Copanlisib (Aliqopa)

Number: 0923

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

1. Criteria for Initial Approval

   Aetna considers copanlisib (Aliqopa) medically necessary for any of the following B-Cell lymphomas:

   1. Follicular Lymphoma (FL)

      For treatment of follicular lymphoma (FL) when the requested medication will be used as subsequent therapy after at least two prior therapies; or

   2. Gastric MALT Lymphoma (Extranodal Marginal Zone Lymphoma of the Stomach) and Non-gastric MALT Lymphoma (Extranodal Marginal Zone Lymphoma of Nongastric Sites)

      For treatment of gastric or non-gastric mucosa-associated lymphoid tissue (MALT) lymphoma (extranodal marginal zone lymphoma of the stomach and nongastric sites) when the requested medication will be used as subsequent therapy after at least two prior therapies; or

   3. Nodal Marginal Zone Lymphoma

      For treatment of nodal marginal zone lymphoma when the requested medication will be used as subsequent therapy after at least two prior therapies as a single agent; or

   4. Splenic Marginal Zone Lymphoma

      For treatment of splenic marginal zone lymphoma when the requested medication will be used as subsequent therapy after at least two prior therapies as a single agent.

   Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).

2. Continuation of Therapy

   Aetna considers continuation of copanlisib (Aliqopa) therapy medically necessary for an indication listed in Section I when there is no evidence of unacceptable toxicity or disease progression while on the current regimen.

3. Related Policies

   • CPB 0314 - Rituximab

Dosage and Administration

Copanlisib (Aliqopa) is available for injection as a 60 mg (or 0.8 mg/kg) lyophilized solid in single-dose vial for reconstitution and dilution for intravenous infusion only. 

Folicular Lymphoma

Recommended dosing per FDA-approved labeling is as follows: Copanlisib dose is 60 mg administered as a 1-hour intravenous infusion on days 1, 8, and 15 of a 28-day treatment cycle on an intermittent schedule (three weeks on and one week off). Continue treatment until disease progression or unacceptable toxicity.

Source: Bayer, 2022

Experimental and Investigational

Aetna considers copanlisib (Aliqopa) experimental and investigational for all other indications including the following (not an all-inclusive list):

• Chronic lymphocytic leukemia
• Head and neck cancer
• Indolent non-Hodgkin's lymphomas other than the B-cell lymphomas listed above
• Inflammatory bowel disease
• Natural killer/T-cell lymphoma
• Osteosarcoma
• Solid tumors (e.g., bile duct, bladder, breast, colon, gallbladder, gastrointestinal stromal tumor, kidney, lung, melanoma, and pancreas)
• Uterine leiomyosarcoma.

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Other CPT codes related to the CPB:
96413 - 96417	Chemotherapy administration
HCPCS codes covered if selection criteria are met:
J9057	Injection, copanlisib, 1 mg
ICD-10 codes covered if selection criteria is met:
C82.00 - C82.99	Follicular lymphoma
C83.00 - C83.09	Small cell B-cell lymphoma [nodal marginal zone lymphoma] [splenic marginal zone lymphoma]
C88.4	Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue [MALT-lymphoma]
ICD-10 codes not covered if selection criteria is met:
C11.0 - C11.9	Malignant neoplasm of nasopharynx
C15.3 - C15.9	Malignant neoplasm of esophagus
C16.0 - C16.9	Malignant neoplasm of stomach
C18.0 - C18.9	Malignant neoplasm of colon
C19 - C21.8	Malignant neoplasm of rectosigmoid junction, rectum, anus and anal canal
C22.0	Liver cell carcinoma
C22.1	Intrahepatic bile duct carcinoma
C23 - C24.9	Malignant neoplasm of gall bladder and other and unspecified parts of biliary tract
C25.0 - C25.9	Malignant neoplasm of pancreas
C31.0 - C31.9	Malignant neoplasm of accessory sinuses (paranasal)
C33 - C34.92	Malignant neoplasm trachea, bronchus, and lung
C37	Malignant neoplasm of thymus
C40.00 - C41.9	Malignant neoplasm of bone and articular cartilage [osteosarcoma]
C43.0 - C43.9	Malignant melanoma of skin
C46.1	Kaposi's sarcoma of soft tissue
C47.0 - C47.9, C49.0 - C49.9	Malignant neoplasm of peripheral nerves, autonomic nervous system, connective and soft tissue
C50.011 - C50.929	Malignant neoplasm of breast
C53.0 - C53.9	Malignant neoplasm of cervix uteri
C54.0 - C54.9	Malignant neoplasm of corpus uteri
C55	Malignant neoplasm of uterus, part unspecified
C57.00 - C57.02	Malignant neoplasm of fallopian tube
C61	Malignant neoplasm of prostate
C64.1 - C64.9, C68.0 - C68.9	Malignant neoplasm of kidney and other and unspecified urinary organs
C67.0 - C67.9	Malignant neoplasm of bladder
C73	Malignant neoplasm of thyroid gland
C7A.1 - C7A.8	Malignant poorly differentiated neuroendocrine tumors
C76.0	Malignant neoplasm of head, face and neck
C80.0 - C80.1	Malignant neoplasm without specification of site
C84.40 – C84.49	Peripheral T-cell lymphoma
C84.90 – C84.99	Mature T/NK-cell lymphomas
C91.10 - C91.12	Chronic lymphocytic leukemia of B-cell type
D00.00 - D09.9	Carcinoma in situ
K50.00 – K50.919	Crohn’s disease
K51.00 -K51.919	Ulcerative colitis

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Background

U.S. Food and Drug Administration (FDA)-Approved Indications

Aliqopa is indicated for the treatment of adult patients with relapsed follicular lymphoma (FL) who have received at least two prior systemic therapies.

