Phase 2 Trial of PD‐1 Inhibitor Sintilimab in Recurrent/Progressive Meningioma

Immune-Related Adverse Events and Outcomes in Patients with Advanced Non–Small Cell Lung Cancer: A Predictive Marker of Efficacy?

e21564 Background: Tissue biomarkers like programmed cell death ligand-1 (PD-L1), microsatellite instability (MSI) and high tumor mutational burden (TMB) are surrogates in identifying patients with non-small cell lung cancer (NSCLC) for treatment with immune checkpoint blockade (ICB) therapy. Although tissue biopsy is widely used for identifying the tumor biology, the invasive nature as well as insufficiency of tissue biopsy specimens limits its application. Liquid biopsy is a minimally invasive procedure and has gained interest in recent times for profiling cancer. We sought to study the correlation in the molecular tumor profile specifically PD-L1, MSI and TMB markers between the tissue and liquid biopsies. Methods: We conducted a retrospective review of patients with Stage 3, 4 and recurrent NSCLC that underwent tissue next generation sequencing (NGS) using Caris life sciences and liquid biopsy using Circulogene molecular diagnostics from January 2018 to December 2019 at East Carolina University. A total of 524 patients were reviewed out of which 199 patients had both liquid and tissue NGS performed at the time of initial diagnosis. TMB high was defined as greater than 10 mut/Mb whereas TMB low as less than or equal to 10 mut/Mb. PD-L1 was divided into negative (0%), 1-49% and ≥50%. The blood MSI was classified as positive or negative. We used frequency table, logistic regression and Pearson bivariate correlation for statistical analysis using SPSS platform. Results: The study cohort had 60% (n = 119) male and 40% (n = 80) female patients of which 53% (n = 105) were Caucasians and 45% (n = 89) were African Americans. A total of 87 patients (44%) had negative tissue PD-L1, 59 patients (30%) had tissue PD-L1 ≥ 50%. A linear correlation was seen between negative tissue PD-L1 and negative blood PD-L1 in 92% of patients (n = 80). However, only 15.3% (n = 9) had correlating tissue PD-L1 and blood PD-L1 ≥ 50%, p = 0.024. The negative blood MSI correlated to low tissue TMB in 83% ( n = 60) whereas positive blood MSI correlated to high tissue TMB in 25% (n = 19), p = 0.023. Conclusions: Our results indicate a linear correlation between tissue PD-L1 and blood PD-L1. Similarly, a linear correlation was seen between blood MSI and tissue TMB. Further studies are needed to elucidate the efficacy of ICB therapy using blood MSI and blood PD-L1 as biomarkers for response to therapy.

In the literature: February 2022

Copy number alterations in programmed cell death ligand 1 (PDL1 or CD274), programmed cell death 1 ligand 2 (PDCD1LG2 or PDL2), and Janus kinase 2 (JAK2) genes (chromosome 9p24.1) characterize Hodgkin lymphoma, resulting in high response rates to programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) blockade. The prevalence and utility of PDL1 amplification as a response biomarker to PD-1/PD-L1 blockade are unknown in other tumors. To examine the prevalence of PDL1 amplification and its utility as a response biomarker to PD-1/PD-L1 blockade in solid tumors. This retrospective study (October 1, 2012, to October 1, 2017) used a deidentified tumor database from a commercial company and annotated clinical records from a subset of patients treated at a university tertiary referral center. The study analyzed 118 187 tumors from the deidentified database, including a clinically annotated subgroup of 2039 malignant tumors. Comprehensive genomic profiling was performed on all samples to determine PDL1 amplification, microsatellite instability, and tumor mutational burden (TMB). A subset of patients was treated with PD-1/PD-L1 blockade. The prevalence of PDL1 amplification was determined among 118 187 patient samples that underwent next-generation sequencing. Solid tumors treated with checkpoint blockade were evaluated for response and progression-free survival (PFS). Of the 118 187 deidentified tumor samples, PDL1 amplifications were identified in 843 (0.7%), including more than 100 types of solid tumors. Most PDL1-amplified tumors (84.8%) had a low to intermediate TMB. PDL1 amplification did not always correlate with high-positive PD-L1 expression by immunohistochemical analysis. Six of 9 patients (66.7%) from 1 center with PDL1-amplified solid tumors had objective responses after checkpoint blockade administration. The median PFS among all treated patients was 15.2 months. Responders included 1 patient with glioblastoma (PFS, ≥5.2 months), 2 patients with head and neck squamous cell cancer (PFS, ≥9 and 15.2 months), 2 patients with metastatic basal cell cancer (PFS, 3.8 and ≥24.1 months), and 1 patient with urothelial cancer (PFS, ≥17.8 months). The results of this study suggest that PDL1 amplification occurs in a small subset of malignant tumors. Additional large-scale, prospective studies of PDL1-amplified cancers are warranted to confirm the responses to checkpoint blockade described herein, even in the absence of microsatellite instability, high PD-L1 expression, and a high TMB.

