ES-SCLC video series

DR. MARK SOCINSKI: Hello and welcome. My name is Dr. Mark Socinski, and I'm the Executive Medical Director of the AdventHealth Cancer Institute in Orlando, Florida. I've been a lifelong thoracic medical oncologist. I'm here today with my colleague, Dr. Tarek Mekhail. 

DR. TAREK MEKHAIL: Oh, hi, I'm Tarek Mekhail. I'm the Associate Medical Director of the AdventHealth Cancer Institute. I work with Dr. Socinski every day, and I am, too, a thoracic medical oncologist.

DR. MARK SOCINSKI: For today's discussion, we'll be talking about the data in real-world experience with TECENTRIQ, or atezolizumab, in the treatment of extensive-stage small cell lung cancer.

DR. MARK SOCINSKI: Before we dive in today's discussion, I would like to review some disclaimers. This video 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 video. This video is intended to provide education about TECENTRIQ; it is not medical advice for any particular patient. And all materials are the property of Genentech; it may not be recorded, photographed, copied, or reproduced.

DR. MARK SOCINSKI: As I mentioned, the topic today is extensive-stage small cell lung cancer. We know historically this has been a difficult-to-treat cancer. Two-thirds of patients present with metastatic disease at the time of diagnosis. They typically present with severe symptoms at diagnosis, either symptoms such as cough or chest pain or hemoptysis that are related to disease in the chest, or to disease relative to metastatic disease—symptoms of CNS metastases, liver metastases, or bone metastases.

DR. TAREK MEKHAIL: So, when I see a patient with extensive-stage small cell lung cancer, I need to frame the disease in a way that's realistic but also not discouraging to the patient. Because we know that small cell lung cancer is highly aggressive disease, often fatal, and we need to give a treatment regimen that is efficacious, patients can adhere to, and patients can have some quality of life. We need to focus on safety, we need to focus on flexibility, so that patients can live the life with that disease. 

DR. MARK SOCINSKI: You know, when we think about treatment for this disease, you know, there are several considerations—efficacy of the treatment and safety of the treatment, particularly as it relates to the tolerability, duration of therapy is also important—and it's nice to have flexibility in choosing the regimen to treat these patients. One of the issues that we have faced historically is the duration of treatment. And, you know, let's—typically we draw information from clinical trials. IMpower133 was the pivotal study which led to the approval of TECENTRIQ, the first-line, extensive-stage small cell lung cancer setting.

DR. MARK SOCINSKI: Why don't you tell us a little bit about the design of that trial?

DR. TAREK MEKHAIL: So, the IMpower133 is the Phase III, multicenter, randomized, double-blind, placebo-controlled trial that really compares TECENTRIQ plus carboplatin/etoposide to placebo plus carboplatin/etoposide. And if you think about the study, it had patients that were eligible—good performance status, good organ function, patients couldn't have untreated brain metastases. And the treatment was divided into 2 phases: the induction phase, where patients got TECENTRIQ with chemotherapy versus placebo with chemotherapy for 4 cycles every 3-week cycles, and then the post-induction phase, which patients were either receiving TECENTRIQ maintenance or placebo until progression of disease or until unacceptable toxicity. The real question that we want to address today how long patients were receiving treatment. And if you look at the IMpower133, the median duration of treatment was around 4.7 months, was almost a third of patients still on treatment 6 months down the line. There are some patients who had to discontinue treatment—and that is actually 11%—and the most common reason for discontinuation was infusion-related reactions.

DR. TAREK MEKHAIL: We know that clinical trials have strict inclusion criteria. Can you take us, Mark, through the demographics and inclusion criteria on this particular study?

DR. MARK SOCINSKI: In IMpower133, two-thirds of patients had performance status of 1; those with worse functional scores were excluded. A third of the patients were female, 9% of the patients had brain metastases, and the median age in the study was 64 years. So, what are your thoughts about this population?

DR. TAREK MEKHAIL: I think this is typical of clinical trials. I must say, however, it's not exactly typical of the patients I see every day. There are plenty of patients that

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I see with small cell lung cancer that are actually performance status 2. Patients are diagnosed in the hospital; there are patients who have asymptomatic brain mets. And I'm usually tempted to treat these patients. How would you treat these patients? What are, what's your experience with these patients that don't exactly fit? 

