Emerging Data Behind 2 Antibody Drug Conjugates for Breast and Prostate Cancer

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Experts addressed ARX788 for patients with HER2-positive breast cancer, and a data update from the update for APEX-01 evaluating ARX517 in patients with prostate cancer was provided during a virtual analyst and investor day.

Two antibody drug conjugates (ADCs), ARX788 and ARX517, are being further investigated to address unmet medical needs for patients with breast cancer and prostate cancer.1

During the virtual analyst and investor day on February 24, 2023, experts, including Hope S. Rugo, MD, FASCO, and Paula R. Pohlmann, MD, MS, PhD, discussed what has already been seen with ARX788 for patients with HER2-positive metastatic breast cancer, and what their expectations are for the agent moving forward.

Then, the first-in-human APEX-01 trial (NCT04662580) was highlighted, and the role of ARX517 for patients with prostate cancer, a proprietary anti-PSMA ADC, was discussed.

ARX788

While trastuzumab deruxtecan (Enheurtu; T-DXd) has shown benefits in patients with breast cancer, data has shown that 24.2% of patients progress while on the agent within 12 months. At 12 months, the progression-free survival (PFS) was 75.8 months (95% CI, 69.8-80.7) with T-DXd and 34.1 months (95% CI, 27.7-40.5) with trastuzumab emtansine (Kadcyla; T-DM1) with a hazard ratio for disease progression of .28 (95% CI, 0.22-0.37; P < .001). As a result, researchers believe ARX788 may potentially fill this gap.

ARX788 is a homogeneous and highly stable ADC targeting the HER2 receptor. It consists of 2 cytotoxic payloads site-specifically conjugated to a trastuzumab (Herceptin)-based antibody, and was developed for maximum performance in the preclinical setting by optimizing the number, position, and chemical bounds conjugating the cytotoxic AS269 payload to the antibody.

In 2021, the FDA granted a fast track designation to ARX788 as a single-agent for patients with advanced or metastatic HER2-positive breast cancer who received at least 1 prior anti-HER2 regimen in the metastatic setting.

“In advanced disease, ARX788 offers us some additional advantages, which is that it delivers a toxin or payload, which patients will not have seen. It has a different mechanism of action than the toxin that's attached to [trastuzumab deruxtecan]. I think that has a big benefit. In addition, the toxin in itself is highly potent, which means that you can deliver a fairly small amount of toxin per antibody drug conjugate in order to have efficacy. Then, there's a high uptake of the antibody drug conjugate within the tumor cell,” Rugo, director of breast oncology and clinical trials at the University of California, San Francisco, said during the meeting.

Rugo is a co-investigator on the ACE-Breast-03 clinical trial (NCT04829604). This trial is a phase 2 study evaluating ARX788 in patients with HER2-positive metastatic breast cancer whose disease is resistant or refractory to T-DM1, and/or T-DXd, and/or tucatinib-containing regimens.2

Previously, the ACE-Breast-01 trial confirmed there to be an ORR of 16 of 29 (66%) patients with HER2-positive breast cancer who were treated with ARX788. The disease control rate (DCR) observed was 100% in the 1.5 mg/kg cohort. This study showed ARX788 to be generally well-tolerated with most adverse events being grade 1 or 2 and manageable.

Now, ACE-Breast-03 is a global, single arm, phase 2 study evaluating the anticancer activity and safety of ARX788 in patients with metastatic HER2-positive breast cancer in patients whose disease is resistant/refractory to T-DM1, and/or T-DXd, and/or tucatinib-containing regimens, and who have adequate organ function.2,3

In the safety lead-in portion of the trial, 20 patients will be randomized between 2 doses (1.6 mg/kg or 1.7 mg/kg every 3 weeks). Once the recommended phase 2 dose is determined, 200 patients with advanced HER2-positive breast cancer will be enrolled in the main study.