BackgroundImmune checkpoint inhibitors (ICIs) prolong overall survival (OS) in patients with advanced lung squamous cell carcinoma (LUSC). However, predictive and prognostic factors related to ICIs in LUSC remain elusive. This study aimed to identify predictors that are related to better clinical benefit and outcomes in LUSC patients treated with immunotherapy.MethodsCapture-based targeted sequencing was performed in 64 patients with advanced LUSC who underwent immunotherapy. Tumor mutational burden (TMB) was defined as the sum of nonsynonymous single nucleotide and indel variants. Programmed cell death ligand-1 (PD-L1) expression was evaluated by immunohistochemical analysis. Clinicopathological characteristics including age, sex, performance status, smoking history, body mass index (BMI), blood fat, brain metastases, liver metastases, previous thoracic radiotherapy, and treatment lines were analyzed.ResultsThe most commonly mutated genes included TP53, CDKN2A, KEAP1, CREBBP, KRAS, BIM, AMER1, and APC. Copy number variations most frequently occurred in AR, SOX2, PIK3CA, EGFR, RICTOR, FGFR1, and ZNF703. The median and mean TMB was 9.35 and 10.62 mutations per megabase, respectively. Positive PD-L1 expression was detected in 29.7% patients. Patients with a history of heavy smoking (≥ 40 pack-years) were more likely to have positive PD-L1 expression (35% vs. 16.7%, P=0.04) and higher TMB (11.1 vs. 9.8 mut/Mb, P=0.04). Gene alterations had no impact on PD-L1 expression or TMB level. The median progression-free survival (PFS) was 6.7 months and median OS was 13.7 months. Higher TMB was independently associated with longer PFS (P=0.01) and OS (P=0.02), and this correlation was more pronounced in patients treated with ICIs as a single agent (P=0.0001). Higher TMB was also associated with better disease control rate (DCR) (P=0.02). Compared with wild-type, patients with KRAS mutation and EGFR amplification had higher objective response rates (ORR, P=0.01).ConclusionsThe predictive value of TMB is more significant in LUSC patients receiving ICI as a single agent than as a combination therapy. The combination of Eastern Cooperative Oncology Group performance status (ECOG-PS), smoking status, TMB, PD-L1, and genomic variation might be helpful for personalized immunotherapy decisions in clinical practice for advanced LUSC.