DR. MARK SOCINSKI: It is important to understand the demographics of a patient population included in a Phase III trial. They often are not exactly what we would see in a real-world analysis. And that really underscores the importance of even retrospective real-world analyses, particularly ones that are done in a community oncology setting—obviously, the patient population there, many of them, which might have been excluded from the clinical trial. We do have a real-world experience with TECENTRIQ here and a sample size of 226 patients. The study design was the same protocols as the IMpower133, and this trial really focused on including a diverse patient population and assessing treatment durations. We can't make definitive conclusions about efficacy or safety for this. But in the real-world study, nearly one-quarter of the patients had performance status of 2 or greater, 23% of patients had brain metastases, nearly half of patients were female, and the median age was 68 years, which was about four years older than we saw in 133. 

DR. TAREK MEKHAIL: This is interesting, because as I was looking at the data that you just presented from this particular study, the median duration of treatment is 4.5 months. And I recall that we talked about median duration of treatment of 4.7 months for the IMpower133, so they are quite similar. Clearly, we cannot make conclusions based on that study, but at least it gives us some real-life experience that fits into my patients, as we are treating extensive-stage small cell lung cancer. So clearly, there are some limitations tothis kind of study, no safety or efficacy conclusions can be drawn based on these results. And the findings might not be reflective of all non-community practice settings. There might be some limitations in generalizing this data from outside the clinical trial setting, factors such as ECOG performance status and decisions regarding treatment discontinuation. It's also important to notice that one of the limitations of this particular study is the median follow-up, which was 5.39 months. 

DR. TAREK MEKHAIL: Yeah, so, as we look at the IMpower133, as well as the real-life data, there are many considerations to talk about with the patient regarding the treatment. But what do you think, Mark, about TECENTRIQ dosing and how that would provide flexibility to the patient? 

DR. MARK SOCINSKI: Yeah, and I think that brings up one of the advantages with regard to TECENTRIQ in this setting. The label includes 3 flexible dosing options. This does allow discussions with the patients about their need to determine what that schedule is. Well, you know as well as I know that we all say we want our patients to live their life. And often that might include trips, vacations, family events, these sorts of things. So, it's nice to have that flexibility of the every-2-week, every-3-week, or every-4-week dosing schedule for these patients.

DR. MARK SOCINSKI: So, to summarize today's discussion, we've talked about duration of treatment for TECENTRIQ, in both the IMpower133 and real-world evidence experience. We've reviewed the TECENTRIQ dosing options. So, as we conclude today, Tarek, what are your thoughts on treatment decisions for patients in this setting? 

DR. TAREK MEKHAIL: Well, I feel empowered, because we have now the IMpower133 data as well as the real-world evidence treating patients similar to the patients I'm treating every day in my practice, and certainly I would think that TECENTRIQ should be considered for the appropriate patient. 

DR. MARK SOCINSKI: Well, thank you very much, Dr. Mekhail. And thank you all for joining us today for this discussion. 

DR. TAREK MEKHAIL: Now, please continue watching this video to hear the Important Safety Information.

AUTOMATED VOICE: IMPORTANT SAFETY INFORMATION: 

Severe and Fatal Immune-Mediated Adverse Reactions

TECENTRIQ is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death-receptor 1 (PD-1) or the PD-ligand 1 (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.

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Immune-mediated adverse reactions can occur in any organ system or tissue and at any time after starting TECENTRIQ. While immune-mediated adverse reactions usually manifest during treatment with TECENTRIQ, they can also manifest after discontinuation of treatment. Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of TECENTRIQ.

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 (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less, then initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy.

