Lymphoma Interview with Prof. Junning Cao: In the Era of New Drugs, Innovative PI3K Inhibitors Bring Survival Benefits to MZL Patients

Marginal zone lymphoma (MZL) is an indolent B-cell lymphoma that accounts for approximately 10% of non-Hodgkin lymphomas
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MZL originates from the marginal zone of lymphoid follicles, and its subtypes include mucosa-associated lymphoid tissue (MALT) lymphoma, intranodal MZL, and splenic MZL
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MZL exhibits high heterogeneity in tumor biology, clinical manifestations, and treatment, and patients with different subtypes should adopt different treatment strategies
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Most MZL patients have good response to first-line treatment and have a longer survival period; however, patients with indolent lymphoma are prone to relapse.
For relapsed and refractory (R/R) MZL patients, there is still a lack of optimal treatment options.
High-efficiency, low-toxicity drugs that improve patient outcomes
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In recent years, the emergence of new targeted drugs such as Bruton's tyrosine kinase (BTK) inhibitors and phosphatidylinositol 3-kinase (PI3K) inhibitors has shown encouraging clinical efficacy and is expected to further improve R /R MZL patients survive and improve their quality of life
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On this occasion, Yimaitong sincerely invites Professor Cao Junning from Fudan University Affiliated Cancer Hospital to be interviewed and share the current status of MZL treatment and the progress of new drugs based on clinical experience
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Yimaitong: Hello Professor Cao, as a clinical expert in the field of lymphoma for many years, you have published a number of B-cell lymphoma related papers in several core journals.
Could you please combine the diagnosis and treatment experience of your center? Briefly introduce the current status of the treatment of marginal zone lymphoma.
What unmet treatment needs still exist for patients with marginal zone lymphoma? Prof.
Junning Cao MZL is a group of B-cell lymphomas originating from the marginal zone of lymphoid follicles, which can occur in the spleen, lymph nodes and mucosa-associated lymphoid tissues, and is a heterogeneous and indolent malignant disease1
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Most MZL patients have slow disease progression and longer survival
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For limited-stage MZL, local therapy is recommended, for example, anti-Helicobacter pylori triple regimen for extranodal MZL and splenectomy for splenic MZL; For external MZL, radiotherapy is still the commonly used treatment method; for some patients who are not suitable for radiotherapy, rituximab monotherapy can be considered; for MZL stage III/IV or failed local radiotherapy, those who meet the indications for systemic therapy For example, in the presence of B symptoms, decreased blood cells, large masses or rapid tumor progression, the commonly used treatment plan is rituximab combined with chemotherapy, but there is still no optimal treatment plan
.

In the absence of the above conditions, the treatment principle of indolent lymphoma can be referred to, and waiting and observation can be given 1
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For R/R MZL patients, there is currently a lack of standard treatment regimens2.
If the previous treatment is effective and the remission period exceeds 2 years, the original regimen treatment (except anthracyclines) can be considered
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However, for patients with progressive disease (POD24) within 2 years after treatment, the overall prognosis is poor, and there is a certain gap compared with non-POD24 patients.
The current clinical diagnosis and treatment urgently needs to improve the clinical prognosis of such patients
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In recent years, with the emergence of new drugs such as BTK inhibitors, PI3K inhibitors and BCL2 inhibitors, they have shown surprising clinical efficacy, which will help to further improve the prognosis of R/R MZL patients
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Yimaitong: BTK inhibitors have shown high anti-tumor activity in clinical studies of MZL.
In the 2021 edition of the CSCO Lymphoma Diagnosis and Treatment Guidelines, it is pointed out that "for MZL patients who fail the second-line regimen or who have a short remission period in the first-line regimen, BTK Inhibitors are reasonable choices", please talk about the progress of BTK inhibitors in the treatment of MZL based on your clinical experience
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Prof.
Junning Cao BTK is a key kinase in the BCR (B cell surface antigen receptor) signaling pathway and plays an important role in the activation, proliferation and differentiation of B cells
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BTK inhibitors inhibit B cell receptor signaling by blocking the BTK signaling pathway, which can impede the migration, proliferation and survival of B cell malignancies 3
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The first BTK inhibitor, ibrutinib, showed promising efficacy in R/R MZL
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A phase II study included 63 patients with R/R MZL who received ibrutinib 560 mg daily.
Long-term follow-up data showed that the overall response rate (ORR) of ibrutinib in the treatment of R/R MZL was 58%, complete The response (CR) rate was 10%
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At a median follow-up of 33 months, the median duration of response (DOR) was 27.
6 months, the median progression-free survival (PFS) was 15.
