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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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CRC: A Molecularly Diverse Entity

CRC is a remarkably diverse disease when it comes to molecular biomarkers. We know that KRAS mutations exist in approximately 40% to 50% of patients with metastatic CRC (mCRC), including mutations in exons 2 through 4.1 There is now increased recognition that other subtypes of CRC—such as BRAF V600E mutated, mismatch repair deficient (dMMR)/MSI-high, subvariants such as KRAS G12C, and HER2 overexpressed/amplified—also must be considered when deciding treatment options for this disease.3

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HER2 is Overexpressed/Amplified in 2% to 4% of CRC

HER2 is overexpressed and in most cases amplified in 2% to 4% of CRC, almost exclusively in the group of patients who are KRAS wild-type. This is supported by a number of the trials, shown in the table, that looked at this fairly comprehensively over a series of retrospective studies. The consensus is that the prevalence of HER2 alterations in CRC ranges from approximately 0.2% to 13.3%, but collectively we are probably talking about 2% to 4% of patients with left-sided, KRAS wild-type mCRC tumors.15,42-45

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HER2-Positive mCRC: A Distinct Subset

NCCN guideline changes over the past few years have suggested that HER2‑positive mCRC indeed represents a distinct subset of patients.3 For example, these tumors are mostly left-sided or distal (odds ratio: 0.50), patients usually have lung metastases (odds ratio: 2.04), and there is a higher incidence of brain metastases (approximately 20%)―similar to that of HER2‑positive breast and gastric cancer―and it is very much enriched in RAS/RAF wild‑type tumors.3

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NCCN Guidelines for mCRC

In patients with HER2-amplified and RAS/BRAF wild-type mCRC, the initial treatment was previously trastuzumab plus either pertuzumab, lapatinib, or tucatinib. More recently, we have been considering T-DXd. In this setting, we expect an ORR of 30% to 50%.

In patients with KRAS/NRAS/BRAF wild-type and left-sided CRC and no HER2 alterations, cetuximab, panitumumab, and irinotecan plus either cetuximab or panitumumab may be considered. In this population, the expected ORR has not been reported. In mCRC with dMMR/MSI-high status (4%-5% of patients), treatment options include pembrolizumab, nivolumab with or without ipilimumab, or dostarlimab. The expected response in this setting is 45% to 55%.

In BRAF V600E mCRC, patients are treated with encorafenib plus either cetuximab or panitumumab, with an expected response of 20%.

For NTRK or RET gene fusion‒positive mCRC, guidelines recommend NTRK inhibitors (larotrectinib or entrectinib) and a RET inhibitor (selpercatinib), with responses of 57% to 80% in those with an NTRK gene fusion and 64% for those with a RET gene fusion.

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HER2 in CRC: A Negative Predictor for Anti-EGFR Therapy

We know based on data from Raghav and colleagues45 that HER2 amplifications in CRC are a predictor for poor outcomes in patients receiving anti-EGFR therapy (cetuximab, panitumumab, erlotinib, or gefitinib).   

A key question then is: What should we do about it?

Until a few years ago, we did not have the clinical trial data for HER2 inhibition in CRC. However, small studies have started to emerge that emphasized the importance of the degree of HER2 amplification in HER2‑positive CRC, such that single‑agent trastuzumab does not have a role to play, and even the studies that looked at HER2 inhibition with chemotherapy were somewhat negative.

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Trials Evaluating Anti-HER2 Treatment in mCRC

Ultimately, a number of studies evaluated combinations of trastuzumab together with another HER2 blocker—such as lapatinib, pertuzumab, or tucatinib—and showed ORRs ranging from 30% to 38.1%, median PFS ranging from 2.9 to 4.8 months, and median OS ranging from 8.8 to 24.7 months.46-50

Data from the MOUNTAINEER-01 study led to the FDA approval of tucatinib plus trastuzumab in HER2‑positive colon cancer51 and to the large, randomized phase III MOUNTAINEER-03 trial evaluating tucatinib plus trastuzumab and FOLFOX (leucovorin calcium [folinic acid]/fluorouracil/oxaliplatin) vs frontline FOLFOX plus investigator’s choice of antibody in HER2‑positive mCRC at diagnosis (NCT05253651).52

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HER2 ADCs in Management of HER2-Positive mCRC

Subsequent trials explored anti-HER2 ADCs including the phase II HERACLES-B evaluating ado-trastuzumab emtansine in refractory HER2-positive mCRC, yielding a response of 5.6%.53,54 The phase II DESTINY‑CRC01 and DESTINY‑CRC02 studies evaluated T-DXd in patients with HER2-positive unresectable/metastatic RAS/BRAF wild-type disease and yielded a response rate of 45.3% and 37.8%, respectively.55,56 These data have led to compendial listing of T‑DXd in this setting, and T-DXd should be considered in patients with HER2‑positive CRC.3

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HER2 Therapies in CRC: Takeaways

HER2 overexpression/amplification is observed in approximately 2% to 8% of CRC and is enriched in RAS/BRAF wild-type tumors.

We now know that HER2 amplification may confer resistance to anti-EGFR therapies in patients with mCRC. Dual HER2 inhibition (eg, with tucatinib plus trastuzumab now approved by the FDA) appears to be effective in this HER2-amplified patient population.

Overall, anti-HER2 ADCs show promise and are under active investigation in mCRC. HER2 testing should be performed early in CRC and patients referred early for clinical trials. Novel strategies and biomarkers for predicting response/resistance are needed.

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