Copanlisib (Aliqopa)

Number: 0923

Policy

Aetna considers copanlisib (Aliqopa) medically necessary as second-line or subsequent therapy for refractory or progressive follicular lymphoma that is refractory to at least 2 prior therapies.

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

• Chronic lymphocytic leukemia
• Indolent non-Hodgkin's lymphoma (including indolent lymphoma and marginal zone lymphoma)
• Solid tumors (e.g., bile duct, bladder, breast, colon, gallbladder, gastrointestinal stromal tumor, kidney, lung, melanoma, and pancreas).

See also CPB 0314 - Rituximab (Rituxan).

Background

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, 2017).

Copanlisib 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 (FDA, 2017).

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).

The National Comprehensive Cancer Network Drugs and Biologics Compendium (NCCN, 2018) recommends copanlisib for follicular lymphoma (grade 1 -2) as second-line or subsequent therapy for refractory or progressive disease that is refractory to at least 2 prior therapies.

Common adverse reactions in greater than 20% of patients include hyperglycemia, diarrhea, fatigue, hypertension, leukopenia, neutropenia, nausea, lower respiratory tract infections, and thrombocytopenia. The most common grade 3-4 adverse reactions include hyperglycemia, leukopenia, hypertension, neutropenia, and lower respiratory tract infections. Serious non-infectious pneumonitis occurred in 6% of patients.

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.

Furthermore, National Comprehensive Cancer Network’s Drugs & Biologics Compendium (2018) does not list chronic lymphocytic leukemia as a recommended indication of copanlisib.

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.

Furthermore, National Comprehensive Cancer Network’s Drugs & Biologics Compendium (2018) does not list indolent lymphoma / indolent non-Hodgkin lymphoma / marginal zone lymphoma as recommended indications of copanlisib.

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.

Furthermore, National Comprehensive Cancer Network’s Drugs & Biologics Compendium (2018) does not list any solid tumor as a recommended indication of copanlisib.

Appendix

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.

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).
• To continue treatment until disease progression or unacceptable toxicity.
• Manage toxicities with dose reduction, treatment delay, or discontinuation of Aliqopa. Recommendation of minimum 7 days between any two consecutive infusions (see Table 1).

Table adapted from the FDA Prescribing Information (FDA, 2017).

Adverse grade reaction based on the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v4.03 (FDA, 2017).

The above policy is based on the following references: