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POLARIX Trial

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POLARIX Trial Design
Patient Characteristics

POLARIX: Designed to evaluate PFS superiority of POLIVY® + R-CHP over R-CHOP in a head-to-head trial1

POLARIX was a double-blind, randomized, multicenter, phase 3 study of 879 patients1

Key Exclusion Criteria: Patients with a history of indolent lymphoma, a contraindication to any component of R-CHOP, previous receipt of anthracycline agents, and known CNS involvement

Stratification factors: IPI score (2 vs 3-5), Bulky disease (≥7.5cm vs absence), Geographic region§

IIPFS was calculated in a time-to-event analysis, in which investigator-assessed disease progression or relapse or death from any cause were counted as events.

POLIVY (1.8 mg/kg) or vincristine (1.4 mg/m2), along with rituximab (375 mg/m2), cyclophosphamide (750 mg/m2), and doxorubicin (50 mg/m2) was administered by IV infusion on Day 1 of Cycles 1-6. All patients received oral prednisone 100 mg once daily on Days 1-5 of each of the first 6 cycles. Rituximab monotherapy (375 mg/m2) was administered on Day 1 of Cycles 7 and 8. Each cycle was 21 days.1

*Recommended dose of POLIVY is 1.8 mg/kg IV + R-CHP every 21 days for 6 cycles.
†In lieu of vincristine.
‡In lieu of POLIVY.
§Western Europe, United States, Canada and Australia vs Asia vs Rest of World.
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.
#Based on PET-CT and determined by BICR.
 

POLIVY + R-CHP was studied in a range of patients with previously untreated LBCL1

Patient characteristics were well-balanced across POLARIX treatment arms1,15

    POLIVY + R-CHP (n=440) R-CHOP (n=439)
Age >60 years, n (%) 300 (68.2) 308 (70.2)
Median (range) 65.0 (19-80) 66.0 (19-80)
Sex, n (%) Male 239 (54.3) 234 (53.3)
Female 201 (45.7) 205 (46.7)
Geographic region, n (%)* W. Europe, USA, CAN, AUS 302 (68.6) 301 (68.6)
Asia 81 (18.4) 79 (18.0)
Rest of world 57 (13.0) 59 (13.4)
ECOG PS, n (%)† 0-1 374 (85.0) 363 (82.7)
2 66 (15.0) 75 (17.1)
Bulky disease, n (%)*,‡   193 (43.9) 192 (43.7)
Ann Arbor stage, n (%)§ I-II 47 (10.7) 52 (11.8)
III-IV 393 (89.3) 387 (88.2)
IPI score, n (%)* 2 167 (38.0) 167 (38.0)
3-5 273 (62.0) 272 (62.0)
Histologic diagnosis, n (%) DLBCL NOS (including GCB and ABC) 373 (84.8) 367 (83.6)
HGBL (including NOS and DHL/THL) 43 (9.8) 50 (11.4)
Other large B cell‖ 24 (5.5) 22 (5.0)

DLBCL, NOS represented ~85% of LBCL cases in POLARIX, similar to real world estimates1,16

*This variable was a stratification factor.
†Patients were to have a baseline ECOG PS score of 0-2 (on a 5-point scale, with higher numbers indicating greater disability). ECOG PS was not reported for 1 patient in the R-CHOP group.
‡Bulky disease was defined as the presence of 1 or more lesions that were 7.5 cm or larger in greatest dimension.
§Stages range from I to IV, with higher stages indicating more extensive disease.
IIOther large B-cell lymphomas by local diagnosis included EBV+ DLBCL, NOS, and T-cell/histiocyte rich large B-cell lymphoma.

ABC = activated B cell; AUS = Australia; BICR = blinded independent central review; CAN = Canada; CNS = central nervous system; DHL = double-hit lymphoma; EBV+ = Epstein-Barr virus-positive; ECOG PS = Eastern Cooperative Oncology Group performance status; EOT = end of treatment; GCB = germinal center B cell; IV = intravenous; LBCL = large B-cell lymphoma; PET-CT = positron emission tomography and computed tomography; THL = triple-hit lymphoma; USA = United States of America; W. Europe = Western Europe.

