Correction: Metastatic sites of baseline as predictors in recurrent or metastatic nasopharyngeal carinoma treated with PD-L1 inhibitor: a secondary analysis of multicenter, single-arm, phase II study (KL-A167)

e20119 Background: PD-1/PD-L1 inhibitors in combination with platinum-etoposide (EP) based chemotherapy have been approved as first-line therapy in extensive-stage small cell lung cancer (ES-SCLC). However, whether PD-1 or PD-L1 inhibitors should be preferably selected is still undetermined. Methods: The retrospective study included 367 ES-SCLC patients who received standard first-line chemoimmunotherapy from 3 cancer centers in China from May 2018 to February 2023. The efficacy, including objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS), as well as safety were evaluated between PD-1 and PD-L1 inhibitors. Results: Among 367 ES-SCLC patients, 80 received PD-1 inhibitors plus EP, and 287 received PD-L1 inhibitors plus EP as first-line treatment. The baseline characteristics between the two groups were well balanced. Although PD-L1 inhibitors had numerically higher ORR (66.2% vs. 56.3%, P = 0.114) and DCR (93.4% vs. 87.5%, P = 0.100) compared with PD-1 inhibitors, the difference were not statistically significant. We then observed similar PFS (7.5 m vs.7.7 m; HR = 0.91[95% CI: 0.68–1.23], P = 0.547) and OS between groups. Further analysis revealed that combination of thoracic radiotherapy (TRT) with PD-1 or PD-L1 inhibitors showed similar efficacy. In addition, PD-1 or PD-L1 inhibitors had comparable efficacy in patients with different sites of metastasis. No additional immune-related adverse reactions (irAEs) were observed in the PD-1 inhibitor group compared with that in the PD-L1 inhibitor group (38.8% vs 39.7%, P = 0.875). Conclusions: PD-1 and PD-L1 inhibitors showed comparable efficacy and safety in the setting of first-line chemoimmunotherapy.

Current Understanding and Biomarker Application of Programmed Death-Ligand 1 Expression in Tumors.

369 Background: Post immunotherapy response and disease progression pattern are still under investigation. In terms of progression, rapid progression pattern called HPD has been observed during the early cycles of PD-1/PD-L1 inhibitors therapy in patients with various cancers. Data of HPD in patients with GU cancer are limited. Methods: This study included 203 patients with GU cancer treated with PD-1/PD-L1 inhibitors between February 2015 and June 2018. HPD was defined as greater than 50% increase in tumor burden compared with before-treatment computed tomography (CT) scan and greater than 2-fold increase in tumor growth rate (TGR) compared with previous TGR. Development of extensive new lesions were also regarded as HPD. Response was evaluated by RECIST v1.1 on at least two consecutive CT scan before the initiation of PD-1/PD-L1 inhibitors and one CT scan within 2 months after initiation of PD-1/PD-L1 inhibitors. Results: 102 patients with renal cell carcinoma (RCC) and 101 patients with urothelial cell carcinoma (UCC) were included. Median age was 64 years (range 56-71) and 141 patients (70%) were male. The most common metastatic site was lymph node (66%), followed by lung (51%) and bone (34%). HPD was observed in 13 out of 230 patients (5.7%; 95% CI, 5.0-6.3). Median OS for patients with progressive disease and HPD were 7.3 months and 3.5 months, respectively ( p=0.09). HPD was more frequently found in patients with UCC than RCC (11% vs. 0.9%, p=0.01). In multivariate analysis, patients of UCC ( p <0.001), presence of liver metastasis ( p=0.002), elevated LDH level (> upper normal limit, p=0.01), and hypoalbumimemia (< 3.5 gm/dL, p<0.001) were independent predictive factors for HPD. Conclusions: The incidence of HPD in GU cancer patients seems to be low compared to previous studies (9-10%). The majority of HPD developed in UCC and the incidence in RCC is negligible. Cares should be taken when treating patients with PD-1/PD-L1 inhibitors, especially when patients have UCC and liver metastases, elevated LDH and hypoalbuminemia.

