Traina Reviews Current Data for Antibody-Drug Conjugates in Breast Cancer

Tiffany A. Traina, MD

Medical Oncologist

Section Head, Triple Negative Breast Cancer Clinical Research Program

Memorial Sloan Kettering Cancer Center

New York, NY

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​
• Hemoglobin A_1c: normal​​
• Tissue sent for genomic testing did not show PIK3CA or other actionable mutations.

TARGETED ONCOLOGY: What are the newer endocrine therapies for metastatic breast cancer?

TRAINA: [If] we have exhausted our endocrine options, there are a lot of new drugs in this space as well, looking at SARMs [selective androgen receptor modulators] and looking at additional oral SERDs [selective estrogen receptor degraders]. [There are] PROTACs [proteolysis-targeting chimeras], and lots of other endocrine approaches that hopefully will delay the time that we ultimately need to move on to chemotherapy. But, as we have all experienced, eventually endocrine resistance does develop. We have a few newer antibody-drug conjugates [ADCs] that have indications now in estrogen receptor–positive disease.

Please discuss recent evidence for sacituzumab govitecan-hziy (Trodelvy) in metastatic breast cancer.

The TROPiCS-02 [NCT03901339] study…was a big phase 3 trial of sacituzumab govitecan in patients with hormone receptor (HR)–positive/HER2- negative metastatic breast cancer.^1,2 Sacituzumab is an ADC against Trop-2. Trop-2 is highly expressed in breast cancer, and the payload here is SN-38, which is a metabolite of irinotecan [Camptosar].

These patients had to have had at least 1 line of endocrine therapy. They had a taxane, and they had a CDK4/6i [inhibitor], and they needed at least 2, but no more than 4, lines of chemotherapy. [This was] a [significantly] pretreated population. Five hundred and forty-three patients were randomly assigned to sacituzumab vs treatment-of-physician’s-choice [TPC] chemotherapy, and the primary end point was PFS [progression-free survival].

The baseline characteristics are as we would expect for women with HR-positive disease.¹ The vast majority of these patients had visceral disease: 95%. Eighty-four percent had liver metastases. About one-third had de novo [metastatic] disease. Their time from initial metastatic disease to [being randomly assigned] was about 4 years. That feels right when you think about what we expect to get out of a first-line CDK4/6i, and then get maybe another line or 2 of endocrine therapy before coming on to this study. Patients had a prior CDK4/6i, and [approximately 60% in each arm] had a prior CDK4/6i for less than a year…vs about 40% who had been [taking it] for more than a year. Patients had a median of 3 prior chemotherapy regimens.

What efficacy outcomes were observed in this trial?

PFS was significantly improved with sacituzumab over TPC chemotherapy.¹ The hazard ratio was 0.66 [95% CI, 0.53-0.83; P = .0003]. What is remarkable to see is right in the beginning there was this drop-off of patients who were doing poorly. But then, at landmark times of 6 months, 9 months, and 12 months, the patients who were receiving sacituzumab had better PFS than those getting standard-of-care [SOC] chemotherapy.

That benefit persisted across multiple subgroups. The benefit of sacituzumab over SOC chemotherapy applied to visceral metastases, whether patients were on endocrine therapy for a long or a short period of time, regardless of number of prior chemotherapies, regardless of age or performance status, and regardless of prior CDK4/6i. The other data…that are important for our patient experience [involve] quality of life. Sacituzumab’s health-related quality-of-life metrics were superior to those of SOC chemotherapy [Table³]. Not only are we seeing better PFS at this landmark analysis and overall, but that applies across subgroups [and is] maintaining quality of life.

Data were updated at ESMO [2022 European Society for Medical Oncology Congress] where Hope S. Rugo, MD, FASCO, showed the second interim analysis for OS [overall survival].² Not only do we have a PFS advantage, but we have a 21% improvement in OS for this population, and that met significance [hazard ratio, 0.79; 95% CI, 0.65-0.96; P = .02]. And at 12 months we have a 61% OS rate with sacituzumab and 47% with TPC chemotherapy. These were exciting data to see. These benefits applied across predefined subgroups: those who had visceral metastases, those who had 3 or more prior chemotherapy lines, those who had endocrine therapy for more than 6 months, across all different clinical features.