7 months, the median overall survival (OS) was not reached, and all subtypes The response to MZL was consistent 3
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The next-generation BTK inhibitor, zanubrutinib, also showed good efficacy in R/R MZL
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Current BTK inhibitors, due to their irreversible inhibition of BTK, have limited long-term efficacy in patients by acquired resistance, most commonly through the BTK C481 mutation
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Novel BTK inhibitors are expected to break this dilemma
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The third-generation BTK inhibitor, LOXO-305, is a highly selective, non-covalently bound BTK inhibitor
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The latest data from the global Phase I/II BRUIN clinical trial of LOXO-305 in patients with previously treated malignant B-cell tumors were presented at the 62nd American Society of Hematology (ASH) Annual Meeting
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The data showed an ORR of 62% in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) previously treated with a BTK inhibitor, regardless of the reason for previous BTK inhibitor discontinuation or BTK mutation status, ORR is consistent, and no MZL subgroup data have been published 4
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In addition, HMPL-760, independently developed by Chi-Med, is also a reversible, non-covalent BTK inhibitor with higher activity against wild-type and C481S mutant kinases, which is expected to solve the resistance of first-generation BTK inhibitors problem
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A Phase I trial of HMPL-760 is underway
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Yimaitong: PI3K inhibitors have attracted much attention as one of the important hot targets for drug development in recent years, and they also have therapeutic prospects in R/R MZL
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At this year's ESMO annual meeting, the phase Ib study led by you revealed the good safety and clinical activity of the PI3Kδ inhibitor HMPL-689 in Chinese R/R lymphoma patients
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Could you please talk about the efficacy and safety of PI3K inhibitors in R/R MZL patients based on the research results
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Professor Cao Junning PI3K/Akt/mTOR signaling pathway is a classic tumor signaling pathway, which is involved in regulating the proliferation, survival, transcription, translation and metabolism of malignant tumor cells
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PI3Kδ inhibitors can act on lymphoma cells to inhibit the expression of PI3Kδ and reduce the phosphorylation level of AKT protein, thereby inducing the apoptosis of malignant B lymphocytes and inhibiting the proliferation of malignant B lymphocytes
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At present, the FDA has successively approved 4 PI3K inhibitors for the treatment of CLL/SLL, follicular lymphoma and marginal zone lymphoma, namely Idelalisib, Copanlisib, Duvelisib and Umbralisib
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The first-generation PI3Kδ inhibitor Idelalisib is poorly tolerated, with side effects involving the liver, digestive tract, immune system, and blood, especially fatal and severe liver toxicity, diarrhea, colitis, and intestinal perforation.
50% treatment discontinuation rate; Duvelisib and Idelalisib have a similar adverse reaction profile with 4 Boxed Warnings 5
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Copanlisib, is a pan-PI3K inhibitor (pan-PI3K) with primary activity against PI3Kα and PI3Kδ isoforms
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The 2-year follow-up results of the CHRONOS-1 study showed that copanlisib had favorable antitumor activity in 23 patients with R/R MZL
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ORR was 78.
3%
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The remission was durable, and the median DOR was 17.
4 months with a 2-year follow-up
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In terms of safety, grade 3/4 treatment-emergent adverse events (TEAEs) occurred in 19 patients (82.
6%), resulting in dose reductions in 9 patients (39.
1%) and treatment interruption/delay in 18 patients (78.
3%), respectively 6
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Umbralisib, a dual inhibitor of PI3Kδ and casein kinase-1ε (CK1-ε)
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In a multi-cohort phase IIb clinical study involving 208 patients with R/R indolent non-Hodgkin lymphoma (including 69 patients with MZL), with a median follow-up of 27.
7 months, the ORR of the patients in the MZL subgroup was 49.
3 % (95% CI, 37.
0-61.
6), the median time to response (TTR) was 2.
8 months, and the median DOR and PFS did not reach 7
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Early research and development of PI3K targeted drugs, with pan-PI3K inhibitors as the main direction
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But pan-PI3K often causes more serious adverse reactions
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At present, the research and development direction of PI3K inhibitors has shifted to subtype specificity to avoid adverse reactions caused by pan-subtype inhibition
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HMPL-689 is a highly selective PI3Kδ inhibitor independently developed by Chi-Med.
Its inhibitory activity on PI3Kδ is more than 100 times stronger than that of other kinases of the same family.
Adverse reactions due to inhibition of other subtypes
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HMPL-689 has shown favorable safety and efficacy in R/R lymphoma patients in its clinical trials
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In the dose-expansion phase of the Phase I study in China, 90 patients received HMPL-689 30 mg daily with a median follow-up of 5.
5 months (95% CI, 3.
68-8.
21); based on 76 evaluable patients (14 of them were MZL patients), the results showed that the ORR of the patients was 53.
9% (the ORR of the MZL subgroup was 50%, see the figure below), and the median onset time was 1.
9 months (95%CI, 1.
84- 1.
91); the median DOR was not reached, and the 6-month DOR rate was 84.
5% (95% CI, 62.
9–94.
1)
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In terms of safety, the most common grade 3+ TEAEs in all patients were pneumonia (13.
3%), neutropenia (11.
1%), and rash (5.
6%), with discontinuation due to AEs in 5.
6%8
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Yimaitong: MZL is a heterogeneous group of B-cell lymphomas.
The emergence of new targeted drugs has brought new hope to MZL patients who have received multi-line therapy in the past.
What are your expectations for the treatment prospects of MZL patients in my country? or Outlook? Professor Cao Junning pointed out that POD24 indicates poor prognosis in MZL patients after treatment.
It is very important to screen high-risk patients with POD24 and further improve the treatment effect and prognosis of POD24 patients
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MZL shows high heterogeneity in tumor biology, clinical manifestations, and treatment.
It is urgent to explore relatively efficient and low-toxic drugs, so that patients can obtain sustained remission and improve the poor prognosis of patients
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With the approval of various drugs that act on cell signaling pathways and modulate the tumor microenvironment, the treatment of MZL has gradually shifted from cytotoxic drugs to targeted therapy
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Precision treatment of diseases requires the integration of different clinical and pathological features, molecular markers, immune microenvironment, and other characteristics in order to provide accurate prognostic prediction and individualized treatment strategies for each patient
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For this rare tumor subtype, multi-center cooperation is required to carry out prospective clinical studies for MZL patients in order to achieve its precise treatment
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At present, Chi-Med has conducted a multi-center, single-arm, open-label phase II clinical trial of "Evaluating the efficacy and safety of HMPL-689 in the treatment of patients with relapsed/refractory marginal zone lymphoma and follicular lymphoma" in several research centers in China.
Study" is in progress (Accession number: CTR20210264)
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