Limin Zou ,Yueli Qi ,Ling Tang ,Yu Du ,Meiyi Xiang ,Xiaoming Chen ,Jun Ma,Zhimin Yang

1Office of Clinical Evaluation 1,Center for Drug Evaluation,National Medical Products Administration,Beijing 100022,China;2 Office of Management and Communication,Center for Drug Evaluation,National Medical Products Administration,Beijing 100022,China;3Harbin Institute of Hematology and Oncology,Harbin 150010,China

Abstract Several phosphoinositide 3-kinase (PI3K) inhibitors are currently approved to treat hematolymphatic malignant diseases worldwide,and many drugs that have the same target are in the clinical research stage.In March 2022,duvelisib became the first PI3K inhibitor approved in China indicated for the treatment of hematolymphatic malignant diseases.Meanwhile,linperlisib and copanlisib have almost completed the technical review of the clinical specialty.The Center for Drug Evaluation (CDE) of the China National Medical Products Administration(NMPA) found that class I PI3K inhibitors can cause various degrees of immune-related adverse events,which are associated with action mechanisms,affecting the benefit-risk assessment of the drugs.On April 21,2021,the United States Food and Drug Administration (FDA) convened the Oncologic Drugs Advisory Committee (ODAC)meeting to discuss the safety of PI3K inhibitors indicated for hematolymphatic malignancies and their related risk of death.The hematological tumor group of CDE of the China NMPA summarized and combined the data on PI3K inhibitors listed or under technical review for marketing authorization applications and found that such products may have unique efficacy and safety characteristics in Chinese patients with malignant lymphoma.

Keywords: Class I PI3K inhibitors;efficacy;hematolymphatic malignancies;safety

Introduction

Phosphoinositide 3-kinase (PI3K) is a kind of lipid kinase that plays crucial roles in cell signal transduction by phosphorylating intracellular inositol lipids. It is an important member of the PI3K/Akt/mTOR signalling pathway and is closely implicated in many biological processes,such as cell survival,growth,RNA transcription and protein translation. Abnormal activation of the PI3K/Akt/mTOR pathway is associated with a variety of hematolymphatic malignancies and solid tumors.The amplification of thePIK3CAgene,which encodes the catalytic subunit P110α of PI3Kiα,is the most common mechanism for the activation of the PI3K/Akt/mTOR pathway,with other mechanisms includingPIK3CAgene mutation,phosphatase and tensin homologue (PTEN)downregulation,and the mutations and/or amplifications of genes encoding tyrosine receptor kinases (1).

PI3K is divided into three classes based on structure and function,and the role of class I PI3K in the development,differentiation and activation of B cells and T cells has been widely studied (2,3).Class I PI3K can be further divided into the class IA subgroup,which includes PI3Kα,PI3Kβ and PI3Kδ,and the class IB subgroup,which includes PI3Kγ,according to differences in action pathways and catalytic subunits (1).Specifically,although PI3Kα and PI3Kβ are widely expressed in tissues,PI3Kα is expressed at low levels in B cells.PI3Kγ is expressed in T lymphocytes but hardly exists in B cells,and the inhibition of PI3Kγ can damage the functions of T lymphocytes,neutrophils and macrophages but has no effect on B lymphocytes;in addition,PI3Kδ is mainly expressed in B lymphocytes and their precursor cells (4).At present,PI3K inhibitors that have been approved for the treatment of lymphatic malignancies or that are undergoing clinical research are all class I PI3K inhibitors.

