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HER2 Targeted ADCs: GI Cancers

CME

Emerging HER2-Targeted Antibody Drug Conjugates in Gastrointestinal Malignancies

Physicians: Maximum of 0.75 AMA PRA Category 1 Credit™

Released: April 09, 2024

Expiration: October 08, 2024

Zev A. Wainberg
Zev A. Wainberg, MD
CME/CE Information

Activity

Progress
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Course Completed

Studies of Anti-HER2 Therapies in Gastric/GEJ Cancer

Numerous studies have evaluated anti-HER2 therapies in gastric and GEJ cancers, including the phase II DESTINY‑Gastric0132 and DESTINY‑Gastric02 trials,33 both of which used the ADC T-DXd. Phase I trials include the ASPEN-01 study of evorpacept, a CD47 antibody,34 together with trastuzumab/ramucirumab and paclitaxel, and the ZWI-ZW25-201 study of zanidatamab, a bispecific antibody against HER2 that recognizes 2 nonoverlapping epitopes (ECD2 and ECD4) that promote receptor crosslinking, plus chemotherapy.35,36 Data from the ZWI-ZW25-201 study led to initiation of the randomized phase III HERIZON-GEA-01 trial of zanidatamab with chemotherapy with or without tislelizumab in patients with no prior HER2, immune checkpoint inhibitor (ICI), or systemic therapy (NCT05152147).37

The randomized phase II DESTINY‑Gastric01 study evaluated T-DXd vs investigator’s choice of chemotherapy in HER2-positive recurrent disease after 2 previous treatments. The study was conducted in patients of Asian descent. In that study, patients who received T‑DXd vs chemotherapy had an ORR of 51% vs 14% (HR: 0.59; P <.0001), median PFS of 5.6 vs 3.5 months (HR: 0.47), and median OS of 12.5 vs 8.4 months (HR: 0.60). The most common adverse events (AEs) in this study included neutropenia (51% vs 24%), anemia (38% vs 23%), white blood cell count decrease (21% vs 11%), and ILD/pneumonitis (2.4% vs 0%). Although this was a randomized phase II trial, the data led to an FDA approval of T-DXd in patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma who have received a prior trastuzumab-based regimen.38 In DESTINY-Gastric02, in patients with previous trastuzumab failure, ORR was 33%, median PFS was 5.6 months, and median OS was 12.1 months.

In the phase I ASPEN-01 study, second-line or later therapy with evorpacept plus trastuzumab/ramucirumab and paclitaxel yielded an ORR of 72% and a median PFS and median OS of 17.1 months. The most common AEs included neutrophil count decrease (44%), hypertension (33%), anemia (22%), and aspartate aminotransferase elevation (6%).

In the phase I ZWI-ZW25-201 study, zanidatamab monotherapy plus physician’s choice of chemotherapy yielded an ORR of 75% and median PFS of 12.5 months; and median OS was not evaluable at the time of the analysis.35,36 The most common AEs included diarrhea (42%), hypokalemia (17%), vomiting (8%), neutropenia (8%), white blood cell count decrease (6%), and nausea (6%).

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Gastric01: Response by Prior ICI in Metastatic Gastric Cancer

After the DESTINY-Gastric01 study completion, investigators conducted an exploratory analysis to see how patients fared if they already had been receiving ICIs. The table shows that T-DXd was more effective than chemotherapy regardless of previous immunotherapy use. In other words, they found there was ORR benefit with T-DXd in both patients who did and patients who did not receive previous ICIs compared with chemotherapy.39

This suggests that in practice, the previous use of ICIs may not be a consideration when deciding to treat with T‑DXd.

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DESTINY Gastric01 Biomarker Analysis

A biomarker analysis from the DESTINY‑Gastric01 study suggested that patients who were HER2 positive after/during treatment with trastuzumab therapy had greater benefit in the form of a higher response rate. Of importance, co‑occurring MET and EGFR amplifications were associated with worse prognosis. Thus, this data led to the FDA urging for biopsy of all patients following progression on trastuzumab, with ctDNA recommended if biopsy is not feasible. Approximately 20% of patients with esophagogastric cancer experience HER2 loss.

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DESTINY-Gastric02: T-DXd in HER2-Positive Advanced Gastric/GEJ Cancer in Western Patients

As previously mentioned, the phase II DESTINY-Gastric01 study was conducted in patients of Asian descent.32 The confirmatory phase II DESTINY-Gastric02 study enrolled patients in the United States and Europe with HER2-expressing gastric or GEJ cancer who experienced failure on trastuzumab‑based therapy.33,40 The figures show the median OS and PFS from that study; to some extent, we had a confirmatory study showing that the benefit seen in the Asian patient population of DESTINY‑Gastric01 could be extended to the Western world. These results lend some comfort to both the regulatory bodies and HCPs using T-DXd in this setting.

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Summary of Anti-HER2 Therapy in Gastric Cancer

We have established that in HER2-positive gastric and GEJ cancers, the SoC begins with a combination of chemotherapy and trastuzumab.24 Previously, we saw that PFS was improved when pembrolizumab was added to that regimen (KEYNOTE-811).20

At this moment in time, the FDA has approved T-DXd in patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma who have received a previous trastuzumab-based regimen.38 T-DXd plays an important role in patients who progress on first-line SoC therapy, and we see a response rate and PFS advantage in the group of patients who receive T-DXd.

There are a number of new drugs—such as the bispecific antibody zanidatamab, with promising clinical trial data leading to the development of a randomized phase III study—with the potential to change the current treatment landscape.41

An important point I would like to make is that T-DXd can be associated with serious ILD/pneumonitis, and it has an FDA black box warning.38 It is very important to keep this in mind as we consider the patients who may have preexisting risk factors. We will cover this in more detail and how to monitor for and manage ILD/pneumonitis with T-DXd later in this module.

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