Sacituzumab Govitecan: SABCS 2022 Hope Rugo EAIRs of AEs TROPiCS-02

Sacituzumab Govitecan: SABCS 2022 Hope Rugo EAIRs of AEs TROPiCS-02

What does Sacituzumab Govitecan trial results show for patients with HR+/HER2- metastatic breast cancer (MBC)? Sacituzumab Govitecan is a first in class Trop-2-directed antibody-drug conjugates linked to a Topoisomerase 1 inhibitor. The active metabolite of Irinotecan SN-38 Sacituzumab is already FDA approved for the treatment of metastatic Triple-negative breast cancer (TNBC)  in patients who’ve received at least one line of prior chemotherapy based on data from the ASCENT trial.

Where it showed improvement in progression-free and overall survival compared to chemotherapy of physician choice. In an initial phase one Umbrella trial, Sacituzumab showed efficacy and heavily pretreated hormone receptor positive disease, as well as triple-negative disease. So TROPICS-02 was designed as a phase 3 trial to evaluate the efficacy of Sacituzumabin patients with pretreated hormone receptor positive disease patients were eligible for TROPICS-02 if they had hormone receptor metastatic breast cancer had received a CDK4/6 inhibitor, at least one line of endocrine therapy and a taxane in any setting. In addition, they had to have received two to 4 lines of prior chemotherapy for metastatic disease, so we enrolled a patient population who really had both endocrine and chemotherapy resistant disease. Eligible patients were randomized to receive Sacituzumab Govitecan, or to receive chemotherapy of physician choice or treatment of physician choice TPC, a menu of standard chemotherapy options. The primary endpoint was progression-free survival by blinded independent center of view, and the secondary endpoint included overall survival response and quality of life patient reported outcomes and there was a hierarchical statistical design. So each endpoint had to be positive before you could look at the statistics of this next endpoint. We showed at ASCO 2022 that the case study population was heavily pretreated with a median number of lines of chemotherapy of 3, with almost 60% of patients receiving 3 to 4 lines of chemotherapy, and that 95% of patients had visceral disease.

The median time from diagnosis to metastatic disease was about from, sorry, from diagnosis metastatic disease to randomization on study was about 4 years. So these patients already had metastatic disease for a long time. We were able to look in the first analysis at progression-free survival and progression-free survival was significantly prolonged with a hazard ratio of 0.66 or 34% relative improvement in progression-free survival in patients receiving Sacituzumab compared to TPC which was highly statistically significant. That data is now published in the JCO at the second interim analysis presented at ESMO 2022, we showed a significant improvement in overall survival with a median improvement of 3.2 months, also highly statistically significant.

So the next question that came up was what happened to the other endpoints, and we showed a significant improvement in response as well as a significant improvement in clinical benefit. And a longer duration of response as well as a significant delay in time to deterioration of global health status, quality of life with Sacituzumab compared to treatment of physician choice or TPC.

So that data existed, but then the question came up. What is the relationship of Trop-2 expression? The antibody is targeted to Trop-2. Do you need to measure Trop-2 expression in order to understand which patients would benefit from Sacituzumab? So that was the analysis that we did to present at San Antonio Breast Cancer Symposium (SABCS) this year.

What was the data presented at SABCS?  

So at San Antonio this year, we looked at Trop-2 expression to see whether or not that was a determinant of response for Sacituzumab. It’s a Trop-2 ADC, but what we saw was really interesting. So the majority of patients had samples that we could evaluate for Trop-2 expression and Trop-2 expression was incredibly high, 95% of the samples had at least some expression of Trop-2, and almost 60% had high Trop-2 expression using an H-score that looks at both the percent of cells that stain in the staining intensity with a research based immunohistochemistry test for Trop-2 expression. So then we looked at different categories based on this H-score, we looked at less than 100 and 100 or greater, so a lot or less Trop-2 expression.

And we saw that both PFS and overall survival were similarly improved, regardless of which category of Trop-2 expression you had, and it was actually a fairly similar number of patients in each category of the lower high expression. So that was very encouraging, but then, of course we wanted to look at the very low expression of Trop-2.

