PD-L1 Inhibitor Avelumab Research Articles

INSIGHT-005: A new stratum of the explorative, open-labeled, phase I INSIGHT study to evaluate the feasibility and safety, as well as preliminary efficacy, of subcutaneous injections with IMP321 (eftilagimod alpha) in combination with PD-L1 inhibitor (avelumab) for metastatic or unresectable locally advanced urothelial carcinoma (UC)—IKF-s614.

TPS4620 Background: UCs are the 6th most common malignancies in the Western world being localized in the upper (5-10%) or the lower (90-95%) urinary tract. Metastatic UC (mUC), which accounts for 5% of all cases, is associated with a dismal prognosis and prompt progression. So far, the 1st line therapy for mUC encompassed platinum-based combination regimens. Recent data indicate beneficial patient treatment with immune checkpoint inhibitors. Thus, avelumab was approved for maintenance therapy after progression-free platinum-based chemotherapy for locally advanced (LA) or mUC. Further immune checkpoint inhibitors (e.g. pembrolizumab, atezolizumab, nivolumab) achieved approval or showed promising results for treatment of different patient populations. Eftilagimod alpha (efti) is a soluble LAG-3 fusion protein and a MHC class II agonist activating APCs followed by CD8 T-cell activation. The combination of efti with PD-1/PD-L1 blockade is not yet available and is proposed to enhance efficacy. Based on previous results from the INSIGHT trial and change in treatment landscape we hypothesize that combining avelumab and efti will display clinically relevant efficacy in unresectable LA UC or mUC subgroups with acceptable toxicity. Methods: INSIGHT-005 is a new stratum within the investigator-initiated INSIGHT phase I platform trial ongoing at multiple sites (n=9) in Germany. Patients with unresectable LA UC or mUC will receive efti in combination with avelumab. 30 patients will be enrolled in 3 subgroups: I) Previously untreated, eligible for platinum-based therapy, with PD-L1 CPS≥10; II) Previously untreated, not-eligible for platinum-based therapy, irrespective of the PD-L1 status; III) Suffered disease progression after platinum-based chemotherapy for metastatic disease and did not receive avelumab maintenance therapy, irrespective of the PD-L1 status. Enrolled patients will receive avelumab 800 mg i.v. and efti 30 mg s.c. on the same day Q2W for a maximum of 24 cycles. Tumor evaluation will be performed via CT or MRI every 8 weeks. The primary endpoint of this study is to explore feasibility, safety, and preliminary efficacy of efti when added to avelumab in unresectable LA UC or mUC. Secondary endpoints include safety and efficacy parameters as defined by objective response, time to and duration of response and PFS according to RECIST 1.1, OS and biomarker analyses. First patient was enrolled on 2023-11-29. Currently, recruitment is ongoing. ClinicalTrials.gov ID: NCT03252938 Clinical trial information: NCT03252938 .

Abstract CT184: First-in-human trial of TIGIT inhibitor M6223 as monotherapy or in combination with bintrafusp alfa (BA) in patients (pts) with advanced solid unresectable tumors

Abstract Introduction: M6223 is an intravenous (IV), fully human, antagonistic, anti-TIGIT antibody with an Fc-mediated effector region. In preclinical studies, M6223 combined with BA (a bifunctional fusion protein that simultaneously targets the TGF-β and PD-(L)1 pathways) enhanced antitumor efficacy compared to either agent alone. Methods: This first-in-human, dose escalation study of M6223 as monotherapy (M6223; Part 1A) or in combination with BA (M6223+BA; Part 1B) included pts with advanced solid tumors (aged ≥18 years, ECOG PS ≤1) (NCT04457778). In Part 1A, pts received M6223 at 10 mg, 30 mg, 100 mg, 300 mg, 900 mg, 1600 mg, 2400 mg (all Q2W) or M6223 2400 mg Q3W. In Part 1B, pts received M6223 at 300 mg, 900 mg, or 1600 mg, all in combination with BA 1200 mg (both Q2W, IV). Dose escalation decisions by the Safety Monitoring Committee were assisted by a Bayesian 2-parameter logistic regression model. Primary objectives were safety, tolerability, maximum tolerated dose (MTD), and recommended dose for expansion (RDE). Additional objectives included pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity. Results: At final analysis, 40 pts (21 male, age range 24-79 years) had received M6223 (Q2W: n=32; Q3W: n=8), and 18 pts (7 male, age range 34-80 years) had received M6223+BA. Overall, two dose-limiting toxicities were observed: a grade 3 adrenal insufficiency (M6223, 900 mg) and a grade 3 anemia (M6223+BA, 300 mg; unrelated to M6223). In the M6223 group, grade ≥3 TEAEs were observed in 14 (35.0%) pts and M6223-related grade ≥3 TEAEs in 2 (5.0%) pts. In the M6223+BA group, grade ≥3 TEAEs were observed in 14 (77.8%) pts and M6223-related grade ≥3 TEAEs in 4 (22.2%) pts. No MTD was identified. RDEs were 1600 mg Q2W or 2400 mg Q3W for M6223 monotherapy, and 1600 mg+1200 mg Q2W for M6223+BA. Half-life for the two monotherapy RDEs were 9.0 and 14.6 days, respectively, with moderate accumulation at the selected RDEs. Linear PK was observed for M6223 at 100-2400 mg Q2W and at 2400 mg Q3W; co-administration with BA did not change the PK profile of M6223. PD analyses in blood showed full and sustained TIGIT target occupancy, and depletion of suppressive Tregs at M6223 ≥900 mg. Paired biopsies in the M6223 group (900 mg Q2W, 1600 mg Q2W, 2400 mg Q3W; n=12) showed a trend of decrease in TIGIT+ and increase in CD226+ cells. Median overall survival was 7.6 months (95% CI: 4.9, 12.0) and median progression-free survival was 1.4 months (95% CI: 1.3, 1.8). No pt achieved an objective response (per RECIST v1.1); stable disease as the best response was observed in 13 (32.5%) pts in M6223 and 5 (27.8%) pts in M6223+BA. Conclusion: M6223 monotherapy and in combination with BA had a manageable safety profile, and RDEs for both mono- and combination therapy were defined. Further evaluation of M6223 is ongoing in combination with PD-L1 inhibitor avelumab (JAVELIN Bladder Medley; NCT05327530). Citation Format: Aung Naing, Meredith McKean, Anthony Tolcher, Anja Victor, Ping Hu, Keyvan Tadjalli Mehr, Thomas Kitzing, Daniel Holland, Emilia Richter, Lillian Siu. First-in-human trial of TIGIT inhibitor M6223 as monotherapy or in combination with bintrafusp alfa (BA) in patients (pts) with advanced solid unresectable tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT184.

