Makhlin Evaluates Antibody-Drug Conjugate Trials in Metastatic Breast Cancer

Igor Makhlin, MD

Assistant Professor of Medicine, Hematology-Oncology

Hospital of the University of Pennsylvania

Philadelphia, PA

CASE SUMMARY

• A 62-year-old woman presented with a 6-cm mass in her right breast; it had been present for 1 year.
• Liver function tests: within normal limits
• CT scan showed 2 liver nodules; the largest was 2 cm.
• Bone scan showed extensive disease in her thoracic spine and ribs.
• Biopsy: estrogen receptor (ER)-positive, progesterone receptor (PR)-positive, HER2-negative grade 2 invasive ductal carcinoma
• Staging: T3N1M1
• ECOG performance status: 0
• She started treatment with letrozole (Femara) plus abemaciclib (Verzenio).
• Partial response was achieved.
• Thirty months after treatment initiation, follow-up imaging showed enlarged liver nodules and 2 new lung nodules (largest measuring 1.2 cm).
• ECOG performance status: 1
• Liver function tests: normal
• Glycated hemoglobin A1C: normal
• Tissue sent for genomic testing did not show PIK3CA, ESR1, or other actionable mutations.
• She received fulvestrant (Faslodex)/everolimus (Afinitor) for progressive disease.
• Initial follow-up imaging post treatment showed stable disease. Six-month posttreatment imaging showed liver and lung nodules enlarged from initial posttreatment scan.
• Treated with capecitabine (Xeloda) until progression of disease.

Targeted Oncology: What options are available at this stage of treatment for a patient like this?

MAKHLIN: At this point, they progressed on a chemotherapy, [and] they’ve had 2 lines of endocrine therapy, and so now the question is what else we can do. [I will] cover a couple of the ADC [antibody-drug conjugate] trials because…ER-positive metastatic breast cancer has seen a lot of updates recently, and this is great for our patients.

What data support the use of sacituzumab govitecan (Trodelvy) in this patient population?

The TROPiCS-02 study [NCT03901339] looked at sacituzumab in patients with HR [hormone receptor]-positive/HER2-negative metastatic breast cancer.^1-3 This study looked at patients who had at least 1 prior endocrine therapy taxane and a CDK4/6 inhibitor. They had to have at least 2 but no more than 4 lines of chemotherapy in the metastatic setting, and they were randomized to sacituzumab vs treatment of physician’s choice [TPC] chemotherapy and followed for PFS [progression-free survival] and OS [overall survival].

Based on characteristics, this is a high-risk patient population. Nearly everybody had visceral metastases, [and] most had liver metastases. The median line of prior chemotherapy lines was 3, and most patients had less than 12 months of stable disease or disease response on a prior CDK4/6 inhibitor.

What we saw [at 10.2 months median follow-up] was that there was a modest improvement in progression-free survival with sacituzumab vs TPC from 4.0 to 5.5 months [hazard ratio, 0.66; 95% CI, 0.53-0.83; P = .0003]. The objective response rate was a little bit higher as well, 14% for TPC vs 21% for sacituzumab.

Importantly, they looked at quality-of-life PROs [patient-reported outcomes], and I think this is so important moving forward in trials. What they showed was that there was a little bit of improvement as well in both time to deterioration in global health [and] time to deterioration in fatigue. Overall, this drug works a little bit better than chemotherapy, but it also is tolerated a little bit better. The forest plot showed that almost all the subgroups and key subgroups did favor sacituzumab [Table¹].

There was also an interim overall survival analysis that showed that there was a statistically significant OS benefit by about 3 months [median OS of 14.4 months with sacituzumab vs 11.2 months with TPC] and about a 21% improvement in survival with sacituzumab over standard chemotherapy [hazard ratio, 0.79; 95% CI, 0.65-0.96; P = .020].²

They also did an interesting efficacy [analysis] by TROP2 expression. This was exploratory, and what we learned is [95% of tumor samples showed] TROP2 expression.⁴ It’s ubiquitously expressed, and it doesn’t matter how much TROP2 expression the tumor has. They’re going to benefit, probably as a result of the bystander effect of this ADC.

As we know in the real world, the trial also showed patients had more neutropenia and more diarrhea with sacituzumab, but importantly, there were no ILD [interstitial lung disease] events with sacituzumab, which is unique for this ADC compared with some of the other ADCs we might talk about.¹

What is the significance of trastuzumab deruxtecan (T-DXd) in the metastatic breast cancer setting?

The other ADC for HR-positive patients now is T-DXd. We now know that of all patients with metastatic breast cancer, roughly half have some level of HER2 expression but they’re HER2-negative. It’s more frequent in the HR-positive patients, about 65%, and a little bit less frequent in patients with triple-negative breast cancer, but, overall, about half of your patients who have metastatic disease will have some level of HER2 expression.⁵

That’s important because we have the DESTINY-Breast04 study [NCT03734029], which everybody is certainly familiar with [and] received a standing ovation last year at the American Society of Clinical Oncology Annual Meeting. This trial randomly assigned patients who had HER2-low breast cancer, which is defined as IHC [immunohistochemistry] 1+ or 2+ but FISH [fluorescence in situ hybridization] nonamplified, metastatic disease, and they’ve all had 1 to 2 prior lines of chemotherapy.

