Bev Arm Research Articles

Randomized phase II trial of weekly ixabepilone ± biweekly bevacizumab for platinum-resistant or refractory ovarian/fallopian tube/primary peritoneal cancer (NCT03093155): Updated survival and subgroup analyses

BackgroundIxabepilone may retain activity in paclitaxel-resistant disease. We previously reported improved response rates (ORR), progression-free (PFS), and overall survival (OS) conferred by ixabepilone+bevacizumab (IXA + BEV) compared to monotherapy (IXA) in heavily pre-treated ovarian cancers. We now describe a mature data set. Subset analyses were performed in patients with different taxane sensitivities and dose modifications.MethodsPatients previously treated with paclitaxel were stratified by prior BEV and randomized to receive IXA 20 mg/m2 days 1,8,15 ± BEV 10 mg/kg days 1,15 of a 28-day cycle in a multi-site prospective randomized phase 2 trial.ResultsThirty-seven patients were randomized to IXA and 39 patients to IXA + BEV. At the final data cutoff (05/27/2023), ORR was higher in the IXA + BEV arm (38.4% vs. 8.1%, p = 0.003). Dose reductions were necessary in most participants but did not diminish PFS/OS benefits. Most patients were paclitaxel-refractory/-resistant (51%, n = 19/37;67%, n = 26/39); the remainder were taxane-sensitive. The addition of BEV to IXA conferred benefit in PFS (5.5 vs. 2.2 mo; HR 0.31, 90%CI 0.20–0.49, p < 0.001) and OS (10.3 vs. 6.0 mo; HR 0.56, 90%CI 0.38–0.84, p = 0.02) that persisted after adjusting for prior taxane response.ConclusionsIXA + BEV has activity in heavily pre-treated ovarian cancers and offers significant improvement in ORR and PFS/OS compared to IXA, despite prior taxane response and dose reductions.Clinical Trial RegistrationNCT03093155

Five-year survival outcomes from the PIT-1 trial: Pemetrexed-cisplatin plus bevacizumab or concurrent thoracic radiation therapy followed by surgery in stage IIIA (N2) nonsquamous non-small cell lung cancer.

8064 Background: Personized Induction Therapy-1 (PIT-1) is a multicenter, randomized phase II selection design trial of pemetrexed-cisplatin plus bevacizumab (BEV arm) or concurrent thoracic radiation therapy (TRT arm) followed by surgery in patients with stage IIIA (N2) nonsquamous non-small cell lung cancer (NSCLC). The TRT arm was chosen as the investigational induction treatment strategy for a future phase III study based on the results of a numerically higher 2-year progression-free survival (PFS, primary endpoint) in the TRT arm and fatal postoperative complications observed only in the BEV arm. We report updated, exploratory analyses of survival, approximately 5 years after the last patient was randomly assigned. Methods: Patients with stage IIIA (N2) nonsquamous NSCLC were randomly assigned (1:1) induction therapy consisting of pemetrexed and cisplatin plus bevacizumab (n = 44) or concurrent TRT (n = 44) followed by surgery. Among them, 38 patients in the BEV arm and 37 patients in the TRT arm underwent surgery. Five-year overall survival (OS), 5-year PFS, and patterns of postoperative recurrence were compared between arms. Prognostic factors of OS were analyzed in surgically resected patients using Cox’s proportional hazard model. Results: The median follow-up was 66.4 months. In 82 treated patients, the 5-year OS and PFS rates were 63.5% (95% CI: 46.9-76.1) and 26.2% (95% CI: 14.1-40.0) in the BEV arm (n = 42), and 57.2% (95% CI: 40.5-70.8) and 27.5% (95% CI: 14.9-41.7) in the TRT arm (n = 40), respectively. There were no statistical differences in OS ( P = 0.572) and PFS ( P = 0.356). In 75 surgically resected patients, pathological nodal down stage was the only significant prognostic factor of OS ( P = 0.014). Age, sex, smoking status, clinical T stage, clinical N stage based on a computed tomography scan, preoperative serum CEA and CYFRA level, EGFR mutation status, pathological complete response, and major pathological response did not have a significant prognostic impact on OS. The patterns of postoperative recurrence were different between arms: locoregional only, in four (11%) and one (3%); distant metastasis only, in 16 (42%) and 21 (57%); and both, in five (13%) and four (11%) in the BEV and TRT arms, respectively. The recurrence rate of ipsilateral hilar or mediastinal lymph nodes (the irradiation field) was significantly lower in the TRT arm (3%) than in the BEV arm (21%, P= 0.01). Conclusions: Five-year survival outcomes were not different between the BEV and TRT arms. The TRT arm demonstrated sufficient local control, but insufficient control of distant metastasis so this is an important issue that requires improvement in the future. Clinical trial information: s031180402.

Results from the MORPHEUS-liver study: Phase Ib/II randomized evaluation of tiragolumab (tira) in combination with atezolizumab (atezo) and bevacizumab (bev) in patients with unresectable, locally advanced or metastatic hepatocellular carcinoma (uHCC).

4010 Background: Atezo + bev is the current first-line standard of care for uHCC based on the IMbrave150 study, which demonstrated superior overall survival, progression-free survival (PFS), and objective response rate (ORR) vs sorafenib (Finn, et al. New Engl J Med 2020; Cheng, et al. J Hepatol 2022). TIGIT is a novel inhibitory immune checkpoint present on activated T cells and NK cells. Tira (anti-TIGIT) may synergize with other immunotherapies, such as PD-L1/PD-1 inhibitors. The MORPHEUS platform comprises multiple phase Ib/II trials to identify early efficacy signals and safety of treatment combinations across cancers. Here we report data from a cohort of the MORPHEUS-liver study (NCT04524871) evaluating the combination of tira + atezo + bev vs a control arm (atezo + bev) in patients with uHCC. Methods: Patients with previously untreated uHCC were randomized to receive atezo (1200mg IV) + bev (15mg/kg IV) with or without tira (600mg IV) every three weeks. The primary endpoint was investigator-assessed ORR by RECIST V1.1. Secondary endpoints included PFS and safety. Results: A total of 58 patients were randomized (tira + atezo + bev, n=40; atezo + bev, n=18). As of 28 November 2022, median follow up was 14.0 months in the tira + atezo + bev arm and 11.8 months in the control arm. Confirmed ORR was higher in the tira + atezo + bev arm (42.5%) vs the control arm (11.1%). Median PFS was longer with tira + atezo + bev (11.1 months; 95% CI: 8.2–NE) vs control (4.2 months; 95% CI: 1.6–7.4), corresponding to a PFS hazard ratio (HR) of 0.42 (95% CI: 0.22–0.82). A similar pattern of increased ORR and PFS was observed for the treatment arms in both PD-L1+ (n=23) and PD-L1– (n=27) subgroups. For tira + atezo + bev vs control arm, grade 3/4 treatment-related AEs were 27.5% vs 33.3% and AEs leading to any treatment discontinuation were 22.5% vs 22.2%, respectively. Conclusions: The addition of tira to atezo + bev resulted in higher ORR and longer PFS compared with atezo + bev, and no new safety signals were identified. These data suggest that tira + atezo + bev may be a promising novel first-line treatment option for patients with uHCC, and support further study in this setting. Clinical trial information: NCT04524871 . [Table: see text]

Ombipepimut dosing emulsion (ODE) + bevacizumab (bev) vs bev alone in patients (pts) with recurrent or progressive glioblastoma (rGBM).

2022 Background: ODE is an investigational cancer vaccine derived from Wilms tumor 1. WIZARD was a randomized, adaptive, phase 3 study to test ODE + bev vs bev in rGBM pts (NCT03149003). Patients were stratified prior to randomization based upon KPS [60 or 70] vs [80 to 100] and extent of resection at initial diagnosis. Patients with low KPS (e.g., 60) are generally underrepresented in clinical trials. Methods: Pts ≥18 years with GBM at first recurrence were enrolled. Overall survival (OS) was the primary endpoint; the key secondary endpoint was the 12-month OS rate. The primary and the key secondary endpoints were tested using 1-sided test with an overall significance level 2.5%. The Lan-DeMets error spending function based upon O’Brien-Fleming stopping boundaries was used to adjust the significance level for the interim and final analyses. Results: From April 2018 to Aug 2021, 217 pts were randomized 1:1; 109 to ODE + bev and 108 to bev. OS was analyzed after 185 events with a median follow-up of 31.8 months (mo). Pts at baseline had a median age of 60 years, 45.2% reported corticosteroid use, 29% had KPS 60 or 70, 7.8% had tumors that harbored IDH1 or 2 mutations, and the median tumor volume was 10,532 mm3. Baseline characteristics between treatment arms were balanced in the ITT and KPS subgroups. Pts with KPS 60 or 70 had more corticosteroid use, worse NANO scores, and larger tumor burden than those with KPS 80-100. The study did not meet its primary endpoint of OS by ITT (ODE + bev: 10.2 mo vs bev: 9.4 mo, 1-sided p-value: 0.2159). Pts with KPS 60 or 70 had longer OS when treated with ODE + bev (8.2 vs 6.3 mo, 45% death risk reduction, 1-side p value: 0.0119). Grade 1 or 2 injection site reaction was the most common TEAE in the ODE + bev arm. No clinically significant difference in safety was noted between KPS subgroups. Conclusions: The data in pts with KPS 60 or 70 suggested benefit with ODE + bev that was consistent across different endpoints and that warrants further validation. Clinical trial information: NCT03149003 . [Table: see text]

Trifluridine/tipiracil plus bevacizumab for third-line treatment of refractory metastatic colorectal cancer: The phase 3 randomized SUNLIGHT study.

4 Background: Trifluridine/tipiracil (FTD/TPI) plus bevacizumab (Bev) demonstrated promising efficacy in a randomized phase 2 trial of heavily pretreated patients (pts) with metastatic colorectal cancer (mCRC). SUNLIGHT was conducted to confirm these findings. Methods: The global phase 3 SUNLIGHT study enrolled pts aged ≥18 years with histologically confirmed mCRC, ECOG PS 0/1, and treated with 1-2 prior chemotherapy regimens in an advanced setting, including fluoropyrimidines, irinotecan, oxaliplatin, an anti-VEGF monoclonal antibody (if medically considered) and/or anti-EGFR monoclonal antibody for RAS wild-type tumors. Pts were randomised (1:1) to receive FTD/TPI (35 mg/m2 twice daily on days 1–5 and 8–12 of each 28-day cycle) alone or combined with Bev (5 mg/kg on days 1 and 15). Primary endpoint was overall survival (OS). Results: Between Nov 2020 and Feb 2022, 492 pts were randomised to receive FTD/TPI + Bev (n = 246) or FTD/TPI (n = 246). Baseline characteristics were balanced between arms. FTD/TPI + Bev significantly extended OS over FTD/TPI, median OS was 10.8 months vs 7.5 months, respectively (HR, 0.61; 95% CI, 0.49, 0.77; P&lt; 0.001). OS rates at 12 months were 43% in the FTD/TPI + Bev arm and 30% in the FTD/TPI arm. Median progression-free survival was 5.6 months in the FTD/TPI + Bev arm and 2.4 months in the FTD/TPI arm (HR, 0.44; 95% CI, 0.36,0.54; P&lt; 0.001). Grade ≥3 adverse events (AEs) were not significantly increased in the FTD/TPI + Bev arm vs the FDT/TPI arm (72.4% vs 69.5%). No new safety signals were noted. Conclusions: FTD/TPI + Bev provided a statistically significant and a clinically meaningful 3.3-month improvement in OS, extending mOS up to 10.8 months, with a 39% reduction in the HR of death in pts with refractory mCRC and with a predictable and acceptable safety profile. Clinical trial information: NCT04737187 .

Modified (m)-FOLFOXIRI plus cetuximab versus m-FOLFOXIRI plus bevacizumab as initial treatment of patients with unresectable RAS and BRAF wild-type metastatic colorectal cancer: Survival analysis of the phase II randomized DEEPER trial by JACCRO.

120 Background: Triplet regimen, FOLFOXIRI, plus bevacizumab is considered as one of standard first-line treatments in metastatic colorectal cancer (mCRC). On the contrary, FOLFOXIRI plus anti-EGFR antibody has been shown to be a promising regimen with greater depth of response (DpR) in patients with RAS wild-type mCRC from the VOLFI and MACBETH trials (J Clin Oncol 2019, JAMA Oncol 2018). We therefore performed a randomized phase II study, DEEPER trial (JACCRO CC-13) [NCT02515734], to investigate the efficacy and safety of cetuximab (cet) vs. bevacizumab (bev) in combination with modified (m)-FOLFOXIRI in previously untreated mCRC patients with RAS wild-type tumors. We have reported a significantly better DpR of m-FOLFOXIRI plus cet compared to bev as the primary endpoint (Tsuji A, et al. ASCO 2021). Methods: This trial was a randomized phase II trial to evaluate modified (m)-FOLFOXIRI (irinotecan 150 mg/m2, oxaliplatin 85 mg/m2, 5-FU 2400 mg/m2) plus cet vs. bev as initial treatment in terms of DpR during the entire course as the primary endpoint in 360 patients with RAS wild-type mCRC. The aim of the trial was to show that median DpR of cet arm was more than 12.5% higher than bev arm, with a power of 85% at a significance level of 0.05, in per protocol set (PPS) consisted of patients evaluable for the DpR. Secondary endpoints included progression-free survival, overall survival, overall response rate, early tumor shrinkage rate, secondary resection rate, and toxicity. A total of 359 patients were enrolled between July 2015 and June 2019. For the PPS (median age 65y, 64% male, PS0/1: 91%/9%, left/right primary: 84%/16%), 159 and 162 patients were randomly assigned to the cet and bev arms, respectively. Clinical outcomes will be analyzed according to primary tumor sidedness which is included in the stratification factor. Additionally, we will collect data of BRAF status, and analyze the clinical outcomes in mCRC patients with RAS/ BRAF wild-type tumors and/or left-sided tumors. Pre-planned survival analysis will be performed to compare the two treatment arms at the time of 3 years after last patients’ enrollment using a log-rank test. All statistical tests are two-sided, and P values ≤ 0.05 are deemed significant. Statistical analyses will be performed using SAS version 9.4. Clinical trial information: NCT02515734 .

