Received Immune Checkpoint Inhibitor Monotherapy Research Articles

Clinical impact of concomitant BIO-three use in advanced or recurrent non-small cell lung cancer treated with immune-checkpoint inhibitor.

Immune checkpoint inhibitors (ICIs) have been approved as first-line therapy for advanced non-small cell lung cancer (NSCLC). The probiotic MIYAIRI 588 can potentially improve the outcomes of patients with advanced NSCLC treated with ICI. However, the impact of other probiotics on ICI-treatment efficacy remains unclear. Thus, we aimed to clarify the association between BIO-three use and treatment outcomes in patients with advanced NSCLC treated with ICI. This retrospective study included patients aged ≥ 18years with advanced or recurrent NSCLC who had received ICI monotherapy or ICI plus chemotherapy. Concomitant therapy with probiotic bacteria was defined as receiving it within 180days before ICI therapy. Here, 289 patients were enrolled, including 23 (8.0%) receiving BIO-three. In the multivariable analysis, the progression-free survival (PFS) and overall survival (OS) of patients receiving BIO-three tended to be longer than those of patients not receiving probiotic therapy (PFS, hazard ratio [HR] 0.75; 95% confidence interval [CI] 0.43-1.30; p = 0.33; OS, HR 0.69; 95% CI 0.37-1.28; p = 0.24). After propensity score matching with weighted adjustment, patients receiving BIO-three tended to have prolonged PFS (median PFS [range] 7.6months [2.6-17.4] vs 3.2months [1.6-7.0]; HR 0.53; 95% CI 0.25-1.12; p = 0.09) and OS (median OS [range] 25.6months [10.8-not reached] vs 10.9months [7.3-not reached]; HR 0.57; 95% CI 0.24-1.36; p = 0.20) than those not receiving probiotic therapy. This study suggests the prognostic impact of concomitant BIO-three use in patients with advanced NSCLC on ICI treatment.

Impact of commonly prescribed medications on immune-related adverse events.

e14704 Background: Commonly used medications may have immune modulating properties that affect the risk of immune-related adverse events (irAEs) after immune checkpoint inhibitor (ICI) therapy. Methods: We identified 27,998 patients who received ICI from 2010 to 2023 in the national Veterans Affairs system, matched to 66,488 historical control patients treated with non-ICI systemic therapies. We extracted medication usage in the year before therapy start. We used propensity-weighted Cox regression analysis to assess the effect of each medication on severe irAE (treatment with prolonged course of high-dose steroids, adrenal insufficiency, or new insulin-dependent diabetes). To identify medication effects specific to ICI vs. other therapies, we report the adjusted hazard ratio (aHR) for each medication stratified by cohort (ICI vs. historical control) and the p-value for the interaction between each medication class and cohort. Results: Among ICI patients, 52% of patients were treated in the first line, 72% received ICI monotherapy, and 95% received PD-1/PD-L1 inhibitors alone. The most common cancer types were NSCLC (46%), melanoma (10%), and liver cancer (8%). Among 15 medication classes, metformin, loop diuretics, and PPIs were associated with small, marginally statistically significant differences in toxicity among ICI patients, but similar associations were observed in historical control patients (p for interaction >0.18; Table). After adjustment for multiple comparisons, no medication classes were associated with increased risk of severe irAE in ICI patients. Conclusions: Commonly prescribed medication classes have no significant effects on toxicity specific to ICI therapy. [Table: see text]

Association between antibiotic use and mortality among older persons receiving first-line immune checkpoint inhibitors for non-small cell lung cancer (NSCLC).

