PD-L1 Testing Research Articles

"Off-Label" Use of Checkpoint Inhibitors in Patients With Negative or Unknown PD-L1 Status in Advanced Head and Neck Cancer.

The KEYNOTE-048 study established the checkpoint inhibitor (CPI) pembrolizumab, with/without chemotherapy, as frontline treatment for recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). However, pembrolizumab monotherapy has limited efficacy in PD-L1-negative disease. Clinical practice patterns regarding PD-L1 combined positive score (CPS) testing and PD-L1-guided treatment selection remain unknown. This retrospective analysis included patients who initiated treatment for R/M HNSCC from 2011 to 2023 in a nationwide electronic health record-derived deidentified database. Frontline therapy was categorized as CPI monotherapy, CPI with chemotherapy, or chemotherapy ± cetuximab without CPI. A subset of patients treated in 2019 and beyond (2019+ cohort) were analyzed to investigate PD-L1 testing rates, treatment patterns following FDA approval of pembrolizumab, and the proportion receiving "off-label" CPI monotherapy (single-agent use in patients with metastatic HNSCC and negative/unknown PD-L1 status). Factors associated with "off-label" use were identified using multivariable logistic regression. The total cohort included 7,657 patients with a median age of 65 years (IQR, 58-72); 67% were White, 78% had a history of smoking, 66% had an ECOG performance status (PS) of 0-1, and 31% were HPV-positive. The 2019+ subset included 3,395 patients, of whom nearly half (47%) did not have a known PD-L1 CPS prior to systemic treatment initiation. The most common frontline treatment in the total cohort was CPI monotherapy (43%). CPI monotherapy use was even higher in patients aged ≥75 years (54%) and those with ECOG PS ≥2 (52%). Among the 2019+ subgroup with PD-L1 CPS negative/unknown tumors (n=1,926), 536 (28%) received CPI monotherapy "off-label." Factors associated with "off-label" use on multivariable regression included age ≥75 years (odds ratio [OR], 1.4), community practice setting (OR, 1.5), and earlier year of treatment (OR, 1.3 per year) (all P<.05). Most US patients with R/M HNSCC are now receiving CPI-based therapy in the frontline setting; however, PD-L1 testing remains underutilized. "Off-label" use of CPI monotherapy in PD-L1-negative/unknown HNSCC is common, particularly among elderly patients.

Evaluating the benefits of immunotherapy in metastatic cervical cancer: an observational retrospective analysis.

Cervical cancer is the fourth most commonly diagnosed cancer and the fourth leading cause of cancer-related death in women globally. Recent advances in immunotherapy have demonstrated promising results. This study analyses the real-world impact of adding immunotherapy for patients with stage IV cervical carcinoma. This longitudinal retrospective observational study included patients with stage IV cervical carcinoma in the first metastatic setting treated between 2010 and 2023 at the University Hospital Nuestra Señora de Candelaria in Tenerife, Spain. To evaluate the primary objective, patients were divided into two groups depending on whether they had received immunotherapy with pembrolizumab or not. The primary endpoint was 12-month progression-free survival in patients receiving immunotherapy compared to those not receiving it. A total of 56 patients were analyzed, of whom 31 were tested for PD-L1. Among those tested, 25 patients (84%) were PD-L1 positive, and 18 of them (72%) received immunotherapy. The objective response rate was significantly higher, being 94% in the group that received immunotherapy, compared to 32% in the group that did not (p < 0.001). At 12months, the cumulative probability of progression-free survival was estimated at 94.4% for the immunotherapy group versus 59.7% in the non-immunotherapy group (p = 0.009), with a hazard ratio of 0.116 (CI95%: 0015 - 0.883; p = 0.038). Immunotherapy alone or combined with bevacizumab showed similar progression-free survival probabilities. However, these outcomes were significantly different when compared to patients who received neither therapy (p < 0.001). Our findings confirm that immunotherapy significantly improves progression-free survival and objective response rates in metastatic cervical carcinoma, aligning with the results from the KEYNOTE-826 trial. The implementation of PD-L1 testing and the addition of immunotherapy whenever possible are challenges to be achieved in clinical practice.

Why PD-L1 expression varies between studies of lung cancer: results from a Bayesian meta-analysis.

