Anti PD-L1 Research Articles

Biomarker analysis from the phase 3 CheckMate 9ER trial of nivolumab + cabozantinib v sunitinib for advanced renal cell carcinoma (aRCC).

608 Background: Prior studies investigated determinants of anti–PD-L1 ± anti-angiogenic response in aRCC. The mechanisms underlying response to first-line anti–PD-1 + VEGF-targeted therapy (anti-VEGF) remain largely unknown. In this exploratory post hoc analysis we conducted an analysis of anti–PD-1 (N) + anti-VEGF (C) v S by assessing potential predictive biomarkers for efficacy in CheckMate 9ER. Analyzed biomarkers included CD8 T-cell frequency (% of total tumor cells, CD8%), CD8 topology, PD-L1 immunohistochemistry, gene set enrichment analysis (GSEA), and 7 gene expression signatures (GES). Methods: Progression-free survival (PFS) and overall survival (OS) were evaluated by tumor PD-L1 expression (< 1% or ≥ 1%), CD8% (low, medium, high by tertiles), and CD8 topology phenotype (desert, excluded, inflamed), and assessed for association using Kaplan–Meier (KM) methods with log-rank test (PD-L1 and CD8), and Cox proportional hazard (Cox PH) models (CD8) (to avoid arbitrary or biased categorization of continuous-valued predictor variables, a potential limitation of KM analyses). Pre-ranked GSEA was performed to assess enrichment for hallmark gene sets using all genes ranked by interaction effect estimates derived using Cox PH regression. Seven GES (Angio, Myeloid, Teff, TIS, IFN-γ, EMT8, Javelin), including several previously found to be predictive of anti-PD-L1 ± anti-VEGF outcomes, were assessed for association with PFS within treatment arms. Results: At 44 mo median follow-up, median PFS and OS were improved with N+C v S regardless of PD-L1 status. PD-L1 < 1% v ≥ 1% was associated with longer median PFS in the S arm only ( P = 0.00011). In KM analyses, higher CD8% was associated with improvements in PFS with N+C, but not S. Of the 410 patients (pts) in the CD8 topology analysis, the predominant CD8 phenotype was inflamed (44.6%), then desert (38.5%) and excluded (16.8%). CD8 topology supported an association between the inflamed phenotype and improved survival outcomes with N+C v S (PFS, P < 0.0001; OS, P = 0.0016). However, these associations were not confirmed in Cox PH models. Common hallmark gene sets with positive enrichment (with false discovery rate < 0.05) in genes associated with longer PFS and OS with N+C v S included oxidative phosphorylation, hypoxia, adipogenesis and P53 pathway. Pts receiving N+C had longer median PFS in the high IFN-γ GES tertile ( P = 0.041) and shorter median PFS in the high EMT8 tertile ( P= 0.013). However, all 7 GES tested, including IFN-γ and EMT8, were not predictive for N+C outcomes in Cox PH models. Conclusions: In this exploratory post hoc analysis, biomarkers previously found to be predictive of anti-PD-L1 ± anti-VEGF outcomes, including established GES, were not predictive of efficacy with anti-PD-1 + anti-VEGF (N+C) using Cox PH models. This suggests that key determinants of response to anti–PD-1 v anti–PD-L1 therapies may differ. Clinical trial information: NCT03141177 .

READY: Real-world data from an Italian compassionate use program of avelumab first-line maintenance (1LM) treatment for locally advanced or metastatic urothelial carcinoma (la/mUC).

469 Background: In the phase 3 JAVELIN Bladder 100 trial (NCT02603432), avelumab (anti–PD-L1) 1LM plus best supportive care (BSC) in patients (pts) with la/mUC whose disease did not progress after 1L platinum-based chemotherapy (PBC) significantly extended overall survival (OS) vs BSC alone, and it is now recommended internationally as standard of care with level 1 evidence. We report real-world descriptive pt characteristics and outcomes data from a large, multicenter, Italian compassionate use program (CUP) assessing avelumab 1LM in pts with la/mUC. Methods: This prospective, noninterventional CUP was initiated on Jan 18, 2021, to provide early access to avelumab before reimbursement by the Italian Medicines Agency for pts with la/mUC. Avelumab was provided upon physician request and after approval by local ethics committees in accordance with the Italian compassionate use regulation. Avelumab 800 mg IV was administered every 2 weeks per local prescribing information to adult pts aged ≥18 years with la/mUC who were progression-free following PBC (4-6 cycles, starting 4-10 weeks after last dose of PBC). Pts who had a relapse within 12 months of prior adjuvant or neoadjuvant systemic therapy, including immune checkpoint inhibitors, were not eligible. Results: As of Aug 16, 2022, 464 pts (78.4% male, 21.6% female) were included from 140 Italian centers from Jan 2021-Mar 2022. Median age at inclusion was 70 years (IQR, 63-76 years). At the start of 1L PBC, 346 pts (73.9%) had metastatic disease and 40 (8.6%) had unresectable locally advanced disease (disease stage not defined [N/D] in 78 pts [16.8%]). ECOG PS was 0 in 321 pts (69.2%), 1 in 140 (30.2%), and N/D in 3 (0.7%). Primary tumor site was upper tract in 148 pts (31.9%) and lower tract in 309 (66.6%) (N/D in 7 [1.5%]). 1L PBC comprised carboplatin + gemcitabine in 241 pts (51.9%), cisplatin + gemcitabine in 214 (46.1%), and other PBC in 9 (1.9%); 225 pts (48.5%) received 4 cycles of PBC, 54 (11.6%) received 5 cycles, and 177 (38.2%) received 6 cycles (other or N/D in 8 [1.7%]). Complete response to 1L PBC was achieved in 51 pts (11.0%), partial response in 266 (57.3%), and stable disease in 147 (31.7%). For 391 pts currently evaluable for OS and progression-free survival (PFS) from the start of avelumab, the 12-month OS rate was 69.1% (95% CI, 64.4%-73.6%), while median OS was not reached. The 12-month PFS rate was 38.9% (95% CI, 34.0%-43.7%) and median PFS was 6.6 months (95% CI, 5.6-8.9 months). Grade 3-4 adverse events occurred in 33 pts (7.1%). Conclusions: This CUP included a large pt population representative of daily clinical practice in 140 Italian oncology centers and the results are consistent with those of previous studies. Overall, these real-world data strengthen the findings of JAVELIN Bladder 100 and provide further support for avelumab 1LM as a standard of care in eligible pts with la/mUC.

Expresión de PD-L1 en cáncer renal, características pronósticas y utilidad en la práctica clínica habitual

IntroductionThe expression of PD-L1 in renal cell carcinoma (RCC) is associated with worse survival and prognostic clinical-pathological features. However, they seem to respond better to new therapeutic agents. Knowing the behavior of RCC according to the presence of PD-L1 may have implications for medical counseling and therapeutic approaches. ObjectiveTo identify the presence of PD-L1 in renal tumor cells and analyze its association with patientś prognostic factors, overall survival (OS) and cancer-specific survival (CSS). MethodologyRetrospective analysis of RCC tissue samples, obtained between 2018 and 2021. Immunohistochemistry analysis with mouse monoclonal Anti PD-L1, clone 22C3. Definition of PD-L1 “positive” as a Tumor Proportion Score ≥ 1%. Comparison of prognostic factors according to the presence or absence of PD-L1, and univariate analysis for OS and CSS. Results14% (n=11) of the sample were PD-L1(+). Average age was 59 years. There were no statistically significant differences between PD-L1 status and TNM stages, nuclear grade and histology. PD-L1(+) had worse OS with a HR of 5.27 (CI: 1.1-23.7; p=0.03) and CSS showed a unfavorable tendency for PD-L1(+) with a HR of 4.79 (CI: 0.79-28.95; p=0.08). ConclusionThe prevalence of PD-L1 in RCC is considerable. In this study PD-L1(+) was associated with unfavorable OS and CSS. It seems reasonable to incorporate its routine use in RCC.

