Clinical Study Design

POLARIX: Double-Blind, Placebo-Controlled Phase III Study^1,2

The POLARIX trial was a Phase 3, randomized, double-blind, placebo-controlled study that enrolled 879 patients with previously untreated DLBCL (including DLBCL, NOS and HGBL) and an IPI score of 2 to 5. Patients aged 18 to 80 years with an ECOG performance status of 0 to 2 were eligible. Key exclusion criteria included transformed lymphoma, primary mediastinal large B-cell lymphoma, known central nervous system (CNS) lymphoma, and Grade 2 or higher baseline peripheral neuropathy.

Patients were randomized 1:1 to receive either:

• Polivy plus R-CHP (Arm A): Polatuzumab vedotin-piiq plus rituximab, cyclophosphamide, doxorubicin, and prednisone for six 21-day cycles, followed by two additional cycles of rituximab monotherapy.
• R-CHOP (Arm B): Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone for six 21-day cycles, followed by two additional cycles of rituximab monotherapy.

  Note: The two additional cycles of rituximab monotherapy are not recommended in the approved Polivy plus R-CHP dosing regimen

Randomization was stratified based on IPI score (2 vs. 3–5), presence or absence of bulky disease (≥7.5 cm), and geographical region (Western Europe, United States, Canada and Australia vs Asia vs rest of world).

The primary endpoint was progression-free survival (PFS) by investigator assessment. Secondary endpoints included modified event-free survival (EFS), PET-CT complete response (CR) at the end of treatment (EOT) by blinded independent central review, overall survival (OS), and safety.

POLARIX Double-Blind, Placebo-Controlled Phase III Study Design

1. Previously untreated CD-20 positive DLBCL with diagnoses by 2016 WHO classification of lymphoid neoplasms.
2. Western Europe, United States, Canada and Australia vs Asia vs rest of world.

Differences between POLARIX Clinical Trial Intention-to-Treat Population and the FDA-approved Indication^1,2

Notably, there are some differences between the POLARIX clinical trial intention-to-treat (ITT) population and the FDA-approved indication.

The POLARIX protocol included patients with DLBCL, NOS, including germinal center B‐cell-like (GCB) and activated B-cell-like (ABC) molecular subtypes based on the cell-of-origin, as well as HGBL patients with MYC, BCL2, and/or BCL6 rearrangements, also referred to as double-hit or triple-hit, and patients with HGBL, NOS. Both of these populations are included in the Polivy indication.

However, while patients with T-cell/histiocyte-rich large B-cell lymphoma and Epstein-Barr virus positive DLBCL were enrolled in POLARIX, representing around 5% of the trial population, they are not included in the indication.

Patients with ALK-positive large B-cell lymphoma and HHV8-positive DLBCL were also not included in the indication because they were not enrolled.

The primary and key secondary data, as well as safety information presented in the USPI, are based on the ITT population, and data from exploratory subgroup analyses for PFS and OS, for DLBCL, NOS and HGBL were also included in the label.

Comparison Between the POLARIX Protocol Inclusion Criteria, ITT Patient Population, and Polivy Indication

1. Previously untreated CD-20 positive DLBCL with diagnoses by 2016 WHO classification of lymphoid neoplasms.

Statistical Plan and Efficacy^1-4

Primary and Secondary Endpoints: Results and Statistical Considerations^1,2

A hierarchical testing procedure was used in POLARIX to adjust for multiple statistical testing of the primary and key secondary efficacy endpoints. If the primary endpoint of PFS was positive, then the key secondary endpoints of modified EFS, CR rate at EOT, and OS were hierarchically tested in that order.

POLARIX Primary Endpoint: Progression-Free Survival by Investigator^1,3,a

At the primary analysis in the ITT population (median follow-up of 24.7 months), Polivy plus R-CHP demonstrated a statistically significant improvement in PFS compared to R-CHOP (hazard ratio [HR] 0.73; 95% confidence interval [CI]: 0.57–0.95; p=0.0177), representing a 27% reduction in the risk of disease progression, relapse, or death.

At 2 years, the Kaplan-Meier analysis showed that 76.7% of patients in the Polivy plus R-CHP arm remained alive and progression-free compared to 70.2% in the R-CHOP arm (absolute difference of 6.5%). No statistical hypothesis testing was performed for the 2-year PFS data, therefore no formal inference may be drawn.

Kaplan-Meier Estimates of Progression-Free Survival by Investigator

1. Analysis based on the ITT population. Kaplan–Meier estimate.

POLARIX Secondary Endpoint: Modified Event-Free Survival by Investigator^1,3,a,b

The first key secondary endpoint was modified EFS per investigator. Polivy plus R-CHP reduced the risk of progression, relapse, death from any cause, initiation of treatment for lymphoma, or biopsy-confirmed residual disease after treatment completion by 25% compared to R-CHOP (HR 0.75; 95% CI: 0.58–0.96; p=0.0244).

Kaplan-Meier Estimates of Modified Event-Free Survival by Investigator

1. The EFS_efficacy curve is not included in the Polivy prescribing information.
2. Modified EFS was defined as time from randomization to the earliest occurrence of disease progression or relapse, death, an efficacy finding that led to non-protocol specified lymphoma treatment, or biopsy positive for residual disease.
3. Stratified log-rank test, with a two-sided significance boundary of 0.05. The hierarchical testing order was PFS, modified EFS, then CR rate and overall survival.

The objective response rate at EOT was 86% in the Polivy plus R-CHP arm and 84% in the R-CHOP arm. The secondary endpoint of CR rate at EOT was 78% in the Polivy plus R-CHP arm and 74% in the R-CHOP arm; however, this difference was not statistically significant. Due to the hierarchical testing in POLARIX, the CR rate at EOT was not statistically significant, making the p-value for OS descriptive only.

Prespecified Exploratory Subgroup Analyses: Progression-Free Survival^1,4,a

Exploratory subgroup analyses of PFS and OS were conducted in the POLARIX trial. Due to the FDA-approved indication for Polivy plus R-CHP not encompassing all patients from the POLARIX ITT population, a pre-specified descriptive analysis of the two largest lymphoma subgroups, DLBCL, NOS and HGBL, was included in the USPI. In the DLBCL, NOS subgroup, which represented 84% of patients in POLARIX, the HR for PFS was 0.75, while for patients with HGBL, the PFS HR was 0.48. There was insufficient data to assess the efficacy of Polivy plus R-CHP in the other large B-cell lymphomas.

1. The forest plot is not included in the Polivy prescribing information.
2. Pola-R-CHP and R-CHOP arms were well balanced in terms of histology.

Overall Survival: Prespecified Final Analysis, and Post-hoc Exploratory Subgroup Analyses^1,4,a

Looking at the prespecified final analysis of OS, with a median follow-up of 3.3 years, there was no statistically significant difference observed between the treatment arms, with a HR of 0.94. In a descriptive analysis, patients with DLBCL, NOS had an OS HR of 1.02 and the HGBL subgroup had an OS HR of 0.42 in favor of the Polivy plus R-CHP arm.

1. The forest plot is not included in the Polivy prescribing information.
2. Pola-R-CHP and R-CHOP arms were well balanced in terms of histology.

Summary of Efficacy in POLARIX (ITT): §14.1

Endpoints tested in hierarchical order

1. Estimated median follow-up for PFS was 24.7 months in both arms combined.
2. Stratified log-rank test, with a two-sided significance boundary of 0.05. The hierarchical testing order was PFS, modified EFS, then CR rate and overall survival.
3. Modified EFS was defined as time from randomization to the earliest occurrence of disease progression or relapse, death, an efficacy finding that led to non-protocol specified lymphoma treatment, or biopsy positive for residual disease.
4. By blinded independent central review, per 2014 Lugano response criteria.
5. Cochran-Mantel-Haenszel chi-squared test, with a two-sided significance boundary of 0.01.

Dosage and Administration

Recommended Dosage For All Indicated Patients

The recommended dosage of Polivy is 1.8 mg/kg administered as an intravenous infusion every 21 days for 6 cycles in combination with a rituximab product, cyclophosphamide, doxorubicin, and prednisone. The administration sequence on Day 1 of each cycle is prednisone first, followed by Polivy, rituximab, cyclophosphamide, and doxorubicin, which can be administered in any order. Prednisone is continued once daily for the subsequent 4 days (Days 2-5), followed by a treatment-free interval through Day 21. Then the cycle is repeated for a total of 6 cycles. If for any reason a planned dose of Polivy is missed, it should be administered as soon as possible, and the schedule of administration should be adjusted accordingly to maintain a 21-day interval between doses.

