The randomized, double-blind, placebo-controlled phase III CHRONOS-3 study (NCT02367040) showed a 48% risk reduction in disease progression/death with the PI3K inhibitor copanlisib + rituximab (C+R) vs placebo (P)+R in pts with relapsed indolent non-Hodgkin lymphoma (iNHL). We report a subset analysis in pts with MZL.
Pts with relapsed iNHL progression- and treatment-free for ≥12 months (mo) after R-based therapy or ≥6 mo if unwilling/unfit to receive chemotherapy were randomized 2:1 to C+R or P+R. C 60 mg/P was given i.v. on days (d) 1, 8, and 15 (28-d cycle); R 375 mg/m2 was given i.v. on d 1, 8, 15, and 22 of cycle 1 and d 1 of cycles 3, 5, 7, and 9. Primary endpoint was centrally assessed progression-free survival (PFS).
Of 458 pts in CHRONOS-3, 66 with MZL were randomized to C+R and 29 to P+R. MZL subtypes included nodal (39%), extranodal (37%), and splenic (24%). With a median follow-up of 18.0 mo, C+R significantly reduced the risk of disease progression/death vs P+R; objective response rate (ORR) improved with C+R (Table). Median duration of response was 25.4 mo for C+R vs 9.3 mo for P+R; median time to progression was 33.2 mo vs 11.5 mo. Median overall survival was not evaluable (NE). Most common treatment-emergent adverse events (TEAEs; all grade/grade 3+) with C+R were hyperglycemia (65%/54%) and hypertension (54%/45%). Most common TEAEs with P+R were hyperglycemia (24%/10%), cough (24%/0%) and upper respiratory tract infection (24%/0%). Serious TEAEs were higher with C+R (57%) vs P+R (28%). TEAEs deemed related to C/P included hyperglycemia (63%/24%) and hypertension (54%/17%). Primary efficacy evaluation for PFS based on unstratified log-rank test and unstratified Cox proportional hazard model
Overall MZL Nodal MZL Extranodal MZL Splenic MZL C+R P+R C+R P+R C+R P+R C+R P+R 66 29 25 12 24 11 17 6 22.1 (13.8, NE) 11.5 (5.6, 16.3) 21.5 (13.1, NE) 11.5 (2.5, NE) NE (9.0, NE) 10.8 (1.6, 35.6) Not reliably estimable 0.475 (0.245, 0.923) 0.483 (0.183, 1.276) 0.334 (0.111, 1.010) – 0.012 0.067 0.021 – 75.8 (50) 41.4 (12) 88.0 (22) 33.3 (4) 75.0 (18) 45.5 (5) 58.8 (10) 50.0 (3) 39.4 (26) 10.3 (3) 32.0 (8) 8.3 (1) 58.3 (14) 9.1 (1) 23.5 (4) 16.7 (1)
C+R showed superior efficacy vs P+R in pts with relapsed MZL, including nodal MZL. The safety profile of C+R was consistent with C and R as monotherapy. Copanlisib is the first PI3K inhibitor to be safely combined with R in a phase III setting in pts with relapsed MZL and represents a new therapeutic strategy.
NCT02367040.
Writing support by Ryan Staudt, PhD, Complete HealthVizion.
Bayer AG.
Bayer AG.