Comparison of anti–PD-L1 with anti–PD-1 antibodies in the combination of HAIC and lenvatinib for the treatment of unresectable hepatocellular carcinoma.

509 Background: Previous study showed the combination of hepatic artery infusion chemotherapy (HAIC), Lenvatinib and immune checkpoint inhibitors (ICIs) makes better overall response rate (ORR) as well as survival benefit than pure systematic treatment for unresectable hepatocellular carcinoma (uHCC). But how to choose different ICIs remains unclear. This study aimed to compare the efficacy and safety of anti-PD-1/PD-L1 antibodies combined with HAIC and Lenvatinib. Methods: This study retrospectively included 184 patients with uHCC treated with HAIC+ Lenvatinib +PD-1/PD-L1 antibody from June 2019 to January 2022 in the liver surgery department of Sun Yat-sen University Cancer Center. We used propensity score match (PSM) to screen and match 60 patients of HAIC+durvalumab+ Lenvatinib (HIL) versus 60 HAIC+PD-1+ Lenvatinib (HPL) to compare the efficacy and safety profile of these two groups. Results: The baseline is basically equilibrium between HIL and HPL group after matching. The median OS and PFS are not evaluable on the data cut-off date Sep 10, 2022. The ORR was higher in the HIL group than in the HPL group according to modified RECIST (mRECIST) (74.1% vs. 53.6%, p = 0.022) and RECIST 1.1 (60.3% vs. 41.1%, p = 0.040) respectively. In addition, 10 (17.2%) patients in the HIL group achieved complete response (CR) while 3 (5.4%) in the HPL group according to mRECIST. The results of subgroup analyses suggested that HIL approach could bring more survival benefits than HPL approach for patients with tumor smaller than 10cm and bilateral liver involvement. The incidence of grades 3 or 4 adverse events (AEs) was 10.0% and 18.3% with HIL and HPL group, respectively. Conclusions: Anti-PD-L1 antibody seems to be a better companion in the combination therapy of HAIC+ICIs+Lenvatinib than anti-PD-1 antibody for higher ORR and lower incidence of severe AEs. Further prospective study including larger population of patients is required.[Table: see text]

A phase II study of atezolizumab (ATEZO) and bevacizumab (BEV) in combination with Y90 TARE in patients (pts) with hepatocellular carcinoma (HCC): Y90+/- BEAT.

TPS629 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 IMbrave150 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 (NCT04541173). 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. 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. Clinical trial information: NCT04541173 .

Expression of PD-L1 in renal cancer, prognostic features and clinical utility of its routine staining

IntroductionThe expression of PD-L1 in renal cell carcinoma (RCC) is associated with worse survival and prognostic clinical-pathological features. However, they seem to respond better to new therapeutic agents. Knowing the behavior of RCC according to the presence of PD-L1 has implications for medical counseling and therapeutic approaches. ObjectiveTo identify the presence of PD-L1 in renal tumor cells and analyze its association with patients’ prognostic factors, overall survival (OS) and cancer-specific survival (CSS). MethodologyRetrospective analysis of RCC tissue samples, obtained between 2018 and 2021. Immunohistochemistry analysis with mouse monoclonal Anti PD-L1, clone 22C3. Definition of PD-L1 “positive” as a Tumor Proportion Score ≥1%. Comparison of prognostic factors according to the presence or absence of PD-L1, and univariate analysis for OS and CSS. Results14% (n = 11) of the sample were PD-L1(+). Average age was 59 years. There were no statistically significant differences between PD-L1 status and TNM stages, nuclear grade and histology. PD-L1(+) had worse OS with a HR of 5.27 (CI: 1.1–23.7; P = .03) and CSS showed a unfavorable tendency for PD-L1(+) with a HR of 4.79 (CI: 0.79–28.95; P = .08). ConclusionThe prevalence of PD-L1 in RCC is considerable. In this study PD-L1(+) was associated with unfavorable OS and CSS. It seems reasonable to incorporate its routine use in RCC.

