Atezo Monotherapy Research Articles

The safety of atezolizumab plus bevacizumab (atezo/bev) treatment in Chinese patients (pts) with hepatocellular carcinoma (HCC) with active hepatitis B virus (HBV) infection: Results from the TALENTop study.

e16168 Background: HCC pts with active HBV infection were excluded from most clinical trials involving immune checkpoint inhibitors because of safety concerns. We are aiming to evaluate the treatment safety of atezo/bev treatment in the TALENTop study (NCT04649489) which enrolled a large number of pts with active HBV infection. Methods: The TALENTop study is to clarify whether liver resection may provide additional benefits in Chinese HCC pts with macrovascular invasion who responded to conversion therapy with atezo/bev. After two versions of protocol modification, pts with active HBV infection were allowed. This study is ongoing, and the primary analysis is expected later. The current analysis is to evaluate treatment safety in pts with active HBV infection in the induction phase when pts received 3 cycles of atezo/bev and 1 cycle of atezo monotherapy. We compared the adverse events (AEs) between pts with active (baseline serum HBV-DNA ≥500 IU/mL) or inactive HBV infection (HBV-DNA < 500 IU/mL). All pts with detectable HBV-DNA or positive hepatitis B surface antigen received oral antiviral therapy throughout the study. Results: From Apr 2021 to Sep 2023, 296 pts were enrolled and completed induction phase therapy of atezo/bev. 274 pts (92.6%) had HBV-related HCC, and 133 pts (44.9%) had active HBV infection. The baseline characteristics were mainly balanced between groups, except pts with active HBV infection were younger (52 vs 56 years, P = 0.024), had larger tumor size (the diameter of target lesion 88.3 vs 78.1 mm, P = 0.007), and had higher album-bilirubin score (-2.62 vs -2.80, P < 0.001). In the induction phase, the AEs of any grade were higher in pts with active HBV infection (88.0% vs 73.6%, P = 0.002). However, the grade ≥3 AEs (20.3% vs 17.8%, P = 0.584), grade ≥3 treatment-related AEs (12.0% vs 12.3%, P = 0.950) and serious AEs (15.0% vs 13.5%, P = 0.706) were comparable between pts with active and inactive HBV infection. Additionally, the incidence of liver-related AEs was also comparable, including increased AST (17.3% vs 16.0%), increased ALT (17.3% vs 14.7%), and increased bilirubin (10.5% vs 12.9%). AEs leading to treatment withdrawal were also comparable (6.0% vs 6.1%, P = 0.966). In pts with active HBV infection, 20.8% remained serum HBV-DNA ≥500 IU/mL at the end of cycle 4. Conclusions: Active HBV infection did not compromise the safety of atezo/bev therapy. These findings could support that, with concurrent use of oral antiviral therapy, pts with active HBV infection should be not excluded from clinical trials or delayed for immunotherapy. Clinical trial information: NCT04649489 .

Colorectal cancer metastatic dMMR immuno-therapy (COMMIT) study: A randomized phase III study of atezolizumab (atezo) monotherapy versus mFOLFOX6/bevacizumab/atezo in the first-line treatment of patients (pts) with deficient DNA mismatch repair (dMMR) or microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC)—NRG-GI004/SWOG-S1610.

TPS231 Background: Approximately 45% of dMMR/MSI-H mCRC in the immunotherapy arm progressed at 12 mos (KEYNOTE 177). We hypothesize that dMMR/MSI-H mCRC pts may be more effectively treated with the combination of PD-1/PD-L1 (PD-1) pathway blockade and mFOLFOX6/bevacizumab (bev) rather than with anti-PD-L1 therapy (atezo) alone. Preclinical work demonstrated synergistic effects between anti-PD-1/anti-VEGF as well as between oxaliplatin/anti-PD-1 in murine CRC models, and phase II data showed activity of anti-PD-1/anti-VEGF in chemotherapy refractory colon cancer. Upon AtezoTRIBE subgroup analysis of the 8 pts with dMMR mCRC treated with FOLFOXIRI+bev+atezo, median PFS was not reached, with the first patient having progression ~16 mos. Additionally, in other solid tumor malignancies, anti-PD-1 plus anti-VEGFr (i.e., HCC and RCC) as well as anti-PD-1 plus chemotherapy (i.e., gastroesophageal and lung cancers) combinations are standard first-line treatments. Methods: This two-arm prospective phase III open-label trial randomizes (1:1) mCRC dMMR/MSI-H to atezo monotherapy v mFOLFOX6/bev+atezo combination. Key inclusion criteria have been simplified on recent amendments to better mirror clinical practice for pts receiving mFOLFOX6/bev+/-atezo: One cycle of FOLFOX or CAPOX, with or without bev (or biosimilar) prior to enrollment allowed, dMMR tumor determined by local CLIA-certified IHC assay (MLH1/MSH2/MSH6/PMS2) or MSI-H by local CLIA-certified PCR or NGS panel; pts with total bilirubin ≤4.0 x ULN; duration of therapy for up to two years for both arms; imaging frequency on post-treatment follow up have been reduced; as has measurable disease per RECIST. The primary endpoint is PFS. Assuming the atezo monotherapy control arm has a 48% PFS at 24 mos as assessed by site investigator, we have 80% power to detect a hazard ratio of 0.6 (equivalent to 64.4% PFS at 24 mos) with alpha 0.025 one-sided. Stratification factors include BRAFV600E status, metastatic site, and prior adjuvant CRC therapy. Secondary endpoints include overall survival objective response rate, safety profile, disease control rate, and duration of response. Archived tumor tissue and blood samples will be collected for correlative studies. Harmonization of translational analyses is planned between GI004 (COMMIT) and A021502 (ATOMIC). The sample size has been modified with the accrual goal of 120 patients randomized between the two immunotherapy arms needed for study completion. Enrollment actively continues. Support: U10CA180868, -180822, -180888, UG1CA189867, U24CA196067; Genentech, Inc. Clinical trial information: NCT02997228 .

Overall survival (OS) by response to first-line (1L) induction treatment with atezolizumab (atezo) + platinum/gemcitabine (plt/gem) vs placebo + plt/gem in patients (pts) with metastatic urothelial carcinoma (mUC): Updated data from the IMvigor130 OS final analysis.

4503 Background: For pts without disease progression during 1L plt-based chemotherapy (chemo), maintenance immunotherapy is a new mUC treatment option. IMvigor130 was a global, randomized Phase III study evaluating 1L atezo + plt/gem (Arm A) vs atezo monotherapy (Arm B) and placebo + plt/gem (Arm C) in patients with mUC (Galsky Lancet 2020). The final analysis showed that improved OS in Arm A vs Arm C of the intention-to-treat (ITT) population did not reach statistical significance (Galsky ASCO GU 2023). Here we report a post hoc analysis examining OS outcomes by response during atezo/placebo + chemo “induction” based on the final OS analysis. Methods: For Arms A and C, per protocol, investigators pre-specified the type of chemo pts received (gem + either cisplatin [cis] or carboplatin [carbo]), which was also a randomization stratification factor. Pts without progressive disease (PD) were allowed to continue atezo or placebo after 4 to 6 cycles of plt/gem. This post hoc analysis evaluated post-induction (Wk 18) OS in pts who completed 4 to 6 cycles of chemo followed by ≥1 dose of atezo or placebo and who had a best response of at least stable disease (SD) without PD at any time (up to and including Wk 18 tumor assessment). Post-progression OS was evaluated in pts who had PD at any time (up to and including Wk 18 tumor assessment). OS analyses by type of chemo were also performed. Multivariable Cox proportional hazards models were used, with HRs adjusted for known prognostic factors (and response for non-PD pts) and stratified by enrollment stage. Results: The time from last pt randomized to the data cutoff (Aug 31, 2022) was 49 mo (overall ITT population). OS improvements favoring Arm A vs C appeared greater for pts treated with cis than with carbo. In the cis subgroup, OS rates at 36 mo were 47% (Arm A) and 34% (Arm C) for pts who achieved at least SD during induction. Additional efficacy data are shown. Conclusions: In this post hoc analysis, the initial response to induction therapy did not seem to impact OS outcomes. Consistent with prior analyses, these data suggest that cis-treated pts may derive a greater benefit from the addition of atezo than carbo-treated pts. Clinical trial information: NCT02807636 . [Table: see text]

Final overall survival (OS) analysis of atezolizumab (atezo) monotherapy vs chemotherapy (chemo) in untreated locally advanced or metastatic urothelial carcinoma (mUC) from the Phase 3 IMvigor130 study.

