PD-L1 Combined Positive Score Research Articles

A systematic review of neoadjuvant and definitive immunotherapy in locally advanced head and neck squamous cell carcinoma.

Patients with locally advanced head and neck squamous cell carcinoma (HNSCC) require multi-modality treatment. Immune checkpoint inhibitors (ICIs) are now standard of care in management of recurrent/metastatic HNSCC. However, its role in the definitive and neoadjuvant setting remains unclear. A literature search was conducted that included all articles investigating ICI in untreated locally advanced (LA) HNSCC. Data was extracted and summarised and rated for quality using the Cochrane risk of bias tool. Of 1086 records, 29 met the final inclusion criteria. In both concurrent and neoadjuvant settings, the addition of ICI was safe and did not delay surgery or reduce chemoradiotherapy completion. In the concurrent setting, although ICI use demonstrates objective responses in all published trials, there has not yet been published data to with PFS or OS benefit. In the neoadjuvant setting, combination ICI resulted in superior major pathological response rates compared to ICI monotherapy without a significant increase adverse event profiles, but its value in improving survival is not clear. ICI efficacy appears to be affected by tumour characteristics, in particular PD-L1 combined positive score, HPV status and the tumour microenvironment. There is significant heterogeneity of ICI use in untreated LA HNSCC with multiple definitive concurrent and neoadjuvant protocols used. Resultantly, conclusions regarding the survival benefits of adding ICI to standard-of-care regimens cannot be made. Further trials and translational studies are required to elucidate optimal ICI sequencing in the definitive setting as well as better define populations more suited for neoadjuvant protocols.

Genetic and immune microenvironment characterization of HER2-positive gastric cancer: Their association with response to trastuzumab-based treatment.

We aimed to determine the molecular and immune microenvironment characteristics of HER2-positive gastric cancer (GC) related to the patient's response to first-line trastuzumab-based treatment. Eighty-three cases of HER2-positive advanced gastric adenocarcinoma patients treated with trastuzumab were enrolled. Targeted deep sequencing and transcriptome analysis were performed on selected 21 cases (exploration cohort) along with two post-treatment samples. The results were compared between patients progressed before 6 months (Group 2) and others (Group 1), and were validated by FISH and immunohistochemistry in total cohort. Tumor-infiltrating immune cells were evaluated using RNA sequencing data and multiplex immunohistochemistry. Progression-free survival (PFS) analysis was performed. Group 1 showed frequent amplification of G1/S cell cycle checkpoint-related genes and upregulated KEGG pathways related to cell proliferation. In contrast, Group 2 had more frequent EGFR, HER3, and MET amplification and higher RNA expression in immune-related KEGG pathways than Group 1. In total cohort, significant predictors of better PFS were cell cycle-related including CCNE1 amplification, Cyclin A and PLK1 overexpression, and decreased Cyclin D3 and HER3 expression (p< 0.05), or immune-related including high density of CD3- CD57+ NK cells and PD-L1 combined positive score ≥5 (p< 0.05). The best prognostic predictors were a combination of Cyclin A, Cyclin E, p21, and HER3 (p< 0.001). HER2-positive GC with favorable response to trastuzumab were characterized by cell cycle-related gene alterations and increased CD3- CD57+ NK cell infiltration. These findings would be helpful to the fine modulation of therapeutic strategies for patients with HER2-positive GC.

The molecular landscape of breast mucoepidermoid carcinoma.

Mucoepidermoid carcinoma (MEC) of the breast is an extremely rare salivary gland-type tumor characterized by epidermoid, basaloid, intermediate, and/or mucinous cells arranged in solid and cystic patterns. Despite their triple-negative phenotype, breast MECs are generally considered low-risk malignancies but their biology is largely unexplored; therefore, guidelines for clinical management are lacking. Here, we sought to characterize the molecular landscape of breast MECs. Thirteen cases were histologically reviewed, characterized for tumor-infiltrating lymphocytes (TILs), and were subjected to immunohistochemistry for programmed death-ligand 1 (PD-L1, clone 22C3), EGFR, and amphiregulin (AREG). Rearrangements in MAML2 and EWSR1 were investigated by fluorescent in situ hybridization. Targeted next-generation sequencing of 161 genes was performed on eight cases. Most MECs had low histological grade (n= 10, 77%), with the presence of TILs (n= 9/12; 75%) and PD-L1 combined positive score ranging from 10 to 20 (n= 4/6; 67%). All cases showed EGFR and AREG overexpression and were fusion negative. Enrichment of genetic alterations was observed in PI3K/AKT/mTOR and cell cycle regulation pathways, while only one case harbored TP53 mutations. This is the first study providing extensive molecular data on breast MECs and the largest collection of cases available to date in the literature. Breast MECs lack TP53 mutations found in high-grade forms of triple-negative breast cancers and MAML2 or EWSR1 rearrangements pathognomonic of salivary MECs. Triple-negativity and PD-L1 positivity suggest a window of opportunity for immunotherapy in these patients. The EGFR/AREG axis activation, coupled with the mutational patterns in PI3K/AKT/mTOR and cell cycle pathways warrants caution in considering MECs as low-risk neoplasms.

Retrospective Analysis of the Predictive Value of 18F-FDG PET/CT Metabolic Parameters for PD-L1 Expression in Cervical Cancer

Immunotherapy targeting PD-1/PD-L1 has been proven to be effective for cervical cancer treatment. To explore non-invasive examinations for assessing the PD-L1 status in cervical cancer, we performed a retrospective study to investigate the predictive value of 18F-FDG PET/CT. The correlations between PD-L1 expression, clinicopathological characteristics and 18F-FDG PET/CT metabolic parameters were evaluated in 74 cervical cancer patients. The clinicopathological characteristics included age, histologic type, tumor differentiation, FIGO stage and tumor size. The metabolic parameters included maximum standard uptake (SUVmax), mean standard uptake (SUVmean), total lesion glycolysis (TLG) and tumor metabolic volume (MTV). In univariate analysis, SUVmax, SUVmean, TLG, tumor size and tumor differentiation were obviously associated with PD-L1 status. SUVmax (rs = 0.42) and SUVmean (rs = 0.40) were moderately positively correlated with the combined positive score (CPS) for PD-L1 in Spearman correlation analysis. The results of multivariable analysis showed that the higher SUVmax (odds ratio = 2.849) and the lower degree of differentiation (Odds Ratio = 0.168), the greater probability of being PD-L1 positive. The ROC curve analysis demonstrated that when the cut-off values of SUVmax, SUVmean and TLG were 10.45, 6.75 and 143.4, respectively, the highest accuracy for predicting PD-L1 expression was 77.0%, 71.6% and 62.2%, respectively. The comprehensive predictive ability of PD-L1 expression, assessed by combining SUVmax with tumor differentiation, showed that the PD-L1-negative rate was 100% in the low probability group, whereas the PD-L1-positive rate was 84.6% in the high probability group. In addition, we also found that the H-score of HIF-1α was moderately positively correlated with PD-L1 CPS (rs = 0.51). The SUVmax and differentiation of the primary lesion were the optimum predictors for PD-L1 expression in cervical cancer. There was a great potential for 18F-FDG PET/CT in predicting PD-L1 status and selecting cervical cancer candidates for PD1/PD-L1 immune checkpoint therapy.

