ADCs Advance HR+/HER2– Breast Cancer Treatment Paradigm

Hope S. Rugo, MD, FASCO

As more antibody-drug conjugates (ADCs) emerge and investigators foresee fam-trastuzumab deruxtecan-nxki (Enhertu) moving forward in lines of treatment for metastatic disease, the treatment landscape of hormone receptor–positive, HER2-negative breast cancer continues to expand and shift. With approximately 70% of patients with breast cancer falling into the hormone receptor–positive, HER2-negative classification, sacituzumab govitecan-hziy (Trodelvy) may help fill the unmet need for improved later-line treatments for patients with metastatic disease, with agents such as ribociclib (Kisqali) displaying efficacy as well.¹

Data presented by Hope S. Rugo, MD, FASCO, at the 2022 San Antonio Breast Cancer Symposium (SABCS) demonstrated a statistically significant benefit in terms of overall survival (OS) and progression-free survival (PFS) among patients with hormone receptor–positive, HER2-negative metastatic breast cancer who were treated with the ADC sacituzumab govitecan compared with treatment of physician’s choice (TPC) in the phase 3 TROPiCS-02 trial (NCT03901339). ¹

“We have a lot of data that [are] changing the way we’re thinking about treating hormone receptor–positive metastatic disease,” Rugo said. “Most importantly, it is giving us lots of new treatment options to move to the early-stage setting. That’s going to change the outcome for the most common subset of breast cancer.”

Rugo, professor of medicine in the Division of Hematology and Oncology and director of breast oncology and clinical trials education at the University of California San Francisco Helen Diller Family Comprehensive Cancer Center, discussed promising therapies and the efficacy of the CDK4/6 inhibitor ribociclib in an interview with OncologyLive^®. She highlighted the MONALEESA family of trials and the phase 2 AMALEE trial (NCT03822468), which evaluated starting doses of the agent in the first-line treatment of hormone receptor–positive disease.

Sacituzumab Govitecan Gains Prominence

Findings from TROPiCS-02 showed benefit with the first-in-class Trop-2‒directed ADC sacituzumab govitecan compared with TPC in PFS (the primary end point) and OS (a secondary end point), regardless of Trop-2 expression (Table^1,2).

Table. Efficacy Results in TROPiCS-021

At the first interim analysis, sacituzumab govitecan was associated with a 34% relative improvement in PFS compared with TPC (HR, 0.66; P=.0003), with a median figure of 5.5 months vs 4.0 months, respectively. Treatment with sacituzumab govitecan also led to a statistically significant improvement in terms of OS, with a median of 4.4 months compared with 11.2 months (HR, 0.79; P=.020), respectively. Rugo noted that there was an increase at all landmark time points of patients who were free from progression and alive.¹

“95% [of samples] expressed at least some degree of Trop-2; it is a highly expressed receptor,” Rugo said. “Patients [were] divided into high expressers and lower expressers, using an H-score [cutoff] of 100. We found that there was an improvement in PFS and OS regardless of whether [they] fell into the lower or higher Trop-2 expression.”

On February 3, 2023, the FDA approved sacituzumab govitecan for patients with unresectable locally advanced or metastatic hormone receptor–positive, HER2-negative (defined as immunohistochemistry [IHC] 0, IHC 1+, or IHC 2+/in situ hybridization–negative) breast cancer who have received endocrine-based therapy and at least 2 additional systemic therapies in the metastatic setting.³ There was also benefit in a small additional analysis of patients with very low Trop-2 expression H scores of 10 or less.

“We saw a trend for survival in the second interim analysis of OS, [and] we had almost 100 additional survival events, showing how important this treatment is in the late-line setting and emphasizing its unmet need. There, we saw an improvement in OS that was statistically significant, with a median absolute difference of 3.2 months,” Rugo said.

