Supplementary Figure S1-S6; Supplementary Table S1-S2

Supplemental Data: Cancer case counts population estimates and incidence rates by histology and year

Supplementary Figure S1 from Cell Adhesion Molecules, Vascular Endothelial Growth Factor, and Basic Fibroblast Growth Factor in Patients with Non–Small Cell Lung Cancer Treated with Chemotherapy with or without Bevacizumab—an Eastern Cooperative Oncology Group Study

Purpose Overall survival (OS) is the most significant endpoint for evaluation of treatment benefit with checkpoint inhibitors (CPI) in cancer. We evaluated serum C-reactive protein (CRP) in non-small cell lung cancer (NSCLC) trials with atezolizumab (anti-PD-L1) as an early OS surrogate. Methods Serum from patients enrolled in randomized Phase II (n = 240) and Phase III (n = 701) trials of NSCLC patients (POPLAR, OAK) who progressed on prior-platinum chemotherapy, were analyzed for CRP levels over time. Patients were grouped by changes in CRP levels post-treatment as either increased (≥ 1.5 fold), decreased (≤ 1.5 fold) or unchanged (within +1.5 fold) relative to pre-treatment levels to assess association with progression free survival (PFS) and OS. Results Decrease in serum CRP levels at 6 weeks relative to pre-treatment were observed in patients with RECIST1.1 based complete or partial responses (CR/PR) to atezolizumab whereas patients with disease progression (PD) demonstrated an increase in CRP levels in the Phase II POPLAR study, and confirmed in the Phase III OAK study. Decrease in serum CRP as early as six weeks post treatment predicted improved PFS and OS, even in patients who were determined as stable disease (SD) in their first scan. This effect was not observed in the chemotherapy arms. Conclusion Modulation of serum CRP correlates with clinical outcome post-atezolizumab treatment. This routine lab test may provide utility in informing OS signals as early as 6 weeks post-initiation of therapy with CPIs in NSCLC.

Introduction: Cytotoxic agents have immunomodulatory effects, providing a rationale for combining atezolizumab (anti-programmed death-ligand 1 [anti-PD-L1]) with chemotherapy. The randomized phase III IMpower131 study (NCT02367794) evaluated atezolizumab with platinum-based chemotherapy in stage IV squamous NSCLC. Methods: A total of 1021 patients were randomized 1:1:1 to receive atezolizumab+carboplatin+paclitaxel (A+CP) (n = 338), atezolizumab+carboplatin+nab-paclitaxel (A+CnP) (n = 343), or carboplatin+nab-paclitaxel (CnP) (n = 340) for four or six 21-day cycles; patients randomized to the A+CP or A+CnP arms received atezolizumab maintenance therapy until progressive disease or loss of clinical benefit. The coprimary end points were investigator-assessed progression-free survival (PFS) and overall survival (OS) in the intention-to-treat (ITT) population. The secondary end points included PFS and OS in PD-L1 subgroups and safety. The primary PFS (January 22, 2018) and final OS (October 3, 2018) for A+CnP versus CnP are reported. Results: PFS improvement with A+CnP versus CnP was seen in the ITT population (median, 6.3 versus 5.6 mo; hazard ratio [HR] = 0.71, 95% confidence interval [CI]: 0.60-0.85; p = 0.0001). Median OS in the ITT population was 14.2 and 13.5 months in the A+CnP and CnP arms (HR = 0.88, 95% CI: 0.73-1.05; p = 0.16), not reaching statistical significance. OS improvement with A+CnP versus CnP was observed in the PD-L1-high subgroup (HR = 0.48, 95% CI: 0.29-0.81), despite not being formally tested. Treatment-related grade 3 and 4 adverse events and serious adverse events occurred in 68.0% and 47.9% (A+CnP) and 57.5% and 28.7% (CnP) of patients, respectively. Conclusions: Adding atezolizumab to platinum-based chemotherapy significantly improved PFS in patients with first-line squamous NSCLC; OS was similar between the arms. (C) 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc.

BACKGROUND The efficacy and safety of the anti-programmed death ligand 1 (PD-L1) monoclonal antibody atezolizumab, as compared with those of platinum-based chemotherapy, as first-line treatment for patients with metastatic non-small-cell lung cancer (NSCLC) with PD-L1 expression are not known. METHODS We conducted a randomized, open-label, phase 3 trial involving patients with metastatic nonsquamous or squamous NSCLC who had not previously received chemotherapy and who had PD-L1 expression on at least 1% of tumor cells or at least 1% of tumor-infiltrating immune cells as assessed by the SP142 immunohistochemical assay. Patients were assigned in a 1:1 ratio to receive atezolizumab or chemotherapy. Overall survival (primary end point) was tested hierarchically according to PD-L1 expression status among patients in the intention-to-treat population whose tumors were wild-type with respect to EGFR mutations or ALK translocations. Within the population with EGFR and ALK wild-type tumors, overall survival and progression-free survival were also prospectively assessed in subgroups defined according to findings on two PD-L1 assays as well as by blood-based tumor mutational burden. RESULTS Overall, 572 patients were enrolled. In the subgroup of patients with EGFR and ALK wild-type tumors who had the highest expression of PD-L1 (205 patients), the median overall survival was longer by 7.1 months in the atezolizumab group than in the chemotherapy group (20.2 months vs. 13.1 months; hazard ratio for death, 0.59; P = 0.01). Among all the patients who could be evaluated for safety, adverse events occurred in 90.2% of the patients in the atezolizumab group and in 94.7% of those in the chemotherapy group; grade 3 or 4 adverse events occurred in 30.1% and 52.5% of the patients in the respective groups. Overall and progression-free survival favored atezolizumab in the subgroups with a high blood-based tumor mutational burden. CONCLUSIONS Atezolizumab treatment resulted in significantly longer overall survival than platinum-based chemotherapy among patients with NSCLC with high PD-L1 expression, regardless of histologic type. (Funded by F. Hoffmann-La Roche/Genentech; IMpower110 ClinicalTrials.gov number, NCT02409342.).

