Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry

Durvalumab Consolidation Should Be the Standard Therapy in Stage III EGFR-Mutant NSCLC After Chemoradiation

Brief Report: First-line Pembrolizumab in Metastatic Non-Small Cell Lung Cancer Habouring MET Exon 14 Skipping Mutation and PD-L1 ≥50% (GFPC 01-20 Study)

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

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.

9057 Background: Immune checkpoint inhibitors (IO) single agent or in combination with platinum chemotherapy (CT-IO) are standard of care for Stage IV non-small cell lung cancer (NSCLC) according to PD-L1 expression. While the efficacy of IO among patients (pts) with common EGFR and ALK alterations appears to be limited, its activity in pts with novel oncogenic drivers alterations is not well characterized. Compared to non-oncogene-addicted NSCLC, the overall response rate (ORR) seems to be similar in BRAF and c-MET altered NSCLC, lower in RET altered NSCLC, while data are less consistent in HER2 and EGFR exon 20 (EGFRex20) altered NSCLCs. Methods: From January 2016 to January 2022, we retrospectively enrolled pts with Stage IV NSCLC that received IO or combination CT– IO in any line, ECOG PS 0 - 2 and detection of MET exon 14 skipping mutations (METex14), BRAF mutations (V600E or non-V600E), RET rearrangement, HER2 point mutations (HER2mut)/exon 20 insertions (HER2ex20) or uncommon EGFR mutations (uEGFRmut)/EGFRex20. A review of clinicopathologic and molecular features and an analysis of response to combination or single-agent IO were conducted. Results: Among sixty-four pts enrolled, 20 (31%) had METex14, 19 (30%) had EGFR alterations [12 (19%) EGFRex20, 7 (11%) uEGFRmut], 8 (12%) had BRAF mutation (3 V600E and 5 non-V600E), 13(20%) had HER2 alterations [7 (11%) HER2ex20, 6 (10%) HER2mut] and 4 (6%) were RET rearranged. 43 received IO single agent and 21 received CT-IO. With a median follow up of 22 months (m), median progression free survival (mPFS) was 5.40 m (0.95 CI 4.73-6.9) overall, 6.77m in CT-IO arm (0.95 CI 5.37-NA) and 5.10m in IO arm (0.95 CI 2.60-6.7), with a trend to better mPFS for CT-IO (p 0.054). Regarding specific mutations irrespectively from treatment arm, NSCLC harboring METex14 showed a mPFS of 5.33 m (0.95 CI, 2.30-13.9), BRAF 9.9 m (0.95 CI, 6.70-NA), EGFR 4.93 m (0.95 CI, 1.80-6.9), HER2 11.4 (0.95 CI, 4.2-NA), RET 5.28 (0.95 CI, 1.42-NA). Disease control rate (DCR) was better in the CT-IO arm vs IO one in the overall population (84.2% vs 50%, p 0.013). Conclusions: Novel driver alterations seem to show a benefit from IO treatments. CT-IO seems to have a better outcome in terms of DCR. Therefore, IO-based treatment should be evaluated also in tumors harboring novel driver alterations. [Table: see text]

Background:Patients with inflammatory arthritis (IA) exhibit altered immune regulation due to disease mechanisms and long-term immunosuppressant treatment. Several malignant diseases have shown significant improvement with immune checkpoint inhibitors (ICI), amongst...

BackgroundTreatment options for lung cancer patients with epidermal growth factor receptor (EGFR) mutations are limited after tyrosine kinase inhibitor (TKI) resistance. We aimed to evaluate the efficacy and safety of immune checkpoint inhibitors (ICIs) in patients with EGFR-TKI-resistant non-small cell lung cancer (NSCLC).MethodsWe retrieved randomized controlled trials (RCTs) on ICIs in patients with EGFR-TKI resistance from PubMed, Cochrane Library, Web of Science, and EMBASE databases from creation to March 25, 2025. We focused on the endpoints median overall survival (OS), median progression-free survival (PFS), objective response rate (ORR), and safety data.ResultsTwelve eligible RCTs were included in this meta-analysis. The combination of ICIs and chemotherapy was better than chemotherapy alone [PFS: hazard ratio (HR) =0.76, 95% confidence interval (CI): 0.66–0.87, P<0.001; OS: HR =0.86, 95% CI: 0.75–1.00, P=0.045]. ICIs plus anti-angiogenic agents and chemotherapy also improved PFS (HR =0.51, 95% CI: 0.43–0.61), P<0.001), but not OS (HR =0.91, 95% CI: 0.76–1.10, P=0.34). No significant differences were observed in all-grade treatment-related adverse events (TRAEs) between ICIs-based treatment and chemotherapy (RR =1.34, 95% CI: 0.71–2.54, P=0.27).ConclusionsIn patients with EGFR-TKI-resistant NSCLC, the combination of ICIs with chemotherapy significantly improved both PFS and OS compared to chemotherapy alone, while ICIs, chemotherapy, and anti-angiogenic drugs only enhanced PFS. The ICIs-chemotherapy regimen demonstrates acceptable safety, suggesting its potential as a therapeutic option that deserve further investigation.