e14607 Background: There is biologic plausibility that antibiotics (ABX) may reduce the effectiveness of cancer therapy, most notably immune checkpoint inhibitors (ICI). As ABX are commonly prescribed to older persons and more than a third of US persons with cancer are eligible for ICIs, use of ABX has important population health implications. We assess the association between ABX use and mortality among persons with NSCLC who receive first-line (1L) treatment. Methods: Using SEER-Medicare, we assembled a cohort of persons ≥66 years with NSCLC who received 1L treatment with platinum-based chemotherapy (PLT) or ICI (PLT without ICI, PLT with ICI, and ICI monotherapy) within one year of cancer diagnosis between 2017-2019. We assessed overall ABX exposure from 1 month to 1 year prior to treatment initiation and by ABX class. Primary outcome was all cause deaths within three years of treatment initiation or until 12/31/2020. Multivariable Cox proportional hazard models adjusting for individual-level characteristics (demographics, time-to-treatment, comorbidities, healthcare use, SEER registry, and neighborhood socioeconomic status) and landmark analyses of 1-6 months after cancer treatment were used to assess the association between ABX exposure and mortality. Results: Among 4,182 persons (mean age 75 years, 85% white, 68% chemo-immunotherapy within 2 months of NSCLC diagnosis), 63%, 18%, and 18% received PLT, PLT+ICI, and ICI, respectively. ICI+/-PLT increased in prevalence from 20% of treatments (2017) to 55% (2019). The mean age of persons who received ICI alone (78 years old) was higher than PLT or PLT+ICI. Prior to 1L treatment, 22% and 72% of persons received ABX within 30 days and 1 year prior to cancer treatment, respectively. The three most common ABX classes were fluoroquinolones (48%), penicillins (21%), and macrolides (18%). The cohort was followed for 3,274 person-years and included 2,958 deaths within 1 year and 4,144 deaths within 3 years of follow-up. Compared with persons who did not receive ABX within 3 months of cancer treatment, ABX use was associated with higher risk of death within 3 years for ICI alone [HR 1.24 (1.05-1.46) but not for PLT alone or PLT+ICI. Fluoroquinolones were associated with an elevated risk of mortality among persons who received ICI alone HR 1.41(95%CI: 1.1-1.8) and PLT alone HR 1.18 (95%CI: 1.05-1.32) but not PLT+ICI. Our findings were similar across definitions of ABX exposure (30 days to 1 year prior to treatment) and analytic landmarks after treatment initiation. Conclusions: Among patients with NSCLC who received 1L treatment, we identified an association between ABX exposure prior to treatment and increased mortality among persons who received ICI monotherapy but not PLT+ICI. As ICIs expand to more cancer types and earlier stages, ABX use may have a significant impact on outcomes and population health.

5-hydroxymethylcytosine in cell-free DNA as liquid biomarker for immune checkpoint inhibitor therapy in non–small cell lung cancer.

e20563 Background: Immune checkpoint inhibitors (ICIs) targeting programmed cell death 1 (PD-1), and its ligand (PD-L1) are the mainstay of treatment for metastatic non-small cell lung cancer (NSCLC) in patients lacking targetable driver mutations. However, optimal predictive biomarkers are lacking. We used a plasma cell-free DNA (cfDNA) 5-hydroxymethylcytosine (5hmC) signature-based predictive model to assess treatment response and potentially select patients eligible for ICI monotherapy. Methods: 40 plasma samples were collected from adult patients with stage III or IV lung cancer at Houston Methodist Hospital between 2019 and 2022. These were divided into a training (n = 24) and validation (n = 16) set. By identifying genes associated with progression free survival (PFS), a 16-gene signature was used to develop a 5hmC predictive model. A weighted predictive score (wp-score) based on the model was calculated for each patient and grouped into low and high wp-scores. Results: Low wp-scores were associated with higher objective response rate(ORR) in both training and validation set and better correlated with response rates compared to PD-L1. In the training set, PFS was longer in low wp-scores compared to high wp-scores (median 12.3 versus 3.0 months; p = 3.5x10-6; hazard ratio (HR) 4.6x10-10). This was also seen in the validation set (median 7.6 versus 1.8 months p = .0012; HR 0.12). Contrarily, high ( > 1%) or low ( < 1%) PD-L1 was not associated with PFS (median 6.8 versus 6.0 months; p = .40; HR 0.70; 95% CI, 0.30–1.60) or overall survival (OS) (median 10.1 versus 12.0 months; p = .38; HR 0.56; 95% CI, 0.15–2.10). 15 out of the 40 total patients received ICI monotherapy. Among these, low wp-scores (n = 8) were significantly associated with longer PFS compared to high wp-scores (n = 7), (median 19.6 versus 2.8 months; p = .00073; HR: 0.059). OS although longer, was not significant among the two groups (median 38.1 versus 10.5 months; p = .12). Conclusions: Our study provides a proof of concept that cfDNA 5hmC signature can be used to predict response to ICI therapy and select patients appropriate for monotherapy. It is a more sensitive and specific biomarker to PD-L1. Larger studies are underway to further validate cfDNA 5hmC based-signature predictive model. [Table: see text]

Assessment of PSA responses and changes in the rate of tumor growth (g-rate) with immune checkpoint inhibitors in US Veterans with prostate cancer

