Immune Checkpoint Inhibitor Monotherapy Research Articles

Checkpoint Inhibitors in Combination With Stereotactic Body Radiotherapy in Patients With Advanced Solid Tumors

Although immune checkpoint inhibitors (ICIs) targeting programmed cell death 1 (PD-1) and PD-1 ligand 1 have improved the outcome for many cancer types, the majority of patients fails to respond to ICI monotherapy. Hypofractionated radiotherapy has the potential to improve the therapeutic ratio of ICIs. To assess the addition of radiotherapy to ICIs compared with ICI monotherapy in patients with advanced solid tumors. This open-label, multicenter, randomized phase 2 trial was conducted in 5 Belgian hospitals and enrolled participants between March 2018 and October 2020. Patients 18 years or older with locally advanced or metastatic melanoma, renal cell carcinoma, urothelial carcinoma, head and neck squamous cell carcinoma, or non-small cell lung carcinoma were eligible. A total of 99 patients were randomly assigned to either the control arm (n = 52) or the experimental arm (n = 47). Of those, 3 patients (1 in the control arm vs 2 in the experimental arm) withdrew consent and thus were not included in the analysis. Data analyses were performed between April 2022 and March 2023. Patients were randomized (1:1) to receive anti-PD-1/PD-1 ligand 1 ICIs alone as per standard of care (control arm) or combined with stereotactic body radiotherapy 3 × 8 gray to a maximum of 3 lesions prior to the second or third ICI cycle, depending on the frequency of administration (experimental arm). Randomization was stratified according to tumor histologic findings and disease burden (3 and fewer or more than 3 cancer lesions). The primary end point was progression-free survival (PFS) as per immune Response Evaluation Criteria in Solid Tumors. Key secondary end points included overall survival (OS), objective response rate, local control rate, and toxic effects. Efficacy was assessed in the intention-to-treat population, while safety was evaluated in the as-treated population. Among 96 patients included in the analysis (mean age, 66 years; 76 [79%] female), 72 (75%) had more than 3 tumor lesions and 65 (68%) had received at least 1 previous line of systemic treatment at time of inclusion. Seven patients allocated to the experimental arm did not complete the study-prescribed radiotherapy course due to early disease progression (n = 5) or intercurrent illness (n = 2). With a median (range) follow-up of 12.5 (0.7-46.2) months, median PFS was 2.8 months in the control arm compared with 4.4 months in the experimental arm (hazard ratio, 0.95; 95% CI, 0.58-1.53; P = .82). Between the control and experimental arms, no improvement in median OS was observed (11.0 vs 14.3 months; hazard ratio, 0.82; 95% CI, 0.48-1.41; P = .47), and objective response rate was not statistically significantly different (22% vs 27%; P = .56), despite a local control rate of 75% in irradiated patients. Acute treatment-related toxic effects of any grade and grade 3 or higher occurred in 79% and 18% of patients in the control arm vs 78% and 18% in the experimental arm, respectively. No grade 5 adverse events occurred. This phase 2 randomized clinical trial demonstrated that while safe, adding subablative stereotactic radiotherapy of a limited number of metastatic lesions to ICI monotherapy failed to show improvement in PFS or OS. ClinicalTrials.gov Identifier: NCT03511391.

The gut microbiome affects response of treatments in HER2-negative advanced gastric cancer.

Common treatments for metastatic/unresectable HER2-negative gastric cancer include chemotherapy, immune checkpoint inhibitor monotherapy and chemotherapy plus immune checkpoint inhibitor. However, significant drug resistance exists regardless of the treatment regimen. Patients with metastatic/unresectable HER2-negative gastric/gastroesophageal junction adenocarcinoma were enrolled. All patients were divided into three groups according to the treatment regimen and were further divided into responders and non-responders according to efficacy evaluation. Metagenomics sequencing were performed to analyze gut microbiome signature of patients receiving different treatments at baseline and throughout treatment. One hundred seventeen patients with HER2-negative advanced gastric or gastroesophageal junction adenocarcinoma receiving chemotherapy alone, anti PD-1/PD-L1 immunotherapy alone or combined regimen were included in this study. Microbiome signatures related to clinical response are distinct among the three treatment groups. Among which, 14, 8 and 13 species were significantly different between responders and non-responders in immunotherapy, immunotherapy plus chemotherapy and chemotherapy group, respectively. Patients with higher relative abundance of Lactobacillus possessed higher microbiome diversity and significantly better response to anti-PD-1/PD-L1 immunotherapy and had a trend to achieve better progression-free survival. Another cohort of 101 patients has been used as an external validation set to confirm the stability and reliability of these findings. Gut microbiome affects response of treatments in HER2-negative advanced gastric cancer in a treatment-specific way, immunotherapy plus chemotherapy did not equal to a simple superposition of immunotherapy and chemotherapy. Lactobacillus is expected to become a novel choice as an adjuvant agent in promoting the efficacy of immunotherapy in gastric cancer.

Tumor-infiltrating lymphocytes predict efficacy of immunotherapy in advanced non-small cell lung cancer: a single-center retrospective cohort study

Background/Purpose The current study aimed to investigate the correlation between tumor-infiltrating lymphocytes (TILs) and immunotherapy efficacy in patients with advanced non-small cell lung cancer (NSCLC). Materials and methods Eighty-nine patients with advanced NSCLC who received immune checkpoint inhibitors (ICIs) monotherapy were retrospectively enrolled in this study. The density of TILs in paraffin-embedded pathological tissues taken before receiving ICIs was quantitatively analyzed by immunohistochemical staining. The density of TILs was treated as a dichotomous variable using the median as the cutoff value. The Kaplan–Meier analysis was used to assess survival differences between groups. Univariate and multivariate Cox analyses were applied to screen out independent prognostic factors and further construct a nomogram prediction model to predict survival. Results Survival analysis showed that CD8+ TILs, CD4+ TILs, and IFN-γ+ Th1 were significant positive indicators for predicting progression-free survival (PFS) and overall survival (OS) (p < 0.05), whereas Foxp3+ Treg were a significant negative predictor (p < 0.05). The predictive role of IL-4+ Th2 was not apparent in this study and requires further investigation and exploration (p > 0.05). The nomogram prediction model exhibited good discriminative ability, with C-index values of 0.723 (95% CI 0.682-0.764) and 0.793 (95% CI, 0.738-0.848) in the training cohort and validation cohort, respectively. The AUC values indicated that the nomogram prediction model had high predictive value and the calibration curve presented good prediction accuracy. Conclusions TILs could predict the efficacy of immunotherapy and may become a promising predictor.

