ADCs Serve as “Exciting and Effective Drug Delivery System” in HR+/HER2– Breast Cancer

With new antibody-drug conjugates (ADCs) on the horizon for hormone receptor­–positive, HER2-negative breast cancer, it is essential to understand each agent’s safety and efficacy, how to optimally sequence them, and to glean insights on their mechanisms of resistance, according to Hope S. Rugo, MD, FASCO.¹

“What’s key about this new generation of ADCs is not just the antibody target, we know fam-trastuzumab deruxtecan-nxki [T-DXd; Enhertu] and we have the new TROP2 [antibody datopotamab deruxtecan], but the linker technology has improved tremendously to allow better delivery of the drug, both to cells that express the target at high levels, and cells that express the target at low levels,” Rugo, professor of medicine, Winterhof Family Professor of Breast Cancer, Director of Breast Oncology and Clinical Trials Education, Hellen Diller Family Comprehensive Cancer Center, University of California, San Francisco, said during a presentation at the 41st Annual Miami Breast Cancer Conference.¹

She added that the ADC payload has also made a big difference. “Now, there are new payloads targeting different areas, as well. These new toxins are largely membrane permeable, although [they] do not always allow for this idea of the bystander effect, where you would kill nearby tumor cells,” Rugo explained.

Trastuzumab Deruxtecan

First, Rugo discussed data from an updated analysis of the hormone receptor–positive cohort of the phase 3 DESTINY-Breast04 trial(NCT03734029), which involved patients with HER2-low metastatic breast cancer who had received 1 or 2 previous lines of chemotherapy who were randomized 2:1 to receive either T-DXd or the physician’s choice of chemotherapy.²

After a median follow-up of 32 months, the median overall survival (OS) was 23.9 months (95% CI, 21.7-25.2) with T-DXd (n = 331) vs 17.6 months (95% CI, 15.1-20.2) with chemotherapy (n = 163; HR, 0.69; 95% CI, 0.55-0.87). The 24-month OS rates were 49.0% (95% CI, 43.3%-54.5%) and 35.1% (95% CI, 27.3%-43.0%) in the T-DXd and physicians’ choice arms, respectively. Moreover, the median progression-free survival (PFS) was 9.6 months (95% CI, 8.4-10.0) in the T-DXd arm vs 4.2 months (95% CI, 3.4-4.9) in the physician’s choice arm (HR, 0.37; 95% CI, 0.30-0.46). The 24-month PFS rate was 15.4% (95% CI, 11.3%-20.0%) with T-DXd.

The most common treatment-emergent adverse effects (TEAEs) that were grade 3 or higher in the T-DXd arm were neutropenia (14%), anemia (9%), and fatigue (8%). Rugo noted that there were no new cases of interstitial lung disease (ILD); however, 1 patient (1.1%) with ILD had died.

Rugo then highlighted findings from a pooled analysis of nine T-DXd monotherapy trials that included 1150 patients who had a median treatment duration of 5.8 months (range, 0.7-56.3). The overall incidence of ILD was 15.4%. The majority (77.4%) of cases were grade 1 or 2; however, 2.2% of patients experienced grade 5 ILD. Furthermore, 87% of patients in the analysis experienced their first event within 12 months of their first dose.³

“There are specific risk factors that are important to keep in mind when you think about how frequently you should be getting a CT scan to look for asymptomatic grade 1 ILD: ground glass opacities, renal dysfunction is one of the ones that I think is particularly helpful, age, and more lines of prior therapy, which suggests that as we move these drugs earlier, we’ll see less ILD, which will certainly be encouraging,” Rugo said.

Lastly, Rugo discussed the phase 3 DESTINY-Breast06 (NCT04494425), which examines T-DXd vs investigator’s choice of chemotherapy in select patients with HER2-low, hormone receptor–positive, metastatic breast cancer, including 150 patients with ultralow disease status. “These will be fascinating data compared with physician’s choice [of] chemotherapy, after endocrine therapy [in the metastatic setting.] This study has long completed accrual and we’re looking for data later this year.”

Sacituzumab Govitecan

In the phase 3 TROPiCS-02 trial (NCT03901339), after a median follow-up of 12.8 months, treatment with sacituzumab govitecan-hziy (Trodelvy; n = 272) led to a median PFS of 5.5 months (95% CI, 4.2-7.0) vs 4.0 months (95% CI, 3.1-4.4) with physician’s choice of chemotherapy (n = 271), translating to a 35% reduction in the risk for disease progression or death in patients with hormone receptor­–positive/HER2-negative disease (HR, 0.66; 95% CI, 0.53-0.83; P = .0003). In addition, the median OS was 14.5 months (95% CI, 13.0-16.0) vs 11.2 months (95% CI, 10.2-12.6), respectively (HR, 0.79; 95% CI, 0.65-0.95; P = .0133).⁴

“Notably, three times as many patients were free from progression at 1 year who have received sacituzumab govitecan compared with the treatment of physician’s choice,” Rugo underscored.

In this trial, the most common any-grade AEs were neutropenia (71%; grade ≥3, 52%) and diarrhea (62%; grade ≥3, 10%). “We’ve been using growth factors and dose reduction when needed,” Rugo said, adding that is also important to identify patients with these AEs early.

