ASCENT Trial: TRODELVY (sacituzumab govitecan) in mTNBC

ASCENT Trial and Trodelvy (Sacituzumab Govitecan) Improves Progression Free Survival in Metastatic Triple Negative Breast (mTNBC)

5 Key Stats for Trodelvy (Sacituzumab Govitecan) from the ASCENT Trial

• Trodelvy significantly prolonged progression-free survival (median PFS; 4.8 vs 1.7 mo) 

• Overall survival (median OS; 11.8 vs 6.9 mo) vs single-agent chemotherapy of physician’s choice (TPC) in the second line or greater (2L+) mTNBC setting.

• Patients (Pts) with mTNBC who received ≥2 prior systemic therapies (at least 1 for metastatic disease) were randomized to receive Sacituzumab Govitecan (10 mg/kg IV on d 1 and 8, every 21 d) or TPC (capecitabine, eribulin, vinorelbine, or gemcitabine).

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• HRQoL was assessed at baseline (BL), before each cycle, and at end of treatment discontinuation(Tx) using the EORTC QLQ-C30. The HRQoL analysis included all pts with valid HRQoL assessments at BL and at ≥1 post-BL visit. Linear mixed-effect models for repeated measures were calculated using on-Tx data for cycles 2 to 6 (where n was ≥25 in both arms) to estimate differences in overall least-square (LS) mean changes from BL between Tx arms.

• The HRQoL analysis included 419 (236 SG; 183 TPC) pts (median age, 54 y; median prior regimens, 4; brain metastases present, 11%). Mean QLQ-C30 subscale scores at BL were similar between Tx arms. SG showed significantly and meaningfully greater improvement than the TPC arms (Table) in global health status (GHS, 0.7 vs -3.4), physical (1.3 vs -4.4) and emotional functioning (3.3 vs. -0.5), and lower symptomatic impact of fatigue (2.0 vs 7.1), pain (-8.9 vs -1.9), dyspnea (-3.8 vs 4.0), and insomnia (-4.7 vs 0.3). Of all symptoms, only diarrhea was significantly and meaningfully worse with SG (14.1 vs. -1.3).

What is the ASCENT Study’s clinical trial identification?

I’m very happy to share ASCENT clinical trial investigators results of the health-related quality of life study that were recently presented at ESMO. This analysis was a subgroup analysis of the Phase III study, the ASCENT trial of Trodelvy, whose primary endpoint was a randomized open-label study investigating the efficacy and safety of Sacituzumab Govitecan (Trodelvy) versus a single agent of the chemotherapy treatment of physician’s choice in pretreated advanced triple-negative breast cancer (mTNBC). This study has shown that treatment options with Trodelvy significantly improved overall survival, a key outcome of these trials, especially in this incurable setting in clinical oncology, also has an impact on the patient-reported outcomes.

It’s therefore that a health-related quality of life study has been performed. So, the primary endpoint of the ASCENT Trial was obvious, we wanted to see the evolution of the quality of life and check whether there were significant changes between adult patients randomized to the experimental mental arm with pro versus those randomized to the control arm with single-agent chemotherapy or physician choice.

And actually, the results were really reassuring. When we looked at the primary global health-related quality of life aspects, we could see that there was a significant and clinically meaningful improvement in health-related quality of life scores for patients treated with Trodelvy as compared to those treated in the control arm.

How does Sacituzumab Govitecan work?

The drug is made up of irinotecan, a chemotherapeutic medication, linked to an antibody. Antibodies are proteins produced by the immune system that bind to foreign substances in the body to avoid injury. It attaches to and destroys cancer cells.

The ASCENT Trial and Triple Negative Breast Cancer Relevance to the Global Health Status?

This was relevant to the global health status but also for physical functioning and emotional functioning. When we look into the specific symptoms that a patient can have. When we treated them for a disease like advanced triple-negative breast cancer (mTNBC), we saw a lower symptomatic impact of fatigue and pain, but also of dyspnea in Pts treated with pro compared to those treated with a single lesion of the physician’s choice.

And, the only symptom that was significantly and meaningfully worse in patients who were treated with Philadelphia was diarrhea, but this is a well-known adverse events of Trodelvy. And despite this diarrhea, this does not have an adverse effect on the patient’s global health status score or function.

For colleagues that do not yet have experience with this Trodelvy, or, of course, interested in knowing what the safety profile of Trodelvy is, since it might not always be. It is easy to assess this from the safety tables from a phase 3 trial. Colleagues are really interested in knowing how this impacts the patient’s reported outcome.

The general aspects of this analysis show clinically meaningful improvements for heavily pretreated patients with important findings that are discussed among colleagues, and that can leverage and increase the value of a specific anti-cancer treatment. And this is really happening based on the results we see here today.

How is Sacituzumab Govitecan administered?

Trodelvy is injected into a vein (intravenously). This will be administered as a drip (infusion) in the back of the hand or lower arm. Other intravenous procedures may be utilized based on your preferences and how easy it is for your chemotherapy team to identify suitable veins. It is administered in cycles. A “cycle” is when you take the drug on a specific day or days and then take a break to allow your body to recover. A sacituzumab govitecan cycle lasts 21 days, with medication administered on days one and eight of the cycle. The process is then repeated.