PD-L1 expression is an important biomarker for the management of non-small cell lung cancer (NSCLC) but has been highly heterogeneous across studies. We developed a statistical model to reconcile conflicting estimates of PD-L1 prevalence by accounting for between-study variation in test sensitivity, specimen age, and laboratory count. In doing so, we obtained refined estimates for PD-L1 expression prevalence and identified differences by histological subtype, mutational status, and stage. Across 92 studies published between 2015 and 2023, the detectability of PD-L1 declined with increasing specimen age while the consistency of detection rates was greater for studies incorporating data from a higher number of laboratories. Using the 22C3 antibody as a benchmark, we predicted that 58.3% (95% CrI 49.8-66.1%) and 27.0% (95% CrI 21.2-33.1%) of NSCLC will have PD-L1 tumour proportion scores at the ≥ 1% and ≥ 50% threshold. PD-L1 expression was lower in EGFR-mutated NSCLC and higher in NSCLC with ALK, KRAS, MET, ROS1, and RET alterations. PD-L1 expression was more common with later-stage disease. Overall, this work highlights the continuing challenge of consistency in PD-L1 testing. Although the underlying prevalence of PD-L1 expression varies in the lung cancer population based on tumour-related factors, controllable differences in testing parameters also account for variations in PD-L1 prevalence.

Real-world biomarker testing and first-line treatment patterns among locally advanced, unresectable or metastatic gastric and gastroesophageal junction adenocarcinoma patients in the US.

348 Background: Advanced-stage gastric cancer and gastroesophageal junction adenocarcinoma (advG/GEJC) are leading causes of cancer-related morbidity and mortality. Chemotherapy is the traditional first-line (1L) therapy for patients in the advanced setting, with targeted and immunotherapy considered based on biomarker expression. This study aimed to describe real-world HER2 and PD-L1 testing practices and 1L treatment patterns among advG/GEJC patients. Methods: A retrospective cohort study was conducted among adult patients diagnosed with advG/GEJC between 01 Jan 2017 and 30 Jun 2023 usingthe US-based Flatiron Health electronic health record-derived de-identified database. HER2 and PD-L1 testing practices were evaluated prior to and up to 1-month post-1L treatment initiation or 6 months post-advG/GEJC diagnosis date in untreated patients. 1L treatment regimens were described overall and stratified by HER2 and PD-L1 expression. Results: Among 4,256 advG/GEJC patients, the average age was 67 years with the majority male (68%), non-Hispanic white (44%), and with metastatic disease (64%). Nearly three quarters (72%) of patients included received a HER2 test and 55% had a HER2 test with a valid result within the timeframe mentioned above. More than a quarter of patients (27%) received a PD-L1 test and 25% had a PD-L1 test with a valid result. PD-L1 testing before the approval of nivolumab in 1L (i.e. before 2021) showed testing at 19% (490/2,629; 17% with a valid result) and from 2021 onward at 40% (643/1,627; 37% with a valid result). Across the full cohort, half of the patients received chemotherapy alone (52%) and one quarter received no treatment (25%). Similar treatment patterns were observed in the subset of 1,117 patients who did not receive a HER2 or PD-L1 test; 54% received chemotherapy alone and 36% no treatment. Of the 340 patients who were tested for HER2 and were HER2 positive, half (52%) received trastuzumab combination therapy, 23% received chemotherapy alone, and 18% had no treatment. Of the 301 patients who received a PD-L1 test with a combined positive score (CPS) ≥5 from 2021 onward, 41% received immunotherapy, 34% received chemotherapy alone and 18% had no treatment. Prior to 2021, most patients with a PD-L1 test and CPS &gt;5 used chemotherapy alone (57%; 132/233), 13% (31/233) received PD-L1 targeted therapies and 19% (43/233) received no treatment. Conclusions: This study describes a potential subset of US advG/GEJC patients who do not receive a HER2 or PD-L1 test and/or do not receive eligible targeted or immunotherapy as part of routine clinical practice. As precision medicine options continue to evolve, these data suggest an opportunity to further understand the drivers for biomarker testing as well as the factors impacting the use of biomarker-informed treatment options.

Patterns of immune checkpoint inhibitor utilization and PD-L1 testing in advanced gastroesophageal cancers using real-world data.

