Mounzer Agha, MD, University of Pittsburg School of Medicine Hillman Cancer Center, shares data from the multi-cohort phase 2 CARTITUDE-2 study evaluating the efficacy and safety of ciltacabtagene autoleucel (cilta-cel), a BCMA-directed CAR T-cell therapy, in patients with progressive multiple myeloma (MM) who received up to 3 prior lines of therapy, the data of which was presented at the virtual 2021 American Society of Clinical Oncology (ASCO) Annual Meeting.

Transcript

Good morning. I'm Mounzer Agha from the University of Pittsburgh Hillman Cancer Center. It is my pleasure to present to you on behalf of my colleagues our data on the efficacy and safety of the BCMA-directed CAR-T therapy ciltacabtagene autoleucel is patients with progressive multiple myeloma after 1 to 3 lines of therapy.

I have nothing to disclose.

Treatment options are limited for patients who have progressive multiple myeloma after 1 to 3 lines of treatment, who are refractory to lenalidomide and proteasome inhibitors.

There's clearly an unmet need for novel and durable treatment options in this patient population.

Cilta-cel is a CAR T-cell therapy expressing 2 BCMA-targeting single-domain antibodies designed to confer avidity.

CARTITUDE-2 is a multicohort phase 2 study. Cilta-cel is being evaluated in patients with multiple myeloma in earlier-line setting, as opposed to the CARTITUDE-1, which has already been published extensively, with patients who had multiple lines of therapy, basically unlimited prior lines of therapy. In this Cohort A, we have limited the prior lines of therapy to 1 to 3 lines only.

I will present to you the data on our first 20 patients. The median follow-up of data is 5.8 months. As you can see here, we have cohort A, B, C, D, and E. The cohort that I will be discussing today is cohort A and the first 20 patients. Patients who have had progressive disease after one to three lines of therapy. They must be lenalidomide-refractory.

After enrolling on the study, the patient will undergo apheresis, and the T-cell transduction and extension to manufacture the cilta-cel will be started. Once the cells are ready, the patient would undergo lymphodepletion. Then they will have a single infusion of cilta-cel with a target cell dose of 0.75*10^6 CAR T-cells/kg.

It is important to note that we allowed bridging therapy in the interval between the apheresis and during the cilta-cel manufacturing.

The primary objective of the study was MRD -10^-5 as assessed by next-generation sequencing. The secondary objective was the overall response rate, the duration of the response, the time and the duration of the MRD-negativity, and of course the incidence and severity of the adverse effects.

This is the summary of the patient characteristics. As you can see here, patients were allowed up to 3 lines of prior therapy. The median was 2 lines. It's very important to note that 35% of the patients had high-risk cytogenetics, including 17p deletion in 50% of the patients and translocation (14;16) in 25% of the patients.

Eighty-five percent of the patients had undergone autologous stem cell transplantation. Sixty-five percent were triple class-exposed and 40% were triple class-refractory. Although those patients were in the earlier treatment lines, they had significant prior exposure and refractory disease.

Forty percent were refractory to bortezomib, 10% refractory to carfilzomib, 35% refractory to pomalidomide. 60% were actually refractory to daratumumab. In all, 95% of the patients were refractory to the last prior line of therapy.

Despite this, the overall response was a very impressive 95%, with 75% complete remission and 45% stringent complete remissions. The median time to first response was 1 month. The median time to complete remission or better was very short, 1.9 months. All patients with an MRD-evaluable sample to the 10^-5 threshold were MRD-negative at the time of the data collection.

This slide shows that the duration of the response continues. The responses continue to deepen over time. There has been no progression of disease with a median follow-up of 5.8 months.

As you can see, we put a line at the 9-month benchmark because that's the point where we saw the maximum response in CARTITUDE-1. Therefore, this goes on to say that the responses will continue up until that point. We predict that the response will continue to deepen with time.

The safety profile was quite manageable. The majority of the non-hematologic adverse events were mild. There were rare grade 3 to 4 toxicity. The adverse events were primarily hematologic, with neutropenia, thrombocytopenia, anemia, lymphopenia, and leukopenia, which happen in the majority of patients.

They also happen at a grade 3 to 4 significantly, 90% had neutropenia, 35% thrombocytopenia, 40% anemia. However, the incidence of prolonged grade 3 to 4 cytopenia beyond 60 days was only 25% for lymphopenia, none for the thrombocytopenia, and 45% for lymphopenia.

The most important safety profile for any CAR T therapy is the CRS and the neurotoxicity. Eighty-five percent of our patients developed CRS events. The time of onset was 7 days. It's important to note this is delayed onset compared to other CAR T therapy. The duration of the CRS was 3.5 days.

It is also important to note that the maximum grade of CRS was grade 1 to 2. Only 5% of patients developed grade 3 or grade 4 CRS. The CRS resolved or recovered in 94% of the patients at the time of the data cutoff.

The neurotoxicity with ICANS happened in 15% of the patients, with a median time of onset of 8 days and a median duration of 2 days. There were no cases of movement or neurocognitive treatment-emergent adverse events.

We've identified that there are risk factors for the development of movement and neurocognitive treatment-emergent adverse events. These risk factors include high tumor burden, grade 2 CRS, development of ICANS, and high CAR T expansion and persistence.

Because of that, we implemented patient management and mitigation strategies that included enhanced bridging therapy to reduce the tumor burden, early and aggressive treatment of CRS and the ICANS. We implemented handwriting assessment and extended monitoring to alert us on the development of the neurotoxicity.

With that, more than 100 additional patients have been dosed. This was shown to be a reliant and effective implementation of these patient management strategies.

In summary, we showed that a single infusion of cilta-cel has led to an early and deep response in patients with multiple myeloma who received up to 3 lines of therapy but were lenalidomide-refractory. Seventy-five percent of the patients achieved a complete remission or better.

The safety profile was quite manageable. The CRS was predominantly grade 1 to 2. There were no instance of movement or neurocognitive treatment-emergent adverse events. Because of that, cilta-cel is now being evaluated in a phase 3, CARTITUDE-4, in patients with 1 to 3 prior lines of therapy, compared to daratumumab, pomalidomide, and dexamethasone or pomalidomide, bortezomib, and dexamethasone.

I'd like to thank my colleagues, the patients who participated in this study with their families, and the physicians and nurses who cared for them and all the staff who helped us with the research aspects and the data collection. I thank you for your attention.