication before surgery produces a pathologic complete response (pCR), meaning there is no observable cancer left behind at surgery. Patients with a pCR have a lower risk of recurrence than patients with residual disease.The AFT-65/ASCENT-05/OptimICE-RD trial includes people with stage II-III TNBC who have residual cancer after completing their course of pre-surgery anti-cancer medication. All participants have any remaining cancer in their breast and/or lymph nodes removed surgically, after which they are randomly assigned to receive one of two treatments. The experimental therapy consists of pembrolizumab along with a medication called sacituzumab govitecan, which kills cancer cells directly and may strengthen the anti-cancer immune response. Pembrolizumab strengthens the anti-cancer immune response, so the hypothesis of this trial is that the two medications will be more effective together. The control therapy consists of pembrolizumab, alone or in combination with a chemotherapy medication called capecitabine, which is the current standard of care. To study the effectiveness of each treatment, the researchers are following up with all participants to learn if and when their breast cancer returns.

Real-world use patterns, effectiveness, and tolerability of sacituzumab govitecan for second-line and later-line treatment of metastatic triple-negative breast cancer in the United States.

PURPOSE: Patients with metastatic triple-negative breast cancer (mTNBC) have poor prognosis and limited treatment options. Sacituzumab govitecan (SG), a Trop-2-directed antibody-drug conjugate, is approved for patients with mTNBC who have received ≥ 2 systemic therapies (≥ 1 in the metastatic setting) based on the ASCENT study (NCT02574455). The current study describes real-world SG use and outcomes in patients with mTNBC in the United States. METHODS: This retrospective, observational study included adult patients with mTNBC from the ConcertAI Patient360™ database who received SG in the second line (2L) and later from April 2020 to May 2022. SG use patterns, effectiveness, and tolerability are described. RESULTS: This analysis included 230 patients (median age 60 years, 26% Black, 17% with ECOG performance status ≥ 2, 66% in community settings; median of 2 prior lines of treatment in the metastatic setting); median follow-up was 7.2 months. Median (95% CI) real-world overall survival was 10.0 (8.3-11.1) months for all patients and 13.9 (9.8-not estimable) months in the 2L subgroup (n = 77). Granulocyte-colony stimulating factor (G-CSF) was administered concomitantly with SG in 134 (58%) patients; 35 (15%) received G-CSF for the first time. Median (IQR) time from SG start to G-CSF use was 8.5 (8.0-29.0) days. Seventeen (7%) patients discontinued SG due to toxicity. CONCLUSIONS: Using a real-world, ethnically diverse population of patients with mTNBC presenting with poor prognosis, these data reinforced the findings from ASCENT. In routine clinical practice, SG is an effective treatment in the 2L setting, consistent with treatment guidelines.

Current Status and Future Perspectives of Antibody-Drug Conjugates in Hormone Receptor-Positive Breast Cancer.

Breast cancer is the most common cancer type in women. The vast majority of breast cancer patients have hormone receptor-positive (HR+) tumors. In advanced HR+ breast cancer, the combination of endocrine therapy with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors is considered the standard of care in the front-line setting. Nevertheless, resistance to hormonal therapy and CDK4/6 inhibitors eventually occurs, leading to progression of the disease. Antibody-drug conjugates (ADCs) comprise a promising therapeutic choice with significant efficacy in patients with HR+ breast cancer, which is resistant to endocrine treatment. ADCs typically consist of a cytotoxic payload attached by a linker to a monoclonal antibody that targets a specific tumor-associated antigen, offering the advantage of a more selective delivery of chemotherapy to cancer cells. In this review, we focus on the ADC mechanisms of action, their toxicity profile and therapeutic uses as well as on related biomarkers and future perspectives in advanced HR+ breast cancer.

Systematic review of recent advancements in antibody-drug and bicycle toxin conjugates for the treatment of urothelial cancer.

