CME
Physicians: Maximum of 0.25 AMA PRA Category 1 Credit™
Released: October 13, 2023
Expiration: October 12, 2024
HER3 in Breast Cancer
Numerous ADCs have shown great efficacy for the treatment of breast cancer in recent years. Of note, HER2-targeting agents changed the therapeutic landscape for patients with HER2-positive disease. Now, a relatively neglected member of the HER family, HER3, is coming into the light in terms of therapeutic potential. HER3 is known as a crucial heterodimeric partner for HER2 that does not itself have significant kinase activity.1 In the preclinical setting, HER3 can foster tumor progression through heterodimerization with other receptor tyrosine kinases in the EGFR/ERBB family, namely, EGFR (HER1), HER2, and HER4. HER2 is its preferred heterodimeric partner, and it has been shown to mediate acquired resistance to HER2-targeted therapies and contribute to treatment failure.2 Approximately 30% to 50% of breast tumors overexpress HER3, which is associated with poor prognosis.
ADC Landscape in Breast Cancer
Trastuzumab emtansine (T-DM1) pioneered the ADC space in breast cancer with its approval 10 years ago and is still a key therapy for patients with HER2-amplified disease.3 T-DM1 was first approved for patients with residual invasive disease following neoadjuvant therapy based on results from the KATHERINE trial and it remains a key adjuvant modality.4 In the metastatic setting, trastuzumab deruxtecan is now commonly used as a second-line therapy for HER2-amplified or HER2-low disease.5 In addition, the TROP-2–targeting ADC sacituzumab govitecan is approved for patients with triple-negative or hormone receptor (HR)–positive/HER2-negative breast cancer.6 ADCs currently in clinical trials include patritumab deruxtecan, which we will discuss in more detail, and another very interesting TROP-2–targeting agent called datopotamab deruxtecan.
Central to the ADC structure is the antibody that recognizes the target.7 This antibody is connected through a specifically designed linker to a highly potent cytotoxic agent as payload to achieve the goal of specific targeted delivery. Once the ADC reaches the cell surface, it binds to its receptors and is internalized through endocytosis. pH changes within the lysosome cause the linker to be cleaved and the free drug to be released into the cell. Upon death of this host cell, this cytotoxic agent can be further released to the microenvironment causing adjacent cell death.
Phase I/II Trial of Patritumab Deruxtecan in Previously Treated Patients With HER3+ MBC
The initial study of patritumab deruxtecan, the first HER3‑targeting ADC in development, was presented by Krop and colleagues8 at ASCO in 2022. This agent uses the deruxtecan payload with a drug:antibody ratio of 8:1. This multicenter, open‑label, multicohort phase I/II trial enrolled patients with advanced, unresectable, metastatic breast cancer that was HER3 positive, defined as immunochemistry (IHC) 2+ or 3+ for the dose escalation and dose finding cohorts and ≥25% membrane positivity for the dose expansion cohorts. The HR-positive/HER2-negative cohort was heavily pretreated with 2-6 prior lines of chemotherapy (CT) and the triple-negative cohort less so, with 1-2 prior lines.
The dose levels tested in this early phase I trial began at 1.6 mg/kg through 8 mg/kg given IV once every 3 weeks. The dose expansion phase examined 3 populations with approximately 20-30 patients in each. The first 2 cohorts had high HER3 expression and were either HR‑positive/HER2‑negative or triple negative, and the third cohort was HR-positive/HER2‑negative but with low HER3 expression.
The coprimary endpoints were safety and response rate.
Patritumab Deruxtecan in HER3+ MBC: Efficacy
The aggregated dataset showed a confirmed overall response rate (ORR) of 28.6%.8 To break this down into individual cohorts, the HR-positive/HER2-negative cohort including 113 patients with either high or low HER3 expression had an ORR of 30.1% and median overall survival of 14.6 months. The 53 patients with triple-negative disease had an ORR of 22.6% and a median overall survival of 14.6 months, and the 14 patients HER2-positive disease had an ORR of 42.9% and a median overall survival of 19.5 months. Both of these latter cohorts contained only patients with high HER3 expression.
Patritumab Deruxtecan in HER3+ MBC: Response by Subtype
The waterfall plots show individual tumor responses in each population.8 Of interest, for the HR-positive/HER2-negative group containing patients with different levels of HER3 expression, you can see responses in both HER3 low and high populations.
