8506 Background: Pembrolizumab has been the standard first-line treatment for PD-L1 positive advanced NSCLC. Sac-TMT, a TROP2-directed antibody-drug conjugate with a unique bifunctional linker, and PD-1/L1 inhibitors demonstrate complementary mechanisms that enhance antitumor activity in the first-line treatment of NSCLC ( Hong et al., Nat Med, 2025 ). Here, we report the results from the planned interim analysis for PFS in this phase 3 OptiTROP-Lung05 study (NCT06448312). Methods: Eligible patients (pts) had treatment-naïve, locally advanced or metastatic NSCLC without EGFR/ ALK alterations and positive PD-L1 expression (defined as TPS ≥1%, 22C3 assay). Pts were stratified by PD-L1 (TPS 1-49% vs ≥ 50%), histology (squamous vs non-squamous) and ECOG (0 vs 1) and then randomized (1:1) to receive sac-TMT 4 mg/kg Q2W plus P 400 mg Q6W or P 400 mg Q6W. The primary endpoint was PFS per RECIST 1.1 assessed by blinded independent central review (BICR), and the key secondary endpoint was OS. Results: A total of 413 pts (median age 65 yrs; 84.5% ECOG 1; 40.0% squamous; 40.0% PD-L1 TPS ≥ 50%) were randomized to receive sac-TMT + P (n = 208) or P (n = 205). As of Sep 29, 2025, the median follow-up was 10.5 months. PFS by BICR was significantly longer in the sac-TMT + P group than the P group (median, not reached vs 5.7 months; HR, 0.35; 95% CI, 0.26-0.47; p < 0.0001). The data for OS were not mature, and a favorable trend was observed in the sac-TMT + P group (HR, 0.55; 95% CI, 0.36-0.85). The BICR-assessed ORR was 70.2% in the sac-TMT + P group versus 42.0% in the P group. In the pre-specified PD-L1 subgroups, the HRs for PFS in pts with TPS 1-49% and TPS ≥ 50% were 0.28 (95% CI, 0.19-0.41) and 0.47 (95% CI, 0.29-0.77). In the pre-specified histology subgroups, the HRs for PFS in pts with non-squamous and squamous were 0.28 (95% CI, 0.18-0.43) and 0.44 (95% CI, 0.29-0.66). Grade ≥ 3 TEAEs were 55.3% in the sac-TMT + P group and 31.4% in the P group. Most common grade ≥3 TEAEs of special interest for sac-TMT were neutrophil count decreased (17.3%), anemia (9.1%), and stomatitis (5.3%). TEAEs led to discontinuation of sac-TMT/ pembrolizumab in 3.8%/5.3% of pts in the sac-TMT + P group while discontinuation of pembrolizumab occurred in 4.9% of pts in the P group. Conclusions: To our knowledge, this is the first phase 3 study to demonstrate the significant PFS benefit of an antibody-drug conjugate plus pembrolizumab in the first-line treatment of PD-L1 positive advanced NSCLC compared to pembrolizumab. The safety profile of sac-TMT + P was generally manageable and consistent with the safety profile of the components. No new safety signals were seen. These results from phase 3 OptiTROP-Lung05 study support sac-TMT + P as a potential new treatment option for this population. Clinical trial information: NCT06448312 .

Background Studies have indicated that programmed death ligand 1 (PD-L1) expression may have utility as a predictive biomarker in patients with advanced/metastatic urothelial carcinoma (UC). Different immunohistochemical (IHC) assays are in development to assess PD-L1 expression on tumor cells (TCs) and tumor-infiltrating immune cells (ICs). Methods In this post hoc analysis of the single-arm, phase 1/2 Study 1108 (NCT01693562), PD-L1 expression was evaluated from tumor samples obtained prior to second-line treatment with durvalumab in patients with advanced/metastatic UC using the VENTANA (SP263) IHC Assay. The primary objective was to determine whether the TC >= 25%/IC >= 25% algorithm (i.e., cutoff of. 25% TC or >= 25% IC with PD-L1 staining at any intensity above background) was optimal for predicting response to durvalumab. PD-L1 expression data were available from 188 patients. Results After a median follow-up of 15.8 and 14.6 months, higher PD-L1 expression was associated with longer overall survival (OS) and progression-free survival (PFS), respectively, with significant separation in survival curves for PD-L1-high and-low expressing patients for the TC. 25%/IC. 25% cutoff (median OS: 19.8 vs 4.8 months; hazard ratio: 0.46; 90% confidence interval: 0.33, 0.639). OS was also prolonged for PD-L1-high compared with-low patients when samples were categorized using TC/IC combined positive score >= 10 and IC >= 5% cutoffs. In multivariate analysis, IC but not TC PD-L1 expression was significantly associated with OS, PFS, and objective response rate (P < 0.001 for each), although interaction analysis showed similar directionality of benefit for ICs and TCs. Conclusions These findings support the utility of a combined TC/IC algorithm for predicting response to durvalumab in patients with UC, with the TC >= 25%/IC >= 25% cutoff optimal when used with the VENTANA (SP263) IHC Assay.