Abstract P1-14-05: Pembrolizumab and Oral Metronomic Cyclophosphamide in Patients with Chest Wall Breast Cancer (PERICLES): an immune-biomarker analysis of tumor infiltrating lymphocytes (TILs) and programmed cell death ligand protein 1 (PD-L1)

Abstract Background: Breast cancer (BC) with lymphangitic spread to the chest wall is a rare clinical entity affecting about 2% of pts, with poorer survival outcomes. A brisk immune infiltrate is typically reported, with up-regulation of inflammation and immune-tolerogenic genes. PERICLES clinical trial is testing the administration of pembrolizumab 200 mg Q3w plus cyclophosphamide 50 mg daily for BC with chest wall disease. In this exploratory biomarker analysis, we assessed the prevalence of the TILs score and the PD-L1 combined positive score (CPS) obtained from skin biopsies performed at screening. Methods: PERICLES (NCT03971045) is a single-center, single-arm, interventional phase 2 trial. Main inclusion criteria: histologically confirmed, inoperable, locally recurrent and/or metastatic BC with lymphangitic spread to the chest wall (including and not limited to inflammatory BC); PD-L1 positive (CPS≥1; 22C3 pharmDx®) and/or TILs positive (≥1% of CD3 or CD20-positive cells) disease on skin biopsy obtained at screening; progression to at least one prior cytotoxic treatment; no prior immune checkpoint inhibitors. The primary endpoint is objective response rate as per immune-related RECIST criteria. 46 pts will be required for the study to power for the primary hypothesis. In this analysis, we describe the baseline immune-biomarker status, in the overall population enrolled based on hormone receptor status and HER2. Correlative analyses were provided (significance at p-value&amp;lt; 0.05). Results: 37 pts were screened with skin biopsy of the chest wall disease (June 2020-June 2022). Biopsy and biomarker analysis were successful in 35 pts. Median age was 58 years (range: 35-79). Among the 35 pts included in the biomarker analysis, 25 (71%) pts had visceral disease and 20 (57%) had skin metastases at the diagnosis of metastatic disease; median number of previous lines of therapies was 4 (range: 1-12) and of chemotherapies was 4 (range: 1-10). 2 (6%) pts had HER2-positive disease, 13 (37%) HR-positive/HER2-negative disease, and 20 (20%) had triple-negative breast cancer (TNBC). TILs and PD-L1 CPS were &amp;lt; 1 in 15 (43%) pts; 20 pts (57%) were eligible for CPS and/or TILs criteria: 16 (43%) were both PD-L1 positive and TILs positive, 4 only PD-L1 positive. Median PD-L1 CPS score was 5 (range: 0-80%) in the overall population and 17 (range: 2-80%) in eligible patients; 16/35 pts (43%) had CPS≥10. Median TILs score was 0% (range: 0-55%) in the overall population, 0% (range: 0-40%) in the HER2-negative (n=16), 0% (range 0-20%) in the HER2-low (n=18), and 37.5% (range 20-55%) in the HER2-positive (n=2). No significant differences in baseline characteristics were found between positive and negative biopsies (Table). Considering only the TILs, a statistically significant correlation between HER2-positive status and TILs score was demonstrated (p&amp;lt; 0.001); no other correlations between receptor status (estrogen receptor, progesterone receptor, HER2) and PD-L1 CPS or TILs emerged. Conclusions: 57% of patients with chest wall BC have skin metastases positive for PD-L1 CPS and/or TILs score ≥1%. To our knowledge, these are the first prospective data on the prevalence of PD-L1 and TILs in metastatic BC with lymphangitic spread to the chest wall, highlighting potential actionability through therapeutic strategies with new immune-oncology agents in this setting. Table: Characteristics of patients included in the biomarker analysis (n=35) *Calculated with T test or Fisher’s exact test, as appropriate. Keys: BC, breast cancer; CPS, combined positive score; CT, chemotherapy; HR; hormone receptor; n, number; NA; not available; PD-L1, Programmed cell death ligand protein 1; TILs, tumor infiltrating lymphocytes; TNBC, triple negative breast cancer. Citation Format: Carmine Valenza, Pier Paolo Maria Berton Giachetti, Paola Zagami, Eleonora Nicolò, Dario Trapani, Laura Boldrini, Beatrice Taurelli Salimbeni, Liliana Ascione, Gabriele Antonarelli, Chiara Corti, Angela Esposito, Carmen Criscitiello, Nicola Fusco, Giuseppe Curigliano. Pembrolizumab and Oral Metronomic Cyclophosphamide in Patients with Chest Wall Breast Cancer (PERICLES): an immune-biomarker analysis of tumor infiltrating lymphocytes (TILs) and programmed cell death ligand protein 1 (PD-L1) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-14-05.

