DR. CHANDRA BELANI: Hello there! I’m Doctor Chandra Belani, Professor of Medicine. For this video, I am joined by my colleague Doctor Balmanoukian.

DR. ANI BALMANOUKIAN: Hi, I am Doctor Ani Balmanoukian, Director of Thoracic Oncology and Associate Director of the Phase I Immune-oncology Program at the Angeles Clinic and Research Institute.

DR. CHANDRA BELANI: During this video, Doctor Balmanoukian and I would like to highlight the efficacy results from IMpower 133 trial, as well as some TECENTRIQ-important safety information. TECENTRIQ with carboplatin and etoposide is the first FDA-approved cancer immune therapy combination for the first line treatment of adult patients with extensive stage small cell lung cancer.

DR. ANI BALMANOUKIAN: Atezolizumab (TECENTRIQ) with carboplatin and etoposide is a preferred immunotherapy, chemotherapy option in the NCCN guidelines with a Category One recommendation for first line treatment of patients with extensive stage small cell lung cancer. Now, we will review some disclaimers.

This program is presented on behalf of Genentech and the information presented is consistent with FDA guidelines. We have been compensated by Genentech to serve as speakers for this program. This program is intended to provide general information about TECENTRIQ, and not medical advice for any particular patient. Any adverse events included in this presentation today have already been reported to Genentech Drug Safety, and no action is required by any member of the audience. This program may be monitored by Genentech for adherence to program requirements. All materials are the property of Genentech and may not be recorded, photographed, copied, or reproduced.

We reviewed the IMpower 133 study design in one of the other videos in the series, but as a reminder, IMpower 133 was a Phase III multi-center randomized double blind placebo-controlled trial in patients who had received no prior chemotherapy for extensive stage small cell lung cancer. The total number of patients was 403. Patients were randomized one to one to induction treatment with either TECENTRIQ or placebo in combination with carboplatin and etoposide followed by maintenance with TECENTRIQ or placebo alone until disease progression or unacceptable toxicity.

DR. CHANDRA BELANI: Overall survival was one of the co-primary endpoints of the IMpower 133 study. TECENTRIQ with carboplatin and etoposide was the first immunotherapy combination to demonstrate superior overall survival in first line extensive stage small cell lung cancer. This combination resulted in a 33 percent reduction in the risk of death.

DR. ANI BALMANOUKIAN: As you can see with the Kaplan Meier overall survival curves, the median overall survival in the TECENTRIQ with carboplatin and etoposide arm was 12.3 months compared with 10.3 months in the placebo with carboplatin and etoposide arm. Furthermore, the hazard ration was 0.70 with a P value of 0.0069. This is a significant overall survival benefit in first line extensive stage small cell lung cancer where there hadn’t been a new FDA-approved treatment option in 20 years.

DR. CHANDRA BELANI: Looking at the progression-free survival, the other co-primary endpoint in the trial, we find that adding TECENTRIQ to carboplatin and etoposide significantly improved median progression-free survival. The median progression-free survival was 5.02 months in the TECENTRIQ arm with carboplatin and etoposide, and 4.3 months in the placebo with carboplatin and etoposide arm with a hazard of 0.77 and a P value of 0.017. Response rates were similar in both arms.

Additional survival data based on a median follow up of 22.9 months are also available. This exploratory landmark analysis includes 12 and 24-month overall survival rates, which were pre-specified secondary endpoints; and an 18-month overall survival rate, which was exploratory. These analyses are not powered to demonstrate statistically significant differences, and no conclusions can be drawn.

DR. ANI BALMANOUKIAN: Let’s take a look then. We can see that 53 percent of patients treated with TECENTRIQ with carboplatin and etoposide and 39 percent of those treated with placebo with carboplatin and etoposide were alive at one year. At the exploratory 18-month time point, patients treated with TECENTRIQ with carboplatin and etoposide had an overall survival rate of 34 percent. And those treated with placebo with carboplatin and etoposide had an overall survival rate of 21 percent. And at two years, overall survival rates for the two groups

[00:05:00]

were 22 percent and 17 percent respectively. Of note, these 24-month overall survival rates may be subject to change with longer follow up. The safety observed in this updated analysis was generally consistent with the safety observed in the initial analysis.

