Immune Checkpoint Inhibitor Monotherapy Research Articles

Efficacy of immunotherapy in advanced gastric cancer: preliminary results of a multicenter observational study

Background. Due to the low efficacy of PD-L1 antibodies in second and subsequent lines of metastatic gastric cancer (mGC), the optimal treatment strategy of such patients and appropriate choice of predictive biomarkers remain challenging. The aim of our study is to assess the efficacy of immune checkpoint inhibitors monotherapy in patients with mGC in routine clinical practice, especially in heavily-pretreated patients.Materials and methods. We retrospectively analyzed data of patients treated in five oncology centers in Moscow between 2018 and 2023, who received nivolumab or pembrolizumab for advanced gastric cancer. Primary end-point of our study was 6-months PFS. Secondary end-points were overall survival (OS), objective response rate (ORR), and disease control rate (DCR). Toxicity was assessed using CTC AE v5.0 scale.Results. 122 patients with mGC who received immune checkpoint inhibitors were included between 1 January 2018 and 28 February 2023. 6-months PFS rate was 31,6%. The median OS was 7 months (95% CI: 2-20), the median PFS was 3 months (95% CI: 1,5-9,5). A statistically significant difference in OS was detected in patients with MSI compared to MSS (25 months vs 6 months; 95% CI: 0,21 – 0,86; HR: 0,43). A trend towards higher PFS was observed as well (10 months in MSI vs 3 months in MSS; 95% CI:0,26 – 1,01; HR: 0,51). No statistical significance in PFS and OS according to PD-L1 CPS was found among patients with MSS. ORR and DCR were 36,6% and 10,6%, respectively. No cases of pseudoprogression or fatal immune-related AEs were observed.Conclusion. Our real-world data is consistent with published literature and the results from clinical trials. Further studies are needed to determine prognostic factors and to establish prognostic model of patients receiving ICIs for optimal treatment strategy of mGC.

Abstract PS16-01: Comparison of an Atezolizumab monotherapy window followed by Atezolizumab and chemotherapy vs. Atezolizumab and chemotherapy alone in triple negative breast cancer (TNBC) – final analysis of the neoadjuvant neoMono trial

Abstract Background: Improvement of systemic therapy of TNBC still is a medical need. Exploratory data from the neoadjuvant GeparNuevo trial suggested a benefit from an immune checkpoint inhibitor (ICI) monotherapy window in TNBC. The neoMono trial prospectively analyzed whether the addition of a preceding Atezolizumab monotherapy window prior to Atezolizumab and chemotherapy (CTX) improves pCR rates among patients (pts) with early TNBC. In an interim analysis after 100 pCR events, patients with unselected TNBC did not show a significant benefit from an Atezolizumab monotherapy window, while an exploratory analysis suggested a highly clinically relevant benefit among pts with PD-L1 positive TNBC. Here we present the final primary endpoint analysis. Methods: NeoMono is a phase 2 randomized multicenter trial that was planned to recruit a maximum of 458 female and male pts with primary TNBC (defined as ER/PR < 10% and HER2 negative) with tumor stages cT1c – cT4d (cN0 and cN+). As the protocol mandated termination of trial recruitment based on the results of the interim analysis, the final ITT population was limited to 359 pts. PD-L1 status had to be identifiable by central pathology by means of the VENTANA PD-L1 (SP142) assay and was defined by PD-L1 expression on immune cells (IC). Neoadjuvant treatment in both study arms consisted of Atezolizumab 1200 mg every 3 weeks in addition to neoadjuvant CTX (12 x Carboplatin/Paclitaxel q1w followed by 4x Epirubicin/Cyclophosphamide q3w). Combination therapy in arm A was preceded by an Atezolizumab monotherapy window of 840 mg once two weeks prior to initiation of combination therapy, while patients in arm B received no immune monotherapy window. Study goals are to compare the efficacy of neoadjuvant CTX + Atezolizumab with versus without a two-week atezolizumab monotherapy window preceding CTX + ICI (primary endpoint: pCR) and to identify biomarkers for response and resistance through analysis of sequential tissue and liquid biopsies. The neoMono statistical design uses Bayesian posterior probabilities (uniform prior distribution) and logistic regression to analyze the primary endpoint. Results: 180 pts in arm A and 179 in arm B from 34 study sites were included in the final primary endpoint analysis. Demographics and baseline characteristics as well as drug exposure were well-balanced in both arms. Posterior mean pCR rates in the ITT population in study arms A and B were 65.7% (95% high posterior density interval (HPDI): 58.5%, 72.5%) and 69% (62.2%, 75.9%), respectively. In an exploratory analysis stratified by PD-L1 IC status (negative: < 1% versus positive: ≥ 1%), pCR rates in arm A were 91.5% in the PD-L1 IC-positive group and 56.1% in the PD-L1 IC-negative group, the corresponding pCR rates in arm B were 82.2% and 64.5%, respectively. In a multivariate analysis of the ITT population including tumor size, nodal status, tumor grade, age and PD-L1 status, the odds ratio for achieving a pCR was 4.77 (p < 0.001) for PD-L1-positive and 2.36 (p=0.023) for grade 3 tumors. In an exploratory analysis including HER2 status, odds for achieving a pCR were significantly higher for patients with HER2-negative (IHC 0) vs. HER2-low tumors (OR 1.73, p=0.036). No new safety signals were observed. Conclusion: The final primary endpoint analysis of the neoMono trial demonstrated the highest pCR rates ever reported in a phase II/III trial in TNBC. While a significant impact of an ICI monotherapy window on the pCR rate after combination of CTX + ICI in an unselected ITT population could not be demonstrated, neoMono indicates for the first time in a randomized prospective setting that patients with immune active TNBC might derive particular benefit from a preceding ICI monotherapy window. The results of the neoMono trial are mainly justifying the conduction of a confirmative trial in immune active TNBC. However, our results underscore the potential role of pre-therapeutic ICI monotherapy window as part of future therapeutic concepts in TNBC. Citation Format: Hans-Christian Kolberg, Johannes Schumacher, Ramona Erber, Michael Braun, Peter A. Fasching, Eva-Maria Grischke, Christian Schem, Michael P. Lux, Mustafa Deryal, Oliver Hoffmann, Bernhard Heinrich, Georg Kunz, Kristina Lübbe, Petra Krabisch, Arndt Hartmann, Philip Raeth, Sabine Kasimir-Bauer, Cornelia Kolberg-Liedtke. Comparison of an Atezolizumab monotherapy window followed by Atezolizumab and chemotherapy vs. Atezolizumab and chemotherapy alone in triple negative breast cancer (TNBC) – final analysis of the neoadjuvant neoMono trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS16-01.