Abstract P2-23-17: Programmed death ligand-1 expression in triple-negative breast cancer from Nigeria

Abstract Introduction: The incidence of triple negative breast cancer (TNBC) in West Africa appears to mirror the higher incidence of the disease among African American women in the United States. However, there remains a paucity of molecular data on TNBC from sub-Saharan Africa, despite the emergence of effective immunotherapies. Methods: Consecutive patients diagnosed with invasive breast cancer between March 2018-Jan 2020 were identified from a prospective clinical database and paired biobank at Obafemi Awolowo University Teaching Hospital (OAUTH). All specimens were processed and fixed in formalin within 60 minutes of excision by a trained pathologist. Tissue sections (4μm thick) representative of tumor were selected for routine evaluation of estrogen, progesterone and human epidermal growth factor receptor-2 expression by immunohistochemistry. This was performed at OAUTH with adequate controls according to the ASCO/CAP guidelines and verified at an outside institution for quality assurance. Additional sections from the FFPE blocks of TNBC specimens were further stained using the Dako PharmDx 22C3 PD-L1 commercial assay according to manufacturer protocols at Dalhousie University. External on-slide controls included tonsil, PD-L1 negative TNBC, and PD-L1 positive TNBC. PD-L1 expression was scored using the combined positive score (CPS), which is the number of 22C3 staining tumour cells, lymphocytes, and macrophages divided by the number of viable tumour cells, multiplied by 100. The threshold for a positive result was a CPS of ≥10 as per manufacturer instructions and institutional protocol. Research ethics board approval as well as data and material transfer agreements between institutions was obtained for this study. Results: From 85 cases, 32 were TNBC (37.6%). The mean age and BMI were 49.6±SD 7.7 and 26.2±5.7, respectively. The majority of patients presented with locally advanced disease (64.2% Stage III, 14.2% Stage IV). Seventy-nine percent (78.5%) of patients received an average of five cycles of neoadjuvant chemotherapy (SD 2.3). From 32 TNBC specimens, 27 had available FFPE tissue blocks, and of those, 24 had interpretable PD-L1 IHC for inclusion in the analysis. A total of 37.5% (9/24) of cases demonstrated a CPS ≥10. Conclusions: Over a third of breast cancer specimens in this Nigerian cohort were triple negative, 37.5% of which had PD-L1 CPS scores of ≥10. These results suggest a large proportion of patients in Nigeria may benefit from access to immunotherapy. This is the first reported incidence of PD-L1 expression in breast cancer from sub-Saharan Africa. Citation Format: Olalekan Olasehinde, Funmilola Wuraola, Aleksandra Kajetanowicz, Gilllian Bethune, Marcia Edelweiss, Peter Ntiamoah, Oluwole Odujoko, Avinash Sharma, Victoria Mango, Peter Kingham, Olusegun Alatise, Gregory Knapp. Programmed death ligand-1 expression in triple-negative breast cancer from Nigeria [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-23-17.

The clinical impact of testing for biomarkers in gastric cancer patients: a real-world cohort.

In gastric cancer (GC), HER2 was the first biomarker for guided therapy registered for clinical use. Considering the recent approvals of immune check-point blockade (ICB) in gastro-oesophageal cancers, testing for mismatch repair deficiency (dMMR), Epstein-Barr virus (EBV) and PD-L1 combined positive score (CPS) is becoming increasingly important. Here we describe a real-world cohort on biomarker assessment in GC patients. Patients diagnosed with GC between 2017 and 2021 were included. Biomarker results were retrieved from electronic patient files. PD-L1 CPS was determined retrospectively on dMMR and EBV-positive (EBV+) tumours. Data on genomic sequencing were analysed separately. Of 363 patients identified, 45% had metastatic disease. In 335 patients (92%) at least one biomarker was tested. The prevalence of HER2+, dMMR and EBV+ tumours was 10% (32 of 319), 7% (20 of 294) and 1% (three of 235), respectively. Of the dMMR and EBV+ tumours, 95% had a PD-L1 CPS ≥ 5. Therapeutic strategy was adjusted in 31 of 55 patients and consisted of anti-HER2 therapies as well as ICB in clinical trials. Genomic alterations were found in 44 of 60 tested patients. TP53 (73%) and PIK3CA (20%) mutations were most common, followed by KRAS mutations (11%) and amplifications (11%). In this real-world cohort, testing for HER2, dMMR and EBV status affected treatment decisions in 56% of the patients. Although most dMMR and EBV+ tumours had a PD-L1 CPS ≥ 5, not all patients with a high probability of treatment response are identified. Based on these results, a stepwise diagnostic strategy is proposed.

Perioperative enfortumab vedotin (EV) plus pembrolizumab (pembro) versus chemotherapy in cisplatin-eligible patients (pts) with muscle-invasive bladder cancer (MIBC): Phase 3 KEYNOTE-B15/EV-304.

TPS588 Background: Neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy + pelvic lymph node dissection (RC+PLND) is the standard of care for cisplatin-eligible pts with MIBC; however, up to 50% of pts will experience disease recurrence or progression following treatment. Pembro and EV monotherapies are approved for use in select pts with metastatic urothelial carcinoma (mUC). Furthermore, results of the phase 1/2 KEYNOTE-869/EV-103 study showed encouraging antitumor activity and an acceptable safety profile with first-line combination therapy EV + pembro in cisplatin-ineligible pts with mUC. The open-label, multicenter, phase 3, randomized KEYNOTE-B15/EV-304 study (NCT04700124) will compare the efficacy and safety of perioperative EV + pembro versus neoadjuvant cisplatin-based chemotherapy in cisplatin-eligible pts with MIBC. Methods: Eligible pts will have histologically confirmed UC/MIBC (T2-T4aN0M0 or T1-T4aN1M0) with predominant urothelial histology (≥50%), nonmetastatic disease (N≤1, M0) confirmed by blinded independent central review (BICR), ECOG performance status of 0-1, no prior systemic therapy for MIBC, and agree to undergo curative RC+PLND. Approximately 784 pts will be randomly assigned 1:1 to Arm A (4 cycles of neoadjuvant EV + pembro, followed by RC+PLND, followed by 5 cycles of adjuvant EV + 13 cycles of adjuvant pembro) or Arm B (4 cycles of neoadjuvant chemotherapy [gemcitabine + cisplatin] followed by RC+PLND, followed by observation). Neoadjuvant and adjuvant pembro 200 mg + EV 1.25 mg/kg will be administered intravenously every 3 weeks (Q3W) on day 1 (pembro + EV) and day 8 (EV) of each cycle. Neoadjuvant chemotherapy is gemcitabine 1000 mg/m2 + cisplatin 70 mg/m2 Q3W on day 1 (gemcitabine + cisplatin) and day 8 (gemcitabine) of each cycle. Stratification factors are disease stage (T2N0 vs T3/T4aN0 vs T1-T4aN1), PD-L1 combined positive score (≥10 vs &lt;10), and geographic region (United States vs European Union vs most of the world). Imaging by CT (preferred) or MRI will be performed ≤6 weeks before cystectomy and 6 weeks after cystectomy. Imaging will occur following cystectomy then Q12W through year 2 and at discontinuation, then Q24W in year 3 and beyond. Adverse events (AEs) will be monitored throughout the study and for 30 days following cessation of treatment (90 days for serious AEs). The primary end points are pathologic complete response rate and event-free survival by BICR. Secondary end points are OS, DFS, pathologic downstaging rate, safety and tolerability, and patient-reported outcomes. KEYNOTE-B15/EV-304 is enrolling in Africa, Asia, Australia, Europe, and North America. © 2021 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2021 ASCO Annual Meeting. All rights reserved. Clinical trial information: NCT04700124 .

