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The standard treatment for relapsed indolent non-Hodgkin lymphomas is rituximab, which has emerged as an effective CD20-targeted antibody therapy when used alone, or in combination with either chemotherapy or other targeted drugs.1 Copanlisib, an intravenously administered pan-class I inhibitor of phosphoinositide 3-kinase (PI3K) with predominant activity against the α- and δ-isoforms, has also shown promising therapeutic potential. Its efficacy as a monotherapy in the previously summarized phase II CHRONOS-1 trial (NCT01660451) supported accelerated approval from the U.S. Food and Drug Administration (FDA) for the treatment of relapsed follicular lymphoma.1
The phase III CHRONOS-3 study (NCT02367040) of copanlisib combined with rituximab was the first to report superiority of a PI3K inhibitor plus rituximab over rituximab alone, for patients with relapsed indolent B-cell non-Hodgkin lymphomas. Primary trial data has recently been published in Lancet Oncology,1 and we summarize the key findings below.
The CHRONOS-3 trial was a double-blind, randomized, placebo-controlled study performed at 186 medical centers and hospitals.
Characteristics for the eligible cohort are summarized in Table 1.
Table 1. Patient characteristics*
Characteristic |
Copanlisib plus rituximab |
Rituximab plus placebo |
---|---|---|
Sex, female, n (%) |
154 (50) |
66 (44) |
Median age, years (range) |
63 (54–70) |
62 (53–70) |
Histology, % |
|
|
ECOG performance status, % |
|
|
Median time since last systemic therapy, months (range) |
25.1 (15.7–45.8) |
25.3 (15.3–42.8) |
Median time from initial diagnosis, months (range) |
62.8 (36.4–101.7) |
72.4 (35.2–110.9) |
Progression and treatment-free for ≥12 months since last rituximab containing therapy, % |
80 |
80 |
Previous rituximab treatment, % |
99 |
99 |
Previous lines of therapy, % |
|
|
ECOG, Eastern Cooperative Oncology Group; FL, follicular lymphoma; LL-WM, lymphoplasmacytic lymphoma–Waldenström’s macroglobulinemia; MZL, marginal zone lymphoma; SLL, small lymphocytic lymphoma. |
Table 2. Progression-free survival across histology subtypes*
|
FL |
MZL |
SLL |
LL-WM |
||||
---|---|---|---|---|---|---|---|---|
C + R |
R + P |
C + R |
R + P |
C + R |
R + P |
C + R |
R + P |
|
n |
184 |
91 |
66 |
29 |
35 |
15 |
22 |
16 |
Median PFS, months |
22.2 |
18.7 |
22.1 |
11.5 |
14.2 |
5.7 |
33.4 |
16.6 |
HR (95% CI) |
0.580 (0.404–0.833) |
— |
0.475 (0.245–0.923) |
— |
0.243 (0.111–0.530) |
— |
0·443 (0.160–1.231) |
— |
P value |
0.0014 |
— |
0.012 |
— |
<0.0001 |
— |
0.054 |
— |
CI, confidence interval; C + R, copanlisib plus rituximab; HR, hazard ratio; FL, follicular lymphoma; LL-WM, lymphoplasmacytic lymphoma–Waldenström’s macroglobulinemia; MZL, marginal zone lymphoma; PFS, progression-free survival; R + P, rituximab plus placebo; SLL, small lymphocytic lymphoma. |
Of the 307 patients receiving copanlisib plus rituximab, 231 (75%) experienced dose interruptions or delays, compared with 83 of 146 (57%) in the placebo group. Of the 1,128 total interruptions reported in the rituximab plus copanlisib group, 68% were due to AEs, compared with 48% of 259 total interruptions in the placebo group.
AEs related to treatment are summarized in Table 3.
Table 3. Summary of treatment related adverse events*
|
Copanlisib plus rituximab |
Rituximab plus placebo |
---|---|---|
Treatment-emergent AEs (Grade 3–4), % |
86 |
39 |
Serious treatment-emergent AEs, % |
47 |
18 |
Deaths from treatment-emergent AEs, % |
2 |
1 |
Discontinuation due to treatment-emergent AEs, % |
31 |
8 |
AE, adverse event. |
The most common treatment-emergent Grade ≥3 AEs in both treatment groups were hyperglycemia, accounting for 56% in the rituximab plus copanlisib group and 8% in the rituximab plus placebo group, and hypertension, responsible for 40% of Grade ≥3 AEs in the experimental arm and 9% in the placebo group.
To manage these events, insulin was given for hyperglycemia in 36% of patients receiving copanlisib plus rituximab, while 28% received at least one blood-glucose lowering medication other than insulin. For hypertension, 37% of patients in the experimental group received antihypertensive medication.
Overall, the CHRONOS-3 trial met its primary endpoint, observing significant improvement in PFS when using a combination of rituximab and copanlisib compared with rituximab plus placebo, across all subtypes of indolent non-Hodgkin lymphomas. A favorable safety profile was also demonstrated, with no unexpected toxicity, and treatment-related AEs were manageable. Notably, the authors highlighted that CHRONOS-3 was the first study to observe acceptable safety when combining rituximab with a PI3K inhibitor, with previous studies utilizing oral inhibitors abandoned due to serious AEs or death.
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