Polatuzumab vedotin in previously untreated DLBCL: an Asia subpopulation analysis from POLARIX trial

The phase III POLARIX study (NCT03274492) investigated polatuzumab vedotin in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) versus standard of care (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone; R-CHOP) as frontline treatment for patients with diffuse large B-cell lymphoma (DLBCL). Previously, the Lymphoma Hub has reported primary results from POLARIX and the Food and Drug Administration (FDA) approval of polatuzumab vedotin in combination with R-CHP in patients with previously untreated DLBCL. Below, we summarize results from the Asia subpopulation analysis of the POLARIX study investigating the safety and efficacy of polatuzumab vedotin combined with rituximab plus cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP).¹

Study design

This was a double-blind, placebo-controlled, international phase III study. Previously untreated patients with DLBCL were included in the analysis from the Asia subpopulation and the China extension cohort. Patients included were

• aged 18–80 years;
• treatment naïve;
• diagnosed with CD20-positive DLBCL; and
• had an Eastern Cooperative Oncology Group Performance Status of 0 to 2, an International Prognostic Index (IPI) score between 2 and 5, and adequate organ function.

Patients were randomized to Pola-R-CHP (n = 141) and R-CHOP (n = 140). The study protocol, schedule of assessments, and treatment were the same across patients analyzed in this subpopulation and the global cohort; stratification factors included IPI score and bulky disease, defined as absent or present with a lesion >7.5 cm. The primary endpoint was progression-free survival (PFS) and the primary safety endpoint was the incidence of adverse events (AEs).

Results

Overall, 281 patients were included in the study (Asia subpopulation, n = 160; China extension cohort, n = 121). The patient’s baseline demographics and clinical characteristics were balanced across the treatment arms (Table 1).

Table 1. Baseline patient demographics and clinical characteristics (intention-to-treat population)*

ECOG, Eastern Cooperative Oncology Group; IPI score, integrated pulmonary index; Pola-R-CHP, polatuzumab vedotin combined with rituximab plus cyclophosphamide, doxorubicin, and prednisone; R-CHOP, rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. *Data from Song, et al.1 †Based on stratification. ‡Centrally performed tests: cell-of-origin identification was performed by NanoString Lymph 2Cx; MYC and BCL2 immunohistochemistry were performed for DEL; MYC and BCL2, and/or BCL6 rearrangements were performed for double- and triple-hit lymphoma; percentages are calculated from the evaluable population. The remainder of the results were considered unknown and/or represent test failures. §Based on laboratory data at screening (hepatitis B core antibody detected). ‖Based on the safety-evaluable population (Pola-R-CHP, n = 140; R-CHOP, n = 139).
Characteristic, % (unless otherwise stated)	Pola-R-CHP (n = 141)	R-CHOP (n = 140)
Median age range, years	19–79	23–78
Age
<65 years	58.9	52.1
≥65 years	50.4	55.7
Country
Mainland China	53.2	53.6
Japan	30.5	30.0
Republic of Korea	10.6	11.4
Taiwan	5.7	5.0
Ann Arbor stage
I–II	13.5	15.0
III–IV	86.5	85.0
Extranodal sites
0–1	82.3	86.4
2	17.7	13.6
Bulky disease†
<7.5 cm	68.8	66.4
≥7.5 cm	31.2	33.6
ECOG Performance status
0–1	82.3	86.4
2	17.7	13.6
LDH level
Normal	31.9	29.3
Elevated	68.1	70.7
Median time from initial diagnosis to treatment initiation (IQR), days	17 (10–29)	15 (10–26)
IPI score, %†
2	38.3	37.9
3–5	61.7	62.1
Cell of origin‡
GCB	30	40
ABC	55	46
Unclassified	15	14
DEL‡
DEL	31.8	36.3
Non-DEL	68.2	63.7
Double/triple hit lymphoma‡
Yes	2.9	5.1
No	97.1	94.9
Previous history of hepatitis B infection§	32.1‖	42.4

Efficacy

• The study met its primary endpoint of PFS, consistent with the global study population (hazard ratio [HR], 0.64; 95% confidence interval [CI], 0.40–1.03). Primary and key secondary efficacy outcomes are shown in Figure 1.
• In the subpopulation analysis, 74.2% and 66.5% remained progression free at 2 years in the pola-R-CHP and R-CHOP arm, respectively.
• Fewer patients receiving Pola-R-CHP experienced disease relapse and received ≥1 subsequent anti-lymphoma therapy compared with patients receiving R-CHOP (22% vs 32.9%).

DFS, disease free survival; EFS, even free survival; ORR, objective response rate; OS, overall survival; Pola-R-CHP, polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, and prednisone; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone.
*Adapted from Song, et al.¹

Safety

• The most common treatment-emergent Grade 3/4 AEs were neutropenia, neutrophil count decreased, and white blood cell count decreased (Figure 2)
• Grade 5 AEs were reported by two patients in Pola-R-CHP arm (suspected COVID-19 and unexplained death) and one patient in the R-CHOP arm (unexplained death)
• The proportion of patients requiring treatment discontinuation was 5.0% in the Pola-R-CHP arm and 7.2% in the R-CHOP arm

AE, adverse event; Pola-R-CHP, polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, and prednisone; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone.
*Adapted from Song, et al.¹ 

Conclusion

These findings demonstrate the consistent efficacy and safety of Pola-R-CHP vs R-CHOP in the Asia and global populations of previously untreated patients with DLBCL enrolled in the POLARIX study. Of note, the subpopulation analysis is limited by a considerably smaller cohort and variability in follow-up compared with the entire study population.