eCase - HER2 Low Advanced BC: Module

CME

Pushing the Boundaries of Unresectable or Metastatic HER2-Low Breast Cancer Treatment: New Insights and Innovations

Physicians: Maximum of 0.75 AMA PRA Category 1 Credit™

Released: January 26, 2024

Expiration: January 25, 2025

Sara M. Tolaney, MD, MPH

CME/CE Information

Activity

Progress

1 2

Course Completed

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Treatment of Unresectable or Metastatic HER2-Low Breast Cancer Overview Role of T-DXd in HER2-Low Advanced Breast Cancer Novel and Emerging Strategies for HER2-Low Breast Cancer Conclusions References

BEGONIA: Phase Ib/II Trial of Durvalumab Combinations in Advanced TNBC—Updated Results

With the new availability of T-DXd for patients with HER2-low unresectable or metastatic breast cancer, one wonders about the potential future strategies that could be taken. A future approach is the use of combination therapy and there are ongoing studies investigating different T-DXd-based combinations.

BEGONIA is an open-label phase Ib/II trial of the anti–PD-L1 antibody durvalumab in combination with other agents for untreated patients with locally advanced or metastatic triple-negative breast cancer. Intriguing preliminary results from BEGONIA among patients with HER2-low expressing tumors assigned to receive durvalumab plus T-DXd were recently reported.¹⁶ Durvalumab plus T-DXd resulted in a confirmed ORR of approximately 70% among patients with HER2 IHC 1+ triple-negative breast cancer and an ORR of 38% among those with HER2 IHC 2+/ISH- disease.

We will need more data to better understand what the benefits of this combination could be and how to think about this combination based on PD-L1 status. These preliminary results are impressive and make the combination worthy of further study.

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DESTINY-Breast08: Trial of T-DXd Combinations in HER2-Low Advanced Breast Cancer

DESTINY-Breast08 is a nonrandomized phase I trial investigating different T-DXd–based combinations in patients HR-positive and HR-negative HER2-low advanced breast cancer. The T-DXd–based combinations that will be studied include endocrine therapy (anastrozole, fulvestrant) as well as targeted therapy (durvalumab, capivasertib) and even chemotherapy (capecitabine) (NCT04556773). This trial will help to determine if the benefit of T-DXd can be maximized with the use of a combination treatment approach.

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Phase II DAISY Trial: Best Overall Response According to HER2 Expression Levels With T-DXd in Metastatic BC

Another important question is whether or not T-DXd can benefit patients with HER2 IHC 0 disease. Given the promising data from the DAISY trial that demonstrated a 30% ORR in patients with HER2 IHC 0 with a duration of response of 6.8 months and a median PFS of 4.2 months, these result are attractive and promising, and the benefit of T-DXd among patients with HER2 IHC 0 disease needs to be explored further.¹⁷ By so doing, we will be able to better understand exactly how low we can go with HER2 expression and still achieve meaningful clinical benefit from T-DXd.

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DESTINY-Breast06: T-DXd in Chemotherapy Naive and HER2-Ultralow Advanced/Metastatic Breast Cancer

The ongoing randomized phase III DESTINY-Breast06 trial is investigating the efficacy and safety of T-DXd vs physician’s choice of chemotherapy (capecitabine, paclitaxel, or nab-paclitaxel) in patients with HR-positive, advanced or metastatic breast cancer after progression on 2 previous endocrine therapies (NCT04494425). Patients with HER2-low disease are eligible to enroll on the study, as are patients with HER2-ultralow (IHC >0 and <1+) disease. The primary endpoint is PFS by blinded independent central review in patients with HER2 IHC 1+ or IHC 2+. DESTINY-Breast06 will help in the determination of how low we can go with HER2 expression for patients with advanced HR-positive breast cancer to derive benefit from T-DXd.

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Future of HER2-Low Breast Cancer

The future is promising for patients with HER2-low advanced breast cancer, but I think we need to find more sensitive and more quantitative assays for the optimal determination of HER2 expression levels in tumor cells so that all patients with the potential to benefit from T-DXd are able to receive optimal therapy for their disease.¹⁸

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CNS Activity of T-DXd in Patients With Breast Cancer

It is also known that patients with HER2-positive breast cancer unfortunately have high rates of central nervous system (CNS) metastases. On this basis, it is important to determine if T-DXd is effective within the CNS.

