eCase - 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, MD

CME/CE Information

Activity

Progress

1 2

Course Completed

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Introduction HER2 Directed ADCs in Gastrointestinal Malignancies Current Management of HER2-Altered Gastric/GEJ Cancers Recent Data for Anti-HER2 Therapies in Gastric Cancers Current Data for Anti-HER2 Therapies in Metastatic Colorectal Cancer Recent Data for Anti-HER2 ADC Therapies in Biliary Tract Cancers Managing the Safety Profile of Anti-HER2 Antibody‒Drug Conjugates References

ADC Therapies in Management of HER2-Positive BTCs

In BTCs, we have known for some time that HER2-positive status can be seen in up to 16% of tumor samples and is more commonly associated with gallbladder cancer and less so with intrahepatic cancers.⁵⁷ Many studies have explored anti-HER2 therapy combinations, including pertuzumab plus trastuzumab in previously treated HER2-amplified metastatic BTC, with an ORR of 23%⁵⁸; single-agent T-DXd in unresectable/recurrent HER2-expressing BTC, with an ORR of 30%^59,60; and trastuzumab plus FOLFOX in HER2-positive BTC refractory to gemcitabine/cisplatin, with an ORR of 29.4%.⁶¹

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Other Therapies in Management of HER2-Positive BTC

SGNTUC-019, an open-label phase II basket trial, is evaluating the efficacy and safety of tucatinib plus trastuzumab in patients with HER2-altered solid tumors. In the BTC cohort of that study, patients with previously treated HER2-overexpressing or -amplified (HER2-positive) tumors yielded an ORR of 46.6%, with a median PFS of 5.5 months and median OS of 15.5 months.⁶²

Most recently, the global, multicenter phase IIb HERIZON-BTC-01 trial evaluated zanidatamab in patients with HER2-amplified, unresectable, locally advanced, or metastatic BTC who had disease progression while receiving previous gemcitabine-based treatment.⁴¹ In this study, after a median duration of follow-up of 12.4 months, the confirmed ORR by independent central review was 41.3%. This treatment received an FDA breakthrough therapy designation in patients with previously treated HER2-amplified BTC.

DESTINY‑PanTumor02, an open-label phase II basket trial, is evaluating T‑DXd in patients with HER2-positive tumors.⁶³ In the 41 patients with previously treated HER2-positive BTC, T-DXd yielded an ORR of 22% in all patients treated and 56.3% in those with HER2 IHC 3+. This was somewhat reassuring and suggested that there is now a body of evidence with both tucatinib/trastuzumab and T‑DXd with the potential for remarkable response rates.⁶³

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When Should We Incorporate Anti-HER2 ADCs in Patients With BTC?

Thus, when should we be incorporating HER2 testing? Certainly at baseline for every patient, and at some point, all patients with metastatic disease should get HER2 testing. HCPs can order these tests when patients develop metastatic disease and even in the second-line setting. In gastric cancer, it is certainly the SoC to do in frontline therapy, whereas in CRC and BTC, we don’t quite have frontline data yet, so one could consider it in later lines of therapy.

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