Immune-Mediated Pneumonitis

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 3% (83/2616) of patients receiving TECENTRIQ alone, including fatal (<0.1%), Grade 4 (0.2%), Grade 3 (0.8%), and Grade 2 (1.1%) adverse reactions. Pneumonitis led to permanent discontinuation of TECENTRIQ in 0.5% and withholding of TECENTRIQ in 1.5% of patients

Systemic corticosteroids were required in 55% (46/83) of patients with pneumonitis. Pneumonitis resolved in 69% of the 83 patients. Of the 39 patients in whom TECENTRIQ was withheld for pneumonitis, 25 reinitiated TECENTRIQ after symptom improvement; of these, 4% had recurrence of pneumonitis

Immune-Mediated Colitis

TECENTRIQ can cause immune-mediated colitis. Colitis can present with diarrhea, abdominal pain, and lower gastrointestinal (GI) bleeding. Cytomegalovirus (CMV) 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 1% (26/2616) of patients receiving TECENTRIQ alone, including Grade 3 (0.5%) and Grade 2 (0.3%) adverse reactions. Colitis led to permanent discontinuation of TECENTRIQ in 0.2% and withholding of TECENTRIQ in 0.5% of patients. Systemic corticosteroids were required in 50% (13/26) of patients with colitis. Colitis resolved in 73% of the 26 patients. Of the 12 patients in whom TECENTRIQ was withheld for colitis, 8 reinitiated TECENTRIQ after symptom improvement; of these, 25% had recurrence of colitis

Immune-Mediated Hepatitis

TECENTRIQ can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 1.8% (48/2616) of patients receiving TECENTRIQ alone, including fatal (<0.1%), Grade 4 (0.2%), Grade 3 (0.5%), and Grade 2 (0.5%) adverse reactions. Hepatitis led to permanent discontinuation of TECENTRIQ in 0.2% and withholding of TECENTRIQ in 0.2% of patients. Systemic corticosteroids were required in 25% (12/48) of patients with hepatitis. Hepatitis resolved in 50% of the 48 patients. Of the 6 patients in whom TECENTRIQ was withheld for hepatitis, 4 reinitiated TECENTRIQ after symptom improvement; of these, none had recurrence of hepatitis

Immune-Mediated Endocrinopathies

Adrenal Insufficiency

TECENTRIQ can cause primary or secondary adrenal insufficiency. 

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For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated

Adrenal insufficiency occurred in 0.4% (11/2616) of patients receiving TECENTRIQ alone, including Grade 3 (<0.1%) and Grade 2 (0.2%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of TECENTRIQ in 1 patient and withholding of TECENTRIQ in 1 patient. Systemic corticosteroids were required in 82% (9/11) of patients with adrenal insufficiency; of these, 3 patients remained on systemic corticosteroids. The single patient in whom TECENTRIQ was withheld for adrenal insufficiency did not reinitiate TECENTRIQ

 Hypophysitis

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 <0.1% (2/2616) of patients receiving TECENTRIQ alone, including Grade 2 (1 patient, <0.1%) adverse reactions. Hypophysitis led to permanent discontinuation of TECENTRIQ in 1 patient and no patients required withholding of TECENTRIQ. Systemic corticosteroids were required in 50% (1/2) of patients with hypophysitis. Hypophysitis did not resolve in these 2 patients

Thyroid Disorders

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% (4/2616) of patients receiving TECENTRIQ alone, including Grade 2 (<0.1%) adverse reactions. Thyroiditis did not lead to permanent discontinuation of TECENTRIQ in any of these patients, but led to withholding of TECENTRIQ in 1 patient. Hormone replacement therapy was required in 75% (3/4) of patients with thyroiditis. Systemic corticosteroids were required in 25% (1/4) of patients with thyroiditis. Thyroiditis resolved in 50% of patients. The single patient in whom TECENTRIQ was withheld for thyroiditis reinitiated TECENTRIQ, this patient did not have recurrence of thyroiditis

Hyperthyroidism occurred in 0.8% (21/2616) of patients receiving TECENTRIQ alone, including Grade 2 (0.4%) adverse reactions. Hyperthyroidism did not lead to permanent discontinuation of TECENTRIQ in any of these patients, but led to withholding of TECENTRIQ in 0.1% of patients. Antithyroid therapy was required in 29% (6/21) of patients with hyperthyroidism. Of these 6 patients, the majority remained on antithyroid treatment. Of the 3 patients in whom TECENTRIQ was withheld for hyperthyroidism, 1 patient reinitiated TECENTRIQ; this patient did not have recurrence of hyperthyroidism