Compendial Uses

• Gastric MALT lymphoma (extranodal marginal zone lymphoma of the stomach), subsequent therapy for relapsed or refractory disease after 2 prior therapies
• Non-gastric MALT lymphoma (extranodal marginal zone lymphoma of nongastric sites), subsequent therapy for relapsed or refractory disease after 2 prior therapies
• Nodal marginal zone lymphoma, subsequent therapy as a single agent for relapsed or refractory disease after 2 prior therapies
• Splenic marginal zone lymphoma, subsequent therapy as a single agent for relapsed or refractory disease after 2 prior therapies

Copanlisib is available as Aliqopa (Bayer Healthcare Pharmaceuticals, Inc.) is an inhibitor of phosphatidylinositol-3-kinase (PI3K) with inhibitory activity predominantly against PI3K-α and PI3K-δ isoforms expressed in malignant B cells. In a clinical study, copanlisib has been shown to induce tumor cell death by apoptosis and inhibition of proliferation of primary malignant B cell lines. Copanlisib inhibits several key cell-signaling pathways, including B-cell receptor (BCR) signaling, CXCR12 mediated chemotaxis of malignant B cells, and NFκB signaling in lymphoma cell lines (Bayer, 2021).

Per the prescribing information, copanilsib (Aliqopa) carries the following warnings and precautions:

• Infections: The incidence of serious, including fatal, infections was noted in 19% of 317 patients receiving Aliqopa monotherapy. The incidence of serious pneumocystis jiroveci pneumonia (PJP) was noted in 0.6% of 317 patients receiving Aliqopa monotherapy. 
• Hyperglycemia: The incidence of grade 3 or 4 hyperglycemia (blood glucose 250 mg/dL or greater) was noted in 41% of 317 patients receiving Aliqopa montherapy.
• Hypertension: The incidence of grade 3 hypertension (systolic 160 mmgHg or greater or diastolic 100 mmHg or greater) was noted in 26% of 317 patients receiving Aliqopa montherapy.The incidence of serous hypertensive events was noted in 0.9% of 317 patients.
• Non-infections pneumonitis: The incidence of non-infectious pneumonitis was noted in 5% of 317 patients receiving Aliqopa monotherapy.
• Neutropenia: The incidence of grade 3 or 4 neutropenia was noted in 24% of 317 patients receiving Aliqopa monotherapy.
• Severe cutaneous reactions: The incidence of grade 3 or 4 cutaneous reactions was noted in 2.8% and 0.6% of 317 patients receiving Aliqopa montherapy, respectively.
• Embryo-fetal toxicity.

Per the prescribing information, the most common adverse reactions (≥20%) include: hyperglycemia, diarrhea, decreased general strength and energy, hypertension, leukopenia, neutropenia, nausea, lower respiratory tract infections, thrombocytopenia.

Follicular Lymphoma

Follicular lymphoma (FL) is an indolent (slow-growing) form of non-Hodgkin lymphoma (NHL), a type of B-cell lymphoma. FL accounts for approximately 35% of NHLs in the United States. Despite FL’s usual slow-growing nature, most cases are not curable, and some can grow quickly and behave like or transform into a more aggressive form of lymphoma (i.e. diffuse large B-cell lymphoma (DLBCL)). The median age at diagnosis for people with FL is 65, and is known to be rare in children and adolescents. This type of lymphoma usually occurs in many lymph node sites throughout the body, and can involve organs and bone marrow.  Features that usually require treatment include progressively enlarging lymph nodes, fever, weight loss, night sweats, and/or low blood counts.  The two best measures of outcome are the Follicular Lymphoma International Prognostic Index and tumor grade. For patients with advanced forms of FL (i.e. stages III and IV disease), the average survival is approximately 19 years. Rituximab is a medication used to treat FL, and is frequently combined with chemotherapy treatments; however, many patients will relapse with treatment (ACS, 2017; Freedman and Aster, 2023).

On September 14, 2017, the U.S. Food and Drug Administration (FDA) granted accelerated approval for the kinase inhibitor injectable drug, copanlisib (Aliqopa, Bayer HealthCare Pharmaceuticals Inc.) for the treatment of adult patients with relapsed follicular lymphoma who have received at least two prior systemic therapies. 

The accelerated approval of Aliqopa was based on the efficacy outcomes in the CHRONOS-1 (NCT 01660451) phase 2, single-arm, open-label, multicenter clinical trial which included 104 subjects (median age 62; range 25 to 81) with follicular B-cell non-Hodgkin lymphoma who had relapsed disease following at least two prior treatments. Patients must have received rituximab and an alkylating agent. Patients received 0.8 mg/kg or 60 mg of copanlisib by intravenous infusion on days 1, 8, and 15 of a 28-day treatment cycle. The objective response rate was 58.7% (95% CI: 48.6%-68.2%) with an estimated median response duration of 12.2 months (range, 0+ to 22.6 months). The complete response rate was 14.4% and partial response rate was 44.2%. The safety population included 168 patients with follicular lymphoma and other hematologic malignancies treated with the recommended copanlisib dosing regimen. Accelerated approval was granted for this indication based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. It is not known if Aliqopa is safe and effective in pediatric patients (FDA, 2017).

Chronic Lymphocytic Leukemia

Robak and Robak (2017) stated that over the last few years, several new synthetic drugs, particularly Bruton's tyrosine kinase (BTK), phosphatidylinositol 3-kinase (PI3K) and BCL-2 inhibitors have been developed and investigated in chronic lymphocytic leukemia (CLL).  These investigators reviewed key aspects of BTK, PI3K and BCL-2 inhibitors that are currently at various stages of pre-clinical and clinical development in CLL.  A literature review of the Medline database for articles in English concerning CLL, B-cell receptor, BCL-2 antagonists, BTK inhibitors and PI3K inhibitors, was conducted via PubMed.  Publications from 2000 through July 2017 were scrutinized.  The search terms used were acalabrutinib, ACP-196, BGB-3111, ONO-4059, GS-4059, duvelisib, IPI-145, TGR-1202, copanlisib, Bay 80-6946, buparlisib, BKM-120, BCL-2 inhibitors, venetoclax, ABT-263, navitoclax, CDK inhibitors, alvocidib, flavopiridol, dinaciclib, SCH 727,965, palbociclib, PD-0332991, in conjunction with CLL.  Conference proceedings from the previous 5 years of the American Society of Hematology (ASH) and European Hematology Association (EHA) Annual Scientific Meetings were searched manually.  Additional relevant publications were obtained by reviewing the references from the chosen articles.  The authors concluded that the use of new synthetic drugs is a promising strategy for the treatment of CLL.  Data from ongoing and future clinical trials would aid in better defining the status of new drugs in the treatment of CLL.

Indolent Non-Hodgkin's Lymphoma 

Dreyling and colleagues (2017) stated that PI3K signaling is critical for the proliferation and survival of malignant B cells.  Copanlisib, a pan-class I PI3K inhibitor with predominant activity against PI3K-α and -δ isoforms, has demonstrated efficacy and a manageable safety profile in patients with indolent lymphoma.  In a phase-II clinical trial, a total of 142 patients with relapsed or refractory (R/R) indolent lymphoma after 2 or more lines of therapy were enrolled to receive copanlisib 60 mg intravenously on days 1, 8, and 15 of a 28-day cycle.  The primary end-point was objective response rate (ORR); secondary end-points included duration of response, progression-free survival (PFS), and overall survival (OS).  In addition, safety and gene expression were evaluated.  Median age was 63 years (range of 25 to 82 years), and patients had received a median of 3 (range of 2 to 9) prior regimens.  The ORR was 59 % (84 of 142 patients); 12 % of patients achieved a CR.  Median time to response was 53 days.  Median duration of response was 22.6 months, median PFS was 11.2 months, and median OS had not yet been reached.  The most frequent treatment-emergent adverse events (TRAEs) were transient hyperglycemia (all grades, 50 %; grade 3 or 4, 41 %) and transient hypertension (all grades, 30 %; grade 3, 24 %).  Other grade greater than or equal to 3 events included decreased neutrophil count (24 %) and lung infection (15 %).  High response rates to copanlisib were associated with high expression of PI3K/B-cell receptor signaling pathway genes.  The authors concluded that PI3K-α and -δ inhibition by copanlisib demonstrated significant efficacy and a manageable safety profile in heavily pre-treated patients with R/R indolent lymphoma.  These findings need to be further investigated in phase-III clinical trials.  Furthermore, these researchers stated that studies that combine copanlisib with standard immuno-chemotherapy in patients with indolent lymphoma are ongoing.

Lampson and Brown (2017) noted that the efficacy of the PI3K inhibitor idelalisib for the treatment of CLL and indolent non-Hodgkin lymphoma (iNHL) has led to development of multiple compounds targeting this pathway.  These investigators reviewed the hypothesized therapeutic mechanisms of PI3K inhibitors, including abrogation of B cell receptor (BCR) signaling, blockade of micro-environmental pro-survival signals, and enhancement of anti-tumor immunity.  They examined toxicities of idelalisib, including bacterial infections (possibly secondary to drug-induced neutropenia), opportunistic infections (possibly attributable to on-target inhibition of T cell function), and organ toxicities such as transaminitis and enterocolitis (possibly autoimmune, secondary to on-target inhibition of p110δ in regulatory T cells).  These researchers evaluated PI3K inhibitors that have entered trials for the treatment of lymphoma, focusing on agents with selectivity for PI3Kα and PI3Kδ.  The authors concluded that PI3K inhibitors, particularly those that target p110δ, have robust efficacy in the treatment of CLL and iNHL.  However, idelalisib has infectious and autoimmune toxicities that limit its use.  Outside of clinical trials, idelalisib should be restricted to CLL patients with progression on ibrutinib or iNHL patients with progression on 2 prior therapies.  Whether newer PI3K inhibitors will demonstrate differentiated toxicity profiles in comparable patient populations while retaining efficacy remains to be seen.  These researchers stated that a phase-III clinical trial of copanlisib versus placebo in rituximab-refractory iNHL has completed enrollment; and 2 phase-III clinical trials of copanlisib-based therapy regimens are currently enrolling patients with iNHL.  In CHRONOS-3, patients with indolent lymphoma who have progressed after a rituximab containing regimen will be randomized to either rituximab plus copanlisib or rituximab alone, with a primary outcome measure of PFS.  In CHRONOS-4, patients are stratified based on prior therapy.  Those who have progressed after receiving R-CHOP or R-CVP for iNHL will be randomized to BR-copanlisib or BR.  Those who have progressed after BR will be randomized to R-CHOP-copanlisib or R-CHOP.  In this trial, copanlisib is administered for a fixed duration of 12 months in patients without progressive disease.

Zinzani and Broccoli (2017) reviewed the safety, efficacy, and mechanisms of action of novel agents in marginal zone lymphoma patients, both with a nodal and extra-nodal presentation.  Data on lenalidomide, bortezomib and 90yttrium-ibrutumomab tiuxetan were obtained from studies specifically designed for patients affected by marginal zone lymphoma and with various disease presentations.  The role of targeted agents, such as obinutuzumab, ibrutinib and idelalisib, and of some very new drugs (venetoclax, copanlisib, ublituximab and TGR-1202) was also discussed, taking into account the most relevant experiences in patients with indolent NHLs.

Rodgers and Reagan (2018) stated that the BCR pathway is a crucial aspect of mature lymphocytes and is maintained in B-cell neoplasms.  Many small module inhibitors targeting kinases within the BCR pathway are approved, with others in development, offering alternative therapeutic options to standard chemo-immunotherapy.  These investigators reviewed both approved inhibitors and investigational inhibitors of spleen tyrosine kinase (SYK), BTK, and PI3K in the treatment of B-cell lymphomas.  To collect relevant articles, a literature search was completed through the use of PubMed and abstracts from the ASH and American Society of Clinical Oncology (ASCO) national meetings.  Search terms including non-Hodgkin lymphoma (NHL), and BCR inhibitors, as well as the individual drug names, were utilized.  The majority of included studies were dated from 2012 to March 2018.  The authors concluded that BCR pathway inhibitors, such as ibrutinib and idelalisib, are novel treatments for NHL.  While providing alternative therapeutic options to those with high-risk disease, poor functional status, and relapsed disease, outside of chronic lymphocytic leukemia (CLL), they have been limited to the relapsed/refractory setting.  Their mechanisms of action, off/on-target effects, and resistance patterns create unique therapeutic dilemmas.  It is the authors’ opinion that more specific inhibitors, as well as combination therapy, will define the future for BCR inhibitors; copanlisib was one of the key words listed in this study.