DR. CHANDRA BELANI: Doctor Balmanoukian, what are your thoughts on these results?

DR. ANI BALMANOUKIAN: Overall, these efficacy data are encouraging, since survival rates are an important consideration when making a treatment decision.

Here are the adverse reactions occurring in at least 20 percent of patients in the IMpower 133 trial. Serious adverse reactions occurred in 37 percent of patients with TECENTRIQ. The most frequent ones, those occurring in more than two percent of patients were pneumonia, neutropenia, fibral neutropenia, and thrombocytopenia. TECENTRIQ was discontinued due to adverse reactions in 11 percent of patients. Adverse reactions to interruption of TECENTRIQ occurred in 59 percent of patients. Four patients, or two percent who were treated with TECENTRIQ with carboplatin and etoposide experienced fatal adverse reactions. These included pneumonia, respiratory failure, neutropenia and death. Taken as a whole, the safety observed was consistent with the established TECENTRIQ safety profile.

AUTOMATED VOICE: Please refer to the full prescribing information for important dose management information specific to adverse reactions. TECENTRIQ is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death-receptor one (PD-1) or the PD-ligand one (PD-L1) blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. The following immune-mediated adverse reactions may not include all possible, severe and fatal immune-mediated reactions. Immune-mediated adverse reactions can occur in any organ system or tissue and at any time after starting a PD-1/PD-L1 blocking antibody. While immune-mediated adverse reactions usually manifest during treatment with PD-1/PD-L1 blocking antibodies, they can also manifest after discontinuation of treatment. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate liver enzymes, creatinine, and thyroid function at baseline, and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate. Withhold or permanently discontinue TECENTRIQ depending on severity. In general, if TECENTRIQ requires interruption or discontinuation, administer systemic corticosteroid therapy at a dose of one to two milligrams per kilogram per day, Prednisone or equivalent until improvement to Grade One or less. Then, initiate corticosteroid taper and continue to taper over at least one month. Consider administration of other systemic immune-suppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy.

TECENTRIQ can cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in three percent in patients receiving TECENTRIQ as a single agent, including fatal, Grade Four, Grade Three, and Grade Two adverse reactions. Pneumonitis led to permanent discontinuation of TECENTRIQ in 0.5 percent and withholding of TECENTRIQ in 1.5 percent of patients. Systemic corticosteroids were required in 55 percent of patients with pneumonitis.

TECENTRIQ can cause immune-mediated colitis. Colitis can present with diarrhea, abdominal pain, and lower gastrointestinal bleeding. Cytomegalovirus infection reactivation has been reported in patients with corticosteroid, refractory, immune-mediated colitis. In cases of corticosteroid refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in one percent of patients receiving TECENTRIQ as a single agent, including Grade Three and Grade Two adverse reactions. Colitis led to permanent discontinuation of TECENTRIQ in 0.2 percent and withholding of TECENTRIQ in 0.5

[00:10:00]

percent of patients. Systemic corticosteroids were required in 50 percent of patients with colitis. Colitis resolved in 73 percent of the 26 patients. Of the 12 patients in whom TECENTRIQ was withhold for colitis, eight reinitiated treatment with TECENTRIQ after symptom improvement. Of these, 25 percent had recurrence of colitis.

TECENTRIQ can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 1.8 percent of patients receiving TECENTRIQ as a single agent, including fatal, Grade Four, Grade Three and Grade Two adverse reactions. Hepatitis led to permanent discontinuation of TECENTRIQ in 0.2 percent and withholding of TECENTRIQ in 0.2 percent of patients. Systemic corticosteroids were required in 25 percent of patients with hepatitis. Hepatitis resolved in 50 percent of the 48 patients. Of the six patients in whom TECENTRIQ was withheld for hepatitis, four reinitiated treatment with TECENTRIQ after symptom improvement. Of these, none had recurrence of hepatitis.

TECENTRIQ can cause primary or secondary adrenal insufficiency. For Grade Two or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Adrenal insufficiency occurred in 0.4 percent of patients receiving TECENTRIQ as a single agent, including Grade Three and Grade Two adverse reactions. Adrenal insufficiency led to permanent discontinuation of TECENTRIQ in one patient and withholding of TECENTRIQ in one patient. Systemic corticosteroids were required in 81 percent of patients with adrenal insufficiency. Of these, three patients remained on systemic corticosteroids. The single patient in whom TECENTRIQ was withhold for adrenal insufficiency did not reinitiate TECENTRIQ.