The prognostic value of baseline liver metastases (LMs) was evaluated in 569 patients with advanced/metastatic nonesmall-cell lung cancer receiving the programmed cell death ligand 1 (PD-L1) inhibitor durvalumab. LMs were an independent negative prognostic factor for survival and were associated with significantly lower objective response rates. However, PD-L1 as an independent factor predicted benefit from durvalumab. Introduction: Two clinical studies (Study 1108 and ATLANTIC) were analyzed to evaluate the prognostic value of baseline liver metastases (LMs) in advanced/metastatic nonesmall-cell lung cancer patients treated with durvalumab 10 mg/kg every 2 weeks. Patients and Methods: A multivariate Cox proportional hazards analysis was conducted; covariates included performance status, tumor stage, histology, sex, age, smoking status, and programmed cell death ligand 1 (PD-L1) status. Results: In all, 569 patients were included. LMs were present in 31.6% (96/304) of Study 1108 patients and 17.9% (47/263) of ATLANTIC patients. Median overall survival (OS) was shorter in patients with LMs than in those without in both studies. In both studies, LMs were an independent negative prognostic factor for OS and progression-free survival. Objective response rates were also significantly lower. PD-L1 independently predicted benefit across all patients. Conclusion: Liver metastases were associated with worse outcomes irrespective of PD-L1 status, but PD-L1 status predicted benefit from durvalumab irrespective of LMs.

CONTEXT.—:Clinical responses to anti-programmed death receptor-1 and anti-programmed death ligand-1 (PD-L1) agents are generally improved in patients with high PD-L1 expression compared with those with low/negative expression across several tumor types, including urothelial carcinoma. OBJECTIVE.—:To validate a PD-L1 immunohistochemical diagnostic test in urothelial carcinoma patients treated with the anti-PD-L1 monoclonal antibody durvalumab. DESIGN.—:The Ventana PD-L1 (SP263) assay was validated for intended use in urothelial carcinoma formalin-fixed, paraffin-embedded samples in studies addressing sensitivity, specificity, robustness, and precision, and implemented in study CD-ON-MEDI4736-1108 (NCT01693562). Efficacy was analyzed in patients classified according to prespecified PD-L1 expression cutoffs: PD-L1 high (if >1% of the tumor area contained tumor-associated immune cells, ≥25% of tumor cells or ≥25% of immune cells stained for PD-L1; if ≤1% of the tumor area contained immune cells, ≥25% of tumor cells or 100% of immune cells stained for PD-L1) and PD-L1 low/negative (did not meet criteria for PD-L1 high). RESULTS.—:The assay met all predefined acceptance criteria for sensitivity, specificity, and precision. Interreader and intrareader precision overall agreement were 93.0% and 92.4%, respectively. For intraday reproducibility and interday precision, overall agreement was 99.2% and 100%, respectively. Interlaboratory overall agreement was 92.6%. In study CD-ON-MEDI4736-1108, durvalumab demonstrated clinical activity and durable responses in both PD-L1-high and PD-L1-low/negative subgroups, although objective response rates tended to be higher in the PD-L1-high subgroup than in the PD-L1-low/negative subgroup. CONCLUSIONS.—:Determination of PD-L1 expression in urothelial carcinoma patients using the Ventana PD-L1 (SP263) assay was precise, highly reproducible, and clinically relevant.

4530 Background: PD-L1 expression is a useful biomarker in predicting response to PD-1 and PD-L1 directed immunotherapies in a variety of tumor types. In UC, studies have implicated PD-L1 expression in tumor cells (TC) and tumor-infiltrating immune cells (IC) as having clinical utility, but the relative importance of each cellular compartment and the most predictive algorithm and PD-L1 expression cutoff remain unclear. Methods: PD-L1 expression data (SP263 assay) from 188 patients in the UC cohort from single arm (durvalumab monotherapy) Phase 1/2 Study CD-ON-MEDI4736-1108 (NCT01693562; Oct. 2017 data cutoff) were assessed. Regression models were used to evaluate the impact of PD-L1 expression in TC or IC on OS, progression-free survival (PFS), objective response rate (ORR), best percentage tumor change and tumor shrinkage 15 months after last subject randomization. Kaplan–Meier plots were generated to explore the impact of single biomarker and combined (TC or IC [% PD-L1 positive ICs within IC area]) algorithms on OS. Results: Both IC and TC PD-L1 were linked to higher ORR, and IC PD-L1 was associated with better survival in patients treated with durvalumab. IC PD-L1 had a higher impact on response to durvalumab than TC PD-L1, showing significant (P < 0.05) association with OS, PFS, ORR, and tumor shrinkage. The best outcomes were obtained when TC and IC algorithms were combined, with TC25%/IC25% proving optimal (Table). Conclusions: In UC, the TC25%/IC25% algorithm appears to provide optimal predictive value based on efficacy and prevalence of the biomarker. Additional data from randomized trials are needed to confirm these findings. Clinical trial information: NCT01693562.Cutoff/algorithm ORR, % Median OS, months Prevalence of PD-L1 high pts, % PD-L1 high PD-L1 low PD-L1 high PD-L1 low TC1% 21.6 11.1 8.4 10.9 61.7 TC10% 19.5 16.2 6.9 10.9 41.0 TC25% 23.4 15.6 9.3 10.5 25.0 TC50% 19.4 17.1 9.3 10.5 19.1 IC1% 22.4 5.6 11.6 6.4 71.3 IC10% 22.8 6.6 11.6 6.6 67.6 IC25% 28.4 10.5 22.3 5.5 39.4 IC50% 31.1 13.3 22.3 6.6 23.9 TC1%/IC1% 20.9 0.0 10.8 6.4 84.0 TC10%/IC25% 23.3 7.4 12.5 7.8 63.8 TC25%/IC25% 27.5 5.8 19.8 4.8 54.3 TC50%/IC25% 27.1 7.6 20.0 4.8 51.1 N = 188IC: % PD-L1 positive ICs within IC area

2568 Background: Durvalumab is a human monoclonal antibody that binds to PD-L1 and blocks its interaction with PD-1 and CD-80. The objective of this analysis was to evaluate the relationship between durvalumab PK exposure with efficacy and safety following 10 mg/kg Q2W durvalumab. Methods: Data from Study 1108 (Phase 1/2; all tumor types) and ATLANTIC (Phase 2; NSCLC) were used for exposure-safety analysis for Study 1108 UC cohort, Study 1108 all patients and ATLANTIC patients, respectively, whereas the exposure-efficacy analysis was performed using data from Study 1108 UC cohort. The observed PK exposure metrics included PK concentrations after the first, second or steady state doses. Efficacy endpoints used were objective response rate (ORR) and best percentage change in target lesion from baseline per BICR assessment. Safety endpoints included Grade 3+ AE (any AE, drug-related AE, AESI, and drug-related AESI) and AE leading to treatment discontinuation. Results: Overall, no association of PK exposure with efficacy or safety was observed. Distribution of PK metrics were similar between responders and non-responders. The probability of objective response was similar in all quartiles of exposure (p-value ranged from 0.37 to 0.67; n = 96) with no obvious trends between PK exposures and change in tumor size. For Grade 3+ AE (all types) and AE leading to treatment discontinuation, higher PK exposure was not associated with an increased risk of AE (p-value ranged from < 0.00005 to 0.88; n = 158, 929 and 434 for 1108 UC cohort, 1108 all patients and ATLANTIC all patients, respectively). A few inverse trends were observed, likely due to confounding effect of ECOG or albumin since covariate analysis demonstrated that both variables correlated with PK and AEs. In addition, the association of ECOG and albumin versus PK exposure were also observed in the population PK modeling. Conclusions: The exposure-efficacy and exposure-safety analyses suggested that 10 mg/kg IV Q2W regimen was an appropriate dose for durvalumab as single agent in UC patients. Overall, no relationship of PK exposure with either the efficacy or safety was observed following 10 mg/kg IV Q2W regimen. Clinical trial information: NCT02087423 and NCT01693562.

### A1 Intratumoral immunotherapy. B16-F10 murine melanoma model #### J. Ženka1, V. Caisova1, O. Uher1, P. Nedbalova1, K. Kvardova1, K. Masakova1, G. Krejcova1, L. Paďoukova1, I. Jochmanova2, K. I. Wolf3, J. Chmelař1, J. Kopecký1 ##### 1Department of Medical Biology, Faculty of

The objectives of this analysis were to develop a population pharmacokinetics (PK) model of durvalumab, an anti-PD-L1 antibody, and quantify the impact of baseline and time-varying patient/disease characteristics on PK. Pooled data from two studies (1,409 patients providing 7,407 PK samples) were analyzed with nonlinear mixed effects modeling. Durvalumab PK was best described by a two-compartment model with both linear and nonlinear clearances. Three candidate models were evaluated: a time-invariant clearance (CL) model, an empirical time-varying CL model, and a semimechanistic time-varying CL model incorporating longitudinal covariates related to disease status (tumor shrinkage and albumin). The data supported a slight decrease in durvalumab clearance with time and suggested that it may be associated with a decrease in nonspecific protein catabolic rate among cancer patients who benefit from therapy. No covariates were clinically relevant, indicating no need for dose adjustment. Simulations indicated similar overall PK exposures following weight-based and flat-dosing regimens.

4071 Background: Durvalumab, an anti-PD-L1 mAb, has shown early and durable clinical activity with manageable safety in an ongoing Phase 1/2, multicenter, open-label study in pts with advanced solid tumors. Interim analyses from the HCC cohort in the dose-expansion part of this study are reported here. Methods: Patients with HCC (Child-Pugh class A) received durvalumab 10 mg/kg i.v. q2w for 12 months or until confirmed progressive disease, whichever occurred first. The primary objective was to evaluate the safety profile; secondary objective was to assess the antitumor activity (investigator-assessed RECIST v1.1). Clinical activity was evaluated for the total HCC population and by viral status. Results: As of Oct 24 2016, 40 HCC pts with median 23.9 (range 2.4–34.7) weeks follow-up received durvalumab. 93% had prior sorafenib. Treatment-related AEs occurred in 80.0% of pts, most commonly fatigue (27.5%), pruritus (25.0%) and elevated aspartate aminotransferase (AST) (22.5%). Grade 3–4 treatment-related AEs were reported in 20.0% of pts, most commonly elevated AST (7.5%) and elevated alanine aminotransferase (5.0%). 7 (17.5%) pts completed the initial 12-month treatment and 7 (17.5%) pts discontinued treatment because of an AE (none related to treatment). There were no deaths due to treatment-related AEs. Clinical activity is presented in the table. 4 pts achieved a PR; 2 were ongoing at data cut-off. Conclusions: Durvalumab had an acceptable safety profile and showed promising antitumor activity and OS in pts with HCC, particularly HCV+ pts. Clinical trial information: NCT01693562. [Table: see text]

3035 Background: Progression of cancer is often associated with biomarkers of cancer inflammation, cachexia, and increased protein catabolism. Anti-PD1 and PD-L1 therapy have demonstrated durable responses across a number of tumor types. Durvalumab is a human monoclonal antibody that binds to PD-L1 and blocks its interaction with PD-1 and CD80. The primary objective of this analysis was to prospectively assess potential correlations of longitudinal changes in ALB and NLR and durvalumab clearance (CL) rate to maximum decrease in tumor size and overall survival (OS) in patients (pts) with NSCLC and UC receiving durvalumab. Methods: Longitudinal target lesion size, serum chemistry, hematology and pharmacokinetic data were obtained from 3L+ NSCLC pts (n = 418) in study ATLANTIC and 2L+ UC pts (n = 182) in study 1108 during durvalumab treatment. Nonparametric correlations (Spearman’s rho) were evaluated between OS, maximum percent change in target lesion size, and the maximum percent change from baseline observed in ALB, NLR, and CL. Results: In NSCLC, maximum decrease in tumor size was correlated with increased ALB (r = 0.46, p < 0.0001), decreased NLR (r = 0.44, p < 0.0001), and decreased CL (r = 0.66, p < 0.0001). OS was similarly correlated with increased ALB (r = 0.47, p < 0.0001), decreased NLR (r = 0.41, p < 0.0001), and decreased CL (r = 0.76, p < 0.0001). In UC, decreased tumor size also correlated with increased ALB (r = 0.43, p < 0.0001), decreased NLR (r = 0.38, p < 0.0001), and decreased CL (r = 0.65, p < 0.0001). OS in UC also correlated with increased ALB (r = 0.50, p < 0.0001), decreased NLR (r = 0.33, p < 0.0001) and decreased CL (r = 0.82, p < 0.0001). Conclusions: In NSCLC and UC pts receiving durvalumab, tumor shrinkage and longer survival are associated with increased ALB, decreased NLR and decreased clearance of durvalumab. These findings support the hypothesis that durvalumab may be associated with a decrease in protein catabolism, inflammation and cachexia among pts who benefited from therapy. Additional biomarkers of cancer, inflammation and cachexia will be evaluated for relationships to clinical outcomes.

e20504 Background: Single-agent durvalumab demonstrated manageable safety and encouraging clinical activity in advanced squamous and non-squamous NSCLC in preliminary analyses from the Phase 1/2 1108 study (NCT01693562). Here we present updated safety data and clinical activity in NSCLC pts with no prior treatment for advanced disease. Methods: In this Phase 1/2 dose-escalation and expansion study, pts with Stage IIIB/IV NSCLC, ECOG PS 0–1, and availability of a fresh tumor biopsy and/or archival tumor tissue for PD-L1 testing received durvalumab 10 mg/kg every 2 weeks for up to 12 months, with retreatment permitted for those progressing after 12 months of therapy. Tumor PD-L1 expression was assessed using the Ventana PD-L1 (SP263) Assay (PD-L1 high: ≥25% of tumor cells with membrane staining). Results: As of 24 October 2016, 59 pts (63% ECOG PS 1, 49% squamous) received first-line durvalumab. Median duration of follow-up was 17.3 (1.0–36.8) mos. Safety profile was consistent with the overall (N = 304, ≥0 prior lines of therapy) NSCLC cohort. All-grade treatment-related adverse events (AEs) were reported in 56%; the most common were fatigue (15%), diarrhea (13%), and decreased appetite (10%). 7% had a treatment-related AE leading to discontinuation of durvalumab, including diarrhea in 2 pts. Grade ≥3 treatment-related AEs (all n = 1) occurred in 10%; 1 pt died due to drug-related pneumonia. 49 pts had high PD-L1 expression and 9 pts had low/negative PD-L1 expression; data are not summarized for the latter group due to the small number of pts. For the PD-L1 high subpopulation, confirmed ORR (investigator-assessed RECIST v1.1) was 28.6% (95% CI 16.6–43.3) and disease control rate (stable disease ≥24 weeks) was 42.9% (95% CI 28.8–57.8); median PFS was 4.0 months (95% CI 2.3–9.1), median OS was 21.0 months (95% CI 14.5–not estimable), and 12-month OS rate was 72% (95% CI 56–83). Response rates were similar and durable regardless of histology. Conclusions: Consistent with prior data, durvalumab had a tolerable safety profile in advanced treatment-naïve NSCLC. Clinical activity was seen in PD-L1 high pts, with encouraging OS. Clinical trial information: NCT01693562.