In an open-label, single-arm, phase-I clinical trial, Li et al (2022) examine the effectiveness of copanlisib in Chinese patients with R/R iNHL. Patients received a single intravenous 60-mg infusion of copanlisib over 1 hour on days 1, 8, and 15 of a 28-day cycle, with 1 week of rest.  Safety was monitored throughout the study, and plasma copanlisib levels were measured for pharmacokinetic analysis.  Tumor response was determined by independent central radiologic review.  A total of 16 patients were enrolled and 13 were treated with 60-mg copanlisib for a median of 15.0 weeks.  With a Cmax of 566 μg/L and a AUC (0 to 24) of 1,880 μg·hour/L following single intravenous infusion, the pharmacokinetic parameters of copanlisib were consistent with that in previous studies, and no accumulation in plasma was observed.  Treatment-emergent AEs (TEAEs) were reported for all 13 patients, the most common of which were hyperglycemia (100.0 %), hypertension (76.9 %), decreased neutrophil count (76.9 %), and decreased white blood cell (WBC) count (69.2 %); 7 out of 12 evaluated patients achieved PR, resulting in an ORR of 58.3 %.  The authors concluded that copanlisib was well-tolerated in Chinese patients with R/R iNHL at the dose of 60 mg and showed encouraging disease control; therefore, warranting further clinical investigation.

In a phase-Ib/II clinical trial, Fukuhara et al (2023) examined the safety, effectiveness, and pharmacokinetics of copanlisib in Japanese patients with R/R iNHL.  The primary endpoint was safety at the recommended dose; effectiveness endpoints included ORR, PFS, and OS.  In the phase-Ib, patients received copanlisib 45-mg intravenously on days 1, 8, and 15 of a 28-day cycle, and when tolerated, consecutive patients received copanlisib 60 mg.  As no dose-limiting toxicities occurred at the 45-mg (n = 3) or 60-mg (n = 7) dose in phase Ib, the recommended dose for Japanese patients was determined to be 60 mg, and this dose was used in phase II (n = 15).  Although all patients experienced at least 1 TEAE, with hyperglycemia being the most common AE, no AE-related deaths were reported.  The ORR was 68.0 % (17/25 patients), median PFS was 302 (95 % CI: 231 to 484) days, and the duration of response was 330 (range of 65 to 659) days.  The pharmacokinetic properties of copanlisib were similar between Japanese and non-Japanese patients.  The authors concluded that copanlisib 60-mg had an acceptable safety profile and showed promising anti-tumor activity in Japanese patients with R/R iNHL.

Inflammatory Bowel Disease

Winkelmann and colleagues (2021) noted that with glucose being the preferred source of energy in activated T cells, targeting glycolysis has become an attractive therapeutic intervention point for chronic inflammatory bowel diseases (IBD). The switch to glycolysis is mediated by phosphoinositide-3-kinases (PI3K) that relay signals from surface receptors to the AKT pathway. These researchers first confirmed by analysis of the oxygen consumption rate (OCR) and extra-cellular acidification rate (ECAR) that metabolism is shifted towards glycolysis in IBD patients as compared to non-IBD donors. In contrast to non-IBD donors, OCR correlated with ECAR (IBD: cor = 0.79, p = 2E-10; non-IBD: cor = 0.37, p = n.s.), in IBD patients. Second, these investigators tested the PI3K inhibitor copanlisib as a potential therapeutic agent. Ex-vivo, copanlisib suppressed the ECAR significantly in T cells activated by anti-CD3 antibodies and significantly decreased ECAR rates in the presence of copanlisib (anti-CD3: 58.24 ± 29.06; copanlisib: 43.16 ± 20.23, p < 0.000. Furthermore, copanlisib impaired the activation of CD4+ CD25+ T cells (anti-CD3: 42.15 ± 21.46; anti-CD3 + copanlisib: 26.06 ± 21.82 p = 0.013) and the secretion of cytokines (IFNγ: anti-CD3: 6332.0 ± 5,707.61 pmol/ml; anti-CD3 + copanlisib: 6332.0 ± 5,707.61, p = 0.018). In-vivo, copanlisib significantly improved the histological scores (ethanol: 8.5 ± 3.81; copanlisib: 4.57 ± 2.82, p = 0.006) in the NSG-UC mouse model. Orthogonal partial least square discrimination analysis (oPLS-DA) confirmed the efficacy of copanlisib. The authors concluded that these findings suggested that the PI3K pathway provided an attractive therapeutic intervention point in IBD for patients in relapse. Moreover, these researchers stated that it is noteworthy that IBD patients express higher levels of CD69+ CD4+ cells; and the suppression of these cells in-vivo maybe a further indication that copanlisib may be effective in humans. oPLS-DA analysis validated copanlisib as a potential therapeutic in IBD. However, the fact that CR was not achieved by copanlisib suggested that it might be used in combination with other therapeutics such as tacrolimus addressing the alternate T-cell activation pathway. The change of metabolism during activation of T cells has also the potential to identify metabolites as biological markers of active disease. They stated that targeting metabolic pathways have the potential to develop phase-dependent therapies.

Natural Killer/T-Cell Lymphoma / Peripheral T-Cell Lymphoma

Huang and associates (2020) noted that peripheral T-cell lymphomas (PTCLs) and natural killer (NK)/TCLs (NKTCLs) are a heterogeneous group of aggressive malignancies with dismal outcomes and limited therapeutic options.  While the PIK3 pathway has been shown to be highly activated in many B-cell lymphomas, its therapeutic relevance in PTCLs and NKTCLs remains unclear.  These investigators examined the expression of PIK3 and PTEN in these subtypes of lymphoma and identified potential therapeutic targets for clinical testing.  Thus, the expression of PIK3α, PIK3β, PIK3γ, PIK3δ and PTEN was analyzed in 88 cases of PTCLs and NKTCLs samples by immunohistochemistry.  All PTCLs and NKTCLs samples demonstrated high expression of PIK3 isoforms.  In particular, high PIK3α expression was significantly associated with poor survival, even after adjustment for age, International Prognostic Index (IPI) score and anthracycline-based chemotherapy in 1st-line.  Notably, copanlisib, a pan-class I inhibitor with predominant activities towards PIK3α and PIK3δ isoforms, effectively inhibited phosphorylation of AKT, 4E-BP-1 and STAT3, causing G0/G1 cell cycle arrest and resulting in suppression of tumor cell growth in-vitro and in-vivo.  The authors concluded that the findings of this study provided evidence that targeting the PIK3 pathway, especially simultaneous inhibition of PIK3α and δ, could be a promising approach for the treatment of PTCLs and NKTCLs.