Adverse Reactions and Management^1,2

Safety Profile in POLARIX

Overall Safety Profile^1,a

The overall safety profile observed in the POLARIX trial showed similar rates between the Polivy plus R-CHP and R-CHOP arms. The incidence of any grade adverse events was 97.9% in the Polivy plus R-CHP arm versus 98.4% in the R-CHOP arm, and Grade 3 to 4 adverse events were 57.7% versus 57.5%, respectively. Grade 5 adverse events were reported in 3% of patients in the Polivy plus R-CHP arm and in 2.3% of patients in the R-CHOP arm, with these events primarily related to infections. Serious adverse events were 34% versus 30.6%, respectively.

Dose interruption due to adverse events was 23.7% in the Polivy plus R-CHP arm versus 25.3% in the R-CHOP arm, dose reduction due to adverse events were 9.2% versus 13%, respectively, and treatment discontinuation due to adverse events were 6.2% versus 6.6%, respectively.

Overall Safety Profile

1. Clinical cut-off date: June 28, 2021. Incidence rates may differ from the USPI due to differences in definitions.
2. Grade 5 AEs, Pola-R-CHP (13): pneumonia (4), sepsis or septic shock (1), unexplained death (4), cardiac death (1), intestinal perforation (1), acute kidney injury (1), respiratory failure (1); R-CHOP (10): pneumonia (3), sepsis or septic shock (3), unexplained death (1), multiple organ dysfunction syndrome (1), atrioventricular block complete (1), injury (1).
3. Dose interruption, reduction, or discontinuation of any agent.

Select Adverse Reactions Occurring in ≥10% of Patients Treated with POLIVY Plus R-CHP²

Select adverse reactions occurring in ≥10% of patients treated with Polivy plus R-CHP as listed in the USPI are represented as a tornado chart below. This chart includes both adverse reactions and laboratory abnormalities (highlighted in green). The most common adverse reactions in ≥20% of patients treated with Polivy plus R-CHP were peripheral neuropathy, nausea, fatigue, diarrhea, constipation, alopecia, and mucositis. Grade 3 to 4 laboratory abnormalities in ≥10% of patients were lymphopenia, neutropenia, hyperuricemia, and anemia.

Select Adverse Reactions and Laboratory Abnormalities Occurring in ≥10% of Patients Treated with Polivy Plus R-CHP

1. Laboratory values are based on integrated analysis of laboratory and adverse reaction data. Reported investigations exclude electrolytes.

Peripheral Neuropathy: Definitions and Grading^3-5

There are two types of peripheral neuropathy associated with Polivy, peripheral sensory neuropathy and peripheral motor neuropathy. There is a difference in how these are managed while on treatment with Polivy plus R-CHP, so it is important to differentiate them.

Peripheral sensory neuropathy is a disorder characterized by inflammation or degeneration of the peripheral sensory nerves. Damage to sensory nerves can cause:

• Tingling, numbness, or a pins-and-needles feeling in extremities that may spread to limbs
• Inability to feel extremes in temperature
• Inability to feel pain

Peripheral motor neuropathy is a disorder characterized by inflammation or degeneration of the peripheral motor nerves. Damage to motor nerves can cause:

• Weak or achy muscles that may cause patients to lose balance, trip easily, or have impaired manual dexterity (i.e., buttoning shirts or opening jars)
• Muscles that twitch and cramp, or atrophy
• Swallowing or breathing difficulties

Peripheral Neuropathy Grading

Management of Peripheral Neuropathy²

The table below provides management guidelines for peripheral neuropathy in patients receiving Polivy plus R-CHP [also see Warnings and Precautions (5.1)].

1. Graded using NCI CTCAE version 4.0.
2. Starting dose for Polivy is 1.8 mg/kg. First dose reduction level is 1.4 mg/kg. Second dose reduction level is 1 mg/kg. No further dose reduction is recommended beyond 1 mg/kg. If further reduction needed discontinue Polivy.