Utility of pre- and post-pembrolizumab (Pembro) Vesical Imaging–Reporting and Data System (VIRADS) to predict the pathological response in muscle-invasive urothelial bladder cancer (MIBC): An analysis of the PURE-01 cohort.

552 Background: The possibility to predict the pathologic complete response (pT0) or downstaging (pT≤1) after neoadjuvant therapy may have profound impact on the management of MIBC and orient next-generation bladder-sparing trials. The VIRADS is a standardized reporting system that uses mpMRI parameters to predict the probability of MIBC. No studies have analyzed the ability of VIRADS to predict the pT0 or pT≤1 response post-immunotherapy (IO). Methods: In PURE-01 patients (pts) were staged with bladder multiparametric magnetic resonance imaging (mpMRI: T2-weighted imaging, diffusion-weighted imaging, dynamic contrast enhancement) before and after treatment (3 cycles of pembro) prior to radical cystectomy (RC). All mpMRI scans were centrally reviewed. Logistic regression models analyzed pre- and post-pembro VIRADS against pT≤1 (primary endpoint) and pT0 (secondary endpoint). VIRADS scores were dichotomized between 0-3 and 4-5. Covariates included cT-stage, age, gender, PD-L1 combined positive score (CPS) and tumor mutational burden (TMB). Results: In total, 58 pts were had centrally-reviewed MRI scans (N=116 mpMRI), treated between 02/17 and 08/18. Demographic characteristics and outcomes were generally similar between the all-treated and VIRADS-evaluable populations of PURE-01. Median age was 65 years, 52 (89%) had pure/predominant urothelial carcinoma (UC) histology, 25 (43.1%) had cT3-4N0 MIBC. Pre-pembro: 8 pts (13.8%) had no measurable disease (VIRADS=0), 20 (34.5%) a VIRADS 1-3 score, and 30 (51.7%) had a VIRADS 4-5 score. Six pts (10.3%) had a downstage from VIRADS 4-5 to VIRADS 0-3 post-pembro. Both pre-pembro and post-pembro VIRADS 0-3 scores were significantly associated with pT≤1 endpoint on multivariable analyses (MVA): the strongest effect was seen with post-pembro VIRADS 0-3 against pT≤1 response (OR: 30.2, 95%CI: 6.2-223.2, p&lt;0.0001). The AUC of this model was 0.92. Regarding pre-pembro VIRADS 0-3: OR: 4.35, 95%CI: 1.1-19.7, p=0.04; AUC: 0.83. CPS was another significant variable for pT≤1 endpoint only in MVA using pre-pembro VIRADS 0-3 (OR: 1.02, 95%CI: 1-1.05, p=0.02). Post-pembro VIRADS 0-3 was also associated with pT0 on MVA (OR: 4.59, 95%CI: 1.2-19.6, p=0.02; AUC: 0.78), whereas pre-pembro VIRADS was not (p=0.13). Mean apparent diffusion coefficients (ADC) were similar between pre- and post-pembro lesions (0.86 vs 0.87). Conclusions: To our knowledge, this is the first evidence establishing the predictivity of the VIRADS score towards the pathological downstaging, both in the pre and post IO settings. Post-pembro VIRADS, along with the combination of pre-pembro VIRADS and CPS, emerged as the strongest features based on which selecting pts for bladder-sparing strategies. Clinical trial information: NCT02736266 .

The utility of PD-L1 as a prognostic marker in pancreatic ductal adenocarcinoma (PDAC).

753 Background: The PDAC tumor microenvironment is notoriously immune suppressive, and PD-L1 expression is one mechanism by which tumor cells evade immune surveillance. In PDAC, clinical trials evaluating immunotherapy have not been successful in microsatellite stable tumors, and PD-L1 has not been shown to be predictive of immunotherapy response. Studies suggest that high PD-L1 expression may be associated with worse clinical outcomes and more advanced disease. We aimed to evaluate PD-L1 as a prognostic marker in routine clinical practice using a real-world population of patients with PDAC. Methods: We conducted a retrospective study of patients with PDAC at Mount Sinai Health System from 5/2017 to 12/2021 for whom PD-L1 status by immunohistochemistry (22c3) and combined positive score (CPS) were reported. We assessed the association between PD-L1 expression and overall survival (OS) using Kaplan-Meier estimates and multivariable Cox proportional hazards regression models. Chi-squared tests were used to evaluate the association between PD-L1 expression and mutations detected by routine next generation sequencing (NGS) using a standard panel. Results: 107 patients were evaluable. At diagnosis, median age was 68 years, 43% of patients were male, 83% had ECOG performance status 0-1, 38% had resectable disease, 14% had borderline resectable disease, and 48% had unresectable disease. Ultimately, 45 patients (42%) underwent surgery. 44% patients had gemcitabine-based initial therapy, perioperatively or as first-line, and 56% had 5FU-based initial therapy. 35% of patients had radiation therapy (RT) at any time. In the entire cohort, 44 (41%) patients had PD-L1 CPS &lt; 1, and 63 patients had CPS ≥ 1. 93 patients had NGS, but no associations were found between PD-L1 status and commonly mutated genes, such as KRAS and SMAD4. For patients who underwent surgery, the median OS (mOS) of patients with PD-L1 CPS ≥ 1 was 46.1 months, and mOS of PD-L1 CPS &lt; 1 was 29.8 months ( P = 0.13). For patients who did not receive surgery, mOS was 12.3 months for CPS ≥ 1 and 15.8 months for CPS &lt; 1 ( P = 0.07). When adjusted for age, gender, ECOG score, stage, type of chemotherapy, RT, and baseline CA 19-9 level, patients who received surgery and had a CPS ≥ 1 had better OS than those who had CPS &lt; 1 (HR 0.22, 95% CI 0.06-0.77, P = 0.02). For patients without resection, CPS ≥ 1 was not associated with OS in the adjusted model (HR 1.52, 95% CI 0.73-3.15, P = 0.26). However, patients with PD-L1 CPS ≥ 10 without surgery had worse OS compared to patients with CPS &lt; 1 in the adjusted model (HR 11.02, 95% CI 2.89-41.96, P &lt; 0.001). Chemotherapy type and receipt of RT did not modify OS based on PD-L1 expression. Conclusions: In resected PDAC, PD-L1 CPS ≥ 1 was independently associated with improved OS, whereas in unresectable PDAC, PD-L1 CPS ≥ 10 was independently prognostic of worse OS. PD-L1 expression is a potential prognostic factor in PDAC and may be a useful and context-dependent biomarker.

