Atezolizumab for Metastatic Non–Small Cell Lung Cancer Chana Weinstock, Sean Khozin, Daniel Suzman, Lijun Zhang, Shenghui Tang, Sakar Wahby, Kirsten B

Published OnlineFirst June 13, 2017; DOI: 10.1158/1078-0432.CCR-17-0540

CCR Drug Updates Clinical Cancer Research U.S. Food and Drug Administration Approval Summary: Atezolizumab for Metastatic Non–Small Cell Lung Cancer Chana Weinstock, Sean Khozin, Daniel Suzman, Lijun Zhang, Shenghui Tang, Sakar Wahby, Kirsten B. Goldberg, Geoffrey Kim, and Richard Pazdur

Abstract

On October 18, 2016, the FDA approved atezolizumab (TECEN- 9.7 months (95% CI, 8.6–12.0; HR ¼ 0.69; 95% CI, 0.52–0.92) for TRIQ; Genentech, Inc.) for treatment of patients with metastatic the atezolizumab and docetaxel arms, respectively. In patients non–small cell lung cancer (mNSCLC) whose disease progressed treated with atezolizumab, the most common (20%) adverse during or following platinum-containing chemotherapy. Approval reactions were fatigue, decreased appetite, dyspnea, cough, nausea, was based on demonstration of clinically meaningful improve- musculoskeletal pain, and constipation; the most common (2%) ments in overall survival (OS) and an acceptable safety profile in grade 3 to 4 adverse events were dyspnea, pneumonia, hypoxia, two randomized clinical trials (OAK and POPLAR). Median OS in hyponatremia, fatigue, anemia, musculoskeletal pain, aspartate OAK, a phase III trial, was 13.8 months [95% confidence interval aminotransferase increase, alanine aminotransferase increase, dys- (CI), 11.8–15.7] in the atezolizumab arm compared with 9.6 phagia, and arthralgia. Clinically significant immune-related months (95% CI, 8.6–11.2) in the docetaxel arm [hazard ratio adverse events for patients receiving atezolizumab included (HR) ¼ 0.74; 95% CI, 0.63–0.87; P ¼ 0.0004]. Median OS in 1.4% incidence each of grade 3 to 4 pneumonitis, hepatitis, colitis, POPLAR, a phase II trial, was 12.6 months (95% CI, 9.7–16.0) and and thyroid disease. Clin Cancer Res; 23(16); 1–6. 2017 AACR.

Introduction There are several FDA-approved treatment options in the second-line setting for patients with metastatic non–small cell lung Lung cancer is the leading cause of cancer-related deaths in the cancer (mNSCLC) who have progressed on or after initial plat- United States, with an estimated 158,040 deaths occurring in inum-doublet chemotherapy. These options differ slightly based 2015, accounting for 26.8% of all overall cancer-related deaths on tumor histology and by mutational profile, and include (1). The majority of patients present with locally advanced or two agents that target the programmed cell death 1 (PDCD1 or metastatic disease, which has a 5-year survival of less than 5%. PD-1) pathway: nivolumab and pembrolizumab (although pem- First-line therapy has been the use of platinum-doublet chemo- brolizumab is approved for use in PD-L1–positive patients only; therapy, with a median overall survival (OS) for patients ranging refs. 6, 7). from 8 to 13 months, and a 1-year survival rate of approximately Atezolizumab (TECENTRIQ; Genentech, Inc.) is a humanized 33% (2, 3). Those patients whose tumors are found to be positive mAb that binds directly to PD-L1, blocking its interactions with for EGFR activating mutations or ALK receptor tyrosine kinase the PD-1 and CD80 molecule receptors. This binding results in a (ALK) translocations are also eligible for oral-targeted therapies. release of inhibition of the antitumor immune response, which is Objective response rates (ORR) with these therapies is approxi- mediated by PD-L1/PD-1 interaction. The FDA granted atezoli- mately 60% to 70%, and median progression-free survival (PFS) is zumab accelerated approval on May 18, 2016, for the treatment of 9 to 14 months (4, 5). However, the majority of patients develop locally advanced or metastatic urothelial carcinoma. Subsequent- treatment resistance within the first year of therapy. Although ly, the FDA reviewed the use of atezolizumab in mNSCLC in the pembrolizumab is now approved for first-line therapy of patients second-line setting. with CD274/programmed cell death ligand 1 (PD-L1)–positive NSCLC who do not harbor EGFR mutations or ALK translocations, this approval occurred after the atezolizumab action. Clinical Trials The efficacy of atezolizumab was investigated in two multicen- ter, international, randomized, open-label trials in patients with mNSCLC who progressed during or following a platinum-con- Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland. taining regimen. OAK (NCT02008227) enrolled 1,225 patients and POPLAR (NCT01903993) enrolled 287 patients. In both Note: This is a U.S. Government work. There are no restrictions on its use. studies, patients were stratified by PD-L1 expression status in Corresponding Author: Chana Weinstock, U.S. Food and Drug Administration, tumor-infiltrating immune cells (IC), by the number of prior 10903 New Hampshire Avenue, WO22 RM2137, Silver Spring, MD 20993. Phone: chemotherapy regimens, and by histology. Patients were random- 240-402-2625; E-mail: [email protected] ized (1:1) to receive either atezolizumab intravenously at 1,200 doi: 10.1158/1078-0432.CCR-17-0540 mg every 3 weeks until unacceptable toxicity or either radiograph- 2017 American Association for Cancer Research. ic or clinical progression or docetaxel intravenously at 75 mg/m2

