Gregory D. Greenier

	The FDA approved atezolizumab (Tecentriq) to treat advanced or metastatic urothelial carcinoma on May 18, 2016, and metastatic non-small cell lung cancer (NSCLC) on October 18, 2016. Atezolizumab was approved for patients with either of these cancers who experience worsening of their disease during or after treatment with platinum-based chemotherapy. However, those with NSCLC who have epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase tumor (ALK) aberrations should first fail appropriate therapies before starting atezolizumab.

 Patients with urothelial cancer or NSCLC who have recurrence of their cancer after treatment have very poor prognosis. Both urothelial cancer and NSCLC cells express programmed death ligand 1 (PD-L1), a transmembrane protein. PD-L1 binds to programmed death 1 (PD-1) on the surface of T lymphocytes, which inhibits cytotoxic T-cell activity, T-cell proliferation, and cytokine production.

 Atezolizumab works by binding and inhibiting the action of PD-L1 which allows the immune system to help eradicate the cancer. Atezolizumab is a first-in-class medication and the only FDA-approved drug that targets PD-L1. It is also the first new drug in two decades that may be used to treat bladder cancer.

	Atezolizumab was approved for urothelial carcinoma based on the results of the IMvigor 210 study.

 IMvigor 210 was an open-label, multicenter, single-arm, phase 2 trial that enrolled 315 patients with inoperable locally advanced or metastatic urothelial carcinoma in which the cancer was progressing following platinum-based chemotherapy. Three hundred and ten patients received 1200 mg atezolizumab given IV on day 1 of a 21-day cycle. Efficacy was assessed by an independent review of a facility-assessed overall response rates (ORR) (according to Response Evaluation Criteria in Solid Tumors v1.1) and an investigator-assessed ORR dependent on immune-modified RECIST.

	The IMvigor 210 study found that 15% of patients responded to treatment with atezolizumab (95% confidence interval [CI], 11-20, p=0.0058): 5% of all patients achieved complete response (CR) and 10% achieved partial response (PR).

 The median duration of response was not determined despite a median follow-up time of 11.7 months. A subgroup analysis using modified RECIST criteria found patients who displayed ≥5% expression of PD-L1 in tumor infiltrating cells had better outcomes with atezolizumab than those with <5% PD-L1 expression. One hundred patients with ≥5% expression had an ORR of 27%, with CR 8% and PR 19% (95% CI, 19-37, p<0.0001), whereas 107 patients with ≥1% but <5% expression had an ORR of 17%, with CR 6% and PR 11%. The remaining 103 patients with <1% expression had an ORR of 13%, with CR 2% and PR 11%.

	Atezolizumab was approved to treat NSCLC based on results of both a phase 2 study (POPLAR, n=287) and a phase 3 study (OAK, n=850).

 These international, multicenter, open-label studies randomized patients with advanced or metastatic NSCLC patients who progressed after previous treatment. In a 1:1 ratio patients were assigned to receive either 1200mg IV atezolizumab or 75mg/m

In each case the infusion was given once every 3 weeks and both studies used overall survival (OS) as their primary endpoint.

	The OAK study revealed that OS was 13.8 months (range, 11.8 - 15.7) for atezolizumab compared to 9.6 months (range, 8.6 - 11.2) with docetaxel (hazard ratio, 0.74; 95% CI, 0.63–0.87; p=0.0004).

 The POPLAR study determined that the median OS for patients on atezolizumab was 12.6 months (range, 9.7, 16.0) compared to 9.7 months (range, 8.6, 12.0) with docetaxel (HR, 0.69; 95% CI, 0.52–0.92).

 The POPLAR study finds that both docetaxel and atezolizumab had an ORR of 15%. However, 1 patient treated with atezolizumab had a CR compared to none with docetaxel.

	Some of the most common side effects (≥ 20%) experienced by patients treated with atezolizumab include fatigue, decreased appetite, nausea, urinary tract infections. Common side effects unique to treating urothelial cancer include pyrexia or constipation, while some patients treated for NSCLC may experience dyspnea or cough. The most common grade 3 or 4 adverse events (≥ 2%) include urinary tract infection, or anemia. Additional serious side effects unique to treating urothelial cancer included hematuria, acute kidney injury, or venous thromboembolism as well as sepsis, musculoskeletal pain, dysphagia, or pneumonia in patients being treated for NSCLC.

	Atezolizumab has no contraindications at this time; however, immune-mediated inflammatory adverse effects (eg, pneumonitis, hepatitis, colitis, endocrinopathies, etc) can occur and may require treatment interruption or discontinuation depending on severity. For example, if aspartate transaminase (AST) or alanine transaminase (ALT) levels are 3 to 5 times greater than the upper limit of normal (ULN) or if total bilirubin is 1.5 to 3 times ULN during treatment, atezolizumab should be withheld. If AST or ALT are greater than 5 times ULN or bilirubin is greater than 3 times ULN during treatment, atezolizumab should be permanently discontinued.

 Similarly, patients with active infections or immune-modulated inflammation, such as but not limited to pneumonitis, colitis, pancreatitis, and ocular inflammation, may require treatment changes or discontinuation; guidance may be found in the full prescribing information. Patients with endocrine dysfunction, such as thyroid disorders or type 1 diabetes mellitus, should be monitored throughout treatment.

	The potential for atezolizumab to interact with any other medications is unknown at this time. Atezolizumab may cause fetal harm. However, no data exist on use in pregnant women

	Atezolizumab is supplied in single-dose vials at doses of 1200 mg/20mL (60 mg/mL). It is given in a single 1200 mg IV infusion over 60 minutes every 21 days until disease progression or until the patient experiences unacceptable toxicity. If the patient tolerates the first dose, subsequent atezolizumab infusions may be given over 30 minutes.

 No dose adjustments are necessary for hepatic or renal impairment before treatment.

	Atezolizumab should not be given as an IV push or bolus and must not be co-administered with other drugs through the same IV line. An in-line filter that is sterile, non-pyrogenic, and low protein binding with a pore size of 0.2 to 0.22 microns may be used during administration but is not necessary.

			Tecentriq [package insert]. South San Francisco, CA. Genentech, Inc; Revised 10/2016.

			Rosenberg JE, Hoffman-Censits J, Powles T, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. 

			U.S Food & Drug Administration. Atezolizumab (Tecentriq). 

http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm525780.htm

. Published 10/19/2016. Accessed November 11, 2016.

			Fehrenbacher, Louis, Spira, Alexander, Ballinger, Marcus, et al. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet; vol 387; 1837-1846. April 30, 2016. doi 10.1016/S0140-6736(16)00587-0

			Hoffman-La Roche.  A randomized Phase 3 Study of Atezolizumab (an Engineered Anti-PDL1 Antibody) Compared to Docetaxel in Patients with Locally Advanced or Metastatic Non-Small Cell Lung Cancer Who Have Failed Platinum Therapy – “OAK”. https://clinicaltrials.gov/ct2/show/study/NCT02008227. ClinicalTrials.gov identifier NCT02008227. Received December 6, 2013. Updated November 1, 2016. Accessed November 11, 2016.

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Here: an overview of atezolizumab, the first new drug in two decades for bladder cancer and now approved for NSCLC.

Author | Gregory D. Greenier

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Atezolizumab for Urothelial Carcinoma and Non-Small Cell Lung Cancer