LBA441 Background: Two interim OS analyses from IMvigor130 demonstrated non-statistically significant OS benefit with atezo monotherapy (Arm B) vs placebo + platinum (investigator [INV] choice of carboplatin or cisplatin [carbo or cis])/gemcitabine (plt/gem; Arm C) in patients (pts) with PD-L1–high (IC2/3) mUC, as well as a favorable safety profile vs chemo (Galsky Lancet 2020, Davis AACR 2021). Exploratory data showed clinical benefit with atezo monotherapy in cis-ineligible pts with IC2/3 tumors. Here, we report the final OS analysis from IMvigor130 Arms B and C. Methods: Pts were randomly assigned 1:1:1 to Arm A (atezo + plt/gem; not reported here), B or C. Due to the statistical testing hierarchy, no formal comparison of OS (co-primary endpoint) in Arm B vs C was performed in ITT and IC2/3 pts. ORR and DOR, both per INV-assessed RECIST 1.1 (secondary endpoints), and safety were assessed. Subgroup analyses of OS in cis-ineligible pts and disease control rate (DCR, confirmed CR, PR or [SD ≥6 mo]) were exploratory. Results: As of data cutoff Aug 31, 2022, time since last pt randomly assigned was 49 mo. OS data (Table) did not show benefit for ITT pts, while an HR of 0.56 (0.34, 0.91) was seen in the cis-ineligible IC2/3 subgroup. In the ITT population, the 24-mo OS rates were 34% in Arm B and 32% in Arm C. ORR was 24% (87/359; 38% DCR) in Arm B and 44% (158/356; 59% DCR) in Arm C; median DOR was 29.6 and 8.1 mo, respectively. In cis-ineligible IC2/3 pts, ORR was 40% (20/50) in Arm B and 33% (14/43) in Arm C. Median DOR was not evaluable in Arm B and 6.2 mo in Arm C. Of safety-evaluable pts, 57 of 354 in Arm B (16%) and 312 of 389 in Arm C (80%) had a Gr 3/4 treatment-related AE (TRAE); 3 (1%) and 4 (1%), respectively, had a Gr 5 TRAE. Gr 3/4 AEs of special interest occurred in 36 pts (10%) in Arm B and 17 (4%) in Arm C. Conclusions: The final OS analysis was consistent with previous data. Atezo monotherapy continued to show better tolerability vs chemo with no new safety concerns. These exploratory data support the benefit-risk ratio of atezo monotherapy vs chemo for first-line cis-ineligible IC2/3 mUC. Clinical trial information: NCT02807636 . [Table: see text]

NRG-GI004/SWOG-S1610: Colorectal Cancer Metastatic dMMR Immuno-Therapy (COMMIT) study—A randomized phase III study of atezolizumab (atezo) monotherapy versus mFOLFOX6/bevacizumab/atezo in the first-line treatment of patients (pts) with deficient DNA mismatch repair (dMMR) or microsatellite instability high (MSI-H) metastatic colorectal cancer (mCRC).

TPS258 Background: Despite the superiority in progression-free survival (PFS) of inhibition of programmed cell death-1 (PD-1) pathway in dMMR/MSI-H as compared to chemotherapy with either anti-vascular endothelial growth factor receptor (VEGFr) or anti-epithelial growth factor receptor (EGFr) antibodies in mCRC, more pts had progressive disease as the best response in the anti-PD1 monotherapy arm (29.4% v 12.3%) with mean PFS of 13.7 mos, with ~45% of pts in the immunotherapy arm progressed at 12 mos (KEYNOTE 177). We hypothesize that dMMR/MSI-H mCRC pts may be more effectively treated with the combination of PD-1 pathway blockade and mFOLFOX6/bevacizumab (bev) rather than with anti-PD-1 therapy (atezo) alone. Preclinical work demonstrated synergistic effects between anti-PD-1/anti-VEGF and between oxaliplatin/anti-PD-1 in murine CRC models and phase II data, which showed activity of anti-PD-1/anti-VEGF in chemotherapy refractory colon cancer. A recent randomized trial subgroup analysis of 8 pts with dMMR metastatic colon cancer treated with FOLFOXIRI+bev+atezo, with the first patient having progression ~16 mos (AtezoTRIBE). Additionally, in other solid tumor malignancies, anti-PD1 plus anti-VEGFr (i.e., HCC and RCC) as well as anti-PD1 plus chemotherapy (i.e., gastric and esophageal cancers) combinations are standard first-line treatments. Methods: The redesigned COMMIT study was reactivated on 1/29/2021 as a two-arm prospective phase III open-label trial randomizing (1:1) mCRC dMMR/MSI-H to atezo monotherapy v mFOLFOX6/bev+atezo combination. Assuming our control arm, atezo monotherapy (48% PFS at 24 mos as assessed by site investigator), we have 80% power to detect a hazard ratio of 0.6 (equivalent to 64.4% PFS at 24 mos) with alpha 0.025 one-sided. Stratification factors include BRAFV600E status, metastatic site, and prior adjuvant CRC therapy. Secondary endpoints include OS, objective response rate, safety profile, disease control rate, and duration of response. Health-related quality of life is an exploratory objective. Archived tumor tissue and blood samples will be collected for correlative studies. Key inclusion criteria are: mCRC without prior chemotherapy for advanced disease; dMMR tumor determined by local CLIA-certified IHC assay (MLH1/MSH2/MSH6/PMS2) or MSI-H by local CLIA-certified PCR or NGS panel; and measurable disease per RECIST. Enrollment actively continues to the target accrual of 211 patients randomized between the two immunotherapy arms. Clinical trial: NCT02997228. Support: U10CA180868, -180822, -180888, UG1CA189867, U24CA196067; Genentech, Inc. Clinical trial information: NCT05080673 .

Colorectal cancer metastatic dMMR immuno-therapy (COMMIT) study: A randomized phase III study of atezolizumab (atezo) monotherapy versus mFOLFOX6/bevacizumab/atezo in the first-line treatment of patients (pts) with deficient DNA mismatch repair (dMMR) or microsatellite instability high (MSI-H) metastatic colorectal cancer (mCRC)—NRG-GI004/SWOG-S1610.

TPS3647 Background: Despite the superiority in progression-free survival (PFS) of inhibition of programmed cell death-1 (PD-1) pathway in dMMR/MSI-H as compared to chemotherapy with either anti-vascular endothelial growth factor receptor (VEGFr) or anti-epithelial growth factor receptor (EGFr) antibodies in mCRC, more pts had progressive disease as the best response in the anti-PD1 monotherapy arm (29.4% v 12.3%) with mean PFS of 13.7 mos, with ̃45% of pts in the IO arm progressed at 12 mos ( N Engl J Med 2020; 383:2207). We hypothesize that the dMMR/MSI-H mCRC pts may be more effectively treated with the combination of PD-1 pathway blockade and mFOLFOX6/bevacizumab (bev) rather than with anti-PD-1 therapy (atezo) alone. Preclinical work demonstrated synergistic effects between anti-PD-1/anti-VEGF and between oxaliplatin/anti-PD-1 in murine CRC models and phase II data, which showed activity of anti-PD-1/anti-VEGF in chemotherapy refractory colon cancer. A recent randomized trial subgroup analyses of 8 pts with dMMR metastatic colon cancer treated with FOLFOXIRI+bev+atezo, with the first patient having progression ̃16 mos ( ESMO 2021, Abstt LBA20). Additionally, in other solid tumor malignancies, anti-PD1 plus anti-VEGFr (i.e., HCC and RCC) as well as anti-PD1 plus chemotherapy (i.e., gastric and esophageal cancers) combinations are standard first-line treatments. Methods: The redesigned COMMIT study was reactivated on 1/29/2021 as a two-arm prospective phase III open-label trial randomizing (1:1) mCRC dMMR/MSI-H to atezo monotherapy v mFOLFOX6/bev+atezo combination. Assuming our control arm, atezo monotherapy (48% PFS at 24 mos as assessed by site investigator), we have 80% power to detect a hazard ratio of 0.6 (equivalent to 64.4% PFS at 24 mos) with alpha 0.025 one-sided. Stratification factors include BRAFV600E status, metastatic site, and prior adjuvant CRC therapy. Secondary endpoints include OS, objective response rate, safety profile, disease control rate, and duration of response. Health-related quality of life is an exploratory objective. Archived tumor tissue and blood samples will be collected for correlative studies. Key inclusion criteria are: mCRC without prior chemotherapy for advanced disease; dMMR tumor determined by local CLIA-certified IHC assay (MLH1/MSH2/MSH6/PMS2) or MSI-H by local CLIA-certified PCR or NGS panel; and measurable disease per RECIST. Enrollment actively continues to the target accrual of 211 patients randomized between the two immunotherapy arms. Support: U10CA180868, -180822, -180888, UG1CA189867, U24CA196067. Clinical trial information: NCT02997228.

