Benefit Of Immune Checkpoint Inhibitors Research Articles

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.

PD-L1 expression and its prognostic value in metastatic papillary renal cell carcinoma: Results from a GETUG multicenter retrospective cohort

IntroductionPapillary renal cell carcinoma (pRCC) is a rare and aggressive cancer with no specifically established therapeutic strategy in the metastatic setting. Combinations of tyrosine kinase and immune checkpoint inhibitors (ICI) are a promising option. We aimed to study the immune landscape of metastatic pRCC, and its interactions with angiogenesis pathways, to search for potential therapeutic targets. MethodsThe expression of immune markers (PD-L1, PD-1, PD-L2, LAG-3) and angiogenic pathways (CAIX, c-MET), was analyzed by immunohistochemistry on 68 metastatic pRCC retrieved from a retrospective multicenter GETUG cohort.Our primary endpoint was to estimate the prevalence of PD-L1 expression and its prognostic impact in metastatic pRCC. Secondary endpoints included the evaluation of other immune markers (PD-1, PD-L2, and LAG-3) and their association with PD-L1. We also assessed angiogenic markers and their association with PD-L1. ResultsOverall, 27.9 % of tumors were PD-L1 positive. PD-L2 was more frequently expressed (45.6 %), PD-1 and LAG-3 were positive in 17.6 % and 19.1 % respectively. None of these markers was correlated with PD-L1 expression. 66 % (45/68) expressed at least one immune marker, and 43 % (29/68) were “double-positive”, as they expressed both immune and angiogenic markers. OS was significantly shorter for patients with PD-L1 positive pRCC. A multivariate analysis confirmed a significant association between PD-L1 expression and shorter overall survival (HR = 4.0, p = 0.01). ConclusionThese results reinforce clinical data on the expected benefit of ICI in metastatic pRCC treatment, as PD-L1 expression is a factor of poor prognosis in this multicenter cohort.

Huang Lian Jie Du Decoction enhances the anti-tumor efficacy of immune checkpoint inhibitors by activating TLR7/8 signalling in melanoma

BackgroundThe clinical application of immune checkpoint inhibitors (ICIs) is limited by their drug resistance, necessitating the development of ICI sensitizers to improve cancer immunotherapy outcomes. Huang Lian Jie Du Decoction (HLJD, Oren-gedoku-to in Japanese, Hwangryunhaedok-tang in Korean), a famous traditional Chinese medicinal prescription, has exhibited potential in the field of cancer treatment. This study aims to investigate the impact of HLJD on the efficacy of ICIs in melanoma and elucidate the underlying mechanisms.MethodsThe potential synergistic effects of HLJD and ICIs were investigated on the tumor-bearing mice model of B16F10 melanoma, and the tumor infiltration of immune cells was tested by flow cytometry. The differential gene expression in tumors between HLJD and ICIs group and ICIs alone group were analyzed by RNA-seq. The effects of HLJD on oxidative stress, TLR7/8, and type I interferons (IFN-Is) signaling were further validated by immunofluorescence, PCR array, and immunochemistry in tumor tissue.ResultsHLJD enhanced the anti-tumor effect of ICIs, significantly inhibited tumor growth, and prolonged the survival duration in melanoma. HLJD increased the tumor infiltration of anti-tumor immune cells, especially DCs, CD4+ T cells and CD8+T cells. Mechanically, HLJD activated the oxidative stress and TLR7/8 signaling pathway and IFN-Is-related genes in tumors.ConclusionsHLJD enhanced the therapeutic benefits of ICIs in melanoma, through increasing reactive oxygen species (ROS), promoting the TLR7/8 pathway, and activating IFN-Is signaling, which in turn activated DCs and T cells.

Effect of immune checkpoint inhibitors at different treatment time periods on prognosis of patients with extensive-stage small-cell lung cancer.

The application of immune checkpoint inhibitors (ICIs) in treating patients with extensive-stage small-cell lung cancer (ES-SCLC) has brought us new hope, but the real-world outcome is relatively lacking. Our aim was to investigate the clinical use, efficacy, and survival benefit of ICIs in ES-SCLC from real-world data analysis. A retrospective analysis of ES-SCLC patients was conducted between 2012 and 2022. Progression-free survival (PFS) and overall survival (OS) were assessed between groups to evaluate the value of ICIs at different lines of treatment. PFS1 was defