When combined with neoadjuvant chemotherapy, galunisertib induced complete response rates surpassing rates achieved with standard-of-care therapy in locally advanced rectal cancer.
Findings from a phase 2 study (NCT02688712) demonstrated that complete response (CR) rates were improved in patients with locally advanced rectal cancer who received galunisertib (LY2157299) in addition to neoadjuvant chemoradiotherapy.1
Among 38 previously untreated patients enrolled to the investigator-initiated, single-arm trial, 32% (n = 12; 1-sided 95% CI ≥19%) achieved a CR, surpassing the predetermined statistical significance threshold of 20%.
“This clinical trial was designed to test the hypothesis, based on preclinical observations, that TGF-β inhibition enhanced the efficacy of radiotherapy in patients with locally advanced rectal cancer. This study met its primary statistical and safety coprimary end points,” lead study author, Tomoko Yamazaki, PhD, an investigator at the Earle A. Chiles Research Institute and the Providence Cancer Institute of Oregon, and colleagues, wrote in a discussion of the data.
Neoadjuvant radiotherapy with concurrent fluorouracil is the current standard of care (SOC) for patients with locally advanced rectal adenocarcinoma. The SOC induces pathologic complete response (pCR) rates from 8% to 13%. Previous data have shown that intensifying neoadjuvant therapy can improve pCR rates. Notably, total neoadjuvant therapy with chemoradiotherapy and FOLFIRINOX (leucovorin, fluorouracil, irinotecan, and oxaliplatin) or FOLFOX (leucovorin, fluorouracil, and oxaliplatin) can yield pCR rates of 25% to 28%.
TGF-β is a multipotent immunosuppressive cytokine upregulated in colorectal cancer that acts as a tumor suppressor at the in-situ carcinoma stage or in premalignant changes and a tumor promoter at later, invasive stages, where it works through proliferation, differentiation, angiogenesis, and inflammation. It also decreases CD8-positive T-cell proliferation and effector function and antigen presentation and effector function, while promoting activation and proliferation of suppressive regulatory T cells, alternative macrophage differentiation, and macrophage trafficking to the site of inflammation.
In preclinical models of colorectal adenocarcinoma, blockade of TGF-β improved response to chemoradiotherapy. Investigators studied whether adding galunisertib, a TGF-β type 1 receptor kinase inhibitor, to neoadjuvant chemoradiotherapy would improve pCR rates in this population.
Additionally, organ preservation has been associated with improved physical, emotional, cognitive, and global health status quality of life, as well as with improvements in defecation and urinary and sexual function compared with total mesorectal resection. As the SOC for rectal cancer evolved to include non-operative management, this trial adjusted its protocol to allow for this option.
This trial was conducted in 2 medical centers in Portland, Oregon. Eligible patients included those aged at least 18 years with previously untreated, locally advanced, histologically confirmed rectal adenocarcinoma that was stage IIA to IIIC or IV per the American Joint Committee on Cancer and an ECOG performance status of 0 to 2. Patients also needed to be eligible for primary rectal tumor resection.
Ineligible patients included those who had received previous pelvic radiotherapy; those with active autoimmune disease, immunodeficiency, or the need for immunosuppressive medications; those with a previous diagnosis of a solid tumor malignancy within 3 years of enrollment; those with valvular or vascular disease; and those who were pregnant or lactating.
Biochemical parameters evaluated for eligibility included hemoglobin, white blood cells, platelets, creatinine, aspartate aminotransferase, alanine aminotransferase, bilirubin, and prothrombin time with international normalized ratio.
Thirty-eight patients enrolled from October 19, 2016, to August 31, 2020. Patients received two 14-day courses of oral galunisertib at 150 mg twice daily. Before and during galunisertib therapy, they also received fluorouracil-based chemoradiotherapy, which consisted of intravenous (IV) fluorouracil at 225 mg/m2 over 24 hours daily, 7 days per week during radiotherapy, or twice daily oral capecitabine (Xeloda) at 825 mg/m2 5 days per week during radiotherapy. Radiotherapy consisted of 50.4 to 54.0 Gy in 28 to 30 fractions.
From 5 weeks to 9 weeks after therapy, investigators assessed patient response through physical examination, MRI, and endoscopic evaluation by board-certified radiologists and colorectal surgeons. Patients were also reviewed by a multidisciplinary tumor board.