NRG-GI004/SWOG-S1610: Colorectal cancer metastatic dMMR immuno-therapy (COMMIT) study—A randomized phase III study of atezolizumab (atezo) monotherapy versus mFOLFOX6/bevacizumab/atezo in the first-line treatment of patients (pts) with deficient DNA mismatch repair (dMMR) or microsatellite instability high (MSI-H) metastatic colorectal cancer (mCRC).

TPS232 Background: Despite the superiority in progression-free survival (PFS) of inhibition of programmed cell death-1 (PD-1) pathway in dMMR/MSI-H as compared to chemotherapy with either anti-vascular endothelial growth factor receptor (VEGFr) or anti-epithelial growth factor receptor (EGFr) antibodies in mCRC, more pts had progressive disease as the best response in the anti-PD1 monotherapy arm (29.4% vs. 12.3%) with mean PFS of 13.7 months ( N Engl J Med 2020; 383:2207). We hypothesize that the dMMR/MSI-H mCRC pts may be more effectively treated by the combination of PD-1 pathway blockade and mFOLFOX6/bevacizumab (bev) rather than with anti-PD-1 therapy (atezo) alone. Preclinical work demonstrated synergistic effects between anti-PD-1/anti-VEGF and between oxaliplatin/anti-PD-1 in murine CRC models and phase II data showed activity of anti-PD-1/anti-VEGF in chemotherapy refractory colon cancer. Additionally, in other solid tumor malignancies, anti-PD1 plus anti-VEGFr (i.e., HCC and RCC) as well as anti-PD1 plus chemotherapy (i.e., gastric and esophageal cancers) combinations are standard first-line treatments. Methods: The redesigned COMMIT study was reactivated on 1/29/2021 as a two-arm prospective phase III open-label trial randomizing (1:1) mCRC dMMR/MSI-H (211 pts) to atezo monotherapy versus mFOLFOX6/bev+atezo combination. Assuming our control arm, atezo monotherapy, 48% PFS at 24 months, as assessed by site investigator, we have 80% power to detect a hazard ratio of 0.6 (equivalent to 64.4% PFS at 24 months) with alpha 0.025 one-sided. Stratification factors include BRAFV600E status, metastatic site, and prior adjuvant CRC therapy. Secondary endpoints include OS, objective response rate, safety profile, disease control rate, duration of response, and centrally-reviewed PFS. Health-related quality of life is an exploratory objective. Archived tumor tissue and blood samples will be collected for correlative studies. Key inclusion criteria are: mCRC without prior chemotherapy for advanced disease; dMMR tumor determined by local CLIA-certified IHC assay (MLH1/MSH2/MSH6/PMS2) or MSI-H by local CLIA-certified PCR or NGS panel; and measurable disease per RECIST. Enrollment actively continues to the target accrual of 211 patients randomized between the two immunotherapy arms. Support: U10CA180868, -180822, -180888, UG1CA189867, U24CA196067; Genentech, Inc. Clinical trial information: NCT02997228.

Abstract CT040: Updated overall survival (OS) analysis of atezolizumab (atezo) monotherapy vs chemotherapy in untreated locally advanced or metastatic urothelial carcinoma (mUC) in IMvigor130

Abstract Background: In the IMvigor130 primary analysis in patients (pts) with untreated locally advanced or mUC, a trend toward favorable OS with atezo (anti-PD-L1) monotherapy (Arm B) vs placebo + platinum/gemcitabine (plt/gem; Arm C) was seen in pts with PD-L1-expressing immune cells on ≥5% of the tumor area (IC2/3 per VENTANA SP142 IHC assay; Galsky Lancet 2020). We report clinical outcomes in Arm B vs C from the second interim OS analysis, including efficacy in cisplatin-ineligible pts. Methods: Pts were randomized 1:1:1 to Arm A (atezo + plt/gem [not reported here]), B or C. Co-primary endpoint OS was analyzed via hierarchical statistical testing. Since OS in Arm A vs C was not statistically significant, no formal comparison of Arm B vs C was performed in intention-to-treat (ITT) and IC2/3 pts. Objective response rate (ORR) and duration of response (DOR), both per RECIST 1.1 (secondary endpoints), and safety are reported; additional exploratory subgroup analyses of OS by PD-L1 status in ITT and cisplatin-ineligible pts were also done. Results: Efficacy from the updated OS analysis (June 14, 2020 cutoff; median follow-up, 13.3 mo) is shown in the Table. Exploratory subgroup analyses suggested that OS for IC2/3 pts may be higher in Arm B vs C. In ITT pts, ORR was higher in Arm C, but median DOR was longer in Arm B. In the safety population, Grade (Gr) 3/4 treatment-related adverse events (TRAEs) occurred in 16% and 80% of Arm B and C pts, respectively, and Gr 5 TRAEs in 1% of both arms. Gr 3/4 AEs of special interest (AESIs) occurred in 10% and 4%, respectively, and Gr 5 AESIs in <1% of both arms. Conclusions: These exploratory efficacy data from an updated OS analysis of IMvigor130 support the benefit of atezo monotherapy as first-line treatment for PD-L1 IC2/3 cisplatin-ineligible mUC. Atezo monotherapy showed a better tolerability profile than chemotherapy. With this longer follow-up, no new safety concerns arose. IMvigor130 efficacy (second interim OS analysis)Efficacy analysis populationArm B: atezoArm C: placebo + chemotherapyaITTOS events/pts (%)241/360 (66.9)246/359 (68.5)Median OS (95% CI), mo15.2 (13.1, 17.7)13.1 (11.7, 15.1)OS HR (95% CI)b0.99 (0.83, 1.19)Responders/ptsc84/359157/356ORR (95% CI), %23.4 (19.1, 28.1)44.1% (38.9, 49.4)Median DOR (95% CI), mod29.6 (15.9, NE)8.1 (6.3, 8.5)PD-L1 IC2/3 populationOS events/pts (%)43/88 (48.9)52/85 (61.2)Median OS (95% CI), mo27.5 (17.7, NE)16.7 (10.0, 26.1)OS HR (95% CI)b0.67 (0.45, 1.02)PD-L1 IC0/1 populationeOS events/pts (%)198/272 (72.8)194/274 (70.8)Median OS (95% CI), mo13.5 (11.1, 16.3)12.8 (11.3, 15.0)OS HR (95% CI)f1.05 (0.86, 1.28)Cisplatin-ineligible pts with PD-L1 IC2/3OS events/pts (%)28/50 (56)30/43 (70)Median OS (95% CI), mo18.6 (14.0, NE)10.0 (7.4, 18.1)OS HR (95% CI)f0.60 (0.36, 1.01)IC, tumor-infiltrating immune cells; NE, not estimable.aConcurrent control arm, which includes pts randomized in Stage 2 when Arm B was added to the study design.bStratified per randomization stratification factors: PD-L1 status (ITT only), Bajorin risk factor score/liver metastases, investigator's choice of platinum (cisplatin or carboplatin) before randomization.cPatients with measurable disease at baseline.dIn pts who had a confirmed response.eIC0/1 = PD-L1 IC <5%.fUnstratified. Citation Format: Ian D. Davis, Matthew D. Galsky, Xavier Garcia del Muro, Se Hoon Park, Ugo De Giorgi, Boris Alekseev, Marina Mencinger, Kouji Izumi, Javier Puente, Jian-Ri Li, José Ángel Arranz, Aristotelis Bamias, Enrique Grande, Eiji Kikuchi, Almut Mecke, Sanjeev Mariathasan, Xiaodong Shen, Hannah (Xinhui) Huang, Maria De Santis. Updated overall survival (OS) analysis of atezolizumab (atezo) monotherapy vs chemotherapy in untreated locally advanced or metastatic urothelial carcinoma (mUC) in IMvigor130 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT040.

