Pola-R-CHP Generates Long-Term PFS and DFS Advantages vs R-CHOP in Untreated DLBCL

The addition of polatuzumab vedotin-piiq (Polivy) to rituximab (Rituxan), cyclophosphamide, doxorubicin (Adriamycin), and prednisone (Pola-R-CHP) demonstrated consistently sustained and significant long-term progression-free survival (PFS) and disease-free survival (DFS) benefits compared with placebo plus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with previously untreated diffuse large B-cell lymphoma (DLBCL) at the 5-year extended follow-up of the phase 3 POLARIX trial (NCT03274492).1

These findings were presented at the 2024 ASH Annual Meeting and confirmed the results from the primary analysis of PFS at 2 years of follow-up.

In the global intention-to-treat (ITT) population, at a median follow-up of 54.9 months and a data cutoff date of July 5, 2024, the 5-year PFS rates were 64.9% (95% CI, 59.8%-70.0%) and 59.1% (95% CI, 54.0%-64.3%) in the Pola-R-CHP (n = 440) and placebo/R-CHOP (n = 439) arms, respectively (HR, 0.77; 95% CI, 0.62-0.97). In the primary analysis, investigators had shown that the 2-year PFS rates were 76.7% (95% CI, 72.7%-80.8%) and 70.2% (95% CI, 65.8%-74.6%) in these respective arms (HR, 0.73; 95% CI, 0.57-0.95). Additional prior findings showed that these respective 3-year PFS rates were 71.8% (95% CI, 67.1%-76.5%) and 64.1% (95% CI, 59.1%-69.1%; HR, 0.76 [95% CI, 0.60-0.97]).

POLARIX Background and Trial Design

In June 2019, the FDA granted accelerated approval to the antibody-drug conjugate (ADC) polatuzumab vedotin for use in combination with bendamustine and rituximab in the treatment of patients with relapsed/refractory DLBCL who had previously received at least 2 therapies.2 In April 2023, the ADC was granted FDA approval for use in combination with R-CHP for the treatment of patients with previously untreated DLBCL not otherwise specified (NOS) or those with high-grade B-cell lymphoma who have an International Prognostic Index (IPI) score of 2 or greater.3

The multicenter, randomized, double-blind, placebo-controlled POLARIX trial compared the efficacy, safety, and pharmacokinetics of Pola-R-CHP vs placebo plus R-CHOP in patients with DLBCL who were previously untreated.4 Patients needed to be 18 to 80 years of age, have an IPI score of 2 to 5, and have an ECOG performance status of 0 to 2.1 Patients enrolled in the trial were stratified based on IPI score (2 vs 3-5), extent of bulky disease (< 7.5 cm vs ≥ 7.5 cm), and geographic region (Western Europe, United States, Canada, and Australia vs Asia vs rest of world).

Patients were randomly assigned 1:1 to receive 1.8 mg/kg of IV polatuzumab vedotin on day 1 plus R-CHP and a vincristine placebo; or R-CHOP with prednisone placebo consisting of rituximab at 375 mg/m2, cyclophosphamide at 750 mg/m2, doxorubicin at 50 mg/m2, and vincristine at 1.4 mg/m2 on day 1 plus oral prednisone at 100 mg once daily on days 1 through 5. Patients in both arms were treated with the respective regimens for 6 21-day cycles. Thereafter, all patients received rituximab at 375 mg/m2 for cycles 7 and 8.

Among the global population, the ITT population included 879 patients, and the safety-evaluable population included 873 patients (Pola-R-CHP arm, n = 435; R-CHOP arm, n = 438). Of note, 1 patient from the safety-evaluable population was randomly assigned to receive Pola-R-CHP but was not treated with polatuzumab vedotin, and 1 patient from the safety-evaluable population was randomly assigned to receive R-CHOP but was not treated with vincristine.

The primary end point of the trial was PFS per investigator review; secondary end points included event-free survival per investigator review, PET complete remission (CR) at end of treatment per blinded independent central review, and overall survival (OS).

Patient Baseline Demographics

Among patients in the Pola-R-CHP arm, the median age was 65.0 years (range, 19-80); 52.5% were at least 65 years of age; 54.3% were male; 85.0% had an ECOG performance status of 0 or 1; 62.0% had an IPI score of 3 to 5 at screening; 43.5% had bulky disease (defined as disease measuring at least 7.5 cm); 66.1% had baseline lactate dehydrogenase (LDH) levels that were 1 time greater than the upper limit of normal (ULN); 89.3% had Ann Arbor stage III or IV disease; 48.4% had 2 or greater extranodal sites; 84.8% had an investigator-reported histologic diagnosis of DLBCL NOS, activated B-cell (ABC) lymphoma, or germinal center B-cell (GCB) lymphoma; and 55.8% had GCB lymphoma centrally reported by NanoString.

Among patients in the R-CHOP arm, the median age was 66.0 years (range, 19-80); 53.8% were at least 65 years of age; 53.3% were male; 82.7% had an ECOG performance status of 0 or 1; 62.0% had an IPI score of 3 to 5 at screening; 43.7% had bulky disease; 64.7% had baseline LDH levels 1 time greater than the ULN; 88.2% had Ann Arbor stage III or IV disease; 48.5% had 2 or greater extranodal sites; 83.6% had an investigator-reported histologic diagnosis of DLBCL NOS, ABC lymphoma, or GBC lymphoma; and 49.7% had GCB lymphoma centrally reported by NanoString.