We examined data from US Veterans with prostate cancer (PC) to assess disease response to immune checkpoint inhibitors (ICI) as monotherapy or combined with abiraterone or enzalutamide to assess ICI efficacy in the real-world. We queried the VA corporate data warehouse (CDW) to identify Veterans with a diagnosis of PC who received ICI for any malignancy and had ≥1 PSA measurement while receiving ICI. To evaluate ICI monotherapy, we restricted analysis to Veterans who had not received LHRH agonists/antagonists, PC-directed medical therapy, or radiation/extirpative surgery of the bladder/prostate within and preceding the duration of ICI administration. For ICI combination analysis, we identified Veterans who received abiraterone or enzalutamide for PC while on ICI. We calculated rates of tumor (PSA) growth (g-rates), comparing them to a 1:2 matched reference cohort. We identified 787 Veterans with PC and ≥1 PSA measurement while receiving an ICI. Median duration of ICI therapy was 155 days. 223 Veterans received ICI monotherapy, with only 17(8%) having a reduction in PSA (median decline = 43%). 12 (5%) had PSA declines >30% (PSA30) which included 6 (3%) who had PSA reductions greater than 50% (PSA50). Median g-rates for ICI plus abiraterone (n = 20) or enzalutamide (n = 31) were 0.000689/d-1 and 0.002819/d-1, respectively, and were statistically insignificant compared to g-rates of matched cohorts receiving abiraterone (g = 0.000925/d-1, P = 0.73) or enzalutamide (g = 0.001929/d-1, P = 0.58) alone. Our data align with clinical trial data in PC, demonstrating limited benefit from ICI monotherapy and predicting no survival benefit from simultaneous abiraterone or enzalutamide with an ICI using g-rate.

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.

Transient Worsening of Pain After Administration of Immune Checkpoint Inhibitors - A Case Series.

Transient pain enhancement or flare pain, is observed following the administration of immune checkpoint inhibitors (ICIs). However, the detailed mechanism of this phenomenon remains unclear. In this report, we present our experience of documenting the course of flare pain following ICI administration in six cases. Six patients with advanced solid tumors received ICI monotherapy between July 2017 and November 2019. Their pain increased within hours of ICI administration despite being stable before ICI administration. We evaluated the changes in the numerical rating scale (NRS) score over 72 h after ICI administration. Four non-small cell lung cancer patients, one gastric cancer patient, and one renal cell cancer patient were included. Four patients experienced an increase in NRS, as evidenced by scores on two or more scales compared to the day before administration, whereas two patients showed an increase only on one scale. The NRS score decreased to almost the same level as that on the day before administration. Flare pain is observed in the same area as the primary site. Most of the pain was alleviated without the need for rescue analgesics, although one patient experienced a 4-point increase in the NRS scale. Flare pain may occur following ICI administration. Healthcare providers should be aware of these events and provide patients with suitable information and coping techniques.

Efficacy and safety of immune checkpoint inhibitors plus recombinant human endostatin therapy as second-line treatment in advanced non-small-cell lung cancer with negative driver gene: a pilot study.

Immune checkpoint inhibitors (ICIs) have become the standard second-line treatment for advanced non-small cell lung cancer (NSCLC). Recentfindings indicating an intertwined regulation of vascular endothelial growth factor (VEGF) signaling and immunosuppression in the tumor microenvironment suggest that the combination of ICIs and angiogenesis inhibitors could have synergistic antitumor activity, along with favorable tolerability. However, ICIs plus anti-angiogenesis therapy has not been widely evaluated. The purpose of this pilot study was to evaluate the efficacy and safety of ICIs plus recombinant human (rh)-endostatin as second-line treatment in advanced NSCLC with negative driver gene. Prospectively evaluated the efficacy and safety of ICIs plus rh-endostain as second-line treatment in advanced NSCLC with negative driver gene. The primary endpoints of the study were progression-free survival (PFS) and overall survival (OS). The secondary endpoints were objective response rate (ORR), disease control rate (ORR), and safety. A total of 34 patients were recruited in this study. 18 patients received ICIs plus anti-angiogenesis therapy (ICIs combination therapy), and 16 patients received ICIs monotherapy. DCR was 88.9% vs 43.8% (P = 0.009). Median PFS (mPFS) was 8.3 months vs. 3.7 months (HR = 0.276, 95% CI 0.125-0.607, P = 0.001). Median OS (mOS) was 18.0 months vs 9.6 months (HR=0.364, 95% CI 0.147-0.902, P=0.009). In multivariate Cox regression analysis, ICI combination therapy prolonged PFS (HR = 0.069, 95% CI 0.019-0.185, P < 0.001) and OS (HR = 0.044, 95% CI 0.011-0.185, P < 0.001). We did not observe a significant difference in the incidence of adverse events (AEs) between the two groups (P > 0.05). Compared with ICIs monotherapy, ICIs combination therapy improves clinical response in patients with advanced NSCLC with negative driver gene, significantly prolongs PFS and OS, and does not significantly difference the incidence of AEs.