•Bevacizumab (Avastin®), a VEGF-A targeting monoclonal antibody, was the first approved angiogenesis inhibitor.•Approved in a range of solid tumor indications, bevacizumab is an important part of the standard of care in oncology.•The recently identified immune modulatory roles of VEGF provide a powerful rationale for combination therapies.•First clinical studies of the combination of bevacizumab with immune checkpoint inhibitors have shown efficacy.

9012 Background: Atezolizumab (atezo) + bevacizumab (bev) + chemo (carboplatin + paclitaxel [CP]; ABCP) showed improved PFS and OS vs bev + CP (BCP) in pts with chemo-naive NSCLC (IMpower150). Benefit with ABCP vs BCP extended to key subgroups, including pts with baseline (BL) liver mets, which is a poor prognostic factor in metastatic NSCLC. Similar outcomes were not seen with atezo + chemo (IMpower150 [atezo + CP; ACP]; IMpower130; IMpower132), suggesting that the addition of bev to atezo + chemo is important for conferring clinical benefit in these pts. Here we further explore characteristics and responses of pts with BL liver mets in IMpower150. Methods: 1202 ITT pts were randomized 1:1:1 to receive ABCP, ACP or BCP. Doses were: A, 1200 mg; B, 15 mg/kg; C, AUC 6 mg/mL/min; P, 200 mg/m2. Coprimary endpoints were OS and investigator-assessed PFS in ITT–wild-type pts. Exploratory analyses included efficacy and safety in pts with liver mets. Results: The data capture ≥ 20-mo follow-up in ITT pts (data cutoff: Jan 22, 2018). 162 pts had BL liver mets (ABCP, n = 52; ACP; n = 53; BCP, n = 57), with a median of 3 metastatic sites and median BL tumor SLD of 109 mm (range, 10-249). BL characteristics in these pts were generally balanced across study arms. PFS and OS were improved with ABCP vs BCP (Table). Gr 3-4 treatment-related AEs occurred in 52.1%, 36.5% and 54.5% of pts with liver mets in the ABCP, ACP and BCP arms, respectively. Conclusions: ABCP reduced the risk of death in pts with liver mets by 48% vs BCP and may represent an important new treatment option for this population. Clinical trial information: NCT02366143. [Table: see text]

High-grade (CTCAE grade ≥3) CIPN implies severe symptoms and limitation of self-care activities of daily living (ADL). To date, studies characterizing the incidence of and factors associated with CIPN have been conducted almost exclusively in breast cancer populations. As such, they generally evaluate only women and lack assessment of platinum-based chemotherapy. We therefore examined the incidence and factors associated with high-grade CIPN among patients treated on ECOG-ACRIN advanced non-small cell lung cancer (NSCLC) clinical trials. We included two completed trials in the analysis: E1594 (comparison of 4 chemotherapy regimens: cisplatin-paclitaxel, cisplatin-gemcitabine, cisplatin-docetaxel, carboplatin-paclitaxel) and E4599 (carboplatin-paclitaxel ± bevacizumab). We identified patients who developed treatment-related grade ≥3 CIPN. Multivariable logistic regression modeling was performed to estimate adjusted odds ratios. For the treatment variable, the reference group ended up combining the cisplatin+paclitaxel and cisplatin+docetaxel arms since their results were not significantly different from one another. Body-mass index (BMI) was categorized by median value (25.2 kg/m2). Among 1,989 total patients, 167 (8.4%) developed grade ≥3 CIPN. Incidence was highest for the carboplatin-paclitaxel regimen (9.9%) and lowest for cisplatin-paclitaxel (4.5%) (P=0.006). Grade ≥3 CIPN was associated with BMI (9.9% for ≥25.2 kg/m2 vs 6.9% for <25.2 kg/m2; P=0.02) and sex (6.9% for men vs 10.4% for women; P=0.006). There was a non-significant trend toward association with age (10.4% for ≥70 years versus 7.8% for <70 years; P=0.08). In multivariate analysis, chemotherapy regimen, sex, and BMI remained independently associated with grade ≥3 CIPN. Carboplatin-paclitaxel chemotherapy, female sex, and high BMI are associated with the development of high-grade CIPN. Given the clinical severity of this condition and the potential for long-term persistence, consideration of risk-based monitoring and treatment selection may be warranted.

