Traina Examines Impact of Antibody-Drug Conjugates on Sequencing HR+/HER2– Breast Cancer

Publication
Article
Peers & Perspectives in OncologyDecember II, 2023
Volume 1
Issue 11
Pages: 89

During an in-person Targeted Oncology™ Clinical Case Forum event in New Jersey, Tiffany Traina, MD, discussed the role of antibody-drug conjugates in advanced breast cancer.

Traina

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 were within normal limits (WNL).
  • 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–positive (ER+), progesterone receptor–positive, HER2-negative (HER2–) 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: WNL
  • Hemoglobin A1c: normal
  • Tissue sent for genomic testing did not show PIK3CA, ESR1, or other actionable mutations.
  • Patient progressed after endocrine and CDK4/6 inhibitor therapy; received fulvestrant (Faslodex) plus everolimus (Afinitor) for progressive disease.
  • Initial follow-up imaging posttreatment showed stable disease. Six-month posttreatment imaging showed liver and lung nodules enlarged from initial posttreatment scan.
  • Treated with capecitabine until progression of disease.

Targeted Oncology: What recent data impact the choice of therapy for a patient with hormone receptor-positive (HR+) metastatic breast cancer in the second-line metastatic setting?

TRAINA: Now we’re thinking about the second-line chemotherapy setting, and to inform that, we have data from the TROPiCS-02 study [NCT03901339]. Let’s look at this in greater detail because this offers us another option for our patients with HR+ disease, whereas we’ve had this for triple-negative breast cancer [TNBC] for some time. TROPiCS-02 was a randomized phase 3 study looking at sacituzumab govitecan [Trodelvy] up against treatment of physician’s choice [TPC] chemotherapy, and this was in women who had metastatic HR+/HER2– breast cancer. They had seen at least 1 line of endocrine therapy, they must have had a taxane before and a CDK4/6 inhibitor in any prior setting, and they needed to have at least 2 prior lines of chemotherapy, but no more than 4. Neoadjuvant or adjuvant therapy counted if they had a very short disease-free interval. More than 500 women were randomly assigned on the study, and the primary end point was progression-free survival [PFS] by blinded independent review with secondary efficacy and safety [including overall survival (OS), overall response rate (ORR), duration of response (DOR), patient-reported outcomes, and safety].1

If we look at what the characteristics were of the women on this study, you can see that median age was about 57, the majority of women were White, they had good performance status, and almost everybody had visceral metastases. The majority of those were liver metastases. Some of these women had de novo metastatic breast cancer. Approximately two-thirds had seen chemotherapy for early-stage disease, and 86% had had prior endocrine therapy for metastatic disease longer than 6 months. In terms of prior CDK4/6 inhibitor use, the majority of them saw less than 12 months of a CDK4/6 inhibitor with a median of 3 prior lines of chemotherapy.1

What were the results of this trial in this pretreated population as of the 2023 American Society of Clinical Oncology Annual Meeting?

So when I look at this patient population, I’m thinking these are endocrine-refractory patients with short disease-free interval, short amount of time on a CDK4/6 inhibitor, and a median of 3 prior lines of chemotherapy, [which is] a heavily pretreated population for HR+ disease. Yet despite that, sacituzumab outperforms standard-of-care [SOC] chemotherapy, with a 35% improvement in PFS [hazard ratio, 0.65; 95% CI, 0.53- 0.81; P = .0001].2 At each landmark, the patients getting sacituzumab were doing better than those who [were] getting TPC chemotherapy [Figure2].

That benefit seemed to apply across all the prespecified subgroups…. You see these wide confidence intervals on those without visceral metastases [since] that was only 25 patients out of more than 500. [For those with] endocrine therapy for metastatic breast cancer longer than 6 months [n = 74], it had a wide confidence interval that was straddling 1.0. If you look at the OS data, you’re seeing about a 20% improvement in OS [HR, 0.79; 95% CI, 0.65-0.95; P = .0133].2 That impact you see at the 12-month landmark and the 18-month landmark is diminishing over time, and again, applying to nearly all the subgroups….

