Addition of Galunisertib to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer

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In a small phase II trial reported in The Lancet Oncology, Yamazaki et al found that the TGF-β type I receptor kinase inhibitor galunisertib appeared to show activity when added to neoadjuvant chemoradiation in previously untreated patients with locally advanced rectal cancer.

As stated by the investigators, “TGF-β is an immunosuppressive cytokine that is upregulated in colorectal cancer. TGF-β blockade improved response to chemoradiotherapy in preclinical models of colorectal adenocarcinoma.”

Study Details

The investigator-initiated trial included 38 patients enrolled at two medical centers in Portland, Oregon, between October 2016 and August 2020. They received neoadjuvant treatment with two 14-day courses of galunisertib at 150 mg twice daily before and during fluorouracil-based chemoradiotherapy; chemoradiotherapy consisted of fluorouracil at 225 mg/m² over 24 hours daily 7 days per week during radiotherapy or capecitabine at 825 mg/m² twice per day 5 days per week during radiotherapy; radiotherapy was given at 50.4 at 54.0 Gy in 28 to 30 fractions.

At response assessment 5 to 9 weeks after completion of treatment, patients with complete response could opt for nonoperative management and receive modified FOLFOX6 (leucovorin, fluorouracil, oxaliplatin) every 2 weeks for eight cycles or CAPEOX (oxaliplatin, capecitabine) every 3 weeks for four cycles. Patients with less than complete response underwent surgical resection.

The primary endpoint was complete response rate, a composite of pathologic complete response in patients who proceeded to surgery, or clinical complete response maintained at 1 year after last therapy in patients with nonoperative management. If 10 (26%) or more of 38 patients had a complete response, then the null hypothesis, based on historical controls, that galunisertib has no effect could be rejected. Analysis was performed in the intention-to-treat population.

Key Findings

Median follow-up was 27.0 months (interquartile range = 20.9–34.9 months). Among the 38 patients, 35 completed chemoradiotherapy and 25 proceeded to total mesorectal excision surgery; of the 25, 5 (20%) had pathologic complete response. Nonoperative management was performed in 10 patients; of these, 3 ultimately underwent total mesorectal excision, with 2 (67%) having pathologic complete response. Of the remaining seven patients who received nonoperative management, five (71%) had clinical complete responses at 1 year after completion of treatment. In total, 12 (32%) of 38 patients had a complete response.

Median overall survival was not reached; the 2-year rate was 97.4%. Median progression-free survival was not reached; the 2-year rate was 81.5%.

A total of three grade 4 treatment-related adverse events were observed in two patients (chemoradiotherapy-induced diarrhea, dehydration, and intraoperative neurologic ischemic event). The most common grade 3 treatment-related adverse events were hematologic events (18%); diarrhea (16%); electrolyte abnormalities (11%); and cardiovascular, gastrointestinal, and neurologic events (8% each). No grade 3 or 4 toxic effects were attributed to galunisertib. No treatment-related deaths occurred.

The investigators concluded, “The addition of galunisertib to neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer improved the complete response rate to 32%, was well tolerated, and warrants further assessment in randomized trials.”

Kristina H. Young, PhD, of the Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by Eli Lilly and The Providence Foundation. For full disclosures of the study authors, visit

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