The initial infusion of Trodelvy will take three hours. If you do not have a negative reaction to your initial infusion, your subsequent infusions will normally take one to two hours.

How Does Trodelvy(Sacituzumab Govitecan) Impact the Scoring Systems?

For example, this can also impact some important scoring systems that are used in the oncology community to score the value of a new treatment. For example, the ESMO magnitude of clinical benefit scale incorporates health-related quality of life data and when, as we see in the subgroup analysis of essence, the global health-related quality of life significantly improves with a new treatment as compared to the standard treatment, this results in an additional score which would result in Trodelvy reaching the maximum score on this clinical outcome for anti-cancer treatment in curative.

What is the Median Progression Free Survival in Patients With Metastatic Triple Negative Breast Cancer?

We know that the efficacy of Trodelvy has been explored in several treatment lines. So, starting from the second treatment line onwards, in previously treated patients who had received several prior treatment lines, it has been shown that Trodelvy is active in all these settings, but taking into account also the supportive quality of life data.

The book of the data, I think, points towards the more earlier use of it in patients with advanced metastatic triple-negative breast cancer from the second line onwards. And I think that these reassuring findings can lower the threshold of response evaluation criteria that some hesitating physicians could have to use Trodelvy early on as soon as it’s on label and it’s available.

I think that the uptake of Trodelvy will further increase based on these results. We have to acknowledge that it has already been considered in places where it’s available that a new standard of care is available. The results of this research will likely be. In the magnitude of clinical benefit scale.

We can hope that this will result in a maximum score on this scale, which can actually be used by a physician, but also by authorities to prioritize treatment and make decisions when it comes to reimbursement.

It is a very important aspect in the incurable setting that we do not only want to improve efficacy outcomes but we also want to improve the quality of life since we are in an incurable setting. The quality of life perceived by the patient remains one of the most important aspects in assessing the value by the ASCENT clinical trial investigator assessment.

I want to encourage all my colleagues to consider pre-planning health-related quality of life evaluations in similar settings to strengthen the bulk of data we can rely on to be confident in saying that Trodelvy is the best treatment option for patients who fall into the label of advanced metastatic triple-negative breast cancer.

Is Sacituzumab Govitecan an Antibody Drug Conjugate?

Trodelvy is an antibody-drug combination consisting of a human trophoblast cell-surface antigen 2 (Trop-2) antibody conjugated to SN-38 (topoisomerase I inhibitor) via a unique hydrolyzable linker.

FDA approval for Trodelvy (Sacituzumab Govitecan)

On April 7, 2022, the drug was approved for people who have triple-negative breast cancer that has progressed to other parts of the body and cannot be removed surgically. Before receiving Sacituzumab Govitecan, patients must have received two or more breast cancer therapies, including one for metastatic illness.

The speedy clearance in April 2020 was prompted by promising results from a small research study. The FDA approval has now elevated the medicine to a normal approval based on findings from a far larger confirmatory clinical trial, which revealed that Trodelvy extended patients’ lives when compared to standard chemotherapy treatments.

Abstract Origins:

The anti–Trop-2 antibody is linked to SN-38 by a unique hydrolyzable linker in sacituzumab govitecan, which is an antibody-drug conjugate. In the ASCENT study, an intention-to-treat study, SG substantially improved overall survival (PFS; median 4.8 vs 1.7 mo) and overall survival (median overall survival 11.8 vs 6.9 mo) in the second line or larger (2L+) mTNBC scenario compared to chemotherapy of physician’s choice (TPC). In this paper, we look at the effect of SG on HRQoL in the ASCENT trial.

Methodologies:

Patients with metastatic triple-negative breast cancer who had undergone at least two prior systemic therapies (at least one for metastatic disease) were randomly assigned to either SG (10 mg/kg IV on days 1 and 8, every 21 days) or TPC (capecitabine, eribulin, vinorelbine, or gemcitabine). The EORTC QLQ-C30 was used to measure HRQoL at baseline (BL), before each cycle, and at the conclusion of therapy (Tx). All patients with valid HRQoL measurements at baseline and at one post-BL visit were included in the HRQoL analysis. To assess differences in overall least-square (LS) mean changes from BL between Tx arms, linear mixed-effect models for repeated measures were computed using on-Tx data for cycles 2 to 6 (where n was 25 in both arms).

Data Analysis and Outcomes for Sacituzumab Govitecan:

There were 419 points (236 SG; 183 TPC) in the HRQoL study (median age, 54 y; median prior regimens, 4; brain metastasis present, 11% ). At BL, the Tx arms had similar mean QLQ-C30 subscale scores. In terms of global health status (GHS, 0.7 vs. -3.4), physical (1.3 vs. -4.4), and emotional functioning (3.3 vs. -0.5), SG outperformed TPC (Table), with reduced symptomatic effect of tiredness (2.0 vs. 7.1), pain (-8.9 vs. 1.9), dyspnea (-3.8 vs. 4.0), and sleeplessness (-3.8 vs. 4.0). (-4.7 vs 0.3). Only diarrhea was substantially and meaningfully worse with SG of all symptoms (14.1 vs. -1.3).

