Batalini Explores Role of UGT1A1 in Patients Treated With Sacituzumab Govitecan for HR+ MBC

Felipe Batalini, MD

Assistant Professor of Oncology

Mayo Clinic College of Medicine

Phoenix, AZ

PEERS & PERSPECTIVES IN ONCOLOGY: What data impact the choice of therapy for a patient with hormone receptor (HR)-positive metastatic breast cancer (MBC) in the second-line metastatic setting?

BATALINI: This is based in large part on [results from] the phase 3 TROPiCS-02 clinical trial [NCT03901339]. Sacituzumab govitecan [Trodelvy] was initially approved for triple-negative disease based on the ASCENT [NCT02574455] data. TROPiCS-02 was the study that brought sacituzumab govitecan into the ER-positive population or HR-positive population. The trial enrolled more than 500 patients [and randomly assigned them] 1:1 to sacituzumab govitecan vs treatment of physician’s choice [TPC] of capecitabine, vinorelbine, gemcitabine, or eribulin. Patients were stratified by visceral metastasis, endocrine therapy in the metastatic setting within 6 months, and number of prior lines of chemotherapy. End points were typical: progression-free survival [PFS], overall survival [OS], and some other end points.¹

What were the key efficacy outcomes in this trial?

What we see is a benefit in patients who received sacituzumab govitecan as opposed to TPC. These are patients with aggressive disease. The median PFS increased from 4.0 months with TPC to 5.5 months with sacituzumab govitecan with an HR of 0.6, statistically significant [95% CI, 0.53-0.81; P = .0001].² It’s interesting to see that patients who have a response have a durable response. At 1 year, you have only 8% without progression in the TPC arm vs 22% in patients who received sacituzumab govitecan.

There was also an OS advantage, so patients lived a median of 11 months on the TPC arm vs 14.5 months with sacituzumab govitecan with an HR of 0.79 [95% CI, 0.65-0.95; P = .0133]. Another way of looking at different time points at the curve is that 60% of patients [who received sacituzumab govitecan] were alive at the 1-year mark vs 47% with TPC; 40% of patients were alive at 1 1/2 years vs 30%, respectively; and 25% of patients were alive at 2 years vs 21%, respectively. In terms of responses, we see higher response rates [with sacituzumab govitecan] too.

This is not the most important thing for me. What I like is the duration of therapy, [meaning] these patients are not having that progression conversation every time you see them, and patients can be on some therapy for a long period. We have a 20% overall response rate with sacituzumab govitecan vs 14% with TPC.^1,2 There were 2 patients with a complete response [vs 1 with TPC]. The disease control rate was 34% vs 22%, respectively. The duration of response for patients who have a response is 8.1 months [95% CI, 6.7-8.9] vs 5.6 with TPC [95% CI, 3.8-7.9].²

What were the most notable adverse events (AEs) observed in patients who received sacituzumab govitecan?

In terms of AEs, neutropenia is certainly an important one [71% any-grade], as is diarrhea [62%], in part because of the drug that is carried with the antibody.^1,2 Then alopecia [48%], fatigue [39%], and all the AEs [of chemotherapy] that we are very used to dealing with. Rates of [grade 3 or higher] neutropenia were 50% with sacituzumab govitecan as opposed to 40% [with TPC], so not too much higher; but there was more diarrhea,10% grade 3 or higher with sacituzumab govitecan vs 1% with TPC.

What is the significance of the UGT1A1 phenotype status in patients treated with sacituzumab govitecan?

UGT1A1 is a uridine diphosphate-glucuronosyltransferase that glucuronidates SN-38, the active metabolite, and by glucuronidating it gets the drug inactive, metabolized, and eliminated. In the population, it has a wide variation in its alleles. The most common allele is *1/*1, but we have the allele *28, and then we have the typical wild-type phenotype of the gene *1/*1. You can have combination of heterozygous *1/*28 or homozygous *28/*28. The dose intensity [was lower in patients with *28/*28 status], and 9% of patients had the *28/*28, but a lot of patients had wild type, with heterozygous genotype being the most common.³ It’s nice to see this, because I’m someone who often advocates for germline sequencing going way beyond cancer predisposition genes for targeted therapies. If you’re sequencing germline anyway, why don’t we get all this pharmacogenomics testing done? As we learned, it’s not only this drug. There are other genes that are relevant, [such as] CYP2D6 for the estrogenic pathways.

But if you look at the rates of neutropenia, it’s not night and day [Table³]. In the wild type, neutropenia of grade 3 is 45%, and it goes to 57% [with heterozygous] and 64% [with *28/*28 homozygous].³ But as I think critically, as somebody who is going to pay for the test, I’m not sure how much that will make me change my practice, because 45% is already a high risk, so I’m going to be careful with them anyway. Should I dose reduce? Maybe. Some people are discussing that.

To me, it is not the higher chance of neutropenia [that matters so much] but that it doubles the rate of grade 3 diarrhea. That affects patients’ quality of life more than neutropenia. Neutropenia affects [how physicians treat patients], but 24% grade 3 [diarrhea] with the *28/*28 genotype [compared with 13% with heterozygous] is something to consider for sure. Maybe you’re going to be more aggressive in managing that. You may be thinking about dose reduction.

There’s no consensus on how we should necessarily treat these patients. It’s still not mandatory to check UGT1A1 status, but these are the data [we have]. The heterozygous genotype is common in different populations. The *28/*28 genotype is more common in African American patients, and it’s very rare in East Asian patients. So if you want to enrich your testing for patients who are more likely to be homozygous *28/*28, think about that in African American patients.

I feel that if you’re doing germline testing, you should [be able to] just get it. You’re [testing] many genes. It’s not that expensive in the lab. But none of the commercial labs are doing [that]. It would be so [inexpensive] to add 5 genes to that cancer predisposition germline testing, but it’s not how reimbursement works, so that’s not how clinic works.

REFERENCES:

1. Rugo HS, Bardia A, Marmé F, et al. Sacituzumab govitecan in hormone receptor–positive/human epidermal growth factor receptor 2–negative metastatic breast cancer. J Clin Oncol. 2022;40(29):3365-3376. doi:10.1200/JCO.22.01002

2. Tolaney SM, Bardia A, Marmé F, et al. Final overall survival (OS) analysis from the phase 3 TROPiCS-02 study of sacituzumab govitecan (SG) in patients (pts) with hormone receptor–positive/HER2-negative (HR+/HER2–) metastatic breast cancer (mBC). J Clin Oncol. 2023;41(suppl 16):1003. doi:10.1200/JCO.2023.41.16_suppl.1003

3. Marmé F, Rugo HS, Tolaney SM, et al. Safety outcomes by UGT1A1 status in the phase III TROPiCS-02 study of sacituzumab govitecan (SG) in HR+/HER2– metastatic breast cancer (mBC). ESMO Open. 2023;8(1 suppl 4):101383. doi:10.1016/j.esmoop.2023.101383