So we looked at the category of patients who had Trop-2 of 10 or less, and compared them to the group who were greater than 10, but less than 100. And again, although the numbers are very small, so it’s hard to really give confidence for the interpretation. We saw that it appeared that Sacituzumab was still better in those patients who had very low Trop-2 expression, 10 patients had Trop-2 of 0 in the Sacituzumab arm, and one patient responded to Sacituzumab. So we concluded that, the drug is effective, improves progression-free and overall survival in this heavily pre-treated hormone receptor positive HER2-negative population, and that you don’t need to measure Trop-2 expression in order to understand which patients will benefit.

And it was nice to see that safety was not impacted by Trop-2 expression, and the safety profile in TROPICS was very similar to ASCENT. So we have a really good idea of how to manage the neutropenia and diarrhea that we see with this agent.

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5 Key Takeaways about the TROPiCS-02 Sacituzumab Govitecan Clinical Trial

1. The TROPiCS-02 clinical trial is a global, multicenter, open-label, Phase 3 study randomized trial 1:1 to compare Trodelvy (Sacituzumab Govitecan) to the physician’s choice of chemotherapy (Eribulin, Capecitabine, Gemcitabine, or Vinorelbine) in 543 patients with HR+/HER2- metastatic breast cancer who have received endocrine therapy, CDK4/6 inhibitors, and two to four lines of chemotherapy.

2. The primary endpoint is PFS (progression-free survival) according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) as assessed by blinded independent central review for persons treated with Trodelvy (Sacituzumab Govitecan) versus chemotherapy. The study aims to reduce the risk of disease progression or death by 30% and is powered to detect a statistically significant difference in median PFS of at least 0.9 months.

3. The secondary endpoints include overall survival, clinical benefit rate (higher rates), duration of response, and overall response rate, in addition to indicators of safety, tolerability, and quality of life.

4. Key Eligibility Criteria – Confirmation of hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative (HR+/HER2-) metastatic breast cancer (MBC).

   Refractory to at least 2 and no more than 4 prior systemic chemotherapy regimens for MBC, including at least 1 prior anticancer hormonal treatment.

   At least one inhibitor of cyclin-dependent kinase 4/6 in the metastatic situation.

   Eligible to receive one of the chemotherapy therapies specified in the TPC arm, disee progression documented following the most recent therapy.

5. Important Exclusion Criteria – Prior topoisomerase 1 therapy Inhibitors as free compounds or in various forms.

   Significant cardiovascular disease history or electrocardiogram (ECG) abnormalities with clinical significance.

   Those affected with Gilbert’s disease.

   Active, significant, antibiotic-required infection.

   Individuals who have previously experienced an allergic reaction to Irinotecan.

What is the current standard of care and HER2 positive HER2 negative metastatic breast cancer?  

So the standard of care for patients with hormone receptor positive HER2-negative breast cancer is sequential endocrine therapy with targeted agents. And we have a lot of new agents that were talked about at San Antonio this year, and new targeted agents as well. So that’s a moving target, but that’s the standard of care with the new agents that will come in as they have phase 3 data and are approved and after that it’s single agent sequential chemotherapy. Some countries use combination chemotherapy, but in general, that’s not recommended except for very bad disease, rapidly progressive disease. We haven’t had great options, we run out of the chemotherapy, we see cumulative toxicity. We saw data from the Trastuzumab Deruxtecan and HER2-low disease.

That’s an excellent option that improves progression-free and overall survival in patients who have HER2-low disease, patients end up in later lines of therapy or have HER2 0 disease and we don’t have good options. So Sacituzumab Govitecan we feel is a really promising option for patients in that situation.

What is Sacituzumab Govitecan?

Injections of sacituzumab govitecan-hziy are used to treat triple-negative breast cancer that has spread (metastatic) or cannot be surgically removed (unresectable locally advanced). It is administered to patients who have received two or more therapies for cancer, including at least one for metastatic disease.

Sacituzumab govitecan-hziy injection is also used to treat urothelial cancer (bladder cancer and urinary tract cancer) that has spread or cannot be surgically removed in individuals who have received prior cancer medications (eg, immunotherapy medicine, platinum-containing cancer medicine).

Sacituzumab govitecan-hziy is part of the class of drugs known as antineoplastics (cancer medicines). It inhibits the proliferation of cancer cells, which are ultimately eliminated. As the proliferation of normal cells may potentially be influenced by the medication, additional adverse effects are possible.

