Cevostamab Becomes More Efficacious With Double Step-Up Dosing in Pretreated R/R Myeloma

When utilizing cycle 1 (C1) double step-up dosing with cevostamab in patients with heavily pretreated relapsed/refractory multiple myeloma, investigators observed promising responses and efficacious cytokine release syndrome (CRS) mitigation, according to updated data from an ongoing phase 1 trial (NCT03275103) that were presented during the 2021 ASH Annual Meeting and Exposition.¹

Responses were observed from the 20-mg target dose level of cevostamab and above (n = 143).

Moreover, the overall response rate (ORR) was found to increase with each target dose. In the 3.6/90-mg C1 single step-up expansion cohort, the ORR was 29%. The ORR was 54.8% in the 0.3/3.6/160-mg cohort.

Additionally, the median duration of response (DOR) among responders in the C1 single step-up cohorts was 11.5 months (95% CI, 6-18.4), suggesting that responses were durable.

“Cevostamab demonstrated clinically meaningful activity in heavily pretreated patients with relapsed/refractory multiple myeloma,” lead study author Suzanne Trudel, MD, MSc, a clinical scientist at Princess Margaret Cancer Centre, said in a presentation of the data. “The C1 double step-up dosing has an improved CRS profile, with lower incidence and severity of CRS, compared with C1 single step-up dosing. Cevostamab has a safety profile that warrants further development in patients with myeloma.”

Cevostamab is a dual-targeted bispecific antibody directed toward FcRH5 and CD3. FcRH5 is expressed exclusively in B-cell lineage and is more widely and nearly ubiquitously expressed on myeloma cells compared with normal B cells. The agent targets the membrane-proximal domain of FcRH5 and the epsilon domain of CD3 on T cells.

Previously reported data from the dose-findings portion of the phase 1 study demonstrated promising activity with cevostamab in patients with heavily pretreated, relapsed/refractory multiple myeloma.2 Moreover, C1 single step-up dosing appeared to provide a manageable safety profile and CRS mitigation with cevostamab.

The updated data featured additional phase 1 dose-finding results and evaluated the effect of C1 single step-up and C1 double step-up dosing on CRS.

Patients with relapsed/refractory multiple myeloma who had no available, appropriate, or tolerable therapeutic option available were eligible for enrollment. Patients had to have an ECOG performance status of 0 or 1 and could have had prior CAR T-cell therapy, antibody-drug conjugates (ADCs), and bispecific antibodies.

Cevostamab was administered intravenously every 3 weeks for 17 cycles, which equated to approximately 12 months of treatment, or until progressive disease or unacceptable toxicity. Retreatment is allowed at progression, Trudel explained.

In addition to C1 step-up dosing, CRS and infusion-related reaction mitigation strategies comprised premedication with corticosteroids during cycles 1 and 2 and premedication with acetaminophen (Tylenol) and diphenhydramine (Benadryl) during cycles 1 through 17. Additionally, patients were hospitalized for at least 72 hours after each C1 infusion.

In the C1 single step-up escalation cohorts, patients were started on 3.6 mg of cevostamab on day 1 of cycle 1 and escalated on day 8 of cycle 1 to 198 mg (n = 9), 160 mg (n = 8), 132 mg (n = 7), 90 mg (n = 12), 60 mg (n = 7), 40 mg (n = 6), or 20 mg (n = 3). An additional cohort (n = 17) was started between 0.05 mg and 3.6 mg and escalated to 0.15 mg to 10.8 mg.

The 3.6/90-mg cohort was included in the C1 single step-up escalation cohort (n = 31). After step-up dosing in C1, patients remained on 90 mg of cevostamab given on day 1 of all subsequent cycles.

In the C1 double step-up escalation cohorts, patients were started on 0.3 mg and escalated to 160 mg (n = 5), 0.6 mg and escalated to 90 mg (n = 8), 0.3 mg and escalated to 90 mg (n = 8), 1.2 mg and escalated to 90 mg (n = 3), or 1.2 mg and escalated to 60 mg (n = 6).

Initial doses were given on day 1 of C1. Then, all patients received 3.6 mg on day 8 of C1 and escalated doses on day 15 of C1. The 0.3/3.6/160-mg cohort was expanded (n = 31) in the C1 double step-up expansion portion. After step-up dosing in C1, patients remained on 160 mg of cevostamab given on day 1 of all subsequent cycles.

Patients (n = 161) were a median age of 64 years (range, 33-82), and most patients (58.4%) were male.

Conclusive high-risk cytogenetics were observed in 70.5% of patients (n = 67/95), including 1q21 gain (n = 50/90; 55.6%), translocation (4;14) (n = 13/96; 13.5%), translocation (14;16) (n = 2/90; 2.2%), and 17p deletion (n = 27/112; 24.1%). Additionally, 21.1% of patients (n = 34) had extramedullary disease.

The median time since first multiple myeloma therapy was 6.1 years (range, 0.3-22.8).

