Ixotatug Vedotin Elicits Responses in Heavily Pretreated Recurrent Germ Cell Tumors

Ixotatug vedotin (TORL-1-23) monotherapy produced responses in patients with heavily pretreated, recurrent germ cell tumors (GCTs), including those whose disease progressed after high-dose chemotherapy with autologous stem cell transplant (HDCT/ASCT), according to data from the phase 1 CATALINA-1 trial (NCT05103683) presented at the 2026 ESMO Congress.¹

Among all patients with GCTs (n = 11), the objective response rate (ORR) was 45.5% (95% CI, 16.7%-76.6%), and all 5 responses were partial responses. The disease control rate (DCR) was 72.7% (95% CI, 39.0%-94.0%), and the median progression-free survival (PFS) was 5.8 months (95% CI, 1.4-13.8) at a median follow-up of 13.8 months. Among patients who previously received HDCT/ASCT (n = 6), 50.0% had confirmed responses.

Responses occurred at dose levels ranging from 1 mg/kg to 3.4 mg/kg, and 1 patient with testicular GCT maintained a response for 47.4 months, with treatment ongoing at the data cutoff of March 16, 2026. Best overall responses also included stable disease in 27.3% of patients and progressive disease in 18.2%; 1 patient was not evaluable. Duration of response data were immature at the data cutoff.

“We've had some agents that have shown activity, but unfortunately, for one reason or another…they just haven't moved forward,” Darren R. Feldman, MD, of Memorial Sloan Kettering Cancer Center in New York, New York, said in an exclusive interview with OncLive.^® This is one of the agents that has shown, in the 20 years that I've been conducting studies in this refractory germ cell tumor population, some of the best activity of any of the agents I've studied. So I’m really excited about it, and hopeful that we'll have a phase 2 trial.”

How was the phase 1 CATALINA-1 trial of ixotatug vedotin in recurrent GCTs designed?

Ixotatug vedotin is an antibody-drug conjugate that targets claudin 6 (CLDN6) and delivers a monomethyl auristatin E payload. Previously, single-agent ixotatug vedotin was found to have antitumor activity with acceptable safety in heavily pretreated patients with CLDN6-positive ovarian cancer.²

CATALINA-1 is a first-in-human dose-escalation and expansion study of ixotatug vedotin monotherapy in patients with confirmed advanced or metastatic solid tumors, no available standard-of-care therapy, and disease not amenable to surgery; prior HDCT/ASCT was allowed.¹ Dose escalation began with accelerated titration from a starting dose of 0.2 mg/kg every 3 weeks, followed by standard 3 + 3 escalation.

Patients with GCTs were enrolled in dose escalation and in an expansion cohort for other CLDN6-positive refractory cancers. Expansion required CLDN6 positivity, defined as greater than 30% tumor cell membrane staining of any intensity by immunohistochemistry (IHC). Patients with GCTs received ixotatug vedotin at less than 2.4 mg/kg (n = 3), 2.4 mg/kg (n = 3), 3 mg/kg (n = 4), or 3.4 mg/kg (n = 1).

The primary end point was safety, and the secondary end point was investigator-assessed best objective response per RECIST v1.1.

The median patient age was 37 years (range, 23-76), 90.9% of patients were male, and 63.6% had an ECOG performance status of 0 (n = 7). Primary tumor sites were testicular (n = 9), ovarian (n = 1), and mediastinal (n = 1); 10 patients had nonseminoma, and 1 had seminoma. Patients had received a median of 3 prior lines of therapy (range, 1-5), including platinum compounds in 100%, taxanes in 72.7%, and HDCT/ASCT in 54.5%. CLDN6 positivity by IHC was confirmed in 100% of tested patients (n = 10).

What was the safety profile of ixotatug vedotin in heavily pretreated GCTs?

Treatment-emergent adverse effects (TEAEs) of any grade occurred in 90.9% of patients, and grade 3 or higher TEAEs occurred in 63.6%. Three patients experienced reversible grade 4 neutropenia, no febrile neutropenia was observed, and no grade 5 TEAEs occurred. Two patients with grade 1 neuropathy at baseline developed grade 3 peripheral sensory neuropathy.

The most common TEAEs included constipation, arthralgia, back pain, nausea, and vomiting. Overall, 63.6% of patients had a dose reduction, delay, or withdrawal because of any adverse effect (AE), and peripheral sensory neuropathy was the most common cause, leading to dose delay or reduction in 5 patients.

One patient (9.1%) discontinued treatment because of a treatment-related AE, which was grade 3 peripheral sensory neuropathy at the 2.4-mg/kg dose level. Discontinuations not related to AEs were because of progressive disease (n = 6) or physician decision (n = 1). The patient was removed from the trial because of rising alpha-fetoprotein, amylase, and lipase levels despite no radiographic progression per RECIST.

What are the next steps for ixotatug vedotin in platinum-refractory GCTs?

Feldman concluded that the phase 1 data support ongoing clinical investigation of ixotatug vedotin in GCTs that have progressed on or after platinum-based chemotherapy.

Other CATALINA-1 expansion cohorts are evaluating ixotatug vedotin in CLDN6-positive platinum-resistant ovarian cancer and refractory non–small cell lung cancer (NSCLC), as well as in combination with bevacizumab (Avastin) in ovarian cancer and with pembrolizumab (Keytruda) in CLDN6-positive NSCLC.

References

1. Oliai C, Feldman DR, Slotkin E, et al. Clinical safety and efficacy of ixotatug vedotin (TORL-1-23), a claudin 6-targeted ADC, as monotherapy in germ cell tumors (GCT). Presented at: 2026 ESMO Congress; October 23-27, 2026; Madrid, Spain. Abstract 1210RO.
2. Lee J-Y, Kim GM, Hendrickson AEW, et al. Preliminary safety and efficacy of ixotatug vedotin (TORL-1-23), a Claudin-6–targeted ADC, in combination with bevacizumab in recurrent ovarian cancer. Presented at: 2025 ESMO Congress; October 17-25, 2026; Berlin, Germany. Poster 140P.