Abstract PO1-06-04: Immune checkpoint inhibitors for triple-negative inflammatory breast cancer (INCORPORATE): an international multicenter retrospective analysis

Abstract Background: Inflammatory breast cancer (IBC) is an aggressive clinical presentation of breast cancer (BC). Immune checkpoint inhibitors (ICIs) combined with chemotherapy provided an overall survival (OS) benefit in the metastatic setting and an even-free survival (EFS) benefit in patients (pts) with early triple-negative (TN) BC, respectively. Patients with TN-IBC were under-represented or excluded in pivotal trials and commonly not evaluated in subgroup analyses. Methods: We conducted a retrospective, multicenter, international, observational study to evaluate the clinical benefit of ICIs in pts with TN-IBC (defined as cT4d per AJCC TNM, 8th ed., ER < 1% and PgR < 1%, HER2: negative). Pts with early-stage TN-IBC were included if they received an ICI combined with neoadjuvant chemotherapy (NACT) (Group 1). Pts with metastatic TN-IBC were included if they received ICI monotherapy or in association with first-line chemotherapy (Group 2). Treatment was administered according to guideline recommendations (in PD-L1+ metastatic IBC and regardless of PD-L1 in early IBC), in clinical trials, or off-label (regardless of PD-L1 expression status in metastatic IBC). Endpoints were pathological complete response (pCR) and 1-year EFS rate for group 1 (calculated from date of first cycle of NACT to any recurrence or death), and progression-free survival (PFS) for group 2. Correlative analyses were provided (significance at p-value < 0.05). Results: We included 59 pts from 8 international referral centers. 15 pts had early IBC (Group 1), and 44 pts had metastatic disease (Group 2). Patient characteristics and outcomes are shown in Table 1. Among the 15 pts from Group 1, 10 received anthracycline, taxane and carboplatin-based (AC-CbT) NACT with pembrolizumab, 3 neoadjuvant paclitaxel-carboplatin chemotherapy with pembrolizumab, 2 neoadjuvant nab-paclitaxel with atezolizumab. One pt progressed on NACT, 2 pts are still receiving NACT. Among 13 pts evaluable for response, 6/13 (46%) achieved a pCR. After a median follow-up of 7.1 months, the median EFS was 12.9 months and the 1-year EFS rate was 70%. The median OS was 15.7 months. Among pts from Group 2, PD-L1 status was positive (IC 1% or CPS 10) in 27/44 pts (61%), negative in 5/44 pts (11%) and unknown in 6/44 pts (13%). At a median follow-up of 24.3 months, median PFS and OS were 4.1 and 15.7 months. As backbone chemotherapy in first line setting, 6 pts received AC-CbT regardless of PD-L1 status (mPFS: 8.6 months), 21 taxane-based/anthracycline-free chemotherapy (mPFS: 5.3 months), 14 other chemotherapy regimens (mPFS: 2.1 months) and 3 single-agent immunotherapy (mPFS: 50.1 months). Three of 6 patients who received AC-CbT underwent surgery and radiotherapy. In Group 2, after adjusting for the number of metastatic sites (>1 vs. 0-1), PD-L1 status (positive vs. negative vs. unknown) and de novo metastatic disease (yes vs. no), AC-CbT chemotherapy (HR 0.05; 95% CI: 0.01-0.56; p=.015) and taxane-based chemotherapy (HR 0.20; 95% CI: 0.06-0.68; p=.009) were both associated with longer PFS. Conclusions: This multicenter retrospective analysis of TN-IBC treated with combination of chemotherapy and IOs showed relatively low pathology response, EFS and clinical benefit suggesting need to further investigate the role of immunotherapy in this aggressive disease. Table 1. Patient characteristics and outcomes Citation Format: Carmine Valenza, Dario Trapani, Paola Zagami, Gabriele Antonarelli, Luca Boscolo Bielo, Eleonora Nicolò, Joana Mourato Ribeiro, Lorenzo Guidi, Carolina REDUZZI, Martina Spotti, Elisabetta Munzone, Javier Cortés, Barbara Pistilli, Sara Tolaney, Naoto Ueno, Rachel Layman, Massimo Cristofanilli, Lisa Carey, Filipa Lynce, Wendy Woodward, Giuseppe Curigliano. Immune checkpoint inhibitors for triple-negative inflammatory breast cancer (INCORPORATE): an international multicenter retrospective analysis [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-06-04.

The efficacy of immune checkpoint inhibitors on low PD-L1 cervical cancer: A meta-analysis.

The effectiveness of immune checkpoint inhibitors (ICIs) in low programmed death ligand 1 (PD-L1) expression in cervical cancer (CC) patients remains unknown. We aimed to evaluate the efficacy of ICIs in low PD-L1 expression CCpatients. The study is an individual patient data (IPD)-based meta-analysis. IPD were compiled through KMSubtraction and IPDfromKM methodologies from high-quality randomized clinical trials and single-arm studies which reported overall survival (OS) or progression-free survival (PFS) stratified by PD-L1 expression. Kaplan-Meier curves and Cox regression analysis were employed to evaluate the survival benefits of ICIs. A total of eightstudies and 1110 cases were included in the analysis. Within the low PD-L1 expression subgroup, ICI combination therapy, but not ICI monotherapy, demonstrated significant OS benefits over non-ICI treatment (hazard ratio [HR] = 0.61, 95% confidence interval [CI]:0.36-1.04, p = 0.06). Concerning PFS, ICI monotherapy was associated with a negative effect compared to non-ICI treatment (HR = 4.59, 95% CI:2.32-9.07, p < 0.001). Notably, both OS and PFS outcomes were unfavorable for ICI monotherapy compared to both non-ICI and ICI combination therapy in the combined positive score <1 subgroup (OS: HR = 2.60, 95% CI:1.31-5.16, p = 0.008; PFS: HR = 7.59, 95% CI:3.53-16.31, p < 0.001). In patients with CCand low PD-L1 expression, ICI monotherapy may not be considered as the optimal treatment strategy when compared to non-ICI treatment or ICI combination therapy. CRD42023395103.

The relative risk of immune checkpoint inhibitor pneumonitis in advanced non-small- cell lung cancer: Meta-analyses of controlled clinical trials.