PD-1 Inhibitor Combined with Hypofractionated Radiotherapy and GM-CSF with or without IL-2 (PRaG Regimens) Rechallenge for Acquiring Resistance to PD-1/PD-L1 Inhibitor in Advanced Solid Tumors

Pulmonary lymphoepithelioma-like carcinoma (LELC) exhibits a unique immune microenvironment, including high PD-L1 expression and abundant infiltrating-immune cells. However, the availability of PD-1/PD-L1 inhibitors in patients with LELC is still not determined. A total of 36 cases of pulmonary LELC treated with PD-1/PD-L1 inhibitors were reviewed, including 10 cases from our institute and 26 cases included from the literature. The Kaplan-Meier method and log-rank test were utilized to analyze the survival outcomes of LELC patients receiving immunotherapy, and the factors related to immunotherapy response were further examined. Of the 10 patients from our institute, the median age was 53.5 years, adrenal glands and distant lymph nodes were the most common metastatic sites, and 4 of 8 (50%) patients had a PD-L1 TPS ≥50%. The median progression-free survival and overall survival in patients from our institute and from the literature were 11.6 and 27.3 months, 17.2 months and not reached, respectively. In all 36 patients, the objective response rate was as high as 57.6%. Patients with higher PD-L1 expression were more likely to have a tumor response, but the association of PD-L1 expression with survival time remains to be determined. PD-1/PD-L1 inhibitors in patients with pulmonary LELC demonstrated a promising efficacy in retrospective cohorts, and deserve further validation in prospective studies administrating in front-line setting.

2601 Background: Immune checkpoint inhibitors, especially PD-1/PD-L1 inhibitors can promote tumor regression and long-term survival in patients with advanced solid tumors. Despite the characteristic durability of response to ICI, unfortunately some patients may develop acquired resistance after an initial response. The underlying mechanism and effective measure are remarkably limited, perhaps restraining development of immunotherapies. The PRaG trial as a salvage therapy in patients with refractory metastatic solid tumors has obtained satisfactory results(Yuehong Kong et al. ASTRO 2021). With great surprise we found that patients with PD-1/PD-L1 inhibitors acquired resistance are more likely to benefit from the PRaG regimens. This is the PRaG regimen rechallenge that could represent an attractive option in advanced solid tumors. We retrospectively analyzed the clinical efficacy and safety of PRaG regimen (PD-1 inhibitors combined with radiotherapy and GM-CSF with or not IL-2) rechallenge to treat immunotherapy-refractory patients with advanced solid tumors. Methods: This is a retrospective analysis of patients who showed initial resistance to PD-1/PD-L1 inhibitors were retrospectively collected from PRaG serial trails (ChiCTR1900020175 and NCT04892498). Patients received SBRT or HFRT (2-3 doses of 5-8Gy) to a target metastatic site, PD-1 inhibitor was dosing intravenously within one week after completion of SBRT or HFRT, and GM-CSF subcutaneous (SC) injection once daily for 14 days after radiotherapy(the PRaG 2.0 regimen, GM-CSF 200µg SC d1-7, sequentially IL-2 2million IU d8-14.). The specific PRaG regimens had been reported at the meeting of 2020 ASCO. Pooled analysis of response rate (ORR), median progression-free survival (mPFS), and treatment-related adverse events were calculated. Results: A total of 15 multi-metastatic patients were enrolled between October 2020 and February 2022. Thirteen patients showed acquired resistance and underwent at least one assessment, 5 patients were lung cancer, 3 patients were renal cancer, 2 patients were liver cancer, 2 patient was colon cancer, 1 patient was sarcoma. The ORR was 18.2%, and the disease control rate (DCR) was 90.9%. The median PFS was 8.87 months (95%CI, 1.41 to 16.33 months). One lung cancer achieved complete remission, with PFS over 17 months. Treatment-related adverse events of any grade occurred in 11 of 15(73.3%) patients, while there was no grade 3 or higher adverse events. Conclusions: Our preliminary results suggested that PRaG regimens rechallenge maybe an active and feasible strategy in PD-1/PD-L1 inhibitors acquired resistance. The therapy was well tolerated and had acceptable toxicity. A phase III prospective study is being planned to clarify the role of rechallenge after acquired resistance. Clinical trial information: ChiCTR1900020175 and NCT04892498.