TECENTRIQ can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia or visual field cuts. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as clinical indicated. Hypophysitis occurred in less than 0.1 percent of patients receiving TECENTRIQ as a single agent, including Grade Two adverse reactions. Hypophysitis led to permanent discontinuation of TECENTRIQ in one patient and no patients required withholding of TECENTRIQ. Systemic corticosteroids were required in 50 percent of patients with hypophysitis. Hypophysitis did not resolve in these two patients.

TECENTRIQ can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or medical management for hyperthyroidism as clinically indicated. Thyroiditis occurred in 0.2 percent of patients receiving TECENTRIQ as a single agent including Grade Two adverse reactions. Thyroiditis did not lead to permanent discontinuation of TECENTRIQ in any of these patients but led to withholding of TECENTRIQ in one patient. Hormone replacement therapy was required in 75 percent of patients with thyroiditis. Systemic corticosteroids were required in 25 percent of patients with thyroiditis. Thyroiditis resolved in 50 percent of patients. The single patient in whom TECENTRIQ was withhold for thyroiditis reinitiated TECENTRIQ. This patient did not have recurrence of thyroiditis.

Hyperthyroidism occurred in 0.8 percent of patients receiving TECENTRIQ as a single agent including Grade Two adverse reactions. Hypothyroidism did not lead to permanent discontinuation of TECENTRIQ in any of these patients but led to withholding of TECENTRIQ in 0.1 percent of patients. Anti-thyroid therapy was required in 29 percent of patients with hyperthyroidism. Of these six patients, the majority remained on anti-thyroid treatment. Of the three patients in whom TECENTRIQ was withheld for hyperthyroidism, one patient reinitiated TECENTRIQ. This patient did not have recurrence of hyperthyroidism.

Hypothyroidism occurred in 4.9 percent of patients receiving TECENTRIQ as a single agent including Grade Three and Grade Two adverse reactions. Hypothyroidism did not lead to permanent discontinuation of TECENTRIQ in any of these patients but led to withholding of TECENTRIQ in 0.6 percent of patients. Hormone replacement therapy was required in 81 percent of patients with hypothyroidism. The majority of patients with hypothyroidism remained on thyroid hormone replacement. Of the 17 patients in whom TECENTRIQ was withheld

[00:15:00]

for hypothyroidism, eight reinitiated TECENTRIQ after symptom improvement. Hypothyroidism occurred in 11 percent of patients with non-small cell lung cancer and small cell lung cancer, receiving TECENTRIQ in combination with platinum-based chemotherapy including Grade Four, Grade Three and Grade Two adverse reactions. Hypothyroidism led to permanent discontinuation of TECENTRIQ in 0.1 percent and withholding of TECENTRIQ in 1.6 percent of patients. Hormone replacement therapy was required in 71 percent of patients with hypothyroidism. The majority of patients with hypothyroidism remained on thyroid hormone replacement. Of the 39 patients in whom TECENTRIQ was withheld for hypothyroidism, nine reinitiated TECENTRIQ after symptom improvement.

For Type I diabetes Meletus, which can present with diabetic ketoacidosis, monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Type I diabetes Meletus occurred in 0.3 percent of patients receiving TECENTRIQ as a single agent including Grade Three and Grade Two adverse reactions. Type I diabetes Meletus led to permanent discontinuation of TECENTRIQ in one patient and withholding of TECENTRIQ in two patients. Treatment with insulin was required for all patients with confirmed Type I diabetes Meletus, and insulin therapy was continued long term. Of the two patients in whom TECENTRIQ was withhold for Type I diabetes Meletus, both reinitiated TECENTRIQ treatment.

TECENTRIQ can cause immune-mediated nephritis. Immune-mediated nephritis with renal dysfunction occurred in less than 0.1 percent of patients receiving TECENTRIQ as a single agent, and this adverse reaction was a Grade Three adverse reaction. Nephritis led to permanent discontinuation of TECENTRIQ in this patient. This patient required systemic corticosteroids. In this patient, nephritis did not resolve.

