Incorporating Datopotamab Deruxtecan in Advanced Breast Cancer

CASE SUMMARY

• A 60-year-old woman with a history of pT1cN1 estrogen receptor (ER) and progesterone receptor (PR) positive HER2 non-amplified disease had invasive ductal carcinoma and high genomic risk (OncotypeDX RS 35).
• Immunohistochemistry [IHC] score of 1+ and fluorescence in situ hybridization [FISH] negative.
• She was treated with surgery and adjuvant dose-dense chemotherapy, followed by aromatase inhibitor therapy for 10 years.

Two Years After Completing Adjuvant Therapy ​

• The patient presented with persistent rib pain.
• Fludeoxyglucose (FDG) 18F PET/CT scan demonstrated multiple FDG avid lytic osseous metastases and suspicious appearing FDG avid intrathoracic and intra-abdominal lymph nodes​.
• A pelvic lymph node biopsy demonstrated adenocarcinoma consistent with her primary breast cancer; ER 80%, PR 20%, HER2 0 ​
• Next-generation sequencing (NGS) detected a pathogenic hot spot mutation in PIK3CA and no other alterations.
• The patient was treated with first-line letrozole and ribociclib (Kisqali)​.

After 16 Months on Treatment​

• The patient developed disease progression with enlarging and new involvement of intra-thoracic and intra-abdominal lymph nodes.
• Treatment was changed to second-line fulvestrant plus alpelisib.

After 10 Months on Treatment​

• Disease progressed further with new lytic bone metastases and a new liver lesion.
• Biopsy report of liver specimen reported ER 60%, PR 0, HER2 0.
• NGS revealed no new mutations.
• Treatment was changed to third-line capecitabine.

After 8 Months on Treatment​

• The patient developed disease progression with enlarging lymph nodes and enlarging liver metastasis​.
• Liquid biopsy showed detectable circulating tumor DNA (ctDNA), but no new mutations.

Targeted Oncology: What results stood out to you from the phase 3 TROPION-Breast01 trial (NCT05104866) for patients with HR-positive, HER2-negative, or HER2-low breast cancer who were given datopotamab deruxtecan (Dato-DXd)?

VIRGINIA G. KAKLAMANI, MD​: The median progression-free survival [PFS] for patients on chemotherapy was 4.9 months [95% CI, 4.2-5.5] compared with those on Dato-DXd at 6.9 months [95% CI, 5.7-7.4], so this was a 2-month improvement that was statistically significant [HR, 0.63; 95% CI, 0.52-0.76; P < .0001].¹

Virginia G. Kaklamani, MD​

Professor of Medicine

University of Texas Health Science Center San Antonio

San Antonio, TX

We are still waiting for overall survival [OS] results, as it was a pretty early presentation, but there was a hint of improvement in OS [with a median follow-up of 9.7 months and HR of 0.84 (95% CI, 0.62-1.14) in the Dato-DXd arm]. The overall response rate increased from 23% [in the chemotherapy arm] to 36% [in the Dato-DXd arm]. This therapy was also relatively well tolerated as few patients had to have dose reductions and very few had to have a dose discontinuation.¹

What adverse event (AE) outcomes were notable from this study?

The rate of neutropenia [at any grade] with Dato-DXd was lower than [for the patients receiving] chemotherapy at 39% [vs 42%, respectively].¹ Most of these neutropenia cases were grade 1 and 2, with just 1% of patients having grade 3 neutropenia or higher on Dato-DXd [compared with 31% in the chemotherapy arm].

The one AE [to note] was dry eyes…. On the trial patients were mandated to see the ophthalmologist. I don't know if eventually we're going to need to have an ophthalmologist seeing our patients [during treatment with Dato-DXd], and I know that's one of the limitations [with this therapy] as it's not that easy to get [the patient in] to see an ophthalmologist.

Drug-related interstitial lung disease [ILD] was seen in 3 patients on Dato-DXd, and 2 patients just had grade 1 and 2 ILD.¹ So, it's interesting that even though the payload is the same [as the chemotherapy] the rate of toxicity is different, and I was surprised with the low rate of neutropenia.

How do you incorporate NGS into your treatment plan for these patients?

I think that NGS should be part of our standard of care, and what I'll typically do is order NGS on the biopsy [right away]. The companies now, even with bone marrow biopsies, can give us good results for NGS, which is wonderful. We just need to tell the pathologist [what we are looking for] before they process the tissue. I will typically wait and get the ctDNA [collected] at disease progression, because that's when we start seeing more ESR1 mutations.

The rate of ESR1 mutations in that initial presentation of metastatic disease is probably around 5%, but at disease progression we see it gets up to 40%.² Every once in a while, I'll repeat a tissue biopsy, but I'll typically not repeat it as much for the NGS testing, where I'll repeat it to see what the biomarkers [in the patient’s disease] are doing. We need to find out if [the disease] is still ER-positive. Did it switch to HER2-negative or HER2-positive, at this point? So, I'll do that if my treatment response doesn't make sense.

[For example], if I have a patient with a tumor that seems to be ER-positive, and suddenly I get [them on] a duration of a CDK4/6 inhibitor for 6 or 8 months, I'll feel that I'm probably missing something [if there isn’t a response]. That's when I might repeat the tissue biopsy just to see how this tumor has evolved, but the bottom line is that NGS testing has become extremely important. These drugs are expensive, and while they're available [for patients], the only way for us to be able to use them is to know what the mutational background of [the patient's tumor is].

REFERENCES:

1. Bardia A, Jhaveri K, Kalinsky K, et al. TROPION-Breast01: Datopotamab deruxtecan vs chemotherapy in pre-treated inoperable or metastatic HR+/HER2- breast cancer. Future Oncol. 2023. doi:10.2217/fon-2023-0188

2. Brett J, Spring L, Bardia A, Wander SA. ESR1 mutation as an emerging clinical biomarker in metastatic hormone receptor-positive breast cancer. Breast Cancer Res. 2021;23(1):85. doi:10.1186/s13058-021-01462-3