A Phase 1 Trial of Durvalumab in Combination with Bacillus Calmette-Guerin (BCG) or External Beam Radiation Therapy in Patients with BCG-unresponsive Non-muscle-Invasive Bladder Cancer: The Hoosier Cancer Research Network GU16-243 ADAPT-BLADDER Study

BackgroundNovel treatments and trial designs remain a high priority for bacillus Calmette-Guerin (BCG)-unresponsive non–muscle-invasive bladder cancer (NMIBC) patients. ObjectiveTo evaluate the safety and preliminary efficacy of anti–PD-L1 directed therapy with durvalumab (D), durvalumab plus BCG (D + BCG), and durvalumab plus external beam radiation therapy (D + EBRT). Design, setting, and participantsA multicenter phase 1 trial was conducted at community and academic sites. InterventionPatients received 1120 mg of D intravenously every 3 wk for eight cycles. D + BCG patients also received full-dose intravesical BCG weekly for 6 wk with BCG maintenance recommended. D + EBRT patients received concurrent EBRT (6 Gy × 3 in cycle 1 only). Outcome measurements and statistical analysisPost-treatment cystoscopy and urine cytology were performed at 3 and 6 –mo, with bladder biopsies required at the 6-mo evaluation. The recommended phase 2 dose (RP2D) for each regimen was the primary endpoint. Secondary endpoints included toxicity profiles and complete response (CR) rates. Results and limitationsTwenty-eight patients were treated in the D (n = 3), D + BCG (n = 13), and D + EBRT (n = 12) cohorts. Full-dose D, full-dose BCG, and 6 Gy fractions × 3 were determined as the RP2Ds. One patient (4%) experienced a grade 3 dose limiting toxicity event of autoimmune hepatitis. The 3-mo CR occurred in 64% of all patients and in 33%, 85%, and 50% within the D, D + BCG, and D + EBRT cohorts, respectively. Twelve-month CRs were achieved in 46% of all patients and in 73% of D + BCG and 33% of D + EBRT patients. ConclusionsD combined with intravesical BCG or EBRT proved feasible and safe in BCG-unresponsive NMIBC patients. Encouraging preliminary efficacy justifies further study of combination therapy approaches. Patient summaryDurvalumab combination therapy can be safely administered to non–muscle-invasive bladder cancer patients with the goal of increasing durable response rates.

Do proton pump inhibitors alter the response to immune checkpoint inhibitors in cancer patients? A meta-analysis.

Gut microbiota can significantly affect the effectiveness of immune checkpoint inhibitors (ICIs) in cancer patients. Recently, antibiotics were shown to decrease survival rate of patients treated by ICIs. Proton pump inhibitors (PPIs) can indeed modulate microbiota's diversity, therefore altering ICIs response. A meta-analysis was performed based on published data to verify this hypothesis. In this study, over 41 publications, exploring the impact of concomitant PPI treatment on outcomes of ICI-treated patients, were analyzed. Evaluated endpoints were overall survival (OS) and progression-free survival (PFS). Pooled hazard ratios (HRs) with a 95% confidence interval (CI) were reported in ICIs in PPI users versus non-PPI users. Subgroup analyses were performed to minimize the impact of study heterogeneity and to investigate the influence of PPI on the different groups of interest. There was no evidence of publication bias for OS and PFS analysis in subgroup analysis. Forty-one studies were included in the meta-analysis, including a total of 20,042 patients. OS of patients receiving ICIs was negatively correlated in patients concomitantly treated with PPI (HR=1.37; 95%CI, 1.23-1.52). PFS of cancer patients receiving ICIs was also negatively correlated with PPI treatment (HR=1.28; 95%CI, 1.15-1.42). PPI and ICI use was associated with worst OS and PFS not only for non-small-cell lung cancer (NSCLC) or urothelial cancer patients but also for patients treated with anti PD-1 (OS) and anti PD-L1 (OS and PFS) immunotherapies when administered in non-first line and when PPI was received as baseline treatment or in 60 days before ICI initiation. PPI and ICI use also showed the worst OS and PFS for patients from Europe and Asia. This meta-analysis suggests that PPI treatment leads to significantly worse outcomes in advanced cancer patients treated by ICIs in terms of PFS and OS.