Abstract CT042: Atezolizumab (atezo) + platinum/gemcitabine (plt/gem) vs placebo + plt/gem in patients (pts) with previously untreated locally advanced or metastatic urothelial carcinoma (mUC): Updated overall survival (OS) from the randomized phase III study IMvigor130

Abstract Background: The IMvigor130 primary analysis demonstrated a statistically significant progression-free survival (PFS) benefit and encouraging OS with atezo + plt/gem (Arm A) vs placebo + plt/gem (Arm C) as first-line mUC treatment, although interim OS results did not cross the pre-specified threshold for significance (Galsky Lancet 2020). Here we report the 2nd interim OS for Arm A vs C, including efficacy by type of chemotherapy (chemo) given. Methods: Pts were randomized 1:1:1 to Arm A, B (atezo monotherapy) or C. Investigators pre-specified the type of chemo pts would receive if assigned to Arms A or C (gem + either cisplatin or carboplatin). Co-primary endpoints (EPs) were RECIST 1.1 PFS and OS (Arm A vs C; ITT) and OS (Arm B vs C; ITT, IC2/3) tested using a hierarchical approach. Safety and secondary efficacy EPs (objective response rate and duration of response) are reported. Exploratory OS analyses by type of chemo were pre-specified. Results: As of data cutoff, June 14, 2020 (median follow-up, 13.3 mo), OS event rates were 67% in Arm A and 70% in Arm C. Efficacy data are shown (Table). Subsequent non-protocol immunotherapy use was 7% in Arm A vs 24% in Arm C. Of pts in the safety population (Arm A: 454; Arm C: 389), 81% and 80%, respectively, had a Gr 3/4 treatment-related AE (TRAE). No new Gr 5 TRAEs occurred since the 1st analysis (Gr 5 TRAEs: 2% in Arm A vs 1% in Arm C). Gr 3/4 AEs of special interest occurred in 9% in Arm A and 4% in Arm C. Conclusions: OS with atezo + plt/gem vs placebo + plt/gem in this updated analysis of IMvigor130 was consistent with the 1st interim analysis (not yet statistically significant). The impact of atezo plus chemo on outcomes may differ based on the specific platinum regimen; these exploratory findings warrant further investigation. OS follow-up is ongoing. Safety profile of atezo + plt/gem was consistent with each agent. IMvigor130 efficacy (second interim OS analysis)Arm A:Arm C:atezo + plt/gemplacebo + plt/gem(n=451)(n=400)OS HR (95% CI)aITT0.84 (0.71, 1.00); P=0.026bCisplatin (n=273)0.73 (0.54, 0.98)PD-L1 IC2/3 (n=69)c0.66 (0.32, 1.36)PD-L1 IC0/1 (n=204)c0.72 (0.52, 1.01)Carboplatin (n=578)0.91 (0.74, 1.10)PD-L1 IC2/3 (n=130)c0.80 (0.52, 1.23)PD-L1 IC0/1 (n=448)c0.94 (0.75, 1.18)Median OS (95% CI), moITT16.1 (14.2, 18.8)13.4 (11.9, 15.2)Cisplatin21.6 (17.5, 25.4)14.6 (11.7, 18.4)Carboplatin14.3 (12.0, 16.5)13.0 (10.6, 15.2)Objective response rate (95% CI), %ITT (n=844)d48 (43, 53)45 (40, 50)Cisplatin (n=271)d49 (40, 57)50 (41, 58)Carboplatin (n=573)d48 (42, 53)42 (36, 48)Complete response rate (95% CI), %ITT (n=844)d13 (10, 17)7 (5, 10)Cisplatin (n=271)d17 (11, 24)9 (5, 15)Carboplatin (n=573)d12 (9, 16)6 (4, 10)Median duration of response (95% CI), moeAll responders (n=391)9.3 (8.0, 10.7)8.2 (6.3, 8.5)Cisplatin (n=133)13.2 (10.4, 22.5)8.3 (6.3, 13.3)Carboplatin (n=258)8.1 (6.5, 10.2)7.1 (6.2, 8.5)IC, tumor-infiltrating immune cells; ITT, intention to treat.aHR for the ITT population is stratified by PD-L1 IC status (IC0 vs IC1 vs IC2/3), Bajorin risk factor score (0, 1, 2 and/or liver metastases), investigator's choice of cisplatin/gemcitabine vs carboplatin/gemcitabine and enrollment stage. HRs for subgroups are stratified by enrollment stage.bOne-sided; not statistically significant (O'Brien-Fleming stopping boundary P value 0.014).cPD-L1-expressing IC covering ≥5% (IC2/3) or <5% (IC0/1) of the tumor area per VENTANA SP142 IHC assay.dFor objective response analyses, only pts with measurable disease at baseline were included (n=844 of 851). e In patients who had a response. Citation Format: Matthew D. Galsky, José Ángel Arranz, Enrique Grande, Maria De Santis, Ian D. Davis, Eiji Kikuchi, Xavier Garcia del Muro, Se Hoon Park, Ugo De Giorgi, Boris Alekseev, Marina Mencinger, Kouji Izumi, Javier Puente, Jian-Ri Li, Peter H. O'Donnell, Xiaodong Shen, Chooi Lee, Almut Mecke, Sanjeev Mariathasan, Aristotelis Bamias. Atezolizumab (atezo) + platinum/gemcitabine (plt/gem) vs placebo + plt/gem in patients (pts) with previously untreated locally advanced or metastatic urothelial carcinoma (mUC): Updated overall survival (OS) from the randomized phase III study IMvigor130 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT042.

Abstract CT187: Overall survival (OS) by response during “induction” from the global, randomized Phase III IMvigor130 study of atezolizumab (atezo) + platinum/gemcitabine (plt/gem) vs placebo + plt/gem in patients (pts) with previously untreated metastatic urothelial carcinoma (mUC)