9046 Background: The efficacy of immune checkpoint inhibitors (ICI) and PD-L1 status in patients with advanced non-small cell lung cancer (NSCLC) harboring oncogenic alterations has not been fully investigated. We initiated this immuno-oncology biomarker study as part of nationwide genomic screening by LC-SCRUM-Japan (LC-SCRUM-IBIS). Methods: Lung cancer patients enrolled in LC-SCRUM-IBIS underwent targeted next-generation sequencing (NGS) with Oncomine Comprehensive Assay, PD-L1 immunohistochemistry (IHC) assays and further whole-exome sequencing (WES) to determine tumor mutation burden. According to subtype of oncogenic alterations, the efficacy of ICI and PD-L1 status were analyzed. Results: Between Feb 2017 and May 2018, 1017 lung cancer patients were enrolled. Of these, 832 NSCLC patients had adequate tumor samples and were included in this analysis. Targeted NGS showed that major oncogenic alterations included 157 EGFR, 83 KRAS, 33 MET, 30 HER2, 25 FGFR, 22 PIK3CA, 19 ALK, 15 ROS1, 10 RET, 5 BRAF and 13 others. High expression of PD-L1 ( &gt; 50% of tumor cells by 22C3) were observed in RET (70%), MET (67%), ROS1 (53%), KRAS (41%) and BRAF (40%) positive tumors. One-hundred five patients were evaluable for the efficacy of ICI, including 80 non-squamous and 25 squamous histology. Among them, 104 were treated with PD-1/PD-L1 monotherapy and only 1 in combination therapy of ICI. Median treatment line was 2 (range, 1-9). The response rate was 19% (20/105) and median progression-free survival (PFS) and overall survival (OS) were 3.3 and 18.3 months. In 50 patients harboring at least one oncogenic alterations, the response rate, PFS and OS were 18% (9/50), 3.3 and 24.8 months. Among 9 responders to ICI, 3 had KRAS, 2 had MET and 1 each had ALK/EGFR/HER2/RET. Six (26%) of 23 patients with both high PD-L1 expression and at least one oncogenic alterations responded to ICI. Conclusions: PD-L1 status seemed to vary among patients with advanced NSCLC harboring oncogenic alterations. New biomarker for ICI therapy in this population should be moreover explored. Updated results on WES analysis will be presented at the meeting.

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 .

11543 Background: As immunotherapy gains traction in sarcoma treatment, identifying biomarkers and understanding patterns of response to immune checkpoint inhibitors (ICI) remain critical. We expanded a prior cohort to investigate clinical factors, including the neutrophil-to-lymphocyte ratio (NLR) and its changes, in predicting outcomes such as overall survival (OS) and progression-free survival (PFS) in advanced sarcoma. Methods: Patients from The Ohio State University Sarcoma Clinics (2015–2023) were included in a retrospective ICI database. Data included treatment regimens (single-agent ICI or ICI+combination therapy) and clinical variables, particularly baseline and post-treatment NLR stratified into low ( &lt; 5) or high (≥5). Survival outcomes were analyzed using log-rank tests and Cox regression to assess OS and PFS. Results: A total of 192 patients met the inclusion criteria. Most were male (55%), and 83% had Stage 4 disease at ICI initiation. ICI was started as a third-line or later therapy in 52% of cases. The majority received single-agent ICI (57%), while 43% underwent ICI+combination therapy with other modalities (e.g., surgery, radiation, TKI). OS and PFS were similar between single-agent ICI and ICI+combination groups (OS: p = 0.419; PFS: p = 0.834), though clinical variables in the ICI+combination group may confound results. Median OS was 60 weeks, and median PFS was 40 weeks. Significant differences in OS and PFS were associated with NLR. Patients with lower NLR had improved OS (p &lt; 0.0001). Among those with higher NLR at ICI initiation, OS improved with ICI+combination therapy (p = 0.039). After the first ICI cycle, the OS benefit persisted for patients with high NLR (p &lt; 0.0001), regardless of treatment type. However, survival did not differ by treatment modality or by changes in NLR from baseline (p = 0.710). For PFS, patients with low NLR at ICI initiation had improved outcomes (p = 0.0002). Further analysis showed no PFS differences by NLR in the ICI+combination group. After the first cycle, the PFS benefit for low NLR persisted (p = 0.0006). Conversely, an increased NLR ratio from baseline to the first cycle was linked to worse PFS (p = 0.003), particularly in the ICI+combination group (p = 0.0029) but not in single-agent ICI (p = 0.8630). OS and PFS were not influenced by age, gender, or histology. Conclusions: NLR is a promising clinical biomarker for predicting response to ICI in advanced sarcoma. Low baseline NLR predicts improved OS and PFS, while changes in NLR may indicate progression risk. These findings warrant further prospective validation. Variable OS (p-value) PFS (p-value) Low vs. High NLR &lt;0.0001 0.0002 High NLR + Combination 0.039 0.834 NLR Change (Baseline) 0.710 0.003 NLR values.

