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Present and Future Treatments in Advanced Breast Cancer: The Antibody Drug Conjugates

Presentation by Dr Kevin Kalinsky, Emory Clinic, School of Medicine



At the 2024 University of Kansas Breast Cancer Year in Review presented by Total Health, Dr Kevin Kalinsky from Emory Clinic, School of Medicine presented on the topic of antibody drug conjugates, or ADCs, which are rapidly becoming an integral component in the treatment paradigm for patients with advanced or metastatic breast cancers.  ADCs are a type of cancer treatment that incorporates an antibody molecule, which targets a specific cell surface molecule that is present on the cancer cell (the “target”), linked to a cytotoxic drug (the “payload”) that, only upon being internalized and entering the cancer cell, causes cell death, and in some cases, death of the surrounding cancer cells as well (the latter attribute is called a “bystander effect”). 


Metastatic Breast Cancers: An Evolving Treatment Landscape


Dr Kalinsky noted the evolution of ADC therapies, beginning a little more than a decade ago, with the introduction in 2013 of trastuzumab emtansine (T-DM1) which targets breast cancers having positive expression of the cell surface marker human epidermal growth factor receptor 2 (HER2).  This was followed in 2019 and 2020 with the respective approval of the next-generation ADCs trastuzumab deruxtecan (T-DXd) for HER2 positive (HER2+) metastatic breast cancer (mBC) and sacituzumab govitecan (SG) for breast cancers that lack expression of estrogen (ER) and progesterone (PR) receptors, as well as HER2 (called triple negative breast cancers or TNBCs).  Notably, T-DXd and SG have distinct targets (HER2 and Trop2, respectively) and also different payload molecules, and SG also differs in its target molecule as compared with T-DM1.  Dr Kalinsky noted some of the current unresolved issues regarding ADCs, specifically, the need for biomarkers, or measurable molecular markers that can more definitively identify patients who will respond to ADC therapy, and the issue of how are these ADC therapies best used in a sequential manner (i.e., can you use one type of ADC therapy after another without loss of efficacy).


HER2 Low Metastatic Breast Cancers


Dr Kalinsky also highlighted the emerging concept of what are known as “HER2-Low” breast cancers, which essentially express lower (but still detectable) levels of HER2, as defined by specific molecular testing criteria.  Breast cancers that lack expression of ER and PR are considered as hormone receptor negative (HR-), while those which do express both of these receptors are referred to as hormone receptor positive (HR+), and Dr Kalinsky noted current estimates that about 63% and 34% of HR+ and TNBC patients, respectively, may also be designated as HER2-Low.


Trastuzumab Deruxtecan (T-DXd)


Trastuzumab deruxtecan, or T-DXd, was originally approved for patients having HER2+ disease, and some of the molecular characteristics of T-DXd are shown in BOX 1. Dr Kalinsky reviewed the key clinical findings for T-DXd, specifically the phase III Destiny-Breast03 trial, that examined the efficacy of T-DXd or T-DM-1 as a second line (2L) treatment for patients with HER2+ mBC. In this study, T-DXd outperformed T-DM1 with a more than doubling in the median progression-free survival (mPFS) at 12 months (75.8 versus 34.3 months), a result which Dr Kalinsky called “impressive”. 

Box 1. About Trastuzumab Deruxtecan (T-DXd)

Target

Payload Type

Drug to Antibody Ratio

Mechanism of Action

HER2

Deruxtecan

(Topoisomerase I Inhibitor)

8:1 (8 molecules of the payload/antibody molecule)

Binds to HER2 positive cell; becomes internalized; payload is released and causes cell death

In Destiny-Breast04, the use of T-DXd was compared with a chemotherapy treatment of physician’s choice (TPC) for patients with HER2-Low mBC.  The results for PFS showed significant benefit of T-DXd over TPC, with a more than doubling in both the HR+ patients, as well as in the overall population (BOX2).  Even more importantly, T-DXd was associated with a significant improvement in overall survival (OS) as compared with TPC (BOX3).


Box 2. Efficacy of T-DXd Over TPC in the Destiny-Breast04 Trial: Updated PFS Results in HR+ and All Patients

Treatment

HR+ Patients

All Patients

T-DXd

9.6 mo

8.8 mo

TPC

4.2 mo

4.2 mo

Box 3. Efficacy of T-DXd Over TPC in the Destiny-Breast04 Trial: Updated OS Results in HR+ and All Patients

Treatment

HR+ Patients

All Patients

T-DXd

23.9 mo

22.9 mo

TPC

17.6 mo

16.8 mo

In terms of adverse events (AEs), Dr Kalinsky noted the principal AE of nausea, which, at his institution is treated prophylactically with fluids and antinausea medications.  Other AEs which can occur include neutropenia, hair loss (alopecia, seen in some), fatigue, as well as pneumonitis and interstitial lung disease (ILD).   Pneumonitis and ILD, in particular, had been associated with some deaths in the initial studies of T-DXd, however, with increasing clinical awareness and established management protocols, the incidence of serious AEs of this type has been decreasing.


Dr Kalinsky then reviewed results from the DAISY trial, which examined the use of T-DXd or TPC for patients with even lower levels of HER2 (“HER20”).  Results from this trial for best overall response (BOR) and PFS showed responses across a range of HER2 expression levels, including patients with HER20 status (BOX4), and there was a significant difference (P<0.0001) among the groups with respect to BOR and PFS according to HER2 expression.  Dr Kalinsky noted T-DXd is not currently approved in the HER2-0 setting, and that, importantly, patient’s HER2 status in the trial was assessed by biopsy just prior to receiving T-DXd treatment. 