Investigators are assessing efficacy using RECIST 1.1 via imaging every 6 weeks and evaluate the primary end point is ORR, along with secondary end points of duration of response (DOR), best overall response, DCR, PFS, and overall survival (OS). Safety and tolerability will also be assessed.

At the time of the data cutoff, 7 patients were enrolled in the study who previously were treated with T-DM1 and received a median of 5 prior lines of therapies. Four out of the 7 patients were previously treated with HER2 tyrosine kinase inhibitors (TKIs), and the median age of those enrolled was 59 years.

Preliminary findings from phase 2 of the ACE-Breast-03 study were presented at the 2022 San Antonio Breast Cancer Symposium and demonstrated a 57.1% confirmed ORR by RECIST v1.1 along with a DCR of 100% in heavily pre-treated patients with HER2-positive metastatic breast cancer treated with ARX788. The median time on therapy was 7.2 months and treatment remains ongoing.2

Additionally, none of the 7 patients had any drug-related serious adverse events (AEs) and all AEs were well-tolerated with no treatment discontinuations.

“We are encouraged by the response rates and safety results, particularly given the significant need for new therapies among patients whose disease continues to progress after receiving multiple lines of therapy,” stated Sara Hurvitz, MD, professor at David Geffen School of Medicine at UCLA, in a press release.

Then, Pohlmann, MD Anderson Cancer Center, discussed ARX788 in the I-SPY 2 trial (NCT01042379) which is a study evaluating new agents in combination with standard therapy in patients with stage II-III breast cancer and patients who are candidates for surgery.

The study uses a heavy clinical biomarker program to classify the different diseases in 10 subtypes of breast cancer. I-SPY 2 has the goal of identifying treatment strategies for different subsets of patients with breast cancer based on a patient’s molecular characteristics of their disease with high estimated pathological complete response (pCR) rate.4

“We're excited about the drug because it has a very specific construct in terms of the ADC. It has a specific location for the conjugation of the chemotherapy payload to the antibody, and it has a different payload than what the patients are typically exposed to. Our hope would be that we could get the patients to pCR without the need for exposure to, for instance, anthracyclines that have a lot of [adverse events],” stated Pohlmann. “We all respect our backbone chemotherapy, but if we could get more specific and less toxic agents to get the same results, that is what we would like to see. We felt that the ARX788 has this potential and that's why we decided to move forward on this line.”

As a result, a planned study design was discussed during the event. In this study, investigators will enroll approximately 30 patients with HER2-positive metastatic breast cancer that have progressed following T-DXd. Only patients who have had no more than 3 prior lines of therapy will be enrolled in the trial, and researchers want to ensure that the enrollment criteria includes only patients who have had recent assessments of HER2-positive status.

The study currently plans to utilize a 2:1 ratio to randomize patients to receive either ARX788 at 1.5mg every 3 weeks (n = 20) or the physician's choice of standard-of-care (n = 10). Enrollment is estimated to take approximately 18 months from the first patient dose. Investigators will evaluate the primary end point of ORR and the secondary end points of PFS, OS, and DOR.

If the data are compelling, next steps will be evaluated and could potentially lead to the commencement of a registration-enabled study. While efficacy has already been seen from previous data, research will need to see ARX788 specifically used in the population after T-DXd to see if efficacy is retained, according to Rugo.

“I'm excited about plan to reinvigorate ARX788 in patients with breast cancer, I think it has an important role, and I look forward to studying this in HER2-positive disease, as well as further exploration in patients who have HER2-low disease,” added Rugo.