Physicianreported treatment patterns and outcomes in metastatic bladder cancer in the USA: the CancerMPact® Survey 2020.

Aim: This study assessed physician-reported treatment patterns for metastatic bladder cancer. Materials & methods: A total of106 USA-based physicians were surveyed in 2020 using the CancerMPact® online survey. Results: Among cisplatin-eligible patients, 86.1% received first-line (1L) platinum-containing chemotherapy, most commonly cisplatin plus gemcitabine, and 9.8% received immune checkpoint inhibitor monotherapy. Among cisplatin-ineligible patients, 46.5% received 1L platinum-containing chemotherapy, most commonly carboplatin plus gemcitabine and 46.2% received 1L immune checkpoint inhibitor therapy. Approximately 44% of patients who received 1L treatment received second-line (2L) therapy after progression. Conclusion: Platinum-containing chemotherapy was the most widely reported 1L treatment approach. A high proportion of patients received no 2L therapy. Validation in an updated dataset is warranted following the practice-changing approvals of avelumab 1L maintenance and additional 2L options.

Overcoming Resistance to Immune Checkpoint Inhibitor Therapy Using Calreticulin-Inducing Nanoparticle.

Nanoparticles (NPs) have the ability to transform poorly immunogenic tumors into activated 'hot' targets. In this study, we investigated the potential of a liposome-based nanoparticle (CRT-NP) expressing calreticulin as an in-situ vaccine to restore sensitivity to anti-CTLA4 immune checkpoint inhibitor (ICI) in CT26 colon tumors. We found that a CRT-NP with a hydrodynamic diameter of approximately 300 nm and a zeta potential of approximately +20 mV induced immunogenic cell death (ICD) in CT-26 cells in a dose-dependent manner. In the mouse model of CT26 xenograft tumors, both CRT-NP and ICI monotherapy caused moderate reductions in tumor growth compared to the untreated control group. However, the combination therapy of CRT-NP and anti-CTLA4 ICI resulted in remarkable suppression of tumor growth rates (>70%) compared to untreated mice. This combination therapy also reshaped the tumor microenvironment (TME), achieving the increased infiltration of antigen-presenting cells (APCs) such as dendritic cells and M1 macrophages, as well as an abundance of T cells expressing granzyme B and a reduction in the population of CD4+ Foxp3 regulatory cells. Our findings indicate that CRT-NPs can effectively reverse immune resistance to anti-CTLA4 ICI therapy in mice, thereby improving the immunotherapeutic outcome in the mouse model.

Selected cutaneous adverse events in patients treated with ICI monotherapy and combination therapy: a retrospective pharmacovigilance study and meta-analysis.

Introduction: Cutaneous adverse events are commonly reported immune-related adverse events (irAEs), some of which are serious or even life-threatening, and it is essential to study these specific cutaneous AEs to understand their characteristics and risk. Methods: We performed a meta-analysis of published clinical trials for immune checkpoint inhibitors (ICIs) to evaluate the incidence of cutaneous adverse events, using data from PubMed, Embase, and the Cochrane Library databases. Results: A total of 232 trials with 45,472 patients were involved. Results showed that anti-PD-1 and targeted therapy combinations were associated with higher risk for most of the selected cutaneous adverse events. In addition, a retrospective pharmacovigilance study was conducted using the Food and Drug Administration (FDA) Adverse Events System database. Reporting odds ratio (ROR) and Bayesian information components (IC) were used to perform the disproportionality analysis. Cases were extracted from January 2011 to September 2020. We identified 381 (20.24%) maculopapular rash, 213 (11.32%) vitiligo, 215 (11.42%) Stevens-Johnson syndrome (SJS), and 165 (8.77%) toxic epidermal necrolysis (TEN) cases. For vitiligo, anti-PD-1/L1 combined with anti-CTLA-4 therapy showed the strongest signal (ROR: 55.89; 95% CI: 42.34-73.78; IC025: 4.73). Palmar-plantar erythrodysesthesia (PPE) was reported with the most significant association with combined anti-PD-1/L1 and VEGF (R)-TKIs (ROR: 18.67; 95% CI: 14.77-23.60; IC025: 3.67). For SJS/TEN, antiPD-1 inhibitors showed the strongest signal (ROR: 3.07; 95% CI: 2.68-3.52; IC025: 1.39). The median onset time of vitiligo and SJS/TEN was 83 and 24 days, respectively. Conclusion: Overall, in selected cutaneous AEs, each of them showed specific characteristics. It is necessary to realize their differences and take appropriate interventions in patients with different regimens.

AI-based radiomic biomarkers to predict PD-(L)1 immune checkpoint inhibitor response within PD-L1 high/low/negative expression categories in stage IV NSCLC.

