CLDN6-Directed Agents Generate Encouraging Early Activity in Solid Tumors

The tight junction protein claudin 6 (CLDN6) has emerged as a potential therapeutic target in multiple solid tumor types, prompting the development of CLDN6-targeted agents, including antibody-drug conjugates (ADCs) and a chimeric antigen receptor (CAR) T-cell agent that can be used in combination with an accompanying CAR cancer vaccine.

“CLDN6 is an important component of cell-to-cell tight junctions, [and] it plays a role in the regulation of epithelial and endothelial cell proliferation and differentiation,” Manish R. Patel, MD, director of drug development at Florida Cancer Specialists & Research Institute in Sarasota, Florida, said in an interview with OncologyLive. “It is nearly absent in normal adult tissue but is expressed in several tumor types, including ovarian, endometrial, gastric, and non–small cell lung cancer [NSCLC], as well as germ cell tumors. There are also a lot of data [that show CLDN6 expression] can be associated with poor prognosis.”

CLDN6 is one of 27 CLDN family proteins and is located on chromosome 16p13.3.1 It has 4 transmembrane domains and a PDZ-binding region at the carboxyl end of the cytoplasm. CLDN6 can bind with signal proteins and cytoskeletal proteins, allowing it to participate in the cellular response to external and intracellular signal transmission. Notably, it is the only CLDN protein to display potential specificity to activate cell adhesion signals and regulate the activity of nuclear receptors.

During the 2024 European Society for Medical Oncology (ESMO) Congress, investigators presented findings from 3 phase 1 studies evaluating CLDN6-directed agents that showed signals of promising efficacy and tolerability, underscoring the value of the protein as a potential therapeutic target in gynecologic malignancies and other tumor types.2-4

CLDN6-Targeted ADCs Display Single-Agent Activity

Patel presented findings from a first-in-human phase 1 study (NCT05394675) examining DS-9606 monotherapy in patients with advanced or metastatic solid tumors known to express CLDN6, although CLDN6 expression was not required for enrollment.2 “DS-9606 is an ADC composed of a humanized anti-CLDN6 monoclonal antibody with a cleavable linker to a modified pyrrolobenzodiazepine [PBD] payload,” Patel explained.

Eligible patients in the dose-escalation phase needed to experience disease progression on standard-of-care therapies for metastatic disease, have an ECOG performance status of 1 or less, have received no prior CLDN6-targeted agents or ADCs that deliver a PBD payload, and have adequate cardiac and pulmonary function, including no history of or current interstitial lung disease/pneumonitis. During the dose-escalation phase, patients received intravenous DS-9606 every 3 weeks at dose levels ranging from 0.016 mg/kg to 0.225 mg/kg. The study population (n = 53) included patients with ovarian cancer (35.8%), germ cell tumors (20.8%), gastric/gastroesophageal junction (GEJ)/esophageal adenocarcinoma (13.2%), NSCLC (13.2%), pancreatic cancer (9.4%), breast cancer (3.8%), and endometrial cancer (3.8%).

At the June 14, 2024, data cutoff, preliminary efficacy findings from the study demonstrated that the response was highest with the 0.150-mg/kg dose, with 3 of 12 patents achieving a confirmed objective response per RECIST 1.1. Four patients—2 with germ cell tumors, 1 with NSCLC, and 1 with gastric/GEJ/esophageal adenocarcinoma—experienced an objective response per RECIST 1.1.

Among patients with germ cell tumors (n = 7), the 2 responders achieved a partial response (PR) per RECIST 1.1 and remained on treatment for more than 6 months. Most of these patients (n = 5) had a reduction in tumor markers of at least 90%.

“In terms of efficacy, these were some promising results,” Patel said. “There were 4 confirmed PRs, but there were [also] other patients who had reduction of disease, and there were several patients who had reduction of their blood tumor markers. When you look at the waterfall plot and dive into the germ cell tumor responses, those are very interesting.”

Regarding safety, no dose-limiting toxicities (DLTs) were reported, and the maximum tolerated dose (MTD) and recommended dose for expansion were not yet determined (Table).2 Across dose levels, any-grade treatment-emergent adverse effects (TEAEs) occurred in 84.9% of patients, with 52.8% being deemed related to treatment. Grade 3 or higher and serious TEAEs were reported in 30.2% of patients each. There were no grade 5 TEAEs, and the most common any-grade TEAEs included nausea (18.9%), fatigue (18.9%), and anemia (17.0%).

