Clinical Efficacy Observed With BCMA-Directed ADC MEDI2228 in Triple-Refractory Myeloma

Shaji Kumar, MD

MEDI2228, a BCMA-directed antibody-drug conjugate (ADC), demonstrated promising clinical efficacy as treatment of patients with relapsed/refractory multiple myeloma with triple-refractory disease experiencing maintained responses in a phase 1 study (NCT03489525), according to the findings presented during the 2020 ASH Annual Meeting & Exposition.¹

Results showed that MEDI2228 had efficacy across all dose levels evaluated. Specifically, when delivered at the maximum-tolerated dose (MTD) of 0.14 mg/kg (n = 41) every 3 weeks, the agent elicited an overall response rate of 65.9% (n = 27; 95% CI, 49.4-79.9); this was comprised of 1 complete response (CR)/stringent CR (sCR; 2.4%), 10 very good partial responses (VGPRs; 24.4%), and 16 partial responses (PRs; 39.0%).

Additionally, 4.9% of these patients experienced a minimal response (n = 2), 12.2% achieved stable disease (n = 5), 14.6% had progressive disease (n = 6), and 2.4% were not evaluable (n = 1). The median time to response was 2.1 months (95% CI, 0.7-2.8), and patients received a median of 3 cycles of treatment (range, 1.0-6.0).

The median duration of response in patients who received MEDI2228 at the 0.14 mg/kg dose was 5.9 months. However, loss to follow-up following a withdrawal because of an adverse effect (AE) may have impacted the ability to determine DOR.

Of 41 patients, 23 were triple refractory to proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and anti-CD38 agents. Of these patients, 17 achieved a PR or better, including all patients who were immunofixation electrophoresis negative. However, a CR could not be assessed in these patients due to a lack of bone marrow, according to Kumar.

“MEDI2228 demonstrated clinical efficacy across all dose levels evaluated in this heavily pretreated group of patients,” lead study author Shaji Kumar, MD, an oncologist specializing in the development of novel drugs for myeloma at Mayo Clinic, said in a presentation during the meeting. “Most patients received 3-5 doses of MEDI2228 and continued to have a deepening of response even after going off of therapy.”

BCMA is known to be expressed in all stages of multiple myeloma. Normal expression is limited to plasma cells, certain subgroups of terminally differentiated B cells, and plasmacytoid dendritic cells.^2-4 Pro-survival signals to long-lived plasma cells and multiple cells has been produced by BCMA engagement through its ligands BAFF and APRIL.

“MEDI2228 is a monoclonal antibody that is conjugated to a warhead that is a DNA cross-linking agent [known as] pyrrolo benzodiazepine (PBD) through a cleavable linker,” Kumar explained. “Studies have shown that MEDI2228 preferentially binds to BCMA on the membrane compared to soluble BCMA.”

Once the ADC binds to the membrane, it is internalized, the warhead causes lysosomal degradation, and PBD is released; this can then lead to DNA cross-linking and cell death.

The open-label, first-in-human, phase 1 trial enrolled a total of 82 patients with relapsed/refractory multiple myeloma. To be eligible for enrollment, patients needed to be aged 18 years or older, have, measurable disease, and an ECOG performance status of 1 or less. Additionally, patients needed to have experienced disease progression following treatment with 3 classes of standard-of-care agents, such as PIs IMiDs, and monoclonal antibodies.

In the dose-escalation phase of the trial, participants were given a starting dose of 0.0124 mg/kg (n = 3) of MEDI2228. From there, patients were dose escalated to several additional doses, including 0.025 mg/kg (n = 6), 0.05 mg/kg (n = 9), 0.10 mg/kg (n = 18), and 0.20 mg/kg (n = 5). Within the 0.20 mg/kg cohort, 2 patients experienced dose-limiting toxicities of grade 3/4 thrombocytopenia and were dose reduced by 30%. The MTD was determined to be 0.14 mg/kg and 41 patients were enrolled into an expansion cohort to further evaluate this dose.

The primary end point of the study was safety and tolerability, with key secondary end points focused on preliminary efficacy, pharmacokinetic profile, and immunogenicity. The data cutoff for the trial was October 16, 2020.

The median age in both the MTD expansion cohort (n = 41) and the overall population (n = 82) was 69 years, and 65.9% of patients were male. In the MTD cohort, 48.8% of patients received 1-4 prior regimens, 29.2% had 5-7 prior regimens, and 22% had previously received 8 regimens or more. In the overall patient population, 36.6% had been treated with 1-4 prior regimens, 41.5% received 5-7 prior regimens, and 22% received 8 or more prior regimens.

