Peers Discuss Sacituzumab Govitecan in HR+ mBC Post Endocrine Therapy

Tiffany A. Traina, MD

Vice Chair, Department of Medicine

Section Head, Triple Negative Breast Cancer Clinical Research Program

Memorial Sloan Kettering Cancer Center

New York, NY0

CASE SUMMARY

The patient is a 52-year-old postmenopausal woman with a history of T2N0M0 estrogen receptor–positive/progesterone receptor–positive, HER2 IHC 0 (0 expression by immunohistochemistry) breast cancer. She completed adjuvant docetaxel and cyclophosphamide followed by 5 years of letrozole. ​

Eight months after completion of letrozole, she presented with persistent low-back pain and fatigue that restricted exercise. Fludeoxyglucose (FDG) F18 PET/CT avid radiotracer uptake detected in L4-L5 vertebrae and right pubic bone​. Biopsy of L4 bone lesion showed malignant cytokeratin positive cells consistent with breast adenocarcinoma, leading to restaging of ​T2N0M1b (metastatic).

Molecular profile showed no mutations in ESR1, PIK3CA, PTEN, AKT, or pathogenic germline BRCA1/2 mutations​. First-line therapy with fulvestrant plus palbociclib (Ibrance) was initiated, which was well tolerated ​and elicited an initial partial response at 6 months​.

Twenty-two months after starting first-line therapy, she showed evidence of progressive disease with new areas of bone involvement in T-spine, left ribs, and L2​. circulating tumor DNA showed no actionable mutations, including ESR1. She received exemestane plus everolimus for 6 months​, and had radiographic evidence of progressive disease with numerous new bony metastases. Capecitabine (Xeloda) was initiated, which was well tolerated, with grade 1 hand-foot syndrome.

After 9 months of capecitabine​, a CT scan of the chest, abdomen, and pelvis and a bone scan showed significant findings:2 liver lesions measuring 1.8 cm and 2.4 cm respectively; persistent bony metastases consistent with disease progression; and lung lesions too small to characterize, but concerning in setting of other findings for metastatic disease​. Her ECOG performance status was 1 and laboratory profile was within normal limits.

DISCUSSION QUESTIONS

• Please discuss the rationale for your selection.​
• If you chose chemotherapy or other, which agent(s) would you use?​

TIFFANY A. TRAINA, MD: What next-line therapy would you recommend for this patient?

JULIE FASANO, MD: I had voted for ‘other’. I think it might be worthwhile, if possible, to repeat a biopsy at this point to see if there is any HER2-low expression, because she may be a candidate for trastuzumab deruxtecan [Enhertu; T-DXd]. I know that there are data that with repetitive biopsies, eventually, you're likely to find some HER2-low expression. I always prefer soft tissue over bone, but if it's not accessible, and if the patient was willing, I'd like to repeat a bone biopsy.

TRAINA: …It's a great suggestion because there is tumor heterogeneity and there is heterogeneity by metastatic site. We now see that she has visceral disease for the first time. Our biopsies in the past have been in the bone and her primary [tumor] was HER2-zero, but I agree with you, it might be interesting to try for one of the liver or lung lesions to see if there's HER2-low [expression] there.

MARC BRAUNSTEIN, MD: I chose sacituzumab govitecan [Trodelvy] because the randomized data compared with single-agent chemotherapy seems to be better.¹ It seems to be well tolerated and also had some success with central nervous system metastases, although that's not [present] in this patient, but still there may be some benefit there.

TRAINA: You're referring to TROPiCS-02 [NCT03901339] in hormone receptor [HR]-positive breast cancer. Great point.

FASANO: I've had insurance deny sacituzumab with HR-positive disease if they haven't progressed through 2 lines of chemotherapy. Someone had 1 dose of sacituzumab, and I got it approved after progression on capecitabine. She had HER2-zero expression on multiple biopsies. They refused to cover because she had not progressed through 2 lines of chemotherapy in the metastatic setting.

TRAINA: That's very surprising.

…When we get into the second-line setting, this is where HER2 status is important of stratifying our approach. For patients who have HER2-low breast cancer, the National Comprehensive Cancer Network is preferring T-DXd in that setting.² If patients are not candidates for T-DXd, sacituzumab is the preferred option. Otherwise, [we have] other remaining systemic chemotherapies.

The indication for sacituzumab in HR-positive, HER2-negative disease, regardless of [whether] HER2 IHC 0, IHC 1+, or IHC 2+/ISH- is after endocrine therapy and 2 or more lines of therapy for metastatic disease. To Dr Fasano’s point, I think this is the precise letter of the law, although often, when patients have had prior [chemotherapy] exposure in the adjuvant setting [or neoadjuvant setting], or a short disease-free interval, we've been able to count that as a line and still be able to access sacituzumab.³

CASE UPDATE

Sacituzumab govitecan was initiated, and a best response of partial response observed, with further symptomatic improvement. The patient maintained an absolute neutrophil count of 3,900/μL and white blood cell count of 7,800/μL​. Follow-up [18F] FDG PET/CT demonstrates resolution of avidity in vertebral and pelvic bones.

DISCUSSION QUESTIONS

• When would you consider sacituzumab govitecan as second-line therapy for a patient with HR-positive, HER2 IHC 0 metastatic breast cancer, previously treated with adjuvant taxane chemotherapy plus an aromatase inhibitor plus a CDK4/6 inhibitor?

BRAUNSTEIN: I think it's [based on] the approval.

TRAINA: So, whether you're able to get it for your patients?

SALIM CONTRACTOR, MD: The label says [it is indicated after] endocrine therapy plus 2 lines of systemic treatment.³

TRAINA: Right, 2 lines of therapy. PARP inhibitor therapy would count if we're talking about our patients with germline BRCA mutations. As I was saying, often if the disease-free interval was short from their adjuvant treatment, that can count as a line of therapy when we're getting approvals for insurance.³ Is there anything around toxicity or tolerability that might be a concern for anyone?

CONTRACTOR: If they have compromised bone marrow from adjuvant chemotherapy or metastatic breast cancer in the bone marrow, then you have to be a little bit more careful.

TRAINA: Yes, we're a bit worried about cytopenias or neutropenia. Fortunately, we can support a lot of that with growth factor and dose modifications that are built in.

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. NCCN. Clinical Practice Guidelines in Oncology. Breast cancer, version 4.2024. Accessed July 24, 2024. https://tinyurl.com/4hfywr7c

3. FDA approves sacituzumab govitecan-hziy for HR-positive breast cancer. FDA. February 3, 2023. Accessed July 24, 2024. https://tinyurl.com/bcsfwt82