Antibody-drug conjugates and bicycle toxin conjugates represent a tremendous advance in drug delivery technology and have shown great promise in the treatment of urothelial cancer. Previously approved systemic therapies, including chemotherapy and immunotherapy, are often impractical due to comorbidities, and outcomes for patients with advanced disease remain poor, even when receiving systemic therapy. In this setting, antibody-drug and bicycle toxin conjugates have emerged as novel treatments, dramatically altering the therapeutic landscape. These drugs harness unique designs consisting of antibody or bicycle peptide, linker, and cytotoxic payload with more targeted delivery than conventional chemotherapy, thus eliminating malignant cells while reducing systemic toxicities. Potential targets investigated in urothelial cancer include Nectin-4, TROP2, HER2, and EphA2. Initial clinical trials demonstrated efficacy in treatment of refractory advanced urothelial cancer, as well as improvement in quality of life. These initial studies led to FDA approval of two antibody-drug conjugates, enfortumab vedotin and sacituzumab govitecan. Moreover, antibody-drug and bicycle toxin conjugates are being studied in ongoing clinical trials in frontline treatment of advanced disease as well as for localized cancer. These studies highlight the potential for additional future therapies with novel targets, novel antibodies, cytotoxic and immunomodulatory payloads, and unique structural designs enhancing efficacy and safety. There is increasing evidence that combinations with other cancer therapies, especially immunotherapy, improve treatment outcomes. The combination of enfortumab vedotin and pembrolizumab was recently approved for first-line treatment of advanced urothelial carcinoma. Despite the great promise of these novel drugs, robust predictive biomarkers are needed to determine the patients who would maximally benefit. This review surveys the rationale and current state of the evidence for these new drugs and describes future directions actively being explored.

Review of recent advances in novel treatments of urothelial cancer Two new types of drugs, called antibody-drug conjugates (ADCs) and bicycle toxin conjugates (BTCs) have shown great promise in treating urothelial cancer. Both types of drugs consist of a structure targeting a specific protein on bladder cancer cells, linked to a drug that can kill cells. This allows for effective treatment of cancer with potentially less toxicity due to the targeted nature of these treatments. We discuss the potential targets in urothelial cancer and the drugs in these classes that could treat each target. Two of these drugs, enfortumab vedotin and sacituzumab govitecan, are in clinical use for cancers that have spread, while the others are in clinical trials. Moreover, the combination of enfortumab vedotin and pembrolizumab, an immunotherapy drug, has excellent results and was recently approved for first-line treatment of urothelial cancer that has spread. Additional studies are looking into these treatments for cancers that have not spread. In the future, management of side effects, determination of which patients benefit, and overcoming when the drugs become no longer effective will be important.

Gastrointestinal Toxicity of Antibody Drug Conjugates (ADCs) in Metastatic Breast Cancer: A Pooled Analysis.

Trastuzumab emtansine (T-DM1), sacituzumab govitecan (SG), and trastuzumab deruxtecan (T-DXd) are three ADCs approved for the treatment of metastatic breast cancer (MBC). Since gastrointestinal toxicities have been commonly observed with these drugs in clinical trials, a pooled analysis evaluating gastrointestinal adverse events (AEs) in patients with MBC treated with ADCs in clinical trials was performed. PubMed, Embase, and the Cochrane Library were searched from inception until May 2023 for phase II and III clinical trials reporting frequency and severity of gastrointestinal AEs during treatment with ADCs. Data were retrieved for nausea, vomiting, diarrhea, constipation, and abdominal pain: overall and grade 3-4 toxicity rates according to NCI-CTCAE were collected and expressed as proportions. A pre-specified subgroup analysis according to the agent was also carried out. Fourteen studies, comprising 5608 patients, were included in the analysis. Gastrointestinal AEs were frequently registered with SG and T-DXd. A significantly higher frequency of nausea (65.6% with SG, 75% with T-DXd), vomiting (43.7% with SG, 45% with T-DXd), and diarrhea (59.7% with SG, 29% with T-DXd) was noticed with these ADCs compared to TDM-1. Furthermore, diarrhea was more frequently associated with SG (grade 3 in 7.5% of patients), while constipation and abdominal pain were less common. Gastrointestinal AEs, notably nausea and diarrhea, were frequently reported by MBC patients treated with SG and T-DXd in clinical trials. Since these ADCs are administered continuously until disease progression or occurrence of unbearable AEs, gastrointestinal toxicity may have a negative impact on patient quality of life. Therefore, appropriate management of gastrointestinal AEs is mandatory to ensure treatment efficacy and adherence.

Health-related quality of life with sacituzumab govitecan in HR+/HER2- metastatic breast cancer in the phase III TROPiCS-02 trial.

