CHRONOS-1 and CHRONOS-3 Trials in R/R FL and Clinical Implications

Alexey Danilov, MD, PhD: Let me show you some data on these PI3K inhibitors and let me start with the CHRONOS-1 study. CHRONOS-1 evaluated copanlisib monotherapy in patients with relapsed/refractory non-Hodgkin lymphoma. It enrolled about 100 patients with follicular lymphoma. Unlike the other PI3K inhibitors approved, copanlisib is given intravenously on days 1, 8, and 15 over a 28-day cycle, and that’s how this agent was given in this open-label case to study. The current dose is 60 mg, which is a flat dose. This graph is given on an intermittent scale, unlike daily administration of oral drugs.

Because of the alpha isoform inhibition, it’s also associated with some different toxicity profiles. What we see with this agent is hypertension and hypoglycemia. Both tend to occur during or shortly after infusion and don’t necessarily present a problem all the time. But these adverse effects [AEs] aren’t seen with other PI3K-delta–specific inhibitors. Of course, the issue with PI3K inhibitors is long term, with toxicities as well as infections. There are some studies, with not just copanlisib but other agents, using intermittent dosing of PI3K inhibitors, even PI3K-delta–specific inhibitors. This is an interesting field in development, whether we achieve some alternative dosing regimen that will mitigate autoimmune-mitigated toxicities or eliminate toxicities in patients with lymphoma.

The recently published data from CHRONOS-1 were quite encouraging. In addition to overall response of 60% in patients with follicular lymphoma, we see 3 prior therapies for their disease. There was not necessarily an increased rate of late toxicities. The exception was grade 3 diarrhea, which was seen in 5% of patients in the first 6 months, and 10% of patients were on copanlisib for longer than a year. The overall discontinuation rate for adverse events was 25%, which is a good number for patients with PI3K inhibitors. They only had 2 events of pneumonitis. Over time there was additional follow-up from CHRONOS-1. In addition to the hyperglycemia and hypertension reported initially, it did not report any new prohibited toxicities. But high efficacy of the regimen was confirmed with progression-free survival in this patient population of 12 months. Dr Phillips, there were some follow-up studies on that, like CHRONOS-3, right?

Tycel Jovelle Phillips, MD: CHRONOS-3 was recently presented and published in Lancet Oncology. This was a phase 3 randomized study looking at copanlisib of 60 mg on days 1, 8, and 15, plus rituximab given on days 1, 8, 15, and 22 during cycle 1, and then on day 1 of odd cycles 3, 5, 7, 9. The patients could then continue with copanlisib as a single agent. This is compared with placebo plus rituximab given on days 1, 8, 15, 22 during cycle 1 and day 1 of cycle 3, 5, and 7. This large study randomized 458 patients in a 2:1 fashion. Approximately 300 patients who were randomized took copanlisib plus rituximab, and 100 patients who were randomized took placebo plus rituximab.

From this, the study indicated that copanlisib plus rituximab provided an improvement in progression-free survival [PFS] in this patient population with a hazard ratio of 0.520. Median PFS for copanlisib plus rituximab was 21.5 months, whereas placebo plus rituximab was 13.8 months in all patients enrolled. What they did also was break down the PFS in individual subtypes in the individual non-Hodgkin lymphoma as they enrolled patients with follicular lymphoma, marginal zone lymphoma, LPL [lymphoplasmacytic lymphoma], Waldenström [macroglobulinemia], and small lymphocytic leukemia [SLL].

The PFS in patients with follicular lymphoma was 22.2 months for the copanlisib plus rituximab vs 18.7 months for placebo plus rituximab with a hazard ratio of 0.58. This was statistically significant. There was an improvement in PFS in patients with marginal zone lymphoma with a PFS of 22.1 months with copanlisib-rituximab and 11.5 months for single-agent rituximab with a hazard ratio of 0.58. In patients with SLL, it was an improvement of 14.2 months with copanlisib-rituximab vs 5.7 months in single-agent rituximab with a hazard ratio of 0.24. Those with LPL and Waldenström had a PFS of 33.4 months vs 16.6 months for rituximab with a hazard ratio of 0.44. Overall response rates also suggested improvement with the addition of copanlisib to rituximab in this patient population.

The key thing to pull out of this before delta inhibitors is the safety profile. For this study, the safety profile shows that there were serious adverse events in about 47.2% of all enrolled patients on the copanlisib and rituximab vs 18.5% in those treated with placebo plus rituximab. Some of the adverse effects that you mentioned before are the ones we see. Hyperglycemia occurs in 69% of patients on study with all grades, with 48.2% achieving a grade 3 or higher and 8.1% having a grade 4 hyperglycemia. Hypertension was reported in 39.7% of patients as far as grade 3 in this patient population. Diarrhea was noted for grade 3 at 4.9% compared with 0 in those in a rituximab. Pneumonitis was designated as an AE of special interest, which was noted in 21 patients, or 6.8% of enrolled patients.

The key thing about pneumonitis in the study that would need to be realized is that this was a trigger for discontinuation of treatment. As such, 6.2% of patients on the copanlisib-rituximab arm were removed from the study for onset of pneumonitis. Overall, this study indicated that there was a direct benefit to using copanlisib in a second-line setting in this situation. It’s approved in a third-line setting in most other patients in addition to rituximab.

It’s harder to make a direct comparison with some other agents approved in the second-line setting, such as R2 [lenalidomide, rituximab], given the different toxicity profiles. Obviously, there’s a shorter follow-up in this study compared with what we saw in the AUGMENT study. But in patients who can’t get access to Revlimid [lenalidomide], or if there’s some contraindication to using lenalidomide, it does indicate the copanlisib plus rituximab could be an option if it does get a label indication in this patient population.

It also indicates that delta inhibitors are still dogged by the simple fact that drug discontinuation is an issue. We see most patients coming off the study for discontinuation vs disease progression in the study than the copanlisib arm. For those in the rituximab arm, disease progression was the most leading cause of discontinuation from the study protocol. The rewards are there. It indicates that there’s potentially a role for these agents earlier on, but they need to be more compared with some of the contemporary competitors such a R2 [lenalidomide, rituximab] in this situation.

Alexey Danilov, MD, PhD: This was a very important study. Thanks for highlighting all the adverse events and issues with PI3K inhibitors.

Transcript Edited for Clarity