CD200+ cytotoxic T lymphocytes in the tumor microenvironment are crucial for efficacious anti-PD-1/PD-L1 therapy.

Anti-PD-1/PD-L1 therapy, either by anti-PD-1 antibody or anti-PD-L1 antibody, has efficacy by reinvigorating tumor-infiltrating CD8+ T cells in a subset of patients with cancer, but it has unequal effects on heterogeneous CD8+ T cell populations. Hence, the subset crucial to efficacious PD-1 blockade therapy remains elusive. Here, we found an increase in tumor-infiltrating CD200+ cytotoxic T lymphocytes (CTLs) upon PD-1/PD-L1 blockade, with higher proportions of CD200+ T cells positively related to a favorable clinical outcome to anti-PD-1/PD-L1 therapy in three independent cohorts of patients with cancer. Using multiple mouse tumor models, we demonstrated that CD200+ CTLs are essential for efficacious anti-PD-L1 therapy. Mechanistically, we observed a unique chromatin landscape in CD200+ CTLs and found that these cells are enriched for tumor antigen-specific CTLs and have antitumor effector functions. Coinoculation of CD200+ CTLs with tumor cells led to robust tumor regression in two transplanted mouse models. Clinically, we found that infiltration of CD200+ CTLs into tumors could predict immunotherapy efficacy in six patient cohorts. Together, our findings reveal that CD200+ CTLs in the tumor microenvironment are crucial for efficacious anti-PD-1/PD-L1 therapy and could serve as a predictor of successful immunotherapy in the clinic.

Severe and refractory gastrointestinal toxicity due to immune checkpoint inhibitors: clinical experience in a tertiary referral hospital.

immune checkpoint inhibitors (ICI) are increasingly used to treat several types of cancer. These drugs lead to a wide range of toxicities. Immune-related gastrointestinal adverse events are common and potentially severe. In this manuscript, we recount the real clinical experience in a tertiary center. a retrospective and observational study was conducted in adult patients under ICI treatment. Included patients had been referred to the Gastrointestinal Service of Hospital Universitario Vall d'Hebron for evaluation of severe toxicities, from January 2017 to January 2020, for whom the clinical, epidemiological and evolutive data were collected. a total of 18 patients were included. Fifty-five percent received anti-programmed cell death protein 1 (PD-1)/anti-programmed death-ligand 1 (anti PD-L1), 11 % received anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) and 33 % received both treatments. The toxicities were manifested as enterocolitis, microscopic colitis and gastritis. Upper gastrointestinal endoscopy was performed in seven patients; all were proved to have histological changes on duodenum biopsies. Treatment was stopped in all patients and steroids were initiated. Sixty-six per cent achieved clinical remission with steroids. Five patients received anti-TNF treatment (infliximab). Only one of the five had responded. Two anti-TNF refractory patients received ustekinumab, with an appropriate clinical response. One patient received apheresis granulocyte as concomitant treatment. A patient with a steroid-dependent course started vedolizumab. Three patients had other immune-related adverse events. gastrointestinal immune-related adverse events are acquiring a higher profile in daily practice and gastroenterologists play an even greater role in the management of these patients.