BACKGROUND: The TROPiCS-02 study (NCT03901339) demonstrated that sacituzumab govitecan (SG) has superior clinical outcomes over treatment of physician's choice (TPC) chemotherapy in patients with hormone receptor-positive, human epidermal growth factor 2 receptor-negative (HR+/HER2-) metastatic breast cancer (mBC). Here, we present health-related quality of life (HRQoL) patient-reported outcome (PRO) findings from this study. PATIENTS AND METHODS: Eligible adults with HR+/HER2- mBC who previously received a taxane, endocrine-based therapy, a CDK4/6 inhibitor, and 2-4 lines of chemotherapy were randomized 1:1 to receive SG or TPC until progression or unacceptable toxicity. PROs were assessed at baseline and on day 1 of each cycle, using the European Organization for Research and Treatment of Cancer Quality-of-Life Core 30 (EORTC QLQ-C30), EQ-5D-5L, and PRO Common Terminology Criteria for Adverse Events (PRO-CTCAE). RESULTS: Compared to TPC, overall least square mean change from baseline was significantly better for SG for physical functioning and dyspnea, but worse for diarrhea. Time to first clinically meaningful worsening or death was significantly longer for SG in global health status/quality of life, physical functioning, fatigue, emotional functioning, dyspnea, insomnia, and financial difficulties of the EORTC QLQ-C30 and the EQ-VAS, but longer for TPC in diarrhea. Few patients in both arms reported experiencing any worsening to level 3 or 4 treatment-related symptomatic events during treatment, as assessed by 16 PRO-CTCAE items, except for diarrhea frequency and amount of hair loss, which favored TPC. CONCLUSIONS: SG was associated with an HRQoL benefit in most symptoms and functioning, compared with TPC. This supports the favorable profile of SG as a treatment option for patients with pretreated HR+/HER2- mBC.

Sacituzumab Govitecan for the treatment of advanced triple negative breast cancer patients: a multi-center real-world analysis.

Objective: The objective of this multicenter, observational, retrospective analysis was to evaluate the safety and efficacy of sacituzumab govitecan in metastatic triple-negative breast cancer (mTNBC) patients managed according to common clinical practice in Italy. Methods: Data were retrieved by 7 sites. Triple-negative BC was defined by the lack of expression of estrogen receptor (ER <1%), progesterone receptor (PgR <1%) and human-epidermal growth factor receptor-2 (HER2 0, 1+, 2+ ISH-not amplified) according to standard ASCO-CAP criteria. Demographic and clinical characteristics were collected. Premedication, dose modifications and treatment schedule were based on the approved label of the product. Adverse events (AEs) were assessed according to NCI-CTCAE v5.0. Results: Fifty-seven eligible patients who received sacituzumab govitecan for mTNBC were included. Median age was 53 years (range 25-75). Approximately 70% of patients had an initial diagnosis of TNBC. Median time from the diagnosis of metastatic BC to start of sacituzumab govitecan was 17 months (range 0-97) and median number of previous therapies was 3 (range 1-7). The most common sites of metastasis were lymph nodes (63.1% of patients), lung (57.9%), bone (50.8%) and liver (38.6%). Eight (14.0%) patients had a disease-free interval ≤12 months. A total of 32 (56.1%) deaths were observed and the median overall survival (OS) was 12.43 months (95% CI, 7.97 months-not reached). At a median follow-up of 10.6 months, 45 patients (78.9%) had progression and the median progression-free survival (PFS) was 4.9 months (95% CI, 3.7-7.1 months). Partial tumour response was observed in 19 patients (33.3%), stable disease in 16 (28.1%) and disease progression in 22 patients (38.6%). The most common treatment-related AEs were anemia (66.6% of patients), alopecia (66.6%), neutropenia (59.6%), nausea (42.1%) and diarrhea (38.6%). Neutropenia was the most common serious treatment-related AE: 21.0% and 8.7% of patients experienced grade 3 or 4 neutropenia, respectively. Twenty-two patients (38.6%) reduced the dose and 5.3% permanently discontinued treatment. Conclusion: The results of this real-world analysis showed that both safety and efficacy of sacituzumab govitecan in mTNBC patients are consistent with that previously reported in regulatory trials. The use of premedication and supportive measures was associated with a satisfactory toxicity profile.

