Treatment with IMA203 GEN1 monotherapy in Phase 1a and Phase 1b Cohort A at RP2D demonstrated durable objective responses in melanoma patients with one patient exceeding 12 months and two patients exceeding 15 months post infusion and a 50% (6/12) confirmed objective response rate (cORR). In line with previous results, IMA203 GEN1 monotherapy was well tolerated at total doses up to 10x10⁹ TCR-T cells infused.

In addition, the first data on the company’s second-generation product candidate IMA203CD8 demonstrated 56% (5/9) cORR with enhanced pharmacology and a differentiated response pattern compared to IMA203 GEN1. The company plans to develop IMA203 GEN1 in melanoma and to pursue development of IMA203 in ovarian cancer, uterine cancer, NSCLC, triple-negative breast cancer and other tumor types preferentially with IMA203CD8 GEN2.

The melanoma-focused data on IMA203 GEN1 will be presented today by Martin Wermke, MD, Professor at the University Hospital Dresden and Coordinating Investigator of the ACTengine® IMA203 TCR-T trial, at the 20^th International Congress of the Society for Melanoma Research in Philadelphia, PA, taking place November 6^th-9^th, 2023.

In addition, Dr. Wermke together with Cedrik Britten, MD, Chief Medical Officer at Immatics will provide the complete data update during a conference call and webcast today, November 8 at 8:30 am EST/2:30 pm CET. The presentation is available on Immatics’ website – covering the complete data set including Phase 1a, Phase 1b Cohort A and the deprioritized Cohort B (IMA203 GEN1 combined with nivolumab).

“A cancer diagnosis can be the start of a daunting journey characterized by devastating setbacks when conventional therapies fail. I believe that the updated data on IMA203 GEN1 shows meaningful benefit and long-term durability in melanoma patients,” said Martin Wermke, MD, Coordinating Investigator of the ACTengine® IMA203 TCR-T trial. “With the maturation of the clinical data set, it becomes progressively evident for me that targeting PRAME with Immatics’ IMA203 TCR-T approach has the potential to provide a durable benefit for advanced-stage checkpoint- and BRAF-inhibitor refractory melanoma patients.”

"Today, we are excited to report on the continued clinical progress for our ACTengine® IMA203 TCR-T cell therapies, which we believe have demonstrated meaningful clinical benefit for last-line solid cancer patients treated with IMA203 or its second-generation product candidate IMA203CD8. We now plan to progress IMA203 into a registration-enabling Phase 2 trial in melanoma as quickly as possible, while we believe that our second-generation approach is exhibiting unique patterns in pharmacology guiding our development efforts towards other tumor types such as ovarian, uterine, lung and triple-negative breast cancer", commented Dr. Cedrik Britten, Chief Medical Officer at Immatics. "We plan to provide an update on the clinical development plan for IMA203 in the first quarter of 2024 as well as updates across the entire clinical TCR cell therapy and bispecifics portfolio throughout 2024.”

Clinical data on anti-tumor activity and safety

IMA203 GEN1 in melanoma patients treated at RP2D: IMA203 GEN1 demonstrates a high rate of objective responses with ongoing durability of more than 15 months after treatment

• At data cut-off on September 30, 2023, a total of 16 PRAME-positive patients with cutaneous, uveal or melanoma of unknown primary origin were infused with IMA203 GEN1 at the recommended Phase 2 dose (RP2D, 1-10x10⁹ total TCR-T cells) across Phase 1a or Phase 1b Cohort A.
• IMA203 GEN1 monotherapy continues to be well tolerated. All 16 patients experienced cytopenia (Grade 1-4) associated with lymphodepletion as expected. Patients had mostly mild-moderate cytokine release syndrome (CRS), of which 10 patients (63%) had Grade 1, and 5 patients (31%) Grade 2 and 1 patient (6%) Grade 3 CRS. One non-serious, mild (Grade 1) immune effector cell associated neurotoxicity syndrome (ICANS) was observed. No dose-dependent increase of CRS, no dose-limiting toxicities (DLTs) and no IMA203-related death was observed. The safety profile for non-melanoma patients treated with IMA203 GEN1 was generally consistent with safety in the melanoma subset and is provided in the appendix of the presentation.
• 13 out of 16 infused patients were evaluable for efficacy analysis based on at least one tumor response assessment being available post treatment. These patients received a median total infused dose of 1.73x10⁹ IMA203 TCR-T cells (range 1.07-5.12x10⁹ TCR-T cells).
• Most patients were heavily pre-treated with a median of 4 lines of systemic therapies, thereof a median of 2 lines of checkpoint inhibitors; all 8 cutaneous melanoma patients were checkpoint inhibitor-refractory and 5 of 8 were BRAF inhibitor-pretreated.
• 50% (6/12) confirmed objective response rate (cORR) and 62% (8/13) initial ORR (RECIST 1.1).
• Durability of responses ongoing beyond 12 months in one patient and 15 months in two patients after treatment.
• Median duration of response (mDOR) was not reached (min 2.2+ months, max 14.7+ months) at a median follow-up (mFU) of 14.4 months.
• RP2D has been defined at 1-10x10⁹ total TCR-T cells.
• Cell product manufacturing:
  • 7-day manufacturing process plus 7-day release testing
  • Manufacturing success rate: >95% to reach RP2D
• Immatics has recently received Regenerative Medicine Advanced Therapy (RMAT) designation from the FDA for IMA203 GEN1 in multiple PRAME-expressing cancers, including cutaneous and uveal melanoma, and is now targeting a registration-enabling Phase 2 trial in cutaneous melanoma potentially bundled with uveal melanoma in 2024. Discussions with FDA to align on patient populations, trial design and CMC aspects concerning the planned Phase 2 trial are ongoing.