Hypothyroidism occurred in 4.9% (128/2616) of patients receiving TECENTRIQ alone, including Grade 3 (0.2%) and Grade 2 (3.4%) 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% of patients. Hormone replacement therapy was required in 81% (104/128) of patients with hypothyroidism. The majority of patients with hypothyroidism remained on thyroid hormone replacement. Of the 17 patients in whom TECENTRIQ was withheld for hypothyroidism, 8 reinitiated TECENTRIQ after symptom improvement

Hypothyroidism occurred in 11% (277/2421) of patients with NSCLC and SCLC receiving TECENTRIQ in combination with platinum-based chemotherapy, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (5.7%) adverse reactions. Hypothyroidism led to permanent discontinuation of TECENTRIQ in 0.1% and withholding of TECENTRIQ in 1.6% of patients. Hormone replacement therapy was required in 71% (198/277) of patients with hypothyroidism. The majority of patients with hypothyroidism

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remained on thyroid hormone replacement. Of the 39 patients in whom TECENTRIQ was withheld for hypothyroidism, 9 reinitiated TECENTRIQ after symptom improvement

Type 1 Diabetes Mellitus, 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 1 diabetes mellitus occurred in 0.3% (7/2616) of patients receiving TECENTRIQ alone, including Grade 3 (0.2%) and Grade 2 (<0.1%) adverse reactions. Type 1 diabetes mellitus led to permanent discontinuation of TECENTRIQ in 1 patient and withholding of TECENTRIQ in 2 patients. Treatment with insulin was required for all patients with confirmed Type 1 diabetes mellitus and insulin therapy was continued long-term. Of the 2 patients in whom TECENTRIQ was withheld for Type 1 diabetes mellitus, both reinitiated TECENTRIQ treatment

Immune-Mediated Nephritis With Renal Dysfunction

TECENTRIQ can cause immune-mediated nephritis

Immune-mediated nephritis with renal dysfunction occurred in <0.1% (1/2616) of patients receiving TECENTRIQ alone, and this adverse reaction was a Grade 3 (<0.1%) adverse reaction. Nephritis led to permanent discontinuation of TECENTRIQ in this patient. This patient required systemic corticosteroids. In this patient, nephritis did not resolve

Immune-Mediated Dermatologic Adverse Reactions

TECENTRIQ can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome (SJS), DRESS, and toxic epidermal necrolysis (TEN), has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes 

Immune-mediated dermatologic adverse reactions occurred in 0.6% (15/2616) of patients receiving TECENTRIQ alone, including Grade 3 (<0.1%) and Grade 2 (0.2%) adverse reactions. Dermatologic adverse reactions led to permanent discontinuation of TECENTRIQ in 0.1% and withholding of TECENTRIQ in 0.2% of patients. Systemic corticosteroids were required in 20% (3/15) of patients with dermatologic adverse reactions. Dermatologic adverse reactions resolved in 87% of the 15 patients. Of the 4 patients in whom TECENTRIQ was withheld for immune-mediated dermatologic adverse reactions, none reinitiated TECENTRIQ

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) 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-Barré 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/Immune): Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection

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Infusion-Related Reactions

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 1 or 2 infusion-related reactions, consider using pre-medications with subsequent doses

Infusion-related reactions occurred in 1.3% of patients receiving TECENTRIQ alone, including Grade 3 (0.2%) reactions

The frequency and severity of infusion-related reactions were similar whether TECENTRIQ was given as a single agent, in combination with other antineoplastic drugs in NSCLC and SCLC, and across the recommended dose range

Complications of Allogeneic HSCT After PD-1/PD-L1 Inhibitors

Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) 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 (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause)

These complications may occur despite intervening therapy between PD-1/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

Embryo-Fetal Toxicity

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 5 months after the last dose

Use in Specific Populations

Nursing Mothers

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 5 months after the last dose

Fertility

Based on animal studies, TECENTRIQ may impair fertility in females of reproductive potential while receiving treatment

Most Common Adverse Reactions

The most common adverse reactions (rate ≥20%) in patients who received TECENTRIQ in combination with other antineoplastic drugs for NSCLC and SCLC were fatigue/asthenia (49%), nausea (38%), alopecia (35%), constipation (29%), diarrhea (28%), and decreased appetite (27%).