3038 Background: Immunotherapies have improved survival in NSCLC but not all pts benefit. Besides baseline PDL1 expression, routinely measured clinical factors may predict clinical outcomes in immunotherapy trials. LM are associated with poor prognosis in melanoma and bladder cancer pts treated with anti-PD1/L1, respectively. We examined correlation between pretreatment LM and survival in D-treated NSCLC pts. Methods: CP1108/NCT01693562 and ATLANTIC/NCT02087423 were nonrandomized phase 1/2 and 2 trials, respectively, of D 10 mg/kg Q2W in advanced NSCLC. As of Oct 24/Jun 3 2016, 304/265 primarily pretreated pts were enrolled in CP1108/ATLANTIC Cohort 2. Cox proportional hazards analysis was conducted, first among LM+/− pts, then LM+/− and PDL1 high/low pts. Both models accounted for tumor stage, ECOG/WHO PS, histology, sex, age, smoking and PDL1 status. PDL1 high was defined as ≥25% tumor cells immunostained for PDL1 at any intensity. Results: LM absence was a positive independent predictor of OS and PFS in both trials. LM− and PDL1 high or low pts had improved OS and PFS vs PDL1 low/LM+; PDL1 high/LM+ pts had improved PFS vs PDL1 low/LM+. An independent tumor kinetic model indicated LM as a predictive covariate of rapid tumor growth in D-treated pts. Conclusions: LM are associated with shorter survival in D-treated NSCLC pts in 2 trials irrespective of PDL1 status. Clinical trial information: NCT02087423 and NCT01693562. [Table: see text]

Abstract Background: A high quality programmed cell death ligand-1 (PD-L1) diagnostic may help to identify patients (pts) most likely to respond to anti-PD-L1/programmed cell death-1 (PD-1) therapy. Here we describe a PD-L1 immunohistochemical (IHC) diagnostic test developed for urothelial carcinoma (UC) pts treated with durvalumab. Methods: The IHC assay uses an anti-human PD-L1 rabbit mAb optimized for detection of both tumor cell (TC) and tumor-associated immune cell (IC) PD-L1 expression with the OptiView DAB IHC Detection Kit on the automated VENTANA BenchMark ULTRA platform. The assay was validated for intended use in UC formalin-fixed, paraffin-embedded samples in a series of studies that addressed sensitivity, specificity, robustness and precision and implemented in Study CD-ON-MEDI4736-1108 (NCT01693562). Pts were evaluated using the VENTANA PD-L1 (SP263) Assay at a prespecified PD-L1 expression cut-off. Efficacy was analyzed in pts with PD-L1 low/negative (defined as TC <25% and IC <25%) UC and in pts with PD-L1 high (defined as TC ≥25% or IC ≥25%) UC. Results: The VENTANA PD-L1 (SP263) Assay met all the predefined acceptance criteria (average positive agreement and average negative agreement >85%), showing analytical specificity, sensitivity and precision. It demonstrated ≥97% and ≥85% inter-reader precision agreement for TC and IC respectively. For intra-reader precision, it demonstrated >96% and >87% agreement for TC and IC respectively. For intra-day performance, the assay demonstrated ≥96% agreement for TC and IC and for inter-day performance, it demonstrated ≥98% and 100% agreement for TC and IC respectively. Precision studies for inter-antibody lot, inter-detection kit lot and intra-platform demonstrated >97% agreement for both TC and IC. Inter-laboratory testing was performed at 3 external laboratories and demonstrated an overall agreement rate of 92.3%. The VENTANA PD-L1 (SP263) Assay was implemented in Study CD-ON-MEDI4736-1108 and durvalumab demonstrated clinical activity and durability of response in both PD-L1 high and PD-L1 low/negative subgroups, yet with different response rates. In addition, given the high negative predictive value of the assay, it is especially helpful in evaluating the likelihood of response to durvalumab; pts who were classified as PD-L1 high with the VENTANA PD-L1 (SP263) Assay tended to have a higher objective response rate per RECIST v1.1 than pts who were PD-L1 low/negative. Conclusions: These data show that determination of PD-L1 expression in TC and IC in UC pts using the VENTANA PD-L1 (SP263) Assay is precise and highly reproducible and highlight the utility of the assay in a clinical setting. The VENTANA SP263 Assay is especially helpful in informing pts and physicians on the likelihood of response to durvalumab, but not for the purpose of restricting treatment to only PD-L1 high pts. Citation Format: M Zajac, A M. Boothman, Y Ben, A Gupta, J Antal, X Jin, A Nielsen, G Manriquez, C Barker, P Wang, P Patil, N Schechter, M Rebelatto, J Walker. Analytical validation and clinical utility of an immunohistochemical PD-L1 diagnostic assay for treatment with durvalumab in urothelial carcinoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 664. doi:10.1158/1538-7445.AM2017-664