Immunotherapy strategies for EGFR-mutated advanced NSCLC after EGFR tyrosine-kinase inhibitors failure.

This study aimed to investigate the efficacy of immunotherapy, as monotherapy or in combination, comparing to chemotherapy with or without anti-angiogenesis for advanced non-small cell lung cancer (NSCLC) patients progressing to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs). We retrospectively analyzed patients with advanced NSCLC harboring EGFR mutations who received immune checkpoint inhibitors (ICI) and/or chemotherapy after EGFR-TKIs failure at Shanghai Chest Hospital between Aug 2016 and Oct 2022. According to the subsequent immunotherapy regimen, the patients were assigned to ICI monotherapy (IM), IO plus anti-angiogenesis (IA), ICI plus chemotherapy (IC), ICI plus chemotherapy plus anti-angiogenesis (ICA). Eligible patients undergoing standard chemotherapy were assigned to chemotherapy plus anti-angiogenesis (CA) and chemotherapy alone (CM). Efficacy was evaluated according to the RECIST 1.1version, and calculated the objective response rate (ORR) and disease control rate (DCR). Survival curves were plotted using the Kaplan-Meier method, and the median progression-free survival (PFS) was calculated. Differences among survival curves of the six groups were assessed using the log-rank test. A total of 237 advanced NSCLC patients with EGFR mutations were included in this study. Of the 160 patients who received immunotherapy, 57 received ICI monotherapy, 27 received ICI plus anti-angiogenesis therapy, 43 received ICI plus chemotherapy, and 33 received ICI plus anti-angiogenesis plus chemotherapy. 77 patients received standard chemotherapy, of which 30 received chemotherapy plus anti-angiogenesis and 47 received chemotherapy alone. Patients in ICA group showed significant longer PFS than IM (7.2 vs 1.9 months, P=0.011), IA (7.2 vs 4.8 months, P=0.009) and CM group (7.2 vs 4.4 months, P=0.005). There was no significant difference in PFS between the ICA and IC (7.2 vs 5.6 months, P=0.104) or CA (7.2 vs 6.7 months, P=0.959) group. Meanwhile, the ICA group showed the highest ORR and DCR (36.4% and 90.9%) compared to the other five groups. The IC group had a higher ORR than the IA and CA group (32.6% vs 7.4% vs 10.0%, respectively), but the DCR was comparable (79.1% vs 74.1% vs 76.7%, respectively). The ORR of the CM group was 6.4% and the DCR was 66.0%. IM group showed the lowest ORR and DCR (1.8% and 36.8%). Treatment-related adverse events (TRAEs) of grade 3 or worse occurred in 9 (27.3%) patients in the ICA group, 6 (20.0%) in the CA group, 7 (14.9%) in the CM group, 5 (11.6%) in the IC group, 5 (8.8%) in the IM group, and 2 (7.4%) in the IA group. NSCLC patients with positive EGFR mutations after EGFR-TKIs failure received subsequent immunotherapy plus anti-angiogenesis and chemotherapy are likely to have more benefits in ORR, DCR and mPFS.

RBM17 Expression Is Associated With the Efficacy of ICI Monotherapy in NSCLC With Low PD-L1 Expression.

Immune checkpoint inhibitors (ICIs) are currently a standard treatment tool for non-small cell lung cancer (NSCLC). RNA-binding motif protein 17 (RBM17), a splicing factor, is frequently over-expressed in NSCLC, but little is known about the role of RBM17 in the efficacy of ICIs for NSCLC. Thus, we investigated the correlation between RBM17 expression and ICI efficacy in NSCLC. Biopsy or surgical specimens were collected from patients with advanced or recurrent NSCLC who received ICI monotherapy or chemo-immunotherapy in a first-line setting. RBM17 expression was examined using immunohistochemistry. The correlation between the efficacy of ICI monotherapy or chemo-immunotherapy and RBM17 expression was evaluated. Among the 218 cases, 115 (52.8%) cases were positive for RBM17 expression. RBM17 expression was not associated with the objective response rate (ORR) or progression-free survival (PFS) in either of the ICI monotherapy or chemo-immunotherapy groups. However, among those with a low PD-L1 expression level (PD-L1 <50%; n=86), RBM17 expression was significantly associated with a better ORR (p=0.045) and a better PFS (p<0.001) in the ICI monotherapy group, and was significantly associated with a poor ORR in the chemo-immunotherapy group (p=0.041). RBM17 might be a useful predictive marker for a higher efficacy of ICI monotherapy in NSCLC patients with a low PD-L1 expression level.