Abstract CT033: Avelumab combined with regorafenib in solid tumors with tertiary lymphoid structures: A phase 2 REGOMUNE trial cohort

Abstract Background: Mature tertiary lymphoid structures (mTLS) predict improved outcome in patients treated with immune checkpoint inhibitors (ICIs). However, a significant proportion of patients with TLS-positive tumors do not respond to ICI when used as a single agent and may therefore benefit from combination therapy. The multikinase inhibitor, regorafenib, deplete regulatory T cells, an immune population associated with resistance to ICI in TLS-positive tumors. We report the results of the PD-L1 inhibitor avelumab combined with regorafenib in patients with mTLS-positive advanced solid tumors. Methods: ‘Regomune’ is an open-label, multicenter phase II study assessing the combination of avelumab (10mg/kg IV every 14 days) with regorafenib (160 mg daily for 3 weeks in a 4-week cycle) in patients with advanced mTLS-positive solid tumors. The mTLS status was centrally assessed as previously described (Vanhersecke et al Nature Cancer 2021). All patients had confirmed progressive disease at inclusion, based on a central review of imaging. The primary efficacy endpoint was a 6-month non-progression rate using RECIST v1.1 based on blinded central review. 29 assessable patients were deemed necessary, and to meet the primary endpoint, at least 8 patients needed to be progression-free at 6 months. Results: Between January 2021 and July 2022, 132 patients (5 centers) underwent mTLS screening. Of these, 55 (41.7%) were identified as mTLS+, and 38 were included in the study. The top five histological subtypes were MSS colorectal cancer (15.8%), sarcoma (13.1%), oesogastric (10.5%), biliary tract (7.9%), and pancreatic cancer (7.9%). The most frequent grade 3/4 adverse events were palmar-plantar erythrodysesthesia syndrome (23.7%), maculo-papular rash (18.4%), fatigue, and oral mucositis (7.9% each). No treatment-related deaths were reported. Of the 34 patients assessed for efficacy, 16 (47%) showed tumor shrinkage, with 9 achieving a partial response (26.7%) and 7 having stable disease (20.6%). The median duration of response was 6 months. Twelve patients (comprising various tumor types including MSS colorectal cancer, small bowel carcinomas, biliary tract cancer, sarcomas, thyroid and gynecological tumors.) were progression-free at 6 months, marking the study’s primary endpoint achievement. The median progression-free survival and overall survival were 3.6 months and 8.6 months, respectively. Spatial transcriptomics, multiplex immunofluorescence (IF) of tumor tissues, and comprehensive plasma proteomics analysis have collectively uncovered critical biomarkers that significantly determine both sensitivity and resistance to treatment. Conclusions: This is the first histology-agnostic clinical trial employing mTLS as a biomarker for patient selection for treatment with an immune checkpoint inhibitor-based regimen. Durable responses were recorded, even in cases typically resistant to immunotherapy, confirming the predictive value of mTLS. Trial Registration NCT03475953 Citation Format: Antoine Italiano, Sophie Cousin, Carine Bellera, Jean-Philippe Guegan, Jean-Philippe Metges, Antoine Adenis, Rastilav Bahleda, Philippe Cassier, Coralie Cantarel, Michele Kind, Jean Palussiere, Lucile Vanhersecke, Alban Bessede. Avelumab combined with regorafenib in solid tumors with tertiary lymphoid structures: A phase 2 REGOMUNE trial cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT033.

Modern diagnostics and treatment of Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer with epithelial and neuroendocrine differentiation, the incidence of which has increased substantially during the last decades. Risk factors include advanced age, fair skin type, UV exposure, and immunosuppression. Pathogenetically, a type caused by the Merkel cell polyomavirus is distinguished from a UV-induced type with a high tumor mutational burden. Clinically, MCC presents as a mostly painless, rapidly growing, reddish-violet tumor with a shiny surface, which is preferentially localized in the head-neck region and at the distal extremities. A reliable diagnosis can only be made based on histological and immunohistochemical features. At initial diagnosis, 20-26% of patients show locoregional metastases and 8-14% distant metastases, making staging examinations indispensable. If there is no clinical evidence of metastases, a sentinel lymph node biopsy is recommended. Essential columns of therapy are surgery, adjuvant or palliative radiotherapy and, in advanced inoperable stages, medicamentous tumor therapy. The introduction of immune checkpoint inhibitors has led to a paradigm shift, as they provide a considerably longer duration of response and better survival rates than chemotherapy. The PD-L1 inhibitor avelumab is approved for treatment of metastatic MCC in Germany, but the PD-1 antibodies pembrolizumab and nivolumab are also used with success. Adjuvant and neoadjuvant treatment concepts, immune combination therapies and targeted therapies as monotherapy or in combination with immune checkpoint inhibitors are in the clinical trial phase.

Circulating tumor cells (CTCs) dynamics after CDK4/6i for hormone-receptor positive (HR+) metastatic breast cancer (MBC): A biomarker analysis of the PACE randomized phase II study.

