CHRONOS-3 in MZL: Results and Clinical Implications

Tycel Jovelle Phillips, MD: CHRONOS-3 was a phase 3 study comparing outcomes between copanlisib and rituximab versus placebo and rituximab. Copanlisib was given on days 1, 8, and 15 of a 28-day cycle, and rituximab given at a standard dose of 375 mg per meter squared on days 1, 8, 15, and 22 for cycle 1, and then day 1 for the odd cycles, 3, 5, 7, and 9. Copanlisib was able to be continued as a single agent after the discontinuation of rituximab in the study. In the rituximab and placebo arm, rituximab was given on days 1, 8, 15, and 22 of cycle 1, and on day 1 of cycles 3, 5, 7, and 9. The overall study enrolled 458 patients, 95 of those were patients with marginal zone lymphoma. A total of 66 patients were enrolled in the copanlisib and rituximab arm, and 29 patients in the placebo and the rituximab arm. This was a 2:1 randomization to copanlisib and rituximab versus rituximab and placebo in this study population.

The median number of cycles was 9 for the copanlisib and rituximab, and 12 for the placebo plus rituximab. Dose interruptions occurred in 75.2% of patients with copanlisib and rituximab, and 56.8% of patients with placebo and rituximab. This is to the point that you mentioned earlier about some of the issues that come along with the delta inhibitors, including copanlisib, that can lead to dose interruption, delays, and discontinuations. Also, dose reductions to 45 mg occurred in 83 patients overall, which is about 27% of the patients. Dose reductions to 30 mg occurred in 28 patients, about 9.1% of patients. Then discontinuation of the study drug due to AEs [adverse events] accounted for 31.9% of enrolled patients on copanlisib and rituximab compared to 8.2% of patients on placebo and rituximab.

Looking at the response rate, the PFS [progression-free survival] with copanlisib plus rituximab for patients with marginal zone lymphoma was 22.1 months, whereas it was 11.5 months for those with placebo plus rituximab, with a hazard ratio of 0.48. The overall response rate in the patients with marginal zone lymphoma was 76% for copanlisib and rituximab, with a 39% complete response rate, versus 41% in the placebo plus rituximab and a 10% complete response rate. Thus, it indicating that there was a substantial benefit with the addition of copanlisib to rituximab in patients with marginal zone lymphoma.

The safety profile is something you highlighted quite extensively with the CHRONOS-1. With CHRONOS-3, we still see hyperglycemia, hypertension, and diarrhea being the most common treatment-emergent adverse events in this patient population. The AE of special interest was pneumonitis, which was seen in 21 patients, and 19 of those patients had a study discontinuation due to the presence of pneumonitis. Neutropenia was noted in 23.2% of patients, but there was a very low incidence of grade 3 or 4 neutropenia in the total study population. Looking at some of the other key AEs noted with delta inhibitors, such as transaminitis, we see very low incidence of grade 3/4 transaminitis, 1% of grade 3, and 0.3% grade 4 transaminitis. This indicates that at least to some degree, the intermittent schedule with copanlisib has mitigated some of the more common AEs that we typically see in patients exposed to these agents in the clinical trial setting. As such, this does indicate another potential option if it does get a label for these patients in a second-line setting.

But again, in that situation, we must take into consideration some of the other agents that already have approval. Is copanlisib plus rituximab better than what we typically see with, let’s say, zanubrutinib in this situation, or even ibrutinib in this situation, given that these agents all have very different toxicity profiles? Obviously, the key is we would hope to be able to keep these patients on these treatments for a longer period. As time plays out, maybe we will get some sort of study comparing these agents head-to-head to see which of these more novel treatments are better and have a more durable response and better safety profile for our patients in this situation.

Transcript Edited for Clarity