Background: Immune checkpoint inhibitors (ICPIs) have led to dramatic improvement in outcome of several cancers. Program death ligand1 (PD-L1) staining and tumor mutational burden (TMB) have emerged as independent predictive biomarkers of ICPIs in lung cancer. Here we examine the landscape of TMB and PD-L1 expression in breast cancer and present a case of patient with high TMB and PD-L1 negative breast cancer with exceptional response to ICPIs. Methods: Hybrid-capture based comprehensive genomic profiling of 395 cancer related genes using the FoundationOne assay was performed on 14,867 breast carcinomas sequenced in the course of routine clinical care. Ventana (SP-263) PD-L1 status (n=1425) and hormone receptor status was available for a subset of patients. Subgroup analyses were performed based on histological type [invasive lobular carcinoma (ILC, n=740)], molecular subtypes [ER-positive (ER+; n= 1371), HER2-amplified (HER2+; n=1522), and TNBC (n=917)], patient age (≤45, 46-60, ≥61), and local vs. metastatic disease (n=5241 and 6710). Results: Consistent with previous reports, the rates of positive PD-L1 staining are highest in TNBC (14%) and lowest in HER2+, ILC, and ER+ disease (6.0%, 5.1%, 2.3%). Interestingly, the rate of PD-L1 positivity, defined as ≥1% tumor staining, was significantly lower in metastatic disease vs. local disease (6.3% vs. 11.1%; p = 0.005). The frequency of high TMB, defined as >10 mutations/mb, was greatest in ILC and HER2+ disease (13.6% and 9.9%) and lowest in TNBC and ER+ disease (7.0% and 6.9%). Rates of high TMB were associated with increased patient age (3.7%, 9.3%, and 12.8% frequency in patients ≤45, 46-60, and ≥61) and were significantly higher in metastatic vs. local disease (11.1% vs 5.3%; p<2E-23). PD-L1 positive and TMB high populations were not significantly co-occurrent (OR = 1.02, p = 0.87). Similar percentages of PD-L1 positivity were observed in both TMB low (9.3%) and TMB high (9.5%). However, among patients with very high TMB (>20 mut/mb), there was a significant association between TMB and PD-L1 positivity (OR = 2.6, p = 0.023). Nevertheless, even with high cutoff, 79% of the TMB high samples were PD-L1 negative. We also report on a stage IIIb (T4, N2, M0) ER+ HER2- breast cancer patient with high TMB (40muts/mb) and negative PD-L1 IHC who previously progressed on aromatase inhibitor with CDK4/6 inhibitor and chemotherapy but achieved durable complete response of > 1 year with nivolumab in combination with capecitabine. Conclusions: Predictive biomarkers for ICPIs are critical to identify a subset of breast cancer patients who may respond to immunotherapy. TMB high and PD-L1 positivity do not significantly co-occur and the majority of TMB high cases were PD-L1 negative. Nevertheless, this group of patients may still benefit with ICPIs. Further studies are needed to evaluate this subset of patients. Citation Format: Ethan Sokol, Lee Albacker, Aixa Soyano, Ricardo Parrondo, Brenda Ernst, Emmanuel Gabriel, Garrett Frampton, Jeffrey Ross, Siraj Ali, Jon Chung, Saranya Chumsri. Incidence of high tumor mutation burden (TMB) and PD-L1 positivity in breast cancers and potential response to immune checkpoint inhibitors (ICPIs) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4894.

Tumor Mutational Burden and PD-L1 Expression in Hematologic Malignancies

e15141 Background: PD-L1 and TMB are the most widely used immunotherapy biomarkers to identify populations who would benefit from immunotherapy, with the higher values predicting better therapeutic efficacy. We sought to explore the occurrence and correlation of these two biomarkers in a community based cancer center patient population in rural central Nebraska. Methods: One hundred sixty consecutive cancer patients(pts) diagnosed and treated between 2018-2022 at Morrison Cancer Center were evaluated. Malignant tumor tissue specimens were analyzed for PD-L1expression and TMB (Foundation test). PD-L1 expression was classified as low ( < 1%), intermediate (1% ≥ PD-L1 < 50%), high (≥ 50%), and TMB classified as low [1–5 mutations/Megabase (muts/Mb)], intermediate (6–19 muts/Mb), high (≥ 20 muts/Mb)]. PD-L1 and TMB values were treated as continuous variables to calculate a Pearson correlation coefficient and p value. Results: Mean age at diagnosis was 64 years (range 33-89). Malignant histology diagnoses included 55 pts with lung, 18 colorectal, 12 breast, 15 unknown primary, 15 pancreas, 10 renal, 3 melanoma, 1 thyroid, 6 ovary, 5 uterus, 5 head and neck, 5 prostate, 5 biliary, and 1 vulvar. Fifty four percent (86/160) of pts had low, 33% (53/160) had intermediate, and 13% (21/160) had high PD-L1 expression score with a mean PD-L1 value of 13.8% (range 0-100). Sixty six percent (106/160) of pts had low, 30% (48/160) had intermediate, and 4% had high TMB with a mean TMB value of 5.6 muts/Mb (range 0-66). A marginal linear correlation between PD-L1 expression and TMB was observed (Pearson Correlation Coefficient = 0.172, P = 0.0270). Conclusions: PD-L1 and TMB are both important biomarkers for immunotherapy. Increasing availability and use of both PD-L1 and TMB testing in the community oncology practice beseeches the question of frequency of these two biomarkers in various cancers in the community oncology patient population as well as any association between them. The results of our study gives a glimpse of the distribution landscape of these two biomarkers for community oncology patients and suggest that PD-L1 and TMB may be independent markers with a weak association. PD-L1 and TMB may each inform use of immunotherapy by different mechanisms. [Table: see text]

