Delcath Systems’ Chemosat with Ipilimumab Plus Nivolumab Evaluated for Treatment of Metastatic Uveal Melanoma

January 17, 2023—Delcath Systems, Inc., an interventional oncology company focused on the treatment of primary and metastatic cancers of the liver, announced the publication of updated results from the phase 1b CHOPIN trial.

The goal of CHOPIN is to evaluate the safety and potential synergistic effects of systemic immune checkpoint inhibitors (ICI) ipilimumab plus nivolumab (IPI+NIVO) when combined with liver-targeted percutaneous hepatic perfusion (PHP) using the Delcath Chemosat hepatic delivery system with melphalan to treat patients with metastatic uveal melanoma. The study is being conducted at Leiden University Medical Center in Leiden, the Netherlands.

The findings were published by T. M. L. Tong, MD, et al online in CardioVascular and Interventional Radiology. In June 2022, the results were presented at the annual meeting of the American Society of Clinical Oncology in Chicago, Illinois.

Delcath’s PHP system is designed to administer high-dose chemotherapy to the liver while controlling systemic exposure and associated side effects.

In the United States, the PHP system is being developed under the tradename Hepzato Kit (melphalan hydrochloride for injection/hepatic delivery system) for the treatment of patients with unresectable hepatic-dominant metastatic ocular melanoma, also known as metastatic uveal melanoma. It is considered a combination drug-and-device product regulated as a drug by the FDA.

In Europe, the PHP system is now regulated as a class III medical device. It is approved for sale in Europe under the trade name Chemosat hepatic delivery system for melphalan and has been used to treat a wide range of cancers of the liver.

According to the company, the phase 1b portion of the trial enrolled seven patients who were treated with two courses of PHP (melphalan 3 mg/kg, max 220 mg per cycle) combined with four courses IPI+NIVO, escalating the dosing from 1 mg/kg each IPI+NIVO (cohort 1) to IPI 1 mg/kg + NIVO 3 mg/kg (cohort 2).

The best overall response—which was previously reported—included one complete response, five partial responses, and one stable disease, accounting for an objective response rate of 85.7% and a disease control rate of 100%.

At the cutoff date of November 15, 2022, the median follow-up was 29.1 months (range, 8.9-30.2), the median progression-free survival was 29.1 months (95% CI, 11.9-46.3), and the median duration of response was 27.1 months (range, 7.4-28.5). All patients are still alive, and three of four patients who subsequently experienced PD continued with treatment in the form of repeated melphalan PHP (M-PHP) cycles.

The ongoing randomized phase 2 part of the CHOPIN trial comparing M-PHP alone with M-PHP plus IPI+NIVO will include an additional 76 patients (38 per arm). Phase 2 is approximately 50% enrolled and will provide more insight into the efficacy, advised Delcath.

The company noted that the determination of a safe and effective dose was a primary goal of the phase 1b portion of CHOPIN. Grade 1/2 adverse events were seen in all patients, and 71.4% experienced grade 3/4 toxicities. In this phase 1b dose-escalation study combining M-PHP with IPI+NIVO, the safe treatment dose was established at IPI 1 mg/kg and NIVO 3 mg/kg.

The investigators did observe low-grade immune-related toxicities and PHP-related hematologic toxicities in the treated groups. Hematologic toxicity is a common adverse event after M-PHP, affecting approximately three-quarters of patients.

All seven patients in the study experienced grade 1/2 anemia. To prevent severe leukopenia/neutropenia, G-CSF (granulocyte colony-stimulating factor) was administered within 48 hours after M-PHP in their treatment center. The phase 2 part of the CHOPIN study will provide more information on both hepatic and systemic toxicity associated with the combination therapy.

“If similar results are observed in the larger, randomized second phase of this trial, it would represent a meaningful improvement over current treatment options for this patient population,” stated Johnny John, MD, Senior Vice President, Medical and Clinical Affairs, Delcath Systems, in the company’s press release. “In addition, further investigation of this combination protocol may be warranted in patients with liver-dominant disease in other tumor types currently treated with ICI agents.”

As summarized in Delcath’s press release, the rationale for combining ICI therapy with M-PHP in metastatic uveal melanoma is based on uveal melanoma’s specific characteristics and the unique immunomodulatory role of the liver. Uveal melanoma is characterized by a different set of driver mutations and lower mutational load compared to cutaneous melanoma, leading to limited neoantigen presentation and lower efficacy of ICI.

By combining M-PHP with IPI+NIVO, the investigators noted that they aim to increase the efficacy of ICI by turning a “cold tumor” into a “hot tumor.” In addition, while PHP can provide long-lasting disease control in the liver, it does not control extrahepatic disease. Conversely, IPI+NIVO treatment shows a trend toward control of extrahepatic lesions, but hepatic disease progression regularly occurs. With combined treatment, the investigators aim to control hepatic disease, as well as prevent extrahepatic disease in follow-up.

In addition, noted the Delcath press release, it is well documented that the liver has a unique immune-modulating role and liver metastases diminish ICI efficacy systemically regardless of the type of primary tumor; in animal models, it has been shown that this effect can be overcome by localized hepatic therapy.

Current available evidence from studies on isolated limb perfusion (ILP) and isolated hepatic perfusion (IHP), which is the surgical counterpart of M-PHP, show that ILP and IHP can lead to T-cell activation after the procedures. The investigators hypothesize that this is also the case for M-PHP leading to an improved activation of the immune system together with ICI, stated the company.

Citations of referenced studies are available in the company’s press release, here.