370 Background: Globally, gastroesophageal cancer (GEC) is a leading cause of morbidity and mortality, with poor 5-year overall survival (OS). The addition of immune checkpoint inhibitors (ICIs) such as nivolumab and pembrolizumab to chemotherapy has resulted in significant improvement in OS of those patients (pts) with metastatic GEC (mGEC), most notably in those with tumors exhibiting high PD-L1 CPS scores. However, the pattern of ICI utilization in associated PD-L1 testing since the adoption of this treatment (tx) has yet to be elucidated. We evaluated the patterns of ICI utilization and PD-L1/CPS testing in the first-line tx of mGEC pre and post FDA approval of ICI use in this setting. Methods: Pts ≥ 18 years of age, with recurrent/metastatic squamous or adenocarcinoma GEC diagnosed after 2011 were included from the de-identified nationwide Flatiron Health, electronic health record-derived database. We presented the proportion of pts receiving ICI therapy, stratified by line of tx, as well as the proportion of patients who received PD-L1 testing at 6-month intervals. Pts demographics and clinical characteristics, including age, gender, race, ECOG score, documented insurance, and stage at diagnosis (dx) were described and compared using T or Wilcoxon rank-sum tests for continuous variables, and chi-square or Fisher’s exact tests for categorical data. We compared tx rates and PDL-1 testing across four time points: time 1: Jan-June 2020, prior to ASCO data presentation; time 2: July-Dec 2020, ASCO data presentation; time 3: Jan- June 2021, FDA label change; time 4: July 2021 to 6 m after FDA label change using Chi-square test. Results: A total of 9,573 pts were included with 1,593 (16.6%) receiving ICI-based tx. Among these, 62.3% were White, 7% Black. Descriptive statistics indicated that pts with ICI- tx tend to be younger (median age 65y vs. 66.7; (p &lt;0.001). Within the total cohort, 74% pt were dx before FDA approval of ICI tx, while 26% pts were dx after FDA approval. PD-L1 testing was conducted in 4,065 (42.5%) pts. A total of 1,268 (13%) pts received first-line ICI-based tx. Of these, 154 pts (12.1%) were treated before FDA approval, while 1,114 pts (87.9%) received tx following FDA approval. The rate of first-line ICI tx significantly increased at each subsequent time point Time 2: 11.2% (p &lt;0.0001), Time 3: 32.9% (p &lt;0.0001), Time 4: 37.4% (p &lt;0.0001). PD-L1 testing rates also increased over time, particularly after FDA label change. Testing rates at Time 1 was 68%. Comparatively, testing rates at subsequent time points were: Time 2 (67.2%; p 0.88), Time 3 (71.5%; p 0.324) and Time 4 (77.4%; p=0.004). Conclusions: The approval of ICIs for first-line tx of mGEC led to a significant increase in both ICI utilization and PD-L1/CPS testing rates. Despite these advancements, ongoing disparities in tx access and testing highlight the need for further research and efforts to ensure equitable care.

PD-L1 testing patterns in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) in the U.S.

Pembrolizumab with/without platinum+5-FU is approved for the first-line (1L) treatment of R/M HNSCC, and its monotherapy use requires PD-L1 Combined Positive Score (CPS)≥1. We aimed to understand PD-L1 testing patterns and associations with patient characteristics and treatment choice in R/M HNSCC. Adults with R/M HNSCC initiating 1L systemic therapy were included from a U.S. nationwide database primarily compromised of community practices (07/01/2019-12/31/2023). PD-L1 testing patterns, treatment sequence, and time gaps related to testing and treatment initiation were summarized. Logistic regression was used to test associations between patient characteristics and PD-L1 testing patterns, and between CPS scores and 1L pembrolizumab monotherapy use. Of 2,207 patients, 32.7% received PD-L1 testing before 1L therapy initiation, 17.4% after 1L therapy initiation, and 50.0% were never tested. Most patients (55.9%) who tested positive before 1L therapy received pembrolizumab monotherapy while those who tested negative received pembrolizumab+platinum+5-FU most commonly (31.6%). Among patients untested before 1L therapy, the most common 1L treatment was pembrolizumab monotherapy (24.3%). Patients with an ECOG≥2 had higher odds of being tested before 1L therapy (OR: 1.42, p<0.01). CPS scores were associated with higher odds of receiving 1L pembrolizumab monotherapy (OR: 4.11 and 4.96 for CPS 1-19 and≥20, respectively; both p<0.0001). This study revealed low utilization of PD-L1 testing to guide treatment choice and impactful gaps between specimen collection, the receipt of results, and 1L therapy initiation. There is a need to improve clinician awareness of the importance of PD-L1 testing and an opportunity for updated guidelines on testing.

Real-world biomarker testing patterns, first line treatment and drivers of treatment choice in patients with advanced/metastatic gastric/gastroesophageal junction adenocarcinoma in the United States and Europe.