This raises the clinically relevant question: Does expression level really matter when treating with a HER3-targeted agent?
Patritumab Deruxtecan in HER3+ MBC: Pretreatment HER3 Membrane Expression by Response
This slide further shows that HER3 expression does not clearly predict response to HER3-targeted treatment.8 The figure demonstrates responses over a broad range of baseline HER3 membrane expression, and additional data not shown here found that changes in HER3 expression level over time also did not associate with clinical activity. This echoes the recent finding for HER2 in the French DAISY trial that patients with HER2-zero expression actually showed a response rate of 30% when treated with trastuzumab deruxtecan.9 Clearly, the question of how receptor expression level may correspond to the level of treatment benefit experienced by patients needs to be explored further. It may be that HER2 IHC (which has been the model for HER3 IHC) was initially designed to recognize patients with high expression to benefit from treatment with naked antibodies, but now that boundary needs to be redefined to identify a population who will benefit from ADCs. This may be a refinement of the IHC assay or another assay entirely.
Patritumab Deruxtecan in HER3+ MBC: Efficacy by Subtype
This subanalysis further divides the HR‑positive/HER2‑negative and triple-negative cohorts into HER2-zero (IHC 0) vs HER2-low (IHC 1+ or IHC 2+ with negative in situ hybridization).10 Because HER3 dimerizes with HER2, it was suspected that patients’ HER2 expression might influence the clinical activity of the HER3-targeting agent. In 58 patients who were defined as HR-positive/HER2-low, response rate was 36.2% and median progression‑free survival (PFS) was 5.8 months. In the HR‑positive/HER2‑zero population of 39 patients, the ORR was 28.2% and median PFS was 8.2 months. Similarly, in patients with triple‑negative breast cancer, response rate was 20.7% and median PFS was 4.4 months in patients with HER2-low breast cancer vs an ORR of 26.3% and median PFS of 8.4 months in patients with HER2-zero disease. The authors concluded that patritumab deruxtecan showed similar activity in patients with HER2-low vs HER2-zero expression.
Phase II Trial of Patritumab Deruxtecan in Previously Treated HER2- MBC
The next study of patritumab deruxtecan is the multicenter phase II study with partial results presented by Hamilton and colleagues11 at ASCO 2023. Part A, which has reported results, enrolled only patients with HER2-negative locally advanced or metastatic breast cancer but had no requirement for HER3 expression. Patients with HR-positive disease had received 1 prior line of a CDK4/6 inhibitor and 2 or fewer lines of prior CT, with no limitation on prior endocrine therapy. The triple-negative cohort allowed 1-3 lines of CT. Sixty patients received patritumab deruxtecan 5.6 mg/kg every 3 weeks. Coprimary endpoints were ORR and 6-month PFS rate, but PFS data were not mature for this presentation.
Patritumab Deruxtecan in HER2- MBC: Baseline Characteristics
These patients were relatively heavily pretreated; approximately 60% received 3 or more prior regimens for metastatic disease.11 Although HER3 expression was not an enrollment criterion, the majority of patients (63.8%) showed HER3 expression ≥75% at baseline, only 4 patients (8.5%) had expression <25%, and the remainder (27.7%) fell between 25% and 74% HER3 expression. It is also worth noting that 39.6% of this trial population had triple-negative disease.
Patritumab Deruxtecan in HER2- MBC: Response by Receptor Expression
ORR was 35%, which in this heavily pretreated population is quite interesting.11 Response rate varied across HER3 expression levels; the small patient numbers in some of these subgroups do not allow much of a conclusion to be drawn about any association, but the take-home message is that responses were seen at all levels of HER3 expression, as was true for the previous study.
The response rates for patients with triple-negative breast cancer ranged between 18% to 20%.
Patritumab Deruxtecan in HER2- MBC: Safety and Dosing
Regarding the safety profile, patritumab deruxtecan appears to be relatively well tolerated, with gastrointestinal AEs predominating.11 Any‑grade nausea was experienced by 50% of patients and any-grade diarrhea by 36.7%, but grade 3/4 toxicities were low: nausea, 3.3%; diarrhea, 5.0%; vomiting, 1.7%. Considering the well-documented risk of interstitial lung disease with trastuzumab deruxtecan,12 that is something to watch for closely in clinical trials of this similar ADC, but among the 60 patients treated here, only 1 patient developed interstitial lung disease. This rate of 1.7% does not suggest excessive concern regarding pulmonary toxicity with this agent.