Immune checkpoint inhibitor pneumonitis (CIP) is a prevalent form of immunotherapy-induced pulmonary toxicity, ranking among the leading causes of mortality associated with immune checkpoint inhibitors (ICIs). Despite its significance, the risk stratification of CIP in advanced non-small cell lung cancer (NSCLC) remains uncertain. In this study, we conducted a comprehensive analysis, comparing various factors such as histological types, treatment regimens, PD-L1 expression levels, and EGFR/ALK negativity in advanced NSCLC. Our investigation extends to evaluating the relative risk of developing CIP based on previous treatment history. This analysis aims to provide valuable insights for the identification of specific patient subgroups at higher risk, facilitating more effective risk management and precision therapy approaches. PubMed, Embase, and Cochrane databases were systematically searched up to February 16, 2023. We conducted a screening of randomized controlled trials (RCTs) that compared ICI monotherapy or its combination with chemotherapy in advanced NSCLC. The trials were categorized based on histological type, treatment regimen, PD-L1 expression level, EGFR/ALK-negative status, and prior treatment history. Subsequently, the data were stratified into five subgroups, and the occurrences of all-grades (1-5) and high-grades (3-5) pneumonia events were extracted. Odds ratios (OR) and corresponding 95% confidence intervals (CI) were then calculated for further analysis. Twenty-two RCTs, encompassing 13,725 patients with advanced NSCLC, were included in this analysis. Regardless of histology (OR = 2.47, 95% CI 1.41-4.33, P = 0.002; OR = 1.84, 95% CI 1.10-3.09, P = 0.02), treatment regimen (OR = 3.27, 95% CI 2.00-5.35, P < 0.00001; OR = 2.91, 95% CI 1.98-4.27, P < 0.00001), PD-L1 expression level (OR = 5.11, 95% CI 2.58-10.12, P < 0.00001; OR = 5.15, 95% CI 2.48-10.70, P < 0.0001), negative EGFR/ALK expression (OR = 4.32, 95% CI 2.22-8.41, P < 0.0001; OR = 3.6, 95% CI 1.56-8.28, P = 0.003), whether there is a history of treatment (OR = 3.27, 95% CI 2.00-5.35, P < 0.00001; OR = 2.74, 95% CI 1.75-4.29, P < 0.0001), ICI use was associated with a higher risk of all-grade (1-5) and high-grade (3-5) pneumonia compared to chemotherapy. Subgroup analysis revealed that the squamous group, the ICI vs. combination chemotherapy (CT) group, the PD-L1 > 50% group, and the previously untreated group had a higher risk of developing all-grade and grade 3-5 CIP (P < 0.05). In advanced NSCLC, ICI treatment was linked to an elevated risk of pneumonitis across all grades (1-5) as well as high-grade occurrences (3-5) compared to chemotherapy. Notably, individuals with squamous histology and high PD-L1 expression, along with those lacking a history of prior treatment, demonstrated a heightened susceptibility to developing immune-related pneumonitis of all grades (1-5) and high grades (3-5). These observations provide valuable insights for clinicians seeking to enhance the management of pulmonary toxicity associated with immunotherapy.

Managing potential adverse events during treatment with enfortumab vedotin + pembrolizumab in patients with advanced urothelial cancer.

Cisplatin-based chemotherapy has been the standard of care for patients with locally advanced or metastatic urothelial cancer (la/mUC). Enfortumab vedotin, an antibody-drug conjugate directed to Nectin-4, and pembrolizumab, an immune checkpoint inhibitor, are two therapies that have individually provided a survival benefit in patients with la/mUC. The combination regimen of enfortumab vedotin plus pembrolizumab was evaluated in EV-302 (KEYNOTE-A39; NCT0422385), a phase 3 study that showed statistically significant and clinically meaningful improvement in overall survival, progression-free survival, and a key secondary endpoint of overall response rate versus chemotherapy. Based on these results and those from the EV-103 (KEYNOTE-869; NCT03288545) Dose Escalation cohort, Cohort A, and Cohort K, enfortumab vedotin plus pembrolizumab was granted approval from the US Food and Drug Administration for the treatment of adults with la/mUC. While guidelines and recommendations for the management of adverse events (AEs) have been developed for immune checkpoint inhibitor monotherapy and enfortumab vedotin monotherapy, additional guidance is needed for managing AEs that occur with enfortumab vedotin plus pembrolizumab. As monotherapies, enfortumab vedotin and pembrolizumab are both associated with some of the AEs observed with the combination, such as skin reactions, pneumonitis, and diarrhea, which may confound the attribution of the AE to a specific agent and thereby complicate clinical management. In this manuscript, we aim to provide recommendations for best practice for patient care and the management of AEs of clinical interest for patients with la/mUC receiving enfortumab vedotin plus pembrolizumab, including skin reactions, peripheral neuropathy, hyperglycemia, and pneumonitis. These recommendations were developed based on published guidelines, expert opinions, and the clinical experience of the authors, which include oncologist, advanced practice provider, nursing, and pharmacy perspectives. In addition, guidance on patient education and communication is provided. With vigilant monitoring, early detection, and prompt intervention of treatment-emergent AEs based on recommended approaches described herein, it is the authors' experience that most AEs can be managed with supportive therapy and dose modification/interruptions, allowing patients to continue treatment.

Immunotherapy for patients with advanced non-small cell lung cancer harboring oncogenic driver alterations other than EGFR: a multicenter real-world analysis.

The administration of immune checkpoint inhibitors (ICIs) in advanced non-small cell lung cancer (NSCLC) with oncogenic driver alterations other than epidermal growth factor receptor (EGFR) aroused a heated discussion. We thus aimed to evaluate ICI treatment in these patients in real-world routine clinical practice. A multicenter, retrospective study was conducted for NSCLC patients with at least one gene alteration (KRAS, HER2, BRAF, MET, RET, ALK, ROS1) receiving ICI monotherapy or combination treatment. The data regarding clinicopathologic characteristics, clinical efficacy, and safety were investigated. A total of 216 patients were included, the median age was 60 years, 72.7% of patients were male, and 46.8% had a smoking history. The molecular alterations involved KRAS (n=95), HER2 (n=42), BRAF (n=22), MET (n=21), RET (n=14), ALK (n=14), and ROS1 (n=8); 56.5% of patients received immunotherapy in the first-line, and the rest 43.5% were treated as a second-line and above. For the entire cohort who received immunotherapy-based regimens in the first-line, the median progression-free survival (PFS) was 7.5 months and the median overall survival (OS) was 24.8 months. For the entire cohort who received immunotherapy-based regimens in the second-line and above, the median PFS was 4.7 months and median OS was 17.1 months. KRAS mutated NSCLC treated with immunotherapy-based regimens in the first-line setting had a median PFS and OS were 7.8 and 26.1 months, respectively. Moreover, the median PFS and OS of immunotherapy-based regimens for KRAS-mutant NSCLC that progressed after chemotherapy were 5.9 and 17.1 months. Programmed death ligand 1 (PD-L1) expression level was not consistently associated with response to immunotherapy across different gene alteration subsets. In the KRAS group, PD-L1 positivity [tumor proportion score (TPS) ≥1%] was associated with better PFS and OS according to the multivariate Cox analysis. No statistically significant association was found for smoking status, age, or gender with clinical efficacy in any gene group analyses. KRAS-mutant NSCLC could obtain clinical benefits from ICIs either for treatment-naive patients or those who have experienced progression after chemotherapy, and PD-L1 positive expression (TPS >1%) may be a potential positive predictor. For NSCLC with ALK, RET and ROS1 rearrangement, MET exon 14 skipping mutation, or BRAF V600E mutation, effectiveness of single or combined ICI therapy remains limited, therefore, targeted therapies should be considered prior to immunotherapy regimens. Future studies should address the investigation of better predictive biomarkers for immunotherapy response in oncogene-driven NSCLC.