Background: Locally advanced SCCHN is associated with a high risk for local recurrence and distant metastases. Current treatment options include a combination of surgery, radiation therapy and chemotherapy to optimize the chances for long-term disease control and improved survival. As standard of care, patients are monitored after definitive local therapy for local recurrence and/or distant metastases. No effective systemic adjuvant treatment has been identified. Atezolizumab (atezo) is an anti-programmed death-ligand 1 (PD-L1) monoclonal antibody that restores anti-tumor immunity by preventing PD-L1 from binding to its receptors. Efficacy results from a cohort of 32 patients with recurrent/metastatic SCCHN in the Phase I PCD4989g study suggested that atezo offers promising clinical benefit in SCCHN. The objective of IMvoke010 (NCT03452137) is to evaluate the efficacy and safety of adjuvant treatment with atezo in comparison to placebo in patients with locally advanced SCCHN who are at high risk for disease recurrence or progression following definitive curative therapy. Trial design: IMvoke010 is a global, double-blind, placebo-controlled, randomized Phase III trial currently enrolling patients who have completed definitive local/regional therapy for Stage III human papillomavirus (HPV)-positive oropharyngeal carcinoma or Stage IVA or IVB HPV-negative SCCHN involving the oral cavity, oropharynx, larynx or hypopharynx and are at high risk for disease recurrence or progression. Approximately 400 patients will be randomized 1:1 to receive placebo or atezo 1200 mg every 3 weeks for up to a year (≤ 16 cycles) or until unacceptable toxicity, disease recurrence or progression. Patients with nasopharyngeal carcinoma, metastatic disease or progressive disease during or at completion of definitive local therapy will be excluded. Primary endpoints are independent review facility-assessed event-free survival (EFS) and overall survival. Key secondary endpoints include investigator-assessed EFS, safety and patient reported outcomes. Exploratory biomarkers will also be assessed. Citation Format: Deborah J. Wong, Jerome Fayette, Ye Guo, Matthew Kowgier, Ezra Cohen, Ricard Mesia Nin, Arunee Dechaphunkul, Kumar Prabhash, Jessica Geiger, Sarwan Bishnoi, Henning Schafer, Christina Matheny, Fairooz Kabbinavar, Alan Sandler, David Raben, Robert Haddad. IMvoke010: Randomized Phase III study of atezolizumab as adjuvant monotherapy after definitive therapy of squamous cell carcinoma of the head and neck (SCCHN) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT123.

Background Platinum chemotherapy (carboplatin or cisplatin) + etoposide is the current 1L standard of care treatment (tx) for ES-SCLC. Despite high response rates on this regimen, patient (pt) outcomes remain poor. IMpower133 is a Ph1/3, double-blind, randomized, placebo (PBO)-controlled trial that is evaluating the efficacy and safety of adding PD-L1-inhibitor atezo or PBO to 1L tx for ES-SCLC (NCT02763579). Methods IMpower133 enrolled pts without prior tx for ES-SCLC; PD-L1 testing was not required. Pts were randomized 1:1 to four 21-day cycles of carboplatin (AUC 5 mg/mL/min IV, Day 1) + etoposide (100 mg/m2 IV, Days 1-3) with either atezo (1200 mg IV, Day 1) or PBO, then maintenance atezo or PBO until PD, unacceptable toxicity or loss of clinical benefit. Maintenance prophylactic cranial irradiation (PCI) was allowed per protocol, while definitive thoracic radiation (TR) was not. Coprimary endpoints were OS and investigator-assessed PFS. A key exploratory endpoint was outcomes by blood tumor mutation burden (bTMB) analyzed at prespecified cutoffs (≥ 16 vs < 16 and ≥ 10 vs < 10 mutations/Mb). Results Adding atezo to carboplatin + etoposide demonstrated significant improvement in efficacy (OS and PFS) in 1L ES-SCLC (Table). Survival benefits were consistent across key subgroups and prespecified bTMB cutoffs. 44 pts (22 in each arm [per ITT]) received PCI, and 7 (3 in atezo arm, 4 in PBO arm) received TR. Gr 3-4 tx-related adverse events (AEs) occurred in 57% of atezo pts vs 56% of PBO pts; serious tx-related AEs occurred in 23% vs 19%. Occurrence of CNS-related AEs in pts who had PCI are shown in the Table. Conclusion Adding atezo to carboplatin + etoposide resulted in a significant improvement in survival in this 1L ES-SCLC all-comers population. There were no new safety signals, including in pts who received PCI or TR. Atezo + carboplatin + etoposide may represent a new standard regimen for untreated ES-SCLC. Atezo + carboplatin + etoposiden = 201PBO + carboplatin + etoposiden = 202Co-primary endpointsMedian OS, mo12.310.3HR 0.70 (95% CI: 0.54, 0.91); P = 0.0069Median PFS, mo5.24.3HR 0.77 (95% CI: 0.62, 0.96) P = 0.017Secondary efficacy endpointsInvestigator-assessed confirmed ORR, %60.264.4Median DoR, mo4.23.9CNS-related AEs in pts who had PCI, n (%)a,bn = 23n = 21Headache8 (34.8)4 (19.0)Asthenia5 (21.7)2 (9.5)Dizziness2 (8.7)0Insomnia2 (8.7)1 (4.8)Fall2 (8.7)1 (4.8)aSafety population; safety analyses conducted according to tx received (1 pt randomized to the control arm received a dose of atezo).bIncludes AEs occurring in ≥ 2 patients. Citation Format: Aaron S. Mansfield, Stephen V. Liu, Aleksandra Szczęsna, Libor Havel, Maciej Kzrakowski, Maximilian J. Hochmair, Florian Huemer, György Losonczy, Melissa L. Johnson, Makoto Nishio, Martin Reck, Tony S. Mok, Sivuonthanh Lam, David S. Shames, Juan Liu, Fairooz Kabbinavar, Alan Sandler, Leora Horn. IMpower133: Primary efficacy and safety + CNS-related adverse events in a Ph1/3 study of first-line (1L) atezolizumab (atezo) + carboplatin + etoposide in extensive-stage SCLC (ES-SCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT199.