Rugo also noted three ongoing trials of sacituzumab govitecan in the neoadjuvant setting, including the GBG: SASCIA Post-Neoadjuvant Trial (NCT04595565) in HER2-negative early breast cancer; the SACI-IO trials in metastatic triple-negative (NCT04468061) and hormone receptor–positive metastatic (NCT04448886) breast cancer, evaluating the ADC with and without pembrolizumab (Keytruda) in the frontline setting; and the ASCENT-07 trial (NCT05840211), which is comparing the agent vs first-line chemotherapy in hormone receptor–positive metastatic breast cancer.

Datopotamab Deruxtecan

In addition to the 2 currently FDA-approved ADCs, Rugo highlighted positive data regarding the novel TROP2-targeting agent, datopotamab deruxtecan (Dato-DXd).

In the phase 3 TROPION-Breast01 trial (NCT05104866), treatment with Dato-DXd (n = 365) led to an investigator-assessed median PFS of 6.9 months (95% CI, 5.9-7.1) vs 4.5 months (95% CI, 4.2-5.5) with chemotherapy (n = 367; HR, 0.64; 95% CI, 0.53-0.76). The median PFS by blinded independent central review was 6.9 months in the Dato-DXd arm vs 4.9 months in the chemotherapy arm (HR, 0.63; 95% CI, 0.52-0.76; P < .001).⁵

In addition, the median time to subsequent therapy in the Dato-DXd arm was 8.2 months (95% CI, 7.4-8.9) vs 5.0 months (95% CI, 4.6-5.7) in the chemotherapy arm (HR, 0.53; 95% CI, 0.45-0.64).

“OS is still early, and of course, we brought up the question of whether or not you can cross over to these 2 other ADCs, whether or not the OS is still feasible for these trials?” Rugo added.

She also noted that the primary toxicity experienced with Dato-DXd was stomatitis, but was easily managed and that a low incidence of hematologic toxicities was observed.

Dato-DXd is being evaluated in the ongoing, phase 3 TROPION Breast04 trial (NCT06112379) for patients with triple-negative or hormone receptor–low, HER2-negative breast cancer, as well as in the multi-arm, phase 2 I-SPY 2.2 trial (NCT01042379) in high-risk breast cancer.

Patritumab Deruxtecan

“Patritumab deruxtecan [HER3-DXd] is sort of the next in line of the active ADCs, with a different antibody target of HER3,” explained Rugo.

In a phase 2 study (NCT04699630) of HER3-DXd, the overall response rate was 35.0% and the clinical benefit rate (CBR) was 43.3% among heavily pretreated patients with estrogen receptor (ER)–positive or triple-negative metastatic breast cancer with varying levels of HER3 expression. Furthermore, almost half of patients (47.6%) experienced a duration of response of at least 6 months.⁶

Rugo noted that the most common AEs experienced with the agent were nausea, diarrhea, and fatigue.

What’s Next with ADCs

As a next step, Rugo highlighted that investigators are interested in evaluating combination therapies, either ADCs with checkpoint inhibitors or other immune agonists to enhance dual efficacy or with anti-CD47 antibodies. She added that understanding mechanisms of resistance and the sequencing of ADCs are other areas of interest.

“When we look at the future and the way we’re putting ADCs [in the treatment paradigm], I think our excitement about these agents, the tolerance and efficacy, really [warrants] us to move these drugs earlier in the course of therapy,” Rugo concluded. “…It’s an exciting and effective drug delivery system. We’ve seen efficacy across all of the disease subsets. We have new ADCs on the horizon, and we’re learning more about how to manage the toxicity, keep patients on the drug, and understand sequencing and mechanisms of resistance.”

References

1. Rugo H. Antibody-drug conjugates in HR+/HER2– breast cancer: optimal sequencing and new directions. Presented at: 41st Annual Miami Breast Cancer Conference; March 7-10, 2024; Miami, Florida.
2. Modi S, Jacot W, Iwata H, et al. Trastuzumab deruxtecan (T-DXd) versus treatment of physician’s choice (TPC) in patients with HER2-low unresectable and/or metastatic breast cancer: updated survival results of the randomized, phase 3 DESTINY-Breast04 study. Ann Oncol. 2023;34(suppl 2):S334-S335. doi:10.1016/j.annonc.2023.09.553
3. Powell CA, Modi S, Iwata H, et al. Pooled analysis of drug-related interstitial lung disease and/or pneumonitis in nine trastuzumab deruxtecan monotherapy studies. ESMO Open. 2022;7(4):100554. doi:10.1016/j.esmoop.2022.100554
4. Tolaney SM, Bardia A, Marmé F, et al. Final overall survival (OS) analysis from the phase 3 TROPiCS-02 study of sacituzumab govitecan (SG) in patients (pts) with hormone receptor–positive/HER2-negative (HR+/HER2–) metastatic breast cancer (mBC). J Clin Oncol. 2023;41(suppl 16):1003. doi:10.1200/JCO.2023.41.16_suppl.1003
5. Bardia A, Jhaveri K, Im SA, et al. Randomized phase 3 study of datopotamab deruxtecan vs chemotherapy for patients with previously-treated inoperable or metastatic hormone receptor-positive, HER2-negative breast cancer: results from TROPION-Breast01. Presented at: 2023 San Antonio Breast Cancer Symposium; December 5-9, 2023; San Antonio, TX. Abstract GS02-01.
6. Hamilton EP, Dosunmu O, Shastry M, et al. A phase 2 study of HER3-DXd in patients (pts) with metastatic breast cancer (MBC). J Clin Oncol. 2023;41(suppl_16):1004. doi:10.1200/JCO.2023.41.16_suppl.1004