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 full Prescribing Information for additional Important Safety Information.

DR. MARK SOCINSKI: Hello and welcome. My name is Dr. Mark Socinski, and I'm the Executive Medical Director of the AdventHealth Cancer Institute in Orlando, Florida, and a thoracic medical oncologist. I'm joined today by my colleague, Dr. Mekhail.

DR. TAREK MEKHAIL: And I'm Tarek Mekhail, Associate Medical Director of the AdventHealth Cancer Institute. I work with Dr. Socinski every day. I am, too, a thoracic medical oncologist. Today we'll be talking about TECENTRIQ, or atezolizumab, in extensive-stage small cell lung cancer.

DR. MARK SOCINSKI: Viewers might be familiar with the pivotal data supporting the use of TECENTRIQ, but there is also additional Phase III data we're taking a closer look at. Before we dive into today's discussion, I would like to review some disclaimers. This video 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 video. This video is intended to provide education about TECENTRIQ; it is not medical advice for any particular patient. And all materials are the property of Genentech; it may not be recorded, photographed, copied, or reproduced. 

DR. MARK SOCINSKI: TECENTRIQ plus carboplatin/etoposide is the first FDA-approved cancer immunotherapy combination in first-line treatment of extensive-stage small cell lung cancer. With 4 years of real-world experience, it is the #1 prescribed treatment. However, the journey to achieving additional FDA-approved options for extensive-stage small cell lung cancer was a long one. Let's explore the history of extensive-stage small cell lung cancer treatment in more detail. 

DR. MARK SOCINSKI: We will be discussing the safety information throughout the program. Please note that the full Warnings and Precautions as well as all other Important Safety Information can be found in the full TECENTRIQ Prescribing Information. 

DR. MARK SOCINSKI: Historically, it's been difficult to identify effective treatments for extensive-stage small cell lung cancer, dating all the way back to 1970. There have been over 40 Phase III trials conducted since 1970, and none gained FDA approvals. And in 2019, TECENTRIQ was the first FDA-approved first-line treatment for extensive-stage small cell lung cancer in over 20 years. Let's take a look at the trial behind that approval.

DR. TAREK MEKHAIL: Yeah, we're talking about IMpower133, which is a Phase III, randomized, placebo-controlled clinical trial of TECENTRIQ plus carboplatin/etoposide versus carboplatin/etoposide plus placebo. You can think about the treatment as 2 phases: the induction phase where patients got TECENTRIQ with carboplatin/etoposide versus placebo carboplatin/etoposide for 4 cycles, and patients who did not progress went on to receive TECENTRIQ versus placebo until progression of disease or unacceptable toxicity. Patients had to be eligible for the clinical trial: ECOG performance status 0 or 1, good organ function, no untreated brain metastasis.

DR. MARK SOCINSKI: So, the median overall survival in the TECENTRIQ plus carboplatin/etoposide arm was 12.3 months versus 10.3 months in the placebo, carbo/etoposide arm. There was a 30% reduction in the risk of death versus the control arm. So TECENTRIQ plus carbo/etoposide was the first IO combination to show a statistically significant improved median PFS, with 5.2 months for patients with TECENTRIQ plus chemotherapy—in this case carbo/etoposide—versus 4.3 months with placebo plus the same chemotherapy. This pivotal data had a median follow-up time of approximately 13.9 months, but the trial continued on. In the pre-specified secondary analysis, 52% of patients treated with TECENTRIQ plus carbo/etoposide, and 39% of those treated with placebo plus carbo/etoposide were alive at 1 year. At 2 years, overall survival rates were 22% for TECENTRIQ plus carbo/etoposide and 17% for placebo plus carbo/etoposide. Data at 2 years were considered unstable and may be subject to change with longer follow-up. Note that these landmark analyses were not powered to demonstrate statistically significant differences, and no conclusions can be drawn from these analyses. Now this data may be familiar to many, but let's note that there are now additional Phase III data for TECENTRIQ in extensive-stage small cell lung cancer.