Background: A standard of care for resectable early-stage NSCLC is surgery alone or in combination with adjuvant or neoadjuvant platinum-based doublet chemotherapy (PT-DC). Still, 30%-70% of patients develop recurrence and die from disease progression, highlighting the need for more effective treatments. Atezo, an anti–programmed death-ligand 1 (PD-L1) antibody that restores anti-tumour immunity, has shown promising efficacy as monotherapy and in combination with chemotherapy in advanced NSCLC. It is hypothesised that the combination of atezo and PT-DC may provide clinical benefit in the neoadjuvant setting by enhancing cancer cell killing and eradicating micrometastases, reducing the risk of disease recurrence. The objective of IMpower030 (NCT03456063) is to evaluate the efficacy and safety of atezo in combination with PT-DC as neoadjuvant treatment for patients with resectable early-stage NSCLC. Trial design: IMpower030 is a global, Phase III, double-blind, randomized study in patients with histologically or cytologically confirmed, resectable stage II, IIIA, or select IIIB (T3N2) NSCLC (per AJCC/UICC, 8th ed). Study inclusion requires measurable disease per RECIST v1.1, ECOG PS of 0/1 and eligibility for R0 resection with curative intent and PT-DC. Patients who had received prior therapy for lung cancer or present with nonsquamous NSCLC with activating EGFR mutations or ALK translocation are excluded. Patients will be randomized to receive 4 cycles of neoadjuvant atezo (1200 mg Q3W, Arm A) or placebo (Arm B) in combination with an investigator-selected PT-DC regimen. Following unblinding, patients in Arm A will receive adjuvant atezo treatment for ≤ 16 cycles or until disease recurrence or unacceptable toxicity, and patients in Arm B will receive best supportive care and scheduled observational follow-up. Endpoints will include major pathological response (≤ 10% residual viable tumour tissue at time of resection), investigator-assessed event-free survival and disease-free survival per RECIST v1.1, OS, ORR, pathological complete response and patient-reported outcomes. Exploratory biomarkers will also be evaluated. Clinical trial identification: NCT03456063. Editorial acknowledgement: Medical writing assistance for this abstract was provided by Jessica Men, PharmD, of Health Interactions and funded by F. Hoffmann-La Roche, Ltd. Legal entity responsible for the study: F. Hoffmann-La Roche, Ltd. Funding: F. Hoffmann-La Roche, Ltd. Disclosure: S. Peters: Ad board, honoraria: Daiichi, Debiopharm, FoundMed, Janssen, Merrimack, PharmaMar, Regeneron, Sanofi, Seattle Genetics; Ad boad, honoraria, talk: Lilly, Takeda; Talk, honoraria, investigation in trials: AZ, BI, BMS, Clovis; Ad board, honoraria, talk, investigation in trials: Roche, Merck, Novartis, Pfizer; Ad board, honoraria, investigation in trials: Illumina. A.W. Kim: Full-time employee: University of Southern California; Advisory board: Medtronic, Genentech; Other (support of parent study, funding of editorial support): F. Hoffmann-La Roche. B. Solomon: Support of parent study, funding of editorial support: Roche. D.R. Gandara: Research grants: AstraZeneca, Genentech, Novartis, Merck; Consultant/Advisory board: AstraZeneca, Celgene, CellMax, Genentech, Guardant Health, Inivata, IO Biotech, Lilly, Liquid Genomics, Merck, Samsumg Bioepis; Parent study, medical writing support: Roche. R. Dziadziuszko: Advisor/Board member: Roche, Novartis, Pfizer, Boehringer Ingelheim, AstraZeneca, Bristol-Myers Squibb; Speaker's Bureau: Roche, Pfizer, Foundation Medicine; Support of parent study, funding of editorial support: Roche. A. Brunelli: Support of parent study, funding of editorial support: F. Hoffmann-La Roche. M.C. Garassino: Grants/research support: MSD, BMS, AZ, Roche, Celgene, Medimmune; Advisory board/Speakers' bureau: MSD, BMS, AZ, Roche, Celgene, Medimmune, Incyte, Ignyta; Other (support of parent study, funding of editorial support): Roche. M. Reck: Speakers bureau, consulting, advisory role: Roche, Lilly, Pfizer, BI, AZ, MSD, BMS, Merck, Novartis, Celgene; Other (support of parent study, funding of editorial support): Roche. L. Wang, I. To, S.W. Sun, B.J. Gitlitz: Employee: Genentech; Other (support of parent study, funding of editorial support): Roche. A. Sandler: Employee: Genetech; Stock: Roche; Other (support of parent study, funding of editorial support): Roche. N. Rizvi: Consulting: AbbVie, AstraZeneca, BMS, EMD Sorono, Genentech, GSK, Janssen, Lilly, Merck, Novartis, Pfizer, Regeneron; Advisory boards: Bellicum, Brooklyn Immunotherapeutics, Neogenomics, Gritstone; Equity: Bellicum, Brooklyn Immunotherapeutics, Gritstone, ARMO Board of Director (2017-2018) with Stock options vested with company acquisition by Lilly (June 25, 2018); Royalties: Personal Genome Diagnostics: Royalties related to patent filed by MSKCC, Determinants of cancer response to immunotherapy (PCT/US2015/062208); Research funding: BMS, Merck; Institutional financial interests: Clinical research: AstraZeneca, BMS, Genentech, GSK, Merck, Regeneron.