Patients had a median of 6 prior lines of therapy (range, 2-18); prior therapies included CD38-directed antibodies (88.2%), BCMA-directed therapies (33.5%), CAR T-cell therapy (17.4%), ADCs (16.8%), and bispecific antibodies (8.1%). Moreover, 84.5% of patients were triple-class refractory, 68.3% were penta-drug refractory, and 88.8% of patients were refractory to their last prior therapy.

Patients remained on study for a median of 8.8 months (range 0.2-37.2).

The median follow-up in responders was 14.3 months (range, 2.7-31.8) in C1 single step-up cohorts and 6.5 months (range, 4.8-21.4) in double step-up cohorts.

Additional findings showed that responses occurred early (median time to first response, 1 month; [range, 0.7-5.9]) and deepened over time (median time to best response, 2.1 months [range, 0.7-11.4]).

In the 20- to 90-mg dose level cohorts (n = 83), the ORR was 36.1% and was comprised of stringent complete responses (sCRs; 8.4%), CRs (1.2%), very good partial responses (VGPRs; 10.8%), and partial responses (PRs; 15.7%). In the 132- to 198-mg dose level cohorts (n = 60), the ORR was 56.7% and was comprised of sCRs (6.7%), CRs (1.7%), VGPRs (25%), and PRs (23.3%).

Seven of 10 evaluable patients with VGPRs were minimal residual disease negative by next-generation sequencing (<10-5).

Additionally, 6 patients in the C1 single step-up cohorts were in continued responses for at least 6 months following cessation of treatment, suggesting that responses can be maintained after patients stop cevostamab.

Regarding safety (n = 161), nearly all patients (99.4%) experienced any-grade adverse effect (AE); 32.9% experienced grade 3 AEs and 28.6% experienced grade 4 AEs. Serious AEs were observed in 59.6% of patients.

Common AEs that occurred in at least 15% of patients included hematologic AEs, such as neutropenia, anemia, thrombocytopenia, and lymphopenia, as well as nonhematologic AEs, such as CRS, infection, diarrhea, cough, nausea, fatigue, pyrexia, infusion-related reactions, hypokalemia, hypophosphatemia, hypomagnesemia, and aspartate aminotransferase increase.

Overall, 6 patients (3.7%) experienced grade 5 AEs; 1 event of hemophagocytic lymphohistiocytosis was found to be related to cevostamab treatment. Cevostamab-unrelated grade 5 AEs included acute kidney injury (n = 1), plasma cell myeloma (n = 1), and respiratory failure (n = 3). Additionally, excluded from the safety analysis were 19 patients with grade 5 malignant neoplasm progression reported as AE per protocol.

Twenty-one patients (13%) had an AE that led to treatment discontinuation; 7 of these (4.3%) were found to be related to cevostamab treatment.

Any-grade CRS was observed in 80.7% of patients and included grade 1 (42.9%), grade 2 (36.6%), and grade 3 (1.2%) events. One patient developed CRS that led to treatment discontinuation.

CRS was primarily observed during cycle 1 of treatment. The onset of CRS was typically within 24 hours of cevostamab administration (70%) and resolved within 48 hours of onset (85%).

CRS management strategies included tocilizumab (Actemra; 37.3%), steroids (21.7%), and tocilizumab and steroids (20%).

Overall, 14.3% of patients experienced CRS-associated immune effector cell–associated neurotoxicity syndrome (ICANS), including grade 1 (8.1%), grade 2 (5.6%), and grade 3 (0.6%) events. The most common ICANS-related symptoms included confusion (2.5%) and aphasia (1.2%).

All but 1 patient with ICANS had symptom resolution; the patient who did not have symptom resolution discontinued treatment shortly after because of disease progression.

In the 3.6-mg and 0.3/3.6-mg cohorts, no target-dose dependent increase in CRS incidence was observed in C1. Moreover, a lower rate of grade 1 CRS with symptoms in addition to fever and grade 2 CRS was observed in 0.3/3.6-mg cohort vs the 3.6-mg cohort.

In the 3.6-mg cohort, 14% of patients had grade 1 CRS with fever only, 34.9% had grade 1 CRS with symptoms in addition to fever, 38.4% had grade 2 CRS, and 1.2% had grade 3 CRS. In the 0.3/3.6-mg cohort, these rates were 25%, 20.5%, 31.8%, and 2.3%, respectively.

“Taken together, the results suggest cevostamab may be a beneficial treatment for patients with relapsed/refractory myeloma, leading to the expansion of the clinical development program into 2022,” Trudel concluded.

References

1. Trudel S, Cohen AD, Krishnan A, et al. Cevostamab monotherapy continues to show clinically meaningful activity and manageable safety in patients with heavily pre-treated relapsed/refractory multiple myeloma: updated results from an ongoing phase 1 study. Presented at: 2021 ASH Annual Meeting; December 9-14, 2021; Atlanta, GA. Abstract 157.
2. Cohen AD, Harrison SJ, Krishnan A, et al. Initial clinical activity and safety of BFCR4350A, a FcRH5/CD3 T-cell-engaging bispecific antibody, in relapsed/refractory multiple myeloma. Blood. 2020;136(suppl 1):42-43. doi:10.1182/blood-2020-136985