Although scientists have long known the potential value of class I PI3K inhibitors for the research and development of cancer drugs,there are challenges related to their therapeutic toxicities and their effects on regulating the growth and apoptosis of normal cells.Drug selectivity may have a significant impact on safety owing to the different distributions and functions of the four subtypes of class I PI3K inhibitors.The mechanisms of action of the four class I PI3K subtypes are not yet fully understood,but we can predict their adverse reactions based on the current knowledge of each subtype (4).PI3Kα is involved in the insulin signalling pathway and in angiogenesis,and accounts for specific adverse reactions such as hyperglycaemia,rashes and hypertension.PI3Kβ plays a role in the process of platelet formation and in inflammatory responses,but their specific adverse reactions have yet to be clarified.PI3Kγ and PI3Kδ are closely implicated in regulating the immune process,especially PI3Kδ,which plays a role in maintaining the function of B cells and is always in a hyperactivated state in malignant B cells.PI3Kδ,as the most frequently employed therapeutic target of PI3K inhibitors currently on the market or under development for hematologic malignant diseases,always results in typical immune-related therapeutic toxicity,such as enteritis/colitis,interstitial pneumonia,skin reaction,and immunosuppression-related infections (including Pneumocystis carinii pneumonia).

Effectiveness and safety of class I PI3K inhibitors that have current applications for marketing authorization

Effectiveness

Currently,the single-arm trials or overseas bridging trials of three PI3K inhibitors,duvelisib (5),copanlisib (6) and linperlisib,that are indicated for the treatment of follicular lymphoma (FL) patients who received at least 2 previous lines of systemic therapies have been completed,and the effectiveness data are summarized inTable 1.Although parsaclicib tablets have completed registration studies for FL indications,no application for marketing authorization has been submitted.Duvelisib,copanlisib and parsaclicib also provided domestic and foreign research data as the basis for review.In addition to the data provided inTable 1,results from the CHRONOS-3 study (7),which compared the effectiveness of copanlisib plus rituximabvs.rituximab monotherapy in patients with relapsed/refractory (R/R)non-Hodgkin’s lymphoma following first-line therapy,were provided,and 81 of the 275 patients were from mainland China.

Table 1 Three PI3K inhibitors that have submitted applications for marketing authorization

Objective response rates (ORRs) of duvelisib and linperlisib in the Chinese study were higher than those of the global study,and the remission duration was long lasting with clinical value.The efficacy and safety of parsaclisib in Chinese patients were assessed 6 months after the last subject was enrolled.The results showed that the ORR of 61 Chinese subjects was over 85%,with a complete response rate (CRR) of 30%,which was better than the global registry for parsaclisib (n=126) and similar to the Chinese data for duvelisib and linperlisib.In the CHRONOS-3 trial of copanlisib (7),copanlisib combined with rituximab reduced the risk of disease progression or death by 45% compared with rituximab monotherapy in patients with R/R FL who received first-line therapy,but the overall survival time was not improved.Data from the Chinese subgroup of FL were similar to the overall data,but the median progression-free survival (PFS) for 18 patients treated with rituximab in the Chinese subgroup was only 9.0 months,which was obviously shorter than the 18.7 months for 91 FL subjects in the global study.

The response rate of PI3K inhibitors in Chinese patients with FL seems to be superior to that of the global study,which was observed in a number of clinical trials.However,it cannot be concluded that Chinese FL patients have a better treatment response to PI3K inhibitors based on the existing data,and no persuasive reason can be provided.Reviewers found that the median age of FL patients in a Chinese study was significantly lower than that in the global study.Specifically,the median age of FL patients ranged from 40 to 55 years in the Chinese study,and from 63 to 67 years in the global study.The incidence of FL in Chinese patients appears to be lower than that in Western populations;thus,it cannot be ruled out that Chinese FL patients may differ in pathophysiology from Western FL patients,which may be another factor affecting the treatment response to PI3K inhibitors.Additionally,the response rate to duvelisib was lower in patients who previously received bendamustine,and of these patients,Chinese cohorts had lower response rates than global cohorts.Moreover,the approval of the drug for FL treatment in China lagged behind that in Europe,America,Japan and other countries or regions for a long time,and the differences in clinical practice may also affect the treatment response of patients.

In addition,we compared the efficacy of copanlisib in Asian and non-Asian patients from three clinical trials:CHRONOS-1 (Part B) (6),the Japanese trial and the Chinese trial.The CHRONOS-1 trial included 14 Asian patients,none of which were Chinese,with indolent lymphoma in the efficacy analysis set.The efficacy of the three clinical trials is summarized inTable 2.The ORR and disease-control rate (DCR) of the Asian patients from the three trials were similar to those of non-Asian patients of the CHRONOS-1 trial.However,the median duration of remission (DOR) for Asians in the CHRONOS-1 trial was longer than that of non-Asians in the CHRONOS-1,Japanese and Chinese trials.