Abstract 1208: Plasma proteomics-based models for predicting therapeutic benefit and immune-related adverse events in non-small cell lung cancer patients treated with immunotherapy

Abstract Background: Immune checkpoint inhibitors (ICIs) have significantly improved outcomes for patients with metastatic non-small cell lung cancer (NSCLC). However, clinical management is challenging. The PD-L1 biomarker does not optimally guide the choice between ICI monotherapy and combination ICI-chemotherapy, and there are currently no biomarkers to predict immune-related adverse events (irAEs). Here, we describe a versatile platform based on plasma proteomics and machine learning for generating predictive tools to support treatment decisions. Methods: Pre-treatment plasma samples were collected from 616 NSCLC patients receiving ICI-based therapy (NCT04056247). Clinical benefit (CB) data and irAEs were recorded. Proteomic profiling of plasma samples was performed using the SomaScan® assay, covering ~7000 proteins per sample. Proteins associated with Clinical Benefit (progression-free survival at 12 months) were classified as resistance-associated proteins (RAPs). Proteins associated with grade ≥3 irAEs occurring within the first 100 days of treatment were classified as toxicity-associated proteins (TAPs). RAPs and TAPs were integrated into two separate machine learning-based models, yielding CB and irAE probabilities, respectively. The CB model used a CB probability threshold to assign patients a PROphet-positive or PROphet-negative result. Bioinformatic analysis was performed on RAPs and TAPs. Results: CB and irAE models displayed strong predictive performance with a high correlation between predicted probability and observed CB or irAE rate (CB model: R2=0.98; p-value&amp;lt;0.0001; irAE model: R2= 0.92; p-value &amp;lt;0.0001). In the CB model, patients classified as PROphet-positive achieved significantly longer overall survival (OS) than PROphet-negative patients, with a median OS of 25.9 vs. 10.8 months (hazard ratio, HR = 0.51; p-value&amp;lt;0.001). Furthermore, patients with PD-L1 ≥50% tumors and a PROphet-negative result had significantly longer OS with ICI-chemotherapy in comparison to ICI monotherapy (HR=0.23, p-value = 0.0003), suggesting that combination therapy is preferable for such patients despite high PD-L1 levels. Bioinformatic analysis showed that RAPs related to immune regulation, angiogenesis, chemo-resistance, and other potential resistance mechanisms displayed higher expression levels in patients who did not benefit from treatment. Neutrophil- and inflammation-related proteins were significantly enriched in patients who experienced irAEs. Conclusions: We describe two machine-learning based predictive tools that may be used separately or in combination to inform treatment decisions based on the patient’s likelihood to benefit from ICI therapy and to develop serious irAEs. Our findings also provide biological insights related to treatment resistance and immune-related toxicity. Citation Format: Michal Harel, Petros Christopoulos, Igor Puzanov, Jair Bar, Iris Kamer, Niels Reinmuth, Ina Koch, Mor Moskovitz, Adva Levy-Barda, Alona Zer, Michal Lotem, David Farrugia, Rivka Katzenelson, Gillian Price, Abed Agbarya, Helen Cheley, Adam Hassani, Mahmoud Abu-Amna, Tom Geldart, Anirban Chatterjee, Andreas Polychronis, Maya Gottfried, Yanyan Lou, Tatiana Harkovsky, Alison Brewster, Ido Wolf, Ella Tepper, Ben Yellin, Itamar Sela, Coren Lahav, Yehonatan Elon, Raya Leibowitz, Adam P. Dicker, Young Kwang Chae, Ryan J. Sullivan, David Carbone, David Gandara, Jarushka Naidoo. Plasma proteomics-based models for predicting therapeutic benefit and immune-related adverse events in non-small cell lung cancer patients treated with immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1208.

Abstract 3730: Impact of proton pump inhibitor on ICI with or without chemotherapy for NSCLC with high PD-L1 TPS

Abstract Background and Aim: Immune checkpoint inhibitors (ICIs) have been widely used for the initial treatment of non-small cell lung cancer (NSCLC). Although both ICI monotherapy and the combination of ICI plus chemotherapy (chemo-ICI) are promising therapeutic options for patients with a programmed cell death ligand-1 tumor proportion score of 50% or higher (high PD-L1), the patient's clinical background and biomarkers differentiating the two options are still not well-defined. In our prior research, we found that a history of proton pump inhibitor (PPI) use independently have negative impact with significantly shorter overall survival (OS) and progression-free survival (PFS) in NSCLC patients harboring high PD-L1 with pembrolizumab monotherapy, but not with chemo-ICI. However, this OS data remain immature. Therefore, in our current study, we extended the follow-up period and conduct additional analysis including OS data to confirm this trend. Method: Advanced NSCLC patients with high PD-L1 who had received pembrolizumab or chemo-ICI as the first-line treatment between March 2017 and December 2020 at 13 hospitals in Japan were analyzed. Survival outcomes were estimated using the Kaplan- Meier method and were compared using the log-rank test. Results: A total of 425 patients with NSCLC were included in the study, with 271 patients (median [range] age, 72 [43-90] years; 215 [79%] men) receiving pembrolizumab monotherapy as their first-line treatment and 154 patients (median [range] age, 69 [36-86] years; 121 [79%] men) receiving chemo-ICI as their first-line treatment. The median follow-up duration was 22.8 months. Among patients with a history of PPI use, both median PFS (19.3 months vs. 6.8 months; HR, 0.53; 95% CI, 0.35-0.78; P = .003) and the median OS(not reached vs. 20.4 months; HR, 0.53; 95% CI, 0.34-0.85; P = .04) were significantly longer in the chemo-ICI group compared to the pembrolizumab monotherapy group. For patients without a history of PPI use, both median PFS (11.4 months vs. 10.8 months; HR, 0.99; 95% CI, 0.76-1.3; P = .36) and the median overall survival (42.2 months vs. 29.9 months, HR, 0.84; 95% CI, 0.62-1.16; P = .33) showed no significant differences between the groups. Discussion and Conclusion: This retrospective study showed that a concomitant treatment with PPI is poor prognostic factor in patients harboring high PD-L1 and treated with ICI monotherapy compared with chemo-ICI in Japanese cohort and this tendency is durable in long-term follow-up. These results indicate that when deciding on an ICI treatment, with or without chemotherapy, it is essential to take into account a concomitant treatment with PPI. Citation Format: Ryo Sawada, Hayato Kawachi, Tadaaki Yamada, Motohiro Tamiya, Yoshiki Negi, Yasuhiro Goto, Akira Nakao, Shinsuke Shiotsu, Takayuki Takeda, Asuka Okada, Taishi Harada, Koji Date, Yusuke Chihara, Isao Hasegawa, Takashi Kijima, Koichi Takayama. Impact of proton pump inhibitor on ICI with or without chemotherapy for NSCLC with high PD-L1 TPS [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3730.

