AACR 2017 | Copanlisib in R/R iNHL - Primary results of the CHRONOS-1 study

On April 4^th 2017, during this year’s American Association for Cancer Research (AACR) annual meeting, Martin Dreyling, from the Klinikum Universität München-Großhadern, Munich, Germany, presented the primary results of the CHRONOS-1 pivotal phase II study of copanlisib in patients with R/R indolent B-cell lymphomas. The presentation was given as part of the “Novel Agent and Intervention Clinical Trials” mini-symposium, and the primary endpoint of the study was ORR after 16+ weeks of treatment, with secondary endpoints including PFS, DoR, and OS.

Key Highlights:

• Background:
  • B-Cell Receptor (BCR) and PI3K signaling play key roles in NHL
  • Copanlisib is a pan-class I PI3K inhibitor that targets both α- and δ-isoforms
  • The FDA-approved PI3K inhibitor, idelalisib, targets only the δ-isoform and has warnings against fatal or severe colitis, intestinal perforation, hepatotoxicity, and pneumonitis
• Study:
• Recruited FL (n = 104), MZL (n = 23), SLL (n = 8), or WM (n = 6) pts who had failed 2+ lines of prior-therapy (total = 141 pts)
• All pts had received prior-rituximab and alkylating agent based therapies, 60% were refractory
• Dose: 60mg copanlisib IV on D1, 8, & 15 of each 28-day cycle until PD or unacceptable toxicity
  • Median number of cycles = 5.5 (0.3­–26)
  • Dose interruptions = 73.9% pts (54.9% less than one week)
  • Dose reductions: 26.1% reduced to 45mg, 5.6% reduced to 30mg
• Results:
  • Total: ORR = 59.2%, CR = 12%, PR = 47.2%, SD = 29.6%, PD = 2.1%
  • FL (104pts): ORR = 58.7%, CR = 14.4%, PR = 44.2%, SD = 33.7%, PD = 1.9%
  • MZL (23pts): ORR = 69.6%, CR = 8.7%, PR = 60.9%, SD = 17.4%, PD = 0%
  • SLL (8pts): ORR = 75%, CR = 0%, PR = 75%, SD = 12.5%, PD = 12.5%
  • WM (6pts): ORR = 16.7%, CR = 0%, PR = 16.7%, SD= 50%, PD = 0%
  • Total mDoR = 22.6 months; FL mDoR = 12.2 months
  • Total mPFS = 11.2 months (95% CI, 8.1–24.2); FL mPFS = 11.2 months
  • Median OS not yet reached
• Safety:
  • Grade 3 pneumonitis = 2 pts (1.4%), grade 4 colitis = 1 pt (0.7%), 3 deaths due to drug-related AE (respiratory failure, lung infection, thromboembolic event)
  • Grade 3 treatment-related AE = 50% pts (hypertension 22.5% pts, hyperglycemia 33.1% pts, lung infection 9.2%, and neutropenia 6.3% pts)
  • Grade 4 treatment related AE = 21.1% pts (neutropenia 12.7% pts, hyperglycemia 7% pts)

In conclusion, Martin Dreyling stated that copanlisib was shown to have significant efficacy in R/R indolent NHL, and that the safety was manageable compared with other PI3K inhibitors, which he suggested may be due to the dose scheduling or the IV delivery. Professor Dreyling also highlighted that there are two ongoing phase III trials using copanlisib in combination with rituximab-based therapies (NCT02367040, NCT02626455).