Selecting Second-Line Treatment in HR+, HER2-Low Breast Cancer | Targeted Oncology

For patients with ESR1-mutated, hormone receptor (HR)-positive, HER2-low metastatic breast cancer, progression on initial CDK4/6 inhibitor-based therapy presents a key sequencing decision. Claudine Isaacs, MD, professor of medicine and oncology, associate director of Clinical Research, and leader of the Clinical Breast Cancer Program at the Georgetown Lombardi Comprehensive Cancer Center, and the medical director of the Jess and Mildred Fisher Center for Hereditary Cancer and Clinical Genomics Research, moderated a virtual Case-Based Roundtable event for oncologists in Georgia and Virginia. In the event, participants debated whether to use elacestrant (Orserdu) or trastuzumab deruxtecan (T-DXd; Enhertu) in the second-line setting.

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CASE SUMMARY

• A 52-year-old woman with a history of:
  • 2.4-cm, grade 2, node-negative invasive ductal carcinoma (IDC), HR positive, HER2 immunohistochemistry (IHC) 1+, Ki-67 20% of the right breast, 21-gene recurrence score of 27
  • Initial therapy included chemotherapy, radiation therapy, and 5 years of adjuvant anastrozole
• Three years after completing anastrozole, she reported new lower back and hip pain during a routine office visit.
  • Laboratory results: alanine and aspartate aminotransferase normal, elevated alkaline phosphatase, normal bilirubin, mild anemia
  • Imaging: multiple masses (largest 2 cm) in right lobe of liver and sclerotic lesions in multiple vertebrae and bilateral iliac crests
  • Liver biopsy: carcinoma consistent with breast primary; estrogen receptor 90%, progesterone receptor 60%, HER2 IHC 1+
  • ECOG performance status: 1
• Treatment: letrozole (Femara) plus ribociclib (Kisqali) with denosumab
  • Good clinical response with reduction in size of liver masses
  • One dose reduction to 400 mg of ribociclib due to neutropenia

Sixteen months after starting therapy

• Follow-up imaging for response assessment showed new liver lesions and 1 new sclerotic lesion in T12 suspicious for malignancy
  • Mild abdominal pain
  • Laboratory results: mildly elevated transaminases, about 2 times the upper limit normal
• Circulating tumor DNA analysis confirmed an ESR1 mutation; no evidence of PIK3CA/AKT1/PTEN mutations

DISCUSSION QUESTION

What is the rationale for your selection of treatment in this patient?

Claudine Isaacs, MD: For this patient who’s progressed after more than 12 months with an ESR1 mutation and HER2-low disease with no mutation or alteration in the PI3 kinase AKT pathway, would you choose elacestrant, T-DXd, everolimus and endocrine therapy, fulvestrant and abemaciclib [Verzenio], other chemotherapy, or something else?

Soren Caffey, MD: My option is elacestrant, if I’m getting the case correctly with the ESR1 mutation and at the time of progression, more than 12 months on first line therapy. I don’t know what others’ thoughts might be.

Walid L. Shaib, MD: I thought the same. Patients who were exposed to elacestrant who had longer time on the CDK4/6 inhibitor had better progression-free survival [PFS], as opposed to the overall population that was discussed in the paper.¹ I will try to use the T-DXd maybe later on, at the time of progression.

Cesar Santa-Maria, MD, MSCI: I think elacestrant is a very reasonable option. Another option to consider is fulvestrant and abemaciclib. I’m not terribly impressed by the net improvement and PFS of either. But I’ve certainly seen some patients do well with that CDK4/6 inhibitor after CDK4/6 inhibitor approach, so I think that’s reasonable. You get a little more toxicity with it, though.

Rao Moravineni, MD: I’m not impressed with elacestrant as well…. I thought there would be much more benefit, however, [with the patient] being more than 3 years out of therapy…I would do elacestrant first.

Nagender Mankan, MD: I was leaning towards T-DXd, then elacestrant. I’ve never had a similar scenario, but I have had other patients with good response to T-DXd, even for 1+ IHC. I have very few patients with ESR1, much more within HER2 1+ IHC.

Isaacs: When you’re thinking about sequencing then in somebody like that, would you reach for T-DXd first or would you reach for elacestrant, or some other endocrine therapy at this point? Is there something in this patient that’s making you think about T-DXd first or at some point?

Mankan: I don’t know the data to compare the 2, but T-DXd response rate was more than the ESR1-based response rate [with elacstrant]….^1,2 I don’t know how that plays a role, but my heart is [leaning] towards T-DXd.

Ming Chi, MD: I personally would prefer the elacestrant over T-DXd in this situation, only because it’s a slow progression and it seems like the newer lesions are not a high disease burden. Otherwise, after a year or so, if the disease progression is dramatic, I’d probably want to jump to T-DXd, because I am not comfortable with elacestrant in that situation.

Isaacs: The thing that we’re always grappling with and trying to figure out the best thing to do in this country, where we have access to so many different agents, is the best way to sequence them. I think we would all agree that with a patient like this with an ESR1 mutation and HER2-low disease, we have lots of options. I personally would reach for elacestrant first in this patient, because she has an ESR1 mutation and because she’s had an appropriate and good response to endocrine therapy plus a CDK4/6 inhibitor, and T-DXd would certainly be in the next line or a further down line of therapy for this patient, given the data that are out there on T-DXd and its activity.²

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_{DISCLOSURES: Isaacs previously reported consulting role for Arvinas, AstraZeneca, Genentech, Novartis, Pfizer, Gilead Sciences, Merck, and Seattle Genetics, and receiving royalties from Wolters Kluwer (UptoDate), and McGraw-Hill (Goodman and Gillman).}

_{Santa-Maria previously reported a consulting or advisory role for Polyphor, Genomic Health, Halozyme, Bristol Myers Squibb, Athenex, Seattle Genetics, Merck, and Pfizer.}

_References:

_{1. Bidard FC, Kaklamani VG, Neven P, et al. Elacestrant (oral selective estrogen receptor degrader) versus standard endocrine therapy for estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: Results from the randomized phase III EMERALD trial. J Clin Oncol. 2022;40(28):3246-3256. doi:10.1200/JCO.22.00338}

_{2. 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}