Pharmacotherapeutic group: antineoplastic agents; other antineoplastic agents; monoclonal antibodies.
ATC code: L01XC37.
Pharmacology: Pharmacodynamics: Mechanism of action: Polatuzumab vedotin is a CD79b-targeted antibody-drug conjugate that preferentially delivers a potent anti-mitotic agent (monomethyl auristatin E, or MMAE) to B-cells, which results in the killing of malignant B-cells. The polatuzumab vedotin molecule consists of MMAE covalently attached to a humanized immunoglobulin G1 (IgG1) monoclonal antibody via a cleavable linker. The monoclonal antibody binds with high affinity and selectivity to CD79b, a cell surface component of the B-cell receptor. CD79b expression is restricted to normal cells within the B-cell lineage (with the exception of plasma cells) and malignant B-cells; it is expressed in > 95% of DLBCL. Upon binding CD79b, polatuzumab vedotin is rapidly internalized and the linker is cleaved by lysosomal proteases to enable intracellular delivery of MMAE. MMAE binds to microtubules and kills dividing cells by inhibiting cell division and inducing apoptosis.
Pharmacodynamic effects: Cardiac electrophysiology: Polatuzumab vedotin did not prolong the mean QTc interval to any clinically relevant extent based on ECG data from two open-label studies in patients with previously treated B-cell malignancies at the recommended dosage.
Clinical efficacy and safety: The efficacy of Polivy plus BR was evaluated in an international, multicenter, open-label study (GO29365) which included a randomized cohort (n=80) and an extension cohort (n=106) of patients with previously treated DLBCL.
Eligible patients were not candidates for autologous hematopoietic stem cell transplant (HSCT) and had relapsed or refractory disease after receiving at least one prior systemic chemotherapy regimen. The study excluded patients with prior allogeneic HSCT, central nervous system lymphoma, transformed follicular lymphoma (FL), and grade 3b FL, significant cardiovascular or pulmonary disease, active infections, AST or alanine transaminase (ALT) >2.5 × ULN or total bilirubin ≥1.5 x ULN, creatinine >1.5 x ULN (or CrCl <40 mL/min) unless due to underlying lymphoma.
Polivy was given intravenously at 1.8 mg/kg administered on Day 2 of Cycle 1 and on Day 1 of Cycles 2-6. Bendamustine was administered at 90 mg/m
2 intravenously daily on Days 2 and 3 of Cycle 1 and on Days 1 and 2 of Cycles 2-6. Rituximab was administered at 375 mg/m
2 intravenously on Day 1 of Cycles 1-6.
The primary endpoint of the study was complete response (CR) rate at end of treatment (6-8 weeks after day 1 of cycle 6 or last study treatment) as assessed by independent review committee (IRC). Efficacy results are summarized in Table 1-2 and in Figures 1-3.
Randomized Cohort (n=80): Patients were randomized 1:1 to receive Polivy plus BR or BR alone for six 21-day cycles. Patients were stratified by duration of response to last prior treatment of ≤12 months or >12 months.
Among the 80 patients who were randomized to receive Polivy plus BR (n=40) or BR alone (n = 40) the majority were white (71%) and male (66%). The median age was 69 years (range 30 to 86 years). Sixty-four out of 80 patients (80%) had ECOG performance score (PS) of 0-1 and 14 out of 80 patients (18%) had ECOG PS of 2. The majority of patients (98%) had DLBCL not otherwise specified (NOS). Overall, 48% of patients had activated B-cell (ABC) DLBCL and 40% of patients had germinal center B-cell like (GCB) DLBCL. Primary reasons patients were not candidates for HSCT included age (40%), insufficient response to salvage therapy (26%) and prior transplant failure (20%). The median number of prior therapies was 2 (range: 1-7) with 29% (n=23) receiving one prior therapy, 25% (n=20) receiving 2 prior therapies, and 46% (n=37) receiving 3 or more prior therapies. All except one patient in the pola+BR arm of the randomized Phase II were naïve to bendamustine treatment. 80% of patients had refractory disease. (See Table 1.)
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Overall survival (OS) was an exploratory endpoint which was not type 1 error controlled. The median OS in the Polivy+BR arm was 12.4 months (95% CI: 9.0, NE) vs 4.7 months (95% CI: 3.7, 8.3) in the control arm. The unadjusted estimate for OS HR was 0.42. When accounting for the influence of baseline covariates the OS HR was adjusted to 0.59. Covariates included primary refractory status, number of prior lines of therapy, IPI, and prior stem cell transplant.