Theoretical and experimental studies on the interaction of biphenyl ligands with human and murine PD-L1: Up-to-date clues for drug design

Today it is widely recognized that the PD-1/PD-L1 axis plays a fundamental role in escaping the immune system in cancers, so that anti-PD-1/PD-L1 antibodies have been evaluated for their antitumor properties in more than 1000 clinical trials. As a result, some of them have entered the market revolutionizing the treatment landscape of specific cancer types. Nonetheless, a new era based on the development of small molecules as anti PD-L1 drugs has begun. There are, however, some limitations to advancing these compounds into clinical stages including the possible difficulty in counteracting the PD-1/PD-L1 interaction in vivo, the discrepancy between the in vitro IC50 (HTFR assay) and cellular EC50 (immune checkpoint blockade co-culture assay), and the differences in ligands’ affinity between human and murine PD-L1, which can affect their preclinical evaluation. Here, an extensive theoretical study, assisted by MicroScale Thermophoresis binding assays and NMR experiments, was performed to provide an atomistic picture of the binding event of three representative biphenyl-based compounds in both human and murine PD-L1. Structural determinants of the species’ specificity were unraveled, providing unprecedented details useful for the design of next generation anti-PD-L1 molecules.

Differentiating Acute Interstitial Nephritis From Immune Checkpoint Inhibitors From Other Causes

Differentiating Acute Interstitial Nephritis From Immune Checkpoint Inhibitors From Other Causes

First-in-Maintenance Therapy for Localized High-Grade Osteosarcoma: An Open-Label Phase I/II Trial of the Anti-PD-L1 Antibody ZKAB001.

We investigated the safety and preliminary efficacy of anti-PD-L1 antibody (ZKAB001) as maintenance therapy for localized patients with high-grade osteosarcoma to reduce the risk of recurrence and metastasis. This open-label Phase I/II study was divided into dose-escalation Phase I and expansion Phase II. Phase I used a 3+3 design with ZKAB001 at three escalating doses ranging: 5, 10, 15 mg/kg every 2 weeks in 9 patients with localized high-grade osteosarcoma and Phase II tested 10 mg/kg in 12 patients for up to 24 cycles. Primary endpoints were safety and tolerability assessed using CTCAE4.0.3. Between October 2018 and 2019, 21 eligible patients were enrolled and accepted ZKAB001 treatment: 9 in the dose-escalation phase, and 12 in expansion phase. Six patients with disease progression withdrew from this study and follow-up is ongoing. The MTD was not defined in Phase I. All doses had a manageable safety profile. The recommended dose in Phase II was set at 10 mg/kg. Most frequent immune-related adverse events were thyroiditis (76.2%) and dermatitis (42.9%). Only 1 (4.8%) of 21 patients had a Grade 3 skin rash. The median 3-year event-free survival (EFS) and overall survival (OS) were not established; however, 24-month EFS was 71.4% (95% confidence interval, 47.2-86.0) and 2-year OS was 100%. Preliminary efficacy data showed EFS benefits in patients with PD-L1 positive or an MSI-H sub-population. Switching to maintenance using ZKAB001 showed an acceptable safety profile and provided preliminary evidence of clinical activity in localized patients with osteosarcoma.

61MO IMscin001 (part 2: randomized phase III): Pharmacokinetics (PK), efficacy and safety of atezolizumab (atezo) subcutaneous (SC) vs intravenous (IV) in previously treated locally advanced or metastatic non-small cell lung cancer (NSCLC)

Atezo (anti–PD-L1) IV is approved in NSCLC, SCLC, triple-negative breast cancer, hepatocellular carcinoma, urothelial carcinoma and unresectable/metastatic melanoma. To reduce treatment burden and improve convenience and efficiencies in healthcare, a novel fixed-dose atezo SC co-formulated with recombinant human hyaluronidase is being developed. We report Part 2 (Phase III) of the open-label, randomized, multicentre IMscin001 study (NCT03735121) to investigate non-inferiority of drug exposure at Cycle 1 after atezo SC vs IV administration in NSCLC.

