NEW YORK – In a first-in-human trial, TORL BioTherapeutics' investigational antibody-drug conjugate TORL-1-23 demonstrated encouraging, albeit early, efficacy in patients with advanced solid tumors, particularly those with claudin 6-expressing ovarian cancer.
The drug involves a claudin-6 (CLDN6)-targeting antibody linked to a monomethyl auristatin E (MMAE) cytotoxic payload.
Gottfried Konecny, a gynecologic oncologist at the University of California, Los Angeles, presented data from a Phase I trial at the European Society for Medical Oncology Congress in Barcelona, Spain, on Sunday. The first-in-human trial features dose-escalation and -expansion portions.
The drug's target, the oncofetal protein CLDN6, is highly expressed in certain cancers but not in normal tissue. Konecny demonstrated this during his presentation, based on analysis of 54 types of normal tissues, which lacked CLDN6 expression. Other drug targets such as TROP2, folate receptor 1, and CDH6, on the other hand, are expressed on normal tissues, including in the lung.
In this study, advanced cancer patients didn't have to be positive for CLDN6 expression to enroll. Researchers are still assessing the association of the biomarker with patients' outcomes, and Konecny did not share data on CLDN6 expression levels during the ESMO presentation.
So far, Konecny said 51 patients have enrolled in the dose-escalation portion of the trial, and 31 patients have enrolled in the dose-expansion portion. The patients in the trial are heavily pretreated, having received a median of four prior lines of therapy.
Across all patients, CLDN6 expression levels, and doses, the overall response rate was 26 percent on a less than 2.4 milligram per kilogram dose of TORL-1-23; 42 percent on a 2.4 milligram per kilogram dose of the drug; and 31 percent on a 3 milligram per kilogram dose.
When investigators looked specifically at patients with CLDN6-positive platinum-resistant ovarian cancer, they found particularly encouraging response rates. At the 2.4 milligram per kilogram dose of TORL-1-23, the overall response rate was 50 percent among 19 CLDN6-positive platinum-resistant ovarian cancer patients, and the disease control rate was 89 percent. At the 3 milligram per kilogram dose, the overall response rate was 42 percent among 26 CLDN-positive platinum-resistant ovarian cancer patients, and the disease control rate was 77 percent.
"The promising activity was confirmed as being durable and deep, particularly in the ovarian cancer patients treated at [these dose levels]," Konecny said, highlighting that around 50 percent of high-grade serous ovarian cancer patients express CLDN6 at a level of more than 30 percent.
In terms of toxicities, around half of the patients on TORL-1-23 had neutropenia. "However, we were able to completely ameliorate this … in the expansion cohort," Konecny said, using the agent pegfilgrastim. Roughly half of the patients also experienced neuropathy, though most of it was grade 1 or grade 2. The investigators didn't see any lung toxicities, Konecny said.
"TORL-1-23 is a very well-tolerated antibody-drug conjugate with a favorable safety profile, [and] … we see encouraging antitumor activity in heavily pretreated patients," he said. "Deep and durable responses were seen in CLDN6-positive platinum-resistant ovarian cancer. This product could give us a bigger therapeutic window when trying to avoid toxicities."
Based on the encouraging responses in the ovarian cancer group, Konecny said that TORL BioTherapeutics is now advancing the antibody-drug conjugate into a Phase II, registration-directed clinical trial in CLDN6-positive ovarian cancer. And the molecule is under further evaluation in other CLDN6-positive cancers including non-small cell lung cancer.
Meanwhile, the Phase I trial is still accruing patients in the dose-expansion portion, including those with CLDN6-positive platinum-resistant ovarian cancer, CLDN6-positive refractory non-small cell lung cancer, and other CLDN6-positive refractory cancers as well as a fourth cohort for those with CLDN6-negative or -low refractory cancers.
The trial is "good news so far," agreed Jean Emmanuel Kurtz, a medical oncologist at the University of Strasbourg in France, during a discussion of the trial. "There is significant activity in heavily pretreated patients, [and] the overall response rate is impressive … in the setting of platinum-resistant ovarian cancer."
In contrast to the 40 percent to 50 percent overall response rates observed with TORL-1-23, Kurtz noted that the overall response rate typically seen among platinum-resistant ovarian cancer patients on chemotherapy is between 10 percent and 20 percent. Several other treatment combinations in this patient setting have demonstrated higher response rates but with greater toxicity, he added.
Even so, Kurtz raised several key questions, including the level of responses across different CLDN6 positivity thresholds.
"Is there any correlation between efficacy and staining intensity?" he asked. "Do patients with CLDN6 negativity respond to the drug?"
During a press conference at the ESMO Congress on Saturday morning, Isabelle Ray-Coquard, an oncologist at Lyon University in France, posed similar questions about the association between this biomarker and treatment outcomes. "It's a problem we will have to resolve," she said, whether patients must be tested for CLDN6 expression to decide who gets TORL-1-23. "This question is not answered, but I'm sure it will be in the future."
At this meeting, Konecny did not share how patients fared on TORL-1-23 based on different CLDN6 expression levels, including those who were CLDN6 negative. If TORL BioTherapeutics were to launch a trial that restricts enrollment to only CLDN6-expressing ovarian cancer patients, the enrollment criteria would need a threshold for CLDN6 positivity.
The number of patients who've been treated with TORL-1-23 is, as of now, too small to draw any definitive conclusions, in Ray-Coquard's view, though she said that the early data show that CLDN6 is "definitely a target for ovarian cancer."
Beyond the promising activity of the therapy and the validation it lends to CLDN6 as an ovarian cancer biomarker, Ray-Coquard said that as an academic, she's been encouraged by the fact that an academic group has formed the company now bringing TORL-1-23 to a potentially registration-directed trial.
Los Angeles-based TORL BioTherapeutics, which launched in 2023, was born out of UCLA's Slamon Research Lab. Earlier this year, it raised $158 million in a Series B funding round, which the firm is putting toward developing both TORL-1-23 and a pipeline of other investigational agents, including CLDN18.2 and CLDN6-targeting antibody-drug conjugates and monoclonal antibodies. "This pharma company is the spinoff of a university, and for me, it is important to see that an academic is about to bring a drug for patients," Ray-Coquard said.