Title

Galunisertib plus neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer: a single-arm, phase 2 trial.

Authors

Tomoko Yamazaki, Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, Portland, OR, 97213, USAFollow
Andrew J Gunderson, Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, OregonFollow
Miranda Gilchrist, Earle A Chiles Research Institute, Providence Cancer Institute of Oregon, Portland, OR, USA.
Mark Whiteford
Maria X Kiely
Amanda Hayman
David O'Brien
Rehan Ahmad
Jeffrey V Manchio
Nathaniel E Fox, Earle A. Chiles Research Institute, Portland, OR 97213Follow
Kayla McCarty, Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Cancer Institute, Portland, OR, United States of AmericaFollow
Michaela Phillips, Earle A Chiles Research Institute, Providence Cancer Institute of Oregon, Portland, OR, USA.Follow
Evelyn Brosnan, Earle A Chiles Research Institute, Providence Cancer Institute of Oregon, Portland, OR, USA.Follow
Gina Vaccaro, Providence Cancer Center Oncology and Hematology Care Clinic, Portland, OR, USAFollow
Rui Li, Earle A Chiles Research Institute, Providence Cancer Institute of Oregon, Portland, OR, USA.
Miklos Simon
Eric Bernstein, Earle A Chiles Research Institute, Providence Cancer Institute of Oregon, Portland, OR, USA.
Mary McCormick, Earle A Chiles Research Institute, Providence Cancer Institute of Oregon, Portland, OR, USA.Follow
Lena Yamasaki, Earle A Chiles Research Institute, Providence Cancer Institute of Oregon, Portland, OR, USA.Follow
Yaping Wu, Pathology, Providence Portland Medical CenterFollow
Ashley Drokin, Earle A Chiles Research Institute, Providence Cancer Institute of Oregon, Portland, OR, USA.Follow
Trevor Carnahan, Earle A Chiles Research Institute, Providence Cancer Institute of Oregon, Portland, OR, USA.Follow
Yy To, Earle A Chiles Research Institute, Providence Cancer Institute of Oregon, Portland, OR, USA.
William L. Redmond, Earle A Chiles Research InstituteFollow
Brian Lee
Jeannie Louie
Eric Hansen
Matthew C Solhjem
Julie Cramer, Providence Cancer InstituteFollow
Walter Urba, Earle A. Chiles Research Institute, Providence Cancer Center, Portland, OR, 97213, USA.Follow
Michael J. Gough, Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, PortlandFollow
Marka R Crittenden, Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, PortlandFollow
Kristina H Young, Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Cancer Institute, Portland, OR, United States of AmericaFollow

Document Type

Article

Publication Date

8-8-2022

Publication Title

The lancet oncology

Keywords

oregon; portland; chiles

Abstract

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.

Clinical Institute

Cancer

Clinical Institute

Digestive Health

Department

Earle A. Chiles Research Institute

Department

Oncology

Department

Gastroenterology

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