Safety

Duvelisib selectively inhibits PI3Kγ and PI3Kδ,and leads to typical target-related toxicities,including skin reactions,enterocolitis/colitis,interstitial lung disease,hepatotoxicity,and immunosuppressive infections,in global studies.No enterocolitis was observed in the Chinese clinical trial of duvelisib,which included 23 subjects,but the incidence of≥ grade 3 liver enzyme elevation and skin reaction was higher with the medication.One case of hepatitis B virus reactivation and one case of Stevens-Johnson syndrome were reported.It is speculated that the higher incidences of liver enzyme elevation events may be caused by two reasons: 1) the exposure of Asian subjects to duvelisib is higher than that of non-Asian subjects at a dosage of 25 mg;and 2) the hepatitis B infection rate in the Chinese population is higher than that in other regions of the world. For skin reactions,it is expected that the characteristics of immune-related adverse reactions in the Chinese population receiving PI3K inhibitors may be different from those in Western patients in consideration of the manifestations of events such as diarrhea and enteritis.The applicants failed to find a direct cause from the patient characteristics and the regularity of adverse reactions.Applicants adopt different measures to minimize risk in China.

Copanlisib is a pan-class I PI3K inhibitor that mainly inhibits PI3Kα and PI3Kδ activity.In addition to noninfectious pneumonia,skin reactions and infections caused by immunosuppression,copanlisib treatment also results in specific adverse effects,such as hyperglycaemia (with some subjects reaching grade 4),and type 2 diabetes,as well as alarge proportion of infusion-related hypertension.Only 13 Chinese subjects were treated with copanlisib monotherapy,and the limited data showed similar safety characteristics to that in the global population,except for the higher incidence of ≥grade 3 hyperglycaemia and hypertension.In addition,we compared the safety of copanlisibin in Asian patients and non-Asian patients from the CHRONOS-1 trial (Part B) (6),the Japanese trial and the Chinese trial.As shown inTable 3,the incidence rate and type of treatment-emergent adverse events (TEAEs)following copanlisib treatment in the Asian and non-Asian subgroups were similar.

Table 2 Efficacy of patients from Asian and non-Asian to copanlisib

Parsaclisib is a selective inhibitor of PI3Kδ.Although the application for marketing authorization has not been submitted in China,the registration study of parsaclisib for the treatment of R/R FL after second-line treatment has been completed domestically and overseas.Diarrhea,enteritis,pneumonia and rashes are the main adverse reactions to palsaclisib observed in global monotherapy studies (n=299).The incidence of adverse events,≥3 grade adverse events or severe adverse events was significantly decreased in Chinese studies (n=61),while the incidence of hepatic adverse events was increased in Chinese studies.

The ≥3 grade adverse events of the three PI3K inhibitors which have submitted marketing authorization applications in China are summarized inTable 4.

Table 3 TEAE of class I PI3K inhibitors in Asian and non-Asian patients

Table 4 Summary of ≥3 grade adverse events of PI3K inhibitors that have been applied for marketing authorization in China

Review considerations

Treatment response to PI3K inhibitors differs between domestic and foreign patients

As mentioned above,the ORR and CRR of PI3K inhibitors in Chinese patients with R/R FL are significantly higher than those reported in global studies.Although conclusions cannot be drawn or persuasive reasons cannot be provided,the differences in the treatment responses and population characteristics between Chinese and foreign FL patients cannot be ignored.Center for Drug Evaluation (CDE)encourages applicants to explore whether Chinese patients with hematolymphatic malignancies who receive PI3K inhibitors have advantages over foreign populations in clinical studies,as well as to investigate the underlying mechanisms.