75P Effectiveness and safety data from IMreal cohort 1: Patients (pts) with urothelial cancer (UC) receiving atezolizumab after platinum-containing chemotherapy (plt chemo) under real-world conditions

Atezolizumab (atezo; anti–PD-L1) is used to treat pts with locally advanced/metastatic UC after plt chemo or who are cisplatin-ineligible and whose tumours have PD-L1 expression ≥5%. IMreal (NCT03782207) is a non-interventional, global, multi-centre, multi-cohort prospective study evaluating the short- and long-term outcomes and safety with atezo in the real-world setting. We report the second interim effectiveness and safety data for Cohort 1.

338P Anti PD1 is superior to anti PDL1 when combined with chemotherapy in first-line treatment for metastatic non-small cell lung cancer (mNSCLC): A network meta-analysis

Platinum based chemotherapy (CT) with anti PD1/PDL1 is now a standard first line therapy in the management of mNSCLC without targetable driver mutations. PDL1 is expressed on tumour cells and PD1 is expressed on immune cells and these alternate mechanisms may alter clinical outcomes after tumour cell death. A network meta-analysis (NWM) showed anti PD1 + CT was superior to anti PDL1 + CT in overall survival (OS). However, only one anti PDL1, atezolizumab, was included in the analysis. More recently, several randomised controlled trials (RCT) involving newer anti PD1/PD L1 agents have been reported.

137MO Avelumab first-line (1L) maintenance for advanced urothelial carcinoma (UC): Longer-term follow-up from the Asian subgroup of the JAVELIN Bladder 100 trial

In the JAVELIN Bladder 100 trial (NCT02603432), avelumab (anti–PD-L1) 1L maintenance + best supportive care (BSC) significantly prolonged overall survival (OS) and progression-free survival (PFS) vs BSC alone in patients with advanced UC that had not progressed with 1L platinum-based chemotherapy. Previously reported initial data from patients enrolled in Asia were consistent with data from the overall trial population. Here, we report longer-term efficacy and safety data from the Asian subgroup.

OR11-2 RNA Sequencing Reveals Unique Transcriptomic Signatures of the Thyroid in a Murine Lung Cancer Model Treated with PD-1 and PD-L1 Antibodies

Abstract Immune checkpoint inhibitors (ICI) have revolutionized cancer therapy, however, are associated with immune-related adverse events (irAEs). Thyroid dysfunction is among the most common irAEs, yet its mechanism has not been fully elucidated. To further explore the molecular mechanism of ICI-induced thyroid dysfunction, we profiled changes in transcription induced by PD-1/PD-L1 antibody treatment in a non-small cell lung cancer murine model using RNA-seq. We used bioinformatic tools to compare transcriptional changes in our model to previously published transcription data sets of drug-induced thyroiditis. C57BL6/129SvJ mice harboring LKR-M (Lung cancer K-ras metastatic tumor) flank tumors were treated with PD-1 antibody, PD-L1 antibody, or vehicle every 3 days over a period of 7 days when mice were sacrificed, and thyroid glands were removed. The tumor volume increased in the control mice (1.38 ± 0.19) and decreased in the anti PD-1 treated (0.64 ± 0.15; P=0.0001) and PD-L1 treated mice (0.74 ± 0.11; P=0.004). RNA-seq was performed in the LKR-M tumor-bearing control mice and in the anti PD-1/PD-L1 treated mice (n=4 per group). A total of 952 differentially expressed genes (DEGs), including 265 upregulated and 688 downregulated, were identified with anti PD-1 treatment (fold-change ≥1.8, FDR ≤0.05). Only 35 genes were differentially expressed with anti PD-L1 treatment, and we therefore chose to focus on the anti PD-1 treated group alone. Using Ingenuity Pathway Analysis (IPA), we determined that of the DEGs in the PD-1 treatment group, 362 were associated with functions of cell death and survival, with a predicated activation of pathways for apoptosis and necrosis (Z=2.89 and 3.21, respectively) and negative activation of pathways for cell viability and cell survival (Z=-6.22 and -6.45, respectively). When compared to previously published datasets of interleukin-1β and interferon gamma-treated human thyroid cells, the apoptosis pathways were similarly activated. To our knowledge this is the first study to evaluate transcriptomic changes in thyroid tissue following ICI therapy. Our data suggest that there are unique changes in gene expression in the thyroid associated with anti PD-1 therapy. ICI-induced thyroid dysfunction may be mediated by increased tissue apoptosis resulting in destructive thyroiditis. Presentation: Sunday, June 12, 2022 11:15 a.m. - 11:30 a.m.