1517 Background: Recent efforts exploring the utility of quantitative imaging (radiomic) biomarkers to predict response to immune checkpoint inhibitors (ICI) have shown promise to provide a more accurate and scalable method than biopsy-based PD-L1 IHC and tumor mutation burden. One of the challenges of evaluating ICI biomarkers on retrospective real-world data is the inherent association between a physician’s treatment choice and PD-L1 expression status. This work investigates radiomics-based multi-modal biomarkers within patient cohorts receiving first-line therapy (ICI monotherapy, ICI plus chemotherapy, and chemotherapy), and in cohorts of all patients receiving ICI (all-lines) subdivided by PD-L1 expression. Methods: Using a large multi-institutional real-world dataset, we analyzed radiomic characteristics of 6,295 primary and metastatic lesions from 1,206 stage IV NSCLC patients treated with PD-(L)1 ICIs from nine institutions across the US and Europe. Patients with unavailable imaging follow-up or with EGFR/ALK oncogenic driver mutations were excluded from analysis, resulting in a total dataset of 791 subjects randomly assigned to training (N = 541) and validation sets (N = 250). Radiomic data was extracted from baseline CT scans capturing tumor heterogeneity, spicularity, and burden in the lung, lymph nodes, and liver. A multi-modal ensemble classifier combining demographic features, PD-L1 TPS, and radiomic data was developed to predict response to ICI therapy per RECIST 1.1 criteria. The model's performance was evaluated in terms of the area under the receiver operating characteristic curve (ROC-AUC) and compared to PD-L1 IHC using the two-tailed DeLong test. Results: In first-line cohorts, the model identified responders with an ROC-AUC of 0.83 (0.72-0.94, P = 0.005; N = 80, 81% PD-L1 &gt; = 50%) in ICI monotherapy, 0.65 (0.47-0.83, P = 0.28; N = 78, 71% PD-L1 &lt; 50%) in ICI plus chemotherapy, and 0.38 (0.002-0.76, P = 0.53; N = 37) in chemotherapy. In all-lines cohorts subdivided into PD-L1 high/low/negative expression categories, the model identified responders with an ROC-AUC of 0.72 (0.57-0.87, P = 0.005, N = 102), 0.74 (0.58-0.89, P = 0.003, N = 71), and 0.60 (0.46-0.74, P = 0.16, N = 77), respectively. Conclusions: Our study demonstrates that multi-modal models can predict ICI response with high performance. The stronger performance in patients receiving ICI therapy alone indicates the model’s predictive, rather than prognostic, power. Furthermore, the model demonstrated good performance in identifying ICI responders within patient sub-cohorts defined by PD-L1 expression status. These insights may be used to inform clinical decision-making, such as escalation or de-escalation of concurrent chemotherapy in stage IV NSCLC patients. In our future work, we will investigate these questions in larger cohorts and prospective studies.

Biomarkers to predict the efficacy of immune checkpoint inhibitors in patients with non-small-cell lung cancer with actionable genetic alterations.

e21175 Background: Although the efficacy of immune checkpoint inhibitors (ICI) in patients with actionable genetic alterations (AGAs) in non-small-cell lung cancer (NSCLC) has been known to be modest, some patients demonstrated improved survival. Thus, this study aimed to find predictive biomarkers for ICI in patients with NSCLC with various AGAs and to identify the predictive biomarkers for ICI efficacy. Methods: We compared the progression-free survival (PFS) of 324 advanced NSCLC patients who received ICI monotherapy (as over second-line therapy) by different AGAs from January 2018 and July 2022 at the Samsung Medical Center. To identify predictive markers of ICI, we adjusted the impacts on PFS of ICI in smoking status, PD-L1 expression, TP53, KEAP, STK11 mutation status, and steroid use during ICI monotherapy. Results: The median age was 63.1 years (range, 27.8–84.8) and 53.1% of patients was male, and 46.3% of patients was an ex-/or current smoker. A total of 324 patients were included with the following AGAs: EGFR mutation (n = 149, 46.0%), ALK rearrangement, (n = 12, 3.7%), KRAS mutation (n = 72, 22.2%), HER2 mutation or amplification (n = 34, 10.5%), and MET ex14 skipping or amplification (n = 32, 9.9%), ROS1 rearrangement (n = 9, 2.8%), BRAF V600E (n = 9, 2.8%), and RET rearrangement (n = 7, 2.2%). The median PFS was 2.0 months (95% confidence interval, 1.8–2.2) in the total AGA group. The 6-month PFS rate was 25.8% (19.5–34.3) in the group with KRAS/ BRAF V600E/ MET/ HER2 and 12.8% (8.6–19.1) in the group with EGFR/ ALK/ ROS1/ RET (P &lt; 0.01). In the group with KRAS/ BRAF V600E/ MET/ HER2, KEAP, or STK11 wild-type (P = 0.03), PD-L1 (≥1%) (P &lt; 0.01) and steroid use during ICI monotherapy due to immune-related adverse events (IRAE) (P &lt; 0.01) were related to a favorable PFS of ICI; however, no statistical significance was found for TP53 mutation and smoking status for PFS of ICI. In the group with EGFR/ ALK/ ROS1/ RET, PD-L1(≥ 50%) was the only factor that was related to a favorable PFS, and not TP53 mutation status, KEAP, or STK11. Conclusions: This study showed a difference in PFS among each type of AGAs. Although there are limitations due to the small number of patients, the KRAS/ BRAF V600E/ MET/ HER2 group had a favorable PFS compared with the EGFR/ ALK/ ROS1/ RET group . KEAP/STK11/PD-L1 status and steroid use due to IRAE predicted favorable PFS of ICI in the KRAS/ BRAF V600E/ MET/ HER2 group .

Sex differences in prognostic utility of peripheral eosinophil count in first-line immune checkpoint therapy against metastatic NSCLC.

