Pola-R-CHP has better PFS than R-CHOP in newly diagnosed DLBCL

Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma, and anti-CD20 monoclonal antibody is added to the CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen Rituximab significantly improves patient outcomes
.

Although most patients can be cured with rituximab combined with CHOP (R-CHOP), up to 40% of patients will develop primary refractory disease or relapse after initial treatment remission
.

To improve treatment outcomes with R-CHOP, the investigators have conducted a number of randomized trials, including boosting the intensity of immunochemotherapy (by increasing the dose or number of cycles or shortening the interval between cycles), increasing maintenance therapy, or using second-generation anti-CD20 monoclonal antibodies , or the introduction of other new drugs
.

However, none of these clinical trials showed clinically meaningful improvement in outcomes, and R-CHOP remains the standard first-line treatment for DLBCL
.

 CD79b is a subunit of the heterodimeric transmembrane component of the B-cell antigen receptor involved in cell signaling and is widely expressed on the surface of mature B-cell lymphomas, including DLBCL
.

Polatuzumab vedotin (Pola) is an antibody-drug conjugate consisting of an anti-CD79b monoclonal antibody conjugated to monomethyl Auristatin E, a potent microtubule inhibitor, via a protease-cleavable linker
.

In a recent randomized trial in patients with relapsed or refractory DLBCL (R/R DLBCL), the addition of Pola to bendamustine and rituximab (BR) compared with BR significantly prolonged patient survival Overall survival (OS)
.

In addition, the results of a phase IB/II clinical trial showed that Pola-R-CHP (Pola combined with rituximab, cyclophosphamide, doxorubicin and prednisone) as first-line treatment of DLBCL, the overall response rate of patients (ORR) reached 89%, and the complete remission (CR) rate reached 77%
.

Based on this, the researchers conducted a randomized, phase III POLARIX trial to compare the efficacy and safety of Pola-R-CHP and R-CHOP in newly diagnosed DLBCL patients
.

Research Methods The POLARIX trial was a randomized, double-blind, placebo-controlled, international Phase III trial
.

The enrolled patients were 18-80 years old, had definite CD20-positive DLBCL, had not received lymphoma treatment before, and had an ECOG performance status score of 0-2; the baseline International Prognostic Index (IPI) score was between 2-5, And have adequate hematology, kidney, liver and heart function
.

Key exclusion criteria were a history of indolent lymphoma, contraindications to any component of R-CHOP, previous anthracycline exposure, and known central nervous system (CNS) involvement
.

Eligible patients were randomized 1:1 to receive either Pola-R-CHP or R-CHOP for a planned 8 cycles (21 days each)
.

During the first 6 cycles, patients received either Pola-R-CHP or R-CHOP, and in cycles 7 and 8, patients in both groups received rituximab monotherapy
.

CNS prophylaxis with intrathecal chemotherapy is permitted
.

Consolidation radiotherapy to the initial site of the large mass or to the extranodal site was permitted at the investigator's discretion
.

The primary endpoint was investigator-assessed progression-free survival (PFS); stratified analyses were performed for key secondary endpoints, including PET-CT-based CR rate at the end of treatment as determined by blinded independent central review, and OS
.

Study Results Patient Characteristics Overall, a total of 1063 patients were screened for eligibility
.

Between November 14, 2017, and June 27, 2019, a total of 879 patients (intention-to-treat population) were randomized, 440 of whom were assigned to the Pola-R-CHP group and 439 to the R-CHOP group (Fig.
1)
.

The safety analysis population included 435 patients in the Pola-R-CHP group and 438 patients in the R-CHOP group
.

The demographic and clinical characteristics of the two groups of patients at baseline were similar (Table 1)
.

The median age of the overall patient population was 65 years (range: 19-80 years)
.

Stratification factors (IPI score, presence or absence of large inclusions, and geographic region) and subtype distribution of DLBCL were largely balanced between the two groups
.

The median time between diagnosis (defined as biopsy date) and initiation of treatment was similar between the two groups (Table 1)
.

Figure 1 Flow chart of the studyTable 1 Baseline characteristics of the intention-to-treat population Patients receiving treatment Most patients received all 6 studies and 85.
9% of patients received all 8 cycles of treatment
.

The median relative dose intensity (ratio of administered dose to planned dose) for rituximab, doxorubicin, and cyclophosphamide was greater than 99% in both treatment groups
.

