Interview with Professor Zhou Shiyong for Lymphoma: Breaking the Dilemma of Relapse and Refractory Treatment

INTRODUCTION Follicular lymphoma (FL) is an indolent lymphoma that originates from follicular center B cells
.

In recent years, immunochemotherapy regimens such as anti-CD20 monoclonal antibody combined with conventional chemotherapy have become the standard first-line treatment for FL with indications or high tumor burden, but this treatment strategy is not effective in second-line and above treatments
.

Due to the incurable nature of FL, most patients face the difficulty of disease recurrence or refractory disease.
The optimization of the back-line treatment plan for such patients has become one of the current research hotspots in the treatment of FL
.

After gaining an in-depth understanding of the molecular mechanisms of lymphoma disease development, researchers have begun to develop specific drugs that act on key tumor signaling pathways
.

The phosphatidylinositol 3-kinase (PI3K) pathway is an important signaling pathway in B-cell lymphoma and plays an important role in cell proliferation and survival
.

What is the current progress of PI3K inhibitors in the field of FL? Yimaitong hereby invites Professor Zhou Shiyong from Tianjin Medical University Cancer Hospital to show us the progress in the application of PI3K inhibitors in the treatment of FL for our readers
.

PI3K inhibitors have promising applications in hematological tumors.
Alterations in the PI3K-AKT-mTOR pathway and the inhibitory phosphatase and tensin homolog (PTEN) pathway are common in B-cell lymphomas, and PI3K inhibitors may help for the elimination of antigen-independent B cell receptor signaling
.

Furthermore, preclinical models have shown that inactivation of the PI3Kδ gene results in the inactivation of regulatory T cells, thereby inhibiting tumor cell proliferation
.

Based on the theoretical basis provided by a number of preclinical studies, many clinical trials of PI3K inhibitors in hematological malignancies (including FL) have been carried out in order to further explore the antitumor activity of the drugs (see Table 1 below)
.

 At present, the U.
S.
Food and Drug Administration (FDA) has successively approved 4 PI3K inhibitors for the treatment of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), FL and marginal zone lymphoma (MZL).
They are Idelalisib, Copanlisib, Duvelise and Umbralisib
.

Idelalisib, an oral PI3Kδ inhibitor with selective inhibition of the δ isoform, demonstrated an overall response rate (ORR) of 56 in 72 patients with FL refractory to rituximab and alkylating agents.
%, the complete response (CR) rate was 14%, and the median duration of response (DOR) was 10.
8 months1
.

Duvelise is also an oral PI3K inhibitor with inhibitory activity against both delta and gamma isoforms
.

Results of a phase II clinical trial involving 83 patients with relapsed and refractory (R/R) FL showed an ORR of 42%2
.

Unlike idelalisib and durvalise, copanlisib is a pan-PI3K inhibitor that inhibits mainly the alpha and delta subtypes, with a similar response rate to idelalisib
.

Innovative PI3K inhibitors boost the efficacy of FL.
Currently approved drugs can effectively treat R/R FL patients, but there are short-term and long-term adverse events (AEs).
Common AEs include hematological AEs (such as neutropenia).
, thrombocytopenia, etc.
) and inflammation (such as pulmonary inflammation, colitis, etc.
); and the duration of remission obtained by monotherapy is short, so further clinical research is needed to improve the efficacy and safety of such drugs.
A variety of drugs targeting the PI3K pathway are in various stages of development
.

Can the upgrade of the mechanism of action improve the efficacy and safety of PI3K inhibitors? Umbralisib is an oral selective inhibitor of PI3Kδ.
It is worth noting that Umbralisib also inhibits casein kinase 1ε (CK1ε), and the signal transduction of CK1ε may mediate and enhance the common autoimmunity of this class of drugs.
Toxicity
.

A Phase I study in subjects with R/R lymphoma initially explored the broad activity of umbralisib
.

Based on data from 17 efficacy-evaluable patients, the ORR was 53% and the CR rate was 12%
.

In the FL subgroup, the median DOR for FL patients was 9.
3 months
.

In 90 safety-evaluable patients, gastrointestinal AEs of all grades were common, but grade ≥3 gastrointestinal and autoimmune AEs were less common 3
.