What did biomarker analyses show about sacituzumab govitecan?

Similar to what was done in the ASCENT study [NCT02574455] for TNBC, the TROPiCS-02 trial also looked at efficacy by Trop-2 expression. Lots of [researchers] have wondered, does it matter whether you have low Trop-2 expression or high Trop-2 expression? The short answer is that regardless of Trop-2 expression, sacituzumab was outperforming standard-of-care chemotherapy.2 We do not need to be looking at Trop-2 expression in our patients. It is there in the vast majority of all breast cancers whether HR+ or triple negative, and so there is no need for Trop-2 expression level testing.

In light of the DESTINY-Breast04 [NCT03734029] data…, there have also been analyses in TROPiCS-02 as well as in the ASCENT trial looking at efficacy of sacituzumab based on HER2 by immunohistochemistry [IHC]. Not surprisingly, regardless of HER2 expression, whether you’re HER2 zero or HER2 low, sacituzumab was outperforming SOC chemotherapy.2

That’s not really a surprise, because this target has nothing to do with HER2; it is highly expressed across all breast cancer. We see that efficacy is outperforming SOC chemotherapy. When we look at other efficacy end points, sacituzumab’s ORR was 21% [vs 14% with TPC].2

There was a higher rate of partial responses [21% vs 14%, respectively] and prolonged stable disease, 52% with sacituzumab vs [39%] with SOC chemotherapy. The clinical benefit rate favored sacituzumab as well [34% vs 22%, respectively] and the DOR was approximately 3 months longer with sacituzumab than with SOC chemotherapy.

What was seen concerning safety of this therapy?

When we look at adverse events [AEs], there were no surprises here from what we’ve known with this agent from the TNBC setting. Remember this is a heavily pretreated population with a median of 3 prior chemotherapies. Neutropenia was seen of any grade in 71%, [52% of which was] grade 3 or higher. But we also see in TPC approximately 40% grade 3 neutropenia. I think diarrhea is the AE of interest here, and 10% grade 3 diarrhea is very consistent with what was seen in the ASCENT trial as well.

CASE UPDATE

  • The patient was treated with sacituzumab govitecan.

What other novel therapy has demonstrated strong efficacy at this line of treatment for HR+ metastatic breast cancer population?

We already primed the conversation about HER2-low breast cancer. HER2-low for now is defined as HER2 1+ or 2+ FISH [fluorescence in situ hybridization] nonamplified. The prevalence of that in HR+ breast cancer is about two-thirds, quite different in TNBC where HER2 low is only about one-third of that population.3

This is relevant because of the results of DESTINY-Breast04. This was a large, randomized trial of [primarily] HR+/ HER2-low breast cancer. Although [there is a wider] label, 90% of these patients had HR+/HER2-low disease, and they were randomly assigned in a 2:1 fashion to trastuzumab deruxtecan [T-DXd; Enhertu] or SOC chemotherapy, including taxane as one of those SOC options.

These patients were less pretreated than the TROPiCS-02 population.4 They had HER2-low disease that was HR+, and they needed to have 1 to 2 prior lines of chemotherapy in the advanced setting. The primary end point is PFS, specifically in the HR+ population. That HR-negative, HER2-low, triple negative setting was an exploratory population.

The median age was approximately 57. Sixty percent of patients had HER2 1+ status, 40% had HER2 2+ status. HR+ disease was in approximately 90% of the study population. There were a few patients who had stable treated brain metastases, approximately 70% had liver lesions, and approximately one-third had lung metastases.