To date, several trials have shown that T-DXd elicits robust activity within the brain. The TUXEDO-1 trial demonstrated a very high intracranial ORR (ORR-IC) of 73.3% with T-DXd in a cohort of patients with HER2-positive breast cancer and active brain metastasis.¹⁹ We have also seen data from the DEBBRAH trial that showed ORR-IC of approximately 44% with T-DXd in patients with HER2-positive or HER2-low breast cancer and active CNS metastasis.²⁰ In a multicenter, retrospective cohort study of patients with HER2-positive breast cancer and stable or active brain metastasis, the ORR-IC was 73% with T-DXd.²¹ However, these are all small cohort studies and we need more definitive data to validate these results.

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DESTINY-Breast12: T-DXd in HER2-Positive Metastatic Breast Cancer ± Brain Metastasis

DESTINY-Breast12 will shed more light on the efficacy of T-DXd in patients with HER2-positive advanced breast cancer with brain metastasis. DESTINY-Breast12 is an open-label, multicenter phase IIIb/IV study of T-DXd for previously treated patients with unresectable/advanced or metastatic HER2-positive breast cancer with or without brain metastasis at baseline (NCT04739761). The primary endpoints are ORR and PFS in patients with brain metastasis at baseline. The study has completed enrollment (N = 506), and I am hoping to see the data from this study soon.

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TUXEDO-4: T-DXd for Patients With HER2-Low Breast Cancer

TUXEDO-4 is a single-arm phase II study of T-DXd for patients with HER2-low breast cancer with newly diagnosed or progressive CNS metastasis without indication for immediate local therapy (NCT06048718). TUXEDO-4 is another study to look out for with regard to ascertaining the benefits of T-DXd in patients with HER2-low breast cancer and brain metastasis.

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Pooled Analysis of 2 Phase I Trials of Disitamab Vedotin in Patients With HER2-Low Advanced BC

In addition to studies with T-DXd, other HER2-directed ADCs are also under investigation. Disitamab vedotin (RC-48) is a novel HER2-directed ADC comprising hertuzumab, an anti-HER2 monoclonal antibody, conjugated to a cytotoxic monomethyl auristatin E (MMAE) payload via a cleavable linker.²² Pooled analysis of data from 2 phase I trials of disitamab vedotin in patients with HER2-low advanced breast cancer showed 40% ORR in the HER2-low metastatic breast cancer setting, with a median PFS of 5.7 months.²³

Given the MMAE cytotoxic payload with this agent, the toxicity profile is different from that seen with T-DXd. The most common adverse events observed with disitamab vedotin were elevated alanine transaminase, elevated aspartate transaminase, hypoesthesia and hematologic toxicities. Disitamab vedotin is currently being investigated in the phase III ROSY trial for patients with HR-positive/HER2-low metastatic breast cancer (NCT05904964).

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Select HER2-Directed Therapies in Development in Breast Cancer

There are multiple other HER2-directed agents in development for patients with breast cancer, including other novel ADCs, bispecific antibodies, tyrosine kinase inhibitors, and a peptide vaccine. The HER2-directed ADCs under investigation include anvatabart opadotin (ARX788), ORM-5029, MRG002, SHR-A1811, and DP303c. With so many HER2-directed agents on the horizon, it is likely that some will emerge in the future for patients with HER2-low breast cancer.

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TRIO-US B-12 (TALENT): Neoadjuvant Trial for HER2-Low BC

Finally, an outstanding question is whether we can use T-DXd earlier in the treatment setting for patients with HER2-low breast cancer. In the early breast cancer setting, the phase II TRIO-US B-12 (TALENT) neoadjuvant trial is investigating T-DXd with or without anastrozole for patients with untreated HR-positive/HER2-low operable stage II/III breast cancer (NCT04553770). We have seen some data emerge from this study suggesting that some patients achieved tumor shrinkage with upfront T-DXd. Certainly, more studies need to be conducted in this space to be able to understand how T-DXd may work in early-stage HER2-low breast cancer.²⁴

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