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Table 1. OAK primary OS analyses, ITT and PD-L1 selected groups ITT population TC1/2/3 or IC1/2/3 Atezolizumab Docetaxel Atezolizumab Docetaxel (N ¼ 425) (N ¼ 425) (N ¼ 241) (N ¼ 222) Number of deaths, n (%) 271 (64%) 298 (70%) 151 (63%) 149 (67%) Median OS (95% CI), months 13.8 (11.8–15.7) 9.6 (8.6–11.2) 15.7 (12.6–18.0) 10.3 (8.8–12.0) HR (95% CI)a 0.74 (0.63–0.87) 0.74 (0.59–0.94) Pb 0.0004 0.012 Abbreviations: CI, confidence interval; HR, hazard ratio; ITT, intent-to-treat. aHR was obtained from a Cox proportional hazards model stratified by PD-L1 IC status, number of prior chemotherapy regimens, and histology as collected from IxRS. bP value was calculated from a log-rank test stratified by PD-L1 IC status, number of prior chemotherapy regimens, and histology as collected from IxRS.

every 3 weeks until unacceptable toxicity or disease progression. Efficacy The trials excluded patients with a history of autoimmune disease The primary efficacy endpoint of OAK was OS in the first 850 and active or corticosteroid-dependent brain metastases. randomized patients. This analysis was conducted when 569 death events occurred, with a median follow-up of approxi- Trial demographics mately 21 months. A statistically significant improvement in Baseline disease and patient characteristics in OAK were median OS for patients on atezolizumab compared with docetaxel age 64 years (range: 33–85), male (61%), white (70%), non- was observed in both the intent-to-treat (ITT) population and squamous histology (74%), known EGFR mutation (10%), known the TC1/2/3 or IC1/2/3 subpopulation (defined as having ALK rearrangements (0.2%), and current or previous smokers PD-L1 staining on either 1% of TC or 1% of IC). There was (82%). Baseline Eastern Cooperative Oncology Group (ECOG) a 4.2-month improvement in median OS in the ITT population performance status was 0 (37%) or 1 (63%). Seventy-five percent and a 5.4-month improvement in median OS in the TC1/2/3 or of patients received only one prior platinum-based therapeutic IC1/2/3 subpopulation. Results are summarized in Table 1, and regimen. Baseline disease and patient characteristics in POPLAR Kaplan–Meier curves appear in Fig. 1. The differences in point were median age 62 years (range 36–84), male (59%), white estimates of median OS and difference between arms appear to (79%), non-squamous histology (66%), known EGFR mutation show that the PD-L1–selected subgroup may derive more (7%), known ALK rearrangements (1%), and current or previous benefit overall than the nonselected subgroup. smokers (80%). Baseline ECOG performance status was 0 (33%) Secondary endpoints in OAK included PFS and overall or 1 (67%). Approximately two thirds of patients received only response rate (ORR). However, this Biological License Applica- one prior platinum-based therapeutic regimen. Overall, 16% of tion (BLA) submission included topline efficacy results only. The patients in both OAK and POPLAR were classified as having high full Clinical Study Report and associated datasets will be required PD-L1 expression [50% of tumor cells (TC) or 10% of IC]. for submission as a postmarketing commitment (PMC).

