The Proposed Mechanism of Action of POLIVY for R/R DLBCL, NOS

DLBCL = diffuse large B-cell lymphoma; NOS = not otherwise specified; R/R = relapsed/refractory

Important Safety Information and Indication

Warnings and Precautions

Vincent Herrin, MD - University of Mississippi Medical Center Jackson, Mississippi

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 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. The peripheral neuropathy was Grade 1 in 26% of cases, Grade 2 in 12%, and Grade 3 in 2.3%. Peripheral neuropathy resulted in POLIVY dose reduction in 3% 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 time to resolution 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, 7% of patients (12/173) in Study GO29365 reported infusion-related reactions after the administration of POLIVY. The reactions were Grade 1 in 67% of patients, Grade 2 in 25%, and Grade 3 in 8%. Symptoms included fever, chills, flushing, dyspnea, hypotension, facial swelling, and urticaria.

Administer an antihistamine and an 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 patients treated with POLIVY plus bendamustine and a rituximab product (BR) (n=45), 42% received primary prophylaxis with granulocyte colony-stimulating factor. Grade 3 or higher hematologic adverse reactions included neutropenia (42%), thrombocytopenia (40%), anemia (24%), lymphopenia (13%), and febrile neutropenia (11%) (see Adverse Reactions [6.1]). 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. Consider prophylactic granulocyte colony-stimulating factor administration.

Serious and Opportunistic Infections

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

Grade 3 or higher infections occurred in 32% (55/173) of patients treated with POLIVY. 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 forPneumocystis jirovecipneumonia and herpesvirus.

Progressive Multifocal Leukoencephalopathy (PML)

PML has been reported after treatment with POLIVY (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 proliferating tumors 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 in Study GO29365 (n=173), Grade 3 and 4 transaminase elevations of AST and/or ALT developed in 1.9% and 1.9%, respectively. Laboratory values suggestive of drug- induced liver injury (both an ALT or AST greater than 3 times upper limit of normal [ULN] and total bilirubin greater than 2 times ULN) occurred in 2.3% 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. When administered to rats, the small molecule component of POLIVY, monomethyl auristatin E, 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 at least 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 at least 5 months after the last dose.

The Most Common Adverse Reactions

The most common adverse reactions (≥20%) included neutropenia, thrombocytopenia, anemia, peripheral neuropathy, fatigue, diarrhea, pyrexia, decreased appetite, and pneumonia.

Lactation

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

Indication Statement

POLIVY in combination with bendamustine and a rituximab product is indicated for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified, after at least 2 prior therapies.

Accelerated approval was granted for this indication based on complete response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

You may report side effects to the FDA at (800) FDA-1088 orwww.fda.gov/medwatch. Youmay also report side effects to Genentech at (888) 835-2555.

Please see fullPrescribing Informationfor additional Important SafetyInformation.