 HMPL-689 is a highly selective PI3Kδ inhibitor, highly targeting PI3Kδ, the inhibitory activity of PI3Kδ is more than 100 times stronger than other kinases of the same family, avoiding adverse reactions caused by inhibiting other isoforms; after structure optimization, After oral administration, the drug concentration in liver and gastrointestinal tract tissue of patients is relatively low, which is beneficial to reduce liver and digestive tract toxicity
.

HMPL-689 demonstrated good efficacy and safety in a Phase Ib clinical study of Chinese R/R lymphoma patients, including 90 R/R lymphoma patients (FL, MZL, CLL/SLL, mantle cell lymphoma, and diffuse large B-cell lymphoma) patients received HMPL-689 30 mg daily
.

Based on 76 efficacy-evaluable patients (including 22 FL patients) with a median follow-up of 5.
6 months, the results showed that HMPL-689 had a rapid onset of action, with a median time to response (TTR) of 1.
9 months (95% CI, 1.
84 -1.
91), ORR was 53.
9%, and the median DOR was not reached; encouraging efficacy was observed in the FL subgroup, with an ORR rate of 81.
8%, a CR rate of 36.
4%, and a 1-year DOR rate of 59.
7% (95%).
%CI, 15.
8-86.
6), and the 1-year PFS rate was 75.
8% (95%CI, 44.
8-90.
8)
.

The safety profile was manageable, and the most common grade ≥3 treatment-emergent adverse events (TEAEs) in all patients in the study were pneumonia (13.
3%), neutropenia (11.
1%), and rash (5.
6%); liver and digestive AEs were mild, liver enzymes (AST/ALT) were mildly to moderately (grade 1-2) elevated, and the incidence of diarrhea was low (2.
2% for ≥ grade 3 diarrhea) 4
.

Figure 1 Can the combination of DOR and PFSPI3K inhibitors and immunochemotherapy in FL patients break the dilemma of relapse and refractory? Multiple ongoing studies evaluating the efficacy of PI3K inhibitors in combination with targeted agents in R/R FL, including one exploring Umbralisib monotherapy and Umbralisib in combination with the novel anti-CD20 monoclonal antibody Ublituximab Phase I/Ib Promising data from the study showed an ORR of 44%, a CR rate of 22%, and a median DOR of 20.
3 months among 18 patients with R/R FL.
In clinical studies of other subtypes of non-Hodgkin lymphoma, whether PI3K inhibitor combination therapy can break the dilemma still needs more data to support
.

Experts comment FL is one of the common subtypes of indolent non-Hodgkin lymphoma, accounting for about 70% of indolent lymphomas
.

With the deepening of the research on the pathogenesis of lymphoma, the continuous emergence of new drugs and the continuous exploration of combined treatment options, the survival of FL patients has been prolonged, and the overall survival of patients has reached 15-18 years, but there are still some patients, especially first-line patients.
Patients with progressive disease within 2 years (POD24) after immunochemotherapy have a poor prognosis 6
.

Since FL progresses slowly and is difficult to cure in the advanced stage, it is very important to optimize the selection of a high-efficiency and low-toxicity treatment regimen for this type of R/R FL
.

 In recent years, with the emergence of various new targeted drugs such as PI3K inhibitors, BTK inhibitors and BCL-2 inhibitors, more treatment options have been brought to R/R FL patients
.

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
.

As a highly selective PI3Kδ inhibitor, HMPL-689 may become an effective treatment for R/R lymphoma, and it has shown considerable efficacy and potential in a multicenter, open-label phase Ib clinical study.
control security
.

With a median follow-up of 5.
6 months, among the 76 patients with evaluable efficacy, the ORR was 53.
9%, the clinical benefit rate (CBR) was 76.
3%, and the median DOR was not reached
.

HMPL-689 showed good antitumor activity in patients with different lymphoma subtypes.
Among them, in the FL subgroup (22 patients), the median follow-up was 8.
3 months, the ORR was 81.
8%, and the CR rate was 36.
4% , CBR was as high as 90.
9%, and for FL patients who achieved CR, the 1-year DOR rate was 75% (95%CI 12.
8-96.
1); and HMPL-689 was well tolerated and had a controllable safety.
The treatment discontinuation rate was 5.
6%4
.

Based on its good clinical trial data, HMPL-689 was included in China's breakthrough therapy drug category in September last year, and the proposed indication is monotherapy who has received at least 2 lines of systemic therapy in the past, and at least 1 line of therapy contains CD20 R/R FL of monoclonal antibody (pathological grade 1-3a)
.

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)
.