Real-world pan-cancer landscape of frameshift mutations and their role in predicting responses to immune checkpoint inhibitors in cancers with low tumor mutational burden

BackgroundPembrolizumab is FDA approved for tumors with tumor mutational burden (TMB) of ≥10 mutations/megabase (mut/Mb). However, the response to immune checkpoint inhibitors (ICI) varies significantly among cancer histologies. We describe...

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 .

Clinical outcomes in patients with metastatic non-small cell lung cancer and head and neck squamous cell cancer treated with immune checkpoint inhibitors according to COVID-19 vaccination status.

e14696 Background: Immune checkpoint inhibitor (ICI) constitute the mainstay of therapy in metastatic non-small cell lung cancer (NSCLC) and head and neck squamous cell cancer (HNSCC). Infectious vaccines administered intratumorally or systemically have been suggested to enhance response to ICI and improve outcomes. No data is available on the effect of COVID-19 vaccines on clinical outcomes in patients treated with ICI. The aim of the study is to investigate overall survival (OS), progression-free survival (PFS), and immune related adverse events (IRAEs) according to mRNA COVID-19 vaccination status in patients with metastatic NSCLC and HNSCC who were treated with ICI. Methods: We performed retrospective analysis of clinical outcomes between a cohort of patients treated with ICI who received at least one dose of COVID-19 vaccine, and a historic control group of patients who did not receive COVID-19 vaccine and did not have documented COVID-19 infection. We included patients with metastatic NSCLC and HNSCC who had received at least one dose of ICI, either as monotherapy or in combination with chemotherapy or targeted therapy. Patients were stratified by age, gender, ethnicity, COVID-19 vaccination status, number of vaccinations, treatment type (monotherapy versus combined), treatment line, and PD-L1 status. Endpoints included IRAEs, PFS and OS. Results: A total of 151 patients met inclusion criteria (94 vaccinated and 57 control). Mean age at diagnosis was 62 years, the majority were female (51%), African American (58.3%), and received ICI monotherapy (57.6%). There was prolonged OS in patients who received COVID-19 vaccination versus control group ( p-value=0.04). In a multivariate analysis, patients in the COVID-19 vaccine arm had significantly reduced hazard of dying (HR:0.49, p =0.0446) when controlled for all of the above variables, and each additional received vaccine was associated with significant reduced hazard (HR=0.701, p-value = 0.0099). Race and type of cancer were statistically associated with PFS. Controlled for these factors, COVID arm patients had reduced hazard of disease progression (HR = 0.58, p-value = 0.0506), and each additional received mRNA vaccine was associated with a significantly reduced hazard of progression (HR = 0.74, p-value = 0.0046). There was no significant difference in the rate of IRAEs between vaccinated and non-vaccinated patients ( p=0.71). Conclusions: In this sample of patients with metastatic NSCLC and HNSCC who received ICI, there was significant improvement in OS between patients who received a COVID-19 vaccine compared patients who did not receive vaccination and did not have COVID-19 infection. There were no significant differences in IRAEs. Further studies are required to assess whether there is a synergistic effect between COVID-19 vaccination and ICI efficacy.

Metabolic syndrome is independently associated with improved overall survival to first-line therapy with immune checkpoint inhibitors in non-small cell lung cancer.