353 Background: For first line (1L) treatment (tx) in HER2- gastric/gastroesophageal junction (G/GEJ) adenocarcinoma (AC), clinical guidelines recommended platinum-fluoropyrimidine (PF) chemotherapy (CT) in patients (pts) with a PD-L1 combined positive score (CPS) &lt;5 and PF CT in combination with immunotherapy (IO) for CPS ≥5. There is little contemporary evidence into IO tx uptake in the real world. This real world study examined biomarker testing, 1L tx characteristics, and reasons for 1L tx choice in pts with HER2- G/GEJ AC to identify unmet needs and opportunities for optimal clinical practice. Methods: Data were derived from the Adelphi G/GEJ Cancer Disease Specific Programme: a systematic approach involving multi-national, multi-faceted data sources including cross-sectional surveys capturing data from physicians and their consulting pts. Physicians reported pt demographics, clinical characteristics, tx received and reasons for tx decisions, via chart review. Data were collected across US and Europe (EU: France, Germany, Spain, the UK) between Oct 2022 to Apr 2023. All pts were alive at data collection and analyses were descriptive. Results: Overall, 243 treating physicians (US n=60/EU n=183) provided data on 642 HER2- pts (US n=83/EU n=559) receiving 1L tx at data collection. For pts from US/EU, median age was 66/67 years, 84%/79% had an ECOG of 0-1 and 52%/75% had metastatic disease at data collection. In the US/EU, 87%/80% of pts were tested for PD-L1 status respectively, of which 63%/69% had a known CPS. For US/EU, 67%/45% of pts (n=30/n=139) had a CPS ≥5. Differences in biomarker testing rates were observed in US v EU pts respectively for MSI/dMMR (66% v 58%), NTRK-gene fusion (31% v 4%) and FGFR2 (27% v 3%). Of US/EU physicians, 70%/85% (n=60/n=183), reported the main reason for conducting biomarker testing was ‘to inform tx decisions’. Cost related concern (50%/39%) and time constraints (23%/15%) were the main perceived barriers to testing. Among pts with PD-L1 CPS &lt;5, 27% of US pts and 2% of EU pts received IO + CT; in pts with CPS ≥5, 63% of US pts and 76% of EU pts received IO + CT. Whilst progression free survival/overall survival benefit were the most common reasons selected by physicians for 1L tx choice across the US/EU (75%/74% and 60%/61%), differences across regions were reported for tx choice based on maintaining and improving pt’s QoL (4%/28%) and pt’s performance status (2%/24%). Conclusions: PD-L1 testing was not performed by 19% of physicians and approximately one third of pts with CPS ≥5 across the US/EU were not receiving IO + CT in 1L. As informing 1L tx choice was a key driver for biomarker testing, there may be scope for improvement in 1L tx by increasing testing rates. Further studies are needed to address barriers to biomarker testing and uptake of IO in pts who can benefit from 1L IO tx.

Clinicopathological factors of ovarian clear cell carcinoma: A single institutional analysis of 247 cases in China.

Ovarian clear cell carcinoma (OCCC) is a subtype of ovarian cancer with a poor prognosis that often shows resistance to chemotherapy. This study retrospectively analyzed 247 patients with OCCC who were admitted to the Cancer Hospital of the Chinese Academy of Medical Sciences (CAMS) between August 2007 and August 2023. Univariate and multivariate Cox regression analyses were used to identify clinicopathological factors associated with OCCC, and a nomogram prediction model was developed to predict OCCC patient survival outcomes. Kaplan‒Meier survival analysis was used to compare survival outcomes among patients with recurrent disease. Compared with systemic therapy, secondary debulking surgery significantly improved the postrecurrence survival (PRS) rate (P = 0.006). Subgroup analysis revealed that the survival benefit was more pronounced in patients with recurrence and satisfactory tumor shrinkage (PPRS = 0.01, PPFS2 = 0.047). The multivariate analysis revealed that positive preoperative ascites, incomplete remission following initial treatment, and undergoing more than six cycles of postoperative chemotherapy were independent prognostic factors affecting overall survival (OS). Additionally, patients with a positive PD-L1 test who received immunotherapy did not experience relapse during the follow-up period. In conclusion, the secondary clearance procedure offers significant benefits for patients with recurrent OCCC, and patients may experience a survival benefit from supplemental immune or targeted therapy at the end of chemotherapy. The development of a personalized treatment plan can help achieve precise treatment, improve prognosis, and enhance patients' quality of life.

Cost-effectiveness analysis of PD-L1 testing associated with pembrolizumab for first-line treatment of advanced non-small cell lung cancer in China.

Lung cancer is the leading cause of cancer-related deaths in China, and pembrolizumab shows differential efficacy in advanced non-small cell lung cancer (NSCLC) with different PD-L1 expression levels. To assess the cost-effectiveness of PD-L1 testing associated with pembrolizumab for first-line treatment of NSCLC from the perspective of Chinese healthcare system. Over a lifetime horizon, a three-state partitioned survival model was developed to assess the cost-effectiveness of PD-L1 testing and no PD-L1 testing. In the PD-L1 testing group, patients were stratified by PD-L1 tumor proportion score ≥ 50%, 1-49%, or < 1% and received pembrolizumab monotherapy, pembrolizumab plus chemotherapy, or chemotherapy alone, respectively. In the non-PD-L1 testing group, all patients received pembrolizumab plus chemotherapy. Model inputs were obtained from published literature and a healthcare price database, and clinical outcomes from two randomized clinical trials were used. The net monetary benefit (NMB) was estimated for the PD-L1 testing group versus the non-PD-L1 testing group. Deterministic and probabilistic sensitivity analyses, and scenario analyses were conducted to assess robustness of results. Using PD-L1 testing to guide treatment led to cost savings of $49,392.7 and a reduction in quality-adjusted life years (QALYs) of 0.234, resulting in a positive NMB of $46,421.7 at a willingness-to-pay (WTP) threshold of $12,680.8/QALY (GDP per capita in China, 2023). Findings were robust across sensitivity and scenario analyses. Using PD-L1 testing to guide first-line pembrolizumab treatment in patients with advanced NSCLC is a cost-effective strategy at a WTP threshold of $12,680.8/QALY for China.