Yhim and colleagues (2021) stated that current therapeutic options for PTCLs in the relapsed/refractory setting are limited and demonstrated modest response rates with rare achievement of CR.  In a phase I/II clinical trial, these investigators examined the safety and efficacy of copanlisib in combination with gemcitabine in 28 patients with relapsed/refractory PTCL.  Patients received escalating doses of intravenous copanlisib on days 1, 8, and 15, administered concomitantly with fixed-dose gemcitabine (1,000 mg/m2 on days 1 and 8) in 28-day cycles; DLT was not observed in the dose-escalation phase and 60-mg copanlisib was selected for phase-II evaluation.  A total of 25 patients were enrolled in phase-II of the study.  Frequent grade greater than or equal to 3 AEs included transient hyperglycemia (57 %), neutropenia (45 %), thrombocytopenia, (37 %), and transient hypertension (19 %); however, AEs were manageable, and none was fatal.  The ORR was 72 % with a CR rate of 32 %.  Median duration of response was 8.2 months, PFS was 6.9 months, and median OS was not reached.  Combination treatment produced a greater CR rate in patients with angioimmunoblastic TCL than those with PTCL-not otherwise specified (55.6 % versus 15.4 %, respectively, p = 0.074) and PFS was significantly longer (13.0 versus 5.1 months, respectively, p = 0.024).  In an exploratory gene mutation analysis of 24 tumor samples, TSC2 mutation was present in 25 % of patients and occurred exclusively in responders.  The authors concluded that the copanlisib/gemcitabine combination demonstrated promising efficacy in relapsed/refractory PTCL, especially in individuals with angioimmunoblastic TCL.  Furthermore, TSC2 mutation occurred exclusively in responders and may have potential as a response marker to combination therapy.

Osteosarcoma

Harrison et al (2023) stated that copanlisib is a pan-class I phosphoinositide 3-kinase (PI3K) inhibitor, with activity against all 4 PI3K class I isoforms (PI3Kα, PI3Kβ, PI3Kγ, and PI3Kδ). Whole-genome and RNA sequencing data have revealed several PI3K aberrations in osteosarcoma tumor samples. The in-vivo anti-cancer effects of copanlisib were evaluated in a panel of 6 osteosarcoma models. Copanlisib induced prolonged event-free survival (EFS) in 5 of 6 osteosarcoma models; however, all models showed progressive disease suggesting minimal activity. The authors concluded that while copanlisib did not result in tumor regression, further investigation is needed to examine the role of the PI3K pathway in the pathogenesis of osteosarcoma.

Solid Tumors

In a phase-I clinical trial, Patnaik and co-workers (2016) evaluated the safety, tolerability, pharmacokinetics, and maximum tolerated dose (MTD) of copanlisib in patients with advanced solid tumors or NHL.  Phase I dose-escalation study including patients with advanced solid tumors or NHL, and a cohort of patients with type 2 diabetes mellitus.  Patients received 3 weekly intravenous infusions of copanlisib per 28-day cycle over the dose range 0.1 to 1.2 mg/kg.  Plasma copanlisib levels were analyzed for pharmacokinetics.  Biomarker analysis included PIK3CA, KRAS, BRAF, and PTEN mutational status and PTEN immunohistochemistry.  Whole-body [(18)F]-fluorodeoxyglucose positron emission tomography ((18)FDG-PET) was carried out at baseline and following the 1st dose to assess early pharmacodynamic effects.  Plasma glucose and insulin levels were evaluated serially.  A total of 57 patients received treatment.  The MTD was 0.8 mg/kg copanlisib.  The most frequent treatment-related adverse events (TRAEs) were nausea and transient hyperglycemia.  Copanlisib exposure was dose-proportional with no accumulation; peak exposure positively correlated with transient hyperglycemia post-infusion; 16 of 20 patients treated at the MTD had reduced (18)FDG-PET uptake; 7 (33 %) had a reduction of greater than 25 %; 1 patient achieved a complete response (CR); endometrial carcinoma exhibiting both PIK3CA and PTEN mutations and complete PTEN loss and 2 had a partial response (PR; both metastatic breast cancer).  Among the 9 NHL patients, all 6 with follicular lymphoma (FL) responded (1 CR and 5 PRs) and 1 patient with DLBCL had a PR by investigator assessment; 2 patients with FL who achieved CR (per post-hoc independent radiologic review) were on treatment for greater than 3 years.  The authors concluded that copanlisib, dosed intermittently on days 1, 8, and 15 of a 28-day cycle, was well-tolerated and the MTD was determined to be 0.8 mg/kg.  Patients included in this trial had diagnoses of breast cancer, NHL, and non-small cell lung cancer.