ObjectiveTo compare the effectiveness and safety of nab-paclitaxel, cisplatin, and capecitabine (nab-TPC) with gemcitabine and cisplatin as an alternative first line treatment option for recurrent or metastatic nasopharyngeal carcinoma.DesignPhase 3,...

Background: Programmed death-1/programmed death ligand 1 (PD-1/PD-L1) inhibitors are approved in a range of tumor types, including non-small cell lung cancer, with PD-L1 immunohistochemistry (IHC) diagnostic assays approved to inform treatment in some settings. There is evidence that PD-L1 expression can vary between primary tumors and metastatic sites, but the relationship remains unclear. In this real-world study, we compared PD-L1 expression between matched primary tumor and metastatic site biopsies in patients with lung cancer. Methods: NeoGenomics Laboratories Inc (Fort Myers, FL), a US national reference laboratory, provided results for PD-L1 tests performed on samples from 21,224 patients with lung cancer between Oct 2015 and Mar 2018. Test results were linked to clinical characteristics provided by Symphony Healthcare Solutions using unique identifiers. PD-L1 tests were performed using the Dako PD-L1 IHC 28-8 or 22C3 pharmDx assays according to the manufacturers' protocols at the time. The percentage of tumor cells (TCs) expressing PD-L1 was determined by trained pathologists. Patients were included in the analysis if they had matched biopsies from a primary lung tumor and a metastatic site that were collected in any order within a 3-month period, and if both samples were tested with the same PD-L1 assay ≤ 3 months apart. Patients were excluded if they received treatment between biopsies or had > 2 biopsies. Statistical analysis was performed by BioStat Solutions Inc. Results: In total, 121 patients had matched primary and metastatic biopsy samples, with sites biopsied in any order; a subgroup of 59 patients had their second biopsy obtained after the PD-L1 test result for the first biopsy was reported. Matched biopsy pairs showed modest concordance (Kendall's tau 0.43 [95% CI, 0.33–0.54]; Spearman's correlation 0.56 [95% CI, 0.42–0.67]). Overall percentage agreement was 69–80% (Cohen's kappa 0.34–0.53) across a range of PD-L1 expression cutoffs (1%, 5%, 10%, 25%, and 50% of TCs). Identical PD-L1 expression was observed in 26% of matched biopsy pairs; 44% of sample pairs had a < 5% difference and 35% of sample pairs had a > 20% difference in PD-L1 expression scores between primary and metastatic sites. PD-L1 expression in primary tumor and metastatic sites was heterogeneous, with no clear trends across biopsy sites. In the subgroup of 59 patients whose second biopsy was obtained after the test result for their first biopsy was reported, 50% of patients (15/30) with PD-L1 expression on < 1% of TCs in their first biopsy had PD-L1 expression on ≥ 1% of TCs in their second biopsy. Conclusion: This real-world study suggests that agreement of PD-L1 expression between matched primary and metastatic biopsy sites is low, further highlighting PD-L1 expression heterogeneity in lung cancer. Variation in PD-L1 expression between biopsy sites may affect treatment decisions relating to PD-1/PD-L1 inhibitors. Citation Format: Emily A. Prince, Vladislav Chizhevsky, Josette William Ragheb, James L. Pratt, Dimple Pandya, David Huron. Comparison of PD-L1 expression in primary and metastatic lung cancer biopsies [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2004.

Phase I Dose Escalation Study of Radiotherapy and Durvalumab (MEDI4736) in Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL): The RaDD Study