Additional Efficacy and Safety Data

Among patients in the ITT population, the DFS rates among patients who achieved CR with Pola-R-CHP were maintained with 5 years of follow-up. The 5-year DFS rates among complete responders were 71.8% (95% CI, 66.4%-77.3%) in the Pola-R-CHP arm (n = 383) and 66.5% (95% CI, 60.8%-72.1%) in the R-CHOP arm (n = 367; HR, 0.75; 95% CI, 0.57-1.00). Previously reported data showed that the 2-year DFS rates among complete responders were 81.8% (95% CI, 77.4%-86.2%) and 77.4% (95% CI, 72.7%-82.0%) in these respective arms (HR, 0.70; 95% CI, 0.50-0.98). Additionally, the 3-year DFS rates among complete responders were 78.2% (95% CI, 73.1%-83.2%) and 72.5% (95% CI, 67.2%-77.8%) in these respective arms (HR, 0.72; 95% CI, 0.53-0.99).

At a median follow-up of 64.1 months, the 5-year OS outcomes also favored the Pola-R-CHP arm. In the global population, the 5-year OS rates were 82.3% (95% CI, 78.7%-85.9%) and 79.5% (95% CI, 75.7%-83.4%) in the Pola-R-CHP and R-CHOP arms, respectively (HR, 0.85; 95% CI, 0.63-1.15). At the 5-year update, 79 and 91 deaths had occurred in these respective arms.

Previously reported data showed that the 2-year OS rates were 88.7% (95% CI, 85.7%-91.7%) and 88.6% (95% CI, 85.6%-91.6%) in the Pola-R-CHP and R-CHOP arms, respectively (HR, 0.94; 95% CI, 0.65-1.37). Additionally, the 3-year OS rates were 85.6% (95% CI, 82.3%-88.9%) and 85.6% (95% CI, 82.2%-88.9%), respectively (HR, 0.94; 95% CI, 0.67-1.33). Of note, at the primary analysis, 53 and 57 deaths were reported in the Pola-R-CHP and R-CHOP arms, respectively.

The 5-year PFS and OS benefits with Pola-R-CHP were generally consistent across patient subgroups in the global population. However, the subgroup analyses were exploratory and generally underpowered, particularly for OS.

Patients who received Pola-R-CHP required fewer subsequent therapies vs those who received R-CHOP, and subsequent therapy patterns in the study reflected those seen in clinical practice at the time the study was conducted. Overall, 209 and 336 subsequent therapies were required by patients in the Pola-R-CHP and R-CHOP arms, respectively. In total, 25.5% and 35.3% of patients in these respective arms received at least 1 new anti-lymphoma treatment. These subsequent therapies included radiotherapy (Pola-R-CHP arm, 9.5%; R-CHOP arm, 14.1%), systemic therapy (20.0%; 28.2%), platinum-based therapy (9.8%; 15.5%), stem cell transplant (5.0%; 8.4%), CAR T-cell therapy (2.3%; 4.1%), and bispecific antibodies (1.4%; 2.1%).

In the global population, deaths associated with disease progression were fewer in the Pola-R-CHP arm vs the R-CHOP arm. Total deaths in the Pola-R-CHP vs R-CHOP arms were 80 (18.2%) vs 92 (21.0%), with 40 (9.1%) vs 51 (11.6%) deaths due to disease progression in the respective arms. Deaths unrelated to disease occurred in 23 (5.2%) and 28 (6.8%) patients in the Pola-R-CHP and R-CHOP arms, respectively. Causes of death not related to disease included infection (Pola-R-CHP arm, 1.6%; R-CHOP arm, 2.7%), secondary malignancies (1.6%; 1.1%), cardiovascular events (0.9%; 0.9%); COVID-19 (0.5%; 0.9%); other causes (0.7%; 1.1%), and unknown causes (3.9%; 2.5%).

References

1. Five-year analysis of the POLARIX study: Prolonged follow-up confirms positive impact of polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) on outcomes. Salles G, Morschhauser F, Sehn LH, et al. Blood. 2024;144(suppl 1):469. doi:10.1182/blood-2024-197938
2. FDA approved polatuzumab vedotin-piiq for diffuse large B-cell lymphoma. FDA. June 10, 2019. Accessed February 7, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-polatuzumab-vedotin-piiq-diffuse-large-b-cell-lymphoma
3. FDA approves polatuzumab vedotin-piiq for previously untreated diffuse large B-cell lymphoma, not otherwise specified, and high-grade B-cell lymphoma. FDA. Updated April 20, 2023. Accessed February 7, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-polatuzumab-vedotin-piiq-previously-untreated-diffuse-large-b-cell-lymphoma-not
4. A study comparing the efficacy and safety of polatuzumab vedotin with rituximab-cyclophosphamide, doxorubicin, and prednisone (R-CHP) versus rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in participants with diffuse large B-cell lymphoma (POLARIX). ClinicalTrials.gov. Updated January 3, 2025. Accessed February 7, 2025. https://www.clinicaltrials.gov/study/NCT03274492