Adding the investigational TGF-β type I receptor kinase inhibitor galunisertib to neoadjuvant chemoradiotherapy was associated with improved response rates in patients with locally advanced rectal cancer compared with historical data on neoadjuvant chemoradiotherapy alone, according to results from the phase II ExIST study.
Among 38 patients, 12 had a complete response with the combination (32%), exceeding the historical response rates observed with neoadjuvant chemoradiotherapy alone (8% to 13%), which surpassed the study’s predetermined statistical threshold for significance (a minimum of 10 patients having a complete response to reject the null hypothesis), reported Kristina H. Young, PhD, of the Providence Cancer Institute in Portland, Oregon, and colleagues.
“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,” the group wrote in Lancet Oncology.
Over a median follow-up of 27 months, 35 patients completed chemoradiotherapy, 25 of whom proceeded to total mesorectal excision. Five of these patients had pathologic complete responses. The remaining 10 patients underwent non-operative management with chemotherapy. Three of those patients ultimately underwent total mesorectal excision, with two having pathologic complete responses. Of the remaining seven patients in the non-operative group, five had clinical complete responses at 1 year after treatment was completed.
Young and colleagues noted that while the original protocol of the study did not allow for non-operative management of patients, the standard of care had evolved to include this pathway. Therefore, the protocol was amended, and participants with clinical complete responses to chemoradiotherapy were allowed to proceed to non-operative management and total neoadjuvant therapy if they chose.
“Organ preservation has been shown to improve quality of life compared with total mesorectal excision, including physical, emotional, cognitive, and global health status, in addition to functional improvements in defecation and urinary and sexual function,” they wrote. “Therefore, it was not surprising that many patients expressed an interest in non-operative management after it became an option.”
However, in a commentary accompanying the study, Paul B. Romesser, MD, and J. Joshua Smith, MD, PhD, both of Memorial Sloan Kettering Cancer Center in New York City, suggested that while amending the protocol was “seemingly well intentioned” it makes assessment of the study’s primary endpoint “difficult to benchmark.”
“Why was consolidative chemotherapy only offered to those with a clinical complete response after induction chemoradiotherapy and not to all patients regardless of response?” they noted, pointing out that Young and colleagues “notably do not present outcome data for patients before and after this amendment to assess its effect on the described endpoints.”
They did point out that the study’s findings on safety provide reassurance in both the operative and non-operative management settings, and observed that despite these limitations in design and protocol execution, “the study met its primary endpoint, providing some justification for a larger, randomized, phase II trial to be conducted.”
This single-arm trial was conducted at two medical centers in Portland from October 2016 to August 2000. The 38 patients (median age 51 years, 68% men) had previously untreated, locally advanced rectal adenocarcinoma, stage IIA-IIIC or IV as per the American Joint Committee on Cancer and an Eastern Cooperative Oncology Group status of 0 to 2.
Patients completed two 14-day courses of oral galunisertib 150 mg twice daily, before and during 5-fluorouracil-based chemoradiotherapy. They underwent response assessment 5 to 9 weeks later.
Patients with a complete response could choose non-operative management and proceed to modified FOLFOX6 every 2 weeks for 8 cycles or CAPEOX every 3 weeks for 4 cycles. Patients with less than complete response underwent surgical resection.
At the time of final analysis, median overall survival (OS) was not reached, while the 2-year OS rate was 97.4%. Median progression-free survival (PFS) was not reached, and the 2-year PFS rate was 81.5%.
Common grade 3 adverse events during treatment included diarrhea in 16% of patients, and hematologic toxicity in 18%. Two patients had grade 4 adverse events, one related to chemoradiotherapy-induced diarrhea and dehydration, and the other an intraoperative ischemic event. No treatment-related deaths occurred.
This study was funded by Eli Lilly via the ExIST program and the Providence Foundation.
Young reported sponsored research agreements with Bristol Myers Squibb; grant funding held through the Susan G. Komen Foundation and Providence Foundation H&N Developmental Research Program; and a patent held jointly with the Providence Portland Medical Center.
Co-authors reported multiple relationships with industry.
Smith reported receiving travel support from Intuitive Surgical, and serving as a clinical advisor for Guardant Health and Foundation Medicine, and serving as a consultant and speaker for Johnson & Johnson. Romesser reported prior research funding from and consulting work for EMD Serono.