A ITT B TC1/2/3 or IC1/2/3

1.0 1.0 Atezolizumab Atezolizumab Docetaxel Docetaxel 0.8 0.8

0.6 0.6

0.4 0.4

Survival probability 0.2 Survival probability 0.2

0.0 0.0 0 3 6 9 12 15 18 21 24 27 0 3 6 9 12 15 18 21 24 27 Months since randomization Months since randomization

Atezolizumab 425 363 305 248 218 188 157 74 28 1 Atezolizumab 241 207 176 145 131 115 98 47 19 1 Docetaxel 425 336 263 195 151 123 98 51 16 Docetaxel 222 172 136 105 81 65 55 28 8

Figure 1. Kaplan–Meier curves of OS in the ITT- and PD-L1–selected subgroups of OAK.

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Table 2. Median OS at each data cutoff: primary (January 30, 2015), first update reason that the applicant proposed the use of a complementary (May 8, 2015), second and final update (December 1, 2015) diagnostic at the TC3/IC3 cutoff to help predict those patients Atezolizumab Docetaxel most likely to respond to atezolizumab. (N ¼ 144) (N ¼ 143) The survival advantage appeared to extend even to those with Final preplanned analysis (January 30, 2015) PD-L1 fi PD-L1 Number of deaths, n (%) 71 (49) 82 (57) little or no expression (TC0 and IC0, de ned as < Median (95% CI), months 11.4 (9.7–NE) 9.5 (8.6–11.9) staining on 1% of TC and IC). HR for death on atezolizumab HR (95% CI) 0.77 (0.55–1.07) compared with docetaxel for the TC0/IC0 subgroup was 0.75 P 0.11 (95% CI, 0.59–0.96) in OAK and 0.88 (95% CI, 0.55–1.43) in Update 1 (May 8, 2015) POPLAR (updated analysis). Thus, efficacy results on OS with n Number of deaths, (%) 78 (54) 95 (66) atezolizumab in the tested NSCLC population do not appear to be Median (95% CI), months 12.6 (9.7–16.4) 9.7 (8.6–12.0) HR (95% CI)a 0.73 (0.54–1.00) driven exclusively by results in the highest expressing TC3/IC3 PD-L1 Update 2 (December 1, 2015) subpopulation of , even though these patients seemed to Number of deaths, n (%) 90 (63) 110 (77) derive benefit from atezolizumab compared with docetaxel that Median (95% CI), months 12.6 (9.7–16.0) 9.7 (8.6–12.0) was strikingly higher than those in all other measured subgroups. HR (95% CI)a 0.69 (0.52–0.92) Abbreviations: CI, confidence interval; NE, not estimable. Patient-reported outcomes a HR was obtained from a Cox proportional hazards model stratified by PD-L1 IC In POPLAR, patient-reported outcomes (PRO) evaluation was status, number of prior chemotherapy regimens, and histology as collected based on data collected using the European Organization for from IxRS. Source: The applicant's response to the FDA's April 26, 2016, Information Research and Treatment of Cancer Quality-of-Life Questionnaire Request; OS update supplemental results report. Core 30 (EORTC QLQ-C30) and the EORTC Lung Cancer Module (QLQ-LC13). Time to deterioration (TTD) in patient-reported lung cancer symptoms (cough, dyspnea, chest pain, and arm/ The prespecified primary OS analysis for POPLAR showed a shoulder pain) was examined. TTD of lung cancer symptoms difference of 1.9 months in median survival favoring the atezo- using EORTC was defined as the time from baseline to the first lizumab arm [hazard ratio (HR) ¼ 0.77]; however, this result did time the patient's score shows a 10-point increase above base- not reach statistical significance (P ¼ 0.11). An exploratory, line in each of the following EORTC transformed scores for cough, updated OS analysis with an additional 10 months of follow-up dyspnea, chest pain, or arm/shoulder pain. An increase in a score showed an improvement of 2.9 months in median survival 10 points above baseline must be held for at least two conse- between arms (HR ¼ 0.69). Results are shown in Table 2. cutive cycles, or an initial score increase of 10 points is followed Secondary efficacy endpoints for POPLAR included PFS, ORR, by death within 3 weeks from the last assessment. and duration of response (DoR). Median investigator-assessed The compliance rates for QLQ-C30 among