Lymphoma interview with Professor Ma Jun: Attacking the spear of "lymphatic", protecting the shield of "inertia", PI3K inhibitors bring clinical benefits to patients with indolent lymphoma

Indolent lymphoma is a group of non-Hodgkin lymphomas (NHL) that progress relatively slowly and include follicular lymphoma (FL), chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), marginal area lymphoma (MZL), etc.

In recent decades, with the breakthrough of basic research and the development of a variety of drugs, the treatment of indolent lymphoma has undergone tremendous changes, please briefly introduce the treatment changes of indolent lymphoma, and what are the unmet treatment needs of indolent lymphoma patients?

In 1997, the marketing of the anti-CD20 monoclonal antibody rituximab changed the chemotherapy-based treatment mode described above, and rituximab combined with chemotherapy significantly improved the remission rate of patients compared with conventional ^{chemotherapy1}

In addition to the continuous emergence of various types of new drugs, new therapies are also booming, CAR-T, CAR-NK cell therapy can accurately target tumor cells, in the clinical treatment of advanced B cell lymphoma shows good efficacy

Although indolent lymphoma progresses slowly, it is still incurable, and most patients face relapse refractory, histological transformation, and rapid disease progression such as POD24, and such patients often have a poor prognosis and limited

With the emergence of new drugs, the survival status of inert lymphoma patients has improved, but there are still some patients, especially POD24 patients, who are still facing the dilemma of relapse and refractory treatment, and the prognosis is poor, please combine your clinical experience to talk about the current progress of new drugs for relapsed refractory (R/R) indolent lymphoma?

Since the emergence of the concept of tumor-targeted therapy, small molecule targeted drugs have been a hot spot

At present, the new generation of PI3Kδ inhibitor HMPL-689 as a promising drug in the field of lymphoma, a number of related research is actively carried out, can you briefly introduce the efficacy and safety
of PI3K inhibitors in patients with indolent lymphoma.

PI3K is involved in the regulation of multiple signaling pathways and plays a role
in cell proliferation, growth, survival, and metabolism.

In B cells, PI3Kδ plays an important role in BCR signaling and B cell activation, therefore, PI3Kδ inhibitors have shown good antitumor activity in patients with relapse refractory and even early indolent lymphoma, bringing new hope
to indolent lymphoma patients in China.

HMPL-689 (Andilise) as an oral type highly selective PI3Kδ inhibitor, the preliminary results of the phase I study in the treatment of R/R lymphoma patients in China have also been officially announced at the 2021 ESMO Annual Meeting, and this multicenter, open-label clinical study of 90 patients showed that efficacy can be assessed in 76 patients, median follow-up time is 5.
6 months, the total patient response rate (ORR) is 53.
9%, the CR rate is 11.
8%, and the clinical benefit rate (CBR) is 76.
3%.
The median duration of response (DoR) was not reached, the 6-month DoR rate was 84.
5%, and the median response time (TTR) was 1.
9 months
.

For each subgroup: FL patients had an ORR of up to 81.
8% and a CR rate of 36.
4%; MZL patients have an ORR of 50%; 100% ORR for patients with CLL/SLL The ORR for patients with MCL is 75%.


In terms of safety, common non-hematologic ≥ grade 3 TEAE are pneumonia (13.
3%) and rash (5.
6%), and the rate of treatment discontinuation due to AE is only 5.
6%⁴
.

In summary, in this phase I clinical study, HMPL-689 in the treatment of indolent lymphoma patients has a rapid onset, significant efficacy, good tolerability, and controllable safety
.

It is expected that more research results will be published in the future and bring sustainable benefits
to more patients.

Figure.
Waterfall of benefits in patients with different lymphoma subtypes

Medical Pulse Pass: "no chemotherapy" program is a hot topic in recent years of inert lymphoma research, small molecule targeted drugs based on chemotherapy-free regimen has shown good efficacy and safety in some indolent lymphoma subtypes, what do you think is the application prospect of "no chemotherapy" in indolent lymphoma? What are your prospects for the future treatment of indolent lymphoma in China?

Patients with indolent lymphoma have a higher five-year survival rate, slow disease progression, but a higher recurrence rate, and most patients will eventually develop relapse refractory, POD24, or conversion to DLBCL, resulting in escalation
of subsequent treatment.

In order to make indolent lymphoma patients get better whole-process management, treatment strategies such as Chemo-free and immunochemotherapy are currently used, which is also the direction
of future development of indolent lymphoma treatment.

With the development of basic research and the clinical application of many new drugs, the monotherapy of EZH2 inhibitors, BTK inhibitors, PI3K inhibitors, PD-1 inhibitors, PD-L1 inhibitors and other targeted drugs and the application of combination programs have shown good clinical advantages in B-cell lymphoma, and we hope to continue to explore
in the future.

The development of PI3K inhibitors has moved forward in the direction of high efficiency and low toxicity, HMPL-689 as a highly selective PI3Kδ inhibitor in the Ib phase clinical research shows good efficacy and safety, bringing hope to patients with indolent lymphoma, looking forward to the publication of follow-up phase II clinical research results, bringing clinical benefits to more inert lymphoma patients, and contributing to the clinical cure of inert lymphoma in the future
.

At present, the "Multicenter, one-arm, open phase II clinical study evaluating the efficacy and safety of HMPL-689 in the treatment of relapsed/refractory marginal lymphoma and follicular lymphoma" is underway at a number of research centers in China (registration number: CTR20210264).