A real-world study of PD-L1 testing patterns and PD-1/PD-L1 inhibitor therapy in patients with metastatic non-small cell lung cancer: An analysis of the Sotiria Hospital lung cancer registry

A real-world study of PD-L1 testing patterns and PD-1/PD-L1 inhibitor therapy in patients with metastatic non-small cell lung cancer: An analysis of the Sotiria Hospital lung cancer registry

Impact of a PD-L1 Learning Collaborative: outcomes from a mixed-methods evaluation

Abstract Introduction/Objective PD-L1 Immunohistochemistry testing is often required to determine eligibility for immune checkpoint inhibitor therapy. An ASCP PD-L1 Learning Collaborative (LC) was formed aiming to: 1) identify ways to streamline PD-L1 testing; 2) encourage members to locally implement changes; and 3) develop a resource guide for the community. Methods/Case Report The PD-L1 LC (n=38 pathologists and laboratory professionals) participated in 3 activities: 1) 4 meetings in which LC members discussed current literature and practice; 2) 3 30-minute on-demand, credit-bearing panel videos, in which selected LC members summarized the LC outputs and shared their experiences; and 3) a guide summarizing resources relevant to streamlining PD-L1 testing. The mixed-methods evaluation included: 1) five- minute surveys before (n=24), immediately after (n=11) and 7-months post-LC (n=17); 2) polling questions (2-4 per meeting); 3) semi-structured interviews (n=5). Quantitative data was analysed using descriptive and inferential analysis, qualitative data using a thematic analysis / inductive reasoning approach. Results (if a Case Study enter NA) Baseline data confirmed delays in testing caused by unstandardized PD-L1 testing processes and suboptimal confidence in PD-L1 validation and methodologies. Post-LC, members self-reported perceived increased knowledge and higher confidence levels regarding discussion of PD-L1 scientific evidence and best practices. At the 7-month follow-up, 59% of respondents reported at least one PD-L1-related practice change, with 29% of participants selecting:1) Improving protocols for specimen acquisition, handling, or processing; 2) Improving communication with multidisciplinary care team; 3) Optimizing biomarker testing workflows. Remaining suboptimal knowledge post-LC suggests need for further educational efforts. Participants identified “Tumor-specific considerations” as the main resource missing for PD-L1 testing. Conclusion A learning collaborative has shown impact in improving PD-L1 testing processes and related practices among a group of pathology professionals. The group successfully made available three panel videos and a resource guide, and PD-L1-related practice changes were reported. Future initiatives should address remaining gaps and develop tumor-specific PD-L1 testing considerations.

Can multiplexing Immunohistochemistry for PD-L1, CD68, and CD3 improve scoring for “Keytruda®” Indication?

Abstract Introduction/Objective FDA-approved companion diagnostics immunohistochemistry scoring for PD-L1 is essential for Keytruda ® treatment in patients with NSCLC. The challenge with PD-L1 testing alone is false positive PD-L1 expression score due to alveolar macrophage infiltration. Multiplexing with PD-L1, CD68, and CD3 could help alleviate this issue. By viewing PD-L1 expression on tumor cells, CD68 expression on macrophages, and the presence of CD3+ T cells on a single slide, pathologists will be able to see the presence of an immune microenvironment (high PD-L1 expression with abundant macrophages) and the potential for response to other types of Immunotherapies (presence of T cells). Methods/Case Report Positive NSCLC FFPE blocks were sectioned and stained using Agilent Dako Omnis. Two combinations of multiplex staining were prepared for each block by staining PD-L1 (brown) alone first followed by CD3 and CD68. First slide: CD3(Vina Green), CD68(Magenta); Second slide: CD3(Magenta), CD68(Vina Green). To prevent wash out, dehydration and clearing occurred with two changes of 100% alcohol and three changes of xylene for manual cover slipping. Results (if a Case Study enter NA) Manual scoring of PD-L1 alone vs two different multiplex combinations was compared to Agilent Proscia digital AI scoring using a preliminary study set (9 positives, 2 negatives). CD68-green and CD3-magenta showed better discrimination than CD68-magenta and CD3-green at a glance. This could be due to the staining intensity and nonspecific background staining of CD68-magenta. Manual scoring was higher compared to digital scoring, which could be due to the human error of positive bias. Digital scoring was significantly lower for PD-L1 alone vs both multiplex stains. The digital scoring for the multiplex stains showed a higher scoring percentage by removing false positive macrophages. Conclusion Reflex scoring workflow is being developed to focus on difficult cases using the multiplex triple stain, i.e. clear negative and clear &amp;gt;50% with 3+ intensity. More cases will be collected and studied to further investigate the improved PD-L1 scoring with digital imaging assisted by artificial intelligence and to compare the multiplex color combinations.

