In a normal immune response, the body can recognize the presence of tumors and mount a response to eradicate them. The process of eradicating a tumor begins with antigen-presenting cells that gather and process the antigens released by tumors. This activates the T cells, which proliferate and attack the tumor.Tumors have learned to evade the normal immune response by exploiting the immune checkpoint pathway. The Programmed Death Receptor-1 (PD-1) is a checkpoint protein expressed on the membrane of activated T cells. The Programmed Death-Ligand 1 (PD-L1) and the Programmed Death-Ligand 2 (PD-L2) are checkpoint proteins expressed on tumor cells and tumor-infiltrating immune cells. When PD-L1 and PD-L2 attach to PD-1 receptors on the T cells, the T cells become inhibited and will not attack the tumor; thus, the tumor can continue to proliferate.Atezolizumab (Tecentriq) is a human monoclonal antibody and immune checkpoint inhibitor that binds to PD-L1 on tumor cells and tumor-infiltrating immune cells and blocks the interaction with PD-1 and B7.1 receptors on T cells and antigen-presenting cells. Consequently, the tumor is no longer able to inactivate the T cells, and the antitumor response continues. ATEZOLIZUMAB (TECENTRIQ) INDICATIONS
ALVEOLAR SOFT PART SARCOMA
A soft tissue sarcoma is a type of cancer that starts in tissues like fat, muscle, nerves, or blood vessels. They are rare and slow growing, and often start in the arms or legs, but can spread to other parts of the body such as, frequently, the lungs. Alveolar soft part sarcomas (ASPS) are caused by a translocation of two chromosomes within the tumor cells themselves, so cannot be passed on through the genes. These sarcomas tend to occur more frequently in adolescents and young adults. Treatment may involve surgical resection of the primary site either with or without adjunctive radiation therapy. If the tumor has spread, local treatment may not be adequate, and systemic therapy may be needed. Traditional chemotherapies are generally ineffective, however.
The efficacy of atezolizumab (Tecentriq) to treat untreated, advanced, or metastatic ASPS that is unresectable is being evaluated in an ongoing phase II, nonrandomized, parallel assignment clinical trial where one cohort receives only atezolizumab (Tecentriq) and a second cohort receives atezolizumab (Tecentriq) along with bevacizumab (Avastin®; NCT03141684). The primary endpoint is objective response rate (ORR). The secondary endpoints are duration of response (DOR), progression-free survival (PFS), Response Evaluation Criteria in Solid Tumors (RECIST) response, immune biomarkers found in paired biopsies, and pediatric pharmacokinetics and anti-drug antibodies. At the time of the US Food and Drug Administration (FDA) approval, 49 adults and pediatric individuals aged 2 years and older were enrolled in the study. The ORR was 24 percent with no complete responses and 12 partial responses. The median DOR has not been reached, but at that time, ranged from 1 to 41 months. The clinical trial is continuing to recruit additional individuals and is expected to be complete late in 2023.
HEPATOCELLULAR CARCINOMA (HCC)
Hepatocellular carcinoma (HCC), the most common type of cancer in the liver, gallbladder, and bile ducts, is usually diagnosed at an advanced stage and is the third leading cause of cancer-related deaths worldwide.