Background: Atezolizumab (atezo) (anti-PD-L1) monotherapy improves overall survival (OS) vs docetaxel in 2L+ NSCLC regardless of PD-L1 status; phase 3, 1L studies have shown clinical benefit of atezo plus chemotherapy and atezo in combination with bevacizumab and chemotherapy. IMpower130 (NCT02367781) evaluated atezo + CnP vs CnP in patients (pts) with measurable (RECIST v1.1) stage IV non-squamous NSCLC. Methods: Pts (randomized 2:1) received atezo (1200 mg IV q3w) + CnP (carboplatin: AUC 6 q3w; nab-paclitaxel: 100 mg/m2 IV qw) (Arm A) or CnP (Arm B), for 4 or 6 21-day cycles and maintenance (Arm A: atezo until loss of clinical benefit; Arm B: best supportive care or pemetrexed q3w until disease progression [PD]). Crossover to atezo at PD was initially permitted for Arm B pts. Co-primary endpoints were investigator-assessed PFS and OS (ITT-WT population: EGFR-WT/ALK-negative). Secondary endpoints were OS and PFS (ITT population and by PD-L1 expression), response rate and safety. ITT population could be formally tested for OS/PFS if ITT-WT OS was positive. Results: 723 ITT (679 ITT-WT) pts were enrolled. Statistically significant, clinically meaningful improvements in OS and statistically significant and clinically meaningful improvements in PFS (ITT and ITT-WT) were observed in Arm A vs Arm B (table). PFS and OS benefit was observed in all PD-L1 subgroups, and consistently across all subgroups, except in pts with liver metastases and EGFR/ALK genomic alterations. In treated pts, 73.2% (Arm A) vs 60.3% (Arm B) had grade 3-4 treatment-related adverse events. Conclusions: Overall, IMpower130 showed statistically significant, clinically meaningful improvements in OS and statistically significant improvements in PFS with atezo + CnP, vs CnP, in 1L, stage IV non-squamous NSCLC, in this predominantly ITT-WT population. No new safety signals were identified. Table.IMpower130 Efficacy AnalysesArm A Atezo + CnPArm B CnPITT-WTn = 451n = 228Median OS (95% CI)18.6 mo (16.0-21.2)13.9 mo (12.0-18.7)HR (95% CI; P value)0.79 (0.64-0.98; 0.033)12-mo OS (95% CI)63.1% (58.59-67.66)55.5% (48.89-62.17)Median PFS (95% CI)7.0 mo (6.2-7.3)5.5 mo (4.4-5.9)HR (95% CI; P value)0.64 (0.54-0.77; < 0.0001)12-mo PFS (95% CI)29.1% (24.83-33.44)14.1% (9.37-18.76)n = 447n = 226Confirmed ORR (investigator assessed) (95% CI)49.2% (44.49-53.96)31.9% (25.84-38.36)n = 220n = 72Median DOR (95% CI)8.4 mo (6.9-11.8)6.1 mo (5.5-7.9)PD-L1 highan = 88n = 42Median OS (95% CI)17.4 mo (14.78-NA)16.9 mo (10.94-NA)HR (95% CI)0.84 (0.51-1.39)Median PFS (95% CI)6.4 mo (5.49-9.76)4.6 mo (3.22-7)HR (95% CI)0.51 (0.34-0.77)PD-L1 lowan = 128n = 65Median OS (95% CI)23.7 mo (18.63-NA)15.9 mo (12.32-25.63)HR (95% CI)0.70 (0.45-1.08)Median PFS (95% CI)8.3 mo (7.16-10.35)6.0 mo (5.29-6.93)HR (95% CI)0.61 (0.43-0.85)PD-L1 negativean = 235n = 121Median OS (95% CI)15.2 mo (12.88-19.15)12.0 mo (8.97-17.71)HR (95% CI)0.81 (0.61-1.08)Median PFS (95% CI)6.2 mo (5.52-7.16)4.7 mo (4.11-5.72)HR (95% CI)0.72 (0.56-0.91)ITTn = 483n = 240Median OS (95% CI)18.1 mo (15.3-20.8)13.9 mo (12.0-18.2)HR (95% CI; P value)0.80 (0.65-0.99; 0.039)Median PFS (95% CI)7.0 mo (6.3-7.3)5.6 mo (4.5-5.9)HR (95% CI; P value)0.65 (0.54-0.77; < 0.0001)a PD-L1 high (TC3 or IC3): Patients with PD-L1 expression in ≥ 50% of tumor cells or ≥ 10% of tumor-infiltrating immune cells; PD-L1 low (TC1/2 or IC1/2): Patients with PD-L1 expression in ≥ 1% and < 50% of tumor cells or ≥ 1% and <10% of tumor-infiltrating immune cells; and PD-L1 negative (TC0 and IC0): Patients with PD-L1 expression in <1% of tumor cells and < 1% of tumor-infiltrating immune cells. Data cut-off: 15 March 2018. Minimum follow up: 13 months. NCT02367781.DOR, duration of response; HR, hazard ratio; IC, immune cells; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; TC, tumor cells. Citation Format: Howard L. West, Michael McCleod, Maen Hussein, Alessandro Morabito, Achim Rittmeyer, Henry J. Conter, Hans-Georg Kopp, Davey Daniel, Steven McCune, Tarek Mekhail, Alona Zer, Niels Reinmuth, Ahad Sadiq, Venice Archer, Tania Ochi Lohmann, Helen Jessop, Lijia Wang, Marcin Kowanetz, Alan Sandler, Federico Cappuzzo. IMpower130: Progression-free survival (PFS) and safety analysis from a randomized phase 3 study of carboplatin + nab-paclitaxel (CnP) with or without atezolizumab as first-line (1L) therapy in advanced non-squamous NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT200.