patients who were PFS at the time of the primary OS analysis was 3.4 months in the alive and still on treatment were higher than 90% at each assess- docetaxel arm versus 2.8 in the atezolizumab arm [HR ¼ 0.99; ment. At assessments up to cycle 14, the compliance rates for 95% confidence interval (CI), 0.75–1.30]. Investigator-assessed QLQ-LC13 were higher than 80%. The analysis of time to lung ORR per RECIST 1.1 was 15.4% and 14.6% in the docetaxel arm cancer symptoms deterioration showed no compelling difference and the atezolizumab arm, respectively. The responders on the between the two treatment arms. atezolizumab arm had a point estimate for median response Although no obvious differences in PROs were demonstrated duration that was more than double that of responders on between arms in this open-label study, this should not be docetaxel, although the 95% CIs overlapped [18.6 months interpreted to mean that atezolizumab had no decrement in (95% CI, 11.6–not estimable [NE]) vs. 7.2 months (95% CI, patient's health-related quality of life compared with docetaxel, 5.6–12.5)]. Median time to onset of response on atezolizumab because the trial did not plan to test specific hypotheses related was almost double that of docetaxel: 84 days (range 40–442) to the PRO outcomes. versus 43 days (range 30–257). On the atezolizumab arm, 50% The OAK trial also collected PROs, and these data will be (n ¼ 11) of responders had ongoing responses at the time of final required for submission as a PMC. OS analysis of December 1, 2015, versus 14% (n ¼ 3) of responders on the docetaxel arm. PFS and ORR were secondary end- Safety points for OAK. However, the BLA submission included topline Of the 287 patients randomized in POPLAR, 277 (atezolizu- efficacy results only, with all data, including secondary endpoint mab: n ¼ 142; docetaxel: n ¼ 135) received at least one dose of data, from 1,225 randomized patients required for submission protocol-specified therapy and were included in the safety anal- as a PMC. ysis. The safety database was supplemented with results from Analyses from both POPLAR and OAK showed preserved 1,026 NSCLC patients on three single-arm phase II trials and one consistency of effect through all PD-L1 staining subgroups. The phase I dose-escalation trial. The demographics and baseline highest PD-L1 expression subgroup, TC3 or IC3, was made up of characteristics of the safety and efficacy populations were 137 patients in OAK (16%) and 47 patients in POPLAR (16%). similar. Table 3 presents the overview of safety in POPLAR and Prolongation of OS for atezolizumab compared with docetaxel the pooled safety population including all atezolizumab-treated was most pronounced in this subgroup, with an HR of 0.41 (95% patients in PCD4989g, FIR, BIRCH, POPLAR, and IMVigor 210. CI, 0.27–0.64) in OAK and 0.45 (95% CI, 0.21–0.95) at the Deaths due to adverse events (AE) on the atezolizumab arm final analysis of POPLAR. Median OS for those in this OAK sub- occurred in nine patients due to pneumothorax, ulcer hemor- group taking atezolizumab compared with docetaxel was 20.5 rhage, intestinal perforation, pulmonary embolism (two months versus 8.9 months. Median OS was not reached in this patients), pneumonia (two patients), cachexia secondary to dys- subpopulation for those on atezolizumab in POPLAR. It is for this phagia, and myocardial infarction. Nonfatal serious AEs (SAE)

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Table 3. Integrated summary of safety POPLAR All NSCLC All patients Total number of patients with at least one (n ¼ 142) (n ¼ 1,026) (n ¼ 1,987) Grade 5 AE 6 (4.2%) 34 (3.3%) 54 (2.9%) Grade 3–4 AE 57 (40%) 426 (41.5%) 782 (42%) SAE 50 (35%) 384 (37%) 713 (39%) AE leading to treatment discontinuation 11 (7.7%) 64 (6.2%) 137 (7.4%) imAE 11 (7.7%) 77 (7.5%) 141 (7.6%) Abbreviations: AE, adverse event; imAE, immune-mediated adverse event.

