T-DXd Reevaluated in HER2-Low/HER2-Negative Breast Cancer After New Trials

CASE SUMMARY

• A 52-year-old postmenopausal women with a history of T2N0M0 estrogen receptor-positive/progesterone receptor-negative, HER2 immunohistochemistry (IHC) 0 breast cancer.
• Received lumpectomy and sentinel lymph node biopsy; 21-gene recurrence score: 27
• 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.

Follow-Up Diagnostic Tests

• ECOG performance status: 0
• Complete blood count and comprehensive metabolic panel: hemoglobin 9.8 g/dL, all other indices within normal limits
• Fluorodeoxyglucose F 18 ([18F] FDG) PET/CT scan: fluorodeoxyglucose-avid radiotracer uptake detected in L4-L5 vertebrae and right pubic bone
• Biopsy of L4 bone lesion: malignant cytokeratin positive cells consistent with breast adenocarcinoma; hormone receptor (HR)-positive, HER2 IHC 0
• Molecular profile showed no alterations in ESR1, PIK3CA, PTEN, AKT, or pathogenic germline BRCA1/2 mutations​

Treatment and Progression

• First-line therapy with fulvestrant plus ribociclib was initiated and well tolerated.
  • Initial response noted on imaging at 3 months​.
• Fourteen months after starting first-line therapy:​
  • Evidence of progressive disease (PD), with new areas of bone involvement in T-spine, left ribs, and L2​
  • Circulating tumor DNA showed no actionable alterations, including ESR1 mutation.
• She then received exemestane plus everolimus for 6 months​.
• Radiographic evidence showed PD with numerous new bony metastases.
• Capecitabine was initiated, which was well tolerated

After 9 Months of Capecitabine​

• CT of chest/abdomen/pelvis and bone scan: 2 liver lesions, 1.8 cm and 2.4 cm; persistent bony metastases consistent with PD; lung lesions too small to characterize, but in setting of other findings concerning for metastatic disease​

Follow-Up Diagnostic Tests​

• ECOG performance status: 1​
• Laboratory profile: within normal limits

Next Line of Therapy

• Sacituzumab govitecan (Trodelvy) was initiated.
• Best response of partial response observed, with further symptomatic improvement.
• 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 scan: resolution of FDG-avidity in vertebral and pelvic bones

Targeted Oncology: Can you discuss therapeutic sequencing for patients with HR-positive, HER2-negative breast cancer?

Laura Huppert, MD: In general, we try to maximize endocrine therapy. Typically, we're using capecitabine in the first line for chemotherapy in these patients and then considering the use of sacituzumab govitecan next. I think with the more recent data with trastuzumab deruxtecan [T-DXd; Enhertu] in HER2-low and now ultra-low disease, I am often emailing the pathologist to see if the patient has any level of [HER2] expression and sliding that in before sacituzumab. It's not technically approved yet in that setting, but I have been able to get it for most patients so far.

What role does T-DXd play in this setting for a patient such as this?

That brings us to DESTINY-Breast04 [NCT03734029]. This trial enrolled patients with HER2-low, unresectable and/or metastatic HR-positive, HER2-negative breast cancer, as well as triple-negative breast cancer with 1 to 2 prior lines of chemotherapy. The majority of the patients, 494 had HR-positive, HER2-low, but there were 58 patients with HR-negative HER2-low…. These patients were randomly assigned 2:1 to T-DXd vs treatment of physician’s choice.

In terms of outcomes, median progression-free survival [PFS] was 10.1 vs 5.4 months with a hazard ratio of 0.51 [95% CI, 0.40-0.64; P < .001], so pretty impressive.¹ Then, there was a median overall survival [OS] advantage as well 23.9 vs 17.5 months with a hazard ratio of 0.64 [P = .003], so a PFS and OS benefit, which was maintained across subgroups.

What are some more recent findings for T-DXd in this patient population?

DESTINY-Breast06 [NCT04494425] was presented at ASCO initially and updated sub-cohorts at ESMO as well. This trial enrolled patients—there's 2 key differences. No. 1, it looked at whether patients with HER2 ultra-low disease could benefit. They included a HER2-low cohort, but then they could also be HER2 ultra-low, which was defined as 0 to 1+. The additional thing that was different is that…they had to progress on endocrine therapy, but it was in the first-line chemotherapy setting. Patients were randomly assigned to T-DXd vs treatment of physician's choice chemotherapy. The majority chose capecitabine.²

The primary end point was median PFS in the HER2-low cohort, and there was a benefit in PFS. We knew that T-DXd outperformed chemotherapy, so unsurprisingly, moving it into that first-line setting, there was still a benefit that was slightly higher numbers, 13.2 vs 8.1 months in the intention-to-treat population [hazard ratio, 0.62; 95% CI, 0.52-0.75; P < .001], including this ultra-low cohort.

How did T-DXd do for patients with HER2 ultra-low disease?

Looking specifically at this subgroup of ultra-low disease, very similar numbers.... I wish they had just done IHC 0, because ultra-low is not even something that our pathologists are comfortable with. There's an ongoing trial looking at T-DXd in true IHC 0, which I anticipate will show benefit in that, and then we can just stop dealing with this altogether. But in the meantime, we now have this ultra-low cohort. The confidence intervals are pretty broad, but the number of patients is fairly small, so I think I'm compelled by these differences being maintained across all subgroups, with pretty consistent hazard ratios even with this smaller cohort. I suspect that the HER2 IHC doesn't matter. It wasn't designed as a biomarker to select T-DXd benefit. I've given it plenty of times with the DAISY data [NCT04132960], for example, as a justification in IHC 0 disease prior to this, but this just makes it easier to get it, which I think is nice.

_References:

_{1. Modi S, Jacot W, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med. 2022;387(1):9-20. doi:10.1056/NEJMoa2203690}

_{2. Bardia A, Hu X, Dent R, et al. Trastuzumab deruxtecan after endocrine therapy in metastatic breast cancer. N Engl J Med. 2024;391(22):2110-2122. doi:10.1056/NEJMoa2407086}