Novel Drug Plus Bevacizumab and Chemo Yields Promising Activity in MSS CRC

“Subgroup analysis demonstrated the greatest benefit in [patients with] rectal/rectosigmoid junction cancer,” according to Meredith Pelster, MD, MSCI.

The use of DKN-01 plus bevacizumab (Avastin) and chemotherapy was well tolerated and produced promising clinical activity as second-line treatment for patients with advanced microsatellite stable (MSS) colorectal adenocarcinoma, according to results from the phase 2 DeFianCe trial (NCT05480306) presented at the 2024 Gastrointestinal Cancer 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 BRAFV600 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