DZD1516 Plus Trastuzumab Deruxtecan Shows Preclinical Synergy in HER2+ Breast Cancer with Brain Metastases

DZD1516 has demonstrated preclinical ability to penetrate the blood–brain barrier (BBB) of patients with metastatic HER2-positive breast cancer and brain metastases. The next step for investigators, according to Nicholas P. McAndrew, MD, MSCE, will be determining an optimal combination partner for the selective and reversible HER2 TKI.

Updated results from a first-in-human phase 1 trial (NCT04509596) presented at the 2022 San Antonio Breast Cancer Symposium (SABCS) showed that DZD1516 monotherapy had full BBB penetration in heavily pretreated patients with HER2-positive breast cancer with central nervous system (CNS) metastases. Among 21 patients who received a median of 7 prior lines of systemic therapy, 82.6% had 1 or more post-treatment tumor assessments. The best response was stable disease in intracranial, extracranial, and overall lesions.

DZD1516 was well tolerated in doses up to 250 mg twice daily.Investigators observed dose-limiting toxicities only in the 300-mg cohort.

Additional data showed that DZD1516 in combination with fam-trastuzumab deruxtecan-nxki (Enhertu) had synergistic antitumor activity in a HER2-positive brain metastasis xenograft model.

“[Treating] metastatic HER2-positive breast cancer with brain metastases remains one of the biggest challenges in the HER2-positive breast cancer [space],” McAndrew said in an interview with OncLive^®. “Now that we have a recommended phase 2 dose [(RP2D) for DZD1516], the next step is to find the right partner for this drug.”

McAndrew discussed the need for HER2-targeted TKIs specifically designed to penetrate the BBB, updated clinical data on the safety and tolerability of DZD1516 monotherapy, and the implications of nonclinical data on DZD1516 plus standard-of-care (SOC) combinations for treating CNS metastases in HER2-positive breast cancer. McAndrew is an assistant clinical professor of medicine at the University of California, Los Angeles (UCLA) and a hematologist-oncologist at the UCLA David Geffen School of Medicine of UCLA Medical Center.

OncLive^®: What was the rationale investigating DZD1516 in patients with HER2-positive breast cancer? What was the importance of determining its ability to penetrate the BBB?

McAndrew: DZD1516 was engineered as a highly-selective HER2 TKI with full BBB penetration. While we do have some agents that have some good BBB penetration, [treating HER2-positive breast cancer with brain metastases] remains a big problem. [Few] drugs in preclinical development have been [designed with a] focus on full BBB penetration [for metastatic HER2-positive breast cancer with brain metastases]. [Additionally,] a lot of phase 1 drug development studies haven't looked at CNS pharmacokinetics in this space, which is what this study was focused on.

What updated clinical data from this study did you present at the 2022 SABCS?

Updated clinical data showed that the drug was safe and tolerable, up to a maximum tolerated dose [MTD] of 250 mg [twice daily]. It was a 3+3 traditional phase 1, dose-escalation, first-in-human study. [DZD1516 monotherapy] started at 25 mg twice daily with oral dosing. The maximum dose at which we experienced some dose-limiting toxicities was 300 mg twice a day. Therefore, 250 mg twice daily was found to be the MTD and the RP2D.

Could you expand on the safety findings for DZD1516?

Safety was the primary end point of the study. The typical toxicities were headache and emesis. [We did not see] much diarrhea, which is what we see often with other TKIs, where there is off-target EGFR activation and activity [that can lead to diarrhea]. The [adverse effect] profile was consistent with the highly selective HER2 nature of the drug.

In addition, the pharmacokinetics [of DZD1516] in the cerebrospinal fluid [CSF] were drawn throughout the study, and these confirmed the drug is fully BBB penetrant. We collected lumbar punctures on patients at cycle 2, or toward the end of cycle 1, and the pharmacokinetics in the CSF confirmed what the company [Dizal Pharmaceutical] had seen preclinically.

Did investigators observe any activity when combining DZD1516 with SOC agents in preclinical models?

Updated preclinical data looked at new combinations of the [DZD1516] in animal models with additional SOC agents. The company had performed additional testing in both brain metastases and mouse models [to evaluate] degrees of bioluminescence and tumor shrinkage. When DZD1516 was combined with trastuzumab deruxtecan, when measuring decrease in bioluminescence in the brain metastases models, they found that the degree of bioluminescence with either DZD1516 or trastuzumab deruxtecan [alone] was higher than the combination. The combination was certainly synergistic, and it was the most synergistic combination that we saw in preclinical testing.

What next steps are planned for this research?

Now that we have an RP2D, the next steps are going to be finding the right partner for [DZD1516]. There aren't any single-agent TKIs on the market. They seem to be most effective in combination with other drugs. Given the preclinical data, the company is going to [aim] to figure out the right partner for [DZD1516]. In our current climate with the difficulty sequencing these drugs, it is going to be an interesting choice [for the optimal combination].

Reference

McAndrew NP, Hu X, Zhang J, et al. Updated data from the phase 1 trial of DZD1516, a BBB-penetrant selective HER2 inhibitor, in patients with HER2 positive metastatic breast cancer. Presented at: 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX; Abstract P4-01-23.