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DR. TAREK MEKHAIL: Yes, that's the SKYSCRAPER-02 study design. It's another Phase III study that incorporated TECENTRIQ plus carboplatin/etoposide with or without an investigational drug for the treatment of patients with extensive-stage small cell lung cancer. It used enrollment criteria very similar to IMpower133 but allowed the inclusion of patients with untreated asymptomatic brain metastasis. While the experimental arm in SKYSCRAPER-02 did not meet the co-primary endpoints of overall survival and progression-free survival, and the investigational molecule is not FDA approved, the control arm examined TECENTRIQ plus carboplatin/etoposide. Median overall survival for patients in TECENTRIQ plus carboplatin/etoposide control arm was 12.9 months, and median PFS for these same patients was 5.4 months. This additional Phase III data helped support data from the IMpower133.

DR. MARK SOCINSKI: The overall safety observed in the IMpower133 trial and the updated analysis support the established TECENTRIQ safety profile. The safety observed in the updated analysis supports the safety observed in the initial analysis. The most common adverse reactions occurring at a rate of at least 20% in patients who received TECENTRIQ in IMpower133 were fatigue, nausea, alopecia, decreased appetite, constipation, and vomiting. TECENTRIQ was discontinued due to adverse events in 11% of patients. ARs leading to interruption of TECENTRIQ occurred in 59% of patients. Serious ARs occurred in 37% of patients treated with TECENTRIQ. The most frequent serious ARs were pneumonia, neutropenia, febrile neutropenia, and thrombocytopenia. Four patients who were treated with TECENTRIQ plus carbo/etoposide experienced fatal ARs. These included pneumonia, respiratory failure, neutropenia, and death. For SKYSCRAPER-02, the most common adverse reactions in the TECENTRIQ plus carboplatin/etoposide plus placebo arm were anemia, neutropenia, alopecia, nausea, constipation, and neutrophil count decrease. Immune-related adverse reaction in IMpower133 reported in patients receiving TECENTRIQ plus carboplatin/etoposide included rash, hypothyroidism, hepatitis, infusion-related reaction, hyperthyroidism, pneumonitis, and colitis.

DR. TAREK MEKHAIL: So, as we've seen, there is wealth of data supporting TECENTRIQ in extensive-stage small cell lung cancer, and this supported the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) recommendation for small cell lung cancer. And really, after decades of minimal advances in the treatment of extensive-stage small cell lung cancer, the approval of TECENTRIQ for first-line treatment in 2019 represented a step forward in the treatment of this complex disease. We have plenty of data now from the Phase III clinical trial IMpower133, as well as the supportive data from SKYSCRAPER-02. 

DR. TAREK MEKHAIL: Clinical data and more than 4 years of real-world experience continue to keep TECENTRIQ a top-of-mind treatment option for patients with extensive-stage small cell lung cancer. When treating patients with extensive-stage small cell lung cancer, consider the breadth of the data and if TECENTRIQ plus carboplatin/etoposide is an appropriate treatment for your patients.

DR. MARK SOCINSKI: Well, thank you very much for that and thank you, our audience, for joining us today for this. Please continue watching this video to hear the Important Safety Information.

AUTOMATED VOICE: IMPORTANT SAFETY INFORMATION: 

Severe and Fatal Immune-Mediated Adverse Reactions

TECENTRIQ is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death-receptor 1 (PD-1) or the PD-ligand 1 (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 TECENTRIQ. While immune-mediated adverse reactions usually manifest during treatment with TECENTRIQ, they can also manifest after discontinuation of treatment. Early identification and management of immune-mediated adverse reactions 

[00:10:00]

are essential to ensure safe use of TECENTRIQ.

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 (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less, then initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy.

