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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

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Current Management of HER2-Altered Gastrointestinal Cancers

I would like to go over some of the clinical data that have led to the approvals of HER2-targeted agents in various GI cancers, starting with gastric and GEJ cancer.

ToGA: Chemotherapy ± Trastuzumab as First-line Therapy in HER2-Positive Metastatic Gastric Cancer

The first pivotal study exploring anti-HER2 therapy was the randomized phase III ToGA study evaluating chemotherapy with or without trastuzumab, an anti-HER2 monoclonal antibody, in patients with newly diagnosed HER2-positive metastatic gastric or GEJ cancer (N = 594).11 The primary endpoint was overall survival (OS) in all patients who received ≥1 dose of study treatment.

The ToGA study demonstrated that addition of trastuzumab to chemotherapy yielded improved median OS (13.8 months vs 11.1 months; HR: 0.74; P = .0046). As a result, the combination of chemotherapy plus trastuzumab became the standard of care (SoC) in patients with metastatic gastric or GEJ cancer.11

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ToGA: HER2 Subgroup Analyses

Subgroup analyses were performed for the ToGA study. The most relevant of these subgroup analyses was the finding that the higher degree of HER2 staining, which included IHC 3+ or FISH positive, had the greatest benefit. In other words, if the patient’s tumor was HER2 IHC 3+ or 2+ and FISH positive, then he or she got the best benefit from adding trastuzumab to chemotherapy.11

A large study recently was reported that added pembrolizumab to the SoC of chemotherapy plus trastuzumab in HER2-positive gastric or GEJ tumors and was supported by the presence of PD-L1 staining and phase Ib/II clinical trial data suggesting a high response rate in this population.19,20

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KEYNOTE-811: First-line Trastuzumab and Chemotherapy ± Pembrolizumab in HER2-Positive Gastric/GEJ Cancer

The randomized phase III KEYNOTE-811 trial is evaluating chemotherapy plus trastuzumab with or without pembrolizumab in patients with HER2-positive advanced gastric or GEJ adenocarcinoma who had not received prior therapy in the advanced setting (N = 694).21,22 The coprimary endpoints were OS and PFS per blinded independent central review.

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KEYNOTE-811: Pembrolizumab/Trastuzumab/CT Antitumor Response at Interim Analysis 3

In interim analysis 3, a significantly higher antitumor response was reported among patients who received pembrolizumab vs placebo. In all patients, the overall response rate (ORR) for the pembrolizumab-containing arm vs the placebo-containing arm was 73% vs 60%, and the disease control rate was 93% vs 87%.21

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KEYNOTE-811: PFS and OS (Third Interim Analysis)

The figures show the Kaplan-Meier data for PFS from the KEYNOTE-811 trial. Median PFS for the addition of pembrolizumab to SoC vs SoC plus placebo was 10.0 months vs 8.1 months (HR: 0.73), and median OS was 20.0 months vs 16.8 months (HR: 0.84) for all patients.

It should be noted that a combined positive score (CPS) ≥1 represented approximately 85% of the total study population, and the magnitude of benefit was even greater for these patients with the addition of pembrolizumab to SoC. In patients with a PD-L1 CPS ≥1, median PFS was significantly improved with pembrolizumab vs placebo at 10.9 months vs 7.3 months (HR: 0.71), as was median OS at 20.0 months vs 15.7 months (HR: 0.81). As shown here, the OS did not reach statistical significance, and we await more events to make a final determination as to OS benefit.

Based on these results, the combination of trastuzumab, fluoropyrimidine, and platinum-containing chemotherapy plus pembrolizumab received FDA accelerated approval for the first-line treatment of patients with locally advanced, unresectable, or metastatic HER2-positive gastric or GEJ adenocarcinoma who are HER2 positive with a PD‑L1 CPS of ≥1, which represents approximately 85% of patients who are HER2 positive.23,24

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Subsequent Negative Phase III Studies in Advanced Gastric Cancer

I want to take a step back and mention that not everything works in gastric cancer the way it does in breast cancer. Several negative studies are listed in this table. Among first‑line studies, JACOB, HELOISE, and TRIO-013/LOGiC all failed to meet their primary endpoint for OS.25-27 In addition, pertuzumab and lapatinib, which are approved in breast cancer, did not obtain approval in gastric cancer.28 Similarly, older combinations such as trastuzumab emtansine and paclitaxel/lapatinib also failed in progressive HER2‑positive disease.29,30

To some extent, this has now changed, with the recognition that the mechanism of drugs that may be best to go after HER2 includes this group of ADCs. ADCs are drugs that do not just take advantage of having the antigen; they also may have this bystander impact. This is something important in a disease such as gastric cancer, as adding a cytotoxic backbone may improve outcomes.31

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