Abstract Background: IMvigor130 evaluated atezo + plt/gem (Arm A) vs placebo + plt/gem (Arm C) as 1L mUC treatment, allowing pts with at least SD to continue atezo or placebo “maintenance” after 4-6 cycles of plt/gem. The primary analysis showed statistically significant PFS benefit for Arm A vs C (Galsky Lancet 2020). The 1st interim OS data for Arm A vs C were encouraging but immature. This exploratory analysis used 2nd interim OS data (ITT median follow-up, 13.3 mo) to examine OS outcomes by response during atezo or placebo + chemo “induction” in Arm A vs C. Methods: Pts were randomized 1:1:1 to Arm A, B (atezo monotherapy) or C. In Arms A and C, chemo was gem + investigator's choice of cis or carbo. Co-primary EPs of PFS and OS in Arm A vs C (ITT) and OS in Arm B vs C (ITT and IC2/3) were tested hierarchically. This post hoc analysis evaluated post-induction (post-wk 18) OS in pts who completed 4-6 (but not >6) cycles of chemo without PD during induction (through wk 18), followed by ≥1 dose of atezo or placebo maintenance. Post-PD OS was evaluated in pts with PD during induction. HRs were adjusted to account for potential imbalances in known prognostic factors between arms. Results: Efficacy data are in the Table. Post-induction OS HR (95% CI) for pts with no PD was 0.86 (0.64, 1.16) (cis: 0.60 [0.35, 1.03], carbo: 0.97 [0.67, 1.41]). Post-progression OS HR for pts with PD was 0.74 (0.53, 1.03) (cis: 0.52 [0.28, 0.96], carbo: 0.78 [0.51, 1.18]). Conclusions: In this exploratory analysis from IMvigor130, OS benefit with atezo + plt/gem vs placebo + plt/gem in both pts with and without PD during induction was consistent with ITT results from the 1st interim analysis. Preliminary data suggest that cis-treated pts may derive greater OS benefit from adding atezo to chemo than carbo-treated pts, which warrants further investigation. OS follow-up is ongoing. IMvigor130 efficacy (second interim OS analysis)No PD during inductiona (post-induction OS)bPD during induction (post-progression OS)Arm A (n=166)Arm C (n=152)Arm A (n=91)Arm C (n=93)OS events, n (%)ITT97 (58.4)92 (60.5)82 (90.1)84 (90.3)Cisplatinc27/57 (47.4)35/59 (59.3)24/29 (82.8)30/33 (90.9)Carboplatinc70/109 (64.2)57/93 (61.3)58/62 (93.5)54/60 (90.0)Median OS (95% CI), moITT20.5 (17.6, 25.9)18.8 (14.4, 21.9)4.3 (3.5, 5.8)3.3 (2.5, 4.4)Cisplatin28.2 (19.8, NE)19.9 (11.0, 26.5)6.6 (4.8, 10.1)2.5 (1.6, 5.2)Carboplatin18.5 (12.9, 21.6)18.8 (12.9, 22.8)3.8 (3.2, 5.6)3.4 (2.6, 4.5)OS HR (95% CI)dITT0.86 (0.64, 1.16)0.74 (0.53, 1.03)Cisplatin0.60 (0.35, 1.03)0.52 (0.28, 0.96)Carboplatin0.97 (0.67, 1.41)0.78 (0.51, 1.18)Data cutoff: June 14, 2020. 1L, first-line; carbo, carboplatin; chemo, chemotherapy; cis, cisplatin; CR, complete response; EP, endpoint; HR; hazard ratio; ITT, intention to treat; mets, metastases; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease. a Pts who achieved at least SD (CR, PR, or SD without PD) during induction. b Post-week 18 OS. c Denominators refer to the number of pts in each chemotherapy subgroup/treatment arm. d Multivariable Cox proportional hazards model stratified by enrollment stage (1/2); adjusted for age, ECOG PS (0, 1, 2), cisplatin ineligibility (Y/N), liver mets (Y/N), lymph node mets only (Y/N), ≥3 metastatic sites (Y/N), renal impairment (Y/N), alkaline phosphatase ≥upper limit of normal (Y/N), glomerular filtration rate (<60 vs ≥60 mL/min), PD-L1 status (IC0/1, IC2/3), Bajorin risk score (0, 1, 2 and/or liver mets). For pts without PD, model was additionally adjusted for best response (CR, PR, SD) during induction. Citation Format: Enrique Grande, Aristotelis Bamias, Matthew D. Galsky, Eiji Kikuchi, Ian D. Davis, José Ángel Arranz, Arash Rezazadeh Kalebasty, Xavier Garcia del Muro, Se Hoon Park, Ugo De Giorgi, Boris Alekseev, Marina Mencinger, Kouji Izumi, Javier Puente, Jian-Ri Li, Xiaodong Shen, Beiying Ding, Qian Zhu, Jeremy Linsenmeier, Maria De Santis. Overall survival (OS) by response during “induction” from the global, randomized Phase III IMvigor130 study of atezolizumab (atezo) + platinum/gemcitabine (plt/gem) vs placebo + plt/gem in patients (pts) with previously untreated metastatic urothelial carcinoma (mUC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT187.

Colorectal Cancer Metastatic dMMR Immuno-Therapy (COMMIT) Study: A randomized phase III study of atezolizumab (atezo) monotherapy versus mFOLFOX6/bevacizumab/atezo in the first-line treatment of patients (pts) with deficient DNA mismatch repair (dMMR) or microsatellite instability high (MSI-H) metastatic colorectal cancer (mCRC)—NRG-GI004/SWOG-S1610.

TPS3618 Background: The superiority of inhibition of programmed cell death-1 (PD-1) pathway in dMMR/MSI-H over chemotherapy with either anti-vascular endothelial growth factor receptor (VEGFr) or anti- epithelial growth factor receptor (EGFr) antibodies in mCRC has been demonstrated in a phase III trial (N Engl J Med 2020; 383:2207). However, more patients had progressive disease as the best response in the anti-PD1 monotherapy arm (29.4% vs. 12.3%) with mean progression-free survival (PFS) of 13.7 months. Preclinical models have demonstrated synergistic interactions between FOLFOX, anti-VEGF, and anti-PD-1. We hypothesize that the dMMR/MSI-H mCRC patients may be more effectively treated by the combination of PD-1 pathway blockade and mFOLFOX6/bevacizumab (bev) rather than with anti-PD-L1 therapy (atezo) alone. Methods: Initially a three-arm study, the mFOLFOX6/bev arm was closed to new enrollment on 6-4-20 due to emerging data; the redesigned COMMIT trial was reactivated on 1/29/2021 as a prospective phase III open-label trial that randomizes (1:1) mCRC dMMR/MSI-H pts (N=211) to either atezo monotherapy or mFOLFOX6/bev+atezo combination. Stratification factors include BRAFV600E status, metastatic site, and prior adjuvant CRC therapy. Primary endpoint is PFS as assessed by site investigator. Secondary endpoints include overall survival (OS), objective response rate (RECIST v1.1), safety profile, disease control rate, duration of response, and centrally-reviewed PFS. Health-related quality of life is an exploratory objective. Archived tumor tissue and blood samples will be collected for correlative studies. Key inclusion criteria are: mCRC without prior chemotherapy for advanced disease; dMMR tumor determined by local CLIA-certified IHC assay (MLH1/MSH2/MSH6/PMS2) or MSI-H by local CLIA-certified PCR or NGS panel; and measurable disease per RECIST. Clinical trial: NCT02997228. Support: U10CA180868, -180822, -180888, -180819, UG1CA189867, U24CA196067; Genentech, Inc. Clinical trial information: NCT02997228.

IMpower010: Primary results of a phase III global study of atezolizumab versus best supportive care after adjuvant chemotherapy in resected stage IB-IIIA non-small cell lung cancer (NSCLC).

8500 Background: Adjuvant platinum-based chemotherapy (chemo) provides only a modest 5-year survival benefit in fully resected, high-risk early-stage NSCLC. We report the primary disease-free survival (DFS) results from the pre-planned interim analysis of IMpower010, a randomized phase 3 open-label trial of adjuvant atezolizumab (atezo; anti–PD-L1) vs best supportive care (BSC) after adjuvant chemo in patients (pts) with early-stage resected NSCLC. Methods: Eligible pts had completely resected (4-12 weeks prior to enrollment) Stage IB (≥4 cm)-IIIA NSCLC (AJCC/UICC v7) and ECOG PS 0-1. A total of 1280 pts were enrolled, and 1269 pts received up to four 21-day cycles of cisplatin-based chemo (plus pemetrexed, docetaxel, gemcitabine or vinorelbine). Of these pts (n=1269), 1005 were subsequently randomized 1:1 to 16 cycles of atezo 1200 mg Q3W or BSC. The primary endpoint of investigator-assessed DFS and secondary endpoint of overall survival (OS) were tested hierarchically: first DFS in the PD-L1 TC ≥1% (SP263) subgroup with Stage II-IIIA disease, then DFS in all randomized pts with Stage II-IIIA disease, then DFS in the ITT population (Stage IB-IIIA) and finally OS in the ITT population. Efficacy assessments were based on randomized pts. Safety was assessed in the safety-evaluable population, defined as pts who received ≥1 dose of atezo or who had ≥1 post-baseline safety assessment if randomized to the BSC arm. Results: At data cutoff (January 21, 2021), median follow-up was 32.2 months in the ITT population. Baseline characteristics were generally balanced between arms. Atezo showed statistically significant DFS benefit vs BSC in the PD-L1 TC ≥1% Stage II-IIIA and all randomized Stage II-IIIA populations; the significance boundary was not crossed for DFS in the ITT population (Table). OS data were immature and not formally tested. Pts in the atezo arm received a median of 16 (range, 1-16) atezo doses. Any-grade AEs occurred in 92.7% (atezo) and 70.7% (BSC); events were Grade 3/4 in 21.8% and 11.5%, respectively. Grade 5 treatment-related AEs occurred in 0.8% of pts in the atezo arm. AEs leading to atezo discontinuation occurred in 18.2% of atezo-treated pts. Conclusions: IMpower010 met its primary endpoint, showing DFS benefit with adjuvant atezo vs BSC after adjuvant chemo in pts with resected Stage II-IIIA NSCLC, with pronounced benefit in the PD-L1 TC ≥1% subgroup. The safety profile of atezo was consistent with prior experience of atezo monotherapy across indications and lines of therapy. Funding: F. Hoffmann-La Roche Ltd. Clinical trial information: NCT02486718. [Table: see text]

Atezolizumab (atezo) monotherapy versus chemotherapy in previously untreated locally advanced or metastatic urothelial carcinoma (mUC): Clinical outcomes by PD-L1 status in cisplatin (cis)-ineligible pts from the phase III IMvigor130 study.