In a phase-I clinical trial, Doi and associates (2017) evaluated the safety, tolerability, pharmacokinetics, and efficacy of copanlisib in Japanese patients with advanced or refractory solid tumors.  Patients received a single intravenous dose of either copanlisib 0.4 mg/kg or copanlisib 0.8 mg/kg, dosed intermittently on days 1, 8, and 15 of a 28-day cycle.  Safety was monitored throughout the study.  Plasma copanlisib levels were measured for pharmacokinetic analysis.  A total of 10 patients were enrolled and treated; 3 received copanlisib 0.4 mg/kg and 7 received copanlisib 0.8 mg/kg.  Overall, median duration of treatment was 6.2 weeks.  No patients treated at 0.4 mg/kg experienced a dose-limiting toxicity (DLT), and the MTD in Japanese patients was determined to be 0.8 mg/kg; AEs were recorded in all 10 patients; the most common were constipation , hyperglycemia, and hypertension.  Copanlisib pharmacokinetic exposures displayed near dose-proportionality, with no accumulation.  No patients achieved a CR or PR, and disease control rate was 40.0 %.  The authors concluded that copanlisib was well-tolerated in Japanese patients with advanced or refractory solid tumors, and the MTD was determined to be 0.8 mg/kg.  Copanlisib demonstrated near dose-proportional pharmacokinetics and preliminary disease control, warranting further investigation.  Patients included in this trial had the following types of tumors – bladder, colon, gastro-intestinal stromal tumor, kidney, non-small cell lung cancer, and pancreatic adenocarcinoma.  These researchers stated that in this small study, copanlisib showed preliminary disease control, and these data support further investigation of the safety and efficacy of copanlisib in Japanese patients with solid tumors and other advanced malignancies.  They noted that a phase-Ib study into the safety of copanlisib in Japanese patients with relapsed, indolent B-cell NHL is ongoing, in addition to a wider program of studies into copanlisib safety, pharmacodynamics, PK, and efficacy in a range of patient populations and cancer types.

Lim and co-workers (2017) stated that the identification of driver mutations in melanoma has changed the field of cancer treatment.  BRAF and NRAS mutations are predominant in melanoma and led to over-activation of the mitogen‐activated protein kinase (MAPK) and PI3K/protein kinase B (AKT) signaling pathways.  Selective inhibitors targeting key effectors of the MAPK pathway have revolutionized the treatment of patients with advanced metastatic BRAF‐mutant melanoma.  However, resistance to therapy is almost universal and remains a major challenge in clinical care, with the majority of patients progressing within 1 year.  Dissecting the mechanisms of resistance to targeted therapies may offer new insights into strategies for overcoming resistance.  These investigators described the efficacy of therapies targeting the MAPK and PI3K/AKT signaling pathways in melanoma, detailed the mechanisms contributing to drug resistance, and discussed current approaches to improving outcomes further.  These researchers noted that copanlisib, a pan‐PI3K inhibitor with preferential activity against the PI3Kα and PI3Kδ isoforms, induced apoptosis and cell cycle arrest in melanoma cells with constitutively activated AKT both in cultures and in xenograft mouse models.  They stated that despite the promising pre-clinical data, the clinical combination of PI3K/AKT inhibitors with BRAF or MEK inhibitors has been disappointing.  A phase-I clinical  trial testing the safety and tolerability of trametinib in combination with the AKT inhibitor afuresertib showed only a PR in a patient with wild‐type BRAF melanoma.  Several clinical trials are currently ongoing; they include a combination of the PI3K inhibitor buparlisib with BRAF inhibitors or MEK inhibitors in solid cancers and a combination of the copanlisib with a MEK inhibitor in melanoma.  However, because of the early‐phase (phase-I) nature of these trials, it is not possible to determine conclusively the efficacy of these combinations until phase-II and phase-III clinical trials with larger patient cohorts have been completed.

Kim and colleagues (2018) noted that copanlisib is a pan-class I PI3K inhibitor with predominant PI3K-α/δ activity that has demonstrated clinical activity and manageable safety when administered as monotherapy in a phase-II clinical trial.  Combination therapy may overcome compensatory signaling that could occur with PI3K pathway inhibition, resulting in enhanced inhibitory activity, and pre-clinical studies of copanlisib with gemcitabine have demonstrated potent anti-tumor activity in-vivo.  A phase-I, open-label, dose-escalation study to evaluate the safety, tolerability and recommended phase-II dose (RP2D) of copanlisib with gemcitabine or with cisplatin plus gemcitabine (CisGem) in patients with advanced malignancies, including an expansion cohort in patients with biliary tract cancer (BTC) at the RP2D of copanlisib plus CisGem.  Copanlisib and gemcitabine were administered on days 1, 8 and 15 of a 28-day cycle; MTD and RP2D of copanlisib were determined.  Copanlisib plus CisGem was administered on days 1 and 8 of a 21-day cycle; pharmacokinetics and biomarkers were assessed.  A total of 50 patients received treatment as follows: dose-escalation cohorts, n = 16; copanlisib plus CisGem cohort, n = 14; and BTC expansion cohort, n = 20.  Copanlisib 0.8 mg/kg plus gemcitabine was the MTD and RP2D for both combinations.  Common treatment-emergent AEs included nausea (86 %), hyperglycemia (80 %) and decreased platelet count (80 %).  Copanlisib exposure displayed a dose-proportional increase.  No differences were observed upon co-administration of CisGem.  Response rates were as follows: copanlisib plus gemcitabine, 6.3 % (1 partial response [PR] in a patient with peritoneal carcinoma); copanlisib plus CisGem, 12 % (1 CR and 3 PRs all in patients with BTC (response rate 17.4 % in patients with BTC)).  Mutations were detected in PIK3CA (1 out of 43), KRAS (10 out of 43) and BRAF (2 out of 22), with phosphate and tensin homologue protein loss in 41 % (12 out of 29).  The authors concluded that copanlisib plus CisGem demonstrated a manageable safety profile, favorable pharmacokinetics, and potentially promising clinical response.  Patients included in this trial had diagnoses of gallbladder cancer, extra-hepatic cholangiocarcinoma, and intra-hepatic cholangiocarcinoma.  These researchers stated that a phase-II clinical trial examining the clinical benefits of copanlisib plus CisGem in patients with advanced cholangiocarcinoma is currently underway.