9067 Background: To date, few studies have associated elevated Absolute Eosinophil Count (AEC) with improved outcome to a single agent immune checkpoint inhibitor (ICI) as first or subsequent line of therapy in patients with NSCLC. Here, we investigated prognostic utility of AEC and the sex difference in patients undergoing standard-of-care first-line ICI with or without chemotherapy for metastatic NSCLC. Methods: This was a retrospective cohort study of 310 patients with Stage IV NSCLC treated with first-line ICI-based therapies (alone or in combination with chemotherapy) under IRB approved protocol 2021C0069. Demographic data are summarized in the table. Peripheral AEC measured by cells/microL was collected within 1 week before the start of therapy. Eosinophil count was evaluated in males and females by both descriptive statistics and Chi-squared test as a continuous and categorical variable, respectively. High level of baseline AEC was defined as 75th percentile (270 cells/microL). Overall Survival (OS) was plotted using the Kaplan-Meier method and p-values from log-rank test were reported. PD‐L1 was assessed by tumor proportion score (TPS) and classified into &lt; 1%, 1 to 49% and ≥ 50%. Results: 14% male vs 6% female patients were found to have peripheral eosinophilia (AEC ≥ 500) at the start of immunotherapy, p = 0.02. Patients with lower AEC had a median OS of 18.6 months vs 29.3 months in those with higher AEC ( p = 0.02, HR: 1.465, 95% Cl: 1.073-2.001). Patients with higher baseline AEC showed a sex difference, with median OS of 23.9 months in males vs NR median OS in females with over 60% survival at the time of last follow up ( p = 0.04, HR: 1.934, 95% Cl: 1.040-3.597). This difference was seen with ICI monotherapy ( p = 0.02, HR: 2.630, 95% Cl: 1.192-5.805), but not ICI with chemotherapy ( p = 0.83, HR: 1.116, 95% Cl: 0.4054-3.070). Higher AEC was associated with TPS ≥ 50% in both males and females ( p = 0.004 and 0.001, respectively), though no significant sex difference was observed. Conclusions: Our data highlight critical sex differences in interpretation of baseline AEC in patients on ICI therapy for metastatic NSCLC. While males have a higher frequency of peripheral eosinophilia, higher AEC correlates to improved OS predominantly in females. Further, this female-biased outcome is seen only with ICI monotherapy, even though higher AEC is associated with high PD-L1 expression in both sexes. Future studies are indicated to assess the longitudinal trend in eosinophil count as well as their active versus passive role in anti-tumor immunity and toxicity in the presence or absence of chemotherapy. [Table: see text]

Patient characteristics, treatment patterns, and clinical outcomes among patients with de novo advanced or metastatic (stage IIIB–IV) non-small cell lung cancer in a real-world setting.

e21032 Background: In the past decade, therapies targeting EGFR, KRAS, ALK, ROS1, BRAF, NTRK, MET, RET variants , and PD-L1 expression were approved and recommended for use in advanced non-small cell lung cancer (aNSCLC). This study describes real-world patient characteristics, biomarker testing, treatment patterns, and clinical outcomes in patients with de novo stage IIIB–IV aNSCLC in the United States. Methods: This is a retrospective cohort study of patients with aNSCLC using TEMPUS oncology data. Patients were included if they were diagnosed with stage IIIB, IIIC, or IV NSCLC (index date) as their primary NSCLC diagnosis between 1/1/2012 and 12/31/2020, and were &gt;18 years of age at index. Patients with an advanced diagnosis within 90-days of their primary diagnosis were defined as having de novo aNSCLC. Patient demographics and clinical characteristics including biomarker testing for EGFR, KRAS, ALK, ROS1, BRAF, NTRK, MET, RET alterations, and/or PD-L1 expression, as well as treatment patterns, were described. Median progression-free survival (PFS) and median overall survival (OS) were stratified by stage at diagnosis (IIIB/IIIC vs IV) and evaluated by Kaplan–Meier analysis. Results: A total of 7,624 patients met the study criteria. 12.5% (n = 955) were diagnosed at stage IIIB/IIIC versus 87.5% (n = 6,669) diagnosed at stage IV. Of the de novo patients with aNSCLC, 47.6% (n = 3,632) were female, median age (IQR) was 65.3 years (58.1–72.4), 67.4% (n = 5,136) were White, and 62.7% (n = 4,781) had evidence of biomarker testing. Biomarker testing was significantly more common among patients diagnosed at stage IV (64.9%, n = 4,325) than stage IIIB/IIIC (47.7%, n = 456; p &lt; 0.001). At index, 10.3% (n = 785) of patients had evidence of brain metastasis, 49.2% (n = 3,749) were current or former smokers, and 66.7% (n = 5,086) had non-squamous histology. 69.1% (n = 5,269) received first-line treatment with chemotherapy (58.5%, n = 3,083), chemotherapy + immune checkpoint inhibitor (ICI) (20.8%, n = 1,096), ICI monotherapy (9.5%, n = 503), tyrosine kinase inhibitors (10.4%, n = 548), or other treatments (0.7%, n = 39). Among patients with de novo aNSCLC overall at stage IIIB/IIIC and stage IV, median PFS was 5.0 months (mos) (95% CI: 4.8, 5.3), 7.2 mos (95% CI: 6.3, 8.1), and 4.8 mos (95% CI: 4.6, 4.9; p &lt; 0.0001), respectively; median OS was 13.9 mos (95% CI: 13.3, 14.5), 19.4 mos (95% CI: 16.8, 22.0), and 13.2 mos (95% CI: 12.6, 13.8; p &lt; 0.0001), respectively. Conclusions: Among patients with de novo aNSCLC, those diagnosed at stage IIIB/IIIC had significantly longer median PFS and OS than those diagnosed at stage IV. Many real-world patients with aNSCLC were not tested for biomarkers for which there are now approved targeted therapies. Earlier diagnosis and increased biomarker testing may improve clinical outcomes in real-world patients with aNSCLC.

Immune checkpoint inhibitor (ICI) therapy in glioblastoma: Institutional experience at the Massachusetts General Hospital (MGH).

