Wei Assesses Role of TROP2 and HER2 Status in Treatment With Sacituzumab for ER+ mBC

Mei Wei, MD

Associate Professor (Clinical)

University of Utah School of Medicine

Medical Oncologist

Huntsman Cancer Institute

Salt Lake City, UT

How do you define endocrine resistance in patients with metastatic breast cancer (mBC)?

Wei: In the United States, we are always vague about how to define endocrine therapy resistance. However, the European Society for Medical Oncology has a clear definition of endocrine therapy resistance.¹ Primary endocrine resistance is relapse during the first year of adjuvant endocrine therapy—so if your patient finished surgery or radiation therapy, started endocrine therapy, and within 2 years had relapsed, then that’s primary endocrine resistance. Or in the metastatic setting, if a patient was started on first-line endocrine therapy [and experienced] progression of disease within 6 months, that’s a primary endocrine therapy [resistance].

Our patient does not meet any of these criteria. She developed stage IV disease 8 months after she finished endocrine therapy, and then she was on first-line endocrine therapy for 22 months. So, our patient does not have primary endocrine resistance.

Secondary endocrine resistance is defined as relapse while on adjuvant endocrine therapy after the first 2 years or relapse within 12 months of completion of adjuvant endocrine therapy—so that is our patient— or a patient in the metastatic setting who has progression more than 6 months after initializing endocrine therapy when the patient is still on endocrine therapy. That’s considered a secondary endocrine resistance. So, our patient [has] secondary endocrine resistance.

What treatments would be available for a patient with hormone receptor– positive, HER2-negative recurrent metastatic disease?

In the National Comprehensive Cancer Network [NCCN] guidelines…what I want to point out is that in the second-line setting, if the patient is HER2 low, you could use trastuzumab deruxtecan [T-DXd, Enhertu].² If…not, you could use sacituzumab govitecan [Trodelvy] as well. Both have category 1 evidence. For sacituzumab, the FDA approval is for ER+, HER2-negative, metastatic, after endocrine-based therapy, with 2 or more additional systemic therapies in the metastatic setting. It’s a bit different compared with our NCCN guidelines. They specifically mention at least 2 lines of chemotherapy, one of which was a taxane and at least one of which was in the metastatic setting.

In terms of T-DXd, the FDA approval is a bit clearer. [They must] have received prior chemotherapy in the metastatic setting or developed recurrence within 6 months of completion of adjuvant chemotherapy. That is just the subtle wording the FDA and NCCN.

How did the phase 3 TROPiCS-02 trial (NCT0390133)] evaluate sacituzumab in patients with ER+ advanced breast cancer?

This study was designed [so that] patients had to have at least 1 line of endocrine therapy, a taxane, and a CDK4/6 inhibitor in any setting. For example, if the patient had a taxane in the adjuvant setting, that counts. Patients had to have at least 2 lines but no more than 4 lines of chemotherapy in the metastatic setting. It’s [enrolled over] 500 patients, so it’s not too big, but it’s not small, either.³ They were randomly assigned to sacituzumab vs treatment of physician’s choice [TPC].

What were the key efficacy outcomes in this trial?

[In terms of] progression-free survival [PFS], we can see the median PFS with sacituzumab is 5.5 months compared with 4.0 months with TPC, and the P value is significant as well [stratified HR, 0.65; 95% CI, 0.53-0.81; nominal P = .0001].⁴

When we look at overall survival [OS], it’s even better. The median OS for sacituzumab is 14.4 months, and for TPC, it was 11.2 months.^3,4 That’s a 3.2-month difference with a P value of .02, so we can see the sacituzumab not only improves PFS but also improves OS [HR, 0.79; 95% CI, 0.65-0.96; P = .02]. We don’t see that a lot after the CDK4/6 plus aromatase inhibitor.

What did the exploratory subgroup analysis from the phase 3 ASCENT trial (NCT02574455) show about TROP2 expression?

