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Neoadjuvant Botensilimab/Balstilimab Produces Early Responses in CRC

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Patients with resectable mismatch repair-proficient and -deficient colorectal cancer had robust responses to neoadjuvant botensilimab/balstilimab.

Patients with resectable mismatch repair–proficient and mismatch repair–deficient colorectal cancer treated with neoadjuvant (treatment given to shrink a tumor before the main treatment) botensilimab plus balstilimab had robust responses and prolonged circulating tumor DNA (ctDNA)/minimal residual disease (MRD) negativity.

Findings from the phase 2 NEST-1 trial were presented at the 2024 Gastrointestinal Cancers Symposium.

Of note, patients with mismatch repair–proficient colorectal cancer have a mismatch repair system that functions properly and helps to maintain DNA stability, whereas those with mismatch repair-deficient disease have cells with mutations in genes responsible for correcting mistakes that are made when DNA is copied in a cell.

Study highlights:

  • Positive responses in colorectal cancer: Patients with both resectable mismatch repair–proficient and mismatch repair–deficient colorectal cancer showed strong responses to neoadjuvant treatment with botensilimab plus balstilimab.
  • Extended circulating tumor DNA (ctDNA)/minimal residual disease (MRD) negativity: The treatment resulted in prolonged negativity of ctDNA/MRD, which are indicators of cancer presence. This suggests a positive impact on the disease.
  • Understanding mismatch repair system: Mismatch repair–proficient colorectal cancer has a properly functioning system that helps maintain DNA stability, while mismatch repair-deficient cancer has mutations affecting this system. Knowing this helps tailor treatments.
  • Pathologic responses: A significant number of patients experienced pathologic responses, including tumor reduction. In some cases, the reduction was substantial, reaching at least 50% or even 90%, indicating positive outcomes.
  • Safety and immune response: The neoadjuvant treatment was deemed safe, with no surgical delays or severe side effects. Analysis of tissue samples showed a robust immunogenic response, where immune cells penetrated cancer cells, providing insights into the pattern of immune responses.

ctDNA refers to small pieces of DNA that are released into a patient’s blood by tumor cells as they die, whereas MRD is a very small number of cancer cells in the body after treatment.

A total of 67% of patients with microsatellite-stable (when microsatellite DNA segments are not mutated in the disease) colorectal cancer (nine patients) experienced pathologic responses, defined as tumor reduction of at least 50%, and 100% of patients with microsatellite instability–high (cancer cells with many mutations within microsatellites) colorectal cancer (three patients) experienced major pathologic responses, defined as tumor reduction of at least 90%. In the microsatellite stable population, tumor reductions of 100% (complete response [disappearance of all signs of cancer from treatment]; two patients), 90% (one patient), 85% (one patient), 50% (two patients), 25% (one patient) and 10% (one patient) were observed. In the microsatellite instability–high population, tumor reductions of 100% (complete response; two patients) and 98% (one patient) were observed.

“Neoadjuvant botensilimab/balstilimab is a safe and active regimen in both (resectable mismatch repair–proficient)/microsatellite stable and (mismatch repair–deficient)/(microsatellite instability–high colorectal cancer),” lead study author Dr. Pashtoon Murtaza Kasi, of Weill Cornell Medicine and NewYork Presbyterian Hospital in New York, New York, and colleagues, wrote in a poster of the data.

The single-arm NEST-1 trial evaluated botensilimab plus balstilimab in the neoadjuvant setting in 12 patients with colon and rectal cancer who were eligible for surgery. All patients received one fixed dose of botensilimab plus two fixed doses of balstilimab at two weeks apart. Patients were permitted to proceed to surgery one week after completing the second dose of balstilimab. Less than 25% of patients were permitted to have mismatch repair–deficient/microsatellite instability–high disease.

Pre-treatment disease stages included stage 1 (one patient), stage 3A (one patient), stage 3B (five patients) and stage 3C (four patient). One patient had TXN0 disease, meaning the tumor could not be evaluated and there was no regional lymph node metastasis. Post-treatment disease stages included no tumor (four patients), stage 1 (three patients), stage 2A (two patients), stage 3A (one patient), stage 3B (one patient) and stage 3C (one patient

All patients enrolled in NEST-1 safely received botensilimab/balstilimab without surgical delay or increased risk of severe side effects. Six patients experienced no side effects. The remaining six patients experienced severe diarrhea; mild chills/fever; mild chills/headache and moderate fever; mild chills, headache, dizziness and severe fatigue; mild flu-like symptoms and mild fever; and mild fatigue, rash and headache.

Investigators assessed tissue immune microenvironment correlates on colon and rectal samples before and after immunotherapy. This analysis demonstrated a robust immunogenic pathologic response known as the “inside-out” phenomenon. Contrary to the pattern of response observed with neoadjuvant chemotherapy, targeted therapy and/or radiation, during the “inside-out” response, immune cells penetrate the cancer cells from layers deep within the body.

“Analyses show a significant increase and a diverse array of immune cells in more than one instance, shedding novel insights into the mechanism and pattern of immune responses,” the study authors noted in the poster.

Additionally, 100% of patients who were positive for ctDNA at screening (7 patients) cleared ctDNA. Furthermore, 100% of patients who were tested for ctDNA after surgery (11 patients) remained ctDNA/MRD negative for more than 30 cumulative blood draws.

“Clinical downstaging and deep pathological responses provide a framework for reduced reliance on surgery and/or adjuvant chemotherapy in future studies,” the study authors concluded in the poster.

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