Datopotamab Shows Benefit in HER2– and HER2-Low Breast Cancer

Commentary
Article

During a Case-Based Roundtable® event, Timothy J. Pluard, MD, explores datopotamab deruxtecan as an option in hormone receptor–positive, HER2-negative breast cancer in the second article of a 2-part series.

Timothy J. Pluard, MD

Timothy J. Pluard, MD

Medical Director

Saint Luke’s Cancer Institute

Kansas City, MO

CASE SUMMARY

  • A 60-year-old woman with a history of locally advanced estrogen receptor (ER)– and progesterone receptor (PR)–positive, HER2-nonamplified disease (immunohistochemistry score of 1+, fluorescence in situ hybridization [FISH] negative) had invasive ductal carcinoma and high genomic risk (Oncotype DX recurrence score of 35).
  • 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.
  • Results from a pelvic lymph node biopsy demonstrated adenocarcinoma consistent with her primary breast cancer: ER 80%, PR 20%, HER2 0%.
  • 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 intrathoracic and intra-abdominal lymph nodes.

Next-generation sequencing (NGS) detected a pathogenic hot spot mutation in PIK3CA and no other alterations.

  • Treatment was changed to second-line fulvestrant plus alpelisib (Piqray).

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 results showed detectable circulating tumor DNA (ctDNA) but no new mutations.
  • Treatment was initiated with sacituzumab govitecan (Trodelvy) per National Comprehensive Cancer Network guidelines.

Targeted Oncology: Can you discuss why datopotamab deruxtecan [Dato-DXd] would be an option for this patient and the data behind it?

TIMOTHY J. PLUARD, MD: Dato-DXdis a TROP2-directed antibody-drug conjugate [ADC] and has the same payload as trastuzumab deruxtecan [Enhertu].1 The only thing that's different between this and trastuzumab deruxtecan is the TROP2 antibody as opposed to a HER2 antibody. The drug-to-antibody ratios are a little bit different at 4. It's every-3-week dosing schedule for hormone receptor [HR]–positive, HER2-negative breast cancer and triple-negative breast cancer.

TROPION-Breast01 [NCT05104866] was a trial of patients previously treated with 1 to 2 lines of chemotherapy in the metastatic setting and had to be endocrine refractory or not eligible for endocrine therapy. Dato-DXd was given at 6 mg/kg every 3 weeks and the chemotherapy was treatment of physician's choice. The end points were progression-free survival [PFS] per RECIST and overall survival [OS].

What were the efficacy and safety on the TROPION-Breast01 trial?

The median PFS improved from 4.9 months [with investigator's choice] to 6.9 months in the Dato-DXd arm [HR, 0.63; 95% CI, 0.52-0.76; P < .0001], and median PFS by the investigator was similar [6.9 vs 4.5 months, respectively].2 OS had not matured yet. The overall response rate was higher with Dato-DXd at 36.4% vs 22.9% with investigator’s choice of chemotherapy, so there was a benefit there. Avoiding the pitfalls of cross-trial comparisons, the drug has, at least in this study, fairly comparable benefit with sacituzumab govitecan [Trodelvy]. Looking at...12-month landmark analysis, it's 25.5% PFS rate vs 14.6% [with Dato-DXd vs chemotherapy, respectively].

The only unique toxicity that appeared in this [trial] was some dry eye or ocular events, generally of low grade. But 22% had some grade of dry eye, with 1 patient discontinuing treatment due to ocular toxicity [vs 8% with any-grade dry eye with chemotherapy]. There is a little bit more in terms of stomatitis [when receiving Dato-DXd], with 50% having some degree of stomatitis [vs 13% with chemotherapy].

Do you use Dato-DXd therapy at your practice?

We have this drug as part of a clinical trial here. We've had a few patients on it. It's too early to tell how they're doing, but the more drugs [as options], the better, so I am anxious to see how this matures…. We don't have OS data for this agent; that may change some people's thinking about where and how to use this if the OS data are not comparable to the other TROP2 ADC…. We have a few ADCs to choose from moving forward, so it's going to get more complicated but there are more options for our patients.

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. 2024;20(8):423-436. doi:10.2217/fon-2023-0188
2. Bardia A, Jhaveri K, Im SA, et al. LBA11 Datopotamab deruxtecan (Dato-DXd) vs chemotherapy in previously-treated inoperable or metastatic hormone receptor-positive, HER2-negative (HR+/HER2–) breast cancer (BC): Primary results from the randomised phase III TROPION-Breast01 trial. Ann Oncol. 2023;34(suppl 2):S1264-S1265. doi:10.1016/j.annonc.2023.10.015
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