SOLTI TOT HER3: Preoperative Patritumab Deruxtecan for Early-Stage HR+/HER2- Breast Cancer
Finally, here is a quick overview of SOLTI‑TOT‑HER3, a Spanish window-of-opportunity trial studying a single dose of patritumab deruxtecan in the neoadjuvant setting for patients with HR-positive/HER2-negative breast cancer.13
The primary outcome measure used was CelTIL, which is a combined marker of immunogenicity based on stromal tumor-infiltrating lymphocytes and tumor cellularity. This surrogate marker was developed to assess early response to HER2-directed therapy and has found that biopsy levels measured 2 weeks after initiating neoadjuvant therapy can predict outcomes at 5 years.14 Here, CelTIL was seen to increase from baseline to Day 21 after treatment with patritumab deruxtecan, and this increase was much more pronounced in patients who showed tumor responses. This overall clinical response rate of 45% is itself notable in an HR-positive/HER2-negative population who do not tend to do well with neoadjuvant conventional CT. Again, HER3 expression, which in this trial was assessed by mRNA rather than protein IHC, did not show any association with either response or CelTIL score.
Ongoing Trials of HER3-Targeted Agents in Breast Cancer
This table shows the many ongoing trials of patritumab deruxtecan. The first 2 rows are the studies with data reports already covered earlier, which are continuing to treat and follow up patients. The second trial led by Dr Hamilton is continuing to enroll several subtypes of patients for different study cohorts. In addition, numerous newer trials are enrolling or will begin enrolling soon.
ICARUS-BREAST01, a French single-arm phase II trial in patients with advanced HR-positive/HER2-negative breast cancer that has been previously treated, has reported some early results not covered in this module and is still enrolling patients.15 Several trials are examining outcomes with neoadjuvant patritumab deruxtecan plus endocrine therapy vs CT: SOLTI-VALENTINE compares the combination of patritumab deruxtecan and endocrine therapy to traditional CT in patients with HR-positive/HER2-negative breast cancer at high risk for recurrence. PARAMETer study examines the impact of a single dose of patritumab deruxtecan prior to surgery for brain metastases, which is very interesting because this is an understudied population. And SOLTI-TOT‑HER3, which was covered briefly here, looks at CelTIL score as a biomarker in early‑stage HR-positive/HER2-negative breast cancer. Beyond patritumab deruxtecan, the HER2/HER3 bispecific antibody zenocutuzumab is in clinical development for many solid tumor types and seems to be focusing on non-small-cell lung and pancreatic cancers, but the eNRGy trial is open to patients with any solid tumor, including breast cancer, with an NRG1 gene fusion.
Final Thoughts
To summarize, the wide expression of HER3 in breast cancer seems to make it a promising therapeutic target, regardless of the level of expression seen in an individual patient. We are eagerly anticipating further data with patritumab deruxtecan and will likely see more data from zenocutuzumab and other HER3 agents across solid tumor types in the future.
In considering the future of HER3-targeting agents for breast cancer, the major question will be one of sequencing this new option within the existing landscape of targeted agents including multiple ADCs. Healthcare professionals would benefit from state-of-the-art tools to individualize therapeutic decisions in consideration of each patient’s prior treatment exposures and current disease characteristics. Patients will ask, “What is my best option?” and at this point, it would be difficult to answer with certainty, so that is a large need in this space. For example, if a patient has progressed on trastuzumab deruxtecan, should biopsy or another functional analysis be performed, and how should those results be interpreted? Does initial response to the previous agent matter? Is there any loss of efficacy with ADC after another ADC, meaning that conventional CT should be used before another targeted agent? What are the resistance mechanisms to ADCs? Would it be efficacious to rechallenge the same target with a different payload, such as datopotamab deruxtecan after progression on sacituzumab govitecan? All of these open questions lead to a lot of uncertainty in clinical use, so this space will continue to be very interesting as research continues.
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