EP.17E.04 Cost-Effectiveness of PD-L1 Testing for Guiding Immunotherapy in Non-Small Cell Lung Cancer (Stage IIA-IIIB & Stage IV) Patients in China

EP.17E.04 Cost-Effectiveness of PD-L1 Testing for Guiding Immunotherapy in Non-Small Cell Lung Cancer (Stage IIA-IIIB & Stage IV) Patients in China

Brightfield Multiplex Immunohistochemistry Assay for PD-L1 Evaluation in Challenging Melanoma Samples.

Targeting the PD1/PD-L1 immune checkpoint pathway has rapidly become a therapeutic strategy for melanoma patients. Indeed, the quantification of PD-L1 expression by immunohistochemistry (IHC) in melanoma samples is already required, in some contexts, to allow access to anti-PD-1/PD-L1 immunotherapy. Despite a rising demand for PD-L1 testing, paralleling increasing cumulative experience in its assessment and quantification, it is fair to recognize that PD-L1 evaluation in melanoma samples still presents some critical issues. The aim of this technical report is to develop and validate a multiplex double staining protocol for PD-L1/SOX10 in Ventana Benchmark Ultra for routine practice. Our results show that double labeling provides the necessary tools to identify PD-L1 + melanoma cells clearly. The simultaneous visualization of 2 different proteins targets allows the topographical relationship between the 2 labeling to be evaluated within the context of the tissue morphology. Future studies are needed to test this technique's real-world applicability and effectiveness in implementing interpathologist agreement.

Effect on Non-Small Cell Lung Cancer after Combination of Driver Gene Mutations and Anti-PD-1/PD-L1 Immunotherapy as Well as Chemotherapy.

We aimed to reveal the correlation between pathological indicators and PD-L1, between gene mutation status in lung cancer through clinico-pathological data and lung cancer-related gene mutation and PD-L1 expression analysis. The study was conducted in Jinhua Municipal Central Hospital, Zhejiang, China from 2017 to 2022. PD-L1 testing and targeted gene mutations detection were evaluated. The clinical characteristics of these non-small cell lung cancer (NSCLC) samples have been obtained. The groups (LUAD, n=142; LUSC, n=143) were grouped according to clinico-pathological features and PD-L1 expression (Yes/No or High/Low), and the clinico-pathological and genetic and molecular features and correlation with PD-L1 expression were compared across the above groups. Comparisons and analyses were made between different treatment schemes. Lung adenocarcinoma (LUAD, n=142) and lung squamous carcinoma (LUSC, n=143) samples were enrolled (median age: 64 years old). Pleural invasion and M staging were significantly different from PD-L1 alterations (P<0.05). The percentage of patients with PD-L1 tumor proportion score (TPS)≥50% was 36.24% and the percentage of patients with PD-L1 TPS<50% was 29.53%. The percentage of patients with PD-L1 high-expressed and treated by immunotherapy was 75.93% and 63.41% experienced Partial Response/Complete Response. The mutations ratio of EGFR, ALK, KRAS, MET, RET and TP53 were 28.86%, 1.34%, 6.04%, 0.67%, 1.34% and 0.67%, respectively. KRAS mutation was significantly different from PD-L1 alterations (P<0.01). There are individual differences in PD-L1 expression, which can also vary depending on the different clinical features. Specific molecular features correlate with differential PD-L1 expression and may influence the response to therapy.

First-line (1L) anti-PD-1 plus chemotherapy in HER2-negative advanced gastric cancer: Real-world evidence from a single Korean center.

