Copanlisib in the Treatment of Relapsed Follicular Lymphoma: Utility and Experience from the Clinic

Figures & data

Figure 1 The PI3K pathway in the context of BCR signaling along with various targets. The BCR pathway is activated through antigen binding followed by recruitment and stimulation of LYN/SYK, resulting in phosphorylation of tyrosine residues on adapter proteins on the BCR as well as CD19. This enables the docking of PI3K regulator subunit to the BCR and CD19 and activation of the PI3K pathway. Activated PI3K phosphorylates PIP2 into PIP3 which stimulates PH domain signaling molecules including Akt. LYN/SYK also activate the BTK pathway which instigates PLCγ2 activation. The result of these processes is intranuclear transcriptional activation promoting cell survival. PTEN is a prominent negative regulator of this pathway. Also shown is the role of follicular T-helper cells and the PD-1/PDL-1 pathway. Created with BioRender.com.

Abbreviations: Akt, a serine/threonine-specific protein kinase; BCR, B-cell receptor; BTK, Bruton tyrosine kinase; CAR, chimeric-antigen receptor; CR, chemokine receptor; ERK, extracellular-signal-regulated kinase (major signaling cassette of mitogen-activated kinase pathway); IKK-α/β, inhibitor of NF-κB; IRAK 1/4, interleukin-1 receptor-associated kinase 4; JAK, Janus tyrosine kinase; LYN, Lck/yes novel tyrosine kinase; mTOR, mechanistic target of rapamycin; MYD88, myeloid differentiation primary response 88; NEMO, NF-κB essential modulator; NFATc1, nuclear factor of activated T-cells cytoplasmic 1; NF-κB, nuclear factor kappa-B; PD-1, programmed death-1; PDL-1, programmed death-1 ligand; PH, pleckstrin homology; PIP2, phosphatidylinositol 4,5-bisphosphate; PI3K, phosphatidylinositol-3 kinase; PIP3, phosphatidylinositol 3,4,5-triphosphate; PLCγ2, phospholipase C-gamma PTEN, phosphatase and tensin homolog; STAT, signal transducer and activator of transcription; SYK, spleen tyrosine kinase; TLR, toll-like receptor; TRAF6, tumor necrosis factor receptor-associated factor 6.

Table 1 Ongoing Phase III Trials Studying Copanlisib in NHL

NCT Identifier	Phase	Agent(s)	Indication	Actual Study Start date	Estimated Study Completion	Sponsor/Country	Status	Planned Accrual/Actual Enrollment
NCT02369016 CHRONOS-2	III	Copanlisib vs placebo	Rituximab-refractory iNHL, 3rd line	September 22, 2015	November 30, 2020	Bayer/ International	Active/Not recruiting	189/25
NCT02367040 CHRONOS-3	III	Copanlisib + rituximab vs placebo + rituximab	Relapsed iNHL	August 3, 2015	September 30, 2021	Bayer/International	Active/Not recruiting	514/458
NCT02626455 CHRONOS-4	III	Copanlisib + chemo-immunotherapy (BR or RCHOP) vs placebo + BR/RCHOP	Relapsed iNHL	January 6, 2016	April 12, 2022	Bayer/International	Active/Not recruiting	724/551

Table 2 Efficacy and Safety Profile of PI3K Inhibitors in FL

	Copanlisib	Idelalisib	Duvelisib	Umbralisib	ME-401
Current indication(s)	3rd-line FL, CLL, SLL	3rd-line FL, CLL, SLL	CLL/SLL, 3rd-line FL	Orphan drug FL (3rd line), Experimental	Experimental
Mechanism of action	PI3Ki (α, δ)	PI3Ki (δ)	PI3Ki (δ, γ)	PI3Ki (δ), CK1-ε	PI3Ki (δ)
Administration	Intravenous	Oral	Oral	Oral	Oral
Study population	≥3rd line (FL, n=72)	≥3rd line (FL, n=72)	≥2nd line (FL, n=83)	≥2nd line (FL, n=17)^Citation59	≥1 line FL (n=48)^Citation62
ORR (FL)	54%	54%	42%	53%	79%
CR (FL)	8%	8%	1%	12%	26%
Median PFS (FL)	11 months	11 months	8.3 months^Citation2	N/A (Median DOR 9.3 months)	N/A
Black box warning	None	Fatal and/or serious toxicities: Hepatotoxicity (16–18%) Severe diarrhea or colitis (14–20%) Pneumonitis (4%) Infections (21–48%) Intestinal perforation	Fatal and/or serious: Infections (31%) Diarrhea or colitis (18%) Cutaneous reactions (5%) Pneumonitis (5%)	N/A	N/A
Select Grade ≥3 AEs
Hyperglycemia (transient)	40%	None reported	None reported	None reported	None reported
Hypertension (transient)	27%	None reported	None reported	None reported	None reported
Diarrhea	5%	14%	23%	43%	30% on CS 11% on IS
Colitis
Pneumonitis	5%	16%	5%	None reported	N/A
Lung infection	13.7%			13%
ALT increased	None reported	19%	8%	6%	1.8%
AST increased	None reported	12%	6%	7%	1.8%

Ali K, Soond DR, Piñeiro R, et al. Inactivation of PI(3)K p110δ breaks regulatory T-cell-mediated immune tolerance to cancer. Nature. 2014;510(7505):407–411. doi:10.1038/nature1344424919154

 PubMed Web of Science ®Google Scholar

Smith SM, Pitcher BN, Jung SH, et al. Safety and tolerability of idelalisib, lenalidomide, and rituximab in relapsed and refractory lymphoma: the Alliance for clinical trials in oncology A051201 and A051202 phase 1 trials. Lancet Haematol. 2017;4(4):e176–82. doi:10.1016/S2352-3026(17)30028-528314699

 PubMed Web of Science ®Google Scholar

Batlevi CL, Sha F, Alperovich A, et al. Follicular lymphoma in the modern era: survival, treatment outcomes, and identification of high-risk subgroups. Blood Cancer J. 2020;10(7):74. doi:10.1038/s41408-020-00340-z32678074

 PubMed Web of Science ®Google Scholar