CHRONOS-3: Copanlisib plus rituximab in patients with relapsed indolent non-Hodgkin lymphoma

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.

Study design

The CHRONOS-3 trial was a double-blind, randomized, placebo-controlled study performed at 186 medical centers and hospitals.

• Primary endpoint: Progression-free survival (PFS) by central assessment.
• Secondary endpoints: Objective response rate, disease control rate, duration of response, complete response rate, time to progression, overall survival, patient-reported outcomes, and safety and tolerability.

Eligibility criteria

• Adults with confirmed diagnosis of CD20⁺ indolent B-cell lymphoma, including follicular lymphoma, marginal zone lymphoma, small lymphocytic lymphoma, and lymphoplasmacytic lymphoma–Waldenström’s macroglobulinemia.
• Relapse following last rituximab or other anti-CD20 monoclonal antibody therapy.
• Eastern Cooperative Oncology Group performance status ≤2.
• Progression-free and treatment-free for at least 12 months after the last anti-CD20 monoclonal antibody treatment, or unfit or unwilling to receive chemotherapy and treatment-free for at least 6 months after the last anti-CD20 monoclonal antibody treatment.
• Measurable disease.

Treatment schedule

• A total of 458 patients were randomly assigned 2:1 to receive treatment with copanlisib plus rituximab (n = 307) or placebo plus rituximab (n = 151).  
  • Copanlisib (60 mg) was administered by a 1-hour intravenous infusion on Days 1, 8, and 15 of a 28-day cycle.
  • Rituximab (375 mg/m²) was administered intravenously following copanlisib infusion, each week on Days 1, 8, 15, and 22 during Cycle 1 and on Day 1 of Cycles 3, 5, 7, and 9.
• Copanlisib dose reductions from 60 mg to 45 mg, and further to 30 mg, were permitted to manage drug-related toxicities.

Results

Patient characteristics

Characteristics for the eligible cohort are summarized in Table 1.

Table 1. Patient characteristics*

ECOG, Eastern Cooperative Oncology Group; FL, follicular lymphoma; LL-WM, lymphoplasmacytic lymphoma–Waldenström’s macroglobulinemia; MZL, marginal zone lymphoma; SLL, small lymphocytic lymphoma. *Data from Matasar et al.1
Characteristic	Copanlisib plus rituximab (n = 307)	Rituximab plus placebo (n = 151)
Sex, female, n (%)	154 (50)	66 (44)
Median age, years (range)	63 (54–70)	62 (53–70)
Histology, %               FL               MZL               SLL               LL-WM	60 21 11 7	60 19 10 11
ECOG performance status, %               0               1               2	59 37 4	63 36 1
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, %               1               2               3               ≥4	49 24 12 14	47 26 15 11

Primary endpoint

• The primary endpoint was met, with median PFS by central assessment significantly greater in patients treated with copanlisib plus rituximab vs rituximab plus placebo (21.5 months vs 13.8 months; HR, 0.520; 95% CI, 0.393–0.688, p < 0.0001).
• Median PFS was improved across all disease subgroups for patients treated with copanlisib plus rituximab (Table 2).

Table 2. Progression-free survival across histology subtypes*

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. *Data from Matasar et al.1
	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	—

• The estimated 2-year PFS rate was also significantly greater in the copanlisib plus rituximab group vs rituximab plus placebo (46% vs 27%).
• Median PFS by investigator assessment showed 85% concordance with central assessment (22.0 months for copanlisib plus rituximab vs 13.8 months for rituximab plus placebo; p < 0.0001).

Secondary endpoints

• Median time to progression was significantly greater in the copanlisib plus rituximab group compared with the placebo group (22.3 months vs 13.8 months).
• Objective response rate was again significantly greater for patients treated with rituximab plus copanlisib (81%; 95% CI, 76–85) compared with rituximab plus placebo (48%; 95% CI, 40–56), p < 0.0001.
• Median duration of response was 20.4 months (95% CI, 17.0–30.8) in the experimental group vs 17.3 months (11.8–25.3) in the placebo group.
• No significant difference was found in overall survival between the rituximab plus copanlisib and rituximab plus placebo arms at 24 months (86%; 95% CI, 81–90 vs 91%; 95% CI, 86–96) and 36 months (83%; 95% CI, 78–88 vs 81%; 95% CI, 72–89).

Safety

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*

AE, adverse event. *Data from Matasar et al.1
	Copanlisib plus rituximab (n = 307)	Rituximab plus placebo (n = 146)
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

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.

Conclusion

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.