Optimal Sequential Strategies for Antibody-Drug Conjugate in Metastatic Breast Cancer: Evaluating Efficacy and Cross-Resistance.

BACKGROUND: The optimal sequential strategy for antibody-drug conjugates (ADCs) in breast cancer remains uncertain. This study aimed to evaluate the efficacy and potential resistance of second ADC (ADC2) following the first ADC (ADC1) in human epidermal growth factor receptor 2 (HER2)-positive and HER2-low MBC. METHODS: This retrospective, multicenter, real-world study enrolled patients with MBC who received at least 2 different types of ADCs in 3 hospitals in China between July 1, 2017 and May 1, 2023. Outcomes included the objective response rate (ORR) for ADC1 and ADC2, progression free survival 2 (PFS2), defined as the time from initiation of ADC2 to progression, and overall survival (OS). RESULTS: Seventy-nine female patients were included, 64 of whom had HER2-positive disease. The ORR for ADC2 with similar payload of ADC1 was found to be 5.3%. When switching to a different payload, the ORR of ADC2 increased to 22.6%. The PFS2 for ADC2 remained similar regardless of whether the payload was similar or different. Switching to different payload showed a higher ORR in patients with rapid progression and a durable response longer than 6 months (41.2% vs 15.0%). Specifically, significantly longer PFS2 and OS were seen in patients treated with trastuzumab deruxtecan (T-Dxd) compared to those treated with disitamab vedotin (RC48) after progression from trastuzumab emtansine (T-DM1; median PFS2 5.37 months vs 3.30 months, HR = 0.40, 95% CI 0.17-0.93, P = .034; median OS 50.6 months vs 20.2 months, HR = 0.27, 95% CI 0.08-0.91, P = .034). For patients who progressed after T-Dxd, the median PFS2 was 6.05 months for those treated with RC48 versus 0.93 months for those treated with T-DM1 (HR = 0.03, 95% CI 0.002-0.353, P = .0093). Genomic analysis revealed that alternation of retinoblastoma1 was significantly associated with superior PFS. CONCLUSION: The alternation of payload achieves different responses in different settings. T-Dxd followed by RC48 may be a potentially beneficial strategy in HER2-positive disease. Further research is needed to elucidate the mechanism of cross-resistance.

A plain language summary of the TROPHY-U-01 study: sacituzumab govitecan use in people with locally advanced or metastatic urothelial cancer.

WHAT IS THIS SUMMARY ABOUT?: Sacituzumab govitecan (brand name: TRODELVY®) is a new treatment being studied for people with a type of bladder cancer, called urothelial cancer, that has progressed to a locally advanced or metastatic stage. Locally advanced and metastatic urothelial cancer are usually treated with platinum-based chemotherapy. Metastatic urothelial cancer is also treated with immune checkpoint inhibitors. There are few treatment options for people whose cancer gets worse after receiving these treatments. Sacituzumab govitecan is a suitable treatment option for most people with urothelial cancer because it aims to deliver an anti-cancer drug directly to the cancer in an attempt to limit the potential harmful side effects on healthy cells. This is a summary of a clinical study called TROPHY-U-01, focusing on the first group of participants, referred to as Cohort 1. All participants in Cohort 1 received sacituzumab govitecan. WHAT ARE THE KEY TAKEAWAYS?: All participants received previous treatments for their metastatic urothelial cancer, including a platinum-based chemotherapy and a checkpoint inhibitor. The tumor in 31 of 113 participants became significantly smaller or could not be seen on scans after sacituzumab govitecan treatment; an effect that lasted for a median of 7.2 months. Half of the participants were still alive 5.4 months after starting treatment, without their tumor getting bigger or spreading further. Half of them were still alive 10.9 months after starting treatment regardless of tumor size changes. Most participants experienced side effects. These side effects included lower levels of certain types of blood cells, sometimes with a fever, and loose or watery stools (diarrhea). Side effects led 7 of 113 participants to stop taking sacituzumab govitecan. WHAT WERE THE MAIN CONCLUSIONS REPORTED BY THE RESEARCHERS?: The study showed that sacituzumab govitecan had significant anti-cancer activity. Though most participants who received sacituzumab govitecan experienced side effects, these did not usually stop participants from continuing sacituzumab govitecan. Doctors can help control these side effects using treatment guidelines, but these side effects can be serious.Clinical Trial Registration: NCT03547973 (ClinicalTrials.gov) (TROPHY-U-1).