Many co-existing medical conditions may affect the outcome in patients treated with immune checkpoint inhibitors for advanced cancer. There is currently not any information on whether metabolic syndrome (MetS) impacts the clinical outcome in patients treated with immune checkpoint inhibitors (ICIs) for advanced non-small cell line cancer (NSCLC). We carried out a single-center retrospective cohort study to determine the effects of MetS on first-line ICI therapy in patients with NSCLC. One hundred and eighteen consecutive adult patients who received first-line therapy with ICIs and had adequate medical record information for the determination of MetS status and clinical outcomes were included in the study. Twenty-one patients had MetS and 97 did not. There was no significant difference between the two groups in age, gender, smoking history, ECOG performance status, tumor histologic types, pre-therapy use of broad-spectrum antimicrobials, PD-L1 expression, pre-treatment neutrophil:lymphocyte ratio, or proportions of patients who received ICI monotherapy or chemoimmunotherapy. With a median follow-up of 9 months (range 0.5-67), MetS patients enjoyed significantly longer overall survival (HR 0.54, 95% CI: 0.31-0.92) (p = 0.02) but not progression-free survival. The improved outcome was only observed in patients who received ICI monotherapy and not chemoimmunotherapy. MetS predicted for higher probability of survival at 6 months (p = 0.043) and 12 months (p = 0.008). Multivariate analysis indicated that, in addition to the known adverse effects of use of broad-spectrum antimicrobials and the beneficial effects of PD-L1 (Programmed cell death-ligand 1) expression, MetS was independently associated with improved overall survival but not progression-free survival. Our results suggest that MetS is an independent predictor of treatment outcome in patients who received first-line ICI monotherapy for NSCLC.

Dual Biomarker Combining DNA Damage Repair Gene Mutations and PD-L1 Expression for Immune Checkpoint Inhibitors in Non-small Cell Lung Cancer.

Immune checkpoint inhibitors (ICIs) improve long-term survival in advanced non-small cell lung cancer (NSCLC) and require robust predictive biomarkers for the selection of responders. This study investigated the optimal implementation of DNA damage repair (DDR) gene mutations to predict response to ICIs in real-world NSCLC patients. We retrospectively reviewed 55 advanced NSCLC patients who had undergone targeted high-throughput sequencing and received ICIs. Patients with two or more DDR gene mutations were defined as DDR2 positive. The patients' median age was 68 (range=44-82) years, and 48 (87.3%) were men. Seventeen patients (30.9%) showed ≥50% high programmed death-ligand 1 (PD-L1) expression. Ten patients (18.2%) received an ICI-chemotherapy combination as first-line therapy, and 38 (69.1%) received ICI monotherapy as more than second-line therapy. Fourteen patients (25.5%) were DDR2-positive. The objective response rate of patients with DDR2-positive or PD-L1 ≥50% was 45.5%, and that of patients with DDR2-negative and PD-L1 <50% was 11.1% (p=0.007). In the PD-L1 low expression subgroup (<50%), patients with DDR2-positive had improved progression-free survival (PFS) and overall survival (OS) after ICIs compared to those with DDR2-negative (PFS: 5.8 vs. 1.9 months, p=0.026, OS: 14.4 vs. 7.2 months, p=0.078). DDR2-positive patients or those with PD-L1 ≥50% (24, 43.6%) had statistically significant improvement in PFS and OS after ICIs compared to DDR2-negative and those with PD-L1 <50% (PFS: 4.4 vs. 1.9 months, p=0.006, OS: 11.6 vs. 7.2 months, p=0.037). A dual biomarker combining DDR gene mutations and PD-L1 expression improves the prediction of response to ICIs in advanced NSCLC.

Abstract 3376: Non-small cell lung cancer (NSCLC) with higher blood tumor mutational burden (bTMB)/tissueTMB (tTMB) ratio is associated with inferior survival outcome