Because we saw an OS advantage, that triggered a statistical analysis of response.² The overall response rate [ORR] is superior with sacituzumab [21%] vs TPC chemotherapy [14%] [with] wide confidence intervals here [OR, 1.63; 95% CI, 1.03-2.56; P = .035]. Overall, there was a significant risk of neutropenia and grade 3 or 4 diarrhea, which is consistent with what we’ve seen before. But sacituzumab was associated with better quality of life regardless of those grade 3 or 4 events, and there were no surprising safety signals that emerged with these additional data.

Please discuss trastuzumab deruxtecan (Enhertu) for HER2-low breast cancer.

There is another antibody-drug conjugate that my friend and colleague Shanu Modi, MD, presented at ASCO [2022 American Society of Clinical Oncology Annual Meeting] in a plenary session, and this is trastuzumab deruxtecan, which we know well from the HER2-positive algorithms.^4,5 In [the phase 3] DESTINY-Breast04 trial [NCT03734029], trastuzumab deruxtecan was tested in patients with HER2-low breast cancer, defined as IHC [immunohistochemistry] 1+ or 2+ and ISH [in situ hybridization] not amplified. These were patients who had metastatic disease with 1 or 2 prior lines of chemotherapy. If they had HR-positive disease, they needed to be considered endocrine refractory. The patients were randomly assigned to trastuzumab deruxtecan alone or TPC chemotherapy. The statistics for this study were driven by the HR-positive cohort. [There were approximately] 540 patients, but 480 of those patients had HR-positive disease, and the primary end point was PFS in the HR-positive subset.^4,5

The baseline characteristics of the patient population^4,5 [included] the HR-positive cohort and the overall study population. These were largely young women. Most [58%] were HER2 status 1+, although 42% were HER2 status 2+; [and most had] great performance status. Ninety-nine percent of these patients had HR-positive disease in the HR-positive cohort, and approximately 90% overall. A small portion of these patients were previously [identified as] patients with triple-negative disease. There was a small number of patients with brain metastases that were stable, approximately 5% of patients, and many had visceral disease…and liver and lung [metastases].^4,5

The remarkable primary end point data were shared at ASCO.^4,5 The HR-positive population showed a 49% improvement in PFS. The median PFS with trastuzumab deruxtecan was 10 months vs 5.5 months with TPC chemotherapy [hazard ratio, 0.51; 95% CI, 0.40-0.64; P < .0001]. When we looked at OS, this was a secondary end point, but this also showed significant benefit at 35% improvement in median OS with trastuzumab deruxtecan approaching almost 2 years and TPC chemotherapy about 1.5 years [hazard ratio, 0.64; 95% CI, 0.48-0.85; P < .0028]. The median duration of follow-up was just about 1.5 years. In the forest plot for these prespecified end points, [there was] no real difference based on HER2 status, whether 1+ or 2+. [There was] no difference based on prior lines of therapy, by age, by race. We are seeing very small numbers there with wide confidence intervals. [There was] no difference [based on] region of the country, performance status, or visceral disease. Across the board, trastuzumab deruxtecan was favored over SOC chemotherapy.^4,5

Confirmed ORR was 52% in the HR-positive patients with trastuzumab deruxtecan, and only 16% with TPC chemotherapy, and the duration of response favors trastuzumab deruxtecan. [There were] no surprising safety signals. We know with trastuzumab deruxtecan we need to be cautious of interstitial lung disease or pneumonitis, and that remained true in DESTINY-Breast-04 as well.^4,5

How prevalent is HER2-low disease?

It’s more common in the patients with HR-positive disease: 65% with HR-positive disease compared with 37% of patients with triple-negative disease.⁶ This is certainly relevant in our patients who have progressed on their endocrine therapy and are considered endocrine refractory, and those who were found to be HER2-low have a real meaningful option here, as they do also with sacituzumab.

_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. 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}

_{5. 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}

_{6. 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}