Time without symptoms or toxicity (TWiST) in patients with newly diagnosed advanced ovarian cancer receiving maintenance olaparib or placebo plus bevacizumab: Analysis of PAOLA-1/ENGOT-ov25 phase III trial.

5562 Background: In the Phase III PAOLA-1/ENGOT-ov25 trial (NCT02477644), maintenance olaparib plus bevacizumab (bev) provided a significant progression-free survival (PFS) benefit, compared with placebo plus bev, in patients (pts) with newly diagnosed advanced ovarian cancer in response after platinum-based chemotherapy (Ray-Coquard et al. NEJM 2019). A subgroup analysis revealed a substantial PFS benefit in HRD-positive (including BRCA1/BRCA2 mutation) pts (median PFS 37.2 vs 17.7 months) leading to US and EU labels for this combination. We analyzed TWiST in PAOLA-1, using several definitions of toxicity (TOX) and by molecular subgroups. Methods: Pts were randomized 2:1 to maintenance olaparib (300 mg bid) plus bev (15 mg/kg, Day 1, q3w) or placebo plus bev, stratified by first-line treatment outcome and tumor BRCAm status. TWiST is defined as PFS minus time with TOX after randomization and before disease progression or censoring for progression, and was a prespecified exploratory endpoint. Definitions of significant symptoms or TOX were explored using the following approaches: 1) all grade ≥2 adverse events (AEs); and 2) all grade ≥2 AEs selected to be correlated to olaparib (fatigue, nausea, vomiting, and anemia). Area under PFS curve was split into TOX:TWIST ratio and compared between the two arms. Results: Between May 7, 2015 and August 31, 2017, 806 eligible pts were randomly assigned to olaparib plus bev (n = 537) or placebo plus bev (n = 269), with a median duration of treatment with olaparib of 17.3 months (range 0.03–33.0) for olaparib plus bev arm and 15.6 months (range 0.07–26.2) for placebo plus bev at data cutoff for primary endpoint analysis. In the Intent-to-treat population, median duration of TWiST for all grade ≥2 AEs for olaparib plus bev vs placebo plus bev arms was 14.1 months (95% confidence interval [CI] 12.5–16.1) vs 7.7 months (95% CI 5.9–9.1), respectively; and 21.9 months (95% CI 20.2–22.5) vs 16.6 months (95% CI 14.6–18.0) considering only grade ≥2 AEs linked to olaparib. The difference was particularly significant within the HRD-positive subgroup where median duration of TWiST was 24.4 months (95% CI 19.3–not evaluable [NE]) vs 7.4 months (5.8–11.2) for TOX linked to all grade ≥2 AEs, and 36.6 months (95% CI 31.9–NE) vs 17.4 months (15.1–19.4) linked to olaparib AEs only for the olaparib plus bev and placebo plus bev arms, respectively. Conclusions: The substantial PFS benefit provided by maintenance olaparib plus bev vs placebo plus bev in pts with newly diagnosed advanced ovarian cancer was supported by significant TWiST benefit. TWiST analyses, including all grade ≥2 symptoms or toxicity related to treatment, confirmed the clinically meaningful benefit from the combination, notably in the HRD-positive subgroup. Clinical trial information: NCT02477644.

Testing of a machine learning (ML) model for ability to predict oxaliplatin and bevacizumab (bev) benefit in NRG Oncology/NSABP C-07 and C-08.

3607 Background: Through mining The Cancer Genome Atlas (TCGA) data and a large set of transcriptomes of CRC in GEO, we constructed 15 metagenes reflecting the transcriptomic impact of major driver genes of CRC. Independent of any clinical information, we used metagenes as features to further develop an ML model, then tested it using gene expression (GE) data from C-07 and C-08. Methods: We carried out a prospectively designed and double-blind study to evaluate the clinical utility of the ML model in the adjuvant setting. Samples were classified as Sig+ or Sig-. Association of signatures with recurrence free interval were tested using log-rank test, and significance was set at P&lt;0.05. Cox regression models were used to estimate hazard ratios in univariate and multivariate models and for significance testing in multivariate models. Clinical variables included in multivariate models were nodal status, age, sex, and T stage. Results: We tested the ML model for its ability to predict oxaliplatin benefit in all C-07 pts with available GE data (n=846). Sig+ pts received significant benefit from oxaliplatin (HR=0.68, 95% CI=0.48-0.95, p=0.025) but Sig- did not (Sig- HR=1.05, 95% CI=0.72-1.53, p=0.79), however, the int p value showed only a trend for significance (int p=0.091). Sig+ remained significant for oxaliplatin benefit in multivariate analysis (HR=0.67, 95% CI=0.48-0.95, p=0.024). When we combined all C-07 pts (C-07 FULV-trtd n=298, FLOX n=304) with C-08 FOLFOX-treated pts (n=226) the Sig+ was significantly associated with oxaliplatin benefit (HR=0.65, 95% CI=0.48-0.89, p=0.0065) with a significant int p=0.03. We also tested the signature for association with bev benefit in C-08 (n=438), using a different cut off. Sig+ showed only a trend for an association with bev benefit (HR=0.63, 95% CI=0.35-1.12, p=0.11). To increase the power to detect bev benefit, we also tested the signature for association with bev benefit in all C-08 patients and C-07 pts treated with FLOX. The Sig+ group received significant benefit from bev (HR=0.58, 95% CI=0.36-0.94, p=0.025) but the Sig- group did not (HR=1.02, 95% CI=0.64-1.63, p=0.94), however, the int p was not significant (p=0.101). The model also showed an association with prognosis within the FULV treatment arm in C-07 (HR=1.51, 95% CI=1.07-2.14, p=0.018) and the FOLFOX+bev arm in C-08 (HR=0.55, 95% CI=0.30-1.01, p=0.049). Conclusions: Although our study is not optimally powered, our analyses indicate that the ML model was predictive for oxaliplatin benefit in stage II and III CC and may be useful for detecting bev benefit. Importantly, the Sig- population is candidate for omitting oxaliplatin (de-escalation) in adjuvant setting but will require further validation. Support: PA DOH, U10CA-180868, -180822, -196067, Genentech, Sanofi; NSABP. Clinical trial information: 00096278, 00004931.

The role of genetic variants involved with ferroptosis regulator genes in predicting outcomes in patients (pts) with RAS-mutant metastatic colorectal cancer (mCRC): Data from MAVERICC and TRIBE trials.