83 Background: The implementation of immune checkpoint inhibitor combinations as first-line (1L) treatment has shown promising outcomes and is now the standard of care for HER2-negative advanced gastric cancer. However, real-world evidence supporting this approach as 1L treatment remains limited. Here, we present an analysis of real-world outcomes, comparing 1L anti-PD-1 combined with doublet chemotherapy to the previous standard chemotherapy. Methods: Patient from January 2005 to August 2023 were retrospectively reviewed. The study defined the molecular epidemiology cohort (M cohort) as patients with results for HER2, Epstein-Barr virus (EBV), mismatch repair (MMR), or PD-L1. HER2-negative patients who received palliative first-line chemotherapy doublet regimens with or without PD-1 inhibitor were included. Survival analysis included progression-free survival (PFS) and overall survival (OS), as well as subgroup analyses for molecular subtypes. Results: Total 3,028 were enrolled in the M cohort. The incidence rates of HER2-positive, EBV-positive, and deficient Mismatch Repair (dMMR) were 20.0% (606/3028), 3.8% (93/2432), and 4.7% (126/2660), respectively. PD-L1 testing was conducted on 1,394 patients, with 54.3% (1634/3028) having a CPS (Combined Positive Score) of ≥10, and 47.6% (664/1394) having a CPS of ≥1. Among these patients 1,527 had received chemotherapy doublet, and 153 had received chemotherapy doublet with PD-1 inhibitor as their 1L treatment. During a median follow-up of 56.5 months (95% CI,49.9-66.2), patients who had received PD-1 inhibitor combination therapy showed improved PFS (7.1 vs. 6.1 months; Hazard Ratio [HR], 0.77; 95% Confidence Interval [CI], 0.64–0.93) and OS (18.1 vs. 14.6 months; HR 0.80; 95% CI, 0.63–1.01) compared to those without it. The benefits in PFS from PD-1 inhibitor combination therapy were particularly notable in patients with deficient MMR status (HR, 0.22 vs. 0.80 in those without PD-1 inhibitor combination; p for interaction &lt;0.05) and in patients with signet ring cell carcinoma histology (HR, 0.58 vs. 0.92 in those without PD-1 inhibitor combination; p for interaction &lt;0.05). Conclusions: We observed real-world efficacy of the combination of PD-1 inhibitor and chemotherapy doublet as 1L treatment for HER2-negative advanced gastric cancer, consistent with previous clinical trials. [Table: see text]

SUNRAY-01, a pivotal, global study of olomorasib (LY3537982) in combination with pembrolizumab with or without chemotherapy for 1L treatment in KRAS G12C-mutant advanced NSCLC.

TPS218 Background: Mutations in KRAS are among the most frequent oncogenic drivers with the G12C variant found in ~13% of NSCLC. Outcomes for KRAS G12C-mutant NSCLC may be improved by combining KRAS G12C inhibitors with current 1L standard of care (SOC). Olomorasib is a potent and highly selective second-generation inhibitor of KRAS G12C, which delivers &gt;90% sustained target occupancy in preclinical models. In the LOXO-RAS-20001 phase 1/2 study, olomorasib in combination with pembrolizumab demonstrated preliminary efficacy and a favorable safety profile.1 Methods: SUNRAY-01 (NCT06119581) is a pivotal, global, phase 3 study in 1L advanced KRAS G12C-mutated NSCLC designed to seamlessly 1) optimize the dosing of olomorasib in combination with 1L SOC, and then 2) compare efficacy and safety of olomorasib plus SOC with placebo plus SOC. In the open-label randomized dose optimization (pembrolizumab plus olomorasib 50 mg vs 100 mg BID) and single arm safety lead-in (olomorasib plus pembrolizumab, pemetrexed, platinum), the optimal dose of olomorasib for combination therapy will be determined before the phase 3 study (parts A and B) is opened for enrollment. In part A, 384 participants with PD-L1 expression ≥50% are randomized (1:1) to pembrolizumab plus olomorasib or placebo. In part B, 552 participants are randomized (1:1) to pembrolizumab, pemetrexed, platinum plus olomorasib or placebo regardless of PD-L1 expression. Allocation of participants with PD-L1 expression ≥50% to either part A or part B will be at the discretion of the investigator. The primary objective is to compare efficacy based on PFS per RECIST v1.1 by blinded independent central review. Secondary endpoints include OS, ORR, DOR, DCR, TTR, PFS2, safety and tolerability, and patient-reported outcomes. Eligible participants (≥18 years) must have a KRAS G12C mutation in tumor or blood and known PD-L1 expression (0-100%), stage IIIB, IIIC, or IV NSCLC not suitable for curative intent radical surgery or radiation therapy, measurable disease per RECIST v1.1, and an ECOG PS 0-1. Participants can be enrolled based on local KRAS and PD-L1 testing results. Participants should not have received prior systemic therapy for advanced or metastatic NSCLC, however 1 cycle of SOC treatment prior to enrollment is allowed if immediate treatment is clinically indicated. Participants with asymptomatic (lesions ≤1.5 cm) or previously treated radiographically stable brain metastases are eligible. Key exclusion criteria include history of pneumonitis/interstitial lung disease and clinically significant active cardiovascular disease or malabsorption syndrome. The study opened for enrollment in December 2023. Reference: 1. Murciano-Goroff et al. 2023 Cancer Res 83 (8 Suppl): CT028. Clinical trial information: NCT06119581 .

