New ADC Results Mixed in Metastatic Breast Cancer

CHICAGO — The landscape of antibody-drug conjugates, or ADCs, continues to grow more crowded in metastatic breast cancer. Indications are expanding, new agents are emerging, combinations with other drug classes are being tested, and many patients with this disease are now receiving more than one ADC.

ADCs use antibodies to bind to the surface proteins of cancer cells to deliver a potent payload of cytotoxic chemotherapy. Three are approved for use in pretreated patients with metastatic breast cancer: sacituzumab govitecan, or SG, for patients with triple-negative disease; trastuzumab deruxtecan, or T-DXd, for patients with HER2-positive and HER2-low disease; and trastuzumab emtansine, or T-DM1, for patients with HER2-positive disease. A fourth agent, datopotamab deruxtecan, or Dato-DXd, is being assessed by the US Food and Drug Administration (FDA) for use in pretreated HR-positive, HER2-negative patients, and others, including sacituzumab tirumotecan, are being tested in clinical trials.At the annual meeting of the American Society of Clinical Oncology (ASCO) 2024, T-DXd (Enhertu, AstraZeneca) showed better progression free survival than chemotherapy in people with HR-positive, HER 2-low metastatic breast cancers. These findings, from the DESTINY Breast-06 trial, were among the most talked-about at ASCO, and are likely to change clinical practice (J Clin Oncol. 2024;42[suppl 17; abstr LBA1000]).

But other ADC results presented at ASCO showed that there is still much to be worked out about the timing and sequencing of these agents, as well as their synergy with other drug classes, in metastatic breast cancer.

An ADC Gets Its First Test, and Falls Short

Antonio Giordano, MD, PhD, of the Dana-Farber Cancer Institute in Boston, presented findings from an open-label phase 2 study of the ADC enfortumab vedotin (EV), an agent currently approved for use in advanced or metastatic urothelial cancer, at ASCO. This study included two cohorts of previously treated metastatic breast cancer patients: one with triple-negative disease (n = 42) and the other with HR-positive HER2-negative (n = 45).

Dr Giordano and his colleagues’ study is the first to look at this ADC in breast cancer. EV’s antibody targets the cell adhesion molecule Nectin-4.

The researchers found that though EV demonstrated antitumor activity in both cohorts — with 19% of the triple-negative patients and 15.6% of the HR-positive/HER2-negative patients responding — the results did not meet the prespecified response thresholds for either cohort. (J Clin Oncol. 2024;42[suppl 16; abstr 1005]).

In an interview, Dr Giordano said that studies in urothelial cancer had shown better response to EV associated with more expression of Nectin-4, but this study did not see such clear associations between expression and response. While there is no question that Nectin-4 is highly expressed in breast cancer and therefore a viable target, he said, “it may need to be looked at a little more deeply.”

It could also be the case, Dr Giordano said, that the effect of EV’s payload may have been less robust in participants who had been previously treated with taxane chemotherapy, as nearly all patients in the two cohorts were.

“Taxanes are microtubule disruptors. And with this drug we had a payload with pretty much the same mechanism of action,” Dr Giordano said. Ideally, he said, he would like to test the agent in a first-line setting, possibly in combination with an immunotherapy agent.

The timing of ADCs is as important as their targets and their payloads — and something that investigators are still struggling to figure out, he said.

A third of the patients in the triple-negative cohort of his study had been previously treated with SG, and a handful of individuals with T-Dxd, he noted.

“We’re in the middle of an ADC revolution,” he said. “It’s really key to figure out the best sequencing for a patient and if it’s actually worth it to do it. Very often we see patients respond best to the first ADC. But sometimes we see patients that do not respond to the first ADC and then they respond to the second one. It’s not very frequent, but it happens.”

Hint of Benefit From Adding Immunotherapy to SG

In a separate presentation at ASCO, Ana C. Garrido-Castro, MD, also of the Dana-Farber Cancer Institute, presented results from the SACI-IO HR+ trial, a randomized phase 2 study of SG (Trodelvy, Gilead) with and without pembrolizumab (Keytruda, Merck) in 104 patients with metastatic HR-positive/HER2-negative breast cancer who received prior endocrine therapy and up to one chemotherapy regimen for advanced disease. SACI-IO HR+ is the first randomized trial to report the efficacy of a topoisomerase I inhibitor ADC with an immune checkpoint inhibitor for the treatment of breast cancer.