IMA203CD8 GEN2 in Cohort C: First clinical data set on IMA203CD8 shows an enhanced pharmacology profile with a differentiated response pattern compared to IMA203 GEN1

• At data cut-off on September 30, 2023, a total of 12 PRAME-positive patients were infused with IMA203CD8 GEN2 across DL3 (0.2-0.48x10⁹ TCR-T cells/m² BSA), DL4a (0.481-0.8x10⁹ TCR-T cells/m² BSA) and DL4b (0.801-1.2x10⁹ TCR-T cells/m²) in Cohort C with a median total infused dose of 1.17x10⁹ IMA203CD8 TCR-T cells (range 0.64-2.05x10⁹ TCR-T cells).
• All patients were heavily pre-treated with a median of 3 lines of systemic therapies.
• All patients experienced cytopenia (Grade 1-4) associated with lymphodepletion as expected. 11 out of 12 patients (92%) experienced a cytokine release syndrome (CRS), of which 8 patients (67%) had Grade 1 or 2 CRS, 2 patients (17%) had Grade 3 CRS and 1 patient (8%) had a Grade 4 CRS. The latter patient also had a reported Grade 4 neurotoxicity. No ICANS or neurotoxicity was reported for the other patients. No IMA203CD8-related deaths were observed. Dose-limiting toxicities (DLTs) were reported for 2 of 4 patients treated at DL4b. No DLT was reported for all 4 patients treated at DL3, or all 4 patients treated at DL4a. DL4a dose cohort is ongoing.
• Initial clinical activity was observed with a cORR of 56% (5/9) and initial ORR of 58% (7/12) (RECIST 1.1).
• 6 of 7 responses (including two unconfirmed responses with no subsequent scan available at data cut-off) were ongoing at data cut-off with longest response at >12 months after infusion.
• mDOR was not reached (min 2.0+ months, max 11.5+ months) at a mFU of 4.8 months.
• Reduction of tumor size was observed in 11 out of 12 patients, with a deepening of response from initially stable disease (SD) to partial response (PR) observed in two patients.
• Translational data showed enhanced pharmacology of IMA203CD8 GEN2: trend towards responses at lower T cell dose and higher tumor burden compared to IMA203 GEN1; IMA203CD8 GEN2 achieved higher peak expansion (Cmax) when normalized to infused dose and T cells showed higher initial activation levels without exhaustion over time.

Overview of patient characteristics and anti-tumor activity across IMA203 clinical trial cohorts

* Patients with at least one available tumor response assessment post infusion; ^# All patients were PD at data cut-off; Initial ORR: Objective response rate according to RECIST 1.1 at any post infusion scan; Confirmed ORR (cORR): Confirmed objective response rate according to RECIST 1.1 for patients with at least two available post infusion scans or patients with progressive disease (PD) at any prior timepoint, patients with ongoing unconfirmed PR not included in cORR calculation; Duration of response (DOR) in confirmed responders is defined as time from first documented response until disease progression/death. Patients with ongoing response will be censored at date of data cut-off. Median DOR (mDOR) is analyzed by using the Kaplan-Meier method; Median Follow-up (mFU) is analyzed by using the reverse Kaplan-Meier method.

The full data analysis including IMA203 GEN1 in Phase 1a and Cohort A as well as deprioritized Cohort B (IMA203 in combination with a checkpoint inhibitor), is available as part of the presentation on the company’s website.

Development path for IMA203 GEN1 and IMA203CD8 GEN2 monotherapies
The goal of Immatics’ development strategy is to make its cell therapies targeting PRAME available to the broadest possible solid cancer patient population with an initial focus on the US market. To achieve this, Immatics has announced a three-step development strategy for leveraging the full breadth of PRAME, a target that is highly expressed in various solid cancers.

1. Focus on IMA203 GEN1 in cutaneous melanoma (potentially bundled with uveal melanoma), targeted to enter a registration-enabling Phase 2 clinical trial in 2024. Discussions with FDA to align on patient population, clinical trial design and CMC aspects are ongoing under the RMAT designation achieved for IMA203 GEN1 in multiple cancer types including cutaneous and uveal melanoma. There are up to 3,300 HLA-A*02 and PRAME-positive cutaneous and uveal melanoma last-line patients per year in the US. A next update on the clinical development plan is expected in the first quarter of 2024.
    
2. In parallel, commence dedicated dose expansion cohorts for signal finding in ovarian and uterine cancer, preferentially with IMA203CD8 GEN2. Enrollment of patients with these cancer types is already ongoing. There are up to 9,000 HLA-A*02 and PRAME-positive ovarian and uterine last-line cancer patients per year in the US.
    
3. The development of a broader tumor-agnostic label in PRAME+ solid cancers, including in NSCLC, triple-negative breast cancer, and others. This could leverage the full potential of PRAME across multiple solid cancer types.