In TROPiCS-02, patients must have previously received 2 to 4 lines of chemotherapy for metastatic disease and received an endocrine therapy, taxane, and CDK4/6 inhibitor in any setting.^1,2 Rugo said that investigators found sacituzumab govitecan “is effective regardless of Trop-2 expression, and [clinicians] don’t need to test for Trop-2 to determine which patients are eligible for benefit from sacituzumab govitecan.”

Other ADCs Making Waves

Questions remain regarding sequencing therapies for patients after treatment with endocrine therapy in combination with targeted agents, especially for patients who become resistant to endocrine therapy, as there few options in later lines for beneficial treatment.

ADCs such as trastuzumab deruxtecan are moving into earlier lines of therapy for metastatic disease in the postneoadjuvant, high-risk setting and the neoadjuvant setting, according to Rugo. Sacituzumab govitecan is being evaluated in the first-line setting for PD-L1–positive and triple-negative breast cancer, and the agent will be examined in the postneoadjuvant, neoadjuvant, and first-line settings for patients with hormone receptor–positive disease.¹

“ADCs are an exploding area,” Rugo said. “We have trastuzumab deruxtecan for HER2-positive and HER2-low disease, where we’ve seen remarkable improvements, including in OS, in the HER2-low population.” Determining optimal sequencing and combinations of agents continue to be explored in clinical trial, as “there’s preclinical data that suggest that combining [ADCs and immunotherapy] might enhance the efficacy of immunotherapy.”

Rugo also noted that the Trop-2 ADC datopotamab deruxtecan (DS-1062a) is currently being evaluated in patients with metastatic disease, as well as hormone receptor–positive and triple-negative subgroups. The agent aims to join sacituzumab govitecan, which is currently the only FDA-approved Trop-2–directed ADC. The phase 1/2 BEGONIA trial (NCT03742102) is examining datopotamab deruxtecan or trastuzumab deruxtecan with the checkpoint inhibitor durvalumab (Imfinzi). Rugo also noted that agents such as the HER3 ADC patritumab deruxtecan (U3-1402) and ADC enfortumab vedotin (Padcev) are currently in clinical trials.

Determining Ribociclib’s Place in the Treatment Paradigm

The phase 3 MONALEESA-2 (NCT01958021), MONALEESA-3 (NCT02422615), and MONALEESA-7 (NCT02278120) trials examined ribociclib, with the goal of determining whether time to second objective disease progression (PFS2) is affected, according to Rugo. The trials examined the implications of postprogression treatments after ribociclib and endocrine therapy, and “PFS2 was always better regardless of the choice of therapy if you got ribociclib first. So PFS2 is better, and that goes along with this improved outcome overall.”

In MONALEESA-7 trial, patients with hormone receptor–positive, HER2-negative advanced breast cancer who received ribociclib plus endocrine therapy (n=177) achieved a median PFS2 of 44.2 months compared with 31.0 months for patients receiving placebo plus endocrine therapy (n=221; HR, 0.683; 95% CI, 0.56-0.83). A subsequent analysis found that the PFS2 benefit was generally consistent across prespecified subgroups.⁴

Rugo noted the 3 trials demonstrated that patients with the shortest PFS had received chemotherapy after progression. “We’ve seen a lot of data that show that [chemotherapy] doesn’t result in improved outcomes. So we shouldn’t be using chemotherapy, we should be using upper endocrine therapy first. Most patients got endocrine therapy, but patients who got chemotherapy may have gotten it because they had terrible visceral disease or hormone resistance.

“The patients who had the absolute best outcome were those who got CDK4/6 inhibitors in the next-line setting, which is curious. I don’t know [whether] that was a change to a different CDK4/6 inhibitor or it just indicates that those patients had very slow progression, oligo metastatic disease, [or were] very endocrine sensitive. That corresponds to the fact that if you got a CDK4/6 [inhibitor] in the second-line setting, if you got ribociclib first line, [then] you had a very good outcome. It’s more of a correlation with tumor biology than a true finding about the effectiveness of giving CDK4/6 [inhibitor] after CDK4/6 [inhibitor], which still remains to be determined,” Rugo said.