TECENTRIQ can cause immune-mediated rash and dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome, DRESS and toxic epidermal necrolysis has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat to mild to moderate non-exfoliative rashes. Immune-mediated dermatologic adverse reactions occurred in 0.6 percent of patients receiving TECENTRIQ as a single agent including Grade Three and Grade Two adverse reactions. Dermatologic adverse reactions led to permanent discontinuation of TECENTRIQ in 0.1 percent and withholding of TECENTRIQ in 0.2 percent of patients. Systemic corticosteroids were required in 20 percent of patients with dermatologic adverse reactions. Dermatologic adverse reactions resolved in 87 percent of the 15 patients. Of the four patients in whom TECENTRIQ was withheld for immune-mediated dermatologic adverse reactions, none reinitiated TECENTRIQ.

The following clinically significant immune-mediated adverse reactions occurred at an incidence of less than one percent in patients who received TECENTRIQ or were reported with the use of other PD-1/PD-L1 blocking antibodies. Cardiac/vascular: Myocarditis, pericarditis, vasculitis. Nervous system: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome, myasthenia gravis including exacerbation, Guillain-Barre syndrome, nerve paresis, autoimmune neuropathy. Ocular: Uveitis, iritis and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment including blindness can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss. Gastrointestinal: Pancreatitis to include increases in serum amylase and lipase levels, gastritis, duodenitis. Musculoskeletal and Connective Tissue: Myositis/polymyositis, rhabdomyolysis and associated sequelae including renal failure, arthritis, polymyalgia rheumatic. Endocrine: Hypoparathyroidism. Other: Hematologic or immune: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis, sarcoidosis, immune thrombocytopenic purpura,

[00:20:00]

solid organ transplant rejection.

TECENTRIQ can cause severe or life-threatening infusion-related reactions. Monitor for signs and symptoms of infusion-related reactions. Interrupt, slow the rate of, or permanently discontinue TECENTRIQ based on the severity. For Grade One or Two infusion-related reactions, consider using pre-medications with subsequent doses. Infusion-related reactions occurred in 1.3 percent of patients receiving TECENTRIQ as a single agent, including Grade Three reactions. The frequency and severity of infusion-related reactions were similar, whether TECENTRIQ was given as a single agent, in combination with other anti-neoplastic drugs in non-small cell lung cancer and small cell lung cancer, and across the recommended dose range. Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation before or after being treated with a PD-1/PD-L1 blocking antibody. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease after reduced intensity conditioning and steroid-requiring febrile syndrome. These complications may occur despite intervening therapy between PD-!/PD-L1 blockage and allogeneic HSCT. Follow patients closely for evidence of transplant-related complications, and intervene promptly. Consider the benefits versus risks of treatment with a PD-1/PD-L1 blocking antibody prior to or after an allogeneic HSCT.

Based on its mechanism of action, TECENTRIQ can cause fetal harm when administered to a pregnant woman. There are no available data on the use of TECENTRIQ in pregnant women. Animal studies have demonstrated that inhibition of the PD-L1/PD-1 pathway can lead to increased risk of immune-related rejection of the developing fetus, resulting in fetal death. Verify pregnancy status of females of reproductive potential prior to initiating TECENTRIQ. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment with TECENTRIQ and for at least five months after the last dose. There is no information regarding the presence of TECENTRIQ in human milk, the effects on the breastfed infant, or the effects on milk production. As human IGG is excreted in human milk, the potential for absorption and harm to the infant is unknown. Because of the potential for serious adverse reactions in breastfed infants from TECENTRIQ, advise female patients not to breastfeed while taking TECENTRIQ and for at least five months after the last dose. Based on animal studies, TECENTRIQ may impair fertility in females of reproductive potential while receiving treatment.

The most common adverse reactions occurring in at least 20 percent in patients who received TECENTRIQ in combination with other antineoplastic drugs for non-small cell lung cancer and small cell lung cancer were fatigue/asthenia, nausea, alopecia, constipation, diarrhea, and decreased appetite. You may report side -

DR. CHANDRA BELANI: Hello there! I’m Doctor Chandra Belani, Professor of Medicine. For this video, I am joined by my colleague, Doctor Balmanoukian.

DR. ANI BALMANOUKIAN: Hi, I am Doctor Ani Balmanoukian, Director of Thoracic Oncology and Associated Director of the Phase I Immune-oncology Program at the Angeles Clinic and Research Institute.

