Long‐term safety and efficacy of the PI3K inhibitor copanlisib in patients with relapsed or refractory indolent lymphoma: 2‐year follow‐up of the CHRONOS‐1 study

Abstract

Safety profiles of oral PI3K inhibitors have resulted in US FDA black box warnings regarding fatal/serious toxicities. The approved intravenous PI3K inhibitor copanlisib has low incidence of severe toxicities and no black box warnings, but chronic treatment effects were unknown. We provide an update on safety and efficacy of copanlisib with a minimum 2‐year follow‐up of the CHRONOS‐1 study. A total of 142 patients with histologically confirmed indolent B‐cell lymphoma who had relapsed after or were refractory to ≥2 prior treatments received intravenous copanlisib 60 mg on days 1, 8, and 15 (28‐day cycle). The primary efficacy endpoint was objective response rate (ORR) after ≥4 cycles (independent assessment). The predominant histology was follicular lymphoma (n = 104). The ORR was 60.6% (seven additional complete responses since primary analysis). Secondary endpoints of median duration of response, progression‐free survival, and overall survival were 14.1 months (median follow‐up, 16.1 months), 12.5 months (median follow‐up, 14.0 months), and 42.6 months (median follow‐up, 31.5 months), respectively. Median safety follow‐up was 6.7 months; 26% of patients received treatment for >1 year. Common treatment‐emergent adverse events (TEAEs) (all grade/grade 3/grade 4) were transient hyperglycemia (50.0%/33.1%/7.0%), diarrhea (35.2%/8.5%/0%), transient hypertension (29.6%/23.9%/0%), and neutropenia (28.9%/9.2%/14.8%). Serious AEs were largely unchanged, with no new cases of pneumonitis (4.2%), diarrhea (2.8%), or grade 5 events. Note, TEAEs showed no evidence for increased incidence or worsening following longer exposure in patients treated >1 year. Long‐term follow‐up of patients with relapsed/refractory indolent B‐cell lymphoma treated with intravenous copanlisib demonstrated durable, enhanced responses without evidence of worsening TEAEs, as reported for orally administered PI3K inhibitors.

Can Next-Generation PI3K Inhibitors Unlock the Full Potential of the Class in Patients With B-Cell Lymphoma?

“…21,22 In a long-term follow-up of CHRONOS-1, with increased time on treatment, ORR was 61% (CR 17%) in indolent NHL, 59% (CR 20%) in FL, and 78% (CR 13%), representing an increased response rate for patients with MZL and a deepening of responses from partial to complete response for some patients. 23 In the phase 2 DYNAMO trial, following treatment with duvelisib in patients with rituximab-and chemotherapy/radioimmunotherapy-refractory indolent NHL, ORR was 47%, with 2% achieving a CR (ORR was 42% [CR 1%] and 39% [CR 6%] in patients with FL and MZL, J o u r n a l P r e -p r o o f respectively). 24 Although CR is an important endpoint in hematologic malignancies, it is not achieved by the majority of patients treated with PI3K inhibitors as described above.…”

“…22 In the long-term follow-up of CHRONOS-1, median DOR was 14.1 months and median PFS was 12.5 months in patients with indolent NHL. 23 In the phase 2 study of duvelisib in patients with relapsed or refractory indolent NHL, median DOR was 10.0 months and median PFS was 9.5 months. 24 Despite the approval of 3 PI3K inhibitors for relapsed or refractory indolent NHL, there are currently no approved PI3K inhibitors for the treatment of aggressive NHL mainly due to lack of clinical efficacy.…”

“…Long-term follow-up of patients treated with copanlisib did not identify any significant increases in dose interruptions/modifications due to AEs, evidence of new or unexpected AEs, or significant worsening of existing AEs. 23 Table 3 summarizes key toxicities observed with the currently approved PI3K inhibitors as included below.…”

Drug Resistance in Non-Hodgkin Lymphomas

“…Idelalisib was the first-in-class oral phosphatidylinositol 3-kinase (PI3K) inhibitor approved for the treatment of cancer, specifically for the therapy of relapsed CLL and FL [34]. In 2017, the FDA granted accelerated approval to copanlisib, an intravenous pan-class I PI3K inhibitor with predominant activity against the PI3K-α and -δ isoforms, in the therapy of R/R FL [35][36][37]. In 2018, the European Medicines Agency (EMEA) granted orphan designation to copanlisib for the treatment of R/R MZL.…”

Untitled

“…Copanlisib is a highly selective, pan-class I PI3K inhibitor with preferential activity against the p110α and p110Δ isoforms that lead to downregulation of PI3K signaling [14]. Copanlisib has been approved for the treatment of follicular lymphoma in the U.S. and demonstrates manageable safety profile in long-term treatment with no late-onset toxicities [15]. Here, we explored the antitumor activity of copanlisib in HNSCC in preclinical trial setup.…”