Investigator-assessed progression free survival (PFS) was an exploratory endpoint which was not type 1 error controlled. The median PFS in the Polivy+BR arm was 7.6 months (95% CI: 6.0, 17.0) vs 2.0 months (95% CI: 1.5, 3.7) in the control arm. The unadjusted estimate for PFS HR was 0.34.
Immunogenicity: As with all therapeutic proteins, there is the potential for an immune response in patients treated with polatuzumab vedotin. Across all arms (excluding extension cohort) of study GO29365, 8 out of 134 (6.0%) patients tested positive for anti-polatuzumab vedotin antibodies at one or more post-baseline time points. Across seven clinical studies, 14 out of 536 (2.6%) patients tested positive for anti-polatuzumab vedotin antibodies at one or more post-baseline time points. Due to the limited number of anti-polatuzumab vedotin antibody positive patients, no conclusions can be drawn concerning a potential effect of immunogenicity on efficacy or safety.
Immunogenicity assay results are highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications and underlying disease. For these reasons, comparison of incidence of antibodies to polatuzumab vedotin with the incidence of antibodies to other products may be misleading. (See Figures 1 and 2.)
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Results of subgroup analyses: Results of subgroup analysis of overall survival were consistent with the results seen in the overall DLBCL population (see Figure 3 as follows).
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Extension cohort (n=106): The median age was 70 years (range 24 to 94 years) 78% of patients were white and 49% were male. The majority of patients (94%) had DLBCL not otherwise specified (NOS). Overall, 48% of patients had ABC DLBCL and 40% of patients had GCB DLBCL. Primary reasons patients were not candidates for HSCT included age (44%), insufficient response to salvage therapy (29%) and prior transplant failure (14%). The median number of prior therapies was 2 (range: 1-7) with 35% (n=37) receiving one prior therapy, 26% (n=27) receiving 2 prior therapies, and 40% (n=42) receiving 3 or more prior therapies. 76% of patients had refractory disease. (See Table 2.)
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Pharmacokinetics: Antibody-conjugated MMAE (acMMAE) plasma exposure increased dose-proportionally over the 0.1 to 2.4 mg/kg polatuzumab vedotin dose range. After the first 1.8 mg/kg polatuzumab vedotin dose, the acMMAE mean maximum concentration (C
max) was 803 (± 233) ng/mL and the area under the concentration-time curve from time zero to infinity (AUC
inf) was 1860 (± 966) day*ng/mL. Based on the population PK analysis, Cycle 3 acMMAE AUC increased by approximately 30% over cycle 1 AUC, and achieved more than 90% of the Cycle 6 AUC. The terminal half-life at cycle 6 was approximately 12 days (95% CI of 8.1-19.5 days) for acMMAE. Based on population PK analysis, the predicted acMMAE concentration at the end of cycle 6 is approximately 80% of the theoretical steadystate value. Exposures of unconjugated MMAE, the cytotoxic component of polatuzumab vedotin, increased dose proportionally over the 0.1 to 2.4 mg/kg polatuzumab vedotin dose range. MMAE plasma concentrations followed formation rate limited kinetics. After the first 1.8 mg/kg polatuzumab vedotin dose, the Cmax was 6.82 (± 4.73) ng/mL, the time to maximum plasma concentration is approximately 2.5 days, and the terminal half-life is approximately 4 days. Plasma exposures of unconjugated MMAE are < 3% of acMMAE exposures. Based on the population PK analysis there is a decrease of plasma unconjugated MMAE exposure (AUC) after repeated every-three-week dosing.
Based on population pharmacokinetics simulations, a sensitivity analysis predicted exposure to unconjugated MMAE for patients with bodyweight over 100 kg to be increased by 27%.
Absorption: Polivy is administered as an IV infusion. There have been no studies performed with other routes of administration.
Distribution: The population estimate of central volume of distribution for acMMAE was 3.15 L, which approximated plasma volume.
In vitro, MMAE is moderately bound (71% - 77%) to human plasma proteins. MMAE does not significantly partition into human red blood cells
in vitro; the blood to plasma ratio is 0.79 to 0.98.
In vitro data indicate that MMAE is a P-gp substrate but does not inhibit P-gp at clinically relevant concentrations.