68 Background: Previous retrospective analyses have revealed higher response rates and a trend towards longer progression-free survival (PFS) and overall survival (OS) in response to immune checkpoint inhibitors (ICIs) in overweight patients. There are few reports concerning the association between the overweight state and the efficacy of ICIs specifically in non-small cell lung cancer (NSCLC) patients. We investigated the association between the body mass index (BMI) and the efficacy of ICIs in patients with NSCLC. Methods: Patients with advanced NSCLC who received ICI therapy (nivolumab or pembrolizumab) at the National Cancer Center Hospital from January 2016 to December 2018 were included in this retrospective cohort study. Based on their BMI, the patients were categorized into the overweight (A) group (BMI ≥25) and the non-overweight (B) group (BMI &lt; 25). The PFS was compared between the two groups as the primary outcome. Results: Data of a total of 323 patients (median age, 63 years) were analyzed; 87 (26.9%)/43 (13.3%)/193 (59.8%) patients received pembrolizumab as 1st line therapy, pembrolizumab as 2nd line therapy, and nivolumab, respectively. Tumor proportion score was ≥50% in 58.4% (139/238) patients. The ECOG-PS was ≥2 in 37 patients (11.5%). The median body weight was 58.1, and the median BMI was 21.4. Of the 323 patients, 46 (14.2%) were categorized into group A (overweight) and 277 (85.8%) into group B (non-overweight). The median PFS and OS in two groups were as follows: A, 6.9 m/B, 5.6 m (HR 0.84, 95% CI [0.57-1.25], p = 0.38), and A, 22.3 m/B, 15.4 m (HR 0.90, 95% CI [0.56-1.43], p = 0.64), respectively. In accordance with the ICI regimen that the patients received, the PFS was A, 7.9 m/B, 7.8 m (HR 0.86, 95%CI [0.37-2.04], p = 0.74) in the patients who received pembrolizumab as 1st line therapy, A, 7.5 m/B, 5.3 m (HR 0.60, 95% CI [0.18-2.00], p = 0.40) in the patients who received pembrolizumab as 2nd line therapy, and A, 6.5 m/B, 4.4 m (HR 0.84, 95% CI [0.52-1.36], p = 0.48) in the patients who received nivolumab. Conclusions: Overweight NSCLC patients treated with ICIs showed a trend (non-statistically significant) towards a longer PFS as compared to non-overweight patients.