Ribociclib has shown encouraging data, and the phase 2 AMALEE trial indicated that the optimal dosing of the agent is 600 mg rather than 400 mg in the hormone receptor–positive population, according to Rugo. Investigators wanted to determine whether the QT interval and liver enzyme abnormalities were dose related; because they were not, screening remains necessary to determine whether ribociclib is safe.

However, Rugo explained that “if you dose reduce, you have less neutropenia. It’s not going to help your QT interval or your liver enzyme elevations. These are uncommon but real [adverse] effects. [For] most cancers, we’re going to start at 600 mg in the metastatic setting and go down to 400 mg quickly if patients can’t tolerate the 600 mg, knowing it has efficacy.” She also noted that having exposure to the agent can benefit patients, and 400 mg may be too small of a dose for certain patients.

Up-and-Coming Advances in Breast Cancer

The novel, highly potent pan-AKT kinase inhibitor capivasertib has demonstrated promising results, suppressing tumor proliferation and reducing the phosphorylation of biomarkers in recent preclinical studies.5 Data presented at the 2022 SABCS from the phase 2 CAPItello­-291 trial (NCT04305496) showed that in the overall population, the median PFS in the capivasertib plus fulvestrant arm (n = 355) was 7.2 months (95% CI, 5.5-7.4) compared with 3.6 months in the placebo plus fulvestrant arm (n=353; HR, 0.60; 2-­sided P<.001).⁶

With positive results emerging from CAPItello­-291, Rugo said she expects capivasertib to be approved by the FDA in approximately 1 year for tumors that have progressed, following treatment with a CDK4/6 and aromatase inhibitor. “There appeared to be a lot of efficacy in patients of altered PI3K pathway, [as well as] in the intent-to-treat population,” she said. “[Capivasertib] potentially has a toxicity that can be managed better than maybe some other targeted agents in this area.”

Rugo noted that additional areas of interest include new oral selective estrogen receptor degradersand proteolysis-targeting chimeras, with clinical trials emerging to evaluate efficacy in patients with heavily pretreated and resistant hormone receptor–positive metastatic disease.

References

1. Rugo HS, Bardia A, Marmé F, et al. Sacituzumab govitecan vs treatment of physician’s choice: efficacy by trop-2 expression in the TROPiCS-02 study of patients with HR+/HER2– metastatic breast cancer. Presented at: 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX. Abstract GS1-11.
2. Study of sacituzumab govitecan-hziy versus treatment of physician’s choice in participants with HR+/HER2- metastatic breast cancer (TROPiCS-02). ClinicalTrials.gov. Updated November 7, 2022. Accessed February 7, 2023. https://clinicaltrials.gov/ct2/show/NCT03901339
3. FDA approves sacituzumab govitecan-hziy for HR-positive breast cancer. FDA. February 3, 2023. Accessed February 23, 2023. bit.ly/3IDjXZU
4. Lu YS, Im SA, Colleoni M, et al. Updated overall survival of ribociclib plus endocrine therapy versus endocrine therapy alone in pre- and perimenopausal patients with HR+/HER2- advanced breast cancer in MONALEESA-7: a phase III randomized clinical trial. Clin Cancer Res. 2022;28(5):851-859. doi:10.1158/1078-0432.CCR-21-3032
5. Andrikopoulou A, Chatzinikolaou S, Panourgias E, et al. “The emerging role of capivasertib in breast cancer.” Breast. 2022;63:157-167. doi:10.1016/j.breast.2022.03.018
6. Turner N, Oliveria M, Howell SJ, et al. Capivasertib and fulvestrant for patients with aromatase inhibitor-resistant hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: results from the phase III CAPItello-291 trial. Presented at: 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX. Abstract GS3-04