After the First ADC Fails, HR-Positive Breast Cancer Sequencing Runs on Judgment, Not Trial Data

This article is part 2 of a 2-part series from a Case-Based Roundtable event.

Part 1 of this series covered how a pathologist's willingness to distinguish HER2-ultralow from HER2-null disease determines which patients gain access to trastuzumab deruxtecan (T-DXd; Enhertu) after endocrine therapy fails. That question gets harder, not easier, once a patient has already been on an antibody-drug conjugate (ADC). Three agents, each with a different target and payload, are now available in this setting, but none of the pivotal trials enrolled patients who had received a prior ADC, leaving oncologists to sequence largely by extrapolation.

In a virtual Case-Based Roundtable event for oncologists in the Chicago area, Ruta Rao, MD, a breast medical oncologist at Rush University Medical Center, walked participants through the data behind sacituzumab govitecan (SG; Trodelvy) and datopotamab deruxtecan (Dato-DXd; Datroway), and used a second case to work through what happens when an ADC has to be stopped for toxicity rather than progression. In TROPiCS-02 (NCT03901339), SG improved median progression-free survival (PFS) over chemotherapy in a heavily pretreated population that had already received a taxane, endocrine therapy, a CDK4/6 inhibitor, and 2 to 4 lines of chemotherapy (5.5 vs 4 months; HR, 0.66; 95% CI, 0.53-0.83), with a median overall survival (OS) benefit of 14.4 vs 1.2 months (HR, 0.79).^1,2 But when SG was tested in that same first-line, postendocrine setting where T-DXd now has an approval, the ASCENT-07 trial (NCT05840211) was negative, with an identical median PFS of 8.3 months in both arms.³ Dato-DXd improved PFS over chemotherapy in TROPION-Breast01 (NCT05104866; 6.9 vs 4.9 months; HR, 0.63; 95% CI, 0.52-0.76) but did not separate on OS (18.6 vs 18.3 months; HR, 1.01).⁴

Rao was direct about what those trials don't tell oncologists: "This is really a data-free zone," she said, noting that none of the 3 pivotal trials included patients with prior ADC exposure, so sequencing recommendations rely on real-world experience and pharmacologic reasoning rather than randomized comparisons. Several participants said they try to sandwich a line of chemotherapy between 2 ADCs when possible, reasoning that separating agents with overlapping topoisomerase-I payloads, T-DXd's DXd and Dato-DXd's DXd, or SG's SN-38, may reduce the chance of cross-resistance, even though the mechanism driving ADC resistance is still more often the payload than the antibody target.

That reasoning came into sharper focus in the case Rao presented: a 57-year-old woman with HR-positive, HER2-low metastatic breast cancer who had a partial response to T-DXd in the fourth line but developed grade 2 interstitial lung disease (ILD) after 7 cycles, requiring steroids and treatment discontinuation. Once her ILD resolved, the group had to decide whether to rechallenge with T-DXd, switch to a different ADC, or move to chemotherapy. Rao presented previously unpublished data on T-DXd rechallenge after ILD: of 19 patients rechallenged after a grade 2 event, 3 (16%) developed recurrent ILD (1 each of grade 2, 3, and 4), compared with roughly a quarter of patients rechallenged after a grade 1 event. She noted that patients who received steroids promptly had significantly faster radiographic improvement than those who did not, reinforcing the importance of early steroid use whenever ILD is suspected.

Most participants said they would not rechallenge with T-DXd after a grade 2 event. One oncologist who had rechallenged a different patient after grade 2 ILD described lowering the dose and having "a long discussion" with the patient beforehand, since she had run out of other options and did not want additional therapies; that patient tolerated a dose-reduced rechallenge without recurrence. Others said they would move instead to SG, reasoning that switching both the antibody target and away from a second topoisomerase-I payload carries less theoretical risk than reintroducing T-DXd or moving to Dato-DXd, which carries its own, lower-rate ILD signal (3.3% all-grade in TROPION-Breast01 vs 11% with T-DXd). Rao reviewed the toxicity profiles behind that reasoning: T-DXd's signature risk is ILD, SG's is neutropenia and diarrhea, manageable with growth-factor prophylaxis and antidiarrheal regimens, and Dato-DXd's is stomatitis and ocular toxicity, requiring steroid mouthwash prophylaxis and baseline ophthalmologic exams.

The group's polling reflected that caution: 60% chose SG for the case patient both before and after the discussion, a majority that held steady even as participants debated the merits of rechallenge and Dato-DXd. Closing the session, several oncologists returned to the same 2 open questions raised across both cases: how to get pathologists to reliably report HER2-ultralow status, and how to sequence 3 structurally different ADCs once trial-tested options run out. As one participant put it, whichever ADC is used first deserves the most careful selection, since it is typically the one a patient stays on longest, with each subsequent agent, by experience if not yet by data, offering a less durable response.

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DISCLOSURES: Rao reported consulting/advisory relationships with AstraZeneca, Daiichi Sankyo, Lilly, Genentech, and Pfizer.

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. Rugo HS, Bardia A, Marmé F, et al. Overall survival with sacituzumab govitecan in hormone receptor-positive, HER2-negative metastatic breast cancer. Lancet. 2023;402(10411):1423-1433. doi:10.1016/S0140-6736(23)01245-X

3. Bardia A, Rugo HS, Tolaney SM, et al. Final Results From the Randomized Phase III ASCENT Clinical Trial in Metastatic Triple-Negative Breast Cancer and Association of Outcomes by Human Epidermal Growth Factor Receptor 2 and Trophoblast Cell Surface Antigen 2 Expression. J Clin Oncol. 2024 May 20;42(15):1738-1744. doi: 10.1200/JCO.23.01409.

4. Bardia A, Kaufman B, Kalinsky K, et al. Datopotamab deruxtecan versus chemotherapy in previously treated HR+/HER2- metastatic breast cancer (TROPION-Breast01). J Clin Oncol. 2024;43(3):285-296. doi:10.1200/JCO.24.00920