Primary results of the ICONIC phase 2 trial of perioperative FLOT plus avelumab (FLOT-A) in operable oesophagogastric adenocarcinoma (OGA).

446 Background: ICONIC evaluated 4+4 cycles of FLOT-A (2-weekly standard FLOT with 10mg/kg of the anti-PDL1 antibody avelumab) for perioperative treatment of early-stage OGA. We report R0 resection rates, pathologic complete response rates (pCR), pathologic tumour regression grades (TRG) according to Mandard classification and progression free survival (PFS) data in the modified intention to treat population (mITT), and translational analyses. Methods: ICONIC is a single-arm phase II trial of FLOT-A in patients (pts) with ≥cT2-4 or N+ OGA. The pCR rate in surgical specimens was the primary endpoint. Response evaluation according to Mandard, R0 rates and PFS were among secondary endpoints. PD-L1 expression was assessed according to the combined positive score (CPS) with the 22C3 pharmDx kit. Results: The trial closed early after the pCR rate was 15% (95% CI: 49%-83%) once 34 pts in the mITT population (defined as pts who had 1-4 cycles FLOT-A and surgery) as the pre-specified aim to demonstrate a pCR rate of 25% in 40 pts was unlikely to be met. Baseline characteristics of the mITT population were: median age 64y, 79% male, 79% OG junction, 6% oesophageal, 15% stomach, 65% poorly differentiated, 79% T3/4, 59% N+. 91% of pts received all 4 pre-operative cycles and 97% of pts achieved R0 resections. PDL1 CPS ≥1 and CPS ≥5 were nevertheless associated with increased TRG3 and decreased TRG4/5 rates. 3/34 pts (9%) had hypermutated/MMRd tumours and after their exclusion, the association of higher CPS with better TRG3 and decreased TRG4/5 remained. With a median follow up duration of 15.8 months the 12-month PFS was 93.1% (95% CI: 75.1%-98.2%) which is promising compared to historic results with peri-operative FLOT. Conclusions: Although FLOT-A failed to increase pCR rates to 25%, there is a trend towards higher TRG3 and lower TRG4/5 in pts with PDL1 CPS≥1 and CPS≥5 and promising PFS indicate activity of immunotherapy in combination with FLOT chemotherapy. Translational and biomarker analyses by exome- and RNA-sequencing, and multiplex immune cell staining are ongoing and will be reported. Clinical trial information: NCT03399071 . [Table: see text]

Artificial intelligence (AI)-powered immune phenotyping to predict outcomes of immuno-oncology (IO)-based regimens in hepatocellular carcinoma (HCC).

601 Background: Anti-PD-(L)1 monotherapy or combination with bevacizumab or ipilimumab are approved treatment options in HCC. Nevertheless, not all patients benefit from IO treatment, and discovery of predictive biomarkers for IO outcome has not been fully investigated. Immune phenotype analysis by AI-powered spatial tumor-infiltrating lymphocyte (TIL) analyzer in H&amp;E whole-slide images (WSI), Lunit SCOPE IO, has shown predictive effect across multiple cancer types. Here, we investigated the correlation between immune phenotype (IP) and the real-world outcomes in HCC. Methods: Real-world dataset of 177 patients with HCC were retrospectively collected from CHA Bundang Medical Center. Inflamed score was defined by the proportion of area with high intra-tumoral TIL density per 0.5 mm2-sized grid. IP status was sub-analyzed by PD-L1 combined positive score (CPS) and prognostic factors including Child-Pugh class and Barcelona Clinic Liver Cancer (BCLC) stage. We evaluated the correlation between IP and IO outcome by regimen (atezolizumab+bevacizumab [Atez+Bev], n=100; nivolumab+/-ipilimumab [Niv+/-Ipi], n=77). Results: The majority of patients (75.3%) were Child-Pugh class A (75.3%) and BCLC stage C (86.5%), respectively. Atez+Bev was mostly received as first-line therapy (92.0%), whereas Niv+/-Ipi as second-line or beyond (98.7%). The inflamed score was significantly higher in patients who had lymph node metastasis ( p=0.008), but it was not correlated with other metastatic sites, or any other prognostic factors. Of 177 patients, 105 (59.3%) patients were classified as having a high inflamed score (≥10%) and 72 (40.7%) patients as having lower than 10%. PD-L1 CPS was significantly higher in the sample with high score compared to those with low inflamed score ( p=0.01387). PFS of Niv+/-Ipi were significantly favorable in the patients with high inflamed score (3-m PFS rate; 44.0% vs 3.61%, 12-m PFS rate; 17.8% vs 0%, Hazard ratio [HR] 0.37, 95% confidence interval [CI] 0.22-0.63, p&lt;0.001), while PFS of Atez+Bev were not different according to inflamed score (3-m PFS rate; 67.5% vs 57.3%, 12-m PFS rate; 36.6% vs 31.0%, HR 0.80, 95% CI 0.48-1.32, p=0.400). Conclusions: Inflamed score, the proportion of area with high intra-tumoral TIL infiltration, can be a clinically significant predictor of PFS of Niv+/-Ipi, but it was not relevant for Atez+Bev treatment outcomes.

A multicenter, single-arm, phase II study of nivolumab in patients with biliary tract cancer with a PD-L1 combined positive score ≥ 1.