434 Background: Atezo (anti–PD-L1) monotherapy is approved for cis-ineligible pts who have locally advanced or mUC with PD-L1–expressing immune cells on ≥ 5% of the tumor area (IC2/3 per VENTANA SP142 IHC assay). The IMvigor130 primary analysis demonstrated a significant PFS benefit with atezo + platinum/gemcitabine (plt/gem) (arm A) vs placebo (pbo) + plt/gem (arm C) as 1L treatment for mUC (Galsky Lancet 2020); at that time, interim OS data for arm A vs C were encouraging but immature. OS with atezo monotherapy (arm B) could not be formally tested, but favorable efficacy was seen in IC2/3 pts. In this exploratory analysis, we assess outcomes by PD-L1 status in cis-ineligible pts. Methods: Pts were randomized 1:1:1 to arms A, B or C (Galsky Lancet 2020). Evaluation of OS (co-primary EP) was performed via a hierarchical fixed sequence procedure: arm A vs C ITT pts; then, arm B vs C ITT and IC2/3 pts. No formal testing was performed in this exploratory subgroup analyses; OS and RECIST 1.1 ORR (per investigator [secondary EP]) were descriptively evaluated. Results: Efficacy data suggested OS and ORR benefit in atezo-treated cis-ineligible IC2/3 pts (Table). In the overall safety population, all-grade treatment-related AEs (TRAEs) had occurred in 60% and 96% of arm B and C pts, respectively; grade 3-4 TRAEs occurred in 15% and 81%, respectively. Biomarker data evaluating PD-L1 biology (assessed by SP142) and associated transcriptome analysis in arms B vs C will be presented. Conclusions: This exploratory analysis of IMvigor130 pts with 1L cis–ineligible IC2/3 mUC provides additional evidence for clinical benefit with single-agent atezo, a well-tolerated treatment with a distinct safety profile vs chemo. Analyses with longer OS follow-up are warranted. Clinical trial information: NCT02807636 . Research Sponsor: F. Hoffmann-La Roche Ltd[Table: see text]

NRG-GI004/SWOG-S1610: Colorectal Cancer Metastatic dMMR Immuno-Therapy (COMMIT) Study—A randomized phase III study of atezolizumab (atezo) monotherapy versus mFOLFOX6/bevacizumab/atezo in the first-line treatment of patients (pts) with deficient DNA mismatch repair (dMMR) or microsatellite instability high (MSI-H) metastatic colorectal cancer (mCRC).

TPS158 Background: Despite activity of programmed cell death-1 (PD-1) pathway inhibition in dMMR/MSI-H mCRC, approximately one-third of patients demonstrate progressive disease as best response to anti-PD1 monotherapy. Preclinical models have demonstrated synergistic interactions between FOLFOX, anti-VEGF, and anti-PD-1. We hypothesize that the dMMR/MSI-H mCRC subset may be more effectively targeted by the combination of PD-1 pathway blockade and mFOLFOX6/bevacizumab (bev) rather than with anti-PD-1 therapy (atezo) alone. Methods: Initially a three-arm study, the mFOLFOX6/bev arm was closed to new enrollment on 6-4-20 due to emerging data; the redesigned COMMIT is a prospective phase III open-label trial that will randomize (1:1) mCRC dMMR/MSI-H pts (N=211) to either atezo monotherapy or mFOLFOX6/bev+atezo combination. Stratification factors include BRAFV600E status, metastatic site, and prior adjuvant CRC therapy. Primary endpoint is progression-free survival (PFS) as assessed by site investigator. Secondary endpoints include OS, objective response rate, safety profile, disease control rate, duration of response, and centrally-reviewed PFS. Health-related quality of life is an exploratory objective. Archived tumor tissue and blood samples will be collected for correlative studies. Key inclusion criteria are: mCRC without prior chemotherapy for advanced disease; dMMR tumor determined by local CLIA-certified IHC assay (MLH1/MSH2/MSH6/PMS2) or MSI-H by local CLIA-certified PCR or NGS panel; and measurable disease per RECIST. Support: U10CA180868, -180822, -180888, -180819, UG1CA189867, U24CA196067; Genentech, Inc. Clinical trial information: NCT02997228.

986P Efficacy of atezolizumab (atezo) + bevacizumab (bev) after disease progression with atezo monotherapy in patients with previously untreated, unresectable hepatocellular carcinoma (HCC)

Atezo (anti-PD-L1) + bev (anti–VEGF) statistically significantly prolonged overall survival (OS) and progression-free survival (PFS) vs sorafenib in the phase III IMbrave150 study in patients with unresectable HCC. In the phase Ib study GO30140, atezo + bev statistically significantly increased PFS vs atezo. We present efficacy data from GO30140 patients who crossed over to atezo + bev following progression on atezo.

Tumor, immune, and stromal characteristics associated with clinical outcomes with atezolizumab (atezo) + platinum-based chemotherapy (PBC) or atezo monotherapy (mono) versus PBC in metastatic urothelial cancer (mUC) from the phase III IMvigor130 study.

5011 Background: Tumor mutational burden (TMB), PD-L1 expression, T-effector gene expression (GE) and a fibroblast TGF-β–response signature (F-TBRS) are associated with clinical outcomes with atezo mono in mUC (Mariathasan, Nature, 2018). Here we explore the potential predictive role of these biomarkers and APOBEC mutagenesis in IMvigor130. Methods: Pts receiving first-line (1L) mUC treatment (tx) were randomized 1:1:1 to atezo + PBC, atezo mono, or placebo + PBC. Coprimary efficacy endpoints were PFS and OS. Planned exploratory biomarker analyses included PD-L1 expression, TMB (FoundationOne), and T-effector GE (RNA-seq). Results: The 851 biomarker-evaluable pts (BEP) were representative of the 1200 ITT pts. Biomarker results are shown in Table. PD-L1 IC2/3 was associated with significantly longer OS for atezo mono vs placebo + PBC and a combination of PD-L1 IC2/3, and high TMB (> 10 muts/Mb) identified a pt subset (≈ 14% of BEP) with particularly favorable outcomes with atezo mono vs placebo + PBC; similar results for PD-L1 and TMB were not seen with atezo + PBC vs placebo + PBC. APOBEC mutagenesis was associated with improved OS with atezo-containing regimens whereas high F-TBRS was associated with inferior OS with atezo mono. Conclusions: These results reinforce the potential predictive nature of biomarkers associated with response/resistance to atezo and highlight potentially distinct biology driving benefit with atezo and atezo + PBC. These findings suggest a possible biomarker-directed approach to 1L mUC tx that warrants mechanistic interrogation and prospective validation. Clinical trial information: NCT02807636 . [Table: see text]

Abstract P3-09-19: Preliminary safety data of intrahepatic talimogene laherparepvec and intravenous atezolizumab in patients with triple negative breast cancer