Abstract Background: High TMB is known to correlate with better response to immune checkpoint inhibitor (ICI) treatment in certain cancers. bTMB is now being used in place of tTMB at times due to difficulty in obtaining enough tissue samples for sequencing. Concordance between bTMB and tTMB values has been reported. However, the prognostic role of bTMB in relation to tTMB is not well understood. Method: Patients with NSCLC who had both tTMB and bTMB results (collected from 10/2020 to 10/2022) were included. Progression free survival (PFS) and overall survival (OS) were analyzed according to bTMB, tTMB levels (High defined as ≥ 10 Mut/Mb, Low defined as &amp;lt;10 Mut/Mb), and bTMB/tTMB ratio. The Gehan-Breslow-Wilcoxon test was used for survival analysis and the Mantel-Haenszel test was used to calculate the hazard ratio. Survival analysis by bTMB was performed only in 40 patients where bTMB was collected before and within 30 days of treatment initiation. Results: Among 61 pts,18 pts (29%) received ICI monotherapy, 25 pts (41%) received ICI and chemotherapy combination therapy, 8 pts (14%) received chemotherapy, and 10 pts (16%) received targeted therapy. The median interval between bTMB collection and treatment initiation was 20 days (Q1:11, Q3:47) while 40 pts (66%) had the interval of &amp;lt;30 days. 12 pts (20%) were tTMB high, and 32 pts (52%) were bTMB high. There was no difference in OS between groups with tTMB high and low. Similar findings were seen in OS and PFS of pts who received ICI containing regimen (p-value 0.71, 0.59, and 0.18, respectively). Group with high bTMB showed inferior OS compared to the group with low bTMB(p=0.008, OS HR=4.4) regardless of treatment regimens. Among people treated with ICI containing regimen, a similar trend was seen (p=0.009, OS HR=4.9). The median bTMB/tTMB ratio was 2.49. Patients were divided into three groups according to bTMB/tTMB tertiles (1st: 0.31-1.62, 2nd: 1.71-3.65, 3rd: 3.86-11.48). There was a significant difference in OS among the three groups with the 3rd tertile having the worst prognosis (log-rank test for trend, p=0.04). When divided into two groups (1st+2nd vs 3rd), the 3rd tertile group had a significantly inferior OS (p=0.01, HR 5.58). Among people treated with ICI containing regimen, a trend toward inferior OS was seen in the 3rd tertile group (p=0.12, HR 3.03). However, no significant difference in PFS was seen (p-value 0.77, HR 1.05). Conclusion: High bTMB/tTMB ratio was associated with inferior OS regardless of treatment regimen in patients with NSCLC. A high bTMB/tTMB ratio may be indicative of increased tumor heterogeneity and/or higher metastatic tumor burden. Further studies are warranted to explore the role of bTMB/tTMB in various cancers. Citation Format: Leeseul Kim, Jewel Park, Youjin Oh, Young Kwang Chae. Non-small cell lung cancer (NSCLC) with higher blood tumor mutational burden (bTMB)/tissueTMB (tTMB) ratio is associated with inferior survival outcome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3376.

Real‐world data on the efficacy and safety of immune‐checkpoint inhibitors in elderly patients with non‐small cell lung cancer

Immune-checkpoint inhibitors (ICIs) are effective against advanced non-small cell lung cancer (NSCLC). However, whether the efficacy and safety of ICI treatment in elderly patients are similar to those in younger patients is unclear. This study was designed to address this question. We enrolled patients who received ICI monotherapy in Japan between December 2015 and December 2017; those ≥75 years of age comprised the elderly group. We compared the efficacy and safety of ICI monotherapy in elderly patients with those in younger patients and explored prognostic factors in elderly patients. We enrolled 676 patients; 137 (20.3%) were assigned to the elderly group. The median age of the elderly and younger groups was 78 (range, 75-85) and 66 (range, 34-74) years. The median progression-free survival (4.8 months vs. 3.3 months, p = 0.1589) and median overall survival (12.3 months vs. 13.0 months, p = 0.5587) were similar between the elderly and younger groups. Multivariate analysis revealed that a significantly better OS in the elderly group was associated with better responses to first- or second-line ICI treatment (p = 0.011) and more immune-related adverse events (irAEs) (p = 0.02). IrAEs that led to ICI discontinuation occurred in 34 of 137 patients (24.8%) in the elderly group, and their survival was significantly higher than that in those who did not have irAEs. ICI is also effective in elderly NSCLC patients, and treatment discontinuation due to irAEs may be a good prognostic marker.

Tumor-infiltrating lymphocyte enrichment predicted by CT radiomics analysis is associated with clinical outcomes of non-small cell lung cancer patients receiving immune checkpoint inhibitors.