[This was presented in the American Society of Clinical Oncology Annual Meeting] plenary session last year, and it was published that trastuzumab deruxtecan was superior to TPC chemotherapy in this HR+ population with a hazard ratio of 0.51, a [49%] improvement [95% CI, 0.40-0.64; P < .0001], and an absolute difference of almost 5 months [median PFS].4,5

If you look at OS, there was a median OS of approximately 2 years with sacituzumab, and an incremental improvement of about 6.5 months [vs TPC] [hazard ratio, 0.64; 95% CI, 0.48- 0.86; P = .0028]. If you look at all the different prespecified subgroups, again, you can see it all pretty much favors trastuzumab deruxtecan, including those who had seen prior CDK4/6 inhibitor, regardless of their IHC status, even regardless of prior lines of therapy.5 But approximately 200 of these patients had seen just 1 prior line of chemotherapy, and only 127 had seen 2 prior lines or more, so this was a less pretreated population. The confirmed ORR was over 50%, and there was a durable benefit here with a median DOR of [10.7] months.

[In terms of] safety, I think we have [experience] with this agent from treating HER2+ advanced disease. Now we see it in HR+ and triple negative HER2-low disease. We commonly see upper gastrointestinal toxicity, anorexia, nausea, and cytopenia. The [rate of] all-grade neutropenia is 33%, and diarrhea is less likely for this population [than with sacituzumab].4 There is a risk of elevated LFT [liver function test] results. About a quarter of patients had any-grade [aminotransferase increase] but grade 3 or higher toxicity was uncommon.

What is a concerning AE of interest is the ILD [interstitial lung disease] and pneumonitis risks with this agent. Fortunately, we’ve seen as the trials have moved earlier in line of therapy in the HER2+ space and also here that while there is some grade 5 risk from ILD, in total the risk of ILD is looking more like 10% to 12%, and fortunately, the grade 5 events have been rare. That’s with strict monitoring guidelines that have been baked in, [including] stopping the drug, instituting steroids, and clear guidance on how to intervene if it’s seen.

What updates to sequencing therapies for HR+/HER2– metastatic breast cancer have been proposed based on these trials?

[A proposed road map from] Hope S. Rugo, MD…gets at what we’ve all been talking about [in which we] sequence all those endocrine therapy options with one targeted combination or another until we get to the point that we need to graduate to single-agent chemotherapy….6 Then what we do in the second or third line depends on HER2 expression and whether somebody is HER2 low or HER2 0, although there are trials going on right now looking at T-DXd in HER2–ultra low or HER2 0+ status. I think that definition is in flux. We’ll need to watch out for those data.

The National Comprehensive Cancer Network updated their guidelines earlier this year. If we look at what to do in the second-line setting for those patients with HER2-low tumors, T-DXd is considered category 1 preferred.7 If somebody is not a candidate for T-DXd, sacituzumab is also category 1 preferred in the second-line setting and later, and it’s just highlighted at the bottom that this meets that FDA label as well for second-line metastatic treatment.

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. Tolaney SM, Bardia A, Marmé F, et al. Final overall survival (OS) analysis from the phase 3 TROPiCS-02 study of sacituzumab govitecan (SG) in patients (pts) with hormone receptor–positive/HER2-negative (HR+/HER2–) metastatic breast cancer (mBC). J Clin Oncol. 2023;41(suppl 16):1003. doi:10.1200/ JCO.2023.41.16_suppl.1003

3. 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

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. 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

6. 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

7. NCCN. Clinical Practice Guidelines in Oncology. Breast cancer, version 4.2023. Accessed November 22, 2023. https://tinyurl.com/2khn5xtm

Related Videos
Rohit Gosain, MD; Rahul Gosain, MD; and Hope Rugo, MD, presenting slides
Rohit Gosain, MD; Rahul Gosain, MD; and Hope Rugo, MD, presenting slides
Rohit Gosain, MD; Rahul Gosain, MD; and Hope Rugo, MD, presenting slides
Rohit Gosain, MD; Rahul Gosain, MD; and Hope Rugo, MD, presenting slides
Rohit Gosain, MD; Rahul Gosain, MD; and Hope Rugo, MD, presenting slides
Related Content