197 Background: Ferroptosis, an iron-dependent programmed cell death, is one of the anti-tumor mechanisms of anti-angiogenesis drugs. RAS mutation can confer ferroptosis in colorectal cancer (CRC). Previous studies suggested that polymorphisms of ferroptosis regulator genes are associated with the increased risk of CRC. Therefore, we hypothesized that genetic variants in the ferroptosis regulator genes may predict first-line treatment outcome in RAS-mutant mCRC pts treated with bevacizumab (bev)-based chemotherapy. Methods: Genomic DNA from blood samples of mCRC pts enrolled in two independent randomized trials, MAVERICC (FOLFIRI+bev arm: discovery cohort, RAS-mutant, n = 56; control-1: RAS-wildtype, n = 87) and TRIBE (FOLFOXIRI+bev arm: validation cohort, RAS-mutant, n = 57; control-2: RAS-wildtype, n = 34), was genotyped through the OncoArray, a customized array manufactured by Illumina including approximately 530K SNP markers. The impact on outcome of 13 selected SNPs in 5 main ferroptosis regulator genes (ACSL4, LPCAT3, SLC3A2, SLC7A11, ALOX15) was analyzed. Results: In the MAVERICC bev cohort, pts with RAS-mutant tumors carrying ALOX15 rs7217186 any C allele (n = 35) showed significant longer overall survival (OS) than carrier of T/T allele (n = 5) in both univariate (24.97 vs. 12.22 months, hazard ratio [HR] = 0.23; 95% confidence interval [CI]: 0.06-0.9; p = 0.02) and multivariate (HR = 0.06; 95%CI 0.007-0.5; p = 0.009) analysis. In the TRIBE bev cohort, RAS-mutant carriers of any C allele (n = 30) showed numerically longer progression-free survival (PFS), compared to carriers of T/T allele (n = 13) in both univariate (11.91 vs. 9.47 months, HR = 0.45; 95%CI 0.2-1.02; p = 0.05) and multivariate (HR = 0.42; 95%CI 0.16-1.1; p = 0.09) analysis. Conversely, RAS-wildtype carriers of any C allele (n = 17) showed significant shorter PFS than T/T carriers in the TRIBE bev cohort (8.91 vs. 15.59 months, univariate HR = 3.39, 95%CI: 1.03-11.18, p = 0.04). Conclusions: Our study demonstrated for the first time that ALOX15 polymorphisms may have different predictive values for the bev-based treatment in mCRC patients based on RAS mutational status. These findings may provide novel insights for the combination of ferroptosis inducers and anti-VEGF treatment.

IMbrave150: Exploratory efficacy and safety in patients with unresectable hepatocellular carcinoma (HCC) treated with atezolizumab beyond radiological progression until loss of clinical benefit in a global phase III study.

470 Background: First-line atezolizumab (atezo) + bevacizumab (bev) has been approved in &gt; 80 countries based on significantly longer survival vs sorafenib (sor) in systemic treatment (tx)–naive patients (pts) with unresectable HCC in IMbrave150 (NCT03434379; Finn NEJM 2020). This clinically meaningful tx benefit was maintained with an additional 12 months of follow-up (Finn ASCO GI 2021). We report the efficacy and safety in pts who received atezo beyond radiological progression until loss of clinical benefit. Methods: Pts were randomized 2:1 to receive atezo 1,200 mg IV + bev 15 mg/kg IV q3w or sor 400 mg bid until unacceptable toxicity or loss of clinical benefit per investigator (INV). In the presence of clinical benefit, pts with progressive disease (PD) per INV RECIST 1.1 (not at a critical anatomical site) could continue study tx. Pts from the atezo + bev arm who had PD and continued atezo were included. Results: Of the 336 pts who received atezo + bev, 236 had PD, of whom 130 continued atezo (± bev), 60 had other tx, and 46 received no tx on or after first PD. Of the pts who continued atezo, 78% were Barcelona Clinic Liver Cancer (BCLC) stage C and 80% Child-Pugh A5 vs pts receiving other tx (85% BCLC stage C, 72% Child-Pugh A5). Sor (13% and 53%) and lenvatinib (14% and 35%) were the most common other txs received post PD among pts who continued atezo or received other tx, respectively. At clinical cutoff (August 31, 2020), the median number of cycles of atezo received post PD was 5 (range, 1-33) and 41 (32%) pts received ≥ 10 cycles. 60 of 130 (46%) pts who continued atezo died vs 180 of 336 (54%) receiving atezo + bev in the ITT population. See Table for efficacy data from baseline (BL) and PD. Grade (Gr) 3/4 and tx-related Gr 3/4 AEs occurred in 30 (23%) and 21 (16%) pts who continued atezo, respectively. There were 6 (5%) Gr 5 AEs, none tx-related. Conclusions: Atezo + bev is the standard of care for pts with unresectable HCC. In IMbrave150, pts with maintained clinical benefit continuing atezo after PD may have further benefited from staying on tx, although interpretation is limited by selection bias (prespecified criteria excluding pts with loss of clinical benefit). These data suggest that tx with atezo until loss of clinical benefit may contribute to post-PD outcomes. Beyond this exploratory analysis in select pts, the value of tx with atezo beyond formal progression will be assessed prospectively in IMbrave251 (NCT04770896). Clinical trial information: NCT03434379. [Table: see text]

Olaparib in combination with bevacizumab compared to bevacizumab monotherapy for the first-line maintenance treatment of advanced ovarian cancer: a cost-effectiveness analysis

<h3>Objectives:</h3> The addition of maintenance olaparib to bevacizumab (OLAP+BEV) demonstrated significant progression-free survival (PFS) benefit vs BEV alone in the randomized trial PAOLA-1 in advanced ovarian cancer patients with homologous recombination deficiency (HRD)-positive tumors. We aim to quantify the health and economic impact by evaluating the US cost-effectiveness of OLAP+BEV relative to BEV as a maintenance treatment for women with advanced ovarian cancer who had partial or complete response to first-line platinum-based chemotherapy and whose cancer is associated with HRD-positive status <h3>Methods:</h3> Our economic model was a cohort-level four state partitioned survival model with a lifetime horizon. States were progression-free, post first progression, post second progression, and death, modelled using first PFS (PFS1), second PFS (PFS2) and overall survival (OS) outcomes from the PAOLA-1 trial. This approach captured multiple progressions, and the differing health state utility after each progression. PFS1 was modelled through parametric mixture survival modeling to a landmark survival point at 5 years, beyond which, patients who have not progressed are assumed to experience all-cause mortality as the general population. PFS2 and OS were modelled by fitting standard parametric models, and time on treatment data was used directly from PAOLA-1, with a treatment cap of 24 months for OLAP and 15 months for BEV. The cost of HRD testing was calculated as unit cost divided by prevalence and was included as a one-time cost for OLAP+BEV arm. US-based health state utility values were analyzed by applying the methods developed by Pickard. The analyses were conducted from a US healthcare payer perspective, with an annual discount rate of 3%. We also explored the robustness of results using deterministic (DSA) and probabilistic sensitivity analysis. <h3>Results:</h3> At year 5, 45.1% and 16.9% patients remained PFS from OLAP+BEV and BEV arm, respectively. The results showed that compared with bevacizumab alone, OLAP+BEV led to a gain in quality-adjusted life years (2.89 QALYs gain) and life years (3.43 Lys gain) but resulted in higher costs, leading to a deterministic incremental cost-effectiveness ratio (ICER) of $75,276 per QALY. OLAP+BEV had an 87.5% probability of being cost-effective at a willingness-to-pay threshold of $100,000 per QALY. DSA identified efficacy (PFS and OS parameters), subsequent treatment and utility values as key model drivers. <h3>Conclusions:</h3> OLAP+BEV is associated with LY and QALY gain, and is cost effective for US payers relative to BEV monotherapy for the treatment of women with advanced, HRD-positive ovarian cancer