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Important Safety Information and Indication

Indication

POLIVY in combination with a rituximab product, cyclophosphamide, doxorubicin, and prednisone (R-CHP) for the treatment of adult patients who have previously untreated diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS) or high-grade B-cell lymphoma (HGBL) and who have an International Prognostic Index score of 2 or greater.

POLIVY in combination with bendamustine and a rituximab product is indicated for the treatment of adult patients with relapsed or refractory DLBCL, NOS, after at least two prior therapies.

Important Safety Information

Peripheral Neuropathy

POLIVY can cause severe peripheral neuropathy. Peripheral neuropathy occurs as early as the first cycle of treatment and is cumulative. POLIVY may exacerbate preexisting peripheral neuropathy.

In POLARIX, of 435 patients treated with POLIVY plus R-CHP, 53% reported new or worsening peripheral neuropathy, with a median time to onset of 2.3 months. Peripheral neuropathy was Grade 1 in 39% of patients, Grade 2 in 12%, and Grade 3 in 1.6%. Peripheral neuropathy resulted in dose reduction in 4% of treated patients and treatment discontinuation in 0.7%. Among patients with peripheral neuropathy after POLIVY, 58% reported resolution after a median of 4 months.

In Study GO29365, of 173 patients treated with POLIVY, 40% reported new or worsening peripheral neuropathy, with a median time to onset of 2.1 months. Peripheral neuropathy was Grade 1 in 26% of patients, Grade 2 in 12%, and Grade 3 in 2.3%. Peripheral neuropathy resulted in POLIVY dose reduction in 2.9% of treated patients, dose delay in 1.2%, and permanent discontinuation in 2.9%. Sixty-five percent of patients reported improvement or resolution of peripheral neuropathy after a median of 1 month, and 48% reported complete resolution.

The peripheral neuropathy is predominantly sensory; however, motor and sensorimotor peripheral neuropathy also occur. Monitor for symptoms of peripheral neuropathy such as hypoesthesia, hyperesthesia, paresthesia, dysesthesia, neuropathic pain, burning sensation, weakness, or gait disturbance. Patients experiencing new or worsening peripheral neuropathy may require a delay, dose reduction, or discontinuation of POLIVY.

Infusion-Related Reactions

POLIVY can cause severe infusion reactions. Delayed infusion-related reactions as late as 24 hours after receiving POLIVY have occurred.

With premedication, 13% of patients (58/435) in POLARIX reported infusion-related reactions after the administration of POLIVY plus R-CHP. The reactions were Grade 1 in 4.4% of patients, Grade 2 in 8%, and Grade 3 in 1.1%.

With premedication, 7% of patients (12/173) in Study GO29365 reported infusion-related reactions after the administration of POLIVY. The reactions were Grade 1 in 4.6% of patients, Grade 2 in 1.7%, and Grade 3 in 0.6%.

Symptoms occurring in ≥1% of patients included chills, dyspnea, pyrexia, pruritus, rash, and chest discomfort. Administer an antihistamine and antipyretic prior to the administration of POLIVY, and monitor patients closely throughout the infusion. If an infusion-related reaction occurs, interrupt the infusion and institute appropriate medical management.

Myelosuppression

Treatment with POLIVY can cause serious or severe myelosuppression, including neutropenia, thrombocytopenia, and anemia.

In POLARIX, 90% of patients treated with POLIVY plus R-CHP had primary prophylaxis with G-CSF. Grade 3–4 hematologic adverse reactions included lymphopenia (44%), neutropenia (39%), febrile neutropenia (15%), anemia (14%), and thrombocytopenia (8%).