Abstract 3729: Association between clinical characteristics and treatment outcome of immune checkpoint inhibitor with or without chemotherapy in elderly non-small cell lung cancer patients with high PD-L1 expression

Abstract Background and Aim: The proportion of elderly patients diagnosed with advanced stage lung cancer has been increasing owing to the aging of the population. Thus, formulating a treatment strategy for elderly non-small cell lung cancer (NSCLC) patients is essential. For NSCLC with programmed cell death ligand-1 (PD-L1) tumor proportion score (TPS) ≧ 50%, both immune checkpoint inhibitor monotherapy (ICI mono) and combination therapy of ICI and chemotherapy (ICI/Chemo) have been established as standard treatment options. However, evidence based on the clinical trials specifically for elderly patients is limited, and it is not clear whether ICI mono or ICI/Chemo should be used in elderly NSCLC patients with PD-L1 TPS ≧ 50%. This study aimed to clarify which clinical population will benefit from ICI/Chemo in elderly NSCLC patients with PD-L1 TPS ≧ 50%. Method: We retrospectively analyzed 199 NSCLC patients aged ≧ 70 years of Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1 with PD-L1 TPS ≧ 50% who were treated with ICI mono or ICI/Chemo. We analyzed the association between treatment outcome and baseline patient characteristics in each group. Comparing the treatment outcome, propensity score matching was used to reduce bias. Results: Of the 199 patients, 131 received ICI mono, and 68 received ICI/Chemo. The median overall survival (OS; 25.0 vs. 42.2 months, P = 0.116) and median progression-free survival (PFS; 10.9 vs. 11.8 months, P = 0.231) did not significantly differ between the ICI mono and ICI/Chemo groups. Multivariate analysis revealed the factors independently associated with OS: smoking history in the ICI mono group (smoking history/non-smoking history, hazard ratio [HR] 0.36, 95% confidence interval [CI] 0.16-0.78, P = 0.048), and ECOG PS (ECOG PS 1/PS 0, HR 3.84, 95% CI 1.44-10.20, P = 0.007) and histology type in the ICI/Chemo group (Non-squamous cell carcinoma/squamous cell carcinoma, HR 0.17, 95% CI 0.06-0.44, P &amp;lt; 0.001). For patients with ECOG PS 0 (OS: 26.1 months vs. not reached, P = 0.0031, PFS: 6.5 vs. 21.7 months, P = 0.0436) or non-squamous cell carcinoma (OS: 23.8 months vs. not reached, P = 0.0038, PFS: 10.9 vs. 17.3 months, P = 0.0383) in the ICI/Chemo group, PFS and OS were significantly longer than in the ICI mono group. Discussion and Conclusion: In elderly NSCLC patients with high PD-L1 expression, this study suggested that ECOG PS and histological type may be predictive clinical factor when choosing ICI mono or ICI/Chemo treatment. Citation Format: Hayato Kawachi, Shota Takei, Tadaaki Yamada, Motohiro Tamiya, Yoshiki Negi, Yasuhiro Goto, Akira Nakao, Shinsuke Shiotsu, Takayuki Takeda, Asuka Okada, Taishi Harada, Koji Date, Yusuke Chihara, Isao Hasegawa, Nobuyo Tamiya, Takashi Kijima, Koichi Takayama. Association between clinical characteristics and treatment outcome of immune checkpoint inhibitor with or without chemotherapy in elderly non-small cell lung cancer patients with high PD-L1 expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3729.

Abstract 1173: T cell receptor diversity in buffy coat samples from subsets of breast and ovarian cancer patients

Abstract Background: Immunotherapy, mainly by the use of immune checkpoint inhibitors (ICI), has been established as a standard option for both, solid tumors and hematological malignancies. Unfortunately, this success has only been replicated in a subset of patients (pts) with gynecological cancers. In ovarian cancer (OC), response rates to ICI monotherapy were low and in breast cancer (BC), only the subgroup of triple-negative BC (TNBC) pts showed an improved outcome by the addition of ICI. One reason for limited success of immunotherapy might be an impaired immune system. In this regard, monitoring the T cell receptor (TCR) repertoire could provide key insights into adaptive immune responses to ultimately understand disease initiation, progression and treatment response. Here we elucidated TCR alpha, beta, gamma and delta in buffy coats of pts with non-metastatic OC as well as non-metastatic and metastatic TNBC and compared the results with healthy donors (HDs). Methods: RNA was isolated from buffy coat samples of 20 HDs, 10 treatment-naïve primary OC pts, 14 treatment-naïve, non-metastatic TNBC pts (participating in the phase II neomono trial) and 19 pts with metastatic TNBC by a modified QIAamp RNA Blood Mini protocol. A survey of the TCR diversity and mapping of common and unique TCRs was done using the QIAseq Targeted RNA Panel Human TCR panel for all known T-cell receptors (alpha, beta, gamma, delta). Results: Regardless of the cancer entity, a significant reduction in TCR diversity was observed compared to HDs with the greatest differences observed in the delta receptors. When OC samples were compared with HDs, the difference in diversity was highly significant for all TCR subtypes (TCRalpha: p=0.013; TCRbeta: p=0.008; TCRgamma: 0.008; TCRdelta: 0.006). Similar results were obtained for non-metastatic TNBC (TCRalpha: p=0.0002; TCRbeta: p=0.0001; TCRgamma: p=0.002; TCRdelta: p=0.002) as well as metastatic TNBC patients (TCRalpha: p=0.001; TCRbeta: p=0.001; TCRgamma: p=0.005; TCRdelta: p=0.003) when their TCR diversity was compared to HDs. Interestingly, no significant differences in diversity were obtained when treatment-naïve non-metastatic TNBC pts were compared with heavily pretreated metastatic TNBC pts. The lowest diversity was found in BC pts compared to the OC pts. Conclusion: We have initiated a survey of the TCR diversity in TNBC and OC patients. Further evaluations will include the correlation of these findings with clinical characteristics and outcome. Whether the reduced TCR diversity represents T cell exhaustion or T cell specialization cannot yet be deduced from the results. Nevertheless, the addition of a TCR diversity score could provide an additional metric which may help provide patient guidance when integrated into a multi-modal molecular test. Citation Format: Corinna Keup, Cornelia Kolberg-Liedtke, Song Tian, Samuel J. Rulli, Siegfried Hauch, Paul Buderath, Oliver Hoffmann, Rainer Kimmig, Sabine Kasimir-Bauer. T cell receptor diversity in buffy coat samples from subsets of breast and ovarian cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1173.