Immune-Mediated Pneumonitis

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 3% (83/2616) of patients receiving TECENTRIQ alone, including fatal (<0.1%), Grade 4 (0.2%), Grade 3 (0.8%), and Grade 2 (1.1%) adverse reactions. Pneumonitis led to permanent discontinuation of TECENTRIQ in 0.5% and withholding of TECENTRIQ in 1.5% of patients

Systemic corticosteroids were required in 55% (46/83) of patients with pneumonitis. Pneumonitis resolved in 69% of the 83 patients. Of the 39 patients in whom TECENTRIQ was withheld for pneumonitis, 25 reinitiated TECENTRIQ after symptom improvement; of these, 4% had recurrence of pneumonitis

Immune-Mediated Colitis

TECENTRIQ can cause immune-mediated colitis. Colitis can present with diarrhea, abdominal pain, and lower gastrointestinal (GI) bleeding. Cytomegalovirus (CMV) 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 1% (26/2616) of patients receiving TECENTRIQ alone, including Grade 3 (0.5%) and Grade 2 (0.3%) adverse reactions. Colitis led to permanent discontinuation of TECENTRIQ in 0.2% and withholding of TECENTRIQ in 0.5% of patients. Systemic corticosteroids were required in 50% (13/26) of patients with colitis. Colitis resolved in 73% of the 26 patients. Of the 12 patients in whom TECENTRIQ was withheld for colitis, 8 reinitiated TECENTRIQ after symptom improvement; of these, 25% had recurrence of colitis

Immune-Mediated Hepatitis

TECENTRIQ can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 1.8% (48/2616) of patients receiving TECENTRIQ alone, including fatal (<0.1%), Grade 4 (0.2%), Grade 3 (0.5%), and Grade 2 (0.5%) adverse reactions. Hepatitis led to permanent discontinuation of TECENTRIQ in 0.2% and withholding of TECENTRIQ in 0.2% of patients. Systemic corticosteroids were required in 25% (12/48) of patients with hepatitis. Hepatitis resolved in 50% of the 48 patients. Of the 6 patients in whom TECENTRIQ was withheld for hepatitis, 4 reinitiated TECENTRIQ after symptom improvement; of these, none had recurrence of hepatitis

Immune-Mediated Endocrinopathies

Adrenal Insufficiency

TECENTRIQ can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated

Adrenal insufficiency occurred in 0.4% (11/2616) of patients receiving TECENTRIQ alone, including Grade 3 (<0.1%) and Grade 2 (0.2%) 

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adverse reactions. Adrenal insufficiency led to permanent discontinuation of TECENTRIQ in 1 patient and withholding of TECENTRIQ in 1 patient. Systemic corticosteroids were required in 82% (9/11) of patients with adrenal insufficiency; of these, 3 patients remained on systemic corticosteroids. The single patient in whom TECENTRIQ was withheld for adrenal insufficiency did not reinitiate TECENTRIQ

Hypophysitis

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 <0.1% (2/2616) of patients receiving TECENTRIQ alone, including Grade 2 (1 patient, <0.1%) adverse reactions. Hypophysitis led to permanent discontinuation of TECENTRIQ in 1 patient and no patients required withholding of TECENTRIQ. Systemic corticosteroids were required in 50% (1/2) of patients with hypophysitis. Hypophysitis did not resolve in these 2 patients

Thyroid Disorders

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% (4/2616) of patients receiving TECENTRIQ alone, including Grade 2 (<0.1%) adverse reactions. Thyroiditis did not lead to permanent discontinuation of TECENTRIQ in any of these patients, but led to withholding of TECENTRIQ in 1 patient. Hormone replacement therapy was required in 75% (3/4) of patients with thyroiditis. Systemic corticosteroids were required in 25% (1/4) of patients with thyroiditis. Thyroiditis resolved in 50% of patients. The single patient in whom TECENTRIQ was withheld for thyroiditis reinitiated TECENTRIQ, this patient did not have recurrence of thyroiditis

Hyperthyroidism occurred in 0.8% (21/2616) of patients receiving TECENTRIQ alone, including Grade 2 (0.4%) adverse reactions. Hyperthyroidism did not lead to permanent discontinuation of TECENTRIQ in any of these patients, but led to withholding of TECENTRIQ in 0.1% of patients. Antithyroid therapy was required in 29% (6/21) of patients with hyperthyroidism. Of these 6 patients, the majority remained on antithyroid treatment. Of the 3 patients in whom TECENTRIQ was withheld for hyperthyroidism, 1 patient reinitiated TECENTRIQ; this patient did not have recurrence of hyperthyroidism