“At the data cutoff, there were no cases of pneumonitis, and all the AEs after that data cutoff were mostly low-grade cutaneous toxicities,” Patel said. “In terms of the future, dosing continues. The dose hasn’t been declared yet, but once it is there, there are plans to focus on some of these tumor types in further enrollment, either in this trial or in other trials; that’s to be determined.”

Results of another first-in-human, phase 1 study (NCT05103683) were presented during the 2024 ESMO Congress. In the trial, investigators are evaluating TORL-1-23, a novel CLDN6-directed ADC in patients with advanced solid tumors.3 The study included patients with ovarian (n = 14), testicular (n = 1), and endometrial cancers (n = 6), as well as NSCLC (n = 6) and other tumor types (n = 3). The primary objectives were to determine the safety, tolerability, DLTs, MTD, and recommended phase 2 dose of TORL-1-23 monotherapy.

“TORL-1-23 has a very high specificity for CLDN6,” Gottfried E. Konecny, MD, the presenting author of the study, said in an interview with OncologyLive. “There are many CLDN proteins, but it doesn’t cross-react with other CLDNs. This has been shown on a laboratory level, which is very important because the homology [with] CLDN6 is very high. Some of [the proteins] only differentiate each other by a few amino acids. I believe we can safely say that it’s a very specific antibody for CLDN6. It has a cleavable linker and microtubule inhibitor as a payload, monomethyl auristatin, which is in clinic in a number of other ADCs that are approved already.”

Konecny is the lead clinician for gynecologic oncology in the Department of Medicine at UCLA Health in Los Angeles, California.

Preliminary efficacy data from the trial revealed that there was activity in 73% of patients treated across dose levels and tumor types. Patients receiving the 0.2- to 2.0-mg/kg dose (n = 19) achieved an objective response rate (ORR) of 26%; those who received TORL-1-23 at the 2.4-mg/kg (n = 19) or 3.0-mg/kg dose levels (n = 26) experienced ORRs of 42% and 31%, respectively.

Notably, patients with CLDN6-positive platinum-resistant ovarian cancer treated with the 2.4-mg/kg dose (n = 8) achieved an ORR of 50%, and those treated at the 3.0-mg/kg dose (n = 12) experienced an ORR of 42%. The preliminary median duration of response (DOR) among these patients was approximately 22 weeks and approximately 30 weeks at the 2.4-mg/kg and 3.0-mg/kg dose levels, respectively.

In terms of safety, patients across tumor types receiving the 0.2- to 2.0-mg/kg dose (n = 19) experienced any-grade AEs including fatigue (26%) neuropathy (26%), anemia (11%), neutropenia (11%), nausea (11%), diarrhea (11%), and alopecia (11%). At the 2.4-mg/kg dose (n = 6), patients experienced any-grade alopecia (67%), anemia (50%), and neutropenia (50%). Any-grade AEs in the 3.0-mg/kg dosing group (n = 11) included anemia (64%), fatigue (64%), and alopecia (64%). In the dose-expansion part, patients who received TORL-1-23 at the 2.4-mg/kg dose level (n = 16) experienced any-grade AEs including nausea (67%), fatigue (56%), and alopecia (56%).

Determination of the MTD was ongoing at the time of data cutoff. A registrational phase 2 study of TORL-1-23 in patients with CLDN6-positive platinum-resistant ovarian cancer is being initiated, and the agent is also under evaluation in other CLDN6-positive cancers, including NSCLC.

CLDN6 Shows Potential as mRNA Vaccine, CAR T-Cell Therapy Component

Beyond being used as a therapeutic target in the development of ADCs, CLDN6 is also being examined as a target for a novel CAR T-cell agent in combination with a CAR vaccine.4 In a first-in-human phase 1 study (NCT04503278), the investigational candidate BNT211 is combining these 2 approaches for the treatment of patients with relapsed/refractory CLDN6-positive solid tumors. Eligible patients needed to have at least 50% of tumor cells express CLDN6 via an immunohistochemistry score of 2+/3+, measurable disease per RECIST 1.1 or an elevated tumor marker, and an ECOG performance status of 1 or 0.