Sacituzumab govitecan in metastatic triple-negative breast cancer patients treated at Institut Curie Hospitals: efficacy, safety, and impact of brain metastases.

BACKGROUND: Sacituzumab govitecan (SG) has been approved by FDA in April 2021 for pre-treated metastatic triple-negative breast cancer (mTNBC), following the ASCENT trial results. METHODS: We set up an ambispective bicentric cohort study to assess the real-world effectiveness and safety of SG in patients with mTNBC treated at Institut Curie Hospitals, with a focus on patients with brain metastases. RESULTS: This study included 99 patients treated through the French Early Access Program to SG from May 2021 to January 2023. Median age was 55 years [26-89], N = 8 patients (8%) had BRCA1/2 mutation, N = 12 (12%) de novo stage IV disease and N = 31 (31%) brain metastases. Patients had previously received a median of two [1-10] lines of treatment in advanced setting. After a median follow-up of 9.7 months, the median progression-free survival (PFS) and overall survival (OS) were 3.9 months (95%CI[3.4-5.0]) and 8.6 months (95%CI[7.1-11.9]), respectively, while objective response rate was 29% (95%CI[21-39]). Among patients with brain metastases, median PFS and OS were 3.7 months (95%CI[2.6-6.2]) and 6.7 months (95%CI[6.3-NR]), respectively, with intracranial tumor responses. Dose reductions were required in N = 17 patients (17%) within a median of three [2-11] cycles, due to gastrointestinal toxicity (N = 6; 6%), hematological toxicity (N = 9; 9%) including febrile neutropenia (N = 2; 2%), liver enzyme elevation (N = 1; 1%), and physical deterioration (N = 1; 1%). There was no related death to SG. CONCLUSIONS: The observed response rate and safety of SG are consistent with the results of the ASCENT trial, with efficacy observed in patients with brain metastases, but observed PFS and OS are numerically shorter.

Cost-effectiveness of sacituzumab govitecan versus single-agent chemotherapy for metastatic triple-negative breast cancer: a trial-based analysis.

BACKGROUND: Sacituzumab govitecan (SG) has recently been approved in China for the post-line treatment of metastatic triple-negative breast cancer (mTNBC). SG substantially improves progression-free survival and overall survival compared with single-agent chemotherapy for pretreated mTNBC. However, in view of the high price of SG, it is necessary to consider its value in terms of costs and outcomes. This study aimed to estimate the cost-effectiveness of SG versus single-agent treatment of physician's choice (TPC) in the post-line setting for patients with mTNBC from a Chinese healthcare system perspective. METHODS: The cohort characteristics were sourced from the ASCENT randomized clinical trial, which enrolled 468 heavily pretreated patients with mTNBC between November 2017 and September 2019. A partitioned survival model was constructed to assess the long-term costs and effectiveness of SG versus TPC in the post-line treatment of mTNBC. Quality-adjusted life-months (QALMs) and total costs in 2022 US dollars were used to derive incremental cost effectiveness ratio (ICER). QALMs and costs were discounted at 5% annually. The willingness-to-pay (WTP) threshold was defined as $3188 per QALM, three times China's average monthly per capita gross domestic product in 2022. One-way sensitivity analysis, probabilistic sensitivity analysis, and scenario analyses were performed to estimate the robustness of the results. RESULTS: Treatment with SG yielded an incremental 5.17 QALMs at a cost of $44,792 per QALM, much above the WTP threshold of $3188/QALM in China. One-way sensitivity analysis showed that SG price was a crucial factor in the ICER. Probabilistic sensitivity analysis revealed that the cost-effective acceptability of SG was 0% in the current setting. Scenario analyses indicated that the result was robust in all subgroups in ASCENT or under different time horizons. Furthermore, SG must reduce the price to enter the Chinese mainland market. When the monthly cost of SG reduce to $2298, SG has about 50% probability to be a preferred choice than TPC. CONCLUSIONS: SG was estimated to be not cost-effective compared with TPC for post-line treatment for mTNBC in China by the current price in HK under a WTP threshold of $3188 per QALM. A drastic price reduction is necessary to improve its cost-effectiveness.