All patients in the MTD cohort had previously received an IMiDs, such as lenalidomide (Revlimid), pomalidomide (Pomalyst), or thalidomide (Thalomid), versus 98.8% of those in the overall population. All patients in both arms had previously received PIs, including bortezomib (Velcade), carfilzomib (Kyprolis), and ixazomib (Ninlaro). Also, 97.6% of patients in both arms had received monoclonal antibodies, such as daratumumab (Darzalex), isatuximab (Sarclisa), and elotuzumab (Empliciti). Approximately half of all patients in the MTD cohort and overall patient population had triple-refractory disease, at 56.1% and 57.3%, respectively.

At the time of data cutoff, all patients in the MTD cohort had discontinued treatment due to either AEs (n = 27), progressive disease (n = 10), patient decision (n = 2), investigator decision (n = 1), or death (n = 1).

Additional results showed that those who received the starting dose of the ADC experienced an ORR of 33.3% (n = 1; 95% CI, 0.8-90.6). The 0.025 mg/kg cohort had an ORR of 16.7% (n = 1; 95% CI, 0.4-64.1), while those who received the dose of 0.05 mg/kg had an ORR of 33.3% (n = 3; 95% CI, 7.5-70.1). Finally, the 0.10 mg/kg cohort had an ORR of 27.8% (n = 5; 95% CI, 9.7-53.5) and the 0.20 mg/kg cohort achieved an ORR of 40% (n = 2; 95% CI, 5.3-85.3).

When looking at the pharmacokinetics of the agent, investigators found that the linear pharmacokinetics at the therapeutic dose was minimally affected by baseline BCMA levels. Exposure increased proportionally at doses of 0.05 mg/kg or higher with a mean half-life of 6-9 days.

“There was no significant accumulation of the drug at the third week of dosing that was studied,” Kumar said. “The free warhead concentration is less than 1% of the intact MEDI228 concentrations, suggesting that there is very little release of the warhead in the cell.”

It was also determined that binding affinity is greater for membrane-bound BCMA compared to serum BCMA.

With regard to safety, 58.5% of patients in the MTD cohort experienced photophobia; in 41.5% of patients this was grade 1 or 2, while it was grade 3 or 4 in 17.1%. However, no patients in this cohort experienced keratopathy. These patients also experienced other treatment-related AEs (TRAEs), such as rash (grade 1/2, 31.7%; grade 3/4, 0%), thrombocytopenia (grade 1/2, 7.3%; grade 3/4, 24.4%), pleural effusion (grade 1/2, 22%; grade 3/4, 2.4%), and gamma-glutamyl transferase (GGT) increases (grade 1/2, 4.9%; grade 3/4, 19.5%).

Dose delays occurred in 1 patient within the starting dose cohort, 1 patient in the 0.025 mg/kg cohort, 4 patients in the 0.10 mg/kg cohort, 9 in the MTD cohort, and 2 in the 0.20 mg/kg cohort. Dose omissions were noted in every cohort: 1 in the starting dose cohort, 2 in the 0.025 mg/kg cohort, 4 in the 0.05 mg/kg cohort, 13 in the 0.10 mg/kg cohort, 2 in the 0.20 mg/kg cohort, and 30 in the MTD cohort. Twenty-eight of these omissions were due to TRAEs.

When looking specifically at the ocular toxicities that occurred within the MTD cohort, investigators noted a median time to onset of 2 months, ranging from approximately 2-3 cycles of treatment. Photophobia was found to improve in 37% of patients (n = 9/24) over time, with 4 patients having their toxicity resolve. In the majority of cases, patient discontinuations due to photophobia precluded follow-up to resolution of the events.

“[These toxicities] were unexpected based on previous experiences with the warhead. Patients presented predominantly with photophobia, increased tearing, bloody vision, and, in some patients, periorbital swelling,” Kumar noted.

An ongoing analysis of treatment-associated photophobia and its mechanism is being pursued in the ongoing clinical trial. The ongoing expansion of the 0.14 mg/kg cohort is examining alternated dosing and scheduling with a focus on mitigating ocular toxicities.

_References

1. _{Kumar S, Migkou M, Bhutani M, et al. Phase 1 first-in-human study of MEDI2228, a BCMA-targeted ADC in patients with relapsed/refractory multiple myeloma. Presented at: 2020 ASH Annual Meeting and Exposition. December 4-8, 2020; Virtual. Abstract 179.}
2. _{Lee L, Bounds D, Paterson J, et al. Evaluation of B cell maturation antigen as a target for antibody drug conjugate mediated cytotoxicity in multiple myeloma. Br J Haematol. 2016;174(6):911-922. doi:10.1111/bjh.14145}
3. _{Yu HA, Arcila ME, Rekhtman N. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Can Res. 2013;19(8):2048-2060. doi:10.1158/1078-0432.CCR-12-2246}
4. _{Tai YT, Acharya C, An G, et al. APRIL and BCMA promote human multiple myeloma growth and immunosuppression in the bone marrow microenvironment. Blood. 2016;127(25):3225-3236. doi:10.1182/blood-2016-01-691162}