After completion of trial treatment, a total of 11 (2.
5%) and 18 (4.
1%) patients in the Pola-R-CHP and R-CHOP groups, respectively, received pre-planned radiotherapy; Pola-R-CHP and R-CHOP The number of patients in the group receiving CNS prophylaxis was 72 (16.
4%) and 86 (19.
6%), respectively
.

At the cutoff of patient efficacy data (June 28, 2021), with a median follow-up of 28.
2 months, the Pola-R-CHP group had significantly lower risks of progression, recurrence, or death than the R-CHOP group (stratified hazard ratio, 0.
73; 95% CI, 0.
57 to 0.
95; P = 0.
02) (Table 2 and Figure 2A)
.

The milestone analysis showed that the 2-year PFS rate in the Pola-R-CHP group was also better than that in the R-CHOP group by 76.
7% (95% CI, 72.
7-80.
8%) vs 70.
2% (95% CI, 65.
8-74.
6%), respectively
.

Results of exploratory subgroup analyses of PFS varied by demographic and disease characteristics
.

Investigator-assessed PFS analysis showed that the Pola-R-CHP group had a lower relative risk of events than the R-CHOP group, with 2-year PFS rates of 75.
6% (95% CI, 71.
5-79.
7) and 69.
4% (95% CI, 71.
5-79.
7), respectively.
95% CI, 65.
0-73.
8%); the hazard ratio-HR for an event or death was 0.
75 (95% CI, 0.
58-0.
96; P=0.
02) (Table 2 and Figure 2B)
.

There was no significant difference in the rate of patients achieving CR at the end of treatment (as determined by blinded central review) between the two groups, 78.
0% and 74.
0%, respectively (P=0.
16)
.

However, investigator-assessed disease-free survival analysis showed that patients who received Pola-R-CHP with a best response in CR were more likely to have sustained responses (HR for relapse or death) than those who received R-CHOP and CR was 0.
70; 95% CI, 0.
50 to 0.
98) (Table 2 and Figure 2C)
.

There was no significant difference in OS between the two groups (Table 2 and Figure 2D)
.

Disease progression or recurrence with CNS involvement was reported in 13 patients (3.
0%) in the Pola-R-CHP group and in 12 patients (2.
7%) in the R-CHOP group
.

Table 2 Efficacy in the intent-to-treat populationFigure 2 Estimated PFS and OS status of patients in this study Patient safety The overall safety profile of patients in the Pola-R-CHP and R-CHOP groups was basically similar, with any grade and The types and rates of grade 3 or 4 adverse events (AEs) were similar (Table 3)
.

No new safety signals were detected, and the safety profile of Pola-R-CHP was consistent with the known safety profile of each drug
.

The most common grade 3 or 4 AEs in the Pola-R-CHP and R-CHOP groups were neutropenia (28.
3% and 30.
8%, respectively), febrile neutropenia (13.
8%, respectively) and 8.
0%) and anemia (12.
0% and 8.
4%, respectively)
.

Although the incidence of febrile neutropenia was higher in patients treated with Pola-R-CHP than in patients treated with R-CHOP, patients with grade 3 or 4 infections were similar (15.
2% and 12.
6%, respectively).
%)
.

Overall, 27 (6.
2%) and 29 (6.
6%) patients in the Pola-R-CHP and R-CHOP groups, respectively, experienced an AE that led to discontinuation of at least 1 drug in the protocol
.

Of these patients, Pola was discontinued due to an AE in 19 (4.
4%) patients in the Pola-R-CHP group and vincristine was discontinued due to an AE in 22 (5.
0%) patients in the R-CHOP group; related to system events
.

There was no significant difference in the incidence of peripheral neuropathy between the two treatment groups
.

Peripheral neuropathy of any grade was reported in 52.
9% and 53.
9% of the Pola-R-CHP and R-CHOP groups, respectively, and grade ≥2 peripheral neuropathy was reported in 13.
8% and 16.
7%, respectively
.

Very few patients discontinued treatment due to peripheral neuropathy (0.
2% and 0.
9% in the Pola-R-CHP and R-CHOP groups, respectively)
.

Table 3 Conclusions of treatment-related adverse reactions in patients The results of this study showed that, in newly diagnosed DLBCL patients, Pola-R-CHP had a better 2-year PFS rate than R-CHOP and had similar safety profiles
.

References Hervé Tilly , Franck Morschhauser , Laurie H Sehn, et al.
Polatuzumab Vedotin in Previously Untreated Diffuse Large B-Cell Lymphoma.
N Engl J Med.
2022 Jan 27;386(4):351-363.
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