What are the key takeaways from this research and data?

The key takeaways are really just that Sacituzumab Govitecan is an effective antibody drug conjugate for both triple negative and hormone receptor positive breast cancer. The studies looked at patients who had relatively more heavily pretreated disease, particularly true for TROPICS, and patients had endocrine resistance as well.

So where are we going from here? I think that what we know is it’s an effective drug, but of course we wanna be able to move effective drugs earlier in the course of therapy. So there are now two trials looking at Sacituzumab and triple-negative breast cancer in the first line setting. One for Pembrolizumab and PD-L1 positive disease and one without.

And then we’re now working on opening a trial in the first line setting in hormone receptor positive disease that where you’ve already. Endocrine and targeted agent resistance. And the clinician believes that the patient needs to start on chemotherapy and patients will be randomized to receive Sacituzumab Govitecan, or again, treatment of physician choice.

We also, of course, wanna see if we can cure more. Women not get to the metastatic breast cancer setting. So there is planned trials in the post neo-adjuvant setting. There’s an ongoing trial in Germany, in the German Breast Group and a planned trial in the United States that will evaluate patients who have residual triple-negative breast cancer after neo-adjuvant therapy.

And will look at. Sacituzumab Govitecan with Pembrolizumab as well as standard of care with Pembrolizumab and Capecitabine. And then there are neoadjuvant trials ongoing as well. 

Hope Rugo, MD – About The Author, Credentials, and Affiliations

Dr. Hope Rugo specializes in breast cancer research and therapy as a medical oncologist and hematologist. Dr. Rugo, a Clinical Professor of Medicine, joined the Breast Care Center in 1999 after a decade of experience in malignant hematology and bone marrow transplantation for breast cancer and other disorders at UCSF. She entered the field of breast cancer to integrate novel medicines based on an understanding of the biology of cancer with great quality of care into the treatment of breast cancer in women.

Dr. Rugo is the Director of the Breast Oncology Clinical Trials Program and the main investigator of many clinical trials that aim to improve the treatment of early and late-stage breast cancer by combining innovative targeted therapies with standard treatment. In addition, Dr. Rugo is conducting research to measure cognitive function in women undergoing chemotherapy for breast cancer, as well as novel approaches to prevent therapy-related damage. Dr. Rugo has formed agreements with a number of other prominent academic medical institutes for the objective of broadening our patients’ access to innovative medicines, such as herbal compounds with an apparent anticancer impact in the laboratory. She is an active member of CALGB, a founder member of the Breast Cancer Research Consortium, and an investigator in the UCSF Breast SPORE (the Bay Area Specialized Program of Research Excellence in Breast Cancer). Dr. Rugo trains medical students and clinicians and frequently delivers local, national, and international presentations on breast cancer treatment-related topics. At UCSF, Dr. Rugo coordinates the Breast Forum, a biweekly evening educational program for breast cancer patients, their families, and friends from the entire bay area.

In 1983, Dr. Rugo received his medical degree from the University of Pennsylvania School of Medicine in medical oncology. At the University of California, San Francisco, she earned a residency in internal medicine and primary care, followed by a fellowship in hematology and oncology. From 1988 to 1990, she was an immunology postdoctoral fellow conducting laboratory research at Stanford University. Dr. Rugo joined the UCSF Division of Hematology and Oncology faculty in 1990. Dr. Rugo has been acknowledged for her proficiency in patient care, medical student education, and physician training. She has received various prizes, including the Bank of America Gianini Foundation Award and an intramural award from the UCSF Clinical Cancer Center Investigator Research Program. In 2006, the Friends of the Breast Care Center honored her for her contributions to breast cancer research.

Reference

1. Mayo Clinic – Sacituzumab Govitecan-Hziy (Intravenous Route). Mayo Clinic, November 1, 2022

2. Gilead Sciences – Phase 3 TROPiCS-02 clinical trial Met the Primary Endpoint of Progression-Free Survival in Late-Line HR+/HER2- Metastatic Breast Cancer. Gilead Sciences, March 07, 2022

3. Clinical Trials Gov – Study of Sacituzumab Govitecan-hziy Versus Treatment of Physician’s Choice in Participants With HR+/HER2- Metastatic Breast Cancer (TROPiCS-02). Clinical Trials Gov, November 7, 2022