1059 Background: PACE is a multicenter randomized phase II trial investigating palbociclib (P) in combination with fulvestrant (F) after progression on any CDK4/6 inhibitor (CDK4/6i), with or without the PD-L1 inhibitor avelumab (A), in HR+/HER2- MBC. CTCs are rare cells in the blood stream whose detection is associated with worse outcome and treatment resistance. Methods: Eligible patients (pts) had HR+/HER2- MBC with prior progression after ≥ 6 months (mo) of AI and CDK4/6i for MBC, or during/within 12 mo in the adjuvant setting, with ≤ 1 prior chemotherapy for MBC. Pts were randomized 1:2:1 to F, F+P, or F+P+A. CTC detection and enumeration were performed utilizing CellSearch (Menarini Silicon Biosystems) at baseline (BL), at time of first tumor assessment (TTA1), and at progression. Results were dichotomized using the standard CTC threshold (≥ 5 CTCs/7.5 ml) into a novel prognostic classification: StageIVindolent and StageIVaggressive (Cristofanilli et al 2019). Concurrent ctDNA Sequencing was performed using Guardant360 (Guardant Health). Results: Of the 220 randomized pts, 203 (92%) had sample available for BL CTC enumeration, 155 had detectable CTCs (70.5%), and 99 (48.8%) were StageIVaggressive. De novo disease at initial diagnosis was associated with StageIVaggressive (47.5% vs 30.8% StageIVindolent), and distribution of visceral versus non-visceral disease was similar across the two CTCs groups. StageIVaggressive represented 38.3%, 54.8%, and 46.2% of the F, F+P and F+P+A treatment groups, respectively. BL CTCs were prognostic in the overall cohort; median PFS was 5.7mo vs 3.5mo for StageIVindolent vs StageIVaggressive (HR: 1.69, 90%CI 1.27,2.24, P<0.001). Median PFS for the F, F+P and F+P+A arms was 1.9mo, 4.6mo and 5.4mo in StageIVaggressive compared to 8.2mo, 5.3mo and 8.3mo in StageIVindolent. Among patients in the StageIVaggressive subgroup, the F+P and F+P+A arms demonstrated improved outcomes compared to F alone. (F+P vs F HR 0.43, 90% CI 0.25-0.71, and F+P+A vs F HR 0.26, 90% CI 0.14-0.49). No benefit of F+P or F+P+A over F was observed in the StageIVindolent subgroup (F+P vs F HR 1.45, 90% CI 0.87 - 2.40 and F+P+A vs F HR 1.06, 90% CI 0.61 - 1.84, each p(interaction)<0.01). Changes in StageIV CTC characterization (indolent vs aggressive) between BL and TTA1 among the subset of 175/203 pts with both timepoints available are reported. Conclusions: Baseline CTC enumeration is prognostic in patients receiving F with or without CDK4/6i. The StageIVaggressive subgroup may derive preferential benefit with combinations of F+P or F+P+A over F alone. Findings should be confirmed in other studies. ctDNA analyses are ongoing. Clinical trial information: NCT03147287 . [Table: see text]

Immune checkpoint inhibitor in high-risk oral potentially malignant disorders (IMPEDE study): An interim analysis on safety.

2595 Background: Oral Potentially Malignant Disorders (OPMD) represent the most common oral precancerous condition, with a variable risk of malignant transformation. The most effective biomarker in predicting malignant transformation risk is loss of heterozygosity (LOH). Patients (pts) carrying OPMD with LOH at 3p14 and/or 9p21 plus LOH at another locus have an expected 3-year risk of developing oral cancer of 35%. This chromosomal profile is found in about 30% of OPMD. IMPEDE is a phase II, open-label, single-arm trial designed to evaluate the efficacy of PD-L1 inhibitor avelumab in reverting cancer transformation risk in OPMD with LOH. In this analysis, we report the first safety results, while data about treatment activity need longer follow up. Methods: During the screening period, pts undergo OPMD biopsy. If pathological diagnosis of dysplasia is confirmed, LOH valuation is performed and in case of positivity of this biomarker, subjects receive a short course of immunotherapy with avelumab 800 mg every 2 weeks for 4 total administrations. Follow-up after last avelumab dose is performed monthly and adverse event data are collected at every visit. Six months after treatment start, surgery and LOH re-assessment are performed. Results: Between November 2020 and December 2022, 49 pts were screened in 8 Italian centers. Of these, 16 pts (33%) had a LOH and 12 received the treatment (3 males, median age 65.5 years, range 49-81). Nine out of 12 treated patients had a previous oral cancer. After a median follow up of 14 months, 39 adverse events (AE) of any grade were reported, of these 18 were considered as immune related AEs (irAE). The most frequent AEs was grade 1 (G1) oral pain (4/12 pts), managed with local painkillers. Only three G2 irAEs were reported, namely amylase/lipase increase, psoriasis and fever. No grade 3-4 AEs were described, and no patient had to stop immunotherapy because of toxicities. Local excision after immunotherapy was not delayed by any treatment toxicities. Conclusions: This is the first trial with immunotherapy in an enriched population of OPMD selected according to LOH. First results support the feasibility of this approach, showing that immunotherapy with avelumab is safe and does not compromise subsequent local surgery. Clinical trial information: NCT04504552 .

Abstract CT142: TALAVE: Induction talazoparib (tala) followed by combined tala and avelumab in patients (pts) with advanced breast cancer (ABC)