2065 Background: Immune checkpoint inhibitors (ICI) have resulted in promising outcomes in systemic cancer but response in glioblastoma (GBM) has not met early expectations based on early clinical trial results. Conflicting data exists regarding the incidence of pseudoprogression after ICI in brain tumors. Here, we present our institutional experience of the radiographic response following ICI therapy in GBM both at initial diagnosis and recurrence. Methods: We retrospectively identified IDH-wildtype GBM (per 2021 WHO criteria) patients treated either at time of initial diagnosis or at recurrence with nivolumab, pembrolizumab, or durvalumab between 2015 and 2022 at MGH. Overall radiographic and clinical responses after initiation of ICI were assessed in both groups. Results: 56 pts (18 female, 38 male) were identified (average age 58.6). Eight (14.3%) patients had ICI-related non-hematological toxicities, including granulomatosis folliculitis, arthritis and myositis, headache, acneiform rash, transaminitis, and gastritis). Four (7.1%) of the eight patients had to discontinue treatment due to ICI-related severe toxicity (hepatitis and/or gastritis) and were not included in the final response assessment. Of the remaining 52 patients, none had evidence of pseudoprogression related to ICI. We did not identify any complete response (CR) or partial response (PR) secondary to ICI monotherapy. In the 13 patients treated at initial diagnosis, the following radiographic responses were seen: CR=0, PR=0, stable disease (SD)=5 (38.5%), and progressive disease (PD)=8 (61.5%). In the 39 patients treated at disease recurrence, the responses were: CR=0, PR=4 (10.3%), SD=10 (33.3%), PD= 22 (56.4%). Noteworthy, all patients with PR were concurrently treated with bevacizumab. Conclusions: 0/52 patients showed radiographic response after ICI monotherapy. While treatment was overall tolerated, ICI therapy was discontinued due to toxicity in 7% of patients. Pseudoprogression attributable to ICI was not seen in any of the patients treated.

Chemoimmunotherapy for esophageal squamous cell carcinoma—Summary and discussion of recent clinical trials

AbstractAs a kind of carcinoma with increasing morbidity, poor prognosis, and high mortality, esophageal squamous cell carcinoma (ESCC) is challenging for clinical management. Chemotherapy has been the standard treatment for ESCC over decades, while its clinical outcomes remain unsatisfying. And the regimen that combine standard chemotherapy with targeted therapy also demonstrates little effect. However, the advent of immune checkpoint inhibitors (ICI) proved to be a game changer in cancer treatment. Recent clinical trials had sprung up to evaluate the combined effect of ICI and chemotherapy regarding first‐line ESCC treatment. What's more, researchers attempt to explore the possibility to implement ICI monotherapy regarding second‐line ESCC treatment. In conclusion, most of the first‐line trails present inspiring achievement, while ICI monotherapy indicates little improvement for ESCC treatment. To point out the heterogenicity that could be the potential reasons biasing the pooled results, the differences of PD‐L1 immunohistochemistry (IHC) assays, geographic regions, chemotherapy regimens, and sex disparity among these trails are discussed respectively. In addition, the adverse events occurred during the trails are summarized, which confirm the safety of immunotherapy and chemoimmunotherapy. The article comprehensively reviews the representative explorations of using chemoimmunotherapy strategies in ESCC, as well as the deficiencies among them. Moreover, we highlight some feasible approaches. It will be beneficial for conducting more precise clinical trials on chemoimmunotherapy for ESCC in the future, including the use of more appropriate PD‐L1 IHC assays, careful consideration of the heterogeneity of the enrolled population and the optimal combination of chemotherapy and ICI.

A decision-making tool for first-line treatment in advanced non–small-cell lung cancer based on plasma proteome biomarkers.

9122 Background: Initial treatment selection for advanced NSCLC patients without driver mutations is mainly based on evaluating PD-L1 expression levels in the tumor tissue. However, PD-L1 assays are only moderately predictive. In addition, the guidelines for the PD-L1≥50% subpopulation are not definitive, enabling the usage of immune checkpoint inhibitors (ICI) either as a monotherapy or combined with chemotherapy. Here we aim to provide a decision-making tool for the first-line treatment of advanced NSCLC patients based on plasma derived biomarkers obtained before treatment initiation. Methods: Pre-treatment plasma samples were collected from 545 NSCLC patients receiving ICI-based therapy. Clinical benefit was evaluated based on progression-free survival (PFS) at 12 months as a threshold. Deep plasma proteomic profiling was performed using aptamer technology. Based on the proteomic profiles, a computational model, termed PROphet, was developed and evaluated in a blinded manner on the validation subset (n = 272). The model output, clinical benefit probability, was used to stratify the patients into two groups, PROphet-positive or -negative. Results: The model displayed good performance with a high correlation between the predicted clinical benefit and the observed clinical benefit rate (R2= 0.97), outperforming a PD-L1-based prediction model (R2= 0.35). Patients classified as PROphet-positive achieved significantly longer overall survival (OS) than PROphet-negative patients, with a median OS of 25.9 versus 10.8 months (hazard ratio, HR = 0.51; 95% confidence interval, CI = 0.37-0.70; p-value &lt; 0.001). Next, we examined the clinical utility of combining the PROphet output with PD-L1 levels by comparing different treatment modalities. Focusing on PD-L1≥50%, patients with PROphet-positive results displayed similar OS and PFS when receiving ICI monotherapy or ICI-chemotherapy (OS HR = 0.77; CI = 0.42-1.43; p-value = 0.4096), suggesting that these patients may consider monotherapy, thus avoiding chemotherapy-related toxicity. Conversely, PD-L1≥50% patients with a PROphet-negative result displayed a significantly longer OS and PFS when receiving ICI-chemotherapy in comparison to ICI monotherapy, with a median OS that was not reached versus 11.10 months in the combination therapy and monotherapy groups, respectively (HR = 0.29; CI = 0.14-0.59; p-value &lt; 0.001). These patients should consider combination therapy, avoiding a treatment that is suboptimal for them. Results for PD-L1 1-49% and &lt; 1% provide additional clinical information for each subgroup. Conclusions: Plasma proteomic profiling can provide biomarkers that accurately predict the benefit of ICI-based treatment. The model output complements tissue PD-L1 expression levels as a tool to assist therapeutic decisions.

Artificial intelligence algorithm developed to predict immune checkpoint inhibitors efficacy in non–small-cell lung cancer.

