Cholangiocarcinoma presents significant treatment challenges, with limited options after initial therapies fail. The EA2187 trial tested Pevonedistat, revealing a lack of effective responses. The results showed safety issues and indicated a pressing need for better second-line treatments. However, the trial promoted valuable collaboration and research infrastructure in rare disease studies.
Cholangiocarcinoma, a rare and aggressive cancer from bile ducts, poses significant treatment challenges. Patients who see disease progression after the first line of treatment have very few options available. During the 2025 ASCO Annual Meeting, researchers presented the ECOG-ACRIN EA2187 trial aimed at addressing this urgent need for more effective second-line therapies.
Dr. Suneel Kamath from the Cleveland Clinic’s Hematology and Medical Oncology department highlights that first-line treatments usually involve chemotherapy and immunotherapy. However, he stresses that, “once that stops working, we’ve been left with no real satisfying treatments to give next.” He emphasizes the ongoing quest for better second-line therapy alternatives.
The trial focused on Pevonedistat, a candidate with promising activity in earlier studies. This drug targets a specific enzyme involved in protein degradation, potentially making cancer cells more susceptible to DNA damage. As Dr. Kamath explains, “Pevonedistat aims to block the NEDD8-activating enzyme, essentially making the cancer cells more vulnerable to DNA damage and tumor cell death.”
In the EA2187 trial, Pevonedistat was tested as a standalone treatment and also in combination with carboplatin and paclitaxel. They enrolled 40 patients with unresectable or metastatic cholangiocarcinoma who progressed after gemcitabine therapy. Participants were split into two groups: one received Pevonedistat alone and the other received it combined with chemotherapy.
This phase 2 trial used a two-stage minimax design, with the aim of achieving an objective response rate of 30%. The primary endpoint was overall response rate as per RECIST v1.1 criteria. The safety metrics were based on CTCAE v5.0 standards. Out of 40 enrolled patients, 34 (17 per arm) were treated.
After a median follow-up of 29.3 months, results were disappointing. No objective responses were recorded in either treatment group. Stable disease was seen in around 35.3% of patients, with a meager clinical benefit rate of 5.9%. Median progression-free survival clocked in at 1.54 months for the monotherapy group and 2.92 months for the combination cohort.
Safety evaluations showed that severe adverse events occurred more frequently in the combination treatment group (70.6%) compared to those on Pevonedistat alone (17.6%). Issues included fatigue and febrile neutropenia, and troublingly, two deaths related to treatment were noted in the combination arm.
Dr. Kamath concluded that these findings highlighted the difficulty of treating cholangiocarcinoma. “These findings reflect how difficult this disease is to treat,” he mentioned. Higher resistance post-first-line therapies limits options significantly compared to other cancers.
Nevertheless, the trial bolstered collaboration among various research centers, which had not previously worked together. Dr. Kamath remarked on the importance of cooperation and infrastructure in ongoing rare disease research. He noted, “even during the COVID pandemic, we accrued 40 patients in a relatively short period of time. That shows what’s possible when there’s alignment and commitment.”
In essence, while Pevonedistat has fallen short in this particular context, the trial underscores the dire need for more effective and tolerable second-line therapies for cholangiocarcinoma. As Dr. Kamath finally stated, “this trial is a reminder of how high the bar still is for treating cholangiocarcinoma, especially when the first-line fails.” It emphasizes the ongoing need for well-structured studies and continued public investment in combating rare cancers.
The recent trial for Pevonedistat in treating advanced cholangiocarcinoma did not yield the desired results, showing limited effectiveness and safety concerns. Despite the outcomes, the study signifies the importance of collaboration in researching rare cancers and highlights the urgent need to develop better second-line treatments. It reiterates the complicated nature of cholangiocarcinoma treatment, stressing that the field must seek innovative and effective therapeutic options moving forward.
Sumber Asli: consultqd.clevelandclinic.org