In May 2020, the FDA approved atezolizumab (Tecentriq) in combination with bevacizumab (Avastin®) for individuals with unresectable or metastatic HCC who had not received prior systemic therapy. Efficacy was investigated in IMbrave150 (NCT03434379), a multicenter, international, open-label, randomized trial in individuals with locally advanced unresectable or metastatic HCC who had not received prior systemic therapy. A total of 501 individuals were randomly assigned (2:1) to receive either atezolizumab (Tecentriq) 1200 mg as an intravenous intravenous (IV) infusion followed by bevacizumab 15 mg/kg IV on the same day, every 3 weeks, or sorafenib orally twice daily. The main efficacy outcome measures were overall survival (OS) and
independent review facility (IRF)-assessed PFS per RECIST volume (v)1.1. Additional efficacy
outcome measures were IRF-assessed ORR per RECIST v1.1 and modified RECIST (mRECIST). Median OS was not reached in the
individuals who received atezolizumab (Tecentriq) plus bevacizumab and
was 13.2 months (95 percent confidence interval [CI], 10.4 to not
estimable [NE]) in the individuals who received sorafenib (hazard ratio [HR] 0.58;
95 percent CI, 0.42 to 0.79;
P=0.0006). Median PFS was 6.8 months (95 percent CI, 5.7 to 8.3) versus 4.3 months
(95 percent CI, 4.0 to 5.6),
respectively (HR 0.59; 95 percent CI, 0.47 to 0.76; P<0.0001). The ORR per
RECIST v1.1 was 27.3 percent
(95 percent CI, 22.5 to 32.5)
in the atezolizumab (Tecentriq) plus bevacizumab group compared with 11.9
percent (95 percent CI, 7.4 to 18.0)
in the sorafenib group (P<0.0001). The ORR per mRECIST was
33.2 percent (95 percent CI, 28.1 to 38.6) versus 13.3 percent (95 percent CI, 8.4 to 19.6), respectively
(P<0.0001). The most common adverse reactions (reported in 20 percent or greater of individuals) with atezolizumab (Tecentriq) plus bevacizumab in
individuals with HCC were hypertension, fatigue, and proteinuria.
MELANOMA
Melanoma tumors are composed of abnormal melanocytes that have become cancer cells. Melanoma is much less common than some other types of skin cancers. But melanoma is more dangerous because it is much more likely to spread to other parts of the body if not caught and treated early.
In July 2020, the FDA approved atezolizumab (Tecentriq) in combination with cobimetinib and vemurafenib for individuals with proto-oncogene B-Raf (BRAF) V600 mutation-positive unresectable or metastatic melanoma. The efficacy of atezolizumab (Tecentriq) in combination with cobimetinib and vemurafenib was evaluated in a phase III, double-blind, randomized (1:1), placebo-controlled, multicenter trial (IMspire150; NCT02908672) conducted in 514 individuals. Eligible individuals were required to have previously untreated unresectable or metastatic BRAF V600 mutation-positive melanoma. Individuals were enrolled and randomly assigned to the atezolizumab (Tecentriq) group (n=256) or control group (n=258). At a median follow-up of 18.9 months (interquartile range [IQR] 10.4 to 23.8),
PFS as
assessed by the study investigator was significantly prolonged with
atezolizumab (Tecentriq) versus control (15.1 versus 10.6 months; [HR] 0.78; 95 percent CI 0.63 to 0.97; P=0.025). The
addition of atezolizumab (Tecentriq) to targeted therapy with vemurafenib and
cobimetinib was safe and tolerable and significantly increased PFS
in individuals with
BRAF V600 mutation-positive advanced melanoma.
NON-SMALL CELL LUNG CANCER (NSCLC)Lung cancer is the leading cause of cancer-related mortality in both men and women, not only in the United States but also throughout the world. In the United States, lung cancer is the second most common cancer. NSCLC accounts for approximately 85 percent of all lung cancers, and its subtype, squamous cell lung cancer, accounts for 25 to 30 percent of all lung cancers. In October 2016, the FDA granted supplemental approval of atezolizumab (Tecentriq) for the treatment of individuals with metastatic NSCLC whose disease progressed during or following platinum-containing chemotherapy. Individuals with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations should have disease progression on an FDA-approved therapy for these aberrations prior to receiving atezolizumab (Tecentriq).The safety and efficacy of atezolizumab (Tecentriq) for this indication was evaluated in two clinical trials. The first (NCT01903993; POPLAR) was a phase II, multicenter, international, randomized, open-label trial in individuals with advanced or metastatic NSCLC who progressed during or following a platinum-containing regimen, regardless of PD-L1 expression. The study enrolled 287 individuals who were randomly assigned to receive either atezolizumab (Tecentriq) or docetaxel. The study showed that atezolizumab (Tecentriq) doubled the likelihood of survival in individuals whose cancer expressed the highest levels of PD-L1 compared with docetaxel chemotherapy. An improvement in survival was also observed in individuals who had medium and high or any level of PD-L1 expression.
The second study (NCT02008227; OAK) was a phase III multicenter, international, randomized, open-label trial that enrolled 1225 individuals in the same population comparing the same treatments as the phase II trial. The median OS was 13.8 months in the atezolizumab (Tecentriq) cohort versus 9.6 months in the docetaxel cohort (HR 0.74 [0.63 to 0.87]; P=0.0004).