Patients who had CR could choose non-operative management and receive modified FOLFOX6 (IV leucovorin at 400 mg/m2 on day 1, IV fluorouracil at 400 mg/m2 on day 1 then at 2400 mg/m2 over 46 hours, and IV oxaliplatin at 85 mg/m2 on day 1 administered every 2 weeks for 8 cycles) or CAPEOX (IV oxaliplatin at 130 mg/m2 on day 1 and oral capecitabine at 1000 mg/m2 twice a day for 14 days every 3 weeks for 4 cycles).
Patients who had less than a CR received total mesorectal resection and SOC adjuvant chemotherapy.
The primary end point of this study was CR rate, a composite of clinical complete response (cCR) maintained at 1 year after completion of therapy in patients who received non-operative management and pCR in patients who received surgery. cCR was defined as no tumor or lymph nodes by endoscopy, MRI, or digital rectal examination. pCR was defined as no viable tumor cells. Safety was a coprimary end point, and both end points were assessed in the intention-to-treat population.
Key secondary end points included overall survival (OS), defined as alive since diagnosis at least every 6 months for 5 years; progression-free survival (PFS), defined as alive and without disease recurrence or local or distant progression; evaluation of tumor immune infiltrates and their associations with treatment response; and peripheral blood immune monitoring associated with CR or less than a CR.
At a median follow-up of 27.0 months (interquartile range, 20.9-34.9 months), 3 patients had come off the study: 1 who discontinued treatment after 12 doses of galunisertib because of rectal bleeding requiring radiotherapy for hemostasis, 1 who was enrolled in hospice during chemoradiotherapy and died of causes unrelated to treatment toxicities, and 1 who had progression of distant metastatic disease in the lungs and declined to participate in primary tumor evaluation.
Of the 35 patients who completed chemoradiotherapy, 71% (n = 25) proceeded to total mesorectal excision surgery. Of those patients, 20% (n = 5) had pCRs.
A total of 29% (n = 10) of patients who completed chemoradiotherapy had non-operative management, 30% (n = 3) of whom chose to receive total mesorectal excision. Of those 3 patients, 2 (67%) had pCRs. Of the remaining patients in the non-operative management group (n = 7), 71% (n = 5) achieved cCRs at 1 year after their last modified FOLFOX6 infusion.
Two patients from the nonoperative management group experienced local regrowth within the first year after therapy. One had total mesorectal resection with no residual disease and 1 developed concurrent diffuse peritoneal and distant lung metastases and chose palliative care. The investigators observed no locoregional recurrences among enrolled patients.
The most common grade 3 adverse events (AEs) that occurred during treatment were diarrhea (16%; n = 6) and hematological toxicity (18%; n = 7). Investigators observed grade 4 AEs in 5% (n = 2) of patients, 1 an intraoperative ischaemic neuropathy event and the other related to chemoradiotherapy-induced diarrhea and dehydration. All other AEs were grade 3 or lower and were consistent with AEs observed with SOC chemotherapy.
Additionally, galunisertib was well tolerated, with no associated grade 3/4 AEs. The most common galunisertib-related AEs were nausea, headaches, rash, and fatigue. Toxicities did not delay any surgeries.
At the time of analysis, 5% (n = 2) of patients had died, 1 who had come off the study and enrolled in hospice during chemoradiotherapy and 1 who died of progressive metastatic stage IV disease during follow-up. There were no treatment-related deaths.
At the time of final analysis, February 8, 2022, the median OS was not reached (NR; 95% CI-estimable [NE]) and the 2-year OS rate was 97.4% (95% CI, 82.8%-99.6%). In total, 16% (n = 6) of patients had disease progression or had died.
The median PFS was NR (95% CI NE) and the 2-year PFS rate was 81.5% (95% CI, 62.6%-91.4%).
In a post-hoc analysis, which excluded patients with stage IV disease (n = 4), 1 of 34 patients had died at the time of the final analysis. The median OS was NR and the 2-year OS rate was 97.1% (95% CI, 81.0%-99.5%).
At the time of final analysis in this population, 12% (n = 4) of patients had disease progression or had died. The median PFS was NR (95% CI NE) and the 2-year PFS rate was 84.9% (95% CI, 63.8%-94.2%).
“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, with organ preservation as a primary or coprimary end point,” the study authors concluded.