Abstract Background Talimogene laherparepvec (T-VEC) is a genetically modified, oncolytic herpes simplex virus type 1 designed to selectively replicate within tumors and to produce granulocyte-macrophage colony-stimulating factor to enhance systemic antitumor immune responses. The safety and efficacy of T-VEC in treatment of advanced melanoma has been demonstrated as monotherapy and in combination with the checkpoint inhibitors (CPI) pembrolizumab and ipilimumab. Additionally, T-VEC monotherapy has demonstrated tolerable safety for intrahepatic injection (Hecht GICS 2018). Atezolizumab (atezo) is a humanized monoclonal antibody that promotes antitumor immunity by targeting programmed cell death ligand-1 (PD-L1) and is approved for metastatic triple negative breast cancer (mTNBC). We hypothesize that T-VEC in combination with a CPI may be effective in mTNBC and CRC in addition to melanoma. This phase 1b, multicenter study (clinicaltrials.gov identifier: NCT03256344) evaluates the safety of intrahepatic injection of T-VEC in combination with intravenous (IV) atezo in patients (pts) with mTNBC or colorectal cancer (CRC) with liver metastases (LMs). Here we report early safety data in the TNBC cohort. Methods Key eligibility criteria included age ≥ 18 years, confirmed diagnosis of TNBC or CRC with LMs, ECOG PS 0/1, adequate organ function, disease progression during or after ≥ 1 prior standard-of-care systemic therapy for metastatic disease, and ≥ 1 measurable LM suitable for injection. T-VEC (≤ 4mL) was injected by image-guided intralesional injection: 106 PFU/mL day 1, 108 PFU/mL every 21 days thereafter; atezo 1,200 mg IV was given on day 1 and every 21 days thereafter. The primary objective of this study is to evaluate incidence of dose limiting toxicity (DLT) for safety of T-VEC injection into LMs in combination with IV atezo, by tumor type. The DLT analysis set included DLT-evaluable pts who were on treatment for at least 6 weeks from the initial dose of study treatment and received at least 2 doses of T-VEC and 2 doses of atezo in combination or have a DLT during the DLT evaluation period. Key secondary objectives include objective response rate, durable response rate, progression-free survival, and overall survival of the combination therapy, by tumor type. Results Thirty-two pts were enrolled in two parallel cohorts (8 TNBC, 24 CRC). Of the 8 TNBC pts, 4 were evaluable for DLT at the time of this analysis. Of the 4 pts that were not DLT-evaluable, 1 never received study drug, 1 received atezo monotherapy, and 2 received intrahepatic T-VEC and IV atezo but stopped study drugs for unconfirmed progression before the DLT evaluation period was completed. No DLTs were reported in the TNBC cohort. In the 7 TNBC pts who received at least one dose of the study drug, the most common treatment-emergent adverse events (TEAEs) in terms of the subject incidence were pyrexia (71.4%), chills (42.9%), and rash (42.9%). In the 7 TNBC pts who received at least one dose of study drug, T-VEC related AEs in more than one pt were pyrexia (n=3) and chills (n=2). Atezo related AEs in more than one pt were pyrexia (n=5), chills and rash (n=3 each), and fatigue, arthralgia, pain, and pruritus (n=2 each). Study drug-related serious adverse events (SAEs) occurred in 3 (42.9%) pts, including Grade (G) 3 hypersensitivity related to atezo, G3 orthostatic hypotension related to T-VEC and atezo, and G1 pyrexia related to T-VEC and atezo. Procedure-related SAEs occurred in 1 (14.3%) pt, of G3 hepatic hematoma and G3 abdominal infection, but these were not related to the study drugs. One confirmed partial response in the TNBC cohort has been seen thus far. Conclusion T-VEC intrahepatic injection in combination with IV atezo at standard doses has thus far been demonstrated as feasible and tolerable with no DLTs observed in the TNBC cohort to date. Citation Format: Joel Randolph Hecht, Arlene Chan, Jean-Francois Baurain, Miguel Martin, Federico Longo-Munoz, Kevin Kalinsky, Steven Raman, Chunxu Liu, Edward Cha, Emily Chan. Preliminary safety data of intrahepatic talimogene laherparepvec and intravenous atezolizumab in patients with triple negative breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-09-19.

A randomized phase III study of mFOLFOX6/bevacizumab combination chemotherapy with or without atezolizumab or atezolizumab monotherapy in the first-line treatment of patients (pts) with deficient DNA mismatch repair (dMMR) metastatic colorectal cancer (mCRC): Colorectal Cancer Metastatic dMMR Immuno-Therapy (COMMIT) study (NRG-GI004/SWOG-S1610).

TPS260 Background: Deficient DNA mismatch repair (dMMR) colorectal cancer (CRC) is highly immunogenic. Preclinical data showed synergistic interactions among FOLFOX, anti-VEGF, and programmed cell death-1 (PD-1) pathway blockade. Prior phase I study of mFOLFOX6/ bevacizumab (bev) + atezolizumab (atezo) was well tolerated and enhanced intratumoral infiltration of CD8+ T cells. We hypothesize that the dMMR subset of CRC may be effectively targeted with combination of PD-1 pathway blockade and mFOLFOX6/bev. Methods: This is a prospective randomized phase III open-label trial. Pts (N=347) with mCRC dMMR will be randomized to three trial arms (1:1:1): mFOLFOX6/bev; atezo monotherapy; or mFOLFOX6/bev + atezo. Stratification factors include BRAFV600E status, metastatic site, and prior adjuvant CRC therapy. Primary endpoint is progression-free survival (PFS) assessed by study investigator of mFOLFOX6/bev/atezo and atezo monotherapy compared to mFOLFOX6/bev. Secondary endpoints include OS, objective response rate, safety profile, disease control rate, duration of response, and PFS by retrospective central review. Health-related quality of life is an exploratory objective. Archived tumor tissue and blood samples will be collected for correlative studies. Key inclusion criteria are: mCRC without prior chemotherapy for advanced disease; dMMR tumor determined by local CLIA-certified IHC assay (MLH1/MSH2/MSH6/PMS2); availability of archived tumor tissue for central confirmation of dMMR status; and measurable disease per RECIST. Activated 11-7-17. As of 9-11-19, enrollment continues with 44/347 pts enrolled. Clinical trial: NCT02997228. Support:U10CA180868, -180822, -180888, -180819, UG1CA189867, U24CA196067; Genentech, Inc. Clinical trial information: NCT02997228.

LBA7 - Randomised efficacy and safety results for atezolizumab (Atezo) + bevacizumab (Bev) in patients (pts) with previously untreated, unresectable hepatocellular carcinoma (HCC)

BackgroundPts with unresectable HCC have few treatment (tx) options. Checkpoint inhibitors and combination approaches with anti-VEGFs are emerging as potential new tx options. Here we report the first randomised dataset evaluating atezo (anti-PD-L1) as monotherapy vs the combination of atezo + bev (anti-VEGF; Arm F) as well as updated single-arm atezo + bev data (Arm A) from a Ph 1b study. MethodsArms F and A of the Ph 1b study GO30140 enrolled systemic tx-naïve pts with unresectable HCC. Arm F pts were randomised 1:1 to atezo + bev or atezo monotherapy and received atezo 1200 mg IV q3w +/- bev 15 mg/kg IV q3w until unacceptable toxicity or loss of clinical benefit. Arm A pts received atezo + bev. Primary endpoints were progression free survival (PFS; Arm F) and objective response rate (ORR, Arm A) by independent review facility (IRF)-assessed RECIST 1.1, and safety (Arms F and A). ResultsIn Arm F, 60 pts were randomised to atezo + bev (Group F1) and 59 pts to atezo (Group F2). Arm F showed a statistically significant improvement in the primary endpoint median PFS for atezo + bev vs atezo (5.6 vs 3.4 mo, HR 0.55, 80% CI, 0.40 – 0.74, P = 0.0108). Any-Gr TRAEs occurred in 41 (68%) F1 pts and 24 (41%) F2 pts; Gr 3-4 TRAEs occurred in 12 (20%) F1 pts and 3 (5%) F2 pts. There were no Gr 5 TRAEs in Arm F. For the 104 pts in Arm A, primary endpoint ORR was 36% (37 pts) with 76% of responses ongoing. Any-Grade (Gr) tx-related adverse events (TRAEs) occurred in 91 (88%) pts; Gr 3-4 TRAEs occurred in 41 (39%) pts. Gr 5 TRAEs were seen in 3 (3%) pts.Table: LBA7Unlabelled ImageArm FIRF RECIST 1.1IRF HCC mRECISTF1 Atezo + Bev n = 60F2 Atezo n = 59aF1 Atezo + Bev n = 60F2 Atezo n = 59aMedian follow up, mo6.66.76.66.7Median PFS, mo5.6b3.4b5.63.495% CI3.6 – 7.41.9 – 5.23.6 – 7.41.9 – 5.2HR 80% CI0.55b0.40 – 0.74P = 0.01080.540.40 – 0.74Arm A: Atezo + Bev n = 104IRF RECIST 1.1IRF HCC mRECISTMedian follow up, mo12.4Confirmed ORR, n (%)37 (36)b41 (39)95% CI26 – 4630 – 50CR12 (12)16 (15)PR25 (24)25 (24)On-going response28 (76)28 (68)DCR (CR + PR + SD), n (%)74 (71)74 (71)Median DOR, moNENE95% CI11.8 – NE11.8 – NEMedian PFS, mo7.37.395% CI5.4 – 9.95.4 – 9.9Data cut off: 14 Jun 2019.a1 randomised pt did not receive atezo.bPrimary endpoint. ConclusionsBy meeting its primary endpoint of improved PFS for atezo + bev vs atezo alone, Arm F showed the single-agent contribution of atezo and bev to the overall tx effect. With longer follow up, Arm A highlights the clinically meaningful and durable responses of atezo + bev. Coupled with a tolerable safety profile, these data suggest that atezo + bev is a promising first-line tx option for unresectable HCC. Clinical trial identificationNCT02715531. Editorial acknowledgementJonathan Lee, PhD, of Health Interactions and funded by F. Hoffmann-La Roche, Ltd. Legal entity responsible for the studyF. Hoffmann-La Roche, Ltd. FundingF. Hoffmann-La Roche, Ltd. DisclosureC. Hsu: Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Ono Pharmaceutical; Honoraria (self), Research grant / Funding (institution): MSD; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Roche. M.S. Lee: Research grant / Funding (self): Amgen; Research grant / Funding (self): BMS; Research grant / Funding (self): Pfizer; Research grant / Funding (self): EMD Serono; Research grant / Funding (self): Genentech/Roche. K. Lee: Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: AZ; Advisory / Consultancy: Bayer; Advisory / Consultancy: Ono Pharmaceutical; Advisory / Consultancy: Samsung Bioepis; Advisory / Consultancy: Eisai. S. Stein: Advisory / Consultancy: Genentech; Advisory / Consultancy: BMS; Advisory / Consultancy: Eisai; Advisory / Consultancy: Bayer; Advisory / Consultancy: Exelixis. W. Verret: Full / Part-time employment: Genentech. S. Hack: Shareholder / Stockholder / Stock options, Full / Part-time employment: Roche/Genentech. J. Spahn: Shareholder / Stockholder / Stock options, Full / Part-time employment: Roche/Genentech. B. Liu: Full / Part-time employment: Genentech. C. Huang: Full / Part-time employment: Roche. R. He: Speaker Bureau / Expert testimony: Bayer; Speaker Bureau / Expert testimony: BMS; Speaker Bureau / Expert testimony: Eisai Inc; Speaker Bureau / Expert testimony: Exelixis Inc; Advisory / Consultancy, Research grant / Funding (institution): Merck & Co; Advisory / Consultancy: AZ.