Summary of findings:

Sacituzumab govitecan in adult patients with 2L+ mTNBC, SG not only improved HRQoL but significantly extended PFS and OS compared to TPC. Although the symptoms of diarrhea were worsened by SG, this did not appear to have a negative population influence on the adult patients’ overall health or functioning and disease progression free survival.

ASCENT Trial Clinical Study Identification – NCT02574455

From Gilead Sciences, Inc.

Gilead Sciences, Inc. is a biopharmaceutical business that has spent more than three decades pursuing and achieving medical innovations with the objective of creating a better world for all people. The company is dedicated to developing new medicines to prevent adverse events and treat life-threatening diseases such as HIV, viral hepatitis, and cancer. Gilead works in over 35 countries throughout the world, with its headquarters in Foster City, California.

Gilead Sciences, Inc. sponsored the ASCENT trial. Gilead Sciences, Inc. (Nasdaq: GILD) today announced the results of the Phase 3 ASCENT Trial of Trodelvy® in patients with relapsed or refractory metastatic triple-negative breast cancer (TNBC) who had received two or more prior systemic therapies, at least one of which was for metastatic disease. Trodelvy improved median progression-free survival versus physicians’ choice of chemotherapy (4.8 vs. 1.7 months; HR: 0.41; p0.0001) and extended median overall survival (OS) by nearly five months (11.8 vs. 6.9 months; HR: 0.51; p0.0001) in the intent-to-treat population in a follow-up analysis from the final database lock. The two-year OS rate in the Trodelvy arm was 20.5% (95 % CI: 15.4-26.1), compared to 5.5% (95% CI: 2.8-9.4) with physicians’ choice of chemotherapy. Trodelvy also shown clinically significant increases in health-related quality of life (HRQoL) over chemotherapy. The findings were presented at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting (Abstract #1071). They were consistent with the final analysis previously published in The New England Journal of Medicine.

Trodelvy revealed greater clinically relevant gains in all five primary HRQoL areas than chemotherapy, which was consistent with earlier findings. Metastatic TNBC is frequently linked with a significant loss in quality of life, especially when patients are subjected to multiple rounds of intense chemotherapy, and measuring the impact of symptom load is particularly relevant in this situation. Trodelvy vs. chemotherapy improved global health status by -5.8 vs. -9.4, physical functioning by -4.6 vs. -13.5, role functioning by -8.4 vs. -18.8, fatigue by 5.1 vs. 14.0, and pain by 2.8 vs. 6.8.

About the Author and Affiliations

Kevin Punie, MD He works as a medical oncologist at the University Hospitals Leuven Cancer Institute in Gasthuisberg, Belgium, in the department of General Medical Oncology department. His research focuses on metastatic breast cancer, hereditary cancer syndromes, and customized treatment.

In 2010, he received his MD from the Catholic University of Leuven. He worked as a fellow in General Internal Medicine at University Hospitals Leuven and ZNA Jan Palfijn Antwerp before completing his specialty as a medical oncologist at UZ Leuven. He is currently working on a PhD study in a breast cancer center that focuses on liquid biopsies, metabolomics, and miRNAs.

During his fellowship and as a current staff member, he was heavily involved in clinical cancer research as a subinvestigator in many clinical Phase I-III trials in clinical oncology, all of which were overseen by Prof. Dr. Patrick Schöffski. He is now a subinvestigator in over 25 disease-specific clinical trials that are recruiting participants, as well as the principal investigator in 5 breast cancer-specific Phase II-III investigations. He was chosen to attend the 2017 ECCO-AACR-EORTS-ESMO Workshop on Methods in Clinical Cancer Research in Zeist in June 2017.

He is an active member of the BSMO (Belgian Society of Medical Oncology) and the ESMO (European Society of Medical Oncology), where he is also a member of the Young Oncologists Committee, where he actively participates in the organization of the Young Oncologists track at the annual ESMO congress, among other educational tasks. He also belongs to the EORTC (European Organization for Research and Treatment of Cancer) and is a member of the EORTC Breast Cancer Group. He is one of the investigators of the ASCENT Study.

References

1. NIH National Cancer Institute – Clinical Trials Using Sacituzumab Govitecan. NIH Clinical Trials Information, 2022.

2. NIH National Cancer Institute – Sacituzumab Govitecan Earns Full Approval for Triple-Negative Breast Cancer. NIH Cancer Currents Blog, May 12, 2021.

3. Breast Cancer Now The Research & Care Charity –

4. Sacituzumab govitecan (Trodelvy) – Breast Cancer Now The Research & Care Charity Targeted (Biological) Therapy, February 2022.

5. The New England Journal of Medicine – Sacituzumab Govitecan in Metastatic Triple-Negative Breast Cancer, The New England Journal of Medicine Original Article, April 22, 2021