occurred in 35% of patients who received atezolizumab and 34% were sufficient to characterize the safety of atezolizumab for of patients who received docetaxel. The most frequent serious treatment of a serious and life-threatening condition, with the adverse reactions (>2% of atezolizumab-treated patients) were exception of updated safety data from OAK, which will be pneumonia, dyspnea, pleural effusion, pyrexia, and venous obtained as a PMC and additional data regarding the incidence thromboembolism. Dose interruptions occurred in 34 (24%) of thyroid toxicity, which is currently being obtained via an patients on the atezolizumab arm and 44 (33%) patients on the ongoing postmarketing requirement (PMR). Notable toxicities docetaxel arm. included a high incidence of infections, including pneumonia and In POPLAR, the most common AEs (>20% of atezolizumab- upper respiratory tract infections. Incidences of imAEs, including treated patients) were fatigue, decreased appetite, dyspnea, cough, pneumonitis, hepatitis, and diarrhea/colitis, were similar to or nausea, musculoskeletal pain, and constipation. The most com- lower than other checkpoint inhibitors such as nivolumab and mon grade 3 to 4 AEs (>2% of atezolizumab-treated patients) pembrolizumab. Recommendations for safe and effective use of were pneumonia, hypoxia, fatigue, musculoskeletal pain, and atezolizumab, including monitoring for imAEs, are included in arthralgia. Infections, including high-grade pneumonia, occurred the product label, including a patient medication guide (8). at a high rate in patients treated with atezolizumab in this study compared to patients treated with docetaxel. On the basis of the Discussion system organ classification term "infections and infestations," 42% of patients who received atezolizumab experienced an event The FDA review found that this BLA provided substantial evi- compared with 33% of those who received docetaxel. With regard dence to support the use of atezolizumab for the treatment of to pneumonia, the difference in incidence between the two arms is patients with mNSCLC who have disease progression during or not explained by exposure duration alone, as the number of following platinum-containing chemotherapy. The agency granted patient years at risk in the atezolizumab arm was 84 compared approval for atezolizumab for this indication on October 18, 2016. with 46 in the docetaxel arm; however, the incidence of pneu- Patients with EGFR or ALK genomic tumor aberrations should have monia was 18% versus 4%, respectively, for all grades and 6% disease progression on FDA-approved therapy for these aberrations versus 2% for grades 3 to 4. prior to receiving atezolizumab. As summarized in the FDA Ben- Class effects associated with anti–PD-1/anti–PD-L1 drugs, efit–Risk Assessment (Table 5), evidence supporting this approval including nivolumab and pembrolizumab, are primarily came from two randomized, controlled studies that showed con- immune-related and include pneumonitis, colitis, hepatitis, sistent results in efficacy. Treatment with atezolizumab versus hypophysitis, renal failure/nephritis, and hyper/hypothyroidism. docetaxel in the intended patient population in studies POPLAR In POPLAR, immune-mediated AEs (imAE) were identified as and OAK resulted in a 2.9- and a 4.2-month improvement in OS, those in which the date of systemic corticosteroid initiation was respectively. The evidence of improvement in OS, combined with on or up to 30 days after the AE onset date, the date of cortico- the demonstrated safety profile, was considered sufficient for steroid initiation was prior to the AE resolution date, and no clear regular approval of atezolizumab for the proposed indication. Use alternate etiology could be identified. The incidence of these of the PD-L1 assay as proposed for this BLA may identify a group of events is shown in Table 4. Across the integrated safety database, patients who may have a higher OS on atezolizumab. Of note, only including NSCLC and patients with other malignancies, the most the SP142 assay approved as a complementary diagnostic in the common imAEs were pneumonitis and rash, which each occurred context of this BLA should be used to define the PD-L1–positive in 1.2% of patients. population for purposes of the use of atezolizumab, as other The FDA review concluded that the safety profile of atezolizu- available assays were not studied in this context and should not mab in patients with NSCLC who have progressed following be used interchangeably. Preliminary evidence also exists that treatment with a platinum-based regimen is acceptable. The size tumor staining with the SP142 assay differs from other available of the safety database and duration of atezolizumab exposure assays (9). Although the indication for use of atezolizumab includes patients with EGFR mutations and ALK rearrangements who have progressed on prior targeted therapies in addition to Table 4. imAEs (>0.5%) in patients with NSCLC treated with atezolizumab platinum-doublet chemotherapy, it is important to note that only ImAEs All NSCLC (n ¼ 1,027) a limited number of these patients were included in POPLAR Pneumonitis 18 (1.8%) EGFR ALK a (7% of patients had mutations, and 1% had rearrange- Rash 11 (1.1%) ments) and OAK (10% of patients had EGFR mutations, and 0.2% Dyspnea 8 (0.8%) ALK AST increased 7 (0.7%) had rearrangements). Other targeted therapies are approved ALT increased 6 (0.6%) for use in the second-line setting for these patients. PD-1/PD-L1 Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. Two other targeting agents are approved for aIncludes dermatitis, rash maculopapular, and rash pruritic. use in the treatment of second-line mNSCLC: nivolumab and