Abstract Background: PARP inhibitors (PARPi) significantly extend progression-free survival (PFS) compared to chemotherapy in pts with BRCA1/2 mutated (BRCA1/2m) ABC, but responses are not durable. PARPi activate the cGAS-STING pathway leading to increased PD-L1 expression and cytotoxic T-cell recruitment, creating a tumor microenvironment (TME) that may be more vulnerable to immunotherapy. This study was conducted to evaluate the safety, efficacy and effects on the TME of the PARPi tala combined with the PD-L1 inhibitor avelumab in ABC, and to assess the impact of BRCA1/2 status on clinical outcomes. Methods: TALAVE was an open-label, multi-institutional trial (NCT03964532) for pts with HER2-negative ABC. Pts were enrolled in two cohorts: cohort 1 - BRCA1/2m and HER2-negative ABC; cohort 2 - BRCA1/2 wildtype TNBC. Pts received a 4-week induction of tala (1mg po daily D1-D28), followed by a combination of daily tala and avelumab (800mg IV D1, D15). The primary objective was the safety and tolerability of the combination. Secondary objectives included ORR, OS and PFS. Pts underwent serial biopsies to investigate molecular signatures associated with BRCA status or clinical benefit using multiple omics techniques: RNA profiling by NanoString PanCancer IO 360™ Panel, GeoMx® Digital Spatial Profiler (DSP) Whole Transcriptome Atlas (WTA) and protein spatial analysis by multiplex immunofluorescence (mIF) and Cyclic Immunofluorescence (CyCIF). Results: 12 pts were enrolled in each cohort. In cohort 1, 5 pts had gBRCA1, 6 had gBRCA2 and 1 had sBRCA2 mutation. The median age was 50 [IQR:43-59.5]; all pts were female, with median of 1 prior therapy for ABC [IQR: 0-2.5]. 42% pts had prior platinum. ORR was 42% (83% in cohort 1; 0% in cohort 2). There were 10 PRs, all in cohort 1. mPFS was 5.1 months (mo) (95% CI: 3.7-7.3 mo); 9.3mo in cohort 1 and 2.9mo in cohort 2. 5 out of 24 pts remain on treatment, all in cohort 1. Treatment related adverse events (TRAEs) included anemia 33%, neutropenia 25% (gr3+ 13%), thrombocytopenia 21% (gr3+ 13%), fatigue 33% and nausea 29%. Other TRAEs gr3+ included dyspnea (4%) and AST elevation (4%). There were no gr5 events. RNA analysis showed that in cohort 1, tala monotherapy disrupted MMEJ, induced antiproliferative effects and expression of genes in the cGAS-STING pathway, including TBK1-mediated IRF3 activation, with downstream induction of T-cell, dendritic cell and cytokine gene expression. These effects were not seen in biopsies post tala monotherapy in cohort 2. mIF analyses demonstrated T-cell and macrophage infiltration in BRCA1/2m tumors. Analyses of post-combination biopsies is ongoing. Conclusions: There were no new safety signals of PARPi combined with immunotherapy. Responses were limited to pts with BRCA1/2m. RNA and protein analyses indicate cGAS-STING activation and immune cell infiltration in BRCA1/2m tumors, validating murine preclinical findings. Citation Format: Filipa Lynce, Kenichi Shimada, Xue Geng, Edward T. Richardson, Candace Mainor, Mei Wei, Julie M. Collins, Paula P. Pohlmann, Arielle L. Heeke, Kelly F. Zheng, Madeline Townsend, Jane Staunton, Stuart J. Schnitt, Joan S. Brugge, Hongkun Wang, Claudine Isaacs, Geoffrey I. Shapiro, Jennifer L. Guerriero. TALAVE: Induction talazoparib (tala) followed by combined tala and avelumab in patients (pts) with advanced breast cancer (ABC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT142.

Abstract 4387: Total toxicity burden of FDA approved immune checkpoint inhibitors in USA

Abstract Immune checkpoint inhibitors (ICIs) have revolutionized the treatment landscape for multiple cancers, demonstrating effective and durable responses and becoming the standard of care for a variety of malignancies. However, ICI-based treatment has resulted in the rise of unique immune-related adverse events (irAEs). To date, very little information is available on the frequency, significance, and management of single-organ or multiorgan irAEs in clinic. In this study, the irAEs associated with the treatment of seven FDA-approved ICIs, including three PD-1 inhibitors (cemiplimab, nivolumab and pembrolizumab), three PD-L1 inhibitors (atezolizumab, avelumab and durvalumab), and one CTLA4 inhibitor (ipilimumab), were analyzed based on the data of 149,303 report cases (January 1, 2015 - June 30, 2022) collected from FDA Adverse Events Reporting System (FAERS) public dashboard. Our data reveal that irAEs associated with the treatment of anti-PD-1 ICIs (e.g., pembrolizumab) require less hospital care resources compared with anti-PD-L1 and anti-CTLA4 ICIs. Tissue and organ toxicity of ICIs are age and gender specific. ‘Cardiac disorders’ is the main disorder caused by these ICIs in cancer patients aged 65-85, while ‘reproductive system and breast disease’ is the main disorder in cancer patients aged 18-64. There are risks of respiratory and urinary system toxicity in male patients and reproductive system toxicity in female patients when they receive the treatment of ICIs. Studies such as this one provide the statistical data for understanding patients at risk of developing irAEs, which will underscore the importance of further exploring research strategies to predict, detect, and mitigate toxicities from ICIs. Citation Format: Fan Yang, Chloe Shay, Zhaohui Qin, Nabil Saba, Yong Teng. Total toxicity burden of FDA approved immune checkpoint inhibitors in USA. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4387.

Patterns of toxicity burden for FDA-approved immune checkpoint inhibitors in the United States

BackgroundImmune-related adverse events (irAEs) are a common phenomenon in cancer patients treated with immune checkpoint inhibitors (ICIs). Surprisingly, the toxicity burdens of these irAEs have not been illustrated clearly. In this study, we analyzed irAEs for seven FDA-approved ICIs in cancer treatment to show the pattern of toxicity burden among cancer patients.MethodsirAEs associated with seven FDA-approved ICIs, including three PD-1 inhibitors (cemiplimab, nivolumab and pembrolizumab), three PD-L1 inhibitors (atezolizumab, avelumab and durvalumab), and one CTLA-4 inhibitor (ipilimumab), were analyzed based on data from 149,303 reported cases (from January 1, 2015 to June 30, 2022) collected from the FDA Adverse Events Reporting System (FAERS) public dashboard. Proportions of serious irAEs and correlations with tumor type, age and sex were assessed via R package and GraphPad software.ResultsirAEs related to anti-PD-1 ICIs required less hospital care resources compared with anti-PD-L1 and anti-CTLA-4 ICIs. Patients treated with pembrolizumab had relatively fewer serious cases. Treatment with ICIs led to the highest probability of serious irAEs in patients with lung cancer. ‘Respiratory, thoracic and mediastinal disorders’ and ‘gastrointestinal disorders’ were the two most common groups of disorders caused by the seven ICIs studied. ‘Cardiac disorders’ was the main type of disorders caused by these ICIs in cancer patients aged 65–85, while ‘reproductive system and breast disease’ was the main type of disorder in cancer patients aged 18–64. ‘Respiratory, thoracic, mediastinal diseases’ and ‘reproductive system and breast diseases’ were the main types of disorders associated with treatment with these ICIs in male and female patients, respectively.ConclusionTissue and organ toxicities of ICIs are age and sex specific. There are risks of respiratory and urinary system toxicity in male patients and reproductive system toxicity in female patients treated with the ICIs studied. Future studies on the toxicity burden of ICIs should incorporate age and sex differences to better understand the relevance of ICI toxicity burden to human immune function to develop appropriate tumor immune and therapeutic intervention strategies.

