Bardia Explores Outcomes for Antibody-Drug Conjugates in TNBC

Aditya Bardia, MD, MPH

Associate Professor of Medicine

Harvard Medical School

Attending Physician, Medical Oncology

Massachusetts General Hospital

Boston, MA

Targeted Oncology^TM: Can you discuss the most recent National Comprehensive Cancer Network (NCCN) guidelines regarding therapies for TNBC?

BARDIA: The updated NCCN guidelines recommend sacituzumab govitecan [Trodelvy] as a category 1 recommendation for TNBC in the second-line and [later] setting.¹ It can also be used for ER [estrogen receptor]-positive, HER2-negative disease. Then the other [option] is T-DXd, or trastuzumab deruxtecan [Enhertu], for IHC 1+, 2+, the HER2-low category. Besides that, one can use other chemotherapy agents as well.

There was a question that had come up about the use of eribulin [Halaven] or vinorelbine after sacituzumab govitecan. There are some data from the ASCENT trial [NCT02574455].² Patients in the ASCENT trial who got sacituzumab govitecan and then received additional standard therapy like eribulin— that partly contributed to improvement in overall survival [OS]. You can certainly use eribulin or vinorelbine after sacituzumab govitecan.

Can you discuss the ASCENT trial of sacituzumab govitecan?

The ASCENT trial was for patients with metastatic TNBC. Technically, the ASCENT trial was in the third-line [and later] setting, but the FDA approval was for the second line, so clinically I feel comfortable using it in the second-line setting. Patients with pretreated metastatic TNBC were randomly assigned to sacituzumab govitecan 10 mg/kg on day 1 and day 8, every 21 days, vs treatment-of-choice chemotherapy, which could be eribulin, capecitabine [Xeloda], vinorelbine, or gemcitabine. The primary end point was progression-free survival [PFS] and OS was a key secondary end point.

The trial showed improvement in both PFS and OS [Figure³]. Essentially, there was doubling of PFS and there was doubling of OS as well. The OS was 12.1 months with sacituzumab govitecan vs about 6 months with standard chemotherapy [HR, 0.48; 95% CI, 0.39-0.59; P < .0001]. Again, it’s important to note that the trial was done in the third-line or later setting, so we need to be careful when we compare this with other studies, such as DESTINY-Breast04 [NCT03734029], which was in the second-line setting or later.⁴

Because the survival will differ, [depending on] whether a treatment is given in the second-line vs third- or fourth-line setting, we need to be careful with cross-trial comparisons. But the bottom line with the ASCENT trial was [that] there was clearly improvement in PFS and OS with sacituzumab. In terms of subgroups, the important ones to consider would be patients’ race, whether they had 2 prior therapies vs more than 3, prior use of immunotherapy, and patients who initially had ER-positive disease and then later on in the metastatic setting it became TNBC.²

In all the subgroups, there was benefit with sacituzumab govitecan. In terms of overall response rate [ORR], it again confirms that, similar to PFS and OS, there was improvement in ORR: 35% with sacituzumab vs 5% with standard chemotherapy.² So that just highlights that standard chemotherapy, at least in the later-line settings, does not work that well and that’s why this ADC [antibody-drug conjugate] should be the preferred agent.

The 3 most common adverse events [AEs] we see with sacituzumab govitecan are neutropenia, [diarrhea, and alopecia].² Neutropenia…can usually be managed with dose interruptions, reductions, and use of G-CSF [granulocyte colony-stimulating factor].

The second [most common] AE is diarrhea, and that’s largely because of the toxic payload from govitecan, or SN-38. That tends to contribute toward diarrhea. The third [most common] AE that we do see with this agent is alopecia. So it’s important to discuss all 3 AEs with patients. The AEs that we do not see include pneumonitis, and in general, we don’t see peripheral neuropathy or cardiac toxicity either. The AEs we do see include neutropenia, nausea, diarrhea, and alopecia.

Now in terms of looking at sacituzumab govitecan vs type of chemotherapy, be it eribulin or capecitabine or vinorelbine, regardless of the type of chemotherapy, sacituzumab did better as compared to any of the chemotherapy agents.⁵

How does biomarker analysis affect your decision-making?

Essentially, in the ASCENT trial, patients who had a germline BRCA mutation, or known germline BRCA vs wild type, the outcomes were similar with sacituzumab govitecan in terms of improvement in PFS, OS, and ORR.⁶ Clinically, that does not impact the use of sacituzumab govitecan, but it does impact the use of other agents.

For example, if there’s a patient who has metastatic TNBC with a germline BRCA mutation and then gets first-line therapy with a platinum-containing regimen in the second-line setting, you could use sacituzumab govitecan, but you could also consider a PARP inhibitor. It does impact the therapeutic sequencing. And in general, we tend to use PARP inhibitors for patients with germline BRCA. So it pushes sacituzumab govitecan to the post- PARP setting, but just emphasizing the germline BRCA mutation per se does not influence the ORR to sacituzumab govitecan.