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Table 5. FDA Beneﬁt–Risk Assessment Dimension Evidence and uncertainties Conclusions and reasons

Analysis of * Lung cancer is the leading cause of cancer-related deaths in the United States. NSCLC is a common cause of cancer-related condition * The majority of patients present with locally advanced or metastatic disease, which mortality that is not yet curable, and 5-year is incurable with currently available therapies. survival rates remain poor. Effective therapies * The 5-year survival for this population is currently less than 5%. are needed in this setting.

Current treatment * In second-line mNSCLC, once patients have progressed on platinum-doublet Despite recent drug approvals, treatment options chemotherapy, approved options include nivolumab or docetaxel ramucirumab. options in the second-lineþ mNSCLC setting Pemetrexed is approved in those with non-squamous NSCLC. remain limited, and these patients are * Several targeted therapies are approved under accelerated approval. For those considered incurable. whose tumors are positive for EGFR mutations and who have also failed ﬁrst-line targeted therapy, osimertinib is approved. For those whose tumors are positive for ALK rearrangements and who have failed targeted therapy, ceritinib and alectinib are approved. Pembrolizumab is approved in patients whose tumors are positive for PD-L1 as deﬁned by an FDA-approved test.

Beneﬁt * Treatment with atezolizumab in the intended patient population resulted in a 2.9- Substantial evidence of effectiveness for use of and 4.2-month improvement in OS compared to docetaxel in two randomized atezolizumab monotherapy in patients with clinical trials, POPLAR and OAK. non–small cell lung carcinoma who have * Median OS in POPLAR was 12.6 months (95% CI, 9.7–16.0) in the atezolizumab arm progressed on or after platinum-doublet compared with 9.7 months (95% CI, 8.6–12.0) in the docetaxel arm (HR ¼ 0.69; 95% therapy and, where applicable, EGFR- or CI, 0.52–0.92). ALK-directed therapy, supported by similar OS * Median OS in OAK was 13.8 months (95% CI, 11.8–15.7) in the atezolizumab arm improvements, was found from the two compared with 9.6 months (95% CI, 8.6–11.2) in the docetaxel arm (HR ¼ 0.74; 95% randomized, controlled studies. The results are CI, 0.63–0.87; log-rank P ¼ 0.0004). consistent between the two studies. * The result of the prespeciﬁed OS analysis of the PD-L1 selected subset in OAK was similar to the results of the primary analysis population (HR ¼ 0.74; 95% CI, 0.59–0.94; log-rank P ¼ 0.012).

Risk * Tolerated in most study patients. The proﬁle of adverse reactions associated with * The incidence of grade 3–4 reactions was lower in patients treated with atezolizumab is similar to that observed in atezolizumab compared to those treated with docetaxel, although the incidence of other agents targeting the PD-1/PD-L1 nonfatal SAEs was comparable. pathway and compares favorably to that of * Important risks include pneumonitis, hepatitis, endocrine disorders, colitis, docetaxel. infection, and neurologic disorders.