Abstract CT009: IMbrave150: Updated efficacy and safety by risk status in patients (pts) receiving atezolizumab (atezo) + bevacizumab (bev) vs sorafenib (sor) as first-line treatment for unresectable hepatocellular carcinoma (HCC)

Abstract Background: Based on the Ph III IMbrave150 trial, atezo + bev has been approved globally and is the standard of care for pts with unresectable HCC who have not received prior systemic therapy. With an additional 12 mo of follow-up from the primary analysis (median, 15.6 mo), atezo + bev showed consistent clinically meaningful treatment benefit and safety (Finn ASCO GI 2021). Here, we report results of updated analyses considering high-risk factors. Methods: Pts were randomized 2:1 to receive atezo 1200 mg IV q3w + bev 15 mg/kg IV q3w or sor 400 mg PO BID until loss of clinical benefit or unacceptable toxicity. High-risk pts were defined as those who had tumor invasion of the main trunk of the portal vein and/or the portal vein branch contralateral to the primarily involved lobe (Vp4), and/or bile duct invasion and/or tumor occupancy of ≥ 50% of liver. Results: In the ITT population, 64 (19%) pts randomized to atezo + bev and 37 (22%) pts randomized to sor were defined as high risk. 10 pts had bile duct invasion, 73 had Vp4 portal vein invasion and 31 had liver tumor occupancy of ≥ 50%. 9 pts in the atezo + bev arm and 4 pts in the sor arm had 2 high-risk factors. OS, PFS and ORR all favored atezo + bev over sor, in both non-high-risk and high-risk patients. See table for efficacy results. In safety-evaluable pts, Grade 3/4 treatment-related AEs (TRAEs) occurred in 122 (45%) of 269 non-high-risk and 21 (35%) of 60 high-risk atezo + bev pts. Grade 5 TRAEs occurred in 5 (2%) non-high-risk and 1 (2%) high-risk atezo + bev pt. Conclusions: Efficacy benefit was seen with atezo + bev vs sor regardless of the presence of high-risk features. HRs remained similar despite the numerical differences in median OS between non-high-risk and high-risk pts. Further, the overall safety data in the atezo + bev arm were comparable between non-high-risk and high-risk pts and in line with the known safety profile of each drug. Non-High RiskHigh RiskITTAtezo + BevSorAtezo + BevSorAtezo + BevSorEvaluable for OS/PFS, n2721286437336165Median OS (95% CI), mo22.8 (19.1, 24.9)15.7 (13.2, 19.0)7.6 (6.6, 12.8)5.5 (4.1, 6.7)19.2 (17.0, 23.7)13.4 (11.4, 16.9)HR (95% CI)0.68 (0.51, 0.91)0.62 (0.39, 1.00)0.66 (0.52, 0.85)Median PFS (95% CI), moa7.2 (6.5, 9.6)4.4 (4.0, 5.8)5.4 (4.0, 6.9)2.8 (2.5, 5.3)6.9 (5.7, 8.6)4.3 (4.0, 5.6)HR (95% CI)0.61 (0.48, 0.78)0.74 (0.47, 1.17)0.65 (0.53, 0.81)Evaluable for ORR, n2631246335326159Confirmed ORR, n (%)a,b81 (31)13 (10)16 (25)5 (14)97 (30)18 (11)Complete response, n (%)a20 (8)05 (8)1 (3)25 (8)1 (1)Median DOR (95% CI), moa,c19.0 (14.6, NE)12.6 (4.9, 17.0)16.3 (13.5, NE)16.5 (3.9, NE)18.1 (14.6, NE)14.9 (4.9, 17.0)NCT03434379.Clinical cutoff date: Aug 31, 2020.DOR, duration of response; HR, hazard ratio; IRF, independent review facility; NE, not estimable; ORR, objective response rate; OS, overall survival; PFS, progression-free survival.aAssessed by an IRF per RECIST 1.1.bORR IRF RECIST 1.1-evaluable population was based on patients who presented with measurable disease at baseline.cDOR analysis was based on all confirmed responders. Citation Format: Richard S. Finn, Shukui Qin, Masafumi Ikeda, Peter R. Galle, Michel Ducreux, Tae-You Kim, Masatoshi Kudo, Ho Yeong Lim, Valeriy Breder, Philippe Merle, Ahmed Kaseb, Daneng Li, Yin-Hsun Feng, Wendy Verret, Alan Nicholas, Lindong Li, Ning Ma, Andrew X. Zhu, Ann-Lii Cheng. IMbrave150: Updated efficacy and safety by risk status in patients (pts) receiving atezolizumab (atezo) + bevacizumab (bev) vs sorafenib (sor) as first-line treatment for unresectable hepatocellular carcinoma (HCC) [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 CT009.

The randomized phase II study of FOLFOXIRI plus cetuximab versus FOLFOXIRI plus bevacizumab as the first-line treatment in metastatic colorectal cancer with RAS wild-type tumors: The DEEPER trial (JACCRO CC-13).

3501 Background: Triplet regimens, FOLFOXIRI, combined with bevacizumab (bev) or panitumumab have been shown to be superior in terms of early tumor shrinkage (ETS) and depth of response (DpR) compared to doublet combinations in patients with RAS wild-type metastatic colorectal cancer (mCRC), in the TRIBE trial ( N Engl J Med 2014) or the VOLFI trial ( J Clin Oncol 2019), respectively. There have been few studies which directly compared cetuximab (cet) with bev when combined with triplet regimen. Therefore, we investigated the efficacy and safety of bev vs. cet in combination with FOLFOXIRI in previously untreated mCRC patients with RAS wild-type tumors. Methods: This trial was a randomized phase II trial to evaluate modified (m)-FOLFOXIRI (irinotecan 150mg/m2, oxaliplatin 85mg/m2, 5-FU 2400mg/m2) plus cet vs. bev as first-line treatment in terms of DpR during the entire course as the primary endpoint in 360 patients with RAS wild-type mCRC. The aim of the trial was to show that median DpR of cet arm was more than 12.5% higher than bev arm, with a power of 85% at a significance level of 0.05. Secondary endpoints included ETS rate at week 8, overall response rate (ORR), progression-free survival (PFS), overall survival (OS), secondary resection rate, and toxicity. Results: A total of 359 patients were enrolled between July 2015 and June 2019. For the full analysis set (median age 65y, 64% male, PS0/1: 91%/9%, left/right primary: 83%/17%), 173 and 175 patients were randomly assigned to the cet and bev arms, respectively. On the cutoff date of September 2020, the median number of cycles administered was 10 (range, 1-51) for the cet arm and 12 (range, 1-51) for the bev arm. Safety data was already reported at the ASCO GI symposium 2021 (J Clin Oncol 39, 2021 suppl 3; abstr 86). The primary endpoint was met (p =.001); 57.4%（-15.0̃100）for the cet arm versus 46.0% （-0.6̃100）for the bev arm. As for primary tumor sidedness, median DpR were 60.3% versus 46.1% (p =.0007) in the left-side and 50.0% versus 41.2% (p =.46) in the right-side. The ETS rate and ORR as the secondary endpoints were 77.8% and 69.1% in the cet arm versus 74.6% and 71.7% in the bev arm, respectively, with no statistical significance. Although the survival data were immature, PFS and OS of both arms were 12.7 months (95%CI 11.5-14.0) and 37.6 months (95%CI 30.8 to 43.0), respectively. Conclusion: The mFOLFOXIRI plus cet has been shown to be significantly superior to the mFOLFOXIRI plus bev in terms of DpR as the primary endpoint in first-line treatment for RAS wild-type mCRC. Clinical trial information: NCT02515734. Clinical trial information: UMIN000018217.