BackgroundImmune checkpoint inhibitors (ICIs) show optimal treatment effects on recurrent or metastatic nasopharyngeal carcinoma(R/M NPC). Nonetheless, whether metastatic sites impact ICIs efficacy remains unclear.MethodsWe performed a secondary analysis of R/M NPC patients treated with KL-A167, a programmed cell death-ligand 1(PD-L1) inhibitor, based on a multicenter, single-arm, phase II study from China between 2019 and 2021 years, which represents the first and most comprehensive analysis of the effectiveness of a PD-L1 inhibitor in patients who have been previously treated. The Cox proportional hazard model was utilized to evaluate the association between sites and PFS and OS. Sensitivity analysis and subgroup analysis were carried out to confirm the reliability of our findings.ResultsA total of 153 R/M NPC patients were included. The mean age was 47 years and 81% of patients were males. All patients in our study had distant metastasis, with a majority (n = 69) presenting with more than 2 sites of distant metastasis upon admission. The collected sites of metastasis included liver, lung, lymph and bone. Among the 153 patients, 37.9% (58 patients) received anti-PD-L1 treatment for a minimum of 6 months, and 17.6% (27 patients) were treated for at least 12 months. By conducting multivariate analysis, R/M NPC patients with non-liver metastases presented significantly longer progress-free survival (PFS, HR:1.67, CI:1.09–0.2.55, p = 0.018) and overall survival (OS, HR:2.52, CI:1.49–4.28, p < 0.001) compared with those with liver metastasis. The median PFS (72 vs. 144 days, p < 0.0001) and OS (730 vs. 305 days, p < 0.0001) were significantly longer for patients with non-liver metastases. However, lung, bone and lymph node metastasis had no statistical significance on PFS and OS (p > 0.005). Our sensitive analysis showed liver metastases patients with less other site metastases (0 or 1) had shorter OS compared to non-liver metastases patients with more other metastases(≥ 2). Furthermore, subgroup analysis indicated the robustness evidence liver metastasis indeed a valuable prognostic factor for survival.ConclusionsCompared to patients with other metastatic sites, R/M NPC patients with liver metastasis have poor survival patterns when receiving anti-PD-L1 therapy. Our study provides rational evidence for the urgent need to explore more efficacy treatment modalities for NPC patients with liver metastasis.

BackgroundLeiomyosarcoma (LMS) and liposarcoma (LPS) are soft tissue sarcoma subtypes that frequently express PD-L1 and are infiltrated with T cells. They are generally resistant to PD-1/PD-L1 inhibition, possibly due to...

Background: Immune-checkpoint inhibitors treatment (ICIs) like anti-PD-1/PD-L1 checkpoint inhibitors has been considered as a standard treatment and produced significant effects in patients with non-small cell lung cancer (NSCLC). However, various studies have reported that anti-PD-1/PD-L1 treatment may lead to the rapid development of tumors called hyperprogressive disease (HPD). It is urgent to determine biomarkers and develop a nomogram for HPD prediction in patients with NSCLC before anti-PD-1/PD-L1 treatment. Methods: This retrospective cohort study included 176 cases (collected from January 1, 2016 to September 31, 2019) for establishing a model of HPD prediction, and 37 cases (collected from October 1, 2019 to April 31, 2020) for validation in the patients with advanced NSCLC treated with PD-1/PD-L1 inhibitors in Sun Yat-sen University Cancer Center. HPD was defined as tumor growth rate (TGR, ≥ 2), or tumor growth kinetics (TGK, ≥ 2) or time to treatment failure (TTF, ≤ 2 months). Univariate and multivariate logistic regression were used to estimate the specified factors associated with HPD. Then the nomogram was developed and validated. Finding: The anti-PD-1/PD-L1 therapy resulted in 9.66% (17/176) incidences of the HPD phenomenon in advanced NSCLC. The overall survival (OS) and progression free survival (PFS) in patients with HPD were significantly shorter than those patients without HPD (OS: 8.82 months [95%CI, 4.91-12.74 months] vs. 15.74 months [95%CI, 13.95-17.53 months], P<0.01; PFS: 2.29 months [95%CI, 1.90-2.69 months] vs. 11.06 months [9.12-12.85 months], P<0.001), respectively. The HPD prediction nomogram included APTT (P<0.01), CD4+CD25+ cells (Treg cells) (P<0.01), the presence of liver metastasis (P<0.05), and more than two metastatic sites (P<0.05). Then patients could be divided into two groups by “HPD score” calculated by the nomogram: “HPD score” = 0.8225× presence of liver metastasis + 0.3954 × more than two metastatic sites + 0.2140 × APTT+0.0873 × Treg cells – 11.2476, with the cut-off point was -1.37 (patients with “HPD score” ≥ -1.37 have high risk of HPD, while patients with “HPD score” < -1.37 have low risk of HPD). The C-index was 0.845, while the area under the curve (AUC) was 0.830 (95% confidence interval [CI]: 0.719-0.950, sensitivity 75.00%, specificity 91.70%). The calibration plot of HPD probability showed an optimal agreement between the actual observation and prediction by nomogram. The good discrimination [AUC, 0.911, 95% CI (0.745-0.950), sensitivity 79.60%, specificity 87.50%] was still exited in the validation cohort. The decision curve analysis showed that the nomogram was more beneficial to patients than the reported biomarkers (including PD-L1, number of metastases, age ≥ 65). Interpretation: The nomogram was constructed with the presence of liver metastasis, more than two metastatic sites, long APTT and high level of Treg cells, which could be used to predict HPD risk. Thus NSCLC patients could receive reasonable management before anti-PD-1/PD-L1 therapy. Funding Statement: This study was funded by National Natural Science Foundation of China (No. 81473233); Science and Technology Program of Guangzhou (No. 201504010038, 201604020079, 201601010008). Declaration of Interests: The authors declare no conflict of interest. Ethics Approval Statement: Written informed consents were exempted because of retrospective analysis. The Institute Research Ethics Committee of the Sun Yat-Sen University Cancer Center, Guangzhou, China approved this study (IRB No. YB2020-006-01).

