Vembrolizumab: A 'first in class' ADC to challenge first-line lymphoma treatment

By Arale

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma subtype, accounting for 30% to 40% of non-Hodgkin lymphoma (NHL)
.

Currently, the R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) is the first-line standard treatment for DLBCL, but ~40% of patients still develop resistance to initial treatment medication, refractory or relapsed

In recent years, antibody-drug conjugates (ADCs) have become a hot topic in the development of new drugs
.

In the field of lymphoma, based on the success of B cell antigens (eg CD20), scientists continue to explore other B cell surface proteins

B cell receptor complex.
Image from: genentech official website

CD79b is part of the B-cell receptor (BCR) and is expressed in more than 90% of B-cell-NHLs
.

After binding to the antibody, CD79b can trigger the internalization of the BCR and the bound antibody, which suggests that the target molecule can be selectively delivered to B cells

Internalization.
Image from: genentech official website

Degradation.
Image from: genentech official website

Polatuzumab vedotin, an anti-CD79b ADC, consists of three components: an anti-CD79b monoclonal antibody, the cytotoxic component monomethyl auristatin (MMAE) (which inhibits mitosis by inhibiting tubulin), and A cleavable linker [1] that binds the two covalently
.

Exploration of post-line therapy for DLBCL[2]

Exploration of post-line therapy for DLBCL[2]

Clinically, about 50% of R/R DLBCL are not suitable for the second-line regimen of intensive salvage therapy and autologous stem cell transplantation (SCT), and the prognosis of these patients is poor
.

Common treatment options include R-GemOx (rituximab + gemcitabine + oxaliplatin), BR (bendamustine + rituximab), etc.

Vembrolizumab's challenge to DLBCL began with GO29365, a randomized phase Ib/II trial of R/R DLBCL ineligible for hematopoietic stem cell transplantation randomized to vembrolizumab +BR group (n=40) and BR group (n=40)
.

The results showed that the complete remission (CR) rates in the veboltuzumab + BR group and BR group were 40% and 18%, respectively
.

Among the patients in the vebotuzumab + BR group who achieved CR or partial response (PR), 64% had a duration of response (DOR) ≥ 6 months, and 48% had a DOR ≥ 1 year; These two metrics are 30% and 20%, respectively

In January 2022, Blood Advances published the OS results of the GO29365 study
.

After the randomization phase, an additional 106 patients received vebotuzumab plus BR as a single-arm expansion cohort

The results showed that the median PFS was 9.
2 months and 3.
7 months (HR=0.
39), and the median OS was 12.
4 months and 4.
7 months (HR=0.
42), respectively, in the Viboltuzumab + BR group and the BR group.
)
.

In the expansion cohort, the independent review committee (IRC)-assessed ORR was 41.

OS of vebotuzumab + BR group and BR group.

Exploration of first-line treatment of DLBCL  [3]

Exploration of first-line treatment of DLBCL  [3]

The R-CHOP regimen has been in the first-line treatment status for more than 20 years.
Scientists continue to try and explore, hoping to further improve the efficacy
.

However, whether intensive therapy, consolidation therapy, optimization of anti-CD20 monoclonal antibody, or combination of new targeted therapy drugs (ibrutinib, bortezomib, lenalidomide), etc.

Vembrolizumab is also naturally advancing into first-line therapy
.
At the 2021 American Society of Hematology (ASH) annual meeting, vebotuzumab combined with R-CHP (rituximab, cyclophosphamide, doxorubicin, prednisone) versus R-CHOP (rituximab) The phase III POLARIX study of monoclonal antibody, cyclophosphamide, doxorubicin, vincristine, prednisone) in the first-line treatment of DLBCL has released detailed data and published it simultaneously in the New England Journal of Medicine
.

The POLARIX study is a global, multicenter, randomized, double-blind, placebo-controlled Phase III clinical study that enrolled patients with previously untreated DLBCL and randomized 1:1 to vebotuzumab combined with R-CHP group or R-CHOP group
.
The primary endpoint was investigator-assessed PFS, and secondary endpoints included OS and safety
.

A total of 879 patients were included in the study, including 160 Asian patients, and the median follow-up time was 28.
2 months
.
The results showed that compared with the R-CHOP group (70.
2%), the 2-year PFS rate of the vebotuzumab plus R-CHP group was significantly improved (76.
7%), and the risk of disease progression or death was reduced by 27% (HR=0.
73).
, P=0.
02) (below)
.

In terms of secondary endpoints, the 2-year event-free survival (EFS) rate was significantly improved in the vebotuzumab plus R-CHP group compared with the R-CHOP group (75.
6% vs 69.
4%, HR=0.
75, P=0.
02 ), but the 2-year OS rate (88.
7% vs 88.
6%, HR=0.
94, P=0.
75) was not significantly different (bottom panel)
.

Regarding the lack of statistical differences in OS, the investigators analyzed in the Discussion section
.
The EFS of vebotuzumab combined with R-CHP group was significantly higher than that of R-CHOP group, but there was no significant difference in CR rate between groups
.
The median follow-up time of the study was 28.
2 months, which was not long enough to observe the effect of PFS on OS
.
In addition, the emergence of new and effective treatments for R/R DLBCL in recent years may also be a factor in the lack of significant difference in OS between the two groups
.

DLBCL is characterized by a risk of early recurrence followed by a distinct plateau in the survival curve, suggesting a high probability of cure, and late recurrence is uncommon
.
Based on data from previous studies, durable remission is at least 2 years
.
Data from the POLARIX study have not been able to demonstrate that the response associated with vebotuzumab plus R-CHP treatment is durable and will require longer follow-up to determine
.

Furthermore, although this trial was not designed to compare PFS across subgroups, the observed heterogeneity between subgroups needs to be further assessed in future trials
.
Subgroup analysis showed that in patients with age >60 years, International Prognostic Index (IPI) 3-5 points, and activated B-cell subtype (ABC) subtype, the combination of vebotuzumab and R-CHP group showed a PFS benefit However, there was no significant difference in PFS between the two groups in patients ≤60 years of age, with lower IPI scores, bulky disease, and germinal center B-cell-like (GCB) subtypes
.

Summarize

Summarize

Also a Genentech product, can Vibotuzumab continue the glory of its "predecessor" rituximab? It does not seem easy to shake the first-line status of R-CHOP
.
DLBCL is known to be highly heterogeneous
.
Existing studies suggest that, based on gene expression profiles (GFP) and with reference to cell-of-origin (COO) typing, there is no genetic information on driver genes involved in tumor pathogenesis, based on novel genotypes (eg: four Type, seven type) treatment is the research direction
.
In addition, CAR-T therapy, anti-CD20/CD3 double antibody, anti-CD19 monoclonal antibody, etc.
have also shown good efficacy in newly treated DLBCL in clinical trials.
Further improvement of the first-line regimen can be expected in the future
.

references

1.
Drugs.
2019; 79(13): 1467-1475.

2.
Blood Adv.
2022; 6(2): 533-543.

3.
N Engl J Med.
2022; 386(4): 351-363.