The role of PP2A variants to predict outcome in patients (pts) with metastatic colorectal cancer (mCRC): Data from FIRE-3 and TRIBE trials.

3581 Background: Protein phosphatase 2A (PP2A) is a serine/threonine phosphatase with functions that counter-balance kinase-mediated phosphorylation throughout cell signaling networks. PP2A was reported to upregulate the angiogenesis, while negatively regulate the pathways downstream of receptor tyrosine kinases at multiple nodes. Previous studies showed PP2A variants were associated with the increased risk of cancer. Therefore, we hypothesized that PP2A variants may predict first-line treatment outcome in mCRC pts treated with bevacizumab (bev)/cetuximab (cet)-based chemotherapy. Methods: Genomic DNA from blood samples of pts enrolled in two independent randomized trials, TRIBE (bev arm, n=215, as discovery cohort) and FIRE-3 (bev arm, n=107, as validation cohort; cet arm, n=129, as control cohort), was genotyped through the OncoArray, a customized array manufactured by Illumina including approximately 530K SNP markers. The impact on outcome of 17 selected SNPs in 3 main PP2A core subunits (PPP2CA, PPP2R1B, PPP2R1A), one phosphatase activator (PPP2R4) and 2 endogenous inhibitors (TIPRL, CIP2A) was analyzed. Results: In the discovery cohort, pts with PPP2R4 rs2541164 A/A (N=16) showed significantly shorter overall survival (15.3 vs 27.3 months) compared to carriers of any G allele (N=198) in both univariate (hazard ratio [HR]=1.8; 95% confidence interval [CI]: 1.1-3.1; p=0.02) and multivariate (HR=2.4; 95%CI: 1.4-4.4; p=0.006) analysis. These data were validated in the FIRE-3 bev cohort in both univariate (A/A vs. Any G: 17.3 vs 39.9 months, HR=2.8, 95%CI: 1.4-5.9, p=0.004) and multivariate (HR=4.3, 95%CI: 1.5-12.2, p=0.0095) analysis. Conversely, pts carrying CIP2A rs13069780 C/C (N=24) only showed significantly longer progression-free survival (17.7 vs 12.3 months) than carriers of any T allele (n=105) in the FIRE-3 cet cohort in both univariate (HR=0.6; 95%CI 0.4-0.99; p=0.04) and multivariate (HR=0.5; 95%CI 0.3-0.94; p=0.02) analysis, but no association were observed in the bev cohort of TRIBE and FIRE-3. Conclusions: Our study demonstrated for the first time that PPP2R4 polymorphisms could predict outcomes of bev-based treatment in mCRC patients; Meanwhile CIP2A polymorphism could predict outcomes of cet-based treatment in mCRC patients. These findings support a possible role of the PP2A variants in contributing to resistance to anti-VEGF/EGFR treatment.

Immune signatures to affect overall survival (OS) and response to bevacizumab (Bev) or cetuximab (Cet) in patients (pts) with metastatic colorectal cancer (mCRC) of CALGB/SWOG 80405 (Alliance).

3515 Background: CALGB/SWOG 80405 was a randomized phase III trial in first-line mCRC patients treated with Bev, Cet, or both, plus chemotherapy. No difference in OS was found between Bev and Cet. We tested the effect of immune signatures on OS in all the three arms of the study and analyzed differences in OS between the Cet and Bev arms. Methods: 578 primary tumors were profiled by RNAseq. Immune signatures of TGF-β, cytotoxic T cells, wound healing, macrophages, lymphocytes, and INF-γ, as well as relative frequencies of CD8+ T-cells, memory resting CD4+ T cells, memory activated CD4+ T cells, macrophages M1 and M2, and activated mast cells were measured. Multivariate Cox proportional hazard models were applied using elastic-net penalization with covariates (age, race, gender, all RAS and BRAF V600E mutations). For relevant signatures, optimal cut-offs for OS were calculated. Results: In all the three arms of the study, high expression of macrophages M2 (HR 6.81, 95% CI 3.56-30.16) and TGF-β (HR 1.37, 95% CI 1.03-2.10) conferred reduced OS compared to low expression; high expression of plasma cells (HR 0.52, 95% CI 0.27-0.83) and memory-activated CD4+ T cells (HR 0.34, 95% CI 0.10-0.65) conferred increased OS compared to low expression. Using optimal cut-offs from these 4 signatures, pts have been categorized as to whether they had either 4, 3, 2, 1, or 0 beneficial signatures associated with increased OS. In all arms of the study (N = 469, after accounting for covariates), the median (95% CI) OS decreased from 42.5 (35.8-47.8; N = 79), to 31.0 (28.8-34.4; N = 177), 25.2 (20.6-27.9; N = 144), and 17.0 (13.5-20.4; N = 69) months when the number of beneficial signatures decreased from 4, to 3, 2, and 0-1 (combined due to a low number of pts), respectively (p = 3.48e-11). In the Bev arm (N = 205), high expression of macrophages M2 conferred reduced OS compared to low expression (HR 6.6, 95% CI 2.7-67.1). In the Cet arm (N = 165), high expression of macrophages M2 conferred reduced OS compared to low expression (HR 4.3, 95% CI 2.1-79.8); high expression of plasma cells (HR 0.36, 95% CI 0.06-0.55) and memory activated CD4+ T cells (HR 0.37, 95% CI 0.03-0.98) conferred increased OS compared to low expression of either signatures. The plasma cell signature interacted with Bev and Cet on the OS of pts (interaction p = 0.009). Conclusions: Tumor immune signatures in mCRC pts are determinants of survival. In pts treated with Bev- and Cet-combination therapies that are standard of care, immune signatures affect response to therapy. These results, provide new markers for treatment selection and for the development of novel active combinations including immune checkpoint inhibitors. Support: U10CA180821, U10CA180882, U24CA196171; https://acknowledgments.alliancefound.org

Safety analysis of the randomized phase II study of FOLFOXIRI plus cetuximab versus FOLFOXIRI plus bevacizumab as the first-line treatment in metastatic colorectal cancer with RAS wild-type tumors: The DEEPER trial (JACCRO CC-13).