Elster and colleagues (2018) noted that somatic mutations in the ERBB genes (epidermal growth factor receptor: EGFR, ERBB2, ERBB3, ERBB4) promote oncogenesis and lapatinib resistance in metastatic HER2+ (human epidermal growth factor-like receptor 2) breast cancer in-vitro.  These researchers determined the frequency of mutations in 4 genes: EGFR, ERBB2, ERBB3 and ERBB4 and examined if these mutations affect cellular behavior and therapy response in-vitro and outcomes after adjuvant trastuzumab-based therapy in clinical samples.  They performed Agena MassArray analysis of 227 HER2+ breast cancer samples to identify the type and frequency of ERBB family mutations.  Of these, 2 mutations, the somatic mutations ERBB4-V721I and ERBB4-S303F, were stably transfected into HCC1954 (PIK3CA mutant), HCC1569 (PIK3CA wildtype) and BT474 (PIK3CA mutant, ER positive) HER2+ breast cancer cell lines for functional in-vitro experiments.  A total of 12 somatic, likely deleterious mutations in the kinase and furin-like domains of the ERBB genes (3 EGFR, 1 ERBB2, 3 ERBB3, 5 ERBB4) were identified in 7 % of HER2+ breast cancers, with ERBB4 the most frequently mutated gene.  The ERBB4-V721I kinase domain mutation significantly increased 3D-colony formation in 3/3 cell lines, whereas ERBB4-S303F did not increase growth rate or 3D colony formation in-vitro.  ERBB4-V721I sensitized HCC1569 cells (PIK3CA wildtype) to the pan class I PI3K inhibitor copanlisib but increased resistance to the pan-HER family inhibitor afatinib.  The combinations of copanlisib with trastuzumab, lapatinib, or afatinib remained synergistic regardless of ERBB4-V721I or ERBB4-S303F mutation status.  The authors concluded that ERBB gene family mutations, which are present in 7 % of theHER2+ breast cancer cohort, may have the potential to alter cellular behavior and the efficacy of HER- and PI3K-inhibition.

Klinghammer et al (2020) noted that despite recent advances, the treatment of head and neck squamous cell carcinoma (HNSCC) remains an area of high unmet medical need.  HNSCC is frequently associated with either amplification or mutational changes in the PI3K pathway, making PI3K an attractive target especially in cetuximab-resistant tumors.  These researchers examined the anti-tumor activity of the selective, pan-class I phosphatidylinositol 3-kinase (PIK3) inhibitor copanlisib with predominant activity towards PI3Kα and δ in monotherapy and in combination with cetuximab using a mouse clinical trial set-up with 33 patient-derived xenograft (PDX) models with known HPV and PI3K mutational status and available data on cetuximab sensitivity.  Treatment with copanlisib alone resulted in moderate anti-tumor activity with 12/33 PDX models showing either tumor stabilization or regression.  Combination treatment with copanlisib and cetuximab was superior to either of the monotherapies alone in the majority of the models (21/33), and the effect was especially pronounced in cetuximab-resistant tumors (14/16).  While no correlation was observed between PI3K mutation status and response to either cetuximab or copanlisib, increased PI3K signaling activity examined via gene expression profiling showed a positive correlation with response to copanlisib.  The authors concluded that these findings supported further investigation of PI3K inhibition in HNSCC and suggested gene expression patterns associated with PI3K signaling as a potential biomarker for predicting therapeutic responses.

Yan and colleagues (2021) stated that inhibition of the PI3K/mTOR pathway suppresses breast cancer (BC) growth, enhances anti-tumor immune responses, and works synergistically with immune checkpoint inhibitors (ICI).  These researchers identified a subclass of PI3K inhibitors that, when combined with paclitaxel, is effective in enhancing response to ICI.  C57BL/6 mice were orthotopically implanted with syngeneic luminal/triple-negative-like polyomavirus middle T (PyMT) cells exhibiting high endogenous PI3K activity.  Tumor growth in response to treatment with anti-PD-1 + anti-CTLA-4 (ICI), paclitaxel (PTX), and either the PI3Kα-specific inhibitor alpelisib, the pan-PI3K inhibitor copanlisib, or the broad spectrum PI3K/mTOR inhibitor gedatolisib was examined in reference to monotherapy or combinations of these therapies.  Effects of these therapeutics on intra-tumoral immune populations were determined by multi-color fluorescence-activated cell sorting (FACS).  Treatment with alpelisib + PTX inhibited PyMT tumor growth and increased tumor-infiltrating granulocytes but did not significantly affect the number of tumor-infiltrating CD8+ T cells and did not synergize with ICI.  Copanlisib + PTX + ICI significantly inhibited PyMT growth and increased activation of intra-tumoral CD8+ T cells as compared to ICI alone, yet did not inhibit tumor growth more than ICI alone.  In contrast, gedatolisib + ICI resulted in significantly greater inhibition of tumor growth compared to ICI alone and induced durable dendritic-cell, CD8+ T-cell, and NK-cell responses.  Adding PTX to this regimen yielded complete regression in 60 % of tumors.  The authors concluded that given the preferentially high expression levels of PI3KCD and PIK3CG in triple-negative breast cancer (TNBC), and the pre-clinical data from this trial, along with the data from the existing clinical trials testing gedatolisib + PTX, they suggested that combined treatment with gedatolisib, PTX, and ICI may provide a durable therapeutic response for TNBC patients.

Tan and co-workers (2021) noted that biliary tract cancer (BTC) has a poor prognosis despite treatment with 1st-line gemcitabine and cisplatin.  In BTC, PI3K/AKT pathway activation has been shown to increase resistance to chemotherapy, which may be overcome with PI3K inhibition.  In a phase-II clinical trial, these researchers examined the safety and efficacy of copanlisib with gemcitabine and cisplatin in advanced BTCs.  The role of phosphatase and tensin homolog (PTEN) expression in outcomes was also examined.  Patients with advanced/unresectable BTC received gemcitabine, cisplatin, and copanlisib as their 1st-line treatment.  The primary endpoint was PFS at 6 months; secondary endpoints were the RR, median OS/PFS, and safety profile.  An assessment of PTEN expression by immunohistochemistry was also carried out along with molecular profiling.  A total of 24 patients received at least 1 dose of the study drug.  The PFS rate at 6 months was 51 %; the median OS was 13.7 months (95 % CI: 6.8 to 18.0 months), and the median PFS was 6.2 months (95 % CI: 2.9 to 10.1 months); 19 patients were evaluable for RR: 6 patients achieved a PR (31.6 %), and 11 (57.9 %) had stable disease (SD).  The most common grade 3/4 adverse events (AEs) were a decreased neutrophil count (45.83 %), anemia (25 %), increased lipase (25 %), and hypertension (20.8 %); 20 patients had tissue evaluable for the PTEN status.  The PFS for low (n = 9) and high PTEN expression (n = 11) was 8.5 and 4.6 months, respectively (p = 0.19).  The median OS for low and high PTEN expression groups was 17.9 and 7.0 months, respectively (p = 0.19).  The authors concluded that the addition of copanlisib to gemcitabine and cisplatin did not improve PFS at 6 months.  Copanlisib may be more effective and increase survival in patients with low PTEN expression levels; however, further studies are needed to confirm this.