533 Background: Patients with advanced biliary tract cancer (BTC) have a poor prognosis, and high unmet medical needs still exist for the treatment of this disease. Nivolumab has shown its effectiveness against multiple cancer types, especially those with PD-L1 expression. This study assessed the efficacy and safety of nivolumab in BTC patients with a combined positive score (CPS) ≥ 1 who were refractory or intolerant to the standard of care (SOC): gemcitabine, cisplatin and tegafur/gimeracil/oteracil (S-1). Methods: This was a single-arm, multicenter, open-label, prospective phase II study. Key eligibility criteria were as follows: having unresectable or recurrent BTC (intrahepatic bile duct cancer, extrahepatic bile duct cancer, gallbladder cancer, or ampullary cancer); being refractory or intolerant to SOC; having adequate hepatic, renal and hematological function; and having a CPS ≥ 1 in central assessment. Patients received nivolumab (480 mg, every 4 weeks) until disease progression, clinical deterioration, or unacceptable toxicity. The primary endpoint was objective response rate (ORR) assessed by the central review according to RECIST 1.1. The secondary endpoints included overall survival (OS), progression-free survival (PFS), and safety. Results: A total of 84 patients were enrolled between Mar 11, 2020 and Mar 15, 2021, of them 12 received one regimen and 72 received two or more regimens. The median follow-up period was 6.90 months. ORR per central assessment was 10.7% (CR: 3.6%, PR: 7.1%), and ORR per investigator assessment was 15.5% (CR: 2.4%, PR: 13.1%). The median PFS per central and investigator assessment was 1.02 (95% CI 0.95–1.77) months and 2.48 (95% CI 1.87–2.83) months, respectively. The median OS was 6.90 (95% CI 5.26–9.20) months. The median duration of response per central and investigator assessment was not reached (range 2.8–13.0+) and 10.15 (range 2.0–12.8+) months, respectively. The 1-year survival rate was 25.3% (95% CI 15.4–36.4). The most frequent treatment-related adverse events were pyrexia (19.0%), pruritus (16.7%), and decreased appetite (13.1%). Conclusions: Nivolumab may have some activity with a durable response and a manageable safety profile in heavily treated BTC patients with CPS ≥ 1. Clinical trial information: JapicCTI-205097 .

Penpulimab plus chemotherapy with or without anlotinib as first-line treatment for patients with advanced esophageal squamous cell carcinoma (ANSWER): A randomized, two-arm, clinical trial in progress.

TPS482 Background: For patients with advanced esophageal squamous cell carcinoma (ESCC), the combination of immune checkpoint inhibitors with chemotherapy has demonstrated synergistic antitumor activity and manageable safety profile. Anti-angiogenic targeted drugs for ESCC patients are still being explored. Penpulimab is a humanized high-affinity IgG1 anti-programmed cell death 1 (PD-1) monoclonal antibody engineered to completely eliminate Fcγ receptor binding and Fc-mediated effector functions that can compromise antitumor activity. Anlotinib, an oral small molecule tyrosine kinases inhibitor, targeting VEGFR 1/2/3, FGFR 1-4, PDGFR α/β and c-kit, have been recommended by the guidelines for advanced ESCC in China because of its good efficacy and tolerance. The purpose of the study was to investigate the efficacy and safety of penpulimab plus chemotherapy with or without anlotinib as first-line treatment for patients with advanced ESCC. Methods: This is a multi-center, two-arm, phase II study which enrolled patients with advanced ESCC. Eligible patients are aged 18-75 years, ECOG performance status 0~1. Approximately 100 patients will be randomly assigned 1:1 to induction with penpulimab (200mg, iv, d1, q3w) plus chemotherapy (TP: cisplatin [60-75mg/m2, iv, d1-d3, q3w] plus paclitaxel [135-175mg/m2, iv, d1, q3w] or albumin-bound paclitaxel [200-260mg/m2, iv, d1, q3w]) for 4-6 cycles followed by consolidation with penpulimab (200mg, iv, d1, q3w) (arm 1) or induction with penpulimab (200mg, iv, d1, q3w) plus anlotinib (10mg/d [&lt;60kg] / 12mg/d [≥60kg], p.o., d1~14, q3w) plus chemotherapy (TP: cisplatin [60-75mg/m2, iv, d1-d3, q3w] plus paclitaxel [135-175mg/m2, iv, d1, q3w] or albumin-bound paclitaxel [200-260mg/m2, iv, d1, q3w]) for 4-6 cycles followed by consolidation with penpulimab (200mg, iv, d1, q3w) and anlotinib (10mg/d [&lt;60kg)/12mg/d [≥60kg], p.o., d1~14, q3w) (arm 2). Randomization will be stratified by gender (male or female), age (&lt;65, &gt;65), PD-L1 combined positive score (CPS; &lt;1, ≥1, ≥5, ≥10), metastatic site, history of surgery and disease. Patients in arm 1 were treated with second-line anlotinib combined with penpulimab after progression until further disease progression. Patients in arm 2 will continue treated with first-line anlotinib combined with penpulimab until disease progression. Tumor imaging assessment will be performed q6w for 1-6 cycle and q9w thereafter. The primary endpoint was objective response rate (per RECIST v1.1 assessed by investigator). Secondary endpoints included disease control rate, progression-free survival (per RECIST v1.1 assessed by investigator), overall survival, safety and quality of life score. Enrollment in this trial is ongoing. Clinical trial information: NCT05214222 .

Gastric cancer (GC) cohort of a phase 2 trial of E7389-LF (liposomal formulation of eribulin) in combination with nivolumab.

339 Background: Due to a lack of efficacy and long-term survival seen in previously-studied therapies, new therapies for pretreated advanced GC are warranted. E7389-LF is a new formulation that uses liposomes to encapsulate eribulin; this is anticipated to improve eribulin concentration in tumor tissues. E7389-LF and nivolumab have both shown efficacy as monotherapy in pretreated GC. E7389-LF may also synergize well with PD-1 inhibitors by acting as a cytotoxic therapy and by modulating the tumor microenvironment. Methods: Patients (pts) with unresectable and measurable GC, esophageal cancer, or small cell lung cancer who were previously treated with 1 (2 for GC) chemotherapy regimens were enrolled in the phase 2 part of Study 120 and treated with E7389-LF 2.1 mg/m2 plus nivolumab 360 mg every 3 weeks (Q3W). In the GC cohort, pts had to show disease progression from combination therapy including a platinum drug + fluoropyrimidine (1st-line therapy) and a taxane-containing regimen (2nd-line therapy). The primary objective of the phase 2 part was to evaluate the objective response rate (ORR); secondary objectives included safety, progression-free survival (PFS), and pharmacokinetics. Other efficacy (including overall survival [OS]) and biomarker objectives were exploratory. Tumor responses were assessed by the investigators per RECIST v1.1. Results: 31 GC pts were included; median age was 63 years; 18 pts were male, 13 were female. By the data cutoff date (May 31, 2022), 29 pts discontinued (26 due to disease progression, 3 due to adverse events). 8 Pts had a partial response (PR); the ORR was 25.8% (95% CI 11.9–44.6). The median PFS was 2.69 months (95% CI 1.91–2.99). The median OS was 7.85 months (95% CI 4.47–not estimable). The 6-month OS rate was 61.3%; the 9-month OS rate was 44.7%. 30 Pts had ≥1 treatment-related TEAE, most commonly neutropenia (n = 24); 25 pts had at least 1 grade ≥3 treatment-related TEAE, most commonly neutropenia (n = 22). 16 Pts had ≥1 TEAE resulting in dose reduction of E7389-LF. 4 Pts had ≥1 TEAE resulting in withdrawal of E7389-LF or nivolumab, including asthma, cerebral hemorrhage, decreased appetite, pulmonary edema, and upper gastrointestinal hemorrhage (each n = 1). 29 Pts had an evaluable PD-L1 combined positive score (CPS); 5 of 20 pts (25.0%) with a CPS of &lt; 5 and 2 of 9 (22.2%) with a CPS of ≥5 had a PR. Increases in pharmacodynamic markers including vasculature-related markers were observed; antitumor immunity was observed per changes in interferon gamma (IFNγ) and IFNγ-related markers. Conclusions: E7389-LF 2.1 mg/m2 in combination with nivolumab 360 mg Q3W had promising efficacy for pretreated GC, as evidenced by the notable ORR of 25.8% as well as by PFS and OS. No new safety signals were identified for this combination. Biomarker changes suggested vascular remodeling activity and enhancement of antitumor immunity via IFNγ signaling. Clinical trial information: NCT04078295 .