ARX517

Researchers then moved on to discuss ARX517, the only PSMA-targeting ADC currently being tested in clinical trials in the United States. ARX517 is a fully humanized anti-PSMA ADC for patients with prostate cancer who have progressed on at least 2 prior FDA-approved treatments.5

“Recently, [177Lu-PSMA-617 [Pluvicto]], which is a radiopharmaceutical from our point of view, has validated PSMA, is a good and effective target in prostate cancer, and also established what we think is a meaningful commercial opportunity in the metastatic castration-resistant prostate cancer [mCRPC] patient population, which is great. Those are 2 terrific things. However, when we look at [177Lu-PSMA-617] and recognize that it's a radiopharmaceutical, we think that there may be some challenges or conversely, some advantages that ARX517, which is an infused ADC and not a radiopharmaceutical, may have [for patients with mCRPC],” said Daniel O’Connor, chief executive officer of Ambrx, during the event.

APEX-01, a first-in-human multicenter, dose-escalation and dose-expansion study, is evaluating the safety, pharmacokinetics, and preliminary anti-tumor activity of ARX517.

Enrollment in the trial is open to patients who have had at least 2 prior FDA-approved treatment options for prostate cancer and who have 1 of the following 3 criteria: PSA Progression defined by a minimum of 2 rising PSA values, radiographic progression by RECIST v1.1, or disease progression by the presence of new bone lesions.

The trial was a dose-escalation study and patients were evaluated to determine the safety of the agent. Patients were heavily pretreated with a median of 5 prior lines of therapy prior to enrollment in the study. In the dose-escalation portion, a 3+3 design was utilized, and 16-36 patients were dosed every 3 weeks at doses ranging from 0.32 mg/kg to 2.4 mg/kg.

In the dose-expansion phase, up to 40 patients were enrolled to determine the maximum tolerated dose and recommended phase 2 dose of the trial. Findings showed that since starting the study, there were PSA reductions of 30% or more observed in 1 or more patients in all previous cohorts starting at 0.64 mg/kg.

There were promising and early signs of safety and efficacy, no drug-related serious AEs were seen, and there were no dose-limiting toxicities (DLTs) observed in any cohort evaluated as of February 16, 2023.

In cohort 6 which enrolled patients with mCRPC given the 2.0 mg/kg dose, there were confirmed responses in the first 3 patients with a greater than 50% reduction in PSA levels. Two patients in his cohort had a reduction in PSA >90%. Additionally, 1 of these 3 patients had soft tissue measurable disease and experienced a partial response at the first on-treatment scan.

There have also been 3 patients treated in cohort 7 with no DLTs.

“Of the 22 patients evaluated for safety, there were no drug-related serious adverse events. No grade 3 treatment-related or greater than grade 3 treatment-related AEs have been reported. In essence, ARX517 has been well-tolerated with only grade 1 and grade 2 treatment-related adverse events being reported. The maximum tolerated dose has not yet been reached,” added O’Connor.

These 2 agents, ARX517 and ARX788, are believed to be well-positioned to potentially address important unmet medical needs in the breast and prostate cancer spaces.

REFERENCES:
1. Ambrx Biopharma to host analyst and investor day to discuss ARX788 in breast cancer and ARX517 in prostate cancer. News release. Ambrx Biopharma, Inc. February 13, 2023. Accessed February 24, 2023. https://bwnews.pr/3XXFktt
2. Ambrx announces encouraging preliminary safety and efficacy data evaluating ARX788 in HER2 positive metastatic breast cancer patients who progressed following T-DM1 treatment. News release. Ambrx Biopharma, Inc. December 9, 2022. Accessed February 24, 2023. https://bwnews.pr/3SuifNK
3. ARX788 in HER2-positive, metastatic breast cancer subjects (ACE-Breast-03). ClinicalTrials.gov. Updated October 26, 2022. Accessed February 24, 2023. https://clinicaltrials.gov/ct2/show/NCT04829604
4. I-SPY trial: neoadjuvant and personalized adaptive novel agents to treat breast cancer (I-SPY). ClinicalTrials.gov Updated November 22, 2022. Accessed February 24, 2023.
5. ARX517 in subjects with advanced solid tumor (ARX517). ClinicalTrials.gov. Updated November 7, 2022. Accessed February 24, 2023.
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