DR. CHANDRA BELANI: TECENTRIQ with carboplatin and etoposide is the first FDA-approved cancer immunotherapy combination for the first line treatment of adult patients with extensive small cell lung cancer.

DR. ANI BALMANOUKIAN: Atezolizumab (TECENTRIQ) with carboplatin and etoposide is a preferred immunotherapy, chemotherapy option in the NCCN guidelines with a Category One recommendation for first line treatment of patients with extensive stage small cell lung cancer. Dr. Belani and I would now like to talk to you about the small cell lung cancer landscape, the IMpower 133 Study Design and some important safety information from the TECENTRIQ prescribing information.

DR. CHANDRA BELANI: First, we will review some disclaimers. This program is presented on behalf of Genentech and the information presented is consistent with FDA guidelines. We have been compensated by Genentech to serve as speakers for this program. This program is intended to provide general information about TECENTRIQ, and not medical advice for any particular patient. Any adverse events included in this presentation today have already been reported to Genentech Drug Safety, and no action is required by any member of the audience. This program may be monitored by Genentech for adherence to the program requirements. All materials are property of Genentech and may not be recorded, photographed, copied, or reproduced.

DR. ANI BALMANOUKIAN: Over the years, therapeutic progress in small cell lung cancer has been limited. Platinum-based therapy, with or without radio therapy, has been the standard of care for 30 years. And while there’s typically a dramatic response to initial therapy, most patients experience recurring disease.

DR. CHANDRA BELANI: That’s right. Outcomes have not changed dramatically in some time. There have been a number of Phase III trials since the 1970s evaluating novel agents, but there haven't been any additional FDA approvals, specifically in the first line small cell lung cancer apart from chemotherapy in the last four decades.

DR. ANI BALMANOUKIAN: Although progress has been limited for patients for some time, in 2019, the FDA approved the first treatment for first line extensive stage small cell lung cancer in 20 years.

DR. CHANDRA BELANI: The landmark IMpower 133 Trial led to the approval of TECENTRIQ with carboplatin and etoposide. IMpower 133 was a Phase III trial conducted in patients with previously untreated extensive small cell lung cancer. The patients were randomized one is to one. The induction with TECENTRIQ or placebo in combination with carboplatin and etoposide followed by maintenance with TECENTRIQ or placebo until disease progression or unacceptable toxicity.

DR. ANI BALMANOUKIAN: The co-primary endpoints were overall survival and investigator-assessed progression-free survival. Secondary endpoints included 12 month overall survival rate and investigator-assessed objective response rate.

DR. CHANDRA BELANI: We’ve talked about efficacy and safety results from IMpower 133 in other videos in our series.

AUTOMATED VOICE: Please refer to the full prescribing information for important dose management information specific to adverse reactions. TECENTRIQ is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death-receptor one (PD-1) or the PD-ligand one (PD-L1) blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Important to immune-mediated adverse reactions listed under warnings and precautions may not include all possible severe and fatal immune-mediated reactions. Immune-mediated adverse reactions can occur in any organ system or tissue and at any time after starting a PD-1/PD-L1 blocking antibody. While immune-mediated adverse reactions usually manifest during treatment with PD-1/PD-L1 blocking antibodies, they can also manifest after discontinuation of treatment. Early identification and management of immune mediated adverse reactions are essential to ensure safe use of PD-1/PD-L1 blocking antibodies. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. In

[00:05:00]

general, if TECENTRIQ requires interruption or discontinuation, administer systemic corticosteroid therapy at a dose of one to two milligrams per kilogram per day—Prednisone or equivalent—until improvement to Grade One or less. Then initiative corticosteroid taper and continue to taper over at least one month. Consider administration of other systemic immune-suppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy.

