197P - Clinical benefit of HER2-targeted therapies versus prior chemotherapy in refractory HER2 expressing and mutant gastrointestinal malignancies

Background

HER2-directed drugs are established therapies for patients with advanced HER2+ gastroesophageal (GEJ) cancers. However, while various anti-HER2 agents including antibodies, antibody-drug conjugates, and tyrosine kinase inhibitors are active in non-GEJ HER2+ GI tumors, the optimal integration/sequencing of these agents with conventional chemotherapy is unclear.

Methods

We assessed the outcomes of patients with metastatic HER2-expressing or mutated non-GEJ GI cancers who received anti-HER2 drugs at our institution from 2010 –2021. We measured the growth modulation index (GMI) – the ratio of progression-free survival (PFS) of the anti-HER2 drug to the time-to-progression on the immediately prior therapy – for each line of HER2 therapy. GMI ≥1.3 is considered meaningful clinical benefit, and we classified patients with GMI ≥2.6 as exceptional benefiters.

Results

Forty-one patients with adenocarcinomas (19 colorectal, 13 biliary tract, 3 intestinal, 3 pancreatic, 2 ampullary, and 1 appendiceal) were identified; 59% received ≥2 lines of therapy before their first anti-HER2 agent. Twenty-two patients who received ≥1 line of HER2-directed therapy were GMI evaluable. Fifty percent benefited from therapy and 36% derived exceptional benefit. The median PFS to the first anti-HER2 therapy was 5.5 (0.4 – 53.0) months. All HER2 benefiters were either HER2-amplified, 3+ by IHC, or 2+/ISH+; none (0/3) with HER2 mutations derived benefit. Three patients had exceptional benefit to second-line HER2 drugs after deriving no benefit on their first HER2 therapy, with a median GMI of 4.9 (4.7 – 6.5) and a median PFS of 11.0 (4.3 – 13.7) months. One patient remains alive over 60 months since diagnosis and has received 5 lines of anti-HER2 therapy (median PFS of 8.8 months per agent).

Conclusions

Anti-HER2 drugs in later lines can provide durable benefit relative to earlier-line chemotherapy in a large proportion of patients with HER2+ non-GEJ GI malignancies. Patients not benefiting from initial anti-HER2 drugs may still achieve sustained benefit from subsequent HER2-directed regimens. Early and continued incorporation of anti-HER2 agents throughout a patient’s treatment course may optimize clinical outcomes.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

T.P. Johnson: Financial Interests, Personal, Advisory Role: Servier. G. Heestand: Financial Interests, Personal, Advisory Role: Exelixis, Eisai, Elevation Oncology; Financial Interests, Personal, Other, Employment (Spouse): Genentech; Financial Interests, Personal, Other, Stock (Spouse): Roche. G.A. Fisher Jr: Financial Interests, Personal, Stocks/Shares: Seattle Genetics; Financial Interests, Personal, Other, Honoraria: Echina Health; Financial Interests, Personal, Advisory Role: Merck, Taiho Pharmaceutical, Ipsen, Roche/Genentech; Financial Interests, Institutional, Research Funding: Roche/Genentech, Merck; Financial Interests, Personal, Other: CytomX Therapeutics, Silenseed, AstraZeneca, Terumo Clinical Supply, Taiho Pharmaceutical, Hutchison MediPharma. C. Chen: Financial Interests, Personal, Other, Consultant: Boxer Capital, Guidepoint Global Advisors; Non-Financial Interests, Institutional, Local PI: ADC Therapeutics, Gilead Sciences, Kinnate Biopharma, Mersana, Oric Pharmaceuticals, Palleon, Pionyr, Rain Oncology, Ribosciences. All other authors have declared no conflicts of interest.