Those who were HR positive had to have also been refractory to endocrine therapy. They were randomly assigned on a 2:1 basis to T-DXd vs treatment of physician’s choice. The median number of lines of prior [therapies for metastatic disease]…was 3.^6,7 This was essentially a trial of HR-positive [patients]. Eighty-nine percent of patients were HR positive, so it was a small cohort who were triple negative. Again, most patients had liver metastases, and visceral metastases were widespread, so this is a high-risk group.

What they saw was impressive. They doubled PFS with T-DXd [median PFS of 10.1 months with T-DXd in the HR-positive cohort vs 5.4 months with TPC], and they also showed improvement in OS with a roughly 36% improvement [median OS of 23.9 months with T-DXd in the HR-positive cohort vs 17.5 months with TPC; hazard ratio, 0.64; 95% CI, 0.48- 0.86; P = .0028]. This was groundbreaking for this population, which typically isn’t chemotherapy-sensitive.

They also looked at exploratory [end points]. This was exploratory for triple-negative [disease], because the numbers were so much smaller, but they did show consistently that the PFS was essentially doubled [median PFS of 8.5 months with T-DXd vs 2.9 months with TPC], and the overall survival was improved by 10 months [median OS of 18.2 months vs 8.3 months with TPC], so [these were] very striking data.⁷

Just like we saw with TROPiCS-02, again, with DESTINY-Breast04, all the key subgroups appeared to favor T-DXd.^6,7

How has the sequence of treatments for patients with metastatic HR-positive, HER2-negative metastatic breast cancer evolved based on these trials?

[There is] a proposed road map incorporating what we just talked about, where we basically start with a CDK4/6 inhibitor frontline with endocrine therapy.⁸ Then depending on the pace of progression, we can layer in additional targeted therapies with endocrine therapy. One thing we now know is that single-agent endocrine therapy after CDK4/6 inhibitor progression is not a viable option. It’s…not typically going to produce a long-lasting, durable effect. That’s why these targeted therapies, like alpelisib [Piqray], everolimus, [and] PARP inhibitors, if [the tumor is] BRCA mutated…are so vital. [Then we] move on to sequential single-agent chemotherapy, and then [we are] branching by the HER2 status for second- or third-line chemotherapy; [here] we can think about T-DXd [for HER2-low] or sacituzumab [for HER2-zero].

The National Comprehensive Cancer Network updated their second-line therapy recommendations. If you go by HER2 status, for second-line therapy they’re recommending T-DXd for HER2-low and sacituzumab for HER2-zero.⁹

_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 (OS) results from the phase III TROPiCS-02 study of sacituzumab govitecan (SG) vs treatment of physician’s choice (TPC) in patients (pts) with HR+/HER2- metastatic breast cancer (mBC). Ann Oncol. 2022;33(suppl 7):S1386. doi:10.1016/j.annonc.2022.08.012}

_{3. Rugo HS, Schmid P, Tolaney SM, et al. Health-related quality of life (HRQoL) in the phase III TROPiCS-02 trial of sacituzumab govitecan (SG) vs chemotherapy in HR+/HER2- metastatic breast cancer (MBC). Ann Oncol. 2022;33(suppl 7):S713-S742. doi:10.1016/annonc/annonc1075}

_{4. Rugo HS, Bardia A, Marmé F, et al. Sacituzumab govitecan (SG) vs treatment of physician’s choice (TPC): efficacy by Trop-2 expression in the TROPiCS-02 study of patients (pts) with HR+/HER2– metastatic breast cancer (mBC). Presented at the 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX. Abstract GS1-11.}

_{5. Schettini F, Chic N, Brasó-Maristany F, et al. Clinical, pathological, and PAM50 gene expression features of HER2-low breast cancer. NPJ Breast Cancer. 2021;7(1):1. doi:10.1038/s41523-020-00208-2}

_{6. Modi S, Jacot W, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med. 2022;387(1):9-20. doi:10.1056/NEJMoa2203690}

_{7. Modi S, Jacot W, Yamashita T, et al. Trastuzumab deruxtecan (T-DXd) versus treatment of physician’s choice (TPC) in patients (pts) with HER2-low unresectable and/or metastatic breast cancer (mBC): results of DESTINY-Breast04, a randomized, phase 3 study. J Clin Oncol. 2022;40(suppl 17):LBA3. doi:10.1200/JCO.2022.40.17_suppl.LBA3}

_{8. Huppert LA, Gumusay O, Idossa D, Rugo HS. Systemic therapy for hormone receptor-positive/human epidermal growth factor receptor 2-negative early stage and metastatic breast cancer. CA Cancer J Clin. 2023;73(5):480-515. doi:10.3322/caac.21777}

_{9. Gradishar WJ, Moran MS, Abraham J, et al. NCCN Guidelines insights: breast cancer, version 4.2023: featured updates to the NCCN Guidelines. J Natl Compr Canc Netw. 2023;21(6):594-608. doi:10.6004/jnccn.2023.0031}