In preclinical studies, heregulin (HRG) expression was shown to be the most relevant predictive biomarker for response to patritumab, a fully human anti–epidermal growth factor receptor 3 monoclonal antibody. In support of a phase 2 study of erlotinib ± patritumab in non–small cell lung cancer (NSCLC), a reverse-transcription quantitative polymerase chain reaction (RT-qPCR) assay for relative quantification of HRG expression from formalin-fixed paraffin-embedded (FFPE) NSCLC tissue samples was developed and validated and described herein. Test specimens included matched FFPE normal lung and NSCLC and frozen NSCLC tissue, and HRG-positive and HRG-negative cell lines. Formalin-fixed paraffin-embedded tissue was examined for functional performance. Heregulin distribution was also analyzed across 200 NSCLC commercial samples. Applied Biosystems TaqMan Gene Expression Assays were run on the Bio-Rad CFX96 real-time PCR platform. Heregulin RT-qPCR assay specificity, PCR efficiency, PCR linearity, and reproducibility were demonstrated. The final assay parameters included the Qiagen FFPE RNA Extraction Kit for RNA extraction from FFPE NSCLC tissue, 50 ng of RNA input, and 3 reference (housekeeping) genes (HMBS, IPO8, and EIF2B1), which had expression levels similar to HRG expression levels and were stable among FFPE NSCLC samples. Using the validated assay, unimodal HRG distribution was confirmed across 185 evaluable FFPE NSCLC commercial samples. Feasibility of an RT-qPCR assay for the quantification of HRG expression in FFPE NSCLC specimens was demonstrated.

3037 Background: PD-L1 can be induced by IFNG in tumor cells (TC) and immune cells (IC). TC PD-L1 expression prevalence in UC is low and the relevance of scoring TC (in addition to IC) is not fully understood. We recently reported a positive correlation between high levels of an IFNGS and outcome in a cohort of 30 UC pts treated with D. Here, we assessed the potential predictive value of the IFNGS in an additional 32 pts (total N = 62) and further explored the relationship between the IFNGS and TC and/or IC PD-L1 IHC expression patterns. Methods: Study CP1108 was a phase 1/2 trial evaluating D in pts with solid tumors; 191 UC pts received 10 mg/kg D with median follow up of 8.4 mo. 144 of these pts have available ORR and PD-L1 data and 62 pts have ORR, PD-L1 and IFNGS data. Pts with ≥25% TC or IC were scored as PD-L1 high (TC+ or IC+). Pts within the top tertile of IFNGS ( LAG3, PDL1, CXCL9, and IFNG mRNAs) tumor expression were scored positive. Cox proportional hazards models were used adjusting for age, gender, ECOG, smoking status, line of therapy, and liver metastasis at baseline. ORR was evaluated using RECIST v1.1. Results: IFNGS+ pts had increased ORR (45 vs 16%) and improved PFS (adj HR 0.3; p = 0.005) and OS (adj HR 0.18; p = 0.016) over IFNGS- pts. IFNGS expression was significantly higher in pts who were PD-L1 high (TC+/IC+) compared with TC-/IC- (low/negative) pts (mean IFNGS expression 3.5 vs 1.1; p = 0.0155) and also in TC+ or IC+ vs TC-/IC- (mean IFNGS 2.2 vs 1.1; p = 0.000127). TC-/IC+ and TC+/IC- groups had a mean IFNGS expression of 2 and 2.2 respectively. ORR in all 1108 UC pts with available IHC and ORR data (N = 144) was 29% for TC+/- pts, 36% in TC-/IC+ pts, and 7% in the TC-/IC- pts. Conclusions: IFNGS predicted improved outcomes in a cohort of 62 2L+ UC pts treated with D. TC-/IC- PD-L1 pts had lowest levels of IFNGS expression. Observations that TC+ (and IC+) pts contribute to IFNGS enrichment and that TC+/IC-, and TC-/IC+ pts have increased response vs TC-/IC-pts provides rationale for TC+ inclusion (in addition to IC+) in the SP263 PD-L1 scoring algorithm for UC. IFNGS is an additional potential predictive biomarker in UC pts that warrants further investigation.