86 Background: Triplet regimens, FOLFOXIRI, combined with bevacizumab (bev) or panitumumab have been shown to be superior in terms of early tumor shrinkage (ETS) and depth of response (DpR) compared to doublet regimen plus bev or triplet regimen in patients with RAS wild-type metastatic colorectal cancer (mCRC), in the TRIBE trial ( N Engl J Med 2014) or VOLFI trial ( J Clin Oncol 2019), respectively. There have been few studies which directly compared cetuximab (cet) with bev when combined with triplet regimen. Therefore, we investigated the efficacy and safety of bev vs. cet in combination with FOLFOXIRI in previously untreated mCRC patients with RAS wild-type tumors. Methods: This trial was a randomized phase II trial to evaluate modified (m)-FOLFOXIRI (irinotecan 150 mg/m2, oxaliplatin 85 mg/m2, 5-FU 2400 mg/m2) plus cet vs. bev as first-line treatment in terms of the DpR during the entire course as the primary endpoint in 360 patients with RAS wild-type mCRC (ClinicalTrials.gov Identifier: NCT02515734). The experimental arm with cet was considered to be active if the difference of median DpR was over 12.5% compared with the bev arm, under the conditions of significance level of 0.05 and power of 0.85. Secondary endpoints included the ETS at week 8, progression-free survival, overall survival, secondary resection rate, and toxicity. Results: A total of 359 patients were enrolled between July 2015 and June 2019. For the safety analysis set (median age 65y, 64% male, PS0/1:91%/9%, left/right primary:83%/17%), 173 and 175 patients were randomly assigned to the cet and bev arms, respectively, some patients were excluded for the safety analysis due to the violation of inclusion criteria (6 for cet arm and 5 for bev). On the cutoff date of September 2020, median number of cycles administered was 10 (range, 1-51) for the cet arm and 12 (range, 1-51) for the bev arm. The incidence of severe adverse events (AEs) was 25.4% (44/173) for the cet arm and 25.7% (45/175) for the bev arm, respectively. The following AEs of grade 3-4 were observed more frequently in the cet arm compared to the bev arm: oral mucositis (9.2% vs. 2.3%), diarrhea (12.1% vs. 8.0%), dermatitis acneiform (12.1% vs. 0%), and hypomagnesemia (4.0% vs. 0%). The treatment-related death occurred in 2 patients of the cet arm, while no patients in the bev arm. The rate of treatment discontinuation due to AEs of any cause was comparable between the cet and bev arms (7% vs. 9%). Conclusions: This safety analysis indicated that both regimens of m-FOLFOXIRI plus cet or bev were tolerable in RAS wt mCRC patients although some frequent severe AEs were observed. Clinical trial information: UMIN000018217.

A phase II study of atezolizumab (ATEZO) and bevacizumab (Bev) in combination with Y90 TARE in patients (Pts) with hepatocellular carcinoma (HCC).

TPS358 Background: The anti–PD-L1 antibody ATEZO prevents PD-L1 from interacting with PD-1 and B7.1, thus reinvigorating antitumor T cell activity. Anti-VEGF BEV can increase dendritic cell maturation, enhance T cell infiltration, and reduce myeloid-derived suppressor cells and regulatory T-cells in tumors. This combination has been FDA approved for first-line treatment of advanced HCC based on the IMbrave 150 study. On the other hand, locoregional radiotherapy (e.g., Y90 TARE) enhances the diversity of the intratumoral T cell receptor repertoire. It is the standard of care for pts with intermediate-stage HCC (iHCC). Based on preclinical and clinical data, we hypothesize that the combination of Y90 TARE, BEV, and ATEZO induces synergistic tumor-killing. Methods: This is an open-label, multicenter, randomized phase II study of Y90 TARE and BEV plus ATEZO compared with Y90 TARE alone in pts with unresectable IHCC. The primary study objective is to assess and compare the progression-free survival (PFS) (per mRECIST 1.1) of pts in each arm. The main secondary objective is to determine the safety and tolerability (CTCAE v5) of TARE combined with ATEZO and BEV in pts with HCC. Exploratory objectives are to assess the role of the immunoscore and PD-L1 expression levels in the prediction of improved clinical outcome in pts receiving Y-90 TARE and BEV plus ATEZO; the composition of tumor-infiltrating immune cell subtypes in predicting response to a chosen therapy; how Y90 therapy affects the proportion of antigen-presenting cells in the tumor; and symptoms experienced by pts receiving TARE and BEV plus ATEZO treatment, using patient-reported outcomes. Eligible pts have either HCC that is not amenable to surgical resection, confirmed by pathology review, or at least BCLC stage B HCC outside of downstaging criteria. Other standard eligibility criteria apply. Pts must have a pretreatment liver biopsy taken and then be randomized 1:1 to TARE (Arm A) or TARE followed by ATEZO and BEV (Arm B). Pts will have TARE mapping during week (wk) 1 and TARE treatment during wk 2. In Arm B, pts will start BEV plus ATEZO 4 wks (±1 wk) after TARE treatment. Pts will have abdominal MRI or CT scans every 12 weeks, CT scans of the chest every 24 wks, and a second tumor biopsy at 4 wks. Disease progression will be captured by both RECIST 1.1 and mRECIST. We plan to assess the safety of TARE with BEV and ATEZO in the first 10 pts randomized to Arm B for two cycles. If there are no grade ≥ 3 unexpected toxicities possibly, probably or definitely related to combined TARE plus BEV plus ATEZO, the study will continue to accrue 128 pts in total. Pts will continue study treatment (Arm B) for a total of 24 months from initiation of TARE or until intolerable toxicity or disease progression occur, whichever is earlier. Enrollment began in September 2020. Clinical trial information: NCT04541173.

Genetic variants involved in the lipid metabolism pathway to predict outcome in patients (pts) with metastatic colorectal cancer (mCRC): Data from FIRE-3 and MAVERICC trials.

118 Background: Antiangiogenic drug (AAD)-triggered oxygen and nutrient depletion through suppression of angiogenesis switches the glucose-dependent metabolism to lipid-dependent metabolism. Blocking fatty acid oxidation can enhance AAD-mediated anti-tumor effects in colorectal cancer. Previous reports suggested that polymorphisms of the lipid metabolism-related genes are associated with the increased risk of CRC and poor clinical outcome in CRC. Therefore, we hypothesized that genetic variants in the lipid metabolism pathway may predict first-line treatment outcome in mCRC pts. Methods: Genomic DNA from blood samples of pts enrolled in two independent randomized trials, FIRE-3 and MAVERICC, was genotyped through the OncoArray, a customized array manufactured by Illumina including approximately 530K SNP markers. The impact on outcome of 25 selected SNPs in 10 genes involved in the lipid metabolism pathway (CD36, FABP4, LPCAT1, LPCAT2, PPARG, CPT1A, ACSS2, SREBF1, FASN, ACACA) was analyzed. Those treated with FOLFIRI/ bevacizumab (bev) in FIRE-3 (n = 107) and MAVERICC (n = 163) served as discovery and validation cohorts respectively, while FIRE-3 FOLFIRI/ cetuximab (cet) (n = 129) arm was used as the control. Interaction between each SNP and treatment was evaluated in FIRE-3 (FOLFIRI/bev arm vs. FOLFIRI/cet arm). Results: In the discovery (FIRE-3 bev) cohort, pts with FASN rs4485435 any C allele (N = 21) showed significantly shorter progression-free survival (PFS) (8.69 vs 13.48 months) compared to carriers of G/G (N = 62) in both univariate (hazard ratio [HR] = 2.88; 95% confidence interval [CI]: 1.57-5.29; p = 0.00037) and multivariate (HR = 2.87; 95%CI 1.4-5.9; p = 0.00675) analyses. These data were validated in the MAVERICC bev cohort in multivariate analysis (11.17 vs 14.06 months; HR = 2.07; 95%CI: 1.15-3.74; p = 0.02). Pts carrying any T allele in PPARG rs3856806 (N = 36) showed significantly longer overall survival (OS) (Not reached vs 42 months) than carriers of C/C (n = 93) in the FIRE-3 cet cohort in both univariate (HR = 0.4; 95%CI 0.17-0.92; p = 0.03) and multivariate (HR = 0.37; 95%CI 0.15-0.93; p = 0.02) analyses, but the association was not observed in the bev cohort of MAVERICC and FIRE-3. In the comparison of bev arm vs cet arm in FIRE-3, interactions were shown with FASN rs4485435 (p = 0.017) on PFS and PPARG rs3856806 (p = 0.059) on OS. Conclusions: Our study demonstrates for the first time that FASN polymorphism could predict outcomes of bev-based treatment in mCRC patients; Meanwhile PPARG polymorphism could predict outcomes of cet-based treatment in mCRC patients. These findings support a possible role of the lipid metabolism pathway in contributing to resistance to anti-VEGF/EGFR treatment.

