News

Article

DKN-01 Plus Bevacizumab and Chemotherapy Shows Tolerability, Activity in MSS CRC

Author(s):

DKN-01/bevacizumab/chemotherapy had a tolerable safety profile and showcased clinical activity in patients with microsatellite stable colorectal cancer.

Meredith Pelster, MD, MSCI

Meredith Pelster, MD, MSCI

Second-line DKN-01 combined with bevacizumab (Avastin) and chemotherapy had a tolerable safety profile and showcased clinical activity in patients with advanced microsatellite stable (MSS) colorectal cancer, according to findings from the phase 2 DeFianCe trial (NCT05480306), which were presented at the 2024 Gastrointestinal Cancers Symposium.

In all efficacy-evaluable patients, the objective response rate (ORR) was 30%, the disease control rate (DCR) was 93%, 30% of patients had a partial response (PR), 63% had stable disease, and 8% had progressive disease. The median progression-free survival (PFS) was 6.28 months (95% CI, 5.39-8.64) across all patients. The median PFS was 8.64 months (95% CI, 5.59-not available [NA]) among those with left-sided tumors and 4.75 months (95% CI, 1.87-NA) for those with right-sided tumors. Of note, 9 patients remained on therapy at the time of presentation.

“Subgroup analysis demonstrated the greatest benefit in [patients with] rectal/rectosigmoid junction cancer,” Meredith Pelster, MD, MSCI, associate program director of Gastrointestinal Cancer Research at Sarah Cannon Research Institute said during the presentation.

DKN-01 is a novel monoclonal antibody of IgG4 that may neutralize DKK1, which is a regulator of the Wnt signaling pathway. In previous studies, the use of DKN-01 in combination with fluorouracil (5-FU) has been shown to improve treatment outcomes, specifically in esophagogastric cancer.

In part A of the trial, 33 patients were enrolled, with 25 patients having tumors in the left colon and 8 having tumors in the right colon. Of those with tumors in the left colon, 15 were rectal/rectal sigmoid, and 10 were descending colon/sigmoid.

Patients were eligible for treatment if they had previous treatment with 5-FU, RECIST v1.1 measurable disease, and MSS disease without a BRAF V600 mutation. The data cutoff was December 6, 2023.

After part A, a safety review was conducted. Part B is currently enrolling with an estimated population of 130 patients. Patients will be randomly assigned 1:1 to either the DKN-01 plus bevacizumab and chemotherapy arm (n = 65) or the chemotherapy plus bevacizumab arm (n = 65).

Of the patients enrolled in part A, 60.6% were male, the median age was 56.0 years, and 75.8% of patients had left-sided tumors. A majority of patients had an ECOG performance status of 0 (54.5%), 69.7% had liver metastases, and 100% received prior treatment with 5-FU. When genetics were considered, 75.0% of patients had a KRAS mutation, and 91.7% had APC mutations.

ORR was analyzed between the left-sided and right-sided colon, with rates of 33% vs 17%, respectively. The DCR was 100% vs 67%, the PR rate was 33% vs 17%, the stable disease rate was 67% vs 50%, and progressive disease was seen in 0% vs 33% between the left-sided and right-sided colon, respectively. Rectal tumors were also observed for a response with an ORR of 46%, a DCR of 100%, PRs in 46%, stable disease in 54%, and progressive disease in 0%.

The median PFS for patients with rectal tumors was 9.43 months (95% CI, 3.84-NA). The 6-month PFS rate was 57.1%. At the time of the presentation, 6 patients remained on therapy.

A PR occurred in 6 patients who showed high DKN-01 expression, and 7 patients had stable disease. Plasma levels were investigated using the SomaScan platform.

Grade 3 or higher adverse effects (AEs) were observed in 63.6% of patients, 21.2% had serious AEs, and 9.1% of patients died. With respect to AEs relating to DKN-01, grade 3 or higher toxicity occurred in 27.3% of patients, serious AEs in 3.0%, and deaths in 3.0%. AEs leading to DKN-01 dose reduction and discontinuation, respectively, were observed in 6.1% and 3.0%.

Some of the most common AEs reported were diarrhea, fatigue, neutropenia/neutrophil count decrease, nausea, and constipation.

Reference

Pelster M, Strickler JH, Sirad CA, et al. DKN-01 plus bevacizumab and chemotherapy as second-line (2L) investigational therapy in advanced microsatellite stable (MSS) colorectal adenocarcinoma (CRC): DeFianCe trial. J Clin Oncol. 2024;42(suppl 3):104. doi:10.1200/JCO.2024.42.3_suppl.104

Related Videos
Video 8 - 2 KOLs are featured in, "Emerging Trials in the Management of HR+/HER2- mBC"
Video 7 - 2 KOLs are featured in, "Adverse Event Data and Management for Optimal Quality of Life in HR+/HER2- mBC"
Karl Semaan, MD, MSc
Bradley McGregor, MD, discusses findings from a phase 1b study of abemaciclib  in clear cell renal cell carcinoma.
Toni K. Choueiri, MD
Neil J. Shah, MBBS
Chun Chao, PhD, MS
Video 6 - 2 KOLs are featured in, "Other trials of note investigating targeted therapies in later line HR+/HER2- mBC"
Adam M. Brufsky, MD, PhD, and Erika P. Hamilton, MD, experts on breast cancer
Efficacy and Safety of Fruquintinib in Patients With Metastatic Colorectal Cancer According to Prior Treatment Sequence in the Refractory Setting: Results From FRESCO and FRESCO-2