TORL-1-23 Shows Promising Activity in CLDN6-Positive Advanced Solid Tumors
核心洞察
TORL-1-23, a CLDN6 (搜索)-targeted antibody-drug conjugate, demonstrates encouraging responses in heavily pretreated patients with advanced solid tumors (搜索), including platinum-resistant ovarian cancer (搜索).
The overall response rate reached 42% at a 2.4 mg/kg dose, with durable and deep responses observed, particularly in ovarian cancer (搜索) patients treated at 2.4 mg/kg and 3.0 mg/kg.
The antibody-drug conjugate was well-tolerated, with manageable safety profiles, and the risk of neutropenia (搜索) was mitigated by prophylactic pegfilgrastim administration.
TORL-1-23, an antibody-drug conjugate (ADC) targeting Claudin-6 (CLDN6 (搜索)), has shown promising activity and tolerability in patients with heavily pretreated, CLDN6-positive advanced solid tumors (搜索), including platinum-resistant ovarian cancer (搜索). These findings come from the phase 1 TORL-123-001 trial (NCT05103683), presented at the 2024 ESMO Congress, and suggest a potential new treatment option for patients with limited alternatives.
Efficacy Across Dose Levels
The trial evaluated TORL-1-23 at various dose levels. In efficacy-evaluable patients, those treated with doses less than 2.4 mg/kg (n = 19) achieved an overall response rate (ORR) of 26%, consisting entirely of partial responses (PRs). Stable disease (SD) was observed in 42% of patients, while 32% experienced progressive disease (PD). At a dose of 2.4 mg/kg (n = 19), the ORR increased to 42%, with all responders achieving a PR. The rates of SD and PD were 47% and 11%, respectively. A higher dose of 3.0 mg/kg (n = 26) resulted in an ORR of 31%, including a complete response rate of 4% and a PR rate of 27%, with SD and PD rates of 46% and 23%, respectively.
Notable Responses in Ovarian Cancer
Patients with CLDN6 (搜索)-positive platinum-resistant ovarian cancer (搜索) demonstrated particularly encouraging responses. 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.
According to lead study author Dr. Gottfried E. Konecny, the ADC was well-tolerated with a favorable safety profile. Prophylactic pegfilgrastim was used to mitigate the risk of neutropenia (搜索), 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 (搜索) treated at 2.4 mg/kg and 3.0 mg/kg," Dr. Konecny stated during the presentation.
Study Design and Patient Characteristics
The phase 1, two-part, multicenter, first-in-human study enrolled patients aged 18 years or older with advanced solid tumors (搜索), measurable disease per RECIST 1.1 criteria, an ECOG performance status of 0 or 1, and adequate organ function. TORL-1-23 was evaluated at 11 dose levels, ranging from 0.2 mg/kg to 3.6 mg/kg. Prophylactic pegfilgrastim was administered at dose levels 9 (3.0 mg/kg), 10 (4.0 mg/kg), and 11 (3.6 mg/kg).
The dose-expansion portion of the study included patients with CLDN6 (搜索)-positive platinum-resistant ovarian cancer (搜索), CLDN6-positive refractory non–small cell lung cancer (NSCLC (搜索)), other CLDN6-positive refractory cancers, and CLDN6-low refractory cancers. Approximately 10 to 20 patients were treated at both 2.4 mg/kg and 3.0 mg/kg within each group.
In the dose-escalation portion (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 (搜索) (n = 2), and other (n = 2). Patients had received a median of 4 prior lines of therapy (range, 1-9). Thirty-eight patients had CLDN6 (搜索)-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 (搜索) (n = 6), and other (n = 3). Patients received a median of 3 prior lines of therapy (range, 1-4). Twenty-seven patients had CLDN6 (搜索)-positive disease per IHC.
Safety and Tolerability Profile
In patients with platinum-resistant ovarian cancer (搜索), 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 (搜索) (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 (搜索) (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%).
Future Directions
"There is a registrational phase 2 study being initiated globally in CLDN6 (搜索)-positive platinum-resistant [ovarian cancer (搜索)], and the molecule is under further evaluation in other CLDN6-positive cancers, including NSCLC (搜索)," Konecny concluded. This highlights the potential of TORL-1-23 as a targeted therapy for a range of CLDN6-expressing malignancies.