First-line serplulimab or placebo plus chemotherapy in PD-L1-positive esophageal squamous cell carcinoma: a randomized, double-blind phase 3 trial

First-line systemic therapeutic options for advanced esophageal squamous cell carcinoma (ESCC) are limited. In this multicenter, double-blind phase 3 trial, a total of 551 patients with previously untreated, locally advanced or metastatic ESCC and PD-L1 combined positive score of ≥1 were randomized (2:1) to receive serplulimab (an anti-PD-1 antibody; 3 mg/kg) or placebo (on day 1), plus cisplatin (50 mg/m2) (on day 1) and continuous infusion of 5-fluorouracil (1,200 mg/m2) (on days 1 and 2), once every 2 weeks. The study met the primary endpoints. At the prespecified final analysis of progression-free survival (PFS) assessed by the blinded independent radiological review committee, serplulimab plus chemotherapy significantly improved PFS compared with placebo plus chemotherapy (median PFS of 5.8 months and 5.3 months, respectively; hazard ratio, 0.60; 95% confidence interval, 0.48–0.75; P < 0.0001). At the prespecified interim analysis of overall survival (OS), serplulimab plus chemotherapy also significantly prolonged OS compared with placebo plus chemotherapy (median OS of 15.3 months and 11.8 months, respectively; hazard ratio, 0.68; 95% confidence interval, 0.53–0.87; P = 0.0020). Grade 3 or higher treatment-related adverse events occurred in 201 (53%) and 81 (48%) patients in the serplulimab plus chemotherapy group and the placebo plus chemotherapy group, respectively. Serplulimab plus chemotherapy administered every 2 weeks significantly improved PFS and OS in patients with previously untreated, PD-L1-positive advanced ESCC, with a manageable safety profile. This study is registered with ClinicalTrials.gov (NCT03958890).

Cabozantinib plus durvalumab in advanced gastroesophageal cancer and other gastrointestinal malignancies: Phase Ib CAMILLA trial results

This is the phase Ib part of the phase I/II CAMILLA trial evaluating cabozantinib plus durvalumab in advanced chemo-refractory proficient mismatch repair or microsatellite stable (pMMR/MSS) gastrointestinal malignancies including gastric/gastroesophageal junction/esophageal (G/GEJ/E) adenocarcinoma, colorectal cancer (CRC), and hepatocellular carcinoma (HCC). Thirty-five patients are enrolled. There are no observed dose-limiting toxicities during dose escalation. The overall grade 3/4 treatment-related adverse event rate is 34%. Among evaluable patients (n= 30), the objective response rate (ORR) is 30%, disease control rate (DCR) 83.3%, 6-month progression-free survival (PFS) 36.7%, median PFS 4.5months, and median overall survival (OS) 8.7months. Responses are seen in 4 of 17, 3 of 10, and 2 of 3 patients with CRC, G/GEJ/E adenocarcinoma, and HCC, respectively. Participants with a PD-L1 combined positive score (CPS) ≥5 have numerically higher ORR, PFS, and OS. Cabozantinib plus durvalumab demonstrates a tolerable safety profile and potential efficacy in previously treated advanced pMMR/MSS gastrointestinal malignancies.

Comprehensive Analysis of Clinicopathological and Molecular Features to Predict Anti-PD-1-Based Therapy Efficacy in Patients with Advanced Gastric Signet Ring Cell Carcinoma.

Signet ring cell carcinoma (SRCC) is a specific type of gastric cancer. The clinicopathological and molecular characteristics that can be used to predict the response to anti-PD-1 therapy for these patients are still not clear. Patients with advanced SRCC who received first-line anti-PD-1-based treatment were enrolled in this study. The clinicopathological characteristics of these patients were obtained from their medical records. The molecular features of these patients were analyzed by means of a next-generation-sequencing-based panel. The predictive significance of clinicopathological and molecular features for efficacy was analyzed. A total of 71 patients with measurable lesions were included in this study, among which 46 patients had enough tissues for next-generation sequencing. The overall objective response rate (ORR) was 46.4%. ORR was significantly higher in mismatch repair (MMR)-deficient (dMMR) patients than in MMR-proficient (pMMR) patients, in patients with lymph node metastasis only than those with other metastasis sites, and in patients with an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 than with a PS of 1 or 2. The progression-free survival was significantly longer in patients with dMMR, lymph node metastasis only, PD-L1 combined positive score (CPS) ≥ 5, and CDH1 wild type. Several clinicopathological and molecular features are associated with anti-PD-1 treatment efficacy in SRCC, which might be used to identify patients who can benefit most from these therapies.

