Neoadjuvant Tucatinib plus Trastuzumab in HER2-amplified Locally Advanced Rectal Cancer

PROJECT SUMMARY/ABSTRACT Current standard tri-modality therapy (chemotherapy, radiation, and surgery) for locally advanced rectal cancer is associated with high morbidity and only cures disease in about 75% of patients. We hypothesize that a biomarker-driven approach that gives matched targeted therapy to patients early in the treatment of locally

advanced rectal cancers will lead to high anti-tumor activity and provide the chance to avoid radiation and/or surgery and its associated morbidities. We have already pioneered such an approach for mismatch repair deficient locally advanced rectal cancer, where clinical complete response was seen in all patients who

completed 6 months of upfront treatment with immune checkpoint inhibitors (23/23, 100% complete clinical response), allowing for the omission of radiation and/or surgery. In this proposal, we focus on patients with HER2-amplified rectal cancer and hypothesize that induction therapy with HER2-targeted treatment will lead to

tumor regression and modify the need for tri-modality therapy. We propose an investigator-initiated phase II study (NCT05672524; MSK IRB# 22-185) that recently opened to enrollment; all patients will receive tucatinib plus trastuzumab induction HER2-targeted therapy for 6 weeks and continue tucatinib plus trastuzumab with

addition of standard-of-care chemotherapy for 4 months, followed by disease reassessment before standard chemoradiation and before surgery. Patients with clinical complete response to induction HER2 therapy alone or combined with chemotherapy, or to the combination followed by chemoradiation, will undergo observation

with a chance for an organ-sparing management approach. Our central hypothesis is that the primary tumor will be highly sensitive to HER2-targeted therapy alone or in combination with standard chemotherapy, leading to a higher frequency of clinical complete response than with standard total neoadjuvant therapy. Treatment of rectal

cancer in patients provides the unique opportunity to obtain on-treatment longitudinal tumor and blood samples to evaluate mechanisms of response and resistance. We hypothesize that levels of HER2 expression and consequent dependence on HER2 homodimers underlie drug response and will determine HER2 expression in

biopsy samples and with 89Zr-trastuzumab PET/MRI and correlate with response rate and progression-free survival. Circulating tumor DNA will be tested as a biomarker for response. Established and newly generated patient-derived HER2-amplified colorectal cancer organoids will be used to model and study acquired resistance,

taking advantage of our team's expertise in generating these three-dimensional, multi-cellular structures, which both recapitulate the biology of rectal cancer and provide a needed resource that expands the limited HER2- amplified rectal cancer models currently available. We hypothesize that key resistance mechanisms will consist

of decreased HER2 expression, secondary alterations that activate ERK, and shifts in tumor transcriptional programs. Together, we will define the efficacy and biological effects of biomarker-directed therapy and aim to transform treatment for patients with HER2-amplified locally advanced rectal cancer.