FDA Grants Fast Track Designation to OBX-115 for Advanced Melanoma

FDA Grants Fast Track Designation to OBX-115 for Advanced Melanoma

Fast track designation has been granted by the FDA to the novel engineered tumor-derived autologous T-cell immunotherapy OBX-115 as a potential therapy for locally advanced or metastatic melanoma that is refractory to or relapsed after PD-1/PD-L1–based immune checkpoint inhibitors.¹

OBX-115 is tumor-infiltrating lymphocyte (TIL) cell therapy that includes pharmacologically regulatable membrane-bound IL-15 (mbIL-15). Co-administration of IL-2 is not required due to the expression of mbIL-15, which can be induced with the use of acetazolamide.²

The agent is currently being investigated in a phase 1 trial (NCT05470283) in patients with metastatic melanoma, as well as a phase 1 trial (NCT06060613) in patients with non–small cell lung cancer and other advanced solid tumors.¹

“FDA fast track designation underscores the ongoing unmet need for patients with melanoma that has progressed on or after immune checkpoint inhibitor therapy, agnostic of mutational status, and that OBX-115 may have the potential to address that unmet need,” Madan Jagasia, MD, chief executive officer of Obsidian Therapeutics, stated in a news release. “OBX-115 is poised to be a transformative treatment option due to its patient-centric focus, including compatibility with core needle biopsy tumor tissue procurement and positively differentiated safety and tolerability profile relative to non-engineered TIL cell therapy. We are highly encouraged by the most recent safety and efficacy data presented at the 2024 ASCO [Annual] Meeting. With this designation, we look forward to continued collaborative interaction with the FDA as we advance OBX-115 clinical development in the broad post–immune checkpoint inhibitor setting.”

Findings from the phase 1 trial presented at the 2024 ASCO Annual Meeting showed that patients with unresectable or metastatic melanoma resistant to immune checkpoint inhibitors (n = 9) who were treated with OBX-115 plus acetazolamide experienced an objective response rate (ORR) of 44.4%, comprised of complete response and partial response rates of 22.2% each. Stable disease that persisted for at least 12 weeks was reported in 55.6% of patients, and no patients had progressive disease, translating to a disease control rate of 100%. The 24-week progression-free survival (PFS) rate was 75%.²

Regarding safety, at a median follow-up of 29.5 weeks (range, 13.0-69.3), no treatment- or disease-related mortality was reported, and no patients required admission to an intensive care unit. No dose-limiting toxicities were reported, and no patients experienced any instances of cytokine release syndrome, immune effector cell–associated neurotoxicity syndrome, or capillary leak syndrome. Seven patients who received outpatient acetazolamide redosing at week 6 did not experience any adverse effects (AEs). Additionally, AEs did not lead to treatment discontinuation in any patients.

No grade 4 or higher nonhematologic treatment-emergent AEs (TEAEs) were reported. Nonhematologic TEAEs reported among all evaluable patients (n = 10) included increased alanine aminotransferase (any grade, 40.0%; grade 3, 10.0%), abdominal pain (10.0%; 10.0%), and syncope (10.0%; 10.0%).

Hematologic AEs were consistent with the known safety profile of lymphodepletion. Grade 1/2 rash or pruritus was reported in 8 patients. Four patients experienced grade 1/2 uveitis/iritis, and 1 of these patients had grade 3 optic neuritis, which later resolved.

The first-in-human phase 1 trial is enrolling patients with advanced melanoma that is relapsed and/or refractory to immune checkpoint inhibitors. Patients are required to have at least 1 lesion for tumor tissue procurement for the manufacturing of OBX-115, plus at least 1 remaining lesion to assess response per RECIST 1.1 criteria. High-risk patients, such as those with mucosal and uveal melanoma, or those with genomically equivalent mutations, could be enrolled after the initial safety of OBX-115 is established.

OBX-115 is manufactured following tumor tissue procurement, and patients are allowed to undergo bridging therapy during the manufacturing process. Patients then receive lymphodepletion on days –7 to –1 before OBX-115 is given as a single infusion on day 0. Acetazolamide is then administered on days 2 to 9, and optional acetazolamide dosing is allowed at week 6.

The study’s primary end points are safety/tolerability and establishing the recommended doses of OBX-115. Secondary end points include ORR, duration of response, and PFS.

References

1. Obsidian Therapeutics announces FDA fast track designation for OBX-115 for the treatment of advanced melanoma. News release. Obsidian Therapeutics. July 9, 2024. Accessed July 9, 2024. https://obsidiantx.com/news-releases/obsidian-therapeutics-announces-fda-fast-track-designation-for-obx-115-for-the-treatment-of-advanced-melanoma/
2. Amaria RN, McQuade JL, Davies MA, et al. OBX-115, an interleukin 2 (IL2)-sparing engineered tumor-infiltrating lymphocyte (TIL) cell therapy, in patients (pts) with immune checkpoint inhibitor (ICI)-resistant unresectable or metastatic melanoma. J Clin Oncol. 2024;42(suppl 16):9515. doi:10.1200/JCO.2024.42.16_suppl.9515