A phase I study of avelumab, palbociclib, and cetuximab in patients with recurrent or metastatic head and neck squamous cell carcinoma

ObjectivesWe aimed to test the safety of the CDK4/6 inhibitor palbociclib in combination with the EGFR inhibitor cetuximab and the PD-L1 inhibitor avelumab in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). Materials and MethodsThis phase I study enrolled eligible adult patients with R/M HNSCC into three sequential single dose-escalation cohorts of palbociclib (75, 100, and 125 mg) PO daily on days 1 to 21 of a 28-day cycle in combination with avelumab 10 mg/kg IV every 2 weeks and cetuximab 400 mg/m2IV on day 1, then 250 mg/m2weekly thereafter. The study followed a 3 + 3 design with no intra-patient escalation. The primary objective was to identify the recommended phase II dose (RP2D); secondary objectives included overall response rate (ORR), duration of response (DOR), progression free survival (PFS), and overall survival (OS). ResultsPalbociclib in combination with avelumab and cetuximab was well tolerated, with rash and fatigue being the most common adverse events. A single dose-limiting toxicity was observed at the 125 mg dose of palbociclib: a grade 3 infusion reaction related to cetuximab. The RP2D of palbociclib is 125 mg, with avelumab and cetuximab at standard doses. The ORR by RECIST v1.1 was 42 %, the median DOR and OS have not been reached. Median PFS was 6.5 months. ConclusionsThe combination of avelumab, cetuximab, and palbociclib was well tolerated and supports further evaluation in patients with R/M HNSCC.Clinical Trial Registration Number: NCT03498378.

19 (PB005) - DNA Damage Response (DDR) Basket of Baskets (D-BOB) Trial: Phase 1/2 Study of the ATR inhibitor (ATRi) berzosertib and PD-L1 inhibitor avelumab in patients (pts) with advanced solid tumors with DDR molecular alterations

Background: ATR is a central kinase involved in the DDR and replication stress response (RSR) and innate immune activation. This is the first report of the investigator-initiated phase 1/2 D-BOB trial (NCT04266912), funded by EMD Serono (CrossRef Funder ID: 10.13039/100004755).

Short-Interval, Low-Dose Peptide Receptor Radionuclide Therapy in Combination with PD-1 Checkpoint Immunotherapy Induces Remission in Immunocompromised Patients with Metastatic Merkel Cell Carcinoma.

Merkel cell carcinoma (MCC) is a neuroendocrine skin cancer of the elderly, with high metastatic potential and poor prognosis. In particular, the primary resistance to immune checkpoint inhibitors (ICI) in metastatic (m)MCC patients represents a challenge not yet met by any efficient treatment modality. Herein, we describe a novel therapeutic concept with short-interval, low-dose 177Lutetium (Lu)-high affinity (HA)-DOTATATE [177Lu]Lu-HA-DOTATATE peptide receptor radionuclide therapy (SILD-PRRT) in combination with PD-1 ICI to induce remission in patients with ICI-resistant mMCC. We report on the initial refractory response of two immunocompromised mMCC patients to the PD-L1 inhibitor avelumab. After confirming the expression of somatostatin receptors (SSTR) on tumor cells by [68Ga]Ga-HA-DOTATATE-PET/CT (PET/CT), we employed low-dose PRRT (up to six treatments, mean activity 3.5 GBq per cycle) at 3–6 weeks intervals in combination with the PD-1 inhibitor pembrolizumab to restore responsiveness to ICI. This combination enabled the synergistic application of PD-1 checkpoint immunotherapy with low-dose PRRT at more frequent intervals, and was very well tolerated by both patients. PET/CTs demonstrated remarkable responses at all metastatic sites (lymph nodes, distant skin, and bones), which were maintained for 3.6 and 4.8 months, respectively. Both patients eventually succumbed with progressive disease after 7.7 and 8 months, respectively, from the start of treatment with SILD-PRRT and pembrolizumab. We demonstrate that SILD-PRRT in combination with pembrolizumab is safe and well-tolerated, even in elderly, immunocompromised mMCC patients. The restoration of clinical responses in ICI-refractory patients as proposed here could potentially be used not only for patients with mMCC, but many other cancer types currently treated with PD-1/PD-L1 inhibitors.

Ramucirumab, avelumab, and paclitaxel (RAP) as second-line treatment in gastro-esophageal adenocarcinoma, a phase II trial of the Arbeitsgemeinschaft Internistische Onkologie (AIO).

4051 Background: Combination of ramucirumab and paclitaxel is a standard second line therapy in gastro-esophageal adenocarcinoma (GEAC) (RAINBOW trial, Wilke et al., 2014). We integrated the PD-L1 inhibitor avelumab into this regimen aiming for synergistic efficacy. Methods: In a multicenter phase II trial (NCT03966118) pts with metastatic GEAC, after progression on platinum / fluoropyrimidine based palliative 1st-line, ECOG 0 or 1, were treated with ramucirumab 8 mg/kg (d1,15) + avelumab 10 mg/kg (d1,15) + paclitaxel 80 mg/m² (d1,8,15), q4w. Sample size calculation was based on a Simon 2-stage design with overall survival rate at 6 months as the primary endpoint (H0≤50%, H1≥65%). Results: 60 pts were enrolled, 59 were evaluable (ITT), median age 64.0 yrs (range 18-81), male 80%, female 20%, primary gastric 52%, GEJ 48%, histology intestinal 59.6%, diffuse 24.6%, mixed 15.8%. Previous treatment with platin/fluoropyrimidine 100%, previous taxanes 66%. At central pathology MSI-H 7%, PD-L1 CPS < 5: 54%; ≥5: 41%, NA 5%. Response by investigator (%) CR 3.4, PR 27.1, SD 49.2, PD 20.3; DCR 79.7%, independent radiology review will be presented. DOR: 8.2 mo (95%CI 6.7-9.7), PFS 5.4 mo (95%CI 4.2-6.6); 6-mo OS rate 71.2%; 12-mo OS rate 45.8%; med OS (ITT) 10.6 mo (95%CI 8.2-13.1), med OS CPS < 5: 9.4 mo (95%CI 7.2-11.2), CPS ≥5: 14.0 mo (95%CI 12.8-15.3), translational data (ct-DNA) will be analysed. Treatment was generally well tolerated and no unexpected toxicities occurred: Grade 3/4 AE above 5%: anemia 5%, leucopenia 12%, neutropenia 22%, diarrhea 5%, pain 10%, peripheral neuropathy 10%, hypertension 5%, non-neutropenic infection 5% including 1 CTC grade 5 due to an esophago-tracheal fistula. Conclusions: The med OS of 10.6 mo (in a population of 66% pretreated with taxanes) compares very favourably to 8.6 mo in the Western population RAINBOW trial (Shitara et al., 2016) and 7.6 mo in the RAMIRIS trial (Lorenzen et al., 2022). PD-L1 CPS≥ 5 seems to predict for an even better efficacy (med OS 14.0 mo). Second-line RAP is a very efficacious and well tolerated combination. Clinical trial information: NCT03966118.

Immune Checkpoint Inhibitors in Cancer Therapy.

The discovery of immune checkpoint proteins such as PD-1/PDL-1 and CTLA-4 represents a significant breakthrough in the field of cancer immunotherapy. Therefore, humanized monoclonal antibodies, targeting these immune checkpoint proteins have been utilized successfully in patients with metastatic melanoma, renal cell carcinoma, head and neck cancers and non-small lung cancer. The US FDA has successfully approved three different categories of immune checkpoint inhibitors (ICIs) such as PD-1 inhibitors (Nivolumab, Pembrolizumab, and Cemiplimab), PDL-1 inhibitors (Atezolimumab, Durvalumab and Avelumab), and CTLA-4 inhibitor (Ipilimumab). Unfortunately, not all patients respond favourably to these drugs, highlighting the role of biomarkers such as Tumour mutation burden (TMB), PDL-1 expression, microbiome, hypoxia, interferon-γ, and ECM in predicting responses to ICIs-based immunotherapy. The current study aims to review the literature and updates on ICIs in cancer therapy.

The era of immuno-oncology in onco-urology: what have we achieved?
 The review of the symposium of the alliance between Merck and Pfizer held within the framework of the XXV Russian Oncology Congress. November 9, 2021

On November 9, 2021 in the framework of the XXV Russian Oncology Congress the symposium was held where the various issues of approaches of drug treatment and surgical treatment of metastatic renal cell carcinoma and urothelial cancer were discussed. New drugs are being appeared, large clinical studies are being conducted, new prospects for immunotherapy of malignant neoplasms are being developed, nowadays. One of the new options is immune checkpoint inhibitors. In the framework of the symposium were presented the results of two trials the JAVELIN Renal 101 and the JAVELIN Bladder 100, showing the efficacy and safety of the PD-L1 inhibitor avelumab. The symposium was supported by the alliance between Merck and Pfizer.

Avelumab Combined with Stereotactic Ablative Body Radiotherapy in Metastatic Castration-resistant Prostate Cancer: The Phase 2 ICE-PAC Clinical Trial

BackgroundImmune checkpoint inhibitor monotherapy in metastatic castration-resistant prostate cancer (mCRPC) has produced modest results. High-dose radiotherapy may be synergistic with checkpoint inhibitors. ObjectiveTo evaluate the efficacy and safety of the PD-L1 inhibitor avelumab with stereotactic ablative body radiotherapy (SABR) in mCRPC. Design, setting, and participantsFrom November 2017 to July 2019, this prospective phase 2 study enrolled 31 men with progressive mCRPC after at least one prior androgen receptor–directed therapy. Median follow-up was 18.0 mo. InterventionAvelumab 10 mg/kg intravenously every 2 wk for 24 wk (12 cycles). A single fraction of SABR (20 Gy) was administered to one or two disease sites within 5 d before the first and second avelumab treatments. Outcomes measurements and statistical analysisThe primary endpoint was the disease control rate (DCR), defined as a confirmed complete or partial response of any duration, or stable disease/non–complete response/non–progressive disease for ≥6 mo (Prostate Cancer Clinical Trials Working Group 3–modified Response Evaluation Criteria in Solid Tumours version 1.1). Secondary endpoints were the objective response rate (ORR), radiographic progression-free survival (rPFS), overall survival (OS), and safety. DCR and ORR were calculated using the Clopper-Pearson exact binomial method. Results and limitationsThirty-one evaluable men were enrolled (median age 71 yr, 71% with ≥2 prior mCRPC therapy lines, 81% with >5 total metastases). The DCR was 48% (15/31; 95% confidence interval [CI] 30–67%) and ORR was 31% (five of 16; 95% CI 11–59%). The ORR in nonirradiated lesions was 33% (four of 12; 95% CI 10–65%). Median rPFS was 8.4 mo (95% CI 4.5–not reached [NR]) and median OS was 14.1 mo (95% CI 8.9–NR). Grade 3–4 treatment-related adverse events occurred in six patients (16%), with three (10%) requiring high-dose corticosteroid therapy. Plasma androgen receptor alterations were associated with lower DCR (22% vs 71%, p = 0.13; Fisher’s exact test). Limitations include the small sample size and the absence of a control arm. ConclusionsAvelumab with SABR demonstrated encouraging activity and acceptable toxicity in treatment-refractory mCRPC. This combination warrants further investigation. Patient summaryIn this study of men with advanced and heavily pretreated prostate cancer, combining stereotactic radiotherapy with avelumab immunotherapy was safe and resulted in nearly half of patients experiencing cancer control for 6 months or longer. Stereotactic radiotherapy may potentially improve the effectiveness of immunotherapy in prostate cancer.

Abstract CT134: A phase I study of avelumab, palbociclib, and cetuximab (APC) in recurrent or metastatic head and neck squamous cell carcinoma (RM HNSCC)

Abstract Background: Checkpoint inhibitors have activity in RM HNSCC, but response rates to single agent therapy are low. Combination therapy may improve outcomes. We aimed to study a novel combination of palbociclib (P) and cetuximab (C) with the PD-L1 inhibitor avelumab (A) in RM HNSCC. Methods: Eligible patients (pts) with RM HNSCC received P in combination with A 10 mg/kg IV every 2 wks and C 400 mg/m2 IV x 1, then 250 mg/m2 weekly. The starting dose of P was 75 mg PO daily on days 1 to 21 of a 28 day cycle. The 3+3 dose escalation design included planned doses of P 100 mg and P 125 mg, with no intra-patient escalation. The primary objective was to identify the recommended phase II dose (RP2D); secondary objectives included response rate and progression free survival (PFS). Results: As of 10/15/20, 12 pts have been treated in 3 cohorts: P 75 mg PO daily (3 pts), 100 mg PO daily (3 pts), and 125 mg PO daily (6 pts). Median age was 56 yo, 92% were male, with 58% p16+, 25% p16-, 17% p16 unknown. One DLT was observed in cohort 3: a grade 3 infusion reaction related to C. The RP2D was P 125 mg, with A and C at standard doses. Other grade 3 AEs were leukopenia (4 pts), neutropenia (4 pts), acneiform rash (2 pts), cellulitis (1pt), increased WBC (1pt). One pt had grade 4 leukopenia. There were no grade 5 AEs. Tx related AEs occurring in > 30% of pts were: acneiform rash (11pts), fatigue (10pts), mucositis (7pts), dry skin (6 pts), decreased WBCs (5 pts), paronychia (5 pts), nausea (5pts), hypomagnesemia (4pts). Response rate by RECIST 1.1 was 42% (3 CRs, 2PRs); median duration of response has not been reached. Median PFS was 6.5 m. Reasons for discontinuation were disease progression (8 pts), pt choice (1 pt). 3 patients remain on therapy (after 20, 15, and 9 months). Conclusions: The combination of APC was well tolerated in patients with RM HNSCC; no unexpected toxicities were seen. The RP2D is A 10 mg/kg every 2 wks, C 400 mg/m2 x 1 then 250 mg/m2 wkly, and P 125 mg daily, 3 wks on, one wk off. Promising response rates were seen, and several pts have had durable responses. These data support further development of this combination. Biomarker analyses on tissue and blood are ongoing. NCT03498378. Citation Format: Kathryn A. Gold, Assuntina Sacco, Julie Bykowski, Gregory Daniels, Emily Pittman, Karen Messer, Ruifeng Chen, Ezra Cohen. A phase I study of avelumab, palbociclib, and cetuximab (APC) in recurrent or metastatic head and neck squamous cell carcinoma (RM HNSCC) [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 CT134.

Comparative efficacy of treatments for previously treated patients with advanced esophageal and esophagogastric junction cancer: A network meta-analysis.

It remains unclear which treatment is the most effective for previously treated patients with advanced esophageal and esophagogastric junction (EGJ) cancer. We conducted a network meta-analysis to address this important issue. PubMed, Embase, Cochrane Library, and Web of Science databases were searched for relevant phase II and III randomized controlled trials (RCTs). Overall survival (OS) was the primary outcome of interest, which was reported as hazard ratio (HR) and 95% confidence intervals (CIs). Sixteen RCTs involving 3372 patients and evaluating 15 treatments were included in this network meta-analysis. Ramucirumab+chemotherapy (CT) (HR = 0.52, 95% CI: 0.35-0.77) and use of programmed death receptor 1 (PD-1) inhibitors, including camrelizumab (HR = 0.71, 95% CI: 0.57-0.88), sintilimab (HR = 0.70, 95% CI: 0.50-0.98), nivolumab (HR = 0.76, 95% CI: 0.62-0.94), and pembrolizumab (HR = 0.84, 95% CI: 0.72-0.98), conferred better OS than CT; however, this OS benefit was not observed for PD-L1 inhibitor (avelumab) and other target agents (trastuzumab, everolimus, gefitinib, and anlotinib). In subgroup analysis, ramucirumab+CT and pembrolizumab showed significant improvement in OS, when compared to CT, in esophageal/EGJ adenocarcinoma (AC) cases; moreover, all PD-1 inhibitors had significant OS advantage over CT in treating esophageal squamous cell carcinoma (SCC). Based on treatment ranking in terms of OS, ramucirumab+CT and camrelizumab were ranked the best treatments for patients with AC and SCC, respectively. Ramucirumab+CT and PD-1 inhibitors were superior to CT for previously treated cases of advanced esophageal/EGJ cancer. Ramucirumab+CT seemed to be the most effective treatment in patients with esophageal/EGJ AC, while use of PD-1 inhibitors, especially camrelizumab, was likely to be the optimal treatment in patients with esophageal SCC.