Muscle-invasive and metastatic urothelial carcinoma of the urinary bladder : Current state of histopathologic, molecular, and immunologic prognostic and predictive factors

Muscle-invasive and metastatic urothelial carcinoma (UC) represents aheterogeneous disease entity with numerous morphological, molecular, and immunological phenotypes. This article aims to provide an overview of current histopathological, molecular, and immunological prognostic and predictive factors in muscle-invasive and metastatic UC. Muscle-invasive and metastatic UC exhibits awide range of divergent differentiations and histological subtypes. The correct diagnosis of these morphological variants is essential, as they may determine the clinical course and may also present specific and potentially therapeutically targetable molecular alterations (e.g., HER2 alterations in micropapillary UC). The morphological subtypes largely correlate with the six molecular consensus subtypes. Furthermore, morphological and molecular subtypes are associated with immunological properties that are relevant for modern immunotherapies, such as the PD-L1 status. Numerous immunotherapy studies in the setting of curatively treatable muscle-invasive UC will be reported in 2024 and 2025, likely leading to an increasing number of PD-L1 testing indications.

Real-World Biomarker Test Ordering Practices in Non-Small Cell Lung Cancer: Interphysician Variation and Association With Clinical Outcomes.

Patients with metastatic or advanced non-small cell lung cancer (NSCLC) need biomarker testing, including, in most cases, anaplastic lymphoma kinase (ALK), epidermal growth factor receptor (EGFR), and PD-L1, to identify options for targeted therapies and to optimally incorporate immune checkpoint inhibitors into therapeutic regimens. We sought to examine real-world patterns of biomarker testing, quantify interphysician practice variation, and correlate testing with clinical outcomes. We extracted real-world data from a nationwide electronic health record-derived deidentified database from 17,165 patients diagnosed with advanced NSCLC between 2018 and 2021 and receiving care in the community setting. We analyzed data using descriptive analyses, fixed- and mixed-effects logistic regression models, and proportional hazard models. Only 67% of all 17,165 patients and 77% of patients with nonsquamous, metastatic NSCLC had ALK, EGFR, and PD-L1 testing within 90 days of diagnosis. Later diagnosis year (2019-2021 compared with 2018) was associated with higher rates of ALK, EGFR, and PD-L1 testing; stage IIIB/C disease (compared with stage IV), squamous histology, and Black or African American race were associated with lower rates. Interphysician variation was substantial with a median odds ratio between physicians (adjusted for patient factors) of 1.78 for ALK, EGFR, and PD-L1 testing. Patients with nonsquamous, metastatic NSCLC had significantly prolonged survival if tested with all three biomarkers (median, 364 days for all three v 180 for none of the three; hazard ratio, 0.67; P < .001). Rates of biomarker testing appear suboptimal with substantial interphysician variation. Testing correlates with improved survival, although causality cannot be proven from this study. Additional work is needed to address the underlying causes of suboptimal test ordering.

The influence of PD-L1 expression levels on the efficacy of combination therapy in thymic epithelial tumors.

The significant expression of PD-L1 in thymic epithelial tumors (TETs) has been confirmed, and immunotherapy and its combination therapy have been effective in TETs. However, there is no present evidence that the expression levels of PD-L1 affects the efficacy of combination therapy. Our study aimed to shed light on this relationship. Patients with thymic epithelial tumors (TETs) from multicenter hospitals were retrospectively identified. Objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and immune-related adverse events (irAEs) in 22 patients were included. We divided the patients the 22 patients with PD-L1 test into three levels (high expression, low expression and no expression) and analyzed the relationship between the levels of PD-L1 expression and the efficacy of combination therapy. Combination therapy showed an effective benefit in 22 patients with TETs, the median PFS (mPFS) was 16 months (95% CI: 8.5-23.5) and the median OS (mOS) was 38 months (95% CI: 21.5-54.5). Cox-regressive analysis found whether PD-L1 expression affected the PFS of patients (p = 0.017). Among the patients with PD-L1 expression, the levels of expression were correlated with curative effect (Kruskal-Wallis test, PFS: P = 0.012; OS: P = 0.01), and high expression group was along with better efficacy than low expression (Wilcoxon test, P = 0.01). Moreover, in 17 patients treated with immunotherapy combined with chemotherapy, the expression of PD-L1 was also associated with efficacy (Kruskal-Wallis test, p = 0.021). PD-L1 expression affects the PFS of patients. High expression of PD-L1 patients with TETs responded better to combination therapy, which could provide a therapeutic option in clinic. Besides, other targeted treatments should be considered.