Risk management * Non-endocrine imAEs were largely reversible with the use of corticosteroids. The safe use of atezolizumab can be managed * A medication guide for atezolizumab describing the risks of imAEs will be required through accurate labeling and routine to better allow early recognition and initiation of treatment of these events. pharmacovigilance. No REMS is required. * To better estimate the risk of pneumonitis and other immune-mediated events, the applicant will fulfill a PMR to provide the safety datasets from the phase III OAK trial. Abbreviation: REMS, Risk Evaluation and Mitigation Strategy. Source: Weinstock C and Suzman D, Medical Reviews BLA 761041 TECENTRIQ (atezolizumab), U.S. Food and Drug Administration, October 19, 2016, pp. 15–17. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/761041Orig1s000MedR.pdf. pembrolizumab. Pembrolizumab, however, is restricted for use in with mNSCLC whose tumors express PD-L1 as determined those whose tumors are positive for PD-L1 as defined by an FDA- by an FDA-approved test. This was based on a statistically approved assay (7). Nivolumab is approved for second-line use in significant PFS improvement in patients who received pem- all patients regardless of PD-L1 expression levels (6), although the brolizumab compared with platinum-doublet chemotherapy convenience of the every 3-week dosing of atezolizumab com- (HR ¼ 0.50; 95% CI, 0.37–0.68; P < 0.001) and an pared to the every 2-week dosing of nivolumab may be a factor for OS improvement (HR 0.6; 95% CI, 0.41–0.89; P ¼ 0.005; some patients and clinicians. ref. 7). PFS, ORR, and median DoR were all secondary endpoints for Despite the first-line pembrolizumab approval, second-line OAK. However, the BLA submission included topline efficacy atezolizumab may be beneficial for patients who were exclud- results only, with all secondary endpoint data from 1,225 ran- ed from the pembrolizumab first-line indication, such as those domized patients in OAK to be submitted as a PMC. The primary considered PD-L1 negative by the assay used in the pembro- trial publication has published the results of analyses of these lizumab trials (Dako clinical trial assay using the 22C3 clone endpoints on the first 850 randomized patients in OAK, and they against PD-L1)andthosewithEGFR or ALK mutations. In appear consistent with the FDA's secondary endpoint analysis of addition, patients who have previously received platinum- the POPLAR data. Reported median PFS was 2.8 months (95% CI, doublet chemotherapy in the front-line mNSCLC setting 2.6–3.0) versus 4.0 months (95% CI, 3.3–4.2) for atezolizumab would still benefit from atezolizumab in the second-line set- versus docetaxel, ORR was 14% versus 13%, and median DoR was ting, although these patients may be less common in the future 16.3 months (95% CI, 9.7–NE) versus 6.2 months (4.9–9.2), P with the use of pembrolizumab for relevant patients in the value 0.0003 (10). first-line setting. Data on atezolizumab use after prior pem- Six days after this approval, on October 24, 2016, the FDA brolizumab is not known, as these patients were excluded from approved pembrolizumab for first-line treatment of patients both OAK and POPLAR.

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Conclusions Authors' Contributions Conception and design: C. Weinstock, S. Khozin, G. Kim, R. Pazdur The approval of atezolizumab as a single agent for patients with Development of methodology: C. Weinstock, S. Khozin, G. Kim, R. Pazdur metastatic non–small cell lung cancer whose disease has pro- Acquisition of data (provided animals, acquired and managed patients, gressed during or following platinum-containing chemotherapy provided facilities, etc.): C. Weinstock, R. Pazdur adds a survival-extending therapy to the increasing number of Analysis and interpretation of data (e.g., statistical analysis, biostatistics, treatment options available for these patients. computational analysis): C. Weinstock, S. Khozin, L. Zhang, S. Tang, G. Kim, R. Pazdur Writing, review, and/or revision of the manuscript: C. Weinstock, S. Khozin, Disclosure of Potential Conﬂicts of Interest D. Suzman, S. Tang, K.B. Goldberg, G. Kim, R. Pazdur Administrative, technical, or material support (i.e., reporting or organizing No potential conﬂicts of interest were disclosed. data, constructing databases): C. Weinstock, S. Wahby, G. Kim, R. Pazdur Study supervision: S. Khozin Disclaimer The Deputy Editor handling the peer review and decision-making process for Received March 9, 2017; revised May 1, 2017; accepted June 7, 2017; this article has no relevant employment associations to disclose. published OnlineFirst June 13, 2017.

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OF6 Clin Cancer Res; 23(16) August 15, 2017 Clinical Cancer Research

U.S. Food and Drug Administration Approval Summary: Atezolizumab for Metastatic Non−Small Cell Lung Cancer

Chana Weinstock, Sean Khozin, Daniel Suzman, et al.

Clin Cancer Res Published OnlineFirst June 13, 2017.

Updated version Access the most recent version of this article at: doi:10.1158/1078-0432.CCR-17-0540

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