Improved Complete Response Rate Observed With Galunisertib Plus Neoadjuvant CRT in Advanced Rectal Cancer


Results from the phase 2 ExIST trial indicated that the addition of galunisertib to neoadjuvant chemoradiotherapy for patients with locally advanced rectal cancer resulted in an improvement in responses.

Patients with locally advanced rectal cancer experienced an improvement in complete response (CR) rate following treatment with galunisertib (LY2157299) and neoadjuvant chemoradiotherapy, according to results from the phase 2 ExIST study (NCT02688712) published in The Lancet Oncology.

A CR in the overall population occurred inn 32% of patients (one-sided 95% CI, ≥19%). Of 35 patients, 71% completed chemoradiotherapy and continued to receive mesorectal excision surgery, of whom 20% had pathological CR. Among the remaining patients, 29% went on to receive non-operative pain management, of whom 30% decided to undergo mesorectal excision. Of 3 patients, the pathological CR was 67%. Among 7 patients in the non-operative group, 71% had a clinical CR at 1 year after receiving a modified leucovorin calcium (folinic acid), fluorouracil, and oxaliplatin (FOLFOX6) infusion.

A total of 38 patients were enrolled with a median follow-up of 27.0 months. Treatment was given to patients as per protocol and 2 patients with T4 tumors received 54.0 Gy of radiotherapy in 30 fractions. Moreover, 10 patients underwent non-operative pain management, 2 of whom had local regrowth within the first year. One patient underwent endoscopic biopsy that revealed submucosal adenocarcinoma that was removed via mesorectal excision with no further residual disease. Another patient was found to have concurrent distant lung and diffuse peritoneal metastases, which was treated with palliative care. Overall, no patient experienced locoregional recurrence.

At the time of the final analysis, 5% of patients had died, the median overall survival (OS) was not reached and the 2-year OS was 97.4% (95% CI, 82.8%-99.6%). Progressive disease or death occurred in 16% of patients. The median progression-free survival (PFS) was not reached and the 2-year median PFS was 81.5% (95% CI, 62.6%-91.4%).

The post-hoc analysis, which excluded 4 patients with stage IV disease, 1 patient had died at the time of the final analysis. The median OS was not reached, and at 2 years it was 97.1% (95% CI, 81.0%-99.5%). A total of 12% of patients had progressive disease or died. The median PFS was not reached, and the median PFS at 2 years was 84.9% (95% CI, 63.8%-94.2%).

At baselin, 97% of patients were node positive at baseline and 79% of patients who underwent total mesorectal excision were pathologically negative at the time of surgery. The median neoadjuvant rectal score was 8.43.

Treatment with chemoradiotherapy resulted in a reduction in circulating lymphocytes within 2 weeks with minimal recovery by day of surgery. Patients experienced stable absolute monocyte and neutrophil counts during treatment. During chemoradiotherapy in the lymphocyte subset, a decline of CD3-positive, CD4-positive, and CD8-positive cells was observed. Additionally, B-cell subsets decreased with time, however, translation B-cells alone increased at the time of surgery. During chemoradiotherapy, plasmacytoid dendritic cells declined while myeloid dendritic cell levels stayed the same. Of note, there was no statistically significant difference in monocytic myeloid derived suppressor cells overserved from baseline to end of treatment.

Three grade 4 adverse effects (AEs) occurred and included diarrhea and dehydration related to chemoradiotherapy, and ischemic neuropathy related to a hypotensive event intraoperatively. Grade 3 or lower AEs were similar to those observed during standard of care treatment. The most common AEs associated with galunisertib were nausea, headaches, rash, and fatigue. Patients did not experience surgical delays because of AEs.


Yamazaki T, Gunderson AJ, Gilchrist M, et al. Galunisertib plus neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer: a single-arm, phase 2 trial. Lancet Oncol. Published online August 8, 2022. doi:10.1016/S1470-2045(22)00446-6

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