Galunisertib plus neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer: a single-arm, phase 2 trial.
The lancet oncology
oregon; portland; chiles
BACKGROUND: 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. We aimed to test the hypothesis that adding the TGF-β type I receptor kinase inhibitor galunisertib to neoadjuvant chemoradiotherapy would improve pathological complete response rates in patients with locally advanced rectal cancer.
METHODS: This was an investigator-initiated, single-arm, phase 2 study done in two medical centres in Portland (OR, USA). Eligible patients had previously untreated, locally advanced, rectal adenocarcinoma, stage IIA-IIIC or IV as per the American Joint Committee on Cancer; Eastern Cooperative Oncology Group status 0-2; and were aged 18 years or older. Participants completed two 14-day courses of oral galunisertib 150 mg twice daily, before and during fluorouracil-based chemoradiotherapy (intravenous fluorouracil 225 mg/m
FINDINGS: Between Oct 19, 2016, and Aug 31, 2020, 38 participants were enrolled. 25 (71%) of the 35 patients who completed chemoradiotherapy proceeded to total mesorectal excision surgery, five (20%) of whom had pathological complete responses. Ten (29%) patients had non-operative management, three (30%) of whom ultimately chose to have total mesorectal excision. Two (67%) of those three patients had pathological complete responses. Of the remaining seven patients in the non-operative management group, five (71%) had clinical complete responses at 1 year after their last modified FOLFOX6 infusion. In total, 12 (32% [one-sided 95% CI ≥19%]) of 38 patients had a complete response. Common grade 3 adverse events during treatment included diarrhoea in six (16%) of 38 patients, and haematological toxicity in seven (18%) patients. Two (5%) patients had grade 4 adverse events, one related to chemoradiotherapy-induced diarrhoea and dehydration, and the other an intraoperative ischaemic event. No treatment-related deaths occurred.
INTERPRETATION: 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 randomised trials.
FUNDING: Eli Lilly via ExIST program, The Providence Foundation.
Earle A. Chiles Research Institute
Yamazaki, Tomoko; Gunderson, Andrew J; Gilchrist, Miranda; Whiteford, Mark; Kiely, Maria X; Hayman, Amanda; O'Brien, David; Ahmad, Rehan; Manchio, Jeffrey V; Fox, Nathaniel E; McCarty, Kayla; Phillips, Michaela; Brosnan, Evelyn; Vaccaro, Gina; Li, Rui; Simon, Miklos; Bernstein, Eric; McCormick, Mary; Yamasaki, Lena; Wu, Yaping; Drokin, Ashley; Carnahan, Trevor; To, Yy; Redmond, William L.; Lee, Brian; Louie, Jeannie; Hansen, Eric; Solhjem, Matthew C; Cramer, Julie; Urba, Walter; Gough, Michael J.; Crittenden, Marka R; and Young, Kristina H, "Galunisertib plus neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer: a single-arm, phase 2 trial." (2022). Articles, Abstracts, and Reports. 6235.