Abstract 6557: Longitudinal cell-free tumor load dynamics represent an early endpoint for immunotherapy response in non-small cell lung cancer

Abstract Background: Liquid biopsies can inform treatment strategies by rapidly and accurately assessing tumor burden; with emerging data supporting the clinical utility of circulating cell-free tumor DNA (ctDNA) as an early endpoint of immunotherapy response. Methods: We performed targeted error-correction sequencing of ctDNA (n=330) and matched white blood cell (WBC) DNA (n=109) from 109 patients with advanced non-small cell lung cancer (NSCLC) who received immune checkpoint inhibitor monotherapy (n=79) or immunotherapy-containing combination regimens (n=30). Variant cellular origin was determined using a tumor-independent WBC DNA-informed approach. The maximum mutant allele fraction (maxMAF) of tumor-derived mutations was tracked longitudinally to assess changes in total cell-free tumor load (cfTL). Results: Among 3,418 variants with resolved cellular origin, 2,452 (72%) were tumor-derived, 125 (4%) were germline, while 841 (25%) were related to clonal haematopoiesis (CH). Cell-free DNA fragments harbouring tumor-derived mutations were significantly shorter than fragments containing wild-type alleles; however, fragment length alone was insufficient to distinguish CH variants from wild-type. Overall, 97 (89%) patients with &amp;gt;1 detectable tumor mutation were considered for cfTL tracking and molecular response assessment. Clearance of cfTL indicated molecular response (mR) whereas persistence indicated molecular progression (mPD). Time-course analyses, aiming to establish the optimal timing for molecular response assessment, revealed that early cfTL clearance within 3-9 weeks was significantly linked to improved survival outcomes. Notably, blood tumor mutation burden above or below 16 mutations/megabase showed no association with overall survival (OS; log rank p=0.98) or progression-free survival (PFS; log rank p=0.95). Of 81 patients evaluated for early on-therapy molecular responses, 28 (35%) were classified as having an mR, while 53 (65%) patients were classified in the mPD category. The median time to mR was 5 weeks in patients receiving immune checkpoint monotherapy and 6 weeks in patients receiving chemo-immunotherapy combination regimens. Patients in the mR group achieved longer OS (log rank p=0.001) and PFS (log rank p=0.0003) compared to those with mPD. Assessment of landmark PFS at 6 months demonstrated a significant association between ctDNA molecular response and durable clinical benefit (DCB) in patients receiving immune checkpoint monotherapy (p &amp;lt; 0.001, Fisher’s exact test), and a numerical association with DCB in patients on chemo-immunotherapy (p=0.07, Fisher’s exact test). Conclusions: Longitudinal tracking of ctDNA provides a real-time and accurate approach for monitoring immunotherapy response. These findings underscore the clinical utility of employing ctDNA molecular response to inform clinical decision-making. Citation Format: Lavanya Sivapalan, Bahar Alipanahi, Archana Balan, Jamie E. Medina, Noushin Niknafs, Erica Peters, Jaime Wehr, Alissa Konicki, Mimi Najjar, Bryan Chesnick, Gavin Pereira, Sarah Rongione, Nisha Rao, Michael Rongione, Brittany Shavatt, Lorenzo Rinaldi, Benjamin Levy, Victor E. Velculescu, Patrick M. Forde, Valsamo Anagnostou. Longitudinal cell-free tumor load dynamics represent an early endpoint for immunotherapy response in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6557.

Immune checkpoint inhibitor monotherapy is sufficient to promote microenvironmental normalization via the type Iinterferon pathway in PD-L1-expressing head and neck cancer.

Immune checkpoint blockers (ICBs) targeting programmed cell death protein 1 (PD-1) have been proven to be an effective first-line therapy against programmed cell death 1 ligand 1 (PD-L1; also known as CD274 molecule)-expressing head and neck squamous cell carcinoma (HNSCC) in recent KEYNOTE-048 trial. However, associated changes in the tumor microenvironment (TME) and underlying mechanisms remain elusive. Oral tumors in C57/BL6 mice were induced by administering 7,12-dimethylbenzanthracene into the buccal mucosa. Single-cell suspension was isolated from tumor tissue; proliferating cells were injected subcutaneously into the left flank of mice to establish Ajou oral cancer (AOC) cell lines. Subsequently, a syngeneic PD-L1-expressing HNSCC model was developed by injecting AOC cells into the buccal or tongue area. The model recapitulated human HNSCC molecular features and showed reliable in vivo tumorigenicity with significant PD-L1 expression. ICB monotherapy induced global changes in the TME, including vascular normalization. Furthermore, the antitumor effect of ICB monotherapy was superior to those of other therapeutic agents, including cisplatin and inhibitors of vascular endothelial growth factor receptor 2 (VEGFR2). The ICB-induced antitumorigenicity and TME normalization were alleviated by blocking the type I interferon pathway. In summary, ICB monotherapy is sufficient to induce TME normalization in the syngeneic model; the type I interferon pathway is indispensable in realizing the effects of ICBs. Furthermore, these results explain the underlying mechanism of the efficacy of ICB monotherapy against PD-L1-expressing HNSCC in the KEYNOTE-048 trial.

Efficacy of NSCLC Rechallenge with Immune Checkpoint Inhibitors following Disease Progression or Relapse.