9132 Background: Many non-small cell lung cancer (NSCLC) patients with high PD-L1 IHC expression and/or high TMB level do not respond to immune-check point inhibitors (ICIs). Discovery of novel predictive biomarkers for ICI response in NSCLC continues to be a critical unmet medical need, given the expense, potential toxicity, and therapeutic delay due to ICI treatment without benefit. Methods: We developed a supervised deep learning algorithm (Deep-IO) to predict therapeutic response to ICIs in NSCLC patients from standard histology whole slide hematoxylin and eosin (H&amp;E) images, which was trained based on ICI objective response rate. We utilized a convolutional neural network (CNN) implemented in Pytorch. The efficiency of the Deep-IO was evaluated through classification performance metrics and the area under the receiver operating characteristic curve (AUROC). The algorithm was trained and tested on 85218 tiles (size: 512x512 pixels) in 446 advanced stage NSCLC patients from the Dana Farber Cancer Institute (DFCI), all treated with ICI monotherapy. Results: The objective response rate, comprising complete and partial response, was 26% (n = 114) in the overall cohort. The DFCI patient cohort was randomly split into a training set (N=379, 85%) and a test set (N=67, 15%). The classifier’s predicted class (responder vs non-responder) probabilities at the tiles level were averaged for each patient. Quantitative evaluation of whole section test dataset shows that the developed model achieves the accuracy of 0.72, weighted average (WAVG) precision of 0.77, WAVG recall of 0.72 and WAVG F-score of 0.74 on classifying ICI non-responders from responders. Comparing with PD-L1 expression (TPS%) and TMB (mu/Mb), Deep-IO had superior predictive power for ICI response (AUROC=0.75) in the test set. The combined Deep-IO+PD-L1 scores resulted in a significantly greater AUROC value of 0.82 compared to single tests and a 32% improvement in specificity (0.88 vs. 0.56) compared to PD-L1 evaluation alone (Table). Conclusions: This proof-of-concept study shows that an artificial intelligence–powered H&amp;E image classifier can predict ICI effectiveness in NSCLC. Deep-IO outperformed both established predictive biomarkers. We will assess Deep-IO in additional external NSCLC data sets for validation and confirmation. [Table: see text]

Efficacy and safety of immune checkpoint inhibitor without pemetrexed for first-line maintenance therapy in advanced lung adenocarcinoma.

e21058 Background: Currently, the standard first-line treatment for driver gene-negative advanced lung adenocarcinoma (LUAD) is chemotherapy plus immune checkpoint inhibitor (ICI) therapy followed by pemetrexed and ICI. However, pemetrexed is prone to certain adverse reactions and needs to be pretreated. At present, there is no relevant study on the efficacy between pemetrexed combined with ICI and ICI monotherapy in maintenance treatment. The object of this study is to explore the efficacy and safety of ICI as maintenance therapy in such patients. Methods: The study retrospectively analyzed patients with driver gene-negative advanced LUAD in PLA General Hospital from January 2019 to June 2022. These patients had received pemetrexed and platinum-based chemotherapy combined with ICI for 4-6 cycles. Patients who didn’t progress were subsequently entered into maintenance stage. The primary endpoint was progression-free survival (PFS) and overall survival (OS), and the secondary endpoint was objective response rate (ORR) and safety. Results: A total of 93 patients with advanced LUAD who received first-line chemotherapy combined with ICI were collected, including 39 patients receiving pemetrexed plus ICI of maintenance therapy, 30 patients receiving ICI maintenance therapy, and 24 patients who failed to enter the maintenance treatment. Baseline characteristics of ICI group and pemetrexed plus ICI group were as follows: median age, 61.5 (42~81) years vs. 63 (35~74) years; male, 66.7% (20/30) vs. 79.5% (31/39); Smoking history, 63.3% (19/30) vs. 74.4% (29/39); Brain metastases, 10% (3/30) vs. 23.1% (9/39). ORR was 60.0% (95%CI 42.5-77.5) in the ICI monotherapy group and 69.2% (95%CI 54.7~83.7) in the pemetrexed plus ICI group. By November 30, 2022, the median follow-up time was 19.2 months. The median PFS of the two groups were 15.8 months (95%CI 9.84-21.70) in ICI group and 22.8 months (95%CI 4.57-40.97) in pemetrexed plus ICI group and there was no statistical difference between the two groups (P = 0.50). Neither group achieved OS. The incidence of all grade treatment-related adverse events (TRAEs) was 90.0% (27/30) in ICI monotherapy group and 92.3% (36/39) in pemetrexed plus ICI group. Grade 3/4 TRAEs occurred in 23.3% (7/30) and 23.1% (9/39) of each cohort and no grade 5 TRAE occurred. Conclusions: ICI maintenance therapy without pemetrexed showed great therapeutic efficacy in first-line maintenance stage and can be a feasible regimen in advanced lung adenocarcinoma.

Immunotherapy versus tyrosine kinase inhibitors in advanced hepatocellular carcinoma in first-line setting: A systematic review and meta-analysis of randomized controlled trials.

e16132 Background: Hepatocellular carcinoma has a high mortality rate, with an overall 5-year survival of less than 20%. Whether the use of immune checkpoint inhibitors (ICI) is superior to tyrosine kinase inhibitors (TKI) as a first-line therapy remains unclear. Methods: We performed a systematic review and meta-analyses of randomized clinical trials (RCTs) to compare ICI, in monotherapy or combined with TKI or anti-VEGF monoclonal antibody in naïve treatment. We searched Embase, PubMed and Cochrane Library databases from inception to November 2022. The outcomes evaluated were Overall Survival (OS), Progression Free-Survival (PFS), Overall Response Rate (ORR) and Treatment Related Adverse Events (TRAE). Using a random-effects model, statistical analysis was performed with RevMan 5.4 version for proportions and risk ratios for binary outcomes from comparative studies. Results: We included 10 RCTs comprising 6097 patients in the final analysis, 2554 in ICI monotherapy, 1096 in ICI with anti-VEGF and 2447 in ICI with TKI. The use of ICI, alone or in combination therapy, was associated with a better OS (HR 0.77; 95% CI 0.69–0.85; p&lt; 0.00001; I²=46%) and PFS (HR 0.77; 95% CI 0.64-0.92, p=0.005; I²= 85%). In the ICI monotherapy subgroup, there was a statistical difference to TKI in OS (HR 0.82; 95% CI 0.75-0.91; p=0.0001; I² = 0%). Although there was a higher ORR in all ICI groups (RR 2.56; 95% CI 1.89-3.46; p&lt;0.00001, I²=68%), TRAE Grades 3-4 (RR 0.85; 95% CI 0.61-1.18; p=0.33; I²=96%) presented no difference when compared with TKI. Conclusions: Our findings suggest that the use of ICI, alone or in combination with TKI or anti-VEGF, is a superior option for first-line therapy for advanced hepatocellular carcinoma, improving OS, PFS, and ORR without increasing treatment toxicity. These results are important for guiding clinical decision-making and further research in this field.