LBA39 - Randomised efficacy and safety results for atezolizumab (Atezo) + bevacizumab (Bev) in patients (pts) with previously untreated, unresectable hepatocellular carcinoma (HCC)

BackgroundPts with unresectable HCC have few treatment (tx) options. Checkpoint inhibitors and combination approaches with anti-VEGFs are emerging as potential new tx options. Here we report the first randomised dataset evaluating atezo (anti-PD-L1) as monotherapy vs the combination of atezo + bev (anti-VEGF; Arm F) as well as updated single-arm atezo + bev data (Arm A) from a Ph 1b study. MethodsArms F and A of the Ph 1b study GO30140 enrolled systemic tx-naïve pts with unresectable HCC. Arm F pts were randomised 1:1 to atezo + bev or atezo monotherapy and received atezo 1200mg IV q3w, bev 15mg/kg IV q3w until unacceptable toxicity or loss of clinical benefit. Arm A pts received atezo + bev. Primary endpoints were progression free survival (PFS; Arm F) and objective response rate (ORR, Arm A) by independent review facility (IRF)-assessed RECIST 1.1, and safety (Arms F and A). ResultsIn Arm F, 60 pts were randomised to atezo + bev (Group F1) and 59 pts to atezo (Group F2). Arm F showed a statistically significant improvement in the primary endpoint median PFS for atezo + bev vs atezo (5.6 vs 3.4mo, HR 0.55, 80% CI, 0.40 – 0.74, P=0.0108). Any-Gr TRAEs occurred in 41 (68%) F1 pts and 24 (41%) F2 pts; Gr 3-4 TRAEs occurred in 12 (20%) F1 pts and 3 (5%) F2 pts. There were no Gr 5 TRAEs in Arm F. For the 104 pts in Arm A, primary endpoint ORR was 36% (37 pts) with 76% ongoing. Any-Grade (Gr) tx-related adverse events (TRAEs) occurred in 91 (88%) pts; Gr 3-4 TRAEs occurred in 41 (39%) pts. Gr 5 TRAEs were seen in 3 (3%) pts. ConclusionsBy meeting its primary endpoint of improved PFS for atezo + bev vs atezo alone, Arm F showed the single-agent contribution of atezo and bev to the overall tx effect. With longer follow up, Arm A highlights the clinically meaningful and durable responses of atezo + bev. Coupled with a tolerable safety profile, these data suggest that atezo + bev is a promising first-line tx option for unresectable HCC. Clinical trial identificationNCT02715531. Editorial acknowledgementMedical writing assistance was provided by Steffen Biechele, PhD, of Health Interactions and funded by F. Hoffmann-La Roche, Ltd. Legal entity responsible for the studyF. Hoffmann-La Roche, Ltd. FundingF. Hoffmann-La Roche, Ltd. DisclosureM. Lee: Research grant / Funding (self): Amgen; Research grant / Funding (self): Bristol-Myers Squibb ; Research grant / Funding (self): Pfizer; Research grant / Funding (self): EMD Serono; Research grant / Funding (self): Genentech/Roche. C. Hsu: Honoraria (institution), Advisory / Consultancy: BMS; Honoraria (institution), Advisory / Consultancy: Ono Pharmaceutical; Honoraria (institution), Research grant / Funding (self): MSD; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: AZ; Advisory / Consultancy: Roche. S. Stein: Advisory / Consultancy: Genentech; Advisory / Consultancy: BMS; Advisory / Consultancy: Eisai; Advisory / Consultancy: Bayer; Advisory / Consultancy: Exelixis. W. Verret: Full / Part-time employment: Genentech/Roche. S. Hack: Shareholder / Stockholder / Stock options, Full / Part-time employment: Genentech/Roche. J. Spahn: Shareholder / Stockholder / Stock options, Full / Part-time employment: Genentech/Roche. B. Liu: Shareholder / Stockholder / Stock options, Full / Part-time employment: Genentech/Roche. H. Abdullah: Full / Part-time employment: Genentech/Roche. R. He: Speaker Bureau / Expert testimony: Bayer; Speaker Bureau / Expert testimony: BMS; Speaker Bureau / Expert testimony: Eisai Inc.; Speaker Bureau / Expert testimony: Exelixis Inc; Advisory / Consultancy, Research grant / Funding (institution): Merck & Co; Advisory / Consultancy: AZ. K. Lee: Honoraria (self), Speaker Bureau / Expert testimony: AstraZeneca; Honoraria (self): Bayer; Honoraria (self): Eisai; Honoraria (self): Ono Pharmaceuticals; Honoraria (self), Speaker Bureau / Expert testimony: Roche; Honoraria (self): Samsung Bioepis; Speaker Bureau / Expert testimony: Eli Lilly. All other authors have declared no conflicts of interest.TableLBA39TableArm FIRF RECIST 1.1IRF HCC mRECISTF1 Atezo + Bev (n=60)F2 Atezo (n=59)aF1 Atezo + Bev (n=60)F2 Atezo (n=59)aMedian follow-up, mo6.66.76.66.7Median PFS, mo 95% CI5.6b 3.6 – 7.43.4b 1.9 – 5.25.6 3.6 – 7.43.4 1.9 – 5.2HR0.55b0.5480% CI0.40 – 0.74 P=0.01080.40 – 0.74Arm A: Atezo + Bevn=104IRF RECIST 1.1IRF HCC mRECISTMedian follow-up, mo12.4Confirmed ORR, n (%)37 (36)b41 (39)95% CI (%)26 – 4630 – 50Complete Response (CR), n (%)12 (12)16 (15)Partial Response (PR), n (%)25 (24)25 (24)On-going response, n (%)28 (76)28 (68)DCR (CR + PR + SD), n (%)74 (71)74 (71)Median DOR, moNENE95% CI11.8 – NE11.8 – NEMedian PFS, mo7.37.395% CI5.4 – 9.95.4 – 9.9DCR, disease control rate; DOR, duration of response; NE, not estimable; SD, stable disease. Data cut off: 14 June 2019.a1 randomised pt did not receive atezo.bPrimary endpoint.