PI3K inhibitor treatment safety is different between domestic and foreign patients

In reviewing clinical studies of PI3K inhibitors worldwide,a certain difference in the safety profile was found between Chinese subjects and foreign populations.For instance,the common adverse reactions caused by duvelisib,such as enteritis/colitis (including fatal events),observed in overseas studies did not occur in the 23 subjects of the Chinese study,but the incidences of ≥3 grade skin reactions and liver enzyme elevation were increased,and hepatitis B virus reactivation events were also observed.The incidence of ≥3 grade hyperglycaemia and hypertension events in Chinese subjects treated with copanlisib (although the sample size was limited) was higher.No enterocolitis was reported in the 61 Chinese subjects who received parsaclisib,while the incidence of severe colitis in foreign subjects was 7.0%.The incidence of severe diarrhea in Chinese subjects was also significantly lower than that in foreign studies,but the incidence of liver adverse events was higher.Thus,the safety obtained from overseas studies may not be representative of the safety characteristics of Chinese subjects.

Immune-related adverse reactions

The differential diagnosis between infectious events and non-infectious inflammatory reactions,such as pulmonary infection and interstitial lung disease,common diarrhea and enterocolitis,hemorrhagic rash or general mucosal ulceration and immune skin/mucosal reactions,should be highly emphasized in the review process according to the mechanisms of PI3K inhibitors.Attention should be given to events that are judged to be infective but not responsive to active anti-infective therapy,to infections that are treated with glucocorticoids during treatment in accordance with the principles of immune-related adverse reactions,and to immune-related factors in the development of adverse events leading to death.Noticeably,the reviewers find that some subjects are still likely to experience treatment-related immune adverse reactions after a period of drug discontinuation.Thus,we propose to appropriately extend the observation period after drug discontinuation,such as collecting the adverse events within 3 months after drug withdrawal.Additionally,the regularity of immune-related adverse reactions should be summarized,including the occurrence time,duration,clinical manifestations and imaging findings before diagnosis,the characteristics of the high-risk population and treatment outcomes; thereafter,reasonable monitoring,diagnosis and treatment suggestions should be provided.

Dosing

Dose rationality should be reassessed in light of whether the basis for determining the recommended dose/dosing regimen in the exploratory phase is adequate and the safety characteristics shown in key registry studies.Further doseoptimization studies should be required after marketing if the assessed benefits outweigh the risks while the dose remains to be optimized.

Safety of drug combination

Anti-CD20 mAb is a standard therapeutic drug for B-cell malignant diseases.Therefore,it is inevitable to assess thesafety and effectiveness of the combination of PI3K inhibitors with CD20 mAbs.As CD20 mAb works by targeting immune cells,a risk of exacerbating immunerelated adverse events was observed in the drug combination,as expected.Dose exploratory studies should be carried out when PI3K inhibitors are in combination

with other agents that affect B-cell and T-cell function,obtaining the recommended dose regimen for the phase III clinical trial based on the safety assessment from ≥20 subjects prior to entering a pivotal registration study.

Clinical risk management plan

To identify risks with potential harm,the necessity of carrying out additional pharmacovigilance activities and/or taking special risk control measures with applicants should be discussed,for example,conducting post-marketing safety studies,providing doctor-patient education materials,providing safety information and risk management training to doctors in the early stage of marketing,and shortening the submission cycle of periodic safety update reports.

Conclusions and future perspectives

Currently,the therapeutic regimen for patients with R/R hematolymphatic malignant diseases in China is limited.Chinese patients with FL (the data for other indications are limited) appear to have a superior response rate to PI3K inhibitors compared with overseas data,and the ORR and CRR are remarkably higher than the historical data.Based on clinical practice in China,PI3K inhibitors can be conditionally approved for the treatment of patients who experience relapse following multiple systemic therapies or who do not respond well to the existing therapies if the PI3K inhibitors meet “available data from drug clinical trials explicitly demonstrate the efficacy of a drug and are reasonably likely to predict its clinical value”,as evaluated by CDE. Considering the safety risks shown in confirmatory trials of PI3K inhibitors and their adverse effect on overall survival,research institutions should carry out exploratory works to provide supporting data for the confirmatory trials as early as possible and determine the trial protocols for confirmatory trials prior to conditional approval.

Acknowledgements

None.

Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.