Oncogenic JAK2/STAT Signaling Molecules Activation Is Associated with PD-L1 Upregulation in Acute Myeloid Leukemia

Background: Increased evidence suggests the PD-1/PD-L1 axis is involved in the oncogenesis of myeloid neoplasms through promoting cancer immune escape, which suggests potential benefits by blockade of this axis in these neoplasms by immune checkpoint inhibitors. However, the ongoing clinical trials on PD-1/PD-L1 blocker in MDS/AML have reported controversial results, unlike the promising therapeutic efficacy shown in solid tumors. Identifying reliable biomarkers and scoring of PD-L1 expression and targeting the subgroup of patients who might benefit the most from PD-1/PD-L1 blockade are promising directions. Janus kinase 2 (JAK2) pathway activation has been shown to enhance PD-L1 expression in malignancies by in vitro studies. Here, we investigated PD-L1 expression associated with JAK2/STAT oncogenic pathway in AML patients using the combined positive score (CPS) algorithm. Methods: Immunohistochemical staining (IHC) for PD-L1 and pSTAT3 was performed on the marrow biopsies of 31 AML patients (39 cases), including 11 patients (17 cases) with JAK2/STAT mutation and 20 patients (22 cases) with wild-type JAK2/STAT. For PD-L1 IHC, the cases were evaluated for variable staining intensity (weak, moderate, strong) and membrane staining pattern (partial, complete) in tumor and mononuclear immune cells. The PD-L1 CPS was calculated by summing the number of all PD-L1-stained cells and dividing by the total number of tumor cells, multiplied by 100. The pSTAT3 was evaluated by percentage of positive tumor cells among the total tumor cells. The status of JAK2 / STAT mutations and other molecular abnormalities was evaluated by next generation sequencing (NGS) study. Results: Among patients of JAK2/STAT mutations, nine with JAK2 V617F exon 14 mutations, one with JAK2 I540-E543delinsRG exon 12 mutation and one with STAT5B N642H mutation. Evaluation of PD-L1 expression by IHC revealed four major cell staining patterns in our study cohort: 1. Negative (Figure 1A); 2. Partial weak membrane staining (Figure 1B, CPS<10); 3. Partial-complete, weak-moderate membrane staining (Figure 1C, CPS≥10); 4. Complete, moderate-strong membrane staining (Figure 1D, CPS≥10). Patterns 3-4 were classified as positive PD-L1 staining with a CPS cut-off of 10 (CPS≥10). Comparison of the PD-L1 CPS score in the JAK2/STAT wild-type versus the JAK2/STAT mutant groups revealed significantly higher PD-L1 CPS score in the JAK2/STAT mutant group (Figure 1K, P<0.0001, CPS≥10). One patient showed wild-type JAK2 at initial AML diagnosis. At two subsequent relapses, gain of JAK2 exon 12 (I540-E543delinsRG) mutation with increased VAF from 17% to 41% was detected. Interestingly, PD-L1 expression was correspondingly increased with CPS from 25 to 75 in these subsequent biopsies (Figure 1E, F). In another case with wild-type JAK2, STAT5B N642H mutation was detected and strong PD-L1 expression with CPS of 80 was obtained (Figure 1G). To address if JAK2/STAT3 axis is involved in PD-L1 upregulation, we assessed STAT3 phosphorylation by IHC in JAK2 wild-type and mutated groups. The results revealed significantly increased p-STAT3 expression in the JAK2 mutant compared with the wild-type cases, supporting the idea that oncogenic JAK2 mutation leads to STAT3 phosphorylation (Figure 1H-J). Furthermore, p-STAT3 expression showed a significant positive correlation with the PD-L1 CPS score (Figure 1H, r=0.8663, P<0.0001). Conclusion: In the AML patients with oncogenic JAK2 or its downstream signaling molecule STAT5B mutations, there is significantly enhanced PD-L1 expression. In addition, we proposed that the PD-L1 CPS positivity cut-off score of 10 being used as a quantitative measure of PD-L1 expression in this heterogeneous myeloid neoplasm. In the patient with relapsing AML, PD-L1 expression showed a positive correlation with increased JAK2 mutant VAF. Independent of the oncogenic JAK2 mutation, PD-L1 expression upregulation was also noted with STAT5B N642H mutation. Lastly, we demonstrated enhanced p-STAT3 expression in JAK2 mutant cases and a positive correlation between p-STAT3 and PD-L1 expression. Taken together, these data support the model that JAK2/STAT pathway activation is associated with PD-L1 upregulation in AML patients (Figure 1I), together with the proposed PD-L1 CPS cut-off of 10, can serve as scanning biomarkers to select relevant subgroups of AML patients for PD-1/PD-L1 immunotherapeutic study. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

CAMRESBRT: Randomized Phase II Trial of Camrelizumab with Stereotactic Body Radiotherapy vs. Camrelizumab Alone in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma

<h3>Purpose/Objective(s)</h3> Immune checkpoint inhibitor (ICI) therapy has significantly expanded the therapeutic armamentarium for recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). Radiation stimulation of abscopal responses, combined with ICI, has been examined in single-arm trials with various tumor types, but randomized evaluation of nivolumab with stereotactic body radiotherapy (SBRT) in R/M HNSCC was frustrated. We aimed to test whether anti–PD-1 therapy, Camrelizumab, may act synergistically with SBRT to improve response through the abscopal effect. <h3>Materials/Methods</h3> We conducted a single-center, randomized, phase II trial. Patients older than 18 years of age with R/M HNSCC who have not been treated with ICIs, regardless of PD-L1 status, are eligible for this study. This trial planned to enroll approximately 70 patients. Patients were randomly assigned (1:1), stratified by human papillomavirus status and PD-L1 status, to camrelizumab versus camrelizumab plus SBRT. Patients have at least two metastatic lesions: one that could be safely irradiated and one measurable by RECIST version 1.1. Drug: camrelizumab (200mg intravenously every 2 weeks). Radiation: SBRT (27 Gy over 3 fractions given every other day) to single lesion to start by study day (study day 1 is day of first dose of camrelizumab). The primary end point was objective response rate (ORR) in nonirradiated lesions, which was assessed by RECIST 1.1. The secondary objectives were safety and tolerability (adverse events of grade 3-4 or higher, rate of long-term adverse events), 6-month and 1-year disease control rate (DCR), 6-month and 1-year progression free survival (PFS), overall survival (OS). <h3>Results</h3> As of January 2022, 31.4% of the planned 70 subjects have been enrolled. Median age was 54.5 years; 17 patients were male. 14 patients received camrelizumab alone and 8 patients received camrelizumab plus SBRT. The PD-L1 status was known in 14 of 18 patients, including 1 patient with PD-L1 CPS (combined positive score) less than 1, 3 patients more than 20, and 10 patients between 1-20. ClinicalTrials.gov Identifier: NCT04830267. <h3>Conclusion</h3> Clinical trial in progress.