Immune checkpoint inhibitors (ICIs) are at the forefront of advanced non-small-cell lung cancer (NSCLC) treatment. Still, only 27-46% of patients respond to initial therapy with ICIs, and of those, up to 65% develop resistance within four years. After disease progression (PD), treatment options are limited, with 10% Objective Response Rate (ORR) to second or third-line chemotherapy. In this context, ICI rechallenge is an appealing option for NSCLC. Most data on the efficacy of ICI rechallenge are based on retrospective real-world studies of small, heavily pretreated, and heterogeneous patient groups. Despite these limitations, these studies suggest that ICI monotherapy rechallenge in unselected NSCLC patient populations who discontinued initial ICI due to PD is generally ineffective, with a median Progression-Free Survival (PFS) of 1.6-3.1 months and a Disease Control Rate (DCR) of 21.4-41.6%. However, there is a subpopulation that benefits from this strategy, and further characterization of this subgroup is essential. Furthermore, immunotherapy rechallenge in patients who discontinued initial immunotherapy following treatment protocol completion and progressed after an immunotherapy-free interval showed promising efficacy, with a DCR of 75-81%, according to post hoc analyses of several clinical trials. Future research on ICI rechallenge for NSCLC should focus on better patient stratification to reflect the underlying biology of immunotherapy resistance more accurately. In this review, we summarize evidence regarding rechallenge immunotherapy efficacy following NSCLC disease progression or relapse, as well as ongoing trials on immunotherapy rechallenge.

Prognostic impact of clinical factors for immune checkpoint inhibitor with or without chemotherapy in older patients with non-small cell lung cancer and PD-L1 TPS ≥ 50.

The proportion of older patients diagnosed with advanced-stage non-small cell lung cancer (NSCLC) has been increasing. Immune checkpoint inhibitor (ICI) monotherapy (MONO) and combination therapy of ICI and chemotherapy (COMBO) are standard treatments for patients with NSCLC and programmed cell death ligand-1 (PD-L1) tumor proportion scores (TPS) ≥ 50%. However, evidence from the clinical trials specifically for older patients is limited. Thus, it is unclear which older patients benefit more from COMBO than MONO. We retrospectively analyzed 199 older NSCLC patients of Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1 and PD-L1 TPS ≥ 50% who were treated with MONO or COMBO. We analyzed the association between treatment outcomes and baseline patient characteristics in each group, using propensity score matching. Of the 199 patients, 131 received MONO, and 68 received COMBO. The median overall survival (OS; MONO: 25.2 vs. COMBO: 42.2 months, P = 0.116) and median progression-free survival (PFS; 10.9 vs. 11.8 months, P = 0.231) did not significantly differ between MONO and COMBO group. In the MONO group, OS was significantly shorter in patients without smoking history compared to those with smoking history [HR for smoking history against non-smoking history: 0.36 (95% CI: 0.16-0.78), P = 0.010]. In the COMBO group, OS was significantly shorter in patients with PS 1 than those with PS 0 [HR for PS 0 against PS 1: 3.84 (95% CI: 1.44-10.20), P = 0.007] and for patients with squamous cell carcinoma (SQ) compared to non-squamous cell carcinoma (non-SQ) [HR for SQ against non-SQ: 0.17 (95% CI: 0.06-0.44), P < 0.001]. For patients with ECOG PS 0 (OS: 26.1 months vs. not reached, P = 0.0031, PFS: 6.5 vs. 21.7 months, P = 0.0436) or non-SQ (OS: 23.8 months vs. not reached, P = 0.0038, PFS: 10.9 vs. 17.3 months, P = 0.0383), PFS and OS were significantly longer in the COMBO group. ECOG PS and histological type should be considered when choosing MONO or COMBO treatment in older patients with NSCLC and PD-L1 TPS ≥ 50%.

Comparison of immune checkpoint inhibitors related to pulmonary adverse events: a retrospective analysis of clinical studies and network meta-analysis

BackgroundImmune checkpoint inhibitors (ICIs) have transformed tumor treatment. However, the risk of pulmonary adverse events (PAEs) associated with ICI combination therapy is still unclear. We aimed to provide a PAE overview and risk ordering of ICIs used in tumor treatment.MethodsWe searched the databases of PubMed, PsycINFO, Embase, Cochrane Library, CINAHL, Web of Science, Scopus, and clinical trial websites during January 2011–April 2023 to identify phase II and III randomized clinical trials (RCTs) and single-arm clinical trials wherein at least one treatment arm received ICIs (e.g., ICI monotherapy, a combination of two ICIs, or ICIs in combination with conventional cancer therapy). We reported the results of PAEs. Additionally, we compared risks of PAEs between different drug classes using a Bayesian network meta-analysis.ResultsAmong 143 RCTs and 24 single-arm trials, the incidence of all-grade and grade 3–4 PAEs were highest with programmed death L1 (PD-L1) plus cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and plus chemotherapy and anti-PD1 plus anti-CTLA4, the lowest with targeted therapy drug plus chemotherapy and anti-PD1 plus anti-PDL1. Anti-PD1 plus anti-CTLA4 and plus chemotherapy was the intervention with the highest risk for all-grade and 3–4 grade PAEs, and the intervention with the lowest risk was chemotherapy and anti-PD1 plus anti-PDL1. In terms of all-grade PAEs, chemotherapy was safer than ICI monotherapy. Except for the anti-PD1 plus anti-PDL1 regimen, no significant difference in the risk of grade 3–4 PAEs was detected between dual-ICIs and single-ICIs. Furthermore, the risk of PAEs associated with nivolumab, pembrolizumab, and atezolizumab may be dose dependent.ConclusionsIn the single-drug regimen, anti-PD1 caused the greatest incidence of PAEs. The risk of PAEs was higher with all single-ICIs than with chemotherapy. However, no significant difference in the risk of PAEs was detected between single-ICIs. In the combined regimen, anti-PD1 plus anti-CTLA4 and plus chemotherapy showed the greatest risk of PAEs, but there were no significant differences in risk between dual-ICIs and single-ICIs.

Impact of Increasing PD-L1 Levels on Outcomes to PD-1/PD-L1 Inhibition in Patients With NSCLC: A Pooled Analysis of 11 Prospective Clinical Trials.