Box 4. BOR and PFS Results from the DAISY Trial According to HER2 Expression

HER2 Group

BOR

PFS

HER2+

71.0%

11.1 mo

HER2-Low

37.5%

6.7 mo

HER2-0

30.0%

4.2 mo

BOR and PFS rates are different between the cohorts (P<0.0001)


In view of the results of DAISY, Dr Kalinsky reviewed the study design for Destiny-Breast06, which aims to evaluate the efficacy of T-DXd in the HER2 “ultralow” population.  Some of the main differences of this trial from Destiny Breast04 are the inclusion of only HR+ patients, a larger sample size (N=850 patients), the inclusion of the HER2 ultralow patients, and also those who have never received chemotherapy for their disease (chemo-naïve group).  As the trial has the potential to expand the use of T-DXd to a larger number of patients, these results are eagerly awaited.


Dr Kalinsky briefly noted some other ADCs currently under investigation in the HER2-Low setting, including trastuzumab duocarmazine (no longer in development) and disitamab vedotin, which have shown overall response rates (ORRs) of 28% and 40%, respectively, in early studies.  Of note, these two agents have the same target as T-DXd (HER2), but distinct payloads. 


Sacituzumab Govitecan (SG)


Dr Kalinsky then reviewed data for sacituzumab govitecan (SG), which differs in both its target and payload from T-DXd (BOX5), and like T-DXd, SG also has a bystander effect that results in the death of neighboring cancer cells.  SG was approved for use in TNBC based on earlier studies, and also showed activity in patients with HR+ breast cancers.  The TROPiCS-02 trial evaluated the use of SG as compared with chemotherapy TPC in patients with HR+/HER2- mBC, with the primary endpoint of PFS.  Importantly, Dr Kalinsky noted that patients in this trial were more heavily pre-treated (i.e., more treatment resistant) with at least 2 and up to 4 lines of prior therapy, as compared to the population of Destiny-Breast04 (1-2 prior lines). Results from TROPiCS-02 showed a significant benefit of SG over TPC both in PFS and OS, and notably, there was a similar benefit in PFS for patients with HER2-Low or HER2-0 expression. In terms of SG associated AEs, Dr Kalinsky noted neutropenia, nausea, vomiting, fatigue, and alopecia.  He also highlighted a number of trials currently ongoing which are examining the use of SG for patients with early and late stage metastatic TNBC as well as in combination with other agents such as immunotherapy.

Box 5. About Sacituzumab Govitecan (SG)

Target

Payload Type

Drug to Antibody Ratio

Mechanism of Action

Trop2

SN38

(Topoisomerase I Inhibitor)

7.6:1 (7.6 molecules of payload/antibody molecule)

Binds to Trop2 positive cell; becomes internalized; payload is released and causes cell death

Datopotamab Deruxtecan (Dato-DXd)


Datopotamab deruxtecan (Dato-DXd) is another anti-Trop2 ADC currently under investigation in HR+/HER2- mBC, which Dr Kalinsky expects will likely gain approval, based on the results of the TROPION-Breast01 trial.  Notably, this trial enrolled a similar population as Destiny-Breast04, with patients having received 1 to 2 prior lines of treatment (i.e., a less heavily pre-treated/less treatment resistant patient population as compared to TROPiCS-02). There was significant improvement in both PFS as well as time to subsequent therapy with Dato-DXd versus TPC. Dr Kalinsky noted the important AE of stomatitis (inflammation of mucosal tissues such as the mouth and lips) with this agent and encouraged the use of a prophylactic oral steroid rinse and ice chips to help alleviate this event in patients on Dato-DXd.  He also noted several ongoing trials with Dato-DXd, either alone or in combination with immunotherapy, both in the late-stage setting (metastatic TNBC) and in early stage TNBC.


What’s Next for ADCs?


One of the key unresolved issues with the use of ADCs in clinical practice is how best to use them in a sequential manner (i.e., if a patient relapses on one ADC, which ADC to choose next?), and Dr Kalinsky reviewed some initial data to show that, regardless of sequence (i.e., using T-DXd or SG first followed by the other) the first ADC used generally gives the better response compared to the second (as would be expected).  In view of these results, he further noted that T-DXd and SG share neither the same target nor the same payload, and registry studies which are currently underway, to better assess and document outcomes in patients who receive these (or other) ADCs, and when they receive them in the course of their treatment.


Studies are also underway to evaluate the cellular mechanisms by which tumors can develop resistance to ADC therapy, for example, by decreasing expression of the antibody target (e.g., HER2) on the cell surface and thereby escaping the drug’s action, or by molecular alterations within the cancer cells that allow them to become resistant to the payload toxin, once it has been internalized.  Trials are also underway that combine ADCs with other anti-cancer agents such as immunotherapy in patients with mBC, and Dr Kalinsky briefly noted results from the BEGONIA trial combining Dato-DXd with durvalumab immunotherapy which has shown an ORR of up to 79%.  Novel ADCs with new targets and payloads are also under development and currently being investigated in patients with advanced breast cancer, including patritumab deruxtecan, an ADC targeting HER3, and two ADCs targeting another cell surface molecule called B7-H4.  With additional ADC approvals, expanded indications for existing ADCs, and the growing potential for combination therapies expected in the coming years, there will be a growing need for biomarkers to better select which mBC patients will benefit from which therapies, and when they should be used in the course of treatment.

 

Speaker Disclosure Information: Dr Kalinsky reported the following disclosures: Spouse, Stock: EQRX (Prior Employee), ADC Therapeutics; Advisory/Consulting: Genentech/Roche, Immunomedics, Seattle Genetics, AstraZeneca, Daiichi Sankyo, Puma Biotechnology, Mersana, Menarini Silicon Biosystems, Myovant Sciences, Takeda, Merck.

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