2566 Background: Durvalumab is a human monoclonal antibody that binds to PD-L1 and blocks its interaction with PD-1 and CD80. The objectives of this analysis were to develop a population pharmacokinetics (PK) model of durvalumab, to quantitate the effect of patient/disease characteristics on PK, and to compare weight (WT)-based versus fixed dosing regimens. Methods: Data were pooled from two studies: Study 1108 (Phase 1/2; various tumor types) and ATLANTIC (Phase 2; NSCLC). A total of 1324 patients provided data following 0.1 to 20 mg/kg IV durvalumab. The population PK was performed using a non-linear mixed effects modeling approach in NONMEM software. The impact of demographics, clinical indices, and biomarkers on PK was explored. Results: Durvalumab PK was best described using a 2-compartment model with both linear and non-linear clearances. The mean (between-patient variability) linear clearance (CL) and central volume of distribution (V1) were 226 mL/day (~29%) and 3.51 L (~21%), respectively. Although population PK analysis identified a few statistically significant covariates (WT, sex, CrCL, post-baseline ADA, ECOG performance status, LDH, sPDL1 levels, tumor type, and albumin), none were found to be clinically relevant (effect on PK parameters < 30%), indicating no need for dose adjustment. Simulations indicated similar overall PK exposures following WT-based (10 mg/kg Q2W) and fixed dosing regimens (1500 mg Q4W or 750 mg Q2W); with all regimens expected to maintain target trough exposure of ~50 µg/mL in ≥95% patients. In a post-hoc analysis, durvalumab clearance was found to decrease slightly over time, with a mean maximal reduction from baseline value of 15.5%. The decrease in CL was associated with tumor shrinkage, decreased LDH, increased albumin and decreased neutrophil to lymphocyte ratio. The small decrease in CL was not considered relevant to PK exposure or dosing. Conclusions: A population PK model of durvalumab was developed and validated. No dose adjustments were needed based on any patient or disease characteristics. The analysis demonstrated the feasibility of switching to a fixed dose regimen. Clinical trial information: NCT02087423 and NCT01693562.

286 Background: Anti-PD-L1 immunotherapy has shown promising clinical activity in urothelial carcinoma (UC). We report on a planned update of efficacy and follow-up in patients (pts) receiving durvalumab for the treatment of locally advanced or metastatic UC. Methods: Pts received durvalumab 10 mg/kg Q2W up to 12 months (mo), unacceptable toxicity or confirmed progressive disease. Tumor PD-L1 expression was assessed using the validated Ventana SP263 assay (PD-L1 high = TC ≥ 25% or IC ≥ 25%). Primary endpoints were confirmed ORR by RECIST v1.1 with blinded independent central review (BICR) and safety. Duration of response (DoR) and overall survival (OS) were key secondary endpoints. Results: As of July 24, 2016 (data cutoff [DCO]), the primary efficacy population included 103 pts who were followed for at least 13 weeks (median duration of follow up 7.3 mo); 37% had ≥ 2 prior regimens; 97% had prior platinum treatment; 95% had visceral metastases; and 49% had liver metastases at baseline. As of the DCO, 21 pts (20.4%) had a confirmed response per BICR (including 5 pts [4.9%] with a complete response) and an additional 3 pts had an unconfirmed response. Responses were seen in both PD-L1 high and PD-L1 low/negative subgroups (Table). Responses occurred early (median time to response 1.4 mo) and were durable. Median DoR has not been reached. Of the 21 confirmed responders, 18 pts had an ongoing response, 16 pts had DoR ≥ 6 mo and 7 pts had DoR ≥ 9 mo. Treatment-related Grade 3/4 AE rates were low (5.2%; as treated population, n = 191); Grade 3/4 immune-mediated AEs (imAEs) occurred in 3 pts, and 1 pt discontinued treatment due to an imAE of acute kidney injury. Conclusions: Durvalumab administered at 10 mg/kg Q2W showed clinical activity and an excellent safety profile in pts with locally advanced or metastatic UC. Clinical trial information: NCT01693562. [Table: see text]

9085 Background: Preliminary analyses of an ongoing Phase 1/2 study of single-agent durvalumab showed antitumor activity and a tolerable safety profile in advanced NSCLC, with higher ORR and longer OS in pts with high vs. low/negative PD-L1 tumor expression. Here we present updated safety analyses (primary endpoint) for all NSCLC pts and clinical activity based on investigator-assessed RECIST v1.1 in pts who had received prior treatment for advanced NSCLC. Methods: Durvalumab (10 mg/kg q2w) was given until unacceptable toxicity or disease progression, or for up to 12 mos; retreatment was permitted upon disease progression after completion of 12 mos of treatment. PD-L1 expression was assessed using the Ventana PD-L1 (SP263) Assay (PD-L1 high = ≥25% and PD-L1 low/negative = <25% of tumor cells with membrane staining). Results: As of 24 Oct 2016, 245 pts with previously treated NSCLC (53% squamous) received durvalumab and were followed for a median of 29.2 (range 0.3–40.5) mos; 142 pts (58%) had treatment-related adverse events (AEs), most frequent: fatigue (18%), decreased appetite (9%), and nausea, rash, and diarrhea (each 8%). 25 pts (10%) had treatment-related Grade 3/4 AEs, most frequent: fatigue and hyponatremia (each 2%); there were no treatment-related deaths. 4% had treatment-related serious AEs including colitis and pneumonitis (each 2%). In the overall population, 12 mo OS rate was 47% (95% CI 40–53) and 18 mo OS rate was 38% (95% CI 31–45). Antitumor activity and survival by PD-L1 status are shown in the table. Conclusions: Consistent with earlier reports, durvalumab had a manageable safety profile in Stage IIIB/IV NSCLC, with encouraging clinical activity as 2L+ therapy. Higher tumor PD-L1 expression enriched clinical benefit of response rate and survival endpoints. Clinical trial information: NCT01693562. [Table: see text]