In Study GO29365, in patients treated with POLIVY plus BR (n = 45), 42% received primary prophylaxis with G-CSF. Grade 3 or higher hematologic adverse reactions included neutropenia (42%), thrombocytopenia (40%), anemia (24%), lymphopenia (13%), and febrile neutropenia (11%). Grade 4 hematologic adverse reactions included neutropenia (24%), thrombocytopenia (16%), lymphopenia (9%), and febrile neutropenia (4.4%). Cytopenias were the most common reason for treatment discontinuation (18% of all patients).

Monitor complete blood counts throughout treatment. Cytopenias may require a delay, dose reduction, or discontinuation of POLIVY. Administer prophylactic G-CSF for neutropenia in patients receiving POLIVY plus R-CHP. Consider prophylactic G-CSF administration in patients receiving POLIVY plus bendamustine and a rituximab product.

Serious and Opportunistic Infections

Fatal and/or serious infections, including opportunistic infections such as sepsis, pneumonia (including Pneumocystis jiroveci and other fungal pneumonia), herpesvirus infection, and cytomegalovirus infection have occurred in patients treated with POLIVY.

In POLARIX, Grade 3–4 infections occurred in 14% (61/435) of patients treated with POLIVY plus R-CHP and infection-related deaths were reported in 1.1% of patients.

In Study GO29365, Grade 3 or higher infections occurred in 32% (55/173) of patients treated with POLIVY and infection-related deaths were reported in 2.9% of patients within 90 days of last treatment.

Closely monitor patients during treatment for signs of infection. Administer prophylaxis for Pneumocystis jiroveci pneumonia and herpesvirus. Administer prophylactic G-CSF for neutropenia as recommended.

Progressive Multifocal Leukoencephalopathy (PML)

PML has been reported after treatment with POLIVY plus bendamustine and obinutuzumab in study GO29365 (0.6%, 1/173). Monitor for new or worsening neurological, cognitive, or behavioral changes. Hold POLIVY and any concomitant chemotherapy if PML is suspected, and permanently discontinue if the diagnosis is confirmed.

Tumor Lysis Syndrome

POLIVY may cause tumor lysis syndrome. Patients with high tumor burden and rapidly proliferative tumor may be at increased risk of tumor lysis syndrome. Monitor closely and take appropriate measures, including tumor lysis syndrome prophylaxis.

Hepatotoxicity

Serious cases of hepatotoxicity that were consistent with hepatocellular injury, including elevations of transaminases and/or bilirubin, have occurred in patients treated with POLIVY.

In recipients of POLIVY plus R-CHP, Grade 3–4 elevation of ALT and AST developed in 1.4% and 0.7% of patients, respectively.

In Study GO29365, Grade 3 and Grade 4 transaminase elevations each developed in 1.9% of patients.

Preexisting liver disease, elevated baseline liver enzymes, and concomitant medications may increase the risk of hepatotoxicity. Monitor liver enzymes and bilirubin level.

Embryo-Fetal Toxicity

Based on the mechanism of action and findings from animal studies, POLIVY can cause fetal harm when administered to a pregnant woman. The small molecule component of POLIVY, MMAE, administered to rats caused adverse developmental outcomes, including embryo-fetal mortality and structural abnormalities, at exposures below those occurring clinically at the recommended dose.

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with POLIVY and for 3 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with POLIVY and for 5 months after the last dose.

The Most Common Adverse Reactions

The most common adverse reactions (≥20%), excluding laboratory abnormalities, in patients with previously untreated DLBCL treated with POLIVY in combination with R-CHP are peripheral neuropathy, nausea, fatigue, diarrhea, constipation, alopecia, and mucositis. The most common Grade 3 to 4 laboratory abnormalities (≥20%) are lymphopenia and neutropenia.

The most common adverse reactions (≥20%) in patients with relapsed or refractory DLBCL treated with POLIVY in combination with BR are neutropenia, thrombocytopenia, anemia, peripheral neuropathy, fatigue, diarrhea, pyrexia, decreased appetite, and pneumonia.

Lactation

Advise women not to breastfeed during treatment with POLIVY and for 2 months after the last dose.

You may report side effects to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at 1-888-835-2555.
Please see the full Prescribing Information for additional Important Safety Information.

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