Background Atezolizumab (a monoclonal antibody against PD-L1), which restores anticancer immunity, improved overall survival in patients with previously treated non-small-cell lung cancer and also showed clinical benefit when combined with chemotherapy as first-line treatment of non-small-cell lung cancer. IMpower130 aimed to assess the efficacy and safety of atezolizumab plus chemotherapy versus chemotherapy alone as first-line therapy for non-squamous non-small-cell lung cancer. Methods IMpower130 was a multicentre, randomised, open-label, phase 3 study done in 131 centres across eight countries (the USA, Canada, Belgium, France, Germany, Italy, Spain, and Israel). Eligible patients were aged 18 years or older, and had histologically or cytologically confirmed stage IV non-squamous non-small-cell lung cancer, an Eastern Cooperative Oncology Group performance status of 0 or 1, and received no previous chemotherapy for stage IV disease. Patients were randomly assigned (2:1; permuted block [block size of six] with an interactive voice or web response system) to receive atezolizumab (1200 mg intravenously every 3 weeks) plus chemotherapy (carboplatin [area under the curve 6 mg/mL per min every 3 weeks] plus nab-paclitaxel [100 mg/m(2) intravenously every week]) or chemotherapy alone for four or six 21-day cycles followed by maintenance therapy. Stratification factors were sex, baseline liver metastases, and PD-L1 tumour expression. Co-primary endpoints were investigator-assessed progression-free survival and overall survival in the intention-to-treat wild-type (ie, EGFR(wt) and ALK(wt)) population. The safety population included patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, number NCT02367781. Findings Between April 16, 2015, and Feb 13, 2017, 724 patients were randomly assigned and 723 were included in the intention-to-treat population (one patient died before randomisation, but was assigned to a treatment group; this patient was excluded from the intention-to-treat population) of the atezolizumab plus chemotherapy group (483 patients in the intention-to-treat population and 451 patients in the intention-to-treat wild-type population) or the chemotherapy group (240 patients in the intention-to-treat population and 228 patients in the intention-to-treat wild-type population). Median follow-up in the intention-to-treat wild-type population was similar between groups (18.5 months [IQR 15.2-23.6] in the atezolizumab plus chemotherapy group and 19.2 months [15.4-23.0] in the chemotherapy group). In the intention-to-treat wild-type population, there were significant improvements in median overall survival (18.6 months [95% CI 16.0-21.2] in the atezolizumab plus chemotherapy group and 13.9 months [12.0-18.7] in the chemotherapy group; stratified hazard ratio [HR] 0.79 [95% CI 0.64-0.98]; p=0.033) and median progression-free survival (7.0 months [95% CI 6.2-7.3] in the atezolizumab plus chemotherapy group and 5.5 months [4.4-5.9] in the chemotherapy group; stratified HR 0.64 [95% CI 0.54-0.77]; p<0.0001]). The most common grade 3 or worse treatment-related adverse events were neutropenia (152 [32%] of 473 in the atezolizumab plus chemotherapy group vs 65 [28%] of 232 in the chemotherapy group), anaemia (138 [29%] vs 47 [20%]), and decreased neutrophil count (57 [12%] vs 19 [8%]). Treatment-related serious adverse events were reported in 112 (24%) of 473 patients in the atezolizumab plus chemotherapy group and 30 (13%) of 232 patients in the chemotherapy group. Treatment-related (any treatment) deaths occurred in eight (2%) of 473 patients in the atezolizumab plus chemotherapy group and one (<1%) of 232 patients in the chemotherapy group. Interpretation IMpower130 showed a significant and clinically meaningful improvement in overall survival and a significant improvement in progression-free survival with atezolizumab plus chemotherapy versus chemotherapy as first-line treatment of patients with stage IV non-squamous non-small-cell lung cancer and no ALK or EGFR mutations. No new safety signals were identified. This study supports the benefit of atezolizumab, in combination with platinum-based chemotherapy, as first-line treatment of metastatic non-small-cell lung cancer. Copyright (C) 2019 Elsevier Ltd. All rights reserved.

