BNT211 With or Without CARVac Shows Early Activity in CLDN6+ R/R Advanced Solid Tumors

The Claudin-6 (CLDN6)–directed CAR T-cell therapy, BNT211, showed signs of clinical activity in patients with CLDN6-positive relapsed or refractory solid tumors, according to updated data from the phase 1/2a BNT211-01 trial (NCT04503278) presented at the 2023 ESMO Congress.^1,2

At a follow-up of 94.5 days (range, 9-401), 30 patients had experienced treatment-emergent adverse effects (TEAEs) that were grade 3 or higher and related to the investigational medicine; 14 patients had treatment-emergent serious AEs related to the investigational product. Four patients experienced dose-limiting toxicities (DLTs). Moreover, 23 patients had cytokine release syndrome and 2 patients had immune effector cell–associated syndrome. Twelve patients died.

In the 38 efficacy-evaluable patients, the overall response rate (ORR) was 44.7%, which included 17 patients with a partial response (PR) or a complete response (CR) and 11 patients who had stable disease (SD); 10 patients experienced progressive disease (PD). The disease control rate (DCR) was 73.7%.

Notably, in the 22 efficacy-evaluable patients who received the product at dose level 2, which was 1 x 108 CAR T cells, with or without CAR T-cell Amplifying RNA Vaccine (CARVac), the ORR was 59.1%, with 13 patients achieving a PR or CR, 8 patients having SD, and 1 experiencing PD. The DCR in this group was 95.5%.

“CARVac improved CAR T persistence, leading to sustained, ongoing detection up to 100 days in several patients at dose level 2,” said John BAG Haanen, MD, professor of Translational Immunotherapy of Cancer at Leiden University in the Netherlands, in a presentation of the data. “…Toxicities at higher dose level led to further evaluation of safety via backfilling into several cohorts.”

BNT211 is a CAR T-cell therapy that is targeted to the oncofetal antigen CLDN6, which is expressed on several solid tumors like ovarian cancer, sarcoma, testicular cancer, endometrial cancer, and gastric cancer. For BNT211-01, investigators set out to evaluate the autologous CLDN6 CAR T cells alone and paired with a CLDN6-encoding CARVac, which is a nanoparticulate RNA vaccine.

The first-in-human, open-label, multicenter trial enrolled patients with relapsed or refractory advanced CLDN6-positive solid tumors with at least 50% tumor cells with 2+/3+ CLDN6 positivity on immunohistochemistry and measurable disease by RECIST v1.1 criteria. Patients needed to have an ECOG performance status of 0 or 1.

Lymphodepletion was given before the infusion of the CAR T-cell therapy on day 1. Subsequently, escalating doses of the CAR T cells were evaluated with or without CLDN6 CARVec given at a fixed dose from day 4 at 50 ug and then 100 ug every 3 weeks for 5 cycles and then every 6 weeks.

In the phase 1 dose-escalation portion of the trial investigators evaluated a manual product and an automated product. The evaluation of the former was completed and reported at the 2022 ESMO Congress. The latter is ongoing, and the CAR T-cell therapy is being evaluated at dose level 0, which is 1 x 10⁶ CAR T cells (n = 2); dose level 1, which is 1 x 10⁷ CAR T cells (n = 4); dose level 2, which is 1 x 10⁸ CAR T cells (n = 13); and dose level 3, which is 2 to 5 x 10⁸ CAR T cells (n = 7). The product is also under evaluation at dose levels 1 (n = 4), 2 (n = 14), and 3 (n = 0) with fixed CARVac.

The primary end points of the research are safety and tolerability and to evaluate DLTs. Secondary end points include immunogenicity, ORR, DCR, duration of response, and progression-free survival.

The aim of the current analysis was to determine the safety and preliminary efficacy of the automated BNT211 product with or without CARVac. At a data cutoff date of September 10, 2023.

In the total population, the age was 48 years (range, 26-69). Most patients were male (n = 25) and had CLDN6 2+/3+ cells (95%). Patients had epithelial ovarian cancer (n = 17), germ cell tumor (GCT; n = 16), or another indication (n = 11). The number of prior lines of treatment received was 4 (range, 2-9).

Additional data showed that in the 9 efficacy-evaluable patients who received the CAR T-cell product below dose level 2, the ORR was 11.1%, which included 1 patient who had a PR/CR and 1 who experienced SD; 7 patients had PD. The DCR in this group was 22.2%. In the 7 efficacy-evaluable patients who received greater than dose level 2, the ORR was 42.9%, and this comprised 3 PR/CRs and 2 patients who achieved SD. Two patients experienced PD. Here, the DCR was 71.4%.

“Backfilling to determine the recommended phase 2 dose for CLDN6 CAR T cells for a pivotal trial in [patients with] GCT is currently ongoing,” Haanen concluded.

Editor’s Note: Dr Haanen declared consulting or advisory fees from AstraZeneca, Achilles Tx, BioNTech, Bristol Myers Squibb, CureVac, Eisai, Gadeta, Imcyse, Instil Bio, Iovance Bio, Ipsen, Merck Serono, Molecular Partners, MSD, Neogene Therapeutics, Novartis, Pfizer, Roche/Genentech, Sanofi, PokeAcell, Scenic, Third Rock Ventures, and T-Knife. Grant support was received from Amgen, Asher Bio, BioNTech US, Bristol Myers Squibb, MSD, Novartis, and Sastra Cell Therapy. He is also editor-in-chief of ESMO IOTECH.

References

1. Mackensen A, Haanen JBAG, Alsdorf W, et al. LBA35 BNT211-01: interim results from a repeat dose escalation study of CLDN6 CAR-T cells manufactured with an automated process +/- a CLDN6-encoding CAR-T cell-amplifying RNA vaccine (CARVac). Ann Oncol. 2023;34(suppl 2):S1274-S1275. doi:10.1016/j.annonc.2023.10.027
2. BioNTech presents positive phase 1/2 data update for CAR-T cell therapy candidate BNT211 in advanced solid tumors at ESMO Congress 2023. News release. BioNTech SE. October 23, 2023. Accessed November 3, 2023. https://investors.biontech.de/news-releases/news-release-details/biontech-presents-positive-phase-12-data-update-car-t-cell