TECENTRIQ can cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in three percent in patients receiving TECENTRIQ as a single agent, including fatal, Grade Four, Grade Three, and Grade Two adverse reactions. TECENTRIQ can cause immune-mediated colitis. Colitis can present with diarrhea, abdominal pain and lower gastrointestinal bleeding. Cytomegalovirus infection reactivation has been reported in patients with corticosteroid, refractory, immune-mediated colitis. In cases of corticosteroid refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in one percent of patients receiving TECENTRIQ as a single agent, including Grade Three and Grade Two adverse reactions. TECENTRIQ can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 1.8 percent of patients receiving TECENTRIQ as a single agent, including fatal, Grade Four, Grade Three and Grade Two adverse reactions. TECENTRIQ can cause primary or secondary adrenal insufficiency. For Grade Two or higher adrenal insufficiency, initiate symptomatic treatment, including hormone treatment as clinically indicated. Adrenal insufficiency occurred in 0.4 percent of patients receiving TECENTRIQ as a single agent, including Grade Three and Grade Two adverse reactions. TECENTRIQ can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia or visual field cuts. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as clinical indicated. Hypophysitis occurred in less than 0.1 percent of patients receiving TECENTRIQ as a single agent, including Grade Two adverse reactions. TECENTRIQ can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or medical management for hyperthyroidism as clinically indicated. Thyroiditis occurred in 0.2 percent of patients receiving TECENTRIQ as a single agent including Grade Two adverse reactions. Hyperthyroidism occurred in 0.8 percent of patients receiving TECENTRIQ as a single agent including Grade Two adverse reactions. Hypothyroidism occurred in 4.9 percent of patients receiving TECENTRIQ as a single agent including Grade Three and Grade Two adverse reactions. Hypothyroidism occurred in 11 percent of patients with non-small cell lung cancer and small cell lung cancer. Receiving TECENTRIQ in combination with platinum-based chemotherapy including Grade Four, Grade Three and Grade Two adverse reactions.

For Type I diabetes Meletus, which can present with diabetic ketoacidosis, initiate treatment with insulin as clinically indicated. Type I diabetes Meletus occurred in 0.3 percent of patients receiving TECENTRIQ as a single agent including Grade Three and Grade Two adverse reactions. TECENTRIQ can cause immune-mediated nephritis. Immune-mediated nephritis with renal dysfunction occurred in less than 0.1 percent of patients receiving TECENTRIQ as a single agent, and this adverse reaction was a Grade Three adverse reaction. TECENTRIQ can cause immune-mediated rash and dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome, DRESS and toxic epidermal necrolysis has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat to mild to moderate non-exfoliative rashes. Immune-mediated dermatologic adverse reactions occurred in 0.6 percent of patients receiving TECENTRIQ as a single agent including Grade Three and Grade Two adverse reactions.

The following clinically significant immune-mediated adverse reactions occurred at an incidence of less than one percent in patients who received TECENTRIQ or were reported with

[00:10:00]

the use of other PD-1/PD-L1 blocking antibodies. Cardiac/vascular: Myocarditis, pericarditis, vasculitis. Nervous system: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome, myasthenia gravis including exacerbation, Guillain-Barre syndrome, nerve paresis, autoimmune neuropathy. Ocular: Uveitis, iritis and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment, various grades of visual impairment including blindness can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss. Gastrointestinal: Pancreatitis to include increase in serum amylase and lipase levels, gastritis, duodenitis. Musculoskeletal and Connective Tissue: Myositis/polymyositis, rhabdomyolysis and associated sequelae including renal failure, arthritis, polymyalgia rheumatic. Endocrine: Hypoparathyroidism. Other (hematologic or immune): Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis, sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

TECENTRIQ can cause severe or life-threatening infusion-related reactions. Interrupt, slow the rate of infusion or permanently discontinue based on severity. Infusion-related reactions occurred in 1.3 percent of patients including Grade Three reactions. Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after being treated with a PD-1/PD-L1 blocking antibody. Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefits versus risks of treatment with a PD-1/PD-L1 blocking antibody prior to or after an allogeneic HSCT.

TECENTRIQ can cause fetal harm when administered to a pregnant woman. Verify pregnancy status of females of reproductive potential prior to initiating TECENTRIQ. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment with TECENTRIQ and for at least five months after the last dose.

The most common adverse reactions of at least 20 percent in patients who received TECENTRIQ in combination with other antineoplastic drugs for non-small cell lung cancer and small cell lung cancer were fatigue/asthenia, nausea, alopecia, constipation, diarrhea, and decreased appetite. Advise female patients not to breastfeed during treatment and for at least five 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 prescribing information for additional important safety information.