IMpower131 (NCT02367794) is a randomised Phase III trial of atezolizumab + chemotherapy vs chemotherapy alone as first-line therapy in Stage IV squamous NSCLC. Here we report the final OS results (Arm B vs Arm C). Enrolled patients were randomised 1:1:1 to Arm A (atezolizumab 1200 mg q3w + carboplatin AUC 6 q3w + paclitaxel 200 mg/m2 q3w), Arm B (atezolizumab + carboplatin + nab-paclitaxel 100 mg/m2 qw) or Arm C (carboplatin + nab-paclitaxel) for 4 or 6 cycles followed by atezolizumab maintenance therapy (Arms A and B) until loss of clinical benefit or progressive disease. Coprimary endpoints were investigator-assessed PFS and OS in the ITT population. Data cutoff: October 3, 2018. 1021 patients were enrolled, with 343 in Arm B and 340 in Arm C. Median age was 65 years (range, 23-83 [Arm B] and 38-86 [Arm C]) and ≈80% of patients were male. The proportion of patients with high (14% vs 13%), positive (39% vs 37%) or negative (47% vs 50%) PD-L1 expression was similar between arms. Median OS in the ITT population was 14.2 months in Arm B vs 13.5 months in Arm C (HR, 0.88 [95% CI: 0.73, 1.05]; P = 0.158; Table), not crossing the boundary for statistical significance. In the PD-L1–high subgroup, median OS was 23.4 vs 10.2 months, respectively (HR, 0.48 [95% CI: 0.29, 0.81]; not formally tested). Treatment-related Grade 3-4 AEs and treatment-related SAEs occurred in 68.0% and 21.0% (Arm B) and 57.5% and 10.5% (Arm C) of patients; no new safety signals were identified, consistent with previous analyses. Final OS in Arm B vs C did not cross the boundary for statistical significance. Clinically meaningful OS improvement was observed in the PD-L1–high subgroup, despite not being formally tested. No new or unexpected safety signals were reported.Tabled 1Arm B Atezolizumab + Carboplatin + Nab-Paclitaxel (n = 343)Arm C Carboplatin + Nab-Paclitaxel (n = 340)HR (95% CI)Median OS, moITT14.213.50.88 (0.73, 1.05); P = 0.16PD-L1 high (TC3 or IC3)23.410.20.48 (0.29, 0.81)PD-L1 positive (TC1/2/3 or IC1/2/3)14.815.00.86 (0.67, 1.11)PD-L1 negative (TC0 or IC0)14.012.50.87 (0.67, 1.13)Median PFS, mo6.55.60.75 (0.64, 0.88)Confirmed ORR, n/N (%)a170/342 (49.7)139/339 (41.0)—a Patients were classified as missing or unevaluable when no post-baseline response assessments were available or all post-baseline response assessments were unevaluable. CI, confidence interval; HR, hazard ratio; IC, tumour-infiltrating immune cell; ITT, intention-to-treat; OS, overall survival; ORR, objective response rate; PD-L1, programmed death-ligand 1; PFS, progression-free survival; TC, tumour cell.TC3 or IC3: PD-L1 expression on ≥50% of TC or ≥10% of IC; TC1/2/3 or IC1/2/3: PD-L1 expression on ≥1% of TC or IC; TC0 and IC0: PD-L1 expression on <1% of TC and IC. Open table in a new tab

Introduction: Cancer immunotherapy has revolutionized the treatment of patients with advanced or metastatic non-small cell lung cancer (NSCLC). However, specific patient groups (e.g. patients with activating epidermal growth factor receptor [EGFR] mutations) do not appear to derive benefit from immune checkpoint inhibitor (ICI) monotherapy. Combining ICIs, such as atezolizumab, with chemotherapy and/or targeted therapies may help to address this unmet need.Areas covered: Atezolizumab is an anti-programmed death-ligand 1 therapy for several tumor types. We review its clinical efficacy and safety in the treatment of advanced or metastatic NSCLC, with a specific focus on the combination of atezolizumab with bevacizumab, carboplatin, and paclitaxel (ABCP). Data from IMpower150 show that the ABCP regimen provided clinical benefit to patients with non-squamous NSCLC, including those with EGFR mutations.Expert opinion: Combining ICIs with chemotherapy has proven to be superior to chemotherapy alone. However, tumor resistance to ICIs will likely increase as these drugs enter earlier lines of therapy, underscoring a need for effective treatments when immunotherapy fails. Data suggest that the ABCP regimen may circumvent ICI resistance mechanisms. Continued investigation into the regimen's mechanisms, improved patient profiling/selection, and treatment personalization will drive further development/discoveries.

8512 Background: Consolidation durvalumab after chemoradiation (CRT) is the new standard of care in locally advanced NSCLC (LA-NSCLC). We hypothesized that adding immunotherapy concurrently with CRT (cCRT) would increase efficacy without significant additive toxicity. To test this concept, we conducted a phase II trial called DETERRED combining atezolizumab (atezo) with cCRT followed by consolidation full dose carboplatin/paclitaxel (CP) with atezo (CP-atezo) for 2 cycles and then maintenance atezo for 1 year. The primary endpoint was safety/toxicity and feasibility. Methods: This study enrolled patients (pts) between February 2016 - April 2018 and was done in two parts: In part 1 (N=10), conventionally fractionated CRT (60-66 Gy in 30-33 fractions combined with weekly low dose CP) was followed by CP-atezo then maintenance atezo. Part 2 was cCRT (N=30) with atezo followed by CP-atezo then maintenance atezo. Atezo was given at 1200 mg IV Q3 weeks. Severe adverse events (SAEs) ≥ grade 3 were defined by CTCAE v5.0. Evaluable pts received at least one dose of atezo. PD-L1 staining utilizes the DAKO 22C3 platform. Kaplan Meier were analyzed for progression free survival (PFS) and overall survival (OS), and chi-square test for PD-L1 levels on any recurrence, with significance set at <0.05. Results: In Part 1, atezo related SAEs were seen in 4 pts (40%) (2 grade 3 arthralgia, 1 grade 3 dyspnea and 1 grade 5 TE fistula). Grade 2 radiation pneumonitis (RP) was seen in 1 pt. In Part 2, seven (23%) pts had atezo related SAEs (diarrhea, nephritis, dyspnea, fatigue and heart failure). RP was seen in 3 pts, 2 grade 2 and 1 grade 3, which led to atezo discontinuation. In Part 1, with an overall median follow up (f/u) time of 22.5 months and 27.4 months for survivors, the 1-year PFS is 50%, and OS is 79%. In part 2, with a median f/u time of 11.8 months and 13.7 months for survivors, the 1-year PFS was 57%, and OS is 79%. Baseline tumor biopsy PD-L1 status was evaluable for 34 pts. There were no significant differences in cancer recurrence for PD-L1 <1% (7/16=44%) vs ≥1% (6/18=33%), or for the PD-L1 cutoff of <50% (11/26=42%) vs ≥50% (2/8=25%). Conclusions: Concurrent atezo with CRT followed by CP-atezo and maintenance atezo is safe without increased toxicities compared to CRT alone followed by CP-atezo and maintenance atezo. Updated efficacy results from DETERRED will be presented. Ultimately, the clinical benefit of immunotherapy with cCRT followed by consolidation chemo-immunotherapy will need to be compared to the PACIFIC regimen in a larger randomized trial. Clinical trial information: NCT02525757.