Immune-related adverse events after ≥12 months of starting immune checkpoint inhibitors.

e24086 Background: Immune checkpoint inhibitors (ICIs) are well established in the treatment of metastatic renal cell (mRCC) and urothelial carcinomas (mUC). The profile of ICI immune-related adverse events (irAEs) is well described, however, data on timings of toxicity and irAEs occurring at ≥12 months are lacking. Methods: A single-site retrospective audit of mRCC and mUC patients receiving ICI-based therapy for ≥12 months between January 2014 and December 2022. ICI-based therapies included monotherapy and combination therapy with other ICIs or anti-VEGF tyrosine kinase inhibitors (TKIs). Best response to ICI-based therapy and irAEs were described. Results: 199 patients received ICI-based therapy, of which 34% (68/199) received treatment for ≥12 months. Of those on therapy for ≥12 months, 44% (30/68), 25% (17/68), and 31% (21/68) were treated with ICI monotherapy, combination with other ICIs, and TKIs, respectively. At data cut-off, 69% (47/68) were alive. 26% (18/68), 59% (40/68) and 15% (10/68) achieved complete response (CR), partial response (PR) and stable disease (SD), respectively. Overall, 83 irAEs were observed in 74% (50/68) of patients receiving therapy for ≥12 months. Of these, 71% (59/83) occurred at &lt; 12 months and 28% (24/85) at ≥12 months. Corticosteroid therapy was required in 31% (18/59) of irAEs at &lt; 12 months and 63% (15/24) at ≥12 months. Endocrine and cutaneous irAEs mostly occurred at &lt; 12 months, while rheumatic irAEs were more frequently observed at ≥12 months. No ICI-related deaths occurred. At ≥12 months, 71% (17/24) of irAEs were grade 1/2 and 29% (7/24) were grade 3/4. Grade ≥3 irAEs at ≥12 months included colitis (n = 1), proctitis (n = 1), tubulointerstitial nephritis (n = 1), bullous pemphigoid (n = 1) and transaminitis (n = 3). Four patients discontinued treatment, the remainder restarted therapy after irAE resolution. All patients with late-onset grade ≥3 irAEs responded to therapy (CR in 2/7, PR in 5/7). A patient with grade 2 seronegative inflammatory arthritis with onset at ≥12 months also discontinued treatment. Conclusions: Although irAEs are less frequent after 12 months of ICI-based therapy, they remain clinically relevant requiring treatment interruption and discontinuation. Patients require ongoing safety monitoring irrespective of the duration of ICI-based therapy.

Association of tumor homologous recombination deficiency (HRD) score with immune checkpoint inhibitor benefit in metastatic clear cell renal cell carcinoma.

e16538 Background: Genomic aberrations resulting in homologous recombination repair deficiency (HRD) can be successfully targeted with poly (ADP-ribose) polymerase (PARP) inhibitors. Tumors with HRD also have a higher tumor mutation burden (TMB) and immunogenic phenotypes, prompting PARP inhibitor + immune checkpoint inhibitor (ICI) trials across cancer types. Clear cell renal cell carcinoma (ccRCC) rarely harbors canonical genomic aberrations associated with HRD. However, a “BRCA-like” HRD phenotype can be detected from next-gen DNA- or RNA-sequencing using models trained on tumors with BRCA1/2 bi-allelic loss. We hypothesized that this novel HRD phenotype is associated with ICI benefit in metastatic ccRCC. Methods: Patients with metastatic ccRCC who underwent nephrectomy and were treated with anti-PD-1/L1 ICI monotherapy +/- ipilimumab were identified in an institutional database (N = 52), and outcomes were determined by chart review. Progression free survival (PFS) and overall survival (OS) were calculated from the start date of ICI treatment. Targeted next generation DNA and whole transcriptome sequencing were performed from archived nephrectomy specimens using the Tempus xT platform. HRD scores were calculated using DNA (HRD-DNA) and RNA (HRD-RNA) based methods as previously described (Liebowitz BD et al. BMC Cancer 2022). HRD status was analyzed as a continuous rather than binary variable, as biologically relevant cutoff thresholds have not been established for ccRCC. Multivariable Cox regression models were used to evaluate the association between HRD scores and PFS or OS when demographic/pathologic covariates were adjusted. Results: The cohort was predominantly white (n = 48; 92%) and male (n = 37; 71%) with good performance status (ECOG 0-1: n = 47; 90%). Half (n = 26) were current/former smokers; median age 67 years and BMI 28. Twenty-four (46%) nephrectomies were cytoreductive. Most tumors were staged pT3/4 (85%) and grade 3/4 (90%) including 18 (35%) with sarcomatoid histology. ICI monotherapy or ICI + ipilimumab were received by 32 (62%) and 20 (38%) patients, respectively, in the 1st (40%), 2nd (40%), 3rd (17%), or 4th (2%) line. Median PFS and OS for the cohort were 6.4 months (95% CI 4.4-11.1) and 62.7 months (95% CI 32.8-not applicable). HRD-DNA and HRD-RNA could be calculated for 47 and 46 subjects, respectively. HRD-DNA was not found to be associated with PFS nor OS. High HRD-RNA score was associated with improved PFS (HR 0.92 per unit increase; 95% CI 0.85-1.00, p = 0.052) in the multivariable model, but not OS. Conclusions: High HRD-RNA was associated with longer PFS for metastatic ccRCC patients undergoing ICI-treatment. A “BRCA-like” transcriptomic signature may be predictive of ICI benefit in ccRCC.