The addition of the immune checkpoint inhibitor did not result in a significant improvement in median progression-free survival in the overall population, Dr Garrido-Castro reported. Median PFS was 8.1 vs 6.2 months with the combination of SG plus pembrolizumab or sacituzumab govitecan alone, respectively. At a median follow-up of 12.5 months, there was also no significant difference seen in median overall survival (OS): 18.5 vs 18.0 months.

About 40% of participants were found to have PD-L1-positive tumors and, among this subgroup, there was a 4.4-month increase in median PFS and 6.0-month increase in median OS with the addition of pembrolizumab to SG, although this did not reach statistical significance. (J Clin Oncol. 2024;42[suppl 17; abstr LBA1004]).

“While the study did not demonstrate a statistically significant benefit with the addition of the immune checkpoint inhibitor to the ADC, there is an interesting signal for potential synergistic activity between the two agents, particularly in those patients with PD-L1 positive tumors,” Dr Garrido-Castro said in an interview. She noted that the sample sizes for the PD-L1 subgroup were relatively small, and overall survival data are not yet mature.

A separate phase 3 study is looking at the experimental ADC called sacituzumab tirumotecan with and without pembrolizumab compared with chemotherapy in patients with metastatic HR-positive, HER2-negative breast cancer who have received prior endocrine therapy and no prior chemotherapy for metastatic disease, she said.

Similar to SG, sacituzumab tirumotecan is a TROP2-directed ADC with a topoisomerase I inhibitor payload. With an estimated enrollment of 1200 patients, this trial may help shed light on whether adding the immune checkpoint inhibitor to the topoisomerase I inhibitor TROP2-directed ADC improves outcomes in the subgroup of patients with PD-L1 positive tumors, Dr Garrido-Castro said.

Unlocking the Order and Timing of ADCs

Dr Garrido-Castro is also leading a study that will evaluate the sequential use of ADCs in metastatic breast cancer. That trial, to be called TRADE-DXd, will enroll patients with HER2-low metastatic breast cancer who have received up to one prior line of chemotherapy and no previous topoisomerase I inhibitors. Participants will receive either T-DXd or Dato-DXd as the first ADC, and then switch to the other ADC (Dato-DXd or T-DXd, respectively) at the time of progression, thus switching the target of the ADC from HER2 to TROP2 or vice versa.

“In real-world practice now, there are patients who receive sequential ADCs because they are candidates for both,” Dr Garrido-Castro explained. However, more robust data are needed to refine the selection of the initial antibody-drug conjugate and to determine who is more likely to benefit from a second — or maybe even third — ADC.

“One potential mechanism of resistance to antibody-drug conjugates is the downregulation of the target of the antibody-drug conjugate,” Dr Garrido-Castro said. “Thus, an important question is, if you modify the target of the ADC, is it possible to overcome that mechanism of resistance?” Another possible mechanism of resistance is to the chemotherapy payload of the ADCs, she said.

Dr Garrido-Castro’s study will collect tumor samples and blood samples for the purposes of planned correlative analyses to try to better understand the mechanisms that drive response and resistance to these agents.

Dr Giordano commented that Dr Garrido-Castro’s study was likely to result in a much better understanding of ADCs and how to use them strategically.

At Dana-Farber, “we collect a lot of samples of patients receiving ADCs. And we are trying to do all kinds of work on circulating tumor DNA, immunohistochemistry expression, and protein expression,” he said. “We are trying to figure out how ADCs really work, and why they stop working.”

Dr Giordano and colleagues’ study was funded by Astellas Pharma and by Seagen, which was bought by Pfizer in 2023. Dr Giordano disclosed receiving consulting fees from Pfizer, and several of his coauthors reported relationships with this and other companies. Two were Astellas employees.

Dr Garrido-Castro and colleagues’ study was funded by Merck and Gilead Sciences. Dr Garrido-Castro disclosed receiving research support from Gilead Sciences, AstraZeneca, Daiichi Sankyo, Merck, Zenith Epigenetics, Bristol Myers Squibb, Novartis, Biovica, Foundation Medicine, 4D Path, Precede Biosciences; scientific advisory board/consulting fees from AstraZeneca, Novartis, Daiichi Sankyo; speaker honoraria from AstraZeneca, Daiichi Sankyo; and other support from Roche/Genentech, Gilead Sciences, AstraZeneca, Daiichi Sankyo, Novartis, and Merck, while her coauthors reported similar relationships.

This article originally appeared on MDedge.com, part of the Medscape Professional Network.