DR. ANI BALMANOUKIAN: Hello there! If you already listened to the other videos in this series, you’ll recognize that I am Dr. Ani Balmanoukian, Director of Thoracic Oncology and Associate Director of the Phase I Immune-Oncology Program at the Angeles Clinic and Research Institute. TECENTRIQ with carboplatin and etoposide is the first FDA-approved cancer immunotherapy combination for the first line treatment of adult patients with extensive stage small cell lung cancer.

Atezolizumab (TECENTRIQ) with carboplatin and etoposide is a preferred immunotherapy, chemotherapy option in the NCCN guidelines with a Category One recommendation for first line treatment of patients with extensive stage small cell lung cancer. I would now like to take this time to talk to you about the IMpower133 safety data.

First, we will review some disclaimers. This program is presented on behalf of Genentech and the information presented is consistent with FDA guidelines. I have been compensated by Genentech to serve as a speaker for this program. This program is intended to provide general information about TECENTRIQ and not medical advice for any particular patient. Any adverse events included in this presentation today have already been reported to Genentech Drug Safety, and no action is required by any member of the audience. This program may be monitored by Genentech for adherence to the program requirements. All materials are the property of Genentech and may not be recorded, photographed, copied, or reproduced.

Let’s look at immune-related adverse reactions from IMpower133. It is important to recognize and treat immune-related adverse reactions associated with cancer immunotherapy. Early identification and management are critical in helping to prevent serious treatment-related adverse effects. The immune-related adverse reactions occurring in more than one percent of patients receiving TECENTRIQ with carboplatin and etoposide were rash, hypothyroidism, hepatitis via diagnosis, hepatitis via laboratory abnormalities, infusion-related reactions, hyperthyroidism, pneumonitis, and colitis.

Here are the adverse reactions occurring in at least 20 percent of patients in the IMpower133 trial. Serious adverse reactions occurred in 37 percent of patients treated with TECENTRIQ. The most frequent occurring in more than two percent of patients were pneumonia, neutropenia, febrile neutropenia, and thrombocytopenia. TECENTRIQ was discontinued due to adverse reactions in 11 percent of patients. Adverse reactions leading to interruption of TECENTRIQ occurred in 59 percent of patients. Four patients, or two percent who were treated with TECENTRIQ with carboplatin and etoposide experienced fatal adverse reactions. These included pneumonia, respiratory failure, neutropenia, and death.

Taken as a whole, the safety observed was consistent with the established TECENTRIQ safety profile.

This table highlights laboratory abnormalities occurring in at least 20 percent of patients in IMpower133. Hematologic abnormalities noted were anemia, neutropenia, thrombocytopenia, and lymphopenia. In addition, abnormalities in serum chemistries were hyperglycemia, increased alkaline phosphatase, hyponatremia, hypoalbuminemia, and decreased TSH.

Additional laboratory abnormalities and serum chemistries were hypomagnesemia, hypocalcemia, increased ALT, increased AST, increased blood creatinine, hyperphosphatemia, and increased TSH.

AUTOMATED VOICE: Please refer to the full prescribing information for important dose management information specific to adverse reactions. TECENTRIQ is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death-receptor one (PD-1) or the PD-ligand one (PD-L1) blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Important to immune-mediated adverse reactions listed under warnings and precautions may not include all possible severe and fatal immune-mediated reactions. Immune-mediated adverse reactions can occur in any organ system or tissue and at any time after starting a PD-1/PD-L1 blocking antibody. While immune-mediated adverse reactions usually manifest during treatment with PD-1/PD-L1 blocking antibodies, they can also manifest after discontinuation of treatment.

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Early identification and management of immune mediated adverse reactions are essential to ensure safe use of PD-1/PD-L1 blocking antibodies. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. In general, if TECENTRIQ requires interruption or discontinuation, administer systemic corticosteroid therapy at a dose of one to two milligrams per kilogram per day—Prednisone or equivalent—until improvement to Grade One or less. Then initiate corticosteroid taper and continue to taper over at least one month. Consider administration of other systemic immune-suppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy.

