Page 159 - Haematologica Vol. 109 - July 2024

ARTICLE - Sovleplenib Syk inhibitor in R/R B-cell tumors Y. Song et al.
Figure 3. Duration of treatment in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma in the dose-expan- sion phase. CLL: chronic lymphocytic leukemia; SLL: small lymphocytic lymphoma; b.i.d.: twice daily; AE: adverse event; CR: complete response; PD: progressive disease; PR: partial response; PR-L: PR with increased lymphocyte count; q.d.: once daily; SD: stable disease.
Biomarker analysis
During dose expansion, sovleplenib induced reductions in plasma levels of CCL22, CCL17 and CXCL13 chemokines compared with baseline (Online Supplementary Figure S4). A similar trend was observed in separate analysis with cohorts A, B and D (Online Supplementary Figure S5). Consistent reduction was also observed with sovleplenib treatment during dose escalation (data not shown). More- over, decreased levels of CCL3 and CCL4 in three of four CLL patients were observed, but not in other NHL subtypes (data not shown).
Discussion
This phase I study examined safety, tolerability and prelim- inary efficacy of sovleplenib in relapsed/refractory B-cell tumors. The RP2D was determined to be 600 mg q.d. in patients >65 kg and 400 mg q.d. in patients ≤65 kg. Clinical responses were observed in CLL/SLL, DLBCL, MCL, MZL, LPL/WM and FL, including in heavily pretreated patients. The safety profile of sovleplenib was consistent with other Syk inhibitors; most toxicities were manageable, with no new safety concerns.12,14,18,25
Most common TEAE included neutropenia, leukopenia, anemia and platelet count decreased, with similar toxicities across cohorts. Some of the common toxicities reported for other Syk inhibitors, such as diarrhea, nausea, dyspepsia,
headache, hypertension and fatigue, were less frequent in our study.12,16,21 Although in patients treated with fostam- atinib diarrhea was a DLT event (21%) or one of the most common TRAE (41%),12,16 it was not a DLT of sovleplenib. The incidence of diarrhea was 3.7% in the dose escalation and 9.3% in the dose expansion. Pneumonia and interstitial lung disease were reported in the current study; pulmonary toxicities were also seen with entospletinib.17,18,26 The safety profile may be attributable to the high target specificity of sovleplenib, which leads to low off-target adverse effects. Five patients who experienced probably sovleplenib-related TEAE leading to death had other confounding factors, in- cluding previous primary diseases and disease progression. A challenge in treating B-cell malignancies is the het- erogeneity of pathogenesis due to the complex nature of B-cell signaling and diversity of aberrant B-cell constitu- tive activation.27 This study showed that sovleplenib has anti-tumor activity in lymphomas of different histology, including FL, CLL, SLL, indolent B-cell lymphoma, DLBCL and MCL. In a heavily pretreated population, the ORR in FL (grade 1, 2, 3a) was 60.5%. ORR in other cohorts ranged from 28.6% in both MCL and DLBCL cohorts to 56.3% in the CLL/SLL cohort.
The anti-tumor activity of sovleplenib was particularly noted in cohort D, where the overall IRC-assessed ORR was 50.8%, mDOR was 15.7 months, and mPFS was 12.0 months. More specifically, significant anti-tumor activity was demon- strated in FL patients with an IRC-assessed ORR of 60.5%,
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