In December 2018, atezolizumab (Tecentriq) also received the FDA-approved indication of NSCLC, in combination with bevacizumab, paclitaxel, and carboplatin, for the first-line treatment of adult individuals with metastatic nonsquamous NSCLC with no EGFR or ALK genomic tumor aberrations. The safety and efficacy of atezolizumab (Tecentriq) with bevacizumab, paclitaxel, and carboplatin was evaluated in IMpower150 (NCT02366143), a multicenter, international, randomized, open-label trial in 1202 individuals with metastatic nonsquamous NSCLC. Three hundred ninety-three chemotherapy-naïve individuals with metastatic nonsquamous NSCLC received atezolizumab (Tecentriq) 1200 mg with bevacizumab 15 mg/kg, paclitaxel 175 mg/m2 or 200 mg/m2, and carboplatin area under the curve (AUC) 6 mg/mL/min every 3 weeks for a maximum of four or six cycles, followed by atezolizumab (Tecentriq) 1200 mg with bevacizumab 15 mg/kg every 3 weeks until disease progression or unacceptable toxicity. The median OS for individuals receiving atezolizumab (Tecentriq) with bevacizumab, paclitaxel, and carboplatin was 19.2 months versus 14.7 months in individuals not receiving atezolizumab (Tecentriq) along with the other infusions (HR 0.78; 95 percent CI, 0.64 to 0.96; P=0.016). The median PFS for individuals receiving atezolizumab (Tecentriq) with bevacizumab, paclitaxel, and carboplatin was 80.5 months versus 7.0 months in individuals not receiving atezolizumab (Tecentriq) along with other infusions (HR 0.71; 95 percent CI, 0.59 to 0.85; P=0.002). The ORR for individuals receiving atezolizumab (Tecentriq) with bevacizumab, paclitaxel, and carboplatin was 55 percent (4 percent complete responses, 51 percent partial responses) versus 42 percent (1 percent complete responses, 41 percent partial responses) in individuals not receiving atezolizumab (Tecentriq) along with the other infusions. The median DOR for individuals receiving atezolizumab (Tecentriq) with bevacizumab, paclitaxel, and carboplatin was 10.8 months versus 6.5 months in individuals not receiving atezolizumab (Tecentriq) along with the other infusions.
In December 2019, the FDA approved atezolizumab (Tecentriq) for the first-line treatment of adult individuals with metastatic nonsquamous NSCLC with no EFGR or ALK genomic tumor aberrations, in combination with albumin-bound paclitaxel and carboplatin. This was based on a multicenter, randomized, open-label trial (NCT02367781; IMpower130) in individuals with stage IV nonsquamous NSCLC. Individuals were randomly assigned to one of the following treatment regimens: atezolizumab (Tecentriq), albumin-bound paclitaxel, and carboplatin for a maximum of four or six cycles followed by atezolizumab (Tecentriq) until disease progression or unacceptable toxicity, or albumin-bound paclitaxel and carboplatin for a maximum of four or six cycles followed by best supportive care or pemetrexed. Major efficacy outcome measures were PFS by RECIST v1.1 and OS in the subpopulation of individuals evaluated for and documented to have no EGFR or ALK genomic tumor aberrations intention to treat–wild type (ITT-WT). A total of 724 individuals were enrolled; of these, 681 (94 percent) were in the ITT-WT population. Fifty percent of individuals treated with atezolizumab (Tecentriq) died compared to 57 percent treated with placebo (HR, 0.80; 95 percent CI 0.64 to 0.99; P=0.0384). The duration of response was 10.8 months in the atezolizumab (Tecentriq) group compared to 7.8 months in the placebo group.