Genetic alternations and immune characteristics in patients with small cell lung cancer

Although tumor mutation burden (TMB) has been explored as a potential biomarker of immunotherapy efficacy in solid tumors, there still is a lack of consensus about the optimal TMB threshold that best discriminates improved outcomes of immune checkpoint inhibitor therapy among patients with non-small cell lung cancer (NSCLC). To determine the association between increasing TMB levels and immunotherapy efficacy across clinically relevant programmed death ligand-1 (PD-L1) levels in patients with NSCLC. This multicenter cohort study included patients with advanced NSCLC treated with immunotherapy who received programmed cell death-1 (PD-1) or PD-L1 inhibition in the Dana-Farber Cancer Institute (DFCI), Memorial Sloan Kettering Cancer Center (MSKCC), and in the Stand Up To Cancer (SU2C)/Mark Foundation data sets. Clinicopathological and genomic data were collected from patients between September 2013 and September 2020. Data analysis was performed from November 2021 to February 2022. Treatment with PD-1/PD-L1 inhibition without chemotherapy. Association of TMB levels with objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). In the entire cohort of 1552 patients with advanced NSCLC who received PD-1/PD-L1 blockade, the median (range) age was 66 (22-92) years, 830 (53.5%) were women, and 1347 (86.8%) had cancer with nonsquamous histologic profile. A regression tree modeling ORR as a function of TMB identified 2 TMB groupings in the discovery cohort (MSKCC), defined as low TMB (≤19.0 mutations per megabase) and high TMB (>19.0 mutations per megabase), which were associated with increasing improvements in ORR, PFS, and OS in the discovery cohort and in 2 independent cohorts (DFCI and SU2C/Mark Foundation). These TMB levels also were associated with significant improvements in outcomes of immunotherapy in each PD-L1 tumor proportion score subgroup of less than 1%, 1% to 49%, and 50% or higher. The ORR to PD-1/PD-L1 inhibition was as high as 57% in patients with high TMB and PD-L1 expression 50% or higher and as low as 8.7% in patients with low TMB and PD-L1 expression less than 1%. Multiplexed immunofluorescence and transcriptomic profiling revealed that high TMB levels were associated with increased CD8-positive, PD-L1-positive T-cell infiltration, increased PD-L1 expression on tumor and immune cells, and upregulation of innate and adaptive immune response signatures. These findings suggest that increasing TMB levels are associated with immune cell infiltration and an inflammatory T-cell-mediated response, resulting in increased sensitivity to PD-1/PD-L1 blockade in NSCLC across PD-L1 expression subgroups.

Tumor mutational burden.

Tumor mutation burden and checkpoint immunotherapy markers in primary and metastatic synovial sarcoma

Membranous nephropathy (MN) is an autoimmune disease, which is classified into primary and secondary MN. Malignancy-associated MN (M-MN) accounts for about 10% of secondary MN cases. Lung cancer is the most common type of malignancy among M-MN patients. Immune checkpoint inhibitors (ICIs) targeting programmed cell death-1 (PD-1) or programmed cell death ligand-1 (PD-L1) have showed promising efficacy and good safety in many types of solid tumors, including non-small cell lung cancer. To date, whether ICIs could be a treatment option for M-MN patients with PD-L1 expression and or high tumor mutation burden (TMB) level has not been documented. A 68-year-old male patient presented with edema of the lower limbs with increased urine foam in August 2018. Biopsy on the right kidney showed MN at stage I with subepithelially localized immune deposits. Lung squamous cell carcinoma (LSCC)-associated MN with PD-L1 expression (20%) and high TMB level (26.2 mutations/Mb). The patient received immunosuppressive therapy targeting the initially diagnosed primary MN as first-line treatment plus surgery and radiochemotherapy following pembrolizumab targeting the definitively diagnosed lung cancer as second-line treatment. The patient benefited from radiochemotherapy following pembrolizumab (lasting more than 38 months) rather than immunosuppressive therapy. Our work suggests that combined ICIs might be an effective treatment option for M-MN patients who harbor PD-L1 expression. Our work highlights that the presence of malignancy should not be neglected at the initial diagnosis of MN.

