Two long-term follow-up data from GRACELL GC012F are now available

As an industry with scientific research progress as the core driving force, the field of innovative drugs is gradually undergoing baptism and return after a period of ups and downs. Those enterprises that can produce excellent data and actively promote clinical progress will eventually traverse the fog and get back on track.

At the just concluded ASCO and EHA annual meetings, Gracell continuously released the latest clinical data of autologous FasTCAR-T GC012F (BCMA/CD19) and allogeneic CAR-T GC007g from healthy donors. Results of two long-term clinical studies of GC012F for two different indications were included in oral presentations at ASCO and EHA, respectively.

Specifically, ASCO, long-term follow-up data for GC012F in relapsed/refractory multiple myeloma (r/r MM) and B-cell non-Hodgkin lymphoma (B-NHL) strongly validate these findings. The overall response rate (ORR) of GC012F for r/r MM was 93.1%.

Minimal residual disease (MRD) refers to cancer patients during or after treatment, the residual content of malignant tumor cells in the body may be minimal, but it may still cause cancer recurrence.

For GC012F, two long-term follow-up data showed that 82.8% of patients achieved MRD-negative stringent complete remission (MRD-sCR), and 100% of patients achieved MRD-status. With a median follow-up of 30.7 months at the time of data cutoff, the median progression-free survival (mPFS) was 38 months, and GC012F had a longer duration of response.

In particular, patients who achieve MRD-negative (that is, deep response) mentioned above have shown more significant PFS benefits in clinical trials. In the MRD-sCR group (82.8% of the total), 34% of the patients were able to maintain this status for more than 12 months, with a positive result: the progression-free survival rate at 36 months may reach 100%.

The clinical data for GC012F were based on a population of patients who had received an average of five lines of therapy and had triple exposure to standard MM therapies. Among them, 90% of patients belong to the high-risk group, and 83% of patients "do not respond" to the last treatment, leading to disease progression again, so it is difficult to treat.

Compared with the traditional single-target therapy, the CD19/BCMA dual-target design can be more helpful to improve the efficacy and reduce the recurrence rate caused by antigen escape. For 9 B-NHL patients with a high tumor load who had received severe treatment previously, the clinical data results of GC012F showed that after 3 months of treatment, the ORR reached 100% and the CR rate was 78%. By six months, the CR rate was maintained at 67%.

The data showed that only 7% of r/r MM patients treated with GC012F experienced grade ≥ 3 CRS and no ICANS of any type. One patient with B-NHL had grade 3 or higher CRS, and no ICANS occurred. No second primary malignancy (SPM) was observed in the GC012F-r /r MM study.

In EHA 2023, the first phase 1 long-term follow-up data of GC007g treatment for r/r B-ALL patients ineligible for autologous CAR-T therapy were also published. This study showed that GC007g treatment had a rapid response, with 100% of patients achieving MRD-CR /CRi at day 28 after completion of infusion. At the same time, GC007g has long-term potential, with 78% of patients remaining in CR/CRi at a median follow-up of 445 days. The 1-year progression-free survival (PFS) and overall survival (OS) rates were 76.2% and 85.7%, respectively.

The high ORR makes CAR-T therapy a surprise from the beginning. The competition between CAR-T therapies mainly involves the competition of therapeutic effect and safety.

Although showing high efficacy, the marketed CAR-T therapy has been plagued by safety. The elimination of tumor cells by CAR-T cells is accompanied by the release of a large number of cytokines, which will trigger a strong activation of the immune system in vivo, which is easy to cause cytokine release syndrome (CRS). At the same time, if there is CRS in the brain or abnormal expansion of CAR-T cells in the cerebrospinal fluid, it is also easy to cause immune effector cell-associated neurotoxicity syndrome (ICANS).

CRS and ICANS are the most common side effects of CAR-T cell therapy, which may endanger the life of patients once they are not controlled. Although timely clinical detection and early intervention can avoid the occurrence of tragedy, the difficulty is how to ensure timely detection and early intervention, because this requires extremely high medical conditions. Therefore, the safety of CAR-T therapy is one of the key factors affecting the commercialization prospect.

On the one hand, safety directly determines whether the therapy can advance to the front line, and even becomes a key element of first-line medication. Because the core element of becoming a first-line drug is to show superiority at the level of OS data, and the toxic side effects will eventually lower the OS data of patients and affect the PK results with existing therapies.

On the other hand, safety concerns will affect whether a therapy can be used in U.S. outpatient Settings. In the United States, medication for patients with cancer involves both outpatient care and inpatient care. Compared with inpatient treatment, outpatient treatment is more convenient and can reach more patients.

Once CAR-T therapy involves toxic side effects such as grade 3 or above CRS or ICANS, physicians often recommend inpatient administration, which will affect the patient population it can reach.

Clearly, only safer CAR-T therapies can increase patient reach and value. This is also the direction of many pharmaceutical companies.

In the real world, it is expected that 5%-6% of patients will miss the treatment window because the CAR-T product does not meet the release criteria or the manufacturing cycle is delayed. It is reported that under the premise of ensuring efficacy and safety, the FasTCAR next day production technology platform by reducing the tedious and complex in vitro expansion process, only 22-36 hours (traditional process takes several weeks) to complete production.