Background: Durvalumab is a human mAb that binds to PD-L1 and blocks its interaction with PD-1 and CD80. The objectives of this analysis were to describe the longitudinal tumor size profiles, identify factors predicting tumor growth and regression, and associate tumor kinetics with overall survival (OS). Methods: Longitudinal tumor size and OS data obtained from UC patients (Study 1108; NCT# CD-ON-MEDI4736-1108) who received durvalumab were analyzed using a nonlinear mixed effect model that describe tumor growth, tumor killing, and delay in immune response leading to tumor killing. An OS model was developed by linking model-predicted tumor size over time to survival hazard in a constant hazard model. Potential predictive factors of tumor growth and regression, as well as survival were evaluated in a multivariate covariate analysis in the tumor kinetic and OS model, respectively. Results: Tumor kinetic and OS models adequately described the longitudinal tumor size and survival data from UC patients. The most influential factor associated with more rapid tumor growth was high baseline neutrophil-to-lymphocyte ratio (NLR), while lymph node disease was associated with decreased growth rate. Tumor (TC) or immune cell PD-L1 expression (IC), baseline tumor size and liver metastasis were identified as predictive factors for tumor killing. Simulations showed increased response rates with higher TC and/or IC (by 6/9%, and 18/24%, with 25% and 50% cutoff for TC/IC, respectively). After accounting for tumor response, the risk of death decreased with higher TC/IC and lower baseline hemoglobin and albumin levels, while liver metastasis, lymph node disease, and prior carboplatin treatment were associated with higher risk. Conclusions: Tumor kinetic modeling identified factors that predict tumor growth and shrinkage following durvalumab therapy in UC patients, and permits investigation of predictive biomarker strategies considering confounding factors. Joint modeling that associates predicted tumor kinetics with OS allows model-based extrapolation of missing data and evaluation of other factors influencing OS after accounting for change in tumor size over time. Clinical trial identification: NCT01693562 (September 14, 2012) Legal entity responsible for the study: MedImmune Funding: MedImmune Disclosure: Y. Zheng: Corporate sponsored research: MedImmune, Shareholder: Roche, MedImmune, Employee: MedImmune. X. Jin: Employee MedImmune and shareholder AstraZeneca. R. Narwal: Employee and shareholder MedImmune. C-Y. D Jin: Employee and stock holder of AstraZeneca. A. Gupta: Employment MedImmune, shareholder AstraZeneca + Bristol-Myers Squibb. Y. Ben, P. Mukhopadhyay: Employee and shareholder AstraZeneca. B. Higgs, L. Roskos: Employment MedImmune, shareholder AstraZeneca.

11555 Background: Durvalumab is a human monoclonal antibody that binds to PD-L1 and blocks its interaction with PD-1 and CD80. The primary objectives of this analysis were to describe the longitudinal tumor size profiles and identify the key factors predicting tumor growth and regression following durvalumab. Methods: Longitudinal tumor size data obtained from NSCLC patients in study 1108 (all lines of therapy) and ATLANTIC (third line and beyond) following durvalumab treatment were modeled using nonlinear mixed effect modeling. Tumor kinetics were described by four key parameters: tumor growth and killing rate constants, fraction of durvalumab-sensitive tumor cells, and delay time for tumor killing. Potential predictive factors for tumor growth and regression were evaluated in a multi-variable covariate analysis. The model was used to simulate response rates at different tumor PD-L1 expression cutoffs. Results: Tumor kinetic modeling accurately described the longitudinal tumor response profiles from NSCLC patients in both studies. The factors associated with more rapid tumor growth were liver metastases, ECOG score > 0, high neutrophil-to-lymphocyte ratio and EGFR/ALK mutation. Tumor cell PD-L1 expression, baseline tumor size and smoking history were identified as significant predictive factors for tumor killing or the fraction of sensitive tumor cells. Simulations using the tumor kinetic model showed increased response rates in patients with higher tumor cell PD-L1 expression (increased by 9-11% and 10-14% with 25% and 50% cutoff, respectively), patients receiving durvalumab as first-line therapy (increased by 12% vs. 2nd line/above), and patients with smoking histories (increased by 4-5% vs. non-smokers). Conclusions: Tumor kinetic modeling identified factors that predict tumor progression and response following durvalumab in NSCLC patients. The multivariate analysis accounts for various predictive factors within predictive biomarker strata, allowing better interpretation of different biomarker cutoffs. The modeling technique can potentially guide patient selection/enrichment, clinical trial design strategies and tumor biology. Clinical trial information: NCT02087423 and NCT01693562.