In May 2020, the FDA approved atezolizumab (Tecentriq) for the first-line treatment of adult individuals with metastatic NSCLC whose tumors have high PD-L1 expression (PD-L1 stained 50 percent or greater of tumor cells [TC] [TC 50 percent or greater] or PD-L1 stained tumor-infiltrating immune cells [IC] covering 10 percent or greater of the tumor area [IC 10 percent or greater), with no EGFR or ALK genomic tumor aberrations. Efficacy was evaluated in IMpower110 (NCT02409342), a multicenter, international, randomized, open-label trial in individuals with stage IV NSCLC whose tumors express PD-L1 (TC 1 percent or greater or IC 1 percent or greater), who had received no prior chemotherapy for metastatic disease. Individuals were randomly assigned (1:1) to receive atezolizumab (Tecentriq) 1200 mg every 3 weeks until disease progression or unacceptable toxicity or platinum-based chemotherapy. The main efficacy outcome measure was OS. The trial demonstrated a statistically significant improvement in OS for individuals with high PD-L1 tumor expression receiving atezolizumab (Tecentriq) compared to those treated with platinum-based chemotherapy. Median OS was 20.2 months (95 percent CI, 16.5 to NE) for individuals in the atezolizumab (Tecentriq) arm compared with 13.1 months (95 percent CI, 7.4 to 16.5) in the chemotherapy arm (HR, 0.59; 95 percent CI, 0.40 to 0.89; P=0.0106). There was no statistically significant difference in OS for the other two PD-L1 subgroups (TC 5 percent or greater or IC 5 percent or greater; and TC 1 percent or greater or IC 1 percent or greater) at the interim or final analyses. Median PFS per investigator was 8.1 months (95 percent CI, 6.8 to 11.0) in the atezolizumab (Tecentriq) arm and 5.0 months (95 percent CI, 4.2 to 5.7) in the platinum-based chemotherapy arm (HR, 0.63; 95 percent CI, 0.45 to 0.88). Confirmed ORR per investigator was 38 percent (95 percent CI, 29 to 48) and 29 percent (95 percent CI, 20 to 39), respectively.
In October 2021, the FDA approved atezolizumab (Tecentriq) as adjuvant treatment following resection and platinum-based chemotherapy for adult individuals with Stage II to IIIA NSCLC whose tumors have PD-L1 expressions on 1 percent or greater of tumor cells. This was based on interim data from an ongoing Phase III, multicenter, international, randomized, open-label trial (NCT02486718; Impower010) that is evaluating the efficacy and safety of atezolizumab (Tecentriq) versus best supportive care (BSC) in individuals with Stage IB to Stage IIIA NSCLC following resection and adjuvant chemotherapy. The primary endpoint is disease-free survival (DFS). Some secondary endpoints include OS, percentage of individuals who are disease free at year 3, percentage of individuals who are disease free at year 5, percentage of individuals with adverse events, and percentage of individuals who develop anti-therapeutic antibodies to atezolizumab (Tecentriq). At the time of the interim analysis, the study demonstrated a statistically significant improvement in median DFS in the atezolizumab (Tecentriq) cohort versus the BSC cohort: not reached (NR) versus 35.3 months, respectively (HR, 0.66 [0.50 to 0.88]; P=0.004).
SMALL CELL LUNG CANCER (SCLC)Small cell lung cancer (SCLC), previously known as oat cell carcinoma, is considered distinct from other lung cancers, which are called NSCLCs because of their clinical and biologic characteristics. SCLC is a neuroendocrine carcinoma that exhibits aggressive behavior, rapid growth, early spread to distant sites, sensitivity to chemotherapy and radiation, and frequent association with distinct paraneoplastic syndromes.In March 2019, the FDA approved atezolizumab (Tecentriq) for the first-line treatment of adult individuals with extensive-stage SCLC, with carboplatin and etoposide. This was based on a randomized, multicenter, double-blind, placebo-controlled trial (NCT02763579) in 403 individuals with extensive-stage SCLC. Individuals were randomly assigned to atezolizumab (Tecentriq) in combination with carboplatin and etoposide or placebo in combination with carboplatin and etoposide. The major efficacy outcome measures were OS and PFS as assessed by investigators in the ITT population. Fifty-two percent of individuals treated with atezolizumab (Tecentriq) died compared to 66 percent of those treated with placebo (HR, 0.70; 95 percent CI, 0.54 to 0.91; P=0.0069). The duration of response was 4.2 months in the atezolizumab (Tecentriq) group compared to 3.9 months in placebo group.
OFF-LABEL INDICATIONS
There may be additional indications contained in the Policy section of this document due to evaluation of criteria highlighted in the Company's off-label policy, and/or review of clinical guidelines issued by leading professional organizations and government entities.