M. Özcan: Financial Interests, Personal, Other, Honoraria: Amgen; Non-Financial Interests, Personal, Other, Travel support: Amgen; Non-Financial Interests, Personal, Other, Travel support: Bristol Myers Squibb; Financial Interests, Personal, Other, Financial relationships: Abdi İbrahim; Financial Interests, Personal, Other, Financial relationships: Jazz Pharmaceuticals; Financial Interests, Personal, Other, Financial relationships: Sanofi; Financial Interests, Personal, Research Grant: AbbVie; Non-Financial Interests, Personal, Other, Travel support: AbbVie; Financial Interests, Personal, Research Grant: Archigen Biotech; Financial Interests, Personal, Research Grant: Bayer; Financial Interests, Personal, Research Grant: Celgene; Financial Interests, Personal, Research Grant: F. Hoffmann-La Roche Ltd.; Non-Financial Interests, Personal, Other, Travel support: F. Hoffmann-La Roche Ltd.; Financial Interests, Personal, Research Grant: Janssen; Financial Interests, Personal, Other, Travel support: Janssen; Financial Interests, Personal, Research Grant: MSD; Financial Interests, Personal, Research Grant: Takeda. P. Panayiotidis: Financial Interests, Personal, Other, Honoraria: Genesis; Financial Interests, Personal, Other, Honoraria: Gilead; Financial Interests, Personal, Other, Honoraria: Roche; Financial Interests, Personal, Other, Honoraria: Takeda; Financial Interests, Personal, Research Grant: Genesis; Financial Interests, Personal, Research Grant: Roche; Financial Interests, Personal, Research Grant: Takeda. L. Mongay Soler: Financial Interests, Personal, Full or part-time Employment: Bayer HealthCare Pharmaceuticals, Inc. A. Cao: Financial Interests, Personal, Full or part-time Employment: Bayer HealthCare Pharmaceuticals, Inc. F. Hiemeyer: Financial Interests, Personal, Full or part-time Employment: Bayer AG. B.H. Childs: Financial Interests, Personal, Full or part-time Employment: Bayer HealthCare Pharmaceuticals, Inc. M.J. Matasar: Financial Interests, Personal, Research Grant: Bayer; Financial Interests, Personal, Other, Consultancy, honoraria: Bayer; Financial Interests, Personal, Other, Consultancy: Daiichi Sankyo; Financial Interests, Personal, Research Grant: F. Hoffmann-La Roche Ltd.; Financial Interests, Personal, Other, Consultancy, honoraria: F. Hoffmann-La Roche Ltd.; Financial Interests, Personal, Other, Consultancy: Juno Therapeutics; Financial Interests, Personal, Other, Consultancy: Merck; Financial Interests, Personal, Research Grant: Rocket Medical; Financial Interests, Personal, Other, Consultancy: Rocket Medical; Financial Interests, Personal, Research Grant: Seattle Genetics; Financial Interests, Personal, Other, Consultancy, honoraria: Seattle Genetics; Financial Interests, Personal, Other, Consultancy, honoraria: Takeda; Financial Interests, Personal, Other, Consultancy: Teva; Financial Interests, Personal, Research Grant: GlaxoSmithKline; Financial Interests, Personal, Other, Honoraria: GlaxoSmithKline; Financial Interests, Personal, Research Grant: ImmunoVaccine Technologies; Financial Interests, Personal, Other, Honoraria: ImmunoVaccine Technologies; Financial Interests, Personal, Research Grant: Janssen; Financial Interests, Personal, Other, Honoraria: Janssen; Financial Interests, Personal, Research Grant: Pharmacyclics; Financial Interests, Personal, Other, Honoraria: Pharmacyclics. P.L. Zinzani: Financial Interests, Personal, Other, Honoraria, board of directors or advisory committee membership, speakers’ bureau involvement: Gilead; Financial Interests, Personal, Other, Honoraria, board of directors or advisory committee membership, speakers’ bureau involvement: Incyte; Financial Interests, Personal, Other, Honoraria, speakers’ bureau involvement, consultancy: Janssen; Financial Interests, Personal, Other, Honoraria, board of directors or advisory committee membership, speakers’ bureau involvement: Kyowa Kirin; Financial Interests, Personal, Other, Honoraria, board of directors or advisory committee membership, speakers’ bureau involvement: Merck; Financial Interests, Personal, Other, Honoraria, board of directors or advisory committee membership, speakers’ bureau involvement, consultancy: MSD; Financial Interests, Personal, Other, Honoraria, board of directors or advisory committee membership, speakers’ bureau involvement: Roche; Financial Interests, Personal, Other, Honoraria, board of directors or advisory committee membership, speakers’ bureau involvement: Servier; Financial Interests, Personal, Other, Honoraria, board of directors or advisory committee membership, speakers’ bureau involvement: Takeda; Financial Interests, Personal, Other, Honoraria, speakers’ bureau involvement: TG Therapeutics; Financial Interests, Personal, Other, Honoraria, board of directors or advisory committee membership, speakers’ bureau involvement, consultancy: Verastem; Financial Interests, Personal, Other, Honoraria, board of directors or advisory committee membership, speakers’ bureau involvement: ADC Therapeutics; Financial Interests, Personal, Other, Board of directors or advisory committee membership, speakers’ bureau involvement: Celgene; Financial Interests, Personal, Other, Board of directors or advisory committee membership, speakers’ bureau involvement: Celltrion; Financial Interests, Personal, Other, Board of directors or advisory committee membership, speakers’ bureau involvement: Immune Design; Financial Interests, Personal, Other, Board of directors or advisory committee membership, speakers’ bureau involvement: Janssen-Cilag; Financial Interests, Personal, Other, Board of directors or advisory committee membership, speakers’ bureau involvement: Portola; Financial Interests, Personal, Other, Board of directors or advisory committee membership, speakers’ bureau involvement: Sandoz; Financial Interests, Personal, Other, Consultancy: Sanofi. All other authors have declared no conflicts of interest.