2591 Background: Immune checkpoint inhibitors (ICIs) have suboptimal efficacy in non-small cell lung cancer (NSCLC) patients with ERBB2 mutations, including ERBB2 exon 20 insertions. This study aims to investigate the efficacy of ICIs and immune characteristics in NSCLC patients harboring ERBB2 ex20ins and non-ex20ins mutations. Methods: Advanced NSCLC patients harboring ERBB2 mutations were recruited from January 2016 to December 2020. Pre-ICI tumor tissue samples were collected and performed with targeted next-generation sequencing. Patients received ICIs were followed up every 3 months until November 2021. Genomic features were compared between patients with ERBB2 ex20ins and non-ex20ins mutations. Progression-free survival (PFS), overall survival (OS), and tumor immune microenvironment (TIME) features characterized by multiplex immunohistochemistry (IHC) were further analyzed in patients receiving ICIs. Two-sample T-tests were performed to compare means; Cox models were fitted to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Two external datasets of ERBB2-mutant NSCLC patients, including TCGA (n = 23) and META (n = 33), were used for validation. Results: A total of 117 eligible patients were enrolled (median age: 59 [range: 24-82], males 57.3%, stage IV 68.4%, adenocarcinoma 93.2%), of whom 37 received subsequent ICI treatment. similar PD-L1 tumor proportion score (mean: 8.1% vs. 13.2%, p = 0.25) and significantly lower mutation number (mean: 3.0 vs. 6.2 muts/person, p &lt; 0.01) were detected in patients with ERBB2 ex20ins, compared to patients with ERBB2 mutations other than ex20ins. Similarly, in the TCGA cohort, tumor mutation burden was significantly lower in ERBB2 ex20ins patients (mean: 2.2 vs. 10.3 muts/Mb, p = 0.02). Of 37 patients receiving ICIs, ERBB2 non-ex20ins patients displayed superior PFS (mPFS: 13.5 vs. 4.4 months, HR: 0.31, 95% CI: 0.14-0.71), relatively long OS (mOS: 27.5 vs. 8.1 months, HR: 0.47, 95% CI: 0.20-1.14), and a relatively high rate of durable clinical benefit (64.3% vs. 34.8%, p = 0.10) than ex20ins patients, consistent with what was observed in the META cohort (PFS, mPFS: 13.2 vs. 2.5 months, HR: 0.20, 95% CI: 0.06-0.68; OS, mOS: 23.3 vs. 8.0 months, HR: 0.32, 95% CI: 0.11-0.90). Moreover, the CD4+ T cell density appeared to be lower in the tumor stroma of ERBB2 ex20ins patients than that of non-ex20ins patients (300.5 vs. 1288.0 /mm2, p = 0.08), even though the general TIME features of ex20ins patients were similar to those of non-ex20ins patients. Conclusions: NSCLC patients carrying ERBB2 ex20ins demonstrated worse clinical outcome under ICI treatment, similar PD-L1 expression and lower mutation number when compared to those with non-ex20ins mutations. Genomic and TIME characteristics should be further investigated to elucidate the efficacy of ICIs in lung cancer patients carrying ERBB2 mutations.

e21098 Background: HER2 (ERBB2) amplification is a distinct actionable oncogenic driver in 2-3% of non-small cell lung cancer (NSCLC). While HER2-targeted agents are now in development for lung cancers harboring HER2 mutations, the therapeutic landscape for patients with HER2 amplification is not well elucidated. Although immune checkpoint inhibitors (ICIs) alone or in combination with chemotherapy are widely used as treatment for NSCLC, little is known about the impact of ICIs in patients with HER2-amplified NSCLC. This study aimed to assess the efficacy of ICIs in this patient population. Methods: Patients with HER2-amplified NSCLC were identified from January 2014 to October 2021. HER2 amplification was detected by next generation sequencing (NGS) on the MSK-IMPACT platform. Clinicopathologic and molecular features, as well as response to therapy with ICIs were assessed. Patients were excluded if they harbored concurrent HER2 mutations, had localized disease, or received concurrent chemotherapy. Patient records were reviewed to evaluate overall survival (OS), progression free survival (PFS) and overall response rate (ORR). Results: Eighteen patients with metastatic HER2-amplified NSCLC who received ICI alone as first line treatment or subsequent therapy after progression met inclusion criteria. Histologic subtypes included adenocarcinoma (78%) and squamous cell carcinoma (22%). PD-L1 expression was available for 16 patients, with 69% having no expression of PD-L1. The median tumor mutation burden (TMB) was 9.2 mutations/Mb (range 3.0-35.4). The median OS was 11 months (95% CI: 4 to 37), with 6-month and 12-month survival being 67% (95% CI: 40% to 83%) and 49% (95% CI: 25% to 70%), respectively. Median PFS was 2 months (95% CI: 1 to 7). In the 15 patients that were assessed for response, the ORR was 0% (95% CI 0% to 19%), including 3 cases with PD-L1 expression of ≥ 50% and 9 cases with TMB ≥ 10 mutation/Mb. Conclusions: Patients with HER2-amplified NSCLC showed minimal response to immunotherapy, regardless of PD-L1 status and TMB. These findings underscore the importance of developing novel HER2-targeted agents for these patients with unmet medical need.

Background In recent years, the gut microbiome has increasingly emerged as influencing the response to immune checkpoint inhibitors (ICIs). 1–3 Antibiotic (ABX) exposure, that leads to microbiome dysbiosis, was further...

Real-world assessment of response to anti-programmed cell death 1 therapy in advanced cutaneous squamous cell carcinoma