DKN-01 Triplet Shows Encouraging Early Efficacy/Safety in Frontline Gastroesophageal Adenocarcinoma

The combination of DKN-01, tislelizumab, and capecitabine/oxaliplatin (CAPOX) was found to have encouraging clinical activity as frontline treatment of patients with advanced gastroesophageal adenocarcinoma.

The DKN-01/tislelizumab doublet was also found to be well tolerated with clinical responses as a second-line treatment for advanced gastroesophageal adenocarcinoma patients with high DKK1 expression. Efficacy was driven by enhanced objective response rate (ORR), duration of response (DOR) and progression-free survival (PFS) in DKK1-high patients, an aggressive subgroup. Response was associated with DKK1 expression and is independent of PD-L1 expression.

"I would say the take home message is that in this population the biomarker does appear predictive of patients who are going to get the most benefit," said Samuel Klempner, MD, gastrointestinal medical oncologist at Massachusetts General Hospital.

The DisTinGuish trial (NCT04363801) is a phase 2a, multicenter, open-label study of DKN-01, in combination with tislelizumab and chemotherapy used as a first- or second-line therapy for adult patients with gastric or gastroesophageal cancer.

The study is being conducted in 2 parts in both the United States and the Republic of Korea. Part A enrollment has been completed with 25 first-line HER2-negative gastric or gastroesophageal junction (G/GEJ) cancer patients who have tumors that express either high levels of DKK1 (DKK1-high) or low levels of DKK1 (DKK1-low). Thirty patients with second-line DKK1-high G/GEJ cancer have been enrolled in part B of the study. The study will continue to enroll up to 48 patients.

Primary end points included safety and tolerability. Secondary end points consisted of ORR, DOR, PFS, OS, and disease control rate.

To be eligible in part A, participants were required to be 18 or older with inoperable, histologically confirmed locally advanced or metastatic G/GEJ adenocarcinoma with measurable disease (RECIST v1.1). Participants who had received previous therapies for cancer were ineligible for enrollment unless they had prior neoadjuvant, or adjuvant therapy completed without disease recurrence for at least 6 months since last treatment.

Within part B, disease progression during first-line therapy or within 4 months after the last dose of first-line therapy was required along with documentation of elevated DKK1 mRNA expression from a fresh tumor biopsy or a biopsy obtained within the 6 months of screening.

Both parts are designed to evaluate safety, tolerability, and efficacy of the combination therapy of intravenous (IV) DKN-01 plus tislelizumab plus CAPOX in G/GEJ adenocarcinoma patients. In repeating 21-day cycles, treatment was administered until patients either met criteria for discontinuation or were no longer deriving clinical benefit.

Part A patients received intravenous (IV) DKN-01 at 300 mg on days 1 and 15, 200 mg of IV tislelizumab on day 1, 130 mg/m² of IV oxaliplatin on day 1, and oral capecitabine twice a day at 1000 mg/m² on days 1-15 of each 21-day cycle. Patients in part B will receive IV DKN-01 at 600 mg on days 1 and 15 and IV tislelizumab at 200 mg on day 1 of each 21-day cycle.

Findings showed overall preliminary PFS to be 10.7 months. DKK1-high patients had longer PFS at 11.9 months when compared to 10.7 months in DKK1-low patients. Preliminary median DOR was also longer in DKK1-high patients at 10.7 months, compared to 7.9 months in DKK1-low patients. Median OS has not been reached.

Of the 22 patients who received a full first cycle of DKN-01, ORR was 68%, including 1 complete response (CR) and 14 partial responses (PR). ORR was 90% in DKK1-high patients (n = 10) and 56% in DKK1-low patients (n = 9).

In regard to PD-L1 status, findings showed activity to be independent of PD-L1 expression with 79% ORR in PD-L1-low ([verified combined positive score] vCPS < 5) and 67% ORR in PD-L1-high (vCPS > 5) patients. In DKK1-high, PD-L1-low patients (n = 6), ORR was 100%.

For part B of the trial, DKN-01 and tislelizumab administered in DKK1-high, PD-1 naïve patients were shown to be well-tolerated at 300mg and 600-mg DKN-01 doses. Of the evaluable patients who received a full first cycle of DKN-01, the ORR was 25%, including 5 PRs, 4 stable disease, and 1 patient with an additional irPR.

Within the study population, PD-L1 expression is low overall and not correlated with DKK1 expression. However, the study is ongoing and enrolling in the 600-mg DKN-01 cohort.

In regard to safety, the combination of DKN-01, tislelizumab, and CAPOX was found to be well tolerated and have manageable toxicity.

"People always need to know when we're adding a drug, is it adding significant additional side effects? And overall, in this trial population, the tolerability was very good. So, it seems that this can be paired safely with standard chemotherapy and PD-1 agents," said Klempner.

The most common DKN-01-related adverse events (AEs) were either grade 1 or 2 including fatigue, nausea, diarrhea, neutrophil count decreased, and platelet count decreased. Five patients experienced grade 3 DKN-01 AEs including blood phosphorus (2), pulmonary embolism (2), diarrhea (1), neutrophil count decreased (1). No grade 4 events were reported.

Treatment-emergent adverse events (TEAEs) leading to death within 30 days of the last dose were reported in 3 patients. Pulmonary embolism was assessed in 1 patient relating to regimen, and both aspiration pneumonia and hepatic failure were assessed in 1 patient each as being possibly related to disease progression.

Though Part B is currently enrolling in the DKN-01 600-mg cohort, the combination of DKN-01 plus tislelizumab was well tolerated at DKN-01 doses of both 300 mg and 600 mg, according to Klempner.

“The Part B second-line cohort remains pretty early in follow-up. It will be interesting to see if the second-line data also shows an improved response rate because there will be patients who don't get checkpoint inhibitors in the front-line who may have an opportunity to get it in the second-line if they are DKK1-high. But it remains to be seen what will be done with these data,” said Klempner.

Some of the most common DKN-01-related adverse events were grade 1 or 2 and included fatigue and nausea. Four patients experienced grade 3 events including spartate aminotransferase increased (2), Aspartate aminotransferase increased (1), alkaline phosphate increased (1), sodium decreased (1), vomiting (1), and fatigue (1). No grade 5 TEAEs leading to death within 30 days of the last dose or toxicities were found in any participants.

More data are expected to come with results from the ongoing 600-mg arm study.

REFERENCES:

1. Klempner S, Chao J, Uronis H et al. DKN-01 and Tislelizumab ± Chemotherapy as First-line (1L) or Second-line (2L) Investigational Therapy in Advanced Gastroesophageal Adenocarcinoma (GEA): DisTinGuish Trial. Presented at: American Society of Clinical Oncology 2022 ASCO Gastrointestinal Cancers Symposium 2022; Abstract 292

2. A Study of DKN-01 in Combination With Tislelizumab ± Chemotherapy in Patients With Gastric or Gastroesophageal Cancer (DisTinGuish). ClinicalTrials.gov. Accessed March 1, 2022. https://bit.ly/3swPgO7