A phase 1b study of novel immunogenic cell death inducer PT-112 plus PD-L1 inhibitor avelumab in metastatic castrate-resistant prostate cancer (mCRPC) patients.

e17025 Background: PT-112 is a novel pyrophosphate-platinum conjugate that induces immunogenic cell death, reaches highest concentrations in bone (osteotropism), and synergizes with immune checkpoint inhibitors (ICIs) in preclinical models. Phase I studies in solid tumors, as monotherapy and in combination with PD-L1 inhibitor avelumab (“PAVE”), as well as in multiple myeloma as monotherapy have demonstrated that PT-112 is well-tolerated and active. We present updated safety and exploratory efficacy findings in a mCRPC sub-population treated with PAVE, including a cohort of patients at a lower-frequency dosing schedule. Methods: A total of 32 mCRPC patients (pts) received 800 mg of avelumab on days 1 and 15 of a 28-day cycle, of whom 18 received PT-112 on days 1, 8 and 15 at 200mg/m2 (n = 17) or 150 mg/m2 (n = 1); a separate cohort of 14 received PT-112 on days 1 and 15 at 300 mg/m2 (n = 13) or 200mg/m2 (n = 1). Results: Median age was 68 (range 47-87) and number of prior lines of therapy (Tx) was 7 (2-12), including prior platinum-containing therapy in 11 (34%) and ICI Tx in 9 pts (28%). Baseline grade 2 anemia was seen in 7 (22%) pts. The most common treatment-related adverse events (TRAEs) were anemia (47%) and thrombocytopenia (41%); 23 pts (72%) had ≥1 grade 3-4 TRAE, with no cases of bleeding, sepsis, or grade 5 TRAEs. Antitumor effects included 8 (25%) pts with a PSA reduction of ≥50% (PSA50); 5 (16%) were maintained through ≥1 follow-up. Of ten pts with RECIST-measurable disease, 3 had tumor volume reductions, one with a confirmed partial response (PR). Twenty-four (75%) pts experienced a reduction in serum alkaline phosphatase (ALP) (median reduction 15%), and improvement in patient-reported pain and quality of life was observed. For the 13 pts given 300 mg/m2 PT-112 bi-weekly, 7 (54%) had prior platinum-containing Tx and 4 (31%) had baseline grade 2 anemia. The most common TRAEs were anemia (69%) and thrombocytopenia (54%), with 11 (85%) pts having ≥1 grade 3-4 TRAE. Four pts (31%) had PSA50 reductions; 3 (23%) were maintained through ≥1 follow-up. Conclusions: PAVE is safe and generally well tolerated in mCRPC patients at the doses and schedules tested, providing meaningful antitumor effects in heavily pre-treated patients, including tumor volume, PSA and ALP reductions. Reductions in ALP may be indicative of anti-cancer activity at bone sites of disease. Although the sample sizes are small, the frequency of confirmed PSA50 responses and of grade 3-4 TRAEs was slightly higher in the group receiving biweekly 300 mg/m2 PT-112, and higher rates of TRAEs may be explained by higher baseline anemia and/or prior platinum Tx. Further clinical investigation of the combination of PT-112 plus ICIs in a less heavily pre-treated mCRPC population is warranted. A phase 2 study of PT-112 monotherapy in mCRPC is ongoing. Clinical trial information: NCT03409458.

Efficacy of the PD-L1 inhibitor avelumab in neuroendocrine or aggressive variant prostate cancer: Results from a phase II, single-arm study.

89 Background: Men with metastatic neuroendocrine/small cell and aggressive variant prostate cancer (NEPC/AVPC) have poor outcomes despite platinum and taxane chemotherapy. These tumors share common features with small cell lung cancer, including higher tumor mutational burden and genomic alterations, and thus may be responsive to immunotherapy. Methods: We conducted a single arm, 2-stage phase II investigator-sponsored trial, (PICK-NEPC, NCT03179410) with the PD-L1 inhibitor avelumab in patients with NEPC/AVPC. NEPC/AVPC was defined either by histologic criteria (neuroendocrine or small cell features) by central pathology review or by aggressive variant clinical criteria (prior progression on abiraterone or enzalutamide with liver metastasis, bulky radiographic progression and low PSA, or high serum LDH). Prior chemotherapy or hormonal therapy was allowed. Avelumab 10 mg/kg IV every 2 weeks was administered until progression or unacceptable toxicity with ongoing ADT. The primary endpoint was overall response rate (ORR) defined by modified PCWG3 and iRECIST criteria. Results: We consented 19 men with AVPC/NEPC, and 15 initiated treatment with avelumab. The median age was 71 (range 51-85), and 27% had neuroendocrine or small cell histology, while 73% met AVPC clinical criteria with adenocarcinoma histology. Men had received a median of two prior systemic therapies (range 1-3) including carboplatin (27%), docetaxel (73%), enzalutamide (67%), and abiraterone (47%). Median PSA was 54 ng/mL (range 0-393) and 73% had liver metastasis. The ORR by iRECIST was 6.7% (95% CI 0-32%) with 1 CR, 0 PRs, 3 (20%) with stable disease, and 11 (73%) with progressive disease. The patient with a CR had NEPC with a CNS metastasis that was found to be MSI-high/TMB-high due to a somatic MSH2 alteration; he finished 12 months of avelumab and maintains a durable CR and undetectable PSA 6 months after completing all therapy including ADT. Median radiographic progression free survival was 1.8 months (95% CI 1.6-2.0 mo) and median time on therapy was 56 days (range 28-356). Median overall survival was 7.4 mo (85% CI 2.8-12.5 mo). Two grade 3 adverse events (abdominal pain due to hepatic disease progression versus immune hepatitis and pericarditis), and one grade 4 (immune hepatitis) adverse event were attributed to avelumab with no grade 5 adverse events. Grade 1 or 2 infusion-related reactions were experienced by 9 (60%). Conclusions: PD-L1 inhibition with avelumab demonstrated limited clinical efficacy in men with metastatic NEPC/AVPC other than in those with MSI-high disease. Further research is needed into mechanisms of immune evasion in NEPC/AVPC to develop novel immunotherapies. Clinical trial information: NCT03179410.