Biotransformation: Polatuzumab vedotin is expected undergo catabolism in patients, resulting in the production of small peptides, amino acids, unconjugated MMAE, and unconjugated MMAE related catabolites. The levels of MMAE metabolites have not been measured in human plasma.
In vitro studies indicate that MMAE is a substrate for CYP 3A4/5 but does not induce major CYP enzymes. MMAE is a weak time-dependent inhibitor of CYP3A4/5 but does not competitively inhibit CYP3A4/5 at clinically relevant concentrations.
MMAE does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6.
Elimination: Based on a population pharmacokinetic analysis, the conjugate (acMMAE) is primarily eliminated by non-specific linear clearance pathway with a value of 0.9 L/day.
In vivo studies in rats dosed with polatuzumab vedotin (radiolabel on MMAE) demonstrate that the majority of radioactivity is excreted in feces and the minority of radioactivity is excreted in urine.
Pediatric Population: No studies have been conducted to investigate the pharmacokinetics of Polivy in pediatric patients (<18 years old).
Elderly: Age did not have an effect on the pharmacokinetics of acMMAE and unconjugated MMAE based on a population PK analysis with patients aged 20-89 years. No significant difference was observed in the pharmacokinetics of acMMAE and unconjugated MMAE among patients <65 years of age (n=187) and patients ≥65 years of age (n=273).
Renal impairment: In patients with mild (CrCL 60-89 mL/min, n=161) or moderate (CrCL 30-59 mL/min, n=109) renal impairment, acMMAE and unconjugated MMAE exposures are similar to patients with normal renal function (CrCL ≥ 90 mL/min, n=185), based on a population pharmacokinetic analysis. There are insufficient data to assess the impact of severe renal impairment (CrCL 15-29 mL/min, n=3) on PK. No data are available in patients with end-stage renal disease and/or who are on dialysis.
Hepatic impairment: In patients with mild hepatic impairment [AST >1.0 - 2.5×ULN or ALT >1.0 - 2.5×ULN or total bilirubin >1.0 - 1.5×ULN, n=54], acMMAE exposures are similar whereas unconjugated MMAE AUC are 40% higher compared to patients with normal hepatic function (n=399), based on a population pharmacokinetic analysis.
The safety and efficacy of Polivy in patients with (AST >2.5×ULN, ALT>2.5×ULN or total bilirubin>1.5×ULN) has not been formally studied and these patients are likely to have increased exposure to MMAE. The administration of Polivy in patients with moderate or severe hepatic impairment (total bilirubin greater than 1.5 × ULN) should be avoided.
There are insufficient data to assess the impact of moderate hepatic impairment (total bilirubin >1.5 - 3×ULN, n=2) on PK. No data are available in patients with severe hepatic impairment or liver transplantation.
Toxicology: Preclinical safety data: Systemic toxicity: In both rats and cynomolgus monkeys, the predominant systemic toxicities associated with administration of MMAE and polatuzumab vedotin included reversible bone marrow toxicity and associated peripheral blood cell effects.
Genotoxicity: No dedicated mutagenicity studies have been performed with Polivy. MMAE was not mutagenic in the bacterial reverse mutation assay (Ames test) or the L5178Y mouse lymphoma forward mutation assay.
MMAE was a genotoxic in the rat bone marrow micronucleus study probably through an aneugenic mechanism. This mechanism is consistent with the pharmacological effect of MMAE as a microtubule disrupting agent.
Carcinogenicity: No dedicated carcinogenicity studies have been performed with polatuzumab vedotin and/or MMAE.
Impairment of fertility: No dedicated fertility studies in animals have been performed with Polivy. However, results of the 4-week rat toxicity study indicate the potential for polatuzumab vedotin to impair male reproductive function and fertility. Testicular seminiferous tubule degeneration did not reverse following a 6-week treatment-free period and correlated with decreased testes weight and gross at recovery necropsy of small and/or soft testes in males given ≥ 2 mg/kg.
Reproductive toxicity: No dedicated teratogenicity studies in animals have been performed with Polivy. However, treatment of pregnant rats with MMAE at 0.2 mg/kg caused embryolethality and fetal malformations (including protruding tongue, malrotated limbs, gastroschisis, and agnathia). Systemic exposure (AUC) in rats at a dose of 0.2 mg/kg MMAE is approximately 50% of the AUC in patients who received the recommended dose of 1.8 mg/kg Polivy every 21-days.