TECENTRIQ can cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in three percent in patients receiving TECENTRIQ as a single agent, including fatal, Grade Four, Grade Three, and Grade Two adverse reactions. TECENTRIQ can cause immune-mediated colitis. Colitis can present with diarrhea, abdominal pain and lower gastrointestinal bleeding. Cytomegalovirus infection reactivation has been reported in patients with corticosteroid, refractory, immune-mediated colitis. In cases of corticosteroid refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in one percent of patients receiving TECENTRIQ as a single agent, including Grade Three and Grade Two adverse reactions. TECENTRIQ can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 1.8 percent of patients receiving TECENTRIQ as a single agent, including fatal, Grade Four, Grade Three and Grade Two adverse reactions. TECENTRIQ can cause primary or secondary adrenal insufficiency. For Grade Two or higher adrenal insufficiency, initiate symptomatic treatment, including hormone treatment as clinically indicated. Adrenal insufficiency occurred in 0.4 percent of patients receiving TECENTRIQ as a single agent, including Grade Three and Grade Two adverse reactions. TECENTRIQ can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia. or visual field cuts. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as clinically indicated. Hypophysitis occurred in less than 0.1 percent of patients receiving TECENTRIQ as a single agent, including Grade Two adverse reactions. TECENTRIQ can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or medical management for hyperthyroidism as clinically indicated. Thyroiditis occurred in 0.2 percent of patients receiving TECENTRIQ as a single agent including Grade Two adverse reactions. Hyperthyroidism occurred in 0.8 percent of patients receiving TECENTRIQ as a single agent including Grade Two adverse reactions. Hypothyroidism occurred in 4.9 percent of patients receiving TECENTRIQ as a single agent including Grade Three and Grade Two adverse reactions. Hypothyroidism occurred in 11 percent of patients with non-small cell lung cancer and small cell lung cancer, receiving TECENTRIQ in combination with platinum-based chemotherapy including Grade Four, Grade Three and Grade Two adverse reactions.

For Type I diabetes Meletus, which can present with diabetic ketoacidosis, initiate treatment with insulin as clinically indicated. Type I diabetes Meletus occurred in 0.3 percent of patients receiving TECENTRIQ as a single agent including Grade Three and Grade Two adverse reactions. TECENTRIQ can cause immune-mediated nephritis. Immune-mediated nephritis with renal dysfunction occurred in less than 0.1 percent of patients receiving TECENTRIQ as a single agent, and this adverse reaction was a Grade Three adverse reaction. TECENTRIQ can cause immune-mediated rash and dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome, DRESS and toxic epidermal necrolysis has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat to mild to moderate non-exfoliative rashes. Immune-mediated dermatologic adverse reactions occurred in 0.6

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percent of patients receiving TECENTRIQ as a single agent including Grade Three and Grade Two adverse reactions.

The following clinically significant immune-mediated adverse reactions occurred at an incidence of less than one percent in patients who received TECENTRIQ or were reported with the use of other PD-1/PD-L1 blocking antibodies. Cardiac/vascular: Myocarditis, pericarditis, vasculitis. Nervous system: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome, myasthenia gravis including exacerbation, Guillain-Barre syndrome, nerve paresis, autoimmune neuropathy. Ocular: Uveitis, iritis and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment including blindness can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss. Gastrointestinal: Pancreatitis to include increases in serum amylase and lipase levels, gastritis, duodenitis. Musculoskeletal and Connective Tissue: Myositis/polymyositis, rhabdomyolysis and associated sequelae including renal failure, arthritis, polymyalgia rheumatic. Endocrine: Hypoparathyroidism. Other (hematologic or immune): Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis, sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

TECENTRIQ can cause severe or life-threatening infusion-related reactions. Interrupt, slow the rate of infusion or permanently discontinue based on severity. Infusion-related reactions occurred in 1.3 percent of patients including Grade Three reactions. Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after being treated with a PD-1/PD-L1 blocking antibody. Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefits versus risks of treatment with a PD-1/PD-L1 blocking antibody prior to or after an allogeneic HSCT.

TECENTRIQ can cause fetal harm when administered to a pregnant woman. Verify pregnancy status of females of reproductive potential prior to initiating TECENTRIQ. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment with TECENTRIQ and for at least five months after the last dose.

The most common adverse reactions of at least 20 percent in patients who received TECENTRIQ in combination with other antineoplastic drugs for non-small cell lung cancer and small cell lung cancer were fatigue/asthenia, nausea, alopecia, constipation, diarrhea, and decreased appetite. Advise female patients not to breastfeed during treatment and for at least five 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 prescribing information for additional important safety information.