Randomised phase III study of copanlisib plus rituximab vs rituximab/placebo in relapsed indolent non-Hodgkin lymphoma
Dr Matthew Matasar - Memorial Sloan Kettering Cancer Center, NYC, US
CHRONOS-3 was a randomised double-blinded trial comparing the combination of copanlisib and rituximab to rituximab plus placebo in the treatment of relapsed indolent B-cell lymphomas. The background is that for patients with relapsed indolent B-cell lymphoma these are illnesses that are, by their nature, chronically relapsing and will often require multiple lines of therapy. For patients who are still rituximab sensitive, meaning they’ve gone a while since their last rituximab-based treatment, rituximab monotherapy has remained a standard treatment for such patients but responses to rituximab are not as frequent as we would like and not as durable as we would like. The purpose of this trial was to see whether the combination of rituximab with copanlisib, which is an intravenously administered PI3K inhibitor, could improve outcomes for these patients.
What was the methodology used in your study?
This was a randomised double-blinded globally conducted trial with the intention of taking 450 patients with relapsed indolent B-cell lymphoma and randomising them in a two to one fashion to receive either copanlisib plus rituximab or rituximab plus placebo. The rituximab was given in a standard fashion to both arms once a week for four weeks and then once every eight weeks for four more doses without subsequent maintenance. Either copanlisib or placebo was given according to copanlisib’s standard schedule – as a 60mg flat dose as a one hour infusion once a week, days 1, 8 and 15 out of a 28 day cycle. The copanlisib was administered until progression or intolerance.
What were your findings?
The purpose of the study was to determine whether or not the combination of copanlisib plus rituximab improved progression free survival. The study was positive for this primary endpoint. At a median follow-up of just over 19 months we saw an improvement in median progression free survival from approximately 14 months to approximately 21 months. This was both clinically and statistically highly significant.
In looking at the individual histologic subtypes that were eligible for this study, including low grade follicular lymphoma, marginal zone lymphoma, small lymphocytic lymphoma and lymphoplasmacytic lymphoma or Waldenstrom’s macroglobulinemia, we saw improvements in progression free survival across all histologic subtypes, statistically significant for all except the LPL Waldenstrom’s subset which, while having a numerically improved median PFS from 16 to 34 months did not achieve statistical significance, perhaps due to the small number of patients treated.
We also saw improvements in overall response rate, complete response rate and duration of response to patients who received the combination therapy, although no difference in overall survival has been detected.
What are your conclusions from these results?
Our results show that the combination of copanlisib plus rituximab was both tolerable as well as effective in patients with relapsed indolent B-cell lymphoma. The significant improvement in progression free survival establishes this treatment, the combination of copanlisib plus rituximab, as an appropriate therapeutic consideration for patients with relapsed indolent B-cell lymphomas who are sensitive to rituximab.
What is next for this study?
The development of copanlisib as a therapeutic option is ongoing. We have recently completed enrolment to the sister study called CHRONOS-4 which is a comparison of rituximab plus chemotherapy, either rituximab plus bendamustine or rituximab plus CHOP, combined with either copanlisib or placebo to determine whether copanlisib can be safely and effectively combined, not just with rituximab monotherapy but with chemoimmunotherapy in the treatment of relapsed indolent lymphoma.
Is there anything else important that you would like to mention?
It’s important to highlight the toxicity profile of this treatment and we did identify toxicities in the combination of copanlisib plus rituximab. Previous trials attempting to combine PI3K inhibitors with rituximab had been unsuccessful due to unacceptable toxicity, largely hepatitis, enteritis and pneumonitis. In this study, while rates of pneumonitis were low, with only 6% of patients experiencing pneumonitis and fewer than 3% experiencing grade 3 or greater pneumonitis, we did see that there is toxicity of the combination that is aligned with the known toxicity of the component agents. Copanlisib’s toxicity is most notably transient hypoglycaemia and hypertension as well as some modest immunosuppression associated with both copanlisib and rituximab.
That being said, the combination did appear to be safe and effective and there is no new safety signal that we saw from the combination that was not anticipated from the component agents.