Incidence of venous thromboembolism with immune checkpoint inhibitors in a community setting: A single-center retrospective study.

e14681 Background: Immune activation and inflammation caused by immune checkpoint inhibitors (ICIs) are critical pathobiological drivers for venous thromboembolism (VTE). There is a paucity of data about VTE risk in cancer patients receiving ICI. We aimed to describe the incidence of VTE in cancer patients receiving ICI in a community setting. Methods: We conducted a single center, retrospective cohort study at Saint Vincent Hospital. The study cohort was created using our center's pharmacy database of patients who received any of the five ICIs (ipilimumab, nivolumab, pembrolizumab, atezolizumab, or durvalumab) between Jan 2017 and Dec 2022. VTE events including deep venous thrombosis, splanchnic vein thrombosis, and pulmonary embolism, were identified by chart review. We used a self-controlled risk-interval design, with "control period" and "at-risk period" being 6 months before and after the initiation of ICI treatment respectively. VTE events were also analyzed for subgroups: Single-agent ICI therapy (IA), Dual ICI therapy (IB), and ICI + chemotherapy (IC). Descriptive statistics and cox regression were used for statistical analysis. Results: Study population included 170 patients, with 75, 14, and 81 patients in subgroups IA, IB, and IC respectively. The mean age of the patients was 69.51 ± 10.05 years with a majority being males (62.4%). The most common cancer observed was non-small cell lung cancer (43.5%) followed by small cell lung cancer (6.9%), and malignant melanoma (5.7%). Pembrolizumab (55.3%) was the most common ICI used and nivolumab + ipilimumab (7.64%) was the most common dual ICI used. We noted a 1.25-fold higher incidence of VTE post-ICI use (Incidence rate ratio [IRR]: 11.76 per 100 person-year) compared to pre-ICI use (IRR: 9.41 per 100 person-year) at 6 months. On subgroup analysis, Group IB had the highest risk for VTE at 6 months (IRR: 28.57 per 100 person-year), followed by group IC and IA (IRR: 14.12 and 8.0 per 100 person-year respectively). IRR decreased to 6.62 per 100 person-year at 12-month interval indicating increased VTE risk in the first 6 months of ICI exposure. Type of ICI, adjuvant chemotherapy or type of cancer was not able to predict VTE risk on multivariate analysis. Conclusions: ICI treatment was associated with an increased incidence of VTE in our study cohort with the highest risk among patients on dual ICI followed by ICI + chemotherapy and ICI monotherapy. Future prospective studies are needed to identify risk factors and biomarkers to improve risk stratification and risk-adapted thromboprophylaxis.[Table: see text]

A single-arm, open-label phase 2 trial of doxorubicin plus zalifrelimab, a CTLA-4 inhibitor, with balstilimab, a PD-1 inhibitor, in patients with advanced/metastatic soft tissue sarcomas.

11501 Background: Doxorubicin (DOX) is the standard of care for unresectable soft tissue sarcomas (STS). DOX induces immunogenic cell death in numerous preclinical models. Immune checkpoint inhibitors (ICIs) including antibodies (ab) to PD-1 and CTLA-4 have shown modest activity, but most STS are immune “cold” tumors and do not respond. We hypothesized that concurrent DOX would improve immunogenicity of STS and boost efficacy of ICIs, including anti-CTLA-4 ab zalifrelimab (ZAL) and anti-PD-1 ab balstilimab (BAL). Methods: We conducted a single arm Phase 2 trial of combination DOX/ZAL/BAL for patients (pts) with advanced/metastatic STS in the 1st/2nd treatment lines without prior DOX or ICI (NCT04028063). The study was a Simon minimax 2-stage design to accrue 28 pts evaluable for primary endpoint of progression-free survival rate at 6 months (PFS6mo) by RECIST 1.1. We aimed to improve PFS6mo by 20% with DOX/ZAL/BAL over null rate of 43.4% based on average PFS of 2 prior DOX monotherapy trials. Secondary endpoints were objective response rate (ORR), disease control rate (DCR), overall survival (OS), duration of response (DOR), and adverse events (AEs). All pts received up to 6 DOX cycles with concurrent ZAL/BAL; pts on stage 1 began DOX at cycle 2 with ZAL/BAL at cycle 1, pts on stage 2 began DOX/ZAL/BAL at cycle 1. Imaging was obtained prior to the first dose of DOX (baseline), and then every 6 weeks (wks) to 6 mo, and thereafter every 9 wks. Tumor biopsies/peripheral blood were obtained at baseline, on-treatment, and progression for immune profiling. Results: 35 patients were accrued as of 1/25/23. 25 pts are currently evaluable for primary endpoint of PFS6mo and 28 for efficacy (at least one post-treatment scan). PFS6mo is estimated at 52% (95%CI 31-72), with mPFS of 25.6 wks (24.0-44.9). ORR was 36% (19-56), and DCR was 86% (67-96). Median DOR was 12.8 wks (range 6 – 105). Most pts with PR who progressed did so on BAL after DOX completion. Responses were observed in pts with intimal sarcoma, angiosarcoma, MPNST, LPS, LMS, endometrial stromal sarcoma, UPS, and sclerosing epithelioid fibrosarcoma. Improved outcomes were observed in stage 1 pts compared to stage 2 pts, including PFS6mo (56.3% v. 25.0%), mPFS (31.7 v. 25.3 wks), ORR (56% v. 8.3%), and DCR (94% v. 75%). Toxicity was as expected with grade 3/4 TRAEs in 48% of 31 evaluable pts, primarily DOX-related hematologic AEs, and immune-related AEs requiring steroids in 19% of pts. Conclusions: Combination DOX/BAL/ZAL led to meaningful efficacy, including favorable PFS6mo and responses in several STS subtypes unlikely to respond to DOX or ICI monotherapy. Further investigation is required to determine if the stage 1 priming dose of ZAL/BAL prior to DOX improved clinical outcomes. An ongoing cohort is exploring a next-generation CTLA-4 inhibitor, botensilimab in combination with DOX +/- BAL. Clinical trial information: NCT04028063 .