In part 1 of the dose-escalation phase, patients received CLDN6 CAR T-cell monotherapy. In part 2, the CAR T-cell component was combined with the CAR vaccine. The primary end points were safety and tolerability. Secondary end points included ORR, disease control rate (DCR), and DOR.

Preliminary efficacy data shared during the 2024 ESMO Congress showed that response-evaluable patients (n = 64) in the overall population (n = 74) achieved an ORR of 32.8% (95% CI, 18.5%-40.1%), including 3 patients with a complete response. The DCR was 67.2% (95% CI, 46.1%-69.5%). Response-evaluable patients who received the CAR T-cell agent at a dose of at least 1 × 108 cells with 100% lymphodepletion in combination with the CAR vaccine (n = 33) achieved an ORR and DCR of 51.5% (95% CI, 26.3%-57.9%) and 84.8% (95% CI, 51.9%-81.9%), respectively.

Efficacy-evaluable patients with testicular cancer (n = 25) in the overall population (n = 27) achieved an ORR of 24.0% (95% CI, 8.6%-42.3%) and a DCR of 56.0% (95% CI, 32.0%-71.3%). Evaluable patients (n = 12) who received the CAR T-cell agent at a dose of at least 1 × 108 cells with 100% lymphodepletion in combination with the CAR vaccine (n = 14) experienced an ORR of 41.7% (95% CI, 12.8%-64.9%) and a DCR of 75.0% (95% CI, 35.1%-87.2%).

Efficacy-evaluable patients with ovarian cancer (n = 24) in the overall population (n = 30) achieved an ORR of 33.3% (95% CI, 12.3%-45.9%) and a DCR of 75.0% (95% CI, 40.6%-77.3%). Evaluable patients (n = 12) who received the CAR T-cell agent at a dose of at least 1 × 108 cells with 100% lymphodepletion in combination with the CAR vaccine (n = 16) experienced an ORR of 58.3% (95% CI, 19.8%-70.1%) and a DCR of 83.3% (95% CI, 35.4%-84.8%).

In terms of safety, all patients who received CAR T-cell monotherapy and the vaccine-containing combination (n = 78) experienced an any-grade TEAE. Most patients also experienced a grade 3 or higher TEAE (91.0%), a serious AE (57.7%), any-grade treatment-related AEs (TRAEs; 92.3%), and grade 3 or higher TRAEs (66.7%). DLTs and TEAEs leading to treatment discontinuation occurred at rates of 9.0% and 2.6%, respectively.

“CAR T-cell therapy in solid tumors is fraught with high toxicity and, in some cases, mortality,” Konecny said. “There is a clear limitation based on the complexity, toxicity, and cost of this approach. But [the drug’s developer] may have the bandwidth to make it more cost-efficient and possibly safer. I am looking forward to [additional] data. They are expanding beyond platinum-resistant ovarian cancer, with male germ cell tumors particularly of interest.”

References

1. Du H, Yang X, Fan J, Du X. Claudin 6: therapeutic prospects for tumours, and mechanisms of expression and regulation (review). Mol Med Rep. 2021;24(3):677. doi:10.3892/mmr.2021.12316
2. Patel MR, Hamilton EP, Piha-Paul SA, et al.Preliminary results from a phase I, first-in-human study of DS-9606a, a claudin 6 (CLDN6)-directed antibody-drug conjugate (ADC), in patients (pts) with tumor types known to express CLDN6. Ann Oncol. 2024;35(suppl 2):S488-S489. doi:10.1016/j.annonc.2024.08.677
3. Konecny GE, Wahner Hendrickson AE, 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 patient with advanced solid tumors. Ann Oncol. 2024;35(suppl 2):S551. doi:10.1016/j.annonc.2024.08.783
4. Haanen JBAG, Mackensen A, Schultze-Florey C, et al. Updated results from BNT211-01 (NCT04503278), an ongoing, first-in-human, phase I study evaluating safety and efficacy of CLDN6 CAR T cells and a CLDN6-encoding mRNA vaccine in patients with relapsed/refractory CLDN6+ solid tumors. Ann Oncol. 2024;35(suppl 2):S489-S490. doi:10.1016/j.annonc.2024.08.678