The question is, does TROP2 expression matter [for sacituzumab’s efficacy]? The lowest TROP2 level they showed was [an H-score of] from 0 to less than 100. [Medium level] was a TROP2 level from 100 to 200, and then [high level was] TROP2 level above 200 to 300. [Looking at] overall response rate [ORR], we can see as the TROP2 level increases, the ORR in the sacituzumab arm increases as well, and then we can see the difference become bigger and bigger.⁵ It’s 44% vs 1%, 38% vs 11%, and 22% vs 6% [for sacituzumab vs TPC in high, medium, and low TROP2 groups, respectively]. Even though 22% is not as big as 44%, the difference between these 2 arms is still dramatic. I want to mention that in the [low TROP2 groups], we don’t have that many patients; it was relatively small. When we look at median PFS, if the patient had low TROP2, the difference is 2.7 months vs 1.6 months [for sacituzumab vs TPC, respectively], but if it’s medium, the difference is 5.6 months vs 2.2 months, and if high, the difference is 6.9 months vs 2.5 months [respectively], so again, the higher TROP2 expression has the longer PFS as well. However, we still see a significant difference between the 2 arms within each category [Figure⁵].

Next, we look at the median OS [and see] the same thing: 9.3 months vs 7.6 months [in the TROP2 low group]; not too much, but 14.9 months vs 6.9 months [for medium TROP2] and 14.2 months vs 6.9 months [for high TROP2, respectively] so I think that’s why we draw the conclusion that in this patient population, we don’t need to test TROP2. Pretty much everybody responds to sacituzumab regardless of the TROP2 expression. If it is lower, they may have shorter OS. However, compared with physician’s choice, they still perform better.

What is the relevance of HER2 status in TROPiCS-02?

We can see in the HER2-low setting the difference in median PFS is 5.8 months for sacituzumab vs 4.2 months for TPC, and then the HR did not cross 1.0 [HR, 0.60; 95% CI, 0.44-0.82], so that means it’s significant.⁴ Among patients who have HER2 0, the difference is 5.0 months vs 3.4 months and again the HR did not cross 1.0 [HR, 0.70; 95% CI, 0.51-0.98].

If the PFS is translated to OS for the HER2 low, it looks like the benefit remains. [Median OS was] 15.4 months for sacituzumab vs 11.5 months for TPC, and the HR did not cross 1 [HR, 0.75; 95% CI, 0.57-0.97]. However, [it] looks a little different if the patient had HER2 0, even though the difference is about 3 months [13.6 months for sacituzumab vs 10.8 months with TPC]. However, the HR crossed 1.0 [HR, 0.85; 95% CI, 0.63-1.14]. We can see in terms of the HER2 status that it at least [is associated with] improved PFS [and] improved OS if the patient has HER2 low, but maybe not too much if the patient has HER2 0.

How do sacituzumab and T-DXd perform when given in sequence?

That’s the million-dollar question. [Data] were presented at the 2023 American Society of Clinical Oncology Annual Meeting. They did ADC [antibody-drug conjugate] after ADC. Their parameter was PFS1 with the first ADC and PFS2 with the second ADC.⁶ They found out that regardless of which ADC you use first, the second ADC always had a shorter PFS. If you did T-DXd first and sacituzumab second, it had shorter PFS, and if you switched, it would be the same. Those are the data we have now. But again, those are very small [patient numbers], so we still don’t really know. The situation is just getting worse because now we probably will have datopotamab deruxtecan becoming approved. So, we’re going to have 3 [ADCs], and nobody knows what is going to happen with ADC, ADC, then ADC.

What safety concerns are there with sacituzumab in TROPiCS-02?

We want something [that] can improve the OS, but we also want the medication to be tolerable because the goal of metastatic treatment is palliative to maintain the quality of life. With this study, we see 74% of the patients had grade 3 or higher adverse events [AEs] vs 60% with TPC.⁴ Two patients died from [AEs] in this trial, but only 1 is treatment related, and in the TPC arm, nobody died [of AEs].

[In terms of] the clinical challenge when you use sacituzumab, the most common AE is neutropenia. It’s 52% [grade 3 or higher] compared with 39% for TPC. The next and most common [AE] is diarrhea, [and] the rest [include] fatigue and alopecia, which is noticeable as well in my practice.

REFERENCES:

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2. NCCN. Clinical Practice Guidelines in Oncology. Breast cancer, version 4.2024. Accessed August 16, 2024. https://tinyurl.com/58ppyx87

3. Rugo HS, Bardia A, Marmé F, et al. Overall survival with sacituzumab govitecan in hormone receptor-positive and human epidermal growth factor receptor 2-negative metastatic breast cancer (TROPiCS-02): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2023;402(10411):1423-1433. doi:10.1016/S0140- 6736(23)01245-X

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