Memory T Cells in Draining Lymph Nodes Potentiate Anti–PD-L1 Therapy

Tumor-specific memory CD8+ T cells in the draining lymph node promote the response to anti-PD-L1.

Flagging the Merited Lesions-Fibroblast 1 and 4 Imaging to Map the Key Avid Domains for Spiked Antigenicity Using SBRT In Situ Vaccination and Metronomic Radiation with Anti PDL-1 Therapy for Augmented Abscopal-Radscopal Responses in Disseminated Cancers

<h3>Purpose/Objective(s)</h3> Immune stimulating effects of SBRT (stereotactic body radiotherapy) for releasing tumor antigens and the immuno-modulatory property of low dose radiation has been under evaluation over years. Conceptual Radscopal effect for lesions receiving a non-tumoricidal scattered low dose radiation showing abscopal responses led to the concept of combining SBRT to highly avid larger metastatic lesions and low dose radiation to smaller lesions is exciting. However, choosing the right lesions for SBRT to release adequate and appropriate tumor antigen spike to cause a systemic response has been a challenge and area of interest. Cancer Associated Fibroblasts (CAF) 1 and 4 can produce growth factors and cytokines such as transforming growth factor-β (TGF-β) and vascular endothelial growth factor (VEGF) to promote angiogenesis and recruit immunosuppressive cells into the tumor stroma leading to immune evasion and resistant immune microenvironment. Fibroblast Activated protein tagged to CAF 1 and 4 whole body Molecular imaging aids us in identifying regions. Based on the avidity values of CAF 1 and 4 tagged imaging, the most immune resistant (CAF Rich) target lesions were chosen for SBRT in our study. Prominent usage of Anti PDL-1 inhibitors has been proven to be beneficial in disseminated cancers, concept of SBRT with metronomic radiation could be used as immune potentiator with accurate mapping of Immune resistant areas. <h3>Materials/Methods</h3> Five patients with disseminated cancers with indications for approved immune check point inhibitors were recruited after institutional ethical committee clearance. Patients received at least 3 cycles of check point inhibitor therapy prior to initiation of immuno-rad therapy. Based on CAF molecular imaging, 1-3 lesions with maximal avidity >10 standard uptake value were chosen for SBRT to a dose of 24 Gy in 3 fractions while all other metastatic less avid smaller lesions received Low dose 1 Gy metronomic radiotherapy using Image guided radiotherapy. Patients were continued on immunotherapy for 3 more cycles before a re-assessment molecular imaging was done. <h3>Results</h3> Nasopharyngeal (NPC), hepatocellular (HCC), 2 lung and renal cell cancer (RCC) patients were recruited. No grade 2 or above normal tissue toxicity was noted. <h3>Conclusion</h3> Effectively tackling the tumor immune evasion mechanisms by choosing the right lesions for SBRT acting as an in situ-vaccination by extensive release of antigens based on individual CAF biomarker profiling would ultimately aid in improving responses to Immunotherapy. The early results of our study are encouraging.