BackgroundImmunotherapy targeting PD-1/PD-L1 fails to induce clinical responses in most patients with solid cancers. N-803, formerly ALT-803, is an IL-15 superagonist mutant and dimeric IL-15RαSushi-Fc fusion protein complex that enhances CD8+ T and NK cell expansion and function and exhibits anti-tumor efficacy in preclinical models. Previous in vitro studies have shown that IL-15 increases PD-L1 expression, a negative regulator of CD8+ T and NK cell function. Most reported preclinical studies administered N-803 intraperitoneally not subcutaneously, the current clinical route of administration. N-803 is now being evaluated clinically in combination with PD-1/PD-L1 inhibitors. However, the mechanism of action has not been fully elucidated. Here, we examined the anti­tumor efficacy and immunomodulatory effects of combining N-803 with an anti-PD-L1 antibody in preclinical models of solid carcinomas refractory to anti-PD-L1 or N-803.MethodsSubcutaneous N-803 and an anti-PD-L1 monoclonal antibody were administered as monotherapy or in combination to 4T1 triple negative breast and MC38-CEA colon tumor-bearing mice. Anti-tumor efficacy was evaluated, and a comprehensive analysis of the immune-mediated effects of each therapy was performed on the primary tumor, lung as a site of metastasis, and spleen.ResultsWe demonstrate that N-803 treatment increased PD-L1 expression on immune cells in vivo, supporting the combination of N-803 and anti-PD-L1. N-803 plus anti-PD-L1 was well-tolerated, reduced 4T1 lung metastasis and MC38-CEA tumor burden, and increased survival as compared to N-803 and anti-PD-L1 monotherapies. Efficacy of the combination therapy was dependent on both CD8+ T and NK cells and was associated with increased numbers of these activated immune cells in the lung and spleen. Most alterations to NK and CD8+ T cell phenotype and number were driven by N-803. However, the addition of anti-PD-L1 to N-803 significantly enhanced CD8+ T cell effector function versus N-803 and anti-PD-L1 monotherapies, as indicated by increased Granzyme B and IFNγ production, at the site of metastasis and in the periphery. Increased CD8+ T cell effector function correlated with higher serum IFNγ levels, without related toxicities, and enhanced anti-tumor efficacy of the N-803 plus anti-PD-L1 combination versus either monotherapy.ConclusionsWe provide novel insight into the mechanism of action of N-803 plus anti-PD-L1 combination and offer preclinical proof of concept supporting clinical use of N-803 in combination with checkpoint inhibitors, including for patients non- and/or minimally responsive to either monotherapy.

P3-008 - A Prospective Multicenter Phase II Study of Cisplatin and Weekly Docetaxel as First-Line Treatment of Recurrent or Metastatic NAsopharyngeal Cancer (KCSG HN07-01)

A prospective multicentre phase II study of cisplatin and weekly docetaxel as first-line treatment for recurrent or metastatic nasopharyngeal cancer (KCSG HN07-01)