Choi and associates (2021) stated that uterine leiomyosarcomas (uLMS) are aggressive tumors arising from the smooth muscle layer of the uterus.  These researchers analyzed 83 uLMS sample genetics, including 56 from Yale and 27 from the Cancer Genome Atlas (TCGA).  Among them, a total of 55 Yale samples including 2 patient-derived xenografts (PDXs) and 27 TCGA samples had whole-exome sequencing (WES) data; 10 Yale and 27 TCGA samples had RNA-sequencing (RNA-Seq) data; and 11 Yale and 10 TCGA samples had whole-genome sequencing (WGS) data.  These investigators found recurrent somatic mutations in TP53, MED12, and PTEN genes.  Top somatic mutated genes included TP53, ATRX, PTEN, and MEN1 genes.  Somatic copy number variation (CNV) analysis identified 8 copy-number gains, including 5p15.33 (TERT), 8q24.21 (C-MYC), and 17p11.2 (MYOCD, MAP2K4) amplifications and 29 copy-number losses.  Fusions involving tumor suppressors or oncogenes were detected, with most fusions disrupting RB1, TP53, and ATRX/DAXX, and 1 fusion (ACTG2-ALK) being potentially targetable.  WGS results demonstrated that 76 % (16 of 21) of the samples harbored chromoplexy and/or chromothripsis.  Clinically actionable mutational signatures of homologous-recombination DNA-repair deficiency (HRD) and micro-satellite instability (MSI) were identified in 25 % (12 of 48) and 2 % (1 of 48) of fresh frozen uLMS, respectively.  Finally, these researchers found olaparib (PARPi; p = 0.002), GS-626510 (C-MYC/BETi; p < 0.000001 and p = 0.0005), and copanlisib (PIK3CAi; p = 0.0001) mono-therapy to significantly inhibit uLMS-PDXs harboring derangements in C-MYC and PTEN/PIK3CA/AKT genes (LEY11) and/or HRD signatures (LEY16) compared to vehicle-treated mice.  The authors concluded that these findings defined the genetic landscape of uLMS and suggested that a subset of uLMS may benefit from existing PARP-, PIK3CA-, and C-MYC/BET-targeted drugs.

Yang et al (2022) identified the most effective PI3K and EGFR inhibitors in HPV-positive head and neck squamous cell carcinoma (HNSCC) and examined the effectiveness of a combination of an ErbB family kinase inhibitor and a PI3K inhibitor to inhibit cell proliferation of HPV-positive HNSCC.  HPV-positive HNSCC cell lines were treated with the FDA-approved ErbB kinase inhibitor, afatinib or FDA-approved PI3K inhibitor, copanlisib, alone or in combination, and phosphorylation and total protein levels of cells were assessed by Western blot analysis.  Cell proliferation and apoptosis were examined by MTS assay, flow cytometry, and Western blots, respectively.  Copanlisib more effectively inhibited cell proliferation in comparison to other PI3K inhibitors tested.  HPV-positive HNSCC cells differentially responded to cisplatin, afatinib, or copanlisib.  The combination of afatinib and copanlisib more effectively suppressed cell proliferation and induced apoptosis compared to either treatment alone.  Mechanistically, the combination of afatinib and copanlisib completely blocked phosphorylation of EGFR, HER2, HER3, and Akt as well as significantly decreased the HPV E7 expression compared to either treatment alone.  The authors concluded that afatinib and Copanlisib more effectively suppress cell proliferation and survival of HPV-positive HNSCC in comparison to either treatment alone.

Damodaran et al (2022) noted that activating mutations in PIK3CA are observed across multiple tumor types.  The NCI-MATCH (EAY131) is a tumor-agnostic platform trial that enrolled patients to targeted therapies on the basis of matching genomic alterations.  Arm Z1F examined copanlisib, an α and δ isoform-specific phosphoinositide 3-kinase (PI3K) inhibitor, in patients with PIK3CA mutations (with or without PTEN loss).  Patients received copanlisib (60 mg intravenous) once-weekly on days 1, 8, and 15 in 28-day cycles until progression or toxicity.  Patients with KRAS mutations, human EGFR 2-positive breast cancers, and lymphomas were excluded.  The primary endpoint was centrally assessed ORR; secondary endpoints included PFS, 6-month PFS, and OS.  A total of 35 patients were enrolled, and 25 patients were included in the primary efficacy analysis as prespecified in the Protocol.  Multiple histologies were enrolled, with gynecologic (n = 6) and gastro-intestinal (n = 6) being the most common; 68 % of patients had 3 or more lines of prior therapy.  The ORR was 16 % (4 of 25, 90 % CI: 6 to 33) with p = 0.0341 against a null rate of 5 %.  The most common reason for protocol discontinuation was disease progression (n = 17, 68 %). Grade-3/4 toxicities observed were consistent with reported toxicities for PI3K pathway inhibition; 16 patients (53 %) had grade-3 toxicities, and 1 patient (3 %) had grade-4 toxicity (CTCAE v5.0).  Most common toxicities include hyperglycemia (n = 19), fatigue (n = 12), diarrhea (n = 11), hypertension (n = 10), and nausea (n = 10).  The authors concluded that this study met its primary endpoint with an ORR of 16 % (p = 0.0341) with copanlisib showing clinical activity in select tumors with PIK3CA mutation in the refractory setting.

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References