9002 Background: Atezo (anti–PD-L1) inhibits PD-L1 to restore anticancer immunity; bev may enhance atezo efficacy by inhibiting VEGF immunosuppression and promoting T-cell tumor infiltration. IMpower150 is the first randomized Ph 3 trial evaluating atezo + chemo (carboplatin [C] + paclitaxel [P]) ± bev vs CP + bev in 1L NSQ NSCLC. PFS benefit was observed with atezo + CP + bev vs CP + bev regardless of PD-L1 expression. Here we present the IMpower150 interim OS results. Methods: 1202 patients (pts) received atezo 1200 mg + C AUC 6 + P 200 mg/m2 (Arm A) or atezo + CP + bev 15 mg/kg (Arm B) vs CP + bev (Arm C) IV q3w for 4 or 6 cycles per investigator (INV); then maintenance atezo, atezo + bev, or bev, respectively. Co-primary endpoints were INV-assessed PFS in the ITT-WT (EGFR/ALK WT) and in WT pts with expression of a tumor T-effector gene signature (Teff-high WT) and OS in the ITT-WT. Data cutoff: 1/22/2018. Results: 349, 359, and 337 ITT-WT pts were enrolled in Arms A, B, and C, respectively, with median age 63 y, 62% male, 85% current/previous smokers, and 42% ECOG PS 0. With 13.5 mo min FU, OS was improved in Arm B vs C (HR, 0.78 [95% CI: 0.64, 0.96]; P = 0.016) in the ITT-WT; populations of interest are shown in the Table. Arm A vs C OS HR was 0.88 (95% CI: 0.72, 1.08; P = 0.204). In all treated patients, Gr 3-4 treatment-related AEs occurred in 43%, 57%, and 49% of pts in Arms A, B, and C, respectively. Conclusions: IMpower150 showed a significant OS benefit with atezo + CP + bev vs CP + bev in 1L NSQ NSCLC, and no new safety signals were seen. Clinical trial information: NCT02366143. IC, tumor-infiltrating immune cells; NE, not estimable; TC, tumor cells. a WT excludes pts with EGFR or ALK genomic alterations. b Present at baseline. TC1/2/3 or IC1/2/3 = PD-L1+ ≥ 1% of TC or IC; TC0 and IC0 = PD-L1+ < 1% of TC and IC Arm B vs C OS in populations of interest. Population No. of Pts HR (95% CI) mOS, mo Arm B Arm C ITT-WTa 696 0.78 (0.64, 0.96) 19.2 14.7 ITT 800 0.76 (0.63, 0.93) 19.8 14.9 EGFR/ALK+ 104 0.54 (0.29, 1.03) NE 17.5 Liver metastasesb 94 0.54 (0.33, 0.88) 13.2 9.1 Subgroups in ITT-WT TC1/2/3 or IC1/2/3 357 0.77 (0.58, 1.04) 22.5 16.4 TC0 and IC0 339 0.82 (0.62, 1.08) 17.1 14.1 Teff-high 285 0.83 (0.59, 1.17) 25.0 16.7 Teff-low 377 0.78 (0.60, 1.02) 17.6 14.3

BACKGROUND Enhancing tumor-specific T-cell immunity by inhibiting programmed death ligand 1 (PD-L1)-programmed death 1 (PD-1) signaling has shown promise in the treatment of extensive-stage small-cell lung cancer. Combining checkpoint inhibition with cytotoxic chemotherapy may have a synergistic effect and improve efficacy. METHODS We conducted this double-blind, placebo-controlled, phase 3 trial to evaluate atezolizumab plus carboplatin and etoposide in patients with extensive-stage small-cell lung cancer who had not previously received treatment. Patients were randomly assigned in a 1:1 ratio to receive carboplatin and etoposide with either atezolizumab or placebo for four 21-day cycles (induction phase), followed by a maintenance phase during which they received either atezolizumab or placebo (according to the previous random assignment) until they had unacceptable toxic effects, disease progression according to Response Evaluation Criteria in Solid Tumors, version 1.1, or no additional clinical benefit. The two primary end points were investigator-assessed progression-free survival and overall survival in the intention-to-treat population. RESULTS A total of 201 patients were randomly assigned to the atezolizumab group, and 202 patients to the placebo group. At a median follow-up of 13.9 months, the median overall survival was 12.3 months in the atezolizumab group and 10.3 months in the placebo group (hazard ratio for death, 0.70; 95% confidence interval [CI], 0.54 to 0.91; P = 0.007). The median progression-free survival was 5.2 months and 4.3 months, respectively (hazard ratio for disease progression or death, 0.77; 95% CI, 0.62 to 0.96; P = 0.02). The safety profile of atezolizumab plus carboplatin and etoposide was consistent with the previously reported safety profile of the individual agents, with no new findings observed. CONCLUSIONS The addition of atezolizumab to chemotherapy in the first-line treatment of extensive-stage small-cell lung cancer resulted in significantly longer overall survival and progression-free survival than chemotherapy alone.