Programmed death ligand 1 (PD-L1) expression is recognized as a key biomarker in the treatment of non-small cell lung cancer (NSCLC) with anti-PD(L)1 inhibitors. Previous work has highlighted that outcomes in patients with NSCLC treated with anti-PD(L)1 inhibitors generally improve with increasing PD-L1 expression. The objectives of these analyses are to quantitate the effect of PD-L1 expression on outcomes, to characterize the potentially nonlinear relationship between PD-L1 expression and outcomes, and to assess potential differences in these relationships across subgroups. We performed a retrospective, pooled analysis of 11 clinical trials submitted to the US FDA between 2015 and 2022 that included patients with advanced NSCLC treated with anti-programmed death 1 or anti-PD-L1 immune checkpoint inhibitor (ICI) monotherapy in the first-line (1L) or second-line (2L) treatment setting. The clinical outcomes explored were overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). The primary analysis population included 3806 patients with advanced NSCLC, of which 2040 were treated in 1L and 1766 in 2L. For patients with a PD-L1 score of 100% in the 1L setting, the hazard ratio versus a patient with 1% PD-L1 was 0.55 (95% CI, 0.43 to 0.70) for OS and 0.50 (95% CI, 0.41 to 0.61) for PFS. For patients with a PD-L1 score of 100% in the 2L setting, the hazard ratio versus a patient with 0% PD-L1 was 0.55 (95% CI, 0.43 to 0.71) for OS and 0.51 (95% CI, 0.41 to 0.63) for PFS. Subgroup analyses suggested that this relationship may vary by subgroup, particularly by region. These analyses suggest PD-L1 expression has an appreciable impact on clinical outcomes for patients with NSCLC treated with ICI. As the impact of PD-L1 expression on outcomes may vary across regions, it is critical that future trials are multiregional and enroll a diverse patient population.

Nephrotic syndrome with acute kidney injury due to combination therapy of immune checkpoint inhibitors: a case report and review of the literature

BackgroundRecent studies have focused on immune checkpoint inhibitors. Renal complications associated with the use of immune checkpoint inhibitors are uncommon compared with other immune-related adverse events. Acute interstitial nephritis accounts for most of these renal complications, with nephrotic syndrome quite rare. We herein report a case of nephrotic syndrome associated with immune checkpoint inhibitors that was more severe than that in previous cases. By comparing this case with previous reports, the possible reasons for the particular severity of this case are discussed.Case presentationA 75-year-old man developed nephrotic syndrome with acute kidney injury after the first combination therapy of nivolumab and ipilimumab for malignant pleural mesothelioma. The results of a kidney biopsy indicated minimal change disease with mild atherosclerosis, acute interstitial nephritis, and fusion of nearly all podocyte foot processes. Nivolumab and ipilimumab therapy were stopped, and treatment with corticosteroids was initiated. We investigated previously reported cases of nephrotic syndrome using immune checkpoint inhibitors. Seventeen cases of immune checkpoint inhibitor-related nephrotic syndrome, including ours, have been reported. Two of the 17 patients with immune checkpoint inhibitor-related nephrotic syndrome required hemodialysis treatment for acute kidney injury. Unlike many previously reported cases, the present patient was administered two different immune checkpoint inhibitors, which may be one of the reasons for the development of severe nephrotic syndrome.ConclusionsIn addition to previously reported risk factors, immune checkpoint inhibitor combination therapy can exacerbate nephrotic syndrome compared to immune checkpoint inhibitor monotherapy.

Identification of C-PLAN index as a novel prognostic predictor for advanced lung cancer patients receiving immune checkpoint inhibitors.

Increasing studies have highlighted the potential utility of non-invasive prognostic biomarkers in advanced lung cancer patients receiving immune checkpoint inhibitor (ICI) based anti-cancer therapies. Here, a novel prognostic predictor named as C-PLAN integrating C-reactive protein (CRP), Performance status (PS), Lactate dehydrogenase (LDH), Albumin (ALB), and derived Neutrophil-to-lymphocyte ratio (dNLR) was identified and validated in a single-center retrospective cohort. The clinical data of 192 ICI-treated lung cancer patients was retrospectively analyzed. The pretreatment levels of CRP, PS, LDH, ALB and dNLR were scored respectively and then their scores were added up to form C-PLAN index. The correlation of C-PLAN index with the progression-free survival (PFS) or overall survival (OS) was analyzed by a Kaplan-Meier model. The multivariate analysis was used to identify whether C-PLAN index was an independent prognostic predictor. A total of 88 and 104 patients were included in the low and high C-PLAN index group respectively. High C-PLAN index was significantly correlated with worse PFS and OS in ICI-treated lung cancer patients (both p<0.001). The multivariate analysis revealed high C-PLAN index was an independent unfavorable factor affecting PFS (hazard ratio (HR)=1.821; 95%confidence interval (CI)=1.291-2.568) and OS (HR=2.058, 95%CI=1.431-2.959). The high C-PLAN index group had a significantly lower disease control rate than the low C-PLAN index group (p=0.024), while no significant difference was found for objective response rate (p=0.172). The subgroup analysis based on clinical features (pathological type, therapy strategy, TNM stage and age) confirmed the prognostic value of C-PLAN index, except for patients receiving ICI monotherapy or with age ranging from 18 to 65 years old. Finally, a nomogram was constructed based on C-PLAN index, age, gender, TNM stage and smoking status, which could predict well the 1-, 2- and 3-year survival of ICI-treated lung cancer patients. The C-PLAN index has great potential to be utilized as a non-invasive, inexpensive and reliable prognostic predictor for advanced lung cancer patients receiving ICI-based anti-cancer therapies.

The Efficacy of Immune Checkpoint Inhibitors in Microsatellite Stable Colorectal Cancer: A Systematic Review.

The use of immune checkpoint inhibitors (ICIs) has revolutionized cancer care, particularly in immune-inflamed tumors and tumors with a high mutational burden, like microsatellite instable colorectal cancer (CRC). However, their effectiveness in microsatellite stable (MSS) CRC is limited. This systematic review aims to evaluate the efficacy of ICIs in MSS CRC and explore promising combination strategies. A comprehensive search from the Web of Science, Medline, and Embase databases, for studies published until 14 November 2022, identified 53 clinical trials included in the review. ICI monotherapy or ICI-ICI combinations demonstrated limited clinical activity for patients with MSS CRC, with overall response rates below (ORR) 10% in most studies. The ICI and tyrosine kinase inhibitor (TKI) garnered ORRs ranging from 10% to 40% and indicated a higher benefit for patients, particularly those without active liver metastases. The combination of ICIs with anti-VEGF agents showed modest ORRs, especially in the earlier treatment lines and in combination with chemotherapy. While these combinations could lead to modest improvements, well-defined biomarkers for long-term benefit are yet to be delineated. Combinations involving BRAF inhibitors with ICIs were studied, showing promising responses with combination approaches in molecularly defined subgroups. In conclusion, while ICI monotherapy has limited efficacy in MSS CRC, combination strategies hold promise to enhance survival outcomes. Further research is necessary to identify optimal combination approaches, predictive biomarkers for treatment response, as well as enrollment according to tumor molecular characteristics.