Adjusting to Practice Changing ADCs in Advanced Breast Cancer

CASE SUMMARY

A 62-year-old woman presented with a 6 cm right breast mass, which has been slowly growing for 1 year with palpable axillary nodes​. Her liver function test was within normal limits and a CT scan showed 2 liver nodules, with the largest being 2 cm​. A bone scan showed extensive disease in thoracic spine and ribs​ and a breast biopsy showed she had grade 2 invasive ductal carcinoma. Her disease was estrogen receptor (ER) and progesterone receptor (PR) positive, her HER2 immunohistochemistry score was 0, and she was BRCA1/2 negative​. A liver biopsy confirmed metastatic disease with similar markers​, T3N1M1. She had an ECOG performance status of 0.

Treatment with letrozole (Femara) plus ribociclib (Kisqali) was initiated​, and bisphosphonate was given to address bone metastasis. A best response of partial response was achieved​ and 30 months after treatment initiation; follow-up imaging showed enlarging liver nodules and 2 new lung nodules with the largest measuring 1.2 cm. Her ECOG performance status was now 1​, her liver function tests were still normal​, and her HgbA1c was also normal. Circulating tumor DNA was sent for genomic testing, and did not show PIK3CA, ESR1, or other actionable mutations.

The patient progressed after endocrine and CDK4/6 inhibitor therapy, then received fulvestrant plus everolimus for progressive disease. Initial follow-up imaging post-treatment showed stable disease. 6-month post-treatment imaging showed liver and lung nodules enlarged from initial post-treatment scan.​ They were then treated with capecitabine until progression of disease. Afterwards, the patient was treated with sacituzumab govitecan (Trodelvy).

DISCUSSION QUESTIONS

• What efficacy or safety data, from the TROPiCS-02 (NCT03901339) or DESTINY-Breast04 (NCT03734029) are significant and/or practice changing?
• How do you talk to your patients about either treatment’s potential efficacy and safety profile?

ADITYA BARDIA, MD, MPH: Do you feel the results are practice changing? I guess the answer would be yes because both are FDA approved.^1,2 Yet there are drugs that are FDA approved that we might not use in clinical practice, so would anyone consider these drugs not to be practice changing?

Aditya Bardia, MD, MPH

Director, Breast Cancer Research Program

Massachusetts General Hospital

Associate Professor, Medicine

Harvard Medical School

Boston, MA

RICARDO COSTA, MD: I think [these data] are practice changing, and much needed. The enthusiasm that we saw at the American Society of Clinical Oncology Annual meeting last year when the DESTINY-Breast04 results were presented reflected our need for better agents and more options [in this space].³

FRANTZ FRANCISQUE, MD: I have some reservations with trastuzumab deruxtecan [Enhertu] considering the study [had] a small population of [patients with] HER2-low disease. I tend to prefer Sacituzumab govitecan over trastuzumab deruxtecan, because it was [looked at in] a true trial of patients with a negative HER2 status.⁴

OLEG GLIGICH, MD: I think these drugs are revolutionary and have changed the way that we practice medical oncology [for patients with breast cancer], and these are going to change practice for many years [to come]…. I have used both drugs in the estrogen receptor negative setting as well as in the estrogen receptor positive setting…and I have had miraculous responses. So, I think both drugs are amazing, and I look forward to figuring out the next question, which is, how do we sequence these drugs?

BARDIA: That is going to be the next question, which is how do we sequence them? Would you start with trastuzumab deruxtecan first, and then use Sacituzumab govitecan? Or vice-versa? Has anyone done that, and what has their experience been?

SHAACHI GUPTA, MD, MPH: One of the things that I want to mention is that some insurance companies necessitate [prior treatment] based on how these drugs were studied. For example, for sacituzumab govitecan, the patient should have received at least 1 line of chemotherapy in the metastatic setting.

It’s hard to then jump from endocrine therapy, CDK4/6 inhibitor and everolimus and then, [deciding] whether you can go to the oral or injectable selective estrogen receptor degrader or not. You have to use another chemotherapy before you are able to get to any one of these drugs. Isn’t that correct? Or is someone else having a different experience? Because I have to use paclitaxel…before I use any of these drugs.

BARDIA: That is correct. As per the label, you need at least 1 prior line of therapy.² Sometimes that is capecitabine, but after capecitabine, you can use these agents. Others have considered paclitaxel before using these agents, and that is as per label too.

COSTA: My experience has been good, not that I have an elegant way how to justify the sequencing. I don’t think we have the data. Maybe I am biased given the impressive antitumor efficacy results from DESTINY-Breast04…so, I tend to go for trastuzumab deruxtecan first, followed by sacituzumab govitecan after.

But I don’t know that I have an elegant rationale for that. From my experience, patients have been doing well that way with responses to both agents. I think the mechanism of action of these agents are elegant, and patients like to hear from us in terms of how these agents work. I also think they have been disruptive, and they have changed their treatment paradigm, in terms of mechanism of actions for treatments.

BARDIA: Absolutely, we need more data. There are ongoing studies…but we need more prospective data in terms of [finding] the optimal sequence. For now, I think it is reasonable to use one antibody-drug conjugate after the next.

^References

^{1. FDA grants regular approval to fam-trastuzumab deruxtecan-nxki for breast cancer. News release. May 11, 2022. Accessed September 13, 2023. https://tinyurl.com/pmvextzu}

^{2. FDA approves sacituzumab govitecan-hziy for HR-positive breast cancer. News release. February 2, 2023. Accessed September 13, 2023. https://tinyurl.com/mrxx2kek}

^{3. Modi S, Jacot W, Yamashita T, et al; DESTINY-Breast04 Trial Investigators. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med. 2022;387(1):9-20. doi:10.1056/NEJMoa2203690}

^{4. Rugo S, Bardia A, Marme F, et al. Primary results from TROPiCS-02: A randomized phase 3 study of sacituzumab govitecan (SG) versus treatment of physician’s choice (TPC) in patients (Pts) with hormone receptor–positive/HER2-negative (HR+/HER2-) advanced breast cancer. J Clin Oncol. 2022;40(17):LBA1001-LBA1001. doi:10.1200/JCO.2022.40.17_suppl.LBA1001}