TORL-1-23 Well Tolerated in CLDN6+ Solid Tumors, Including Platinum-Resistant Ovarian Cancer

Gottfried E. Konecny, MD

The Claudin-6 (CLDN6)–targeted antibody-drug conjugate (ADC) TORL-1-23 was well tolerated and showed efficacy in patients with heavily pretreated, CLDN6-positive advanced solid tumors, including platinum-resistant ovarian cancer, according to phase 1 TORL-123-001 trial (NCT05103683) findings presented at the 2024 ESMO Congress.¹

Findings showed that among all efficacy-evaluable patients, those treated with TORL-1-23 at doses of less than 2.4 mg/kg (n = 19), the overall response rate (ORR) was 26%, which was comprised exclusively of partial responses (PRs); 42% of patients had stable disease (SD), and 32% of patients had progressive disease (PD). At a dose of 2.4 mg/kg (n = 19), the ORR was 42% with all responders achieving a PR; the rates of SD and PD were 47% and 11%, respectively. At a dose of 3.0 mg/kg (n = 26), the ORR was 31%, including a complete response rate of 4% and a PR rate of 27%; the respective SD and PD rates were 46% and 23%.

In patients with CLDN6-positive platinum-resistant ovarian cancer, the ORRs were 30% at doses less than 2.4 mg/kg, 50% (n = 4/8) at the 2.4-mg/kg dose, and 42% (n = 5/12) at the 3.0 mg/kg dose.

Lead study author Gottfried E. Konecny, MD, said the ADC was well tolerated with a favorable safety profile. The risk of neutropenia was mitigated by prophylactic pegfilgrastim, and the maximum-tolerated dose (MTD) of TORL-1-23 had not yet been reached.

“The promising activity was confirmed as being durable and deep…[there were encouraging data for] all patients treated in dose escalation, particularly in [patients with] ovarian cancer treated at 2.4 mg/kg and 3.0 mg/kg,” Konecny said during a presentation of the data. He is the lead clinician for gynecologic oncology in the Department of Medicine at the University of California, Los Angeles.

Ovary under the microscopic: © sinhyu - stock.adobe.com

CLDN6 is expressed at high levels in a variety of cancers and has little to no expression in normal tissues, Konecny explained during the presentation. Along with targeting CLDN6, TORL-1-23 features a valine-citrulline monomethyl auristatin E linker payload with a drug-to-antibody ratio of approximately 4.

TORL-123-001 Design and Enrollment

The phase 1, 2-part, multicenter, first-in-human study enrolled patients at least 18 years of age with advanced solid tumors who had measurable disease per RECIST 1.1 criteria, an ECOG performance status of 0 or 1, and adequate organ function.²

TORL-1-23 is being evaluated at 11 different dose levels ranging from 0.2 mg/kg to 3.6 mg/kg. At dose level 9 (3.0 mg/kg), dose level 10 (4.0 mg/kg), and dose level 11 (3.6 mg/kg), prophylactic pegfilgrastim is also being administered at a dose of at least 3.0 mg/kg.

The dose-expansion portion of the study includes patients with CLDN6-positive platinum-resistant ovarian cancer, CLDN6-positive refractory non–small cell lung cancer (NSCLC), other CLDN6-positive refractory cancers, and CLDN6-low refractory cancers.1 Within each of those groups, approximately 10 to 20 patients are being treated at both 2.4 mg/kg and 3.0 mg/kg.

The primary objectives of the study are safety, tolerability, dose-limiting toxicities, and determining the MTD and recommended phase 2 dose.

Among patients enrolled in the dose-escalation portion of the study (n = 51), the median age was 61 years (range, 26-78), and most patients were female (n = 45). Tumor types included ovarian (n = 36), testicular (n = 4), endometrial (n = 7), NSCLC (n = 2), and other (n = 2). This patient population received a median of 4 prior lines of therapy (range, 1-9). Thirty-eight patients had CLDN6-positive disease per immunohistochemistry (IHC).

In dose expansion (n = 30), the median age was 65 years (range, 31-79), and most patients were female (n = 24). Tumor types included ovarian (n = 14), testicular (n = 1), endometrial (n = 6), NSCLC (n = 6), and other (n = 3). Patients received a median of 3 prior lines of therapy (range, 1-4). Twenty-seven patients had CLDN6-positive disease per IHC.

Additional Efficacy and Safety Data

In patients with platinum-resistant ovarian cancer, the median duration of response was approximately 22 weeks for those treated with the 2.4-mg/kg dose and approximately 30 weeks for those treated at the 3.0-mg/kg dose in combination with prophylactic pegfilgrastim.

Safety data from dose expansion showed that at the 2.4-mg/kg dose (n = 16), the most common adverse effects (AEs) included anemia (any grade, 25%; grade ≥3, 0%), neutropenia (31%; 19%), nausea (67%; 0%), constipation (6%; 0%), diarrhea (25%; 6%), vomiting (25%; 0%), fatigue (56%; 19%), arthralgia (31%; 0%), myalgia (19%; 6%), neuropathy (25%; 0%), and alopecia (56%; 0%).

At the 3.0-mg/kg dose (n = 14), the most frequent AEs consisted of anemia (any grade, 29%; grade ≥3, 0%), neutropenia (7%; 7%), nausea (64%; 0%), constipation (29%; 0%), diarrhea (21%; 0%), vomiting (21%; 0%), fatigue (79%; 14%), arthralgia (43%; 0%), myalgia (21%; 0%), neuropathy (57%; 0%), and alopecia (69%; 0%).

“There is a registrational phase 2 study being initiated globally in CLDN6-positive platinum-resistant [ovarian cancer], and the molecule is under further evaluation in other CLDN6-positive cancers, including NSCLC,” Konecny concluded.

Disclosures: Dr Konecny reported serving as part of a speaker bureau with AstraZeneca, ImmunoGen, and Merck; receiving research support to his institution from Lilly and Merck; receiving travel support from TORL Biotherapeutics, and providing expert testimony for Foundation Medicine.

REFERENCES:

1. Konecny GE, Hendrickson AW, Winterhoff B, et al. Phase I, two-part, multicenter first-in-human (FIH) study of TORL-1-23, a novel Claudin 6 (CLDN6) targeting antibody drug conjugate (ADC) in patients with advanced solid tumors. Presented at: 2024 ESMO Congress; September 13-17, 2024; Barcelona, Spain. Presentation 721MO.

2. First in human study of TORL-1-23 in participants with advanced cancer (TRIO049). ClinicalTrials.gov. Updated August 9, 2024. Accessed September 15, 2024. https://clinicaltrials.gov/study/NCT05103683