169P IMbrave150: Management of adverse events of special interest (AESIs) for atezolizumab (atezo) and bevacizumab (bev) in unresectable HCC

In the phase III IMbrave150 trial, atezo + bev demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS) and progression-free survival (PFS) vs sorafenib (sor) in patients (pts) with unresectable HCC. Here we report on the AESIs for both atezo and bev in IMbrave150. Eligible pts (N = 501) had unresectable HCC and were randomised 2:1 to receive atezo 1200 mg IV q3w + bev 15 mg/kg IV q3w or sor 400 mg PO bid until unacceptable toxicity or loss of clinical benefit per investigator. Co-primary endpoints were OS and PFS by independent review facility–assessed RECIST 1.1. AESIs were defined by the sponsor and reported without judgement of causality. AESIs for atezo were based on the immune-mediated risks of atezo and other checkpoint inhibitors; AESIs for bev were based on known adverse drug reactions (ADRs) with bev. Analyses explored the incidence, nature and severity of AESIs as well as corticosteroid use. The safety-evaluable population included 329 pts in the atezo + bev arm and 156 pts in the sor arm. Median follow-up was 8.6 mo (data cutoff: 29 Aug 2019); median tx durations were 7.4 (atezo), 6.9 (bev) and 2.8 (sor) mo. AESIs for atezo occurred in 69% of pts receiving atezo + bev and also in 82% of pts receiving sor (Table). 12% of pts in the atezo + bev arm vs 3% of pts in the sor arm experienced AESIs requiring systemic corticosteroid tx within 30 days of AE onset. AESIs for bev occurred in 58% of pts receiving atezo + bev and 49% of pts receiving sor. The reported events were ADRs well known with bev, and their frequency and severity were consistent with the safety profile of bev and the underlying disease. In IMbrave150, AESIs for atezo and bev were manageable. Further, the nature and severity of AESIs were consistent with the known safety profiles of the individual agents and the underlying diseaseTable: 169PAESIs, n (%)aAtezo + Bev n = 329Sor n = 156AllG3-4AllG3-4For atezoPts with ≥ 1226 (69)85 (26)128 (82)47 (30)Hepatic eventsb142 (43)70 (21)62 (40)26 (17)Inc AST64 (20)23 (7)26 (17)8 (5)Inc blood bilirubin43 (13)8 (2)22 (14)10 (6)Inc ALT46 (14)12 (4)14 (9)2 (1)Ascites23 (7)6 (2)9 (6)2 (1)Rash64 (20)2 (1)96 (62)21 (14)Hypothyroidism36 (11)04 (3)0Infusion-related reactions36 (11)8 (2)00For bevPts with ≥ 1190 (58)76 (23)76 (49)29 (19)Hypertension102 (31)50 (15)40 (26)19 (12)Bleeding/haemorrhage83 (25)21 (6)27 (17)9 (6)Epistaxis34 (10)07 (5)1 (1)Upper GI bleedingc24 (7)15 (5)8 (5)8 (5)Proteinuria70 (21)10 (3)13 (8)1 (1)Inc, increased. a In ≥ 5% of pts. b ≥ 1 category possible. c Grouped MedDRA PT Open table in a new tab .

Complete responses (CR) in patients receiving atezolizumab (atezo) + bevacizumab (bev) versus sorafenib (sor) in IMbrave150: A phase III clinical trial for unresectable hepatocellular carcinoma (HCC).

4596 Background: In the Phase III IMbrave150 trial, statistically significant and clinically meaningful improvements in OS and PFS were seen with atezo + bev vs sor in pts with unresectable HCC who had not received prior systemic therapy (Cheng, ESMO Asia, 2019). Historically, CR rates have been low in HCC clinical trials. Here we report the baseline characteristics for IMbrave150 pts with a CR. Methods: IMbrave150 enrolled systemic treatment-naive pts with unresectable HCC. Pts were randomized 2:1 to receive either atezo 1200 mg IV q3w + bev 15 mg/kg IV q3w or sor 400 mg BID until unacceptable toxicity or loss of clinical benefit per investigator. Co-primary endpoints were OS and PFS by independent review facility (IRF)–assessed RECIST 1.1. The key secondary endpoints IRF ORR per RECIST 1.1 and IRF ORR per HCC mRECIST were also part of the study statistical testing hierarchy. Results: The ITT population included 336 pts randomized to atezo + bev and 165 pts randomized to sor. With a median follow-up of 8.6 mo (data cutoff, Aug 29, 2019), OS HR was 0.58 (95% CI: 0.42, 0.79; P = 0.0006) and PFS HR was 0.59 (95% CI: 0.47, 0.76; P &lt; 0.0001) with atezo + bev vs sor. ORR was 27% vs 12% ( P &lt; 0.0001) per IRF RECIST 1.1 and 33% vs 13% ( P &lt; 0.0001) per IRF HCC mRECIST with atezo + bev vs sor, respectively. For responders (per IRF RECIST 1.1), median time to response was 2.8 mo (range, 1.2-11.3) with atezo + bev and 3.3 mo (range, 1.2-7.2) with sor. CR per IRF-assessed RECIST 1.1 was achieved by 18 pts in the atezo + bev arm and 0 pts in the sor arm. The baseline characteristics for atezo + bev CR pts are shown in the table. Additional characteristics will be shown. Conclusions: IMbrave150 demonstrated statistically significant and clinically meaningful improvement in both OS and PFS with atezo + bev vs sor in pts with unresectable HCC who have not received prior systemic therapy. Pts achieved CRs regardless of poor prognostic factors or etiology. Atezo + bev may be a practice-changing treatment for pts with unresectable HCC. Clinical trial information: NCT03434379 . [Table: see text]