Immunotherapy based on programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors has revolutionized the treatment of non-small cell lung cancer (NSCLC). Patients with high PD-L1 expression or DNA mismatch repair deficiency (dMMR)/microsatellite instability-high (MSI-H) cancer are reported to benefit from PD-1/PD-L1 inhibitors. However, additional biomarkers are needed, and whether tumor mutation burden (TMB) can be a robust biomarker or not is still controversial. We conducted this study to assess TMB as a biomarker for PD-1/PD-L1 inhibitor treatment in advanced NSCLC patients in a real-world setting. Chinese NSCLC patients who received a PD-1/PD-L1 inhibitor at the People's Liberation Army General Hospital and who had pathological tissues available for TMB were retrospectively analyzed. Demographic and clinical information were evaluated. Targeted next-generation sequencing (NGS) of the tumor tissue was performed. The relationship between TMB and clinical benefit was assessed. Thirty-four patients treated with PD-1/PD-L1 inhibitors between March 2015 and January 2019 were analyzed. The TMB was greater in patients with complete response (CR)/partial response (PR) versus stable disease (SD) versus progressive disease (PD) (median 11 vs. 9.7 vs. 4.2 mutations/megabase [Mb]; p = 0.049). The median progression-free survival was 10.6months in the TMB-high group versus 3.9months in the TMB-low group (cut-off value = 10 mutations/Mb) (hazard ratio [HR] 0.26 [95% confidence interval 0.12-0.57], p = 0.0007). The median overall survival was 21.0months and 11.6months (HR 0.37 [0.17-0.81], p = 0.0126) in the TMB-high group and the TMB-low group, respectively. The disease control rate was higher in the TMB-high group than in the TMB-low group (100% vs. 70%, p = 0.024). High TMB was associated with a better outcome in advanced NSCLC patients who received PD-1/PD-L1 inhibitors in China. Further studies are needed to confirm our findings.

534 Background: ICIs are frequently used as therapy in mUC, but only a minority of patients (pts) respond to treatment. High TMB is associated with improved outcomes to ICIs. However, much is unknown about biomarkers associated with ICI outcomes in pts with high and low TMB respectively. Methods: We retrospectively identified mUC pts with known TMB status and available next generation sequencing (NGS) results treated with ICI monotherapy at our institution. TMB high was defined as ≥ 10 mutations/Mb, with the rest being TMB low. Somatic alterations present in ≥10% pts ( ARID1A, CCND1, CDKN2A, CDKN2B, ERBB2, FGF3, FGF4, FGF19, FGFR3, KDM6A, MDM2, MLL2, PIK3CA, RB1, TERTp, TP53, TSC1), and presence of DNA damage response (DDR) alterations were assessed as biomarkers of interest. Within the TMB-high and TMB-low pt groups we separately assessed patients based on the presence or absence of these somatic alterations, APOBEC mutational signature and high PD-L1 expression. Log rank test was used to determine differences in overall survival (OS) and progression free survival (PFS) among these groups. P-value ≤0.05 was considered significant. Results: Among 107 mUC pts treated with ICI monotherapy between 12/2014 and 3/2022 who had NGS data (UCSF500, FoundationOne, Strata), 85 pts had TMB data, including 47 TMB high pts and 38 TMB low pts. Among 85 pts with known TMB status, median age was 76 yrs, the majority were male (55, 65%), Caucasian (57, 67%), had pure urothelial histology (46, 55%) and were treated with ICIs in frontline setting (47, 55%). Median OS was 17.2 mos and median PFS was 3.42 mos. In TMB high pts, presence of DDR , MLL2, KDM6A, PIK3CA and TERTp alterations were each associated with improved outcomes, while presence of CDKN2B alterations was associated with inferior outcomes (Table). Among TMB low pts, those with RB1 alterations had shorter mOS (11.3 months vs 17.2 months; p=0.04) compared to wild-type pts. Conclusions: In this single-center retrospective analysis of mUC pts, we identified somatic alterations that were predictive of outcomes with ICI treatment in TMB high and TMB low pts respectively. Further exploration of biomarkers in patients stratified by TMB status is warranted in larger cohorts. [Table: see text]