Adding galunisertib to neoadjuvant chemoradiotherapy may improve responses in patients with locally advanced rectal cancer, according to research published in The Lancet Oncology.

In this phase 2 trial, patients who received galunisertib with neoadjuvant chemoradiotherapy had a complete response (CR) rate of 32%, which is higher than CR rates historically seen with chemoradiotherapy alone. 

The trial ( Identifier: NCT02688712) included 38 patients with previously untreated, locally advanced, stage IIA-IIIC or IV rectal adenocarcinoma. The median follow-up was 27.0 months.

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A total of 35 patients completed neoadjuvant therapy, which consisted of galunisertib (a TGF-β type I receptor kinase inhibitor) plus fluorouracil-based chemotherapy and radiation. 

Twenty-five patients proceeded to total mesorectal excision after neoadjuvant therapy, and 5 of these patients ultimately achieved a pathological CR. 

Ten patients achieved a clinical CR on neoadjuvant treatment and went on to nonoperative management, which consisted of chemotherapy. Nine of these patients received modified leucovorin, fluorouracil, and oxaliplatin (mFOLFOX6), and 1 received oxaliplatin plus capecitabine. 

Three patients who achieved a clinical CR on mFOLFOX6 ultimately went on to excision. Two of those patients achieved a pathological CR.

Of the remaining 7 patients in the nonoperative management group, 5 (71%) had a clinical CR at 1 year after the last mFOLFOX6 infusion.

The overall CR rate was 32%, which met the researchers’ prespecified threshold for a significant improvement over historical results. Response rates historically seen with chemoradiotherapy alone range from 8% to 13%, according to the researchers.

There were no grade 3-4 adverse events (AEs) attributed to galunisertib. The most common grade 1-2 AEs associated with galunisertib were gastrointestinal (21%), neurologic (21%), dermatologic (16%), constitutional (13%), and musculoskeletal (11%). 

There were 2 grade 4 AEs — diarrhea and dehydration — attributed to chemoradiotherapy. One grade 4 AE — ischemic neuropathy — was attributed to a hypotensive event intraoperatively. 

“All other adverse events were grade 3 or lower and similar to adverse events observed with standard of care chemoradiotherapy,” the researchers wrote. “With little toxicity, short duration of therapy, and good response rates, our data support further randomized trials of TGF-β inhibition as a modulator of tumor immunity to enhance the efficacy of radiotherapy.”

Disclosures: This study was supported by Eli Lilly and The Providence Foundation. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.


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