Hypothyroidism occurred in 4.9% (128/2616) of patients receiving TECENTRIQ alone, including Grade 3 (0.2%) and Grade 2 (3.4%) 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% of patients. Hormone replacement therapy was required in 81% (104/128) of patients with hypothyroidism. The majority of patients with hypothyroidism remained on thyroid hormone replacement. Of the 17 patients in whom TECENTRIQ was withheld for hypothyroidism, 8 reinitiated TECENTRIQ after symptom improvement

Hypothyroidism occurred in 11% (277/2421) of patients with NSCLC and SCLC receiving TECENTRIQ in combination with platinum-based chemotherapy, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (5.7%) adverse reactions. Hypothyroidism led to permanent discontinuation of TECENTRIQ in 0.1% and withholding of TECENTRIQ in 1.6% of patients. Hormone replacement therapy was required in 71% (198/277) 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, 9 reinitiated TECENTRIQ after symptom improvement

Type 1 Diabetes Mellitus, Which Can Present With Diabetic Ketoacidosis

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Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated

 Type 1 diabetes mellitus occurred in 0.3% (7/2616) of patients receiving TECENTRIQ alone, including Grade 3 (0.2%) and Grade 2 (<0.1%) adverse reactions. Type 1 diabetes mellitus led to permanent discontinuation of TECENTRIQ in 1 patient and withholding of TECENTRIQ in 2 patients. Treatment with insulin was required for all patients with confirmed Type 1 diabetes mellitus and insulin therapy was continued long-term. Of the 2 patients in whom TECENTRIQ was withheld for Type 1 diabetes mellitus, both reinitiated TECENTRIQ treatment

Immune-Mediated Nephritis With Renal Dysfunction

TECENTRIQ can cause immune-mediated nephritis

Immune-mediated nephritis with renal dysfunction occurred in <0.1% (1/2616) of patients receiving TECENTRIQ alone, and this adverse reaction was a Grade 3 (<0.1%) adverse reaction. Nephritis led to permanent discontinuation of TECENTRIQ in this patient. This patient required systemic corticosteroids. In this patient, nephritis did not resolve

Immune-Mediated Dermatologic Adverse Reactions

TECENTRIQ can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome (SJS), DRESS, and toxic epidermal necrolysis (TEN), has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes 

Immune-mediated dermatologic adverse reactions occurred in 0.6% (15/2616) of patients receiving TECENTRIQ alone, including Grade 3 (<0.1%) and Grade 2 (0.2%) adverse reactions. Dermatologic adverse reactions led to permanent discontinuation of TECENTRIQ in 0.1% and withholding of TECENTRIQ in 0.2% of patients. Systemic corticosteroids were required in 20% (3/15) of patients with dermatologic adverse reactions. Dermatologic adverse reactions resolved in 87% of the 15 patients. Of the 4 patients in whom TECENTRIQ was withheld for immune-mediated dermatologic adverse reactions, none reinitiated TECENTRIQ

Other Immune-Mediated Adverse Reactions

 The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) 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-Barré 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/Immune): Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection

Infusion-Related Reactions

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 1 or 2

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infusion-related reactions, consider using pre-medications with subsequent doses

Infusion-related reactions occurred in 1.3% of patients receiving TECENTRIQ alone, including Grade 3 (0.2%) reactions

The frequency and severity of infusion-related reactions were similar whether TECENTRIQ was given as a single agent, in combination with other antineoplastic drugs in NSCLC and SCLC, and across the recommended dose range

Complications of Allogeneic HSCT After PD-1/PD-L1 Inhibitors

Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) 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 (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause)

These complications may occur despite intervening therapy between PD-1/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

Embryo-Fetal Toxicity

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 5 months after the last dose

Use in Specific Populations

Nursing Mothers

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 5 months after the last dose

Fertility

Based on animal studies, TECENTRIQ may impair fertility in females of reproductive potential while receiving treatment

Most Common Adverse Reactions

The most common adverse reactions (rate ≥20%) in patients who received TECENTRIQ in combination with other antineoplastic drugs for NSCLC and SCLC were fatigue/asthenia (49%), nausea (38%), alopecia (35%), constipation (29%), diarrhea (28%), and decreased appetite (27%).

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 full Prescribing Information for additional Important Safety Information.