Then, in terms of Trop-2: Trop-2 is usually overexpressed in TNBC, and in the ASCENT trial, the majority of tumors had high or medium Trop-2 expression.⁵ Even in tumors with low Trop-2 expression, the benefit with sacituzumab govitecan was greater than that of standard chemotherapy. In current clinical practice, it’s not used because it does not influence decision-making. As was brought up earlier, there are also issues about clinical validity of the assay and analytical consideration. So it’s not something that’s used in clinical practice.

Can you discuss how patient age affects the use of sacituzumab govitecan?

Briefly about ASCENT—there is a question in terms of patients who are aged over 65 years vs under 65 years. In both subgroups, there was benefit with sacituzumab govitecan, but the incidence of AEs was a bit higher in patients who were more than 65 years of age.⁷ So it’s particularly with that group that I would have a low threshold for dose reduction if a patient is having AEs. But in terms of efficacy, it does work in both these subgroups.

Can you discuss the data on trastuzumab deruxtecan for patients with TNBC?

DESTINY-Breast04…was a trial of patients with HER2-low metastatic breast cancer.⁴ HER2-low was defined as IHC 1+ or 2+, and those who had IHC 2+ needed to have HER2 ISH [in situ hybridization] negative, so a ratio of less than 2, or HER2 copy number of less than 4. [They needed to have] unresectable metastatic breast cancer with at least 1 prior line of chemotherapy, so essentially it was in the second-line setting or later. The trial was for patients with ER-positive, endocrine-refractory breast cancer. The primary end point was PFS by independent review for ER-positive breast cancer. But then there was also a secondary end point of PFS for all patients, including patients with TNBC, because the trial did enroll some patients with ER-negative breast cancer.

In terms of baseline characteristics, it was well balanced between both the arms.⁴ This was predominantly in the second-line setting, in terms of the trial design. Now to emphasize PFS for the ER-negative subgroup was an exploratory end point, it was not even a secondary end point. It was more of a tertiary end point, and that’s why you will not see a P value with these HRs and PFS outcomes, because it was not a primary or secondary end point. But you could clearly see benefit with T-DXd: a median PFS of 8.5 months vs 2.9 months with standard chemotherapy [HR, 0.46; 95% CI, 0.24-0.89], and an improvement in OS as well [HR, 0.48; 95% CI, 0.24-0.95].

As I mentioned earlier, this was in the second-line setting; so that’s why if you look at the control arm, the overall survival was 8.3 months, which was higher than what was seen in ASCENT, which was more of a third-line and later [treatment] study.^3,4 So that’s why we have to be careful about cross-trial comparisons. But regardless, it clearly showed improvement with T-DXd, both in PFS and OS. Given that it’s a major unmet need, I think that’s why, despite it being an exploratory end point, the FDA granted approval to T-DXd, given that patients need better options.

There was clear improvement in ORR: 50% ORR with T-DXd vs 16% with standard chemotherapy.⁴

_REFERENCES

_{1. NCCN. Clinical practice guidelines in oncology. Breast cancer, version 4.2022. Accessed December 21, 2022. https://bit.ly/3kxcYWm}

_{2. Bardia A, Hurvitz SA, Tolaney SM, et al. Sacituzumab govitecan in metastatic triple-negative breast cancer. N Engl J Med. 2021;384(16):1529-1541. doi:10.1056/NEJMoa2028485}

_{3. Bardia A, Tolaney SM, Loirat D, et al; ASCENT Clinical Trial Investigators. Sacituzumab govitecan (SG) versus treatment of physician’s choice (TPC) in patients (pts) with previously treated, metastatic triple-negative breast cancer (mTNBC): Final results from the phase 3 ASCENT study. J Clin Oncol. 2022;40(suppl 16):1071. doi:10.1200/JCO.2022.40.16_suppl.1071}

_{4. 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}

_{5. O’Shaughnessy J, Punie K, Oliveira M, et al. Assessment of sacituzumab govitecan (SG) versus treatment of physician’s choice (TPC) cohort by agent in the phase 3 ASCENT study of patients (pts) with metastatic triple-negative breast cancer (mTNBC). J Clin Oncol. 2021;39(suppl 15):1077. doi:10.1200/ JCO.2021.39.15_suppl.1077}

_{6. Bardia A, Tolaney SM, Punie K, et al. Biomarker analyses in the phase III ASCENT study of sacituzumab govitecan versus chemotherapy in patients with metastatic triple-negative breast cancer. Ann Oncol. 2021;32(9):1148-1156. doi:10.1016/j. annonc.2021.06.002}

_{7. Kalinsky K, Oliveira M, Traina T, et al. Outcomes in patients (pts) aged ≥65 years in the phase 3 ASCENT study of sacituzumab govitecan (SG) in metastatic triple-negative breast cancer (mTNBC). J Clin Oncol. 2021;39(suppl 15):1011. doi:10.1200/JCO.2021.39.15_suppl.1011}