Enrichment of tumor-infiltrating lymphocytes (TIL) in the tumor microenvironment (TME) is a reliable biomarker of immune checkpoint inhibitors (ICI) in non-small cell lung cancer (NSCLC). Phenotyping through computed tomography (CT) radiomics has the overcome the limitations of tissue-based assessment, including for TIL analysis. Here, we assess TIL enrichment objectively using an artificial intelligence-powered TIL analysis in hematoxylin and eosin (H&E) image and analyze its association with quantitative radiomic features (RFs). Clinical significance of the selected RFs is then validated in the independent NSCLC patients who received ICI. In the training cohort containing both tumor tissue samples and corresponding CT images obtained within 1 month, we extracted 86 RFs from the CT images. The TIL enrichment score (TILes) was defined as the fraction of tissue area with high intra-tumoral or stromal TIL density divided by the whole TME area, as measured on an H&E slide. From the corresponding CT images, the least absolute shrinkage and selection operator model was then developed using features that were significantly associated with TIL enrichment. The CT model was applied to CT images from the validation cohort, which included NSCLC patients who received ICI monotherapy. A total of 220 NSCLC samples were included in the training cohort. After filtering the RFs, two features, gray level variance (coefficient 1.71 x 10-3) and large area low gray level emphasis (coefficient -2.48 x 10-5), were included in the model. The two features were both computed from the size-zone matrix, which has strength in reflecting intralesional texture heterogeneity. In the validation cohort, the patients with high predicted TILes (≥ median) had significantly prolonged progression-free survival compared to those with low predicted TILes (median 4.0 months [95% CI 2.2-5.7] versus 2.1 months [95% CI 1.6-3.1], p = 0.002). Patients who experienced a response to ICI or stable disease with ICI had higher predicted TILes compared with the patients who experienced progressive disease as the best response (p = 0.001, p = 0.036, respectively). Predicted TILes was significantly associated with progression-free survival independent of PD-L1 status. In this CT radiomics model, predicted TILes was significantly associated with ICI outcomes in NSCLC patients. Analyzing TME through radiomics may overcome the limitations of tissue-based analysis and assist clinical decisions regarding ICI.

CT-based delta radiomics in predicting the prognosis of stage IV gastric cancer to immune checkpoint inhibitors.

To explore the prognostic value of CT-based delta radiomics in predicting the prognosis of patients with stage IV gastric cancer treated with immune checkpoint inhibitors (ICI). Forty-two patients with stage IV gastric cancer, who had received ICI monotherapy, were enrolled in this retrospective study. Baseline and first follow-up CT scans were analyzed. Intratumoral and peritumoral regions of interest (ROI) were contoured, enabling the extraction of 192 features from each ROI. The intraclass correlation coefficients were used to select features with high stability. The least absolute shrinkage and selection operator was used to select features with high weights for predicting patient prognosis. Kaplan-Meier analysis and log-rank test were performed to explore the association between features and progression free survival (PFS). Cox regression analyses were used to identify predictors for PFS. The C-index was used to assess the prediction performance of features. Two radiomics features of ΔVintra_ZV and postVperi_Sphericity were identified from intratumoral and peritumoral regions, respectively. The Kaplan-Meier analysis revealed significant differences in PFS between patients with low and high feature value (ΔVintra_ZV: P=0.000; postVperi_Sphericity: P=0.012), and the multivariable cox analysis demonstrated that ΔVintra_ZV was independent predictor for PFS (HR, 1.911; 95% CI: 1.163-3.142; P=0.011), with C-index of 0.705. Based on CT scans at baseline and first follow-up, the delta radiomics features could efficiently predict the PFS of gastric cancer patients treated with ICI therapy.

Safety of COVID-19 vaccines in subjects with solid tumor cancers receiving immune checkpoint inhibitors

ABSTRACT The incidence of severe immune-related adverse events (irAEs) in cancer subjects receiving immune checkpoint inhibitors (ICIs) following COVID-19 vaccination and the relationship between the incidence of severe irAE and the interval between COVID-19 vaccination and ICI dose have not been established. We performed a retrospective study evaluating the incidence of irAEs in solid tumor subjects receiving ICI therapy who received any COVID-19 vaccinations since FDA authorization. irAEs were defined as severe with one or more grade 3 or above events (CTCAE v5.0), multiple organ involvement, or requiring hospitalization for management. Two hundred and eighty-four subjects who received COVID vaccinations from December 2020 and February 2022 were included in this analysis [median age at vaccination 67 years (IQR 59.0–75.0); 67.3% male]. Twenty-nine subjects (10.2%) developed severe irAEs, of which 12 subjects (41.4%) received ICI monotherapy, 10 subjects (34.5%) received combination ICI therapy with nivolumab and ipilimumab, and 7 subjects (24.1%) received ICI plus VEGFR-TKI therapy. Hospitalization occurred in 62% of subjects with severe irAEs, with a median duration of 3 days (IQR: 3.0–7.5 days). Immunosuppressive therapy was required in 79.3%, with a median duration of 103 days (IQR: 42.0–179.0). ICI therapy was discontinued in 51.7% of subjects with severe irAE; dosing was held or interrupted in 34.5%. Among severe irAEs, the median interval between vaccination and ICI treatment closest to the occurrence of severe irAE was 15.5 days (IQR: 10.0–23.0). In solid tumor cancer subjects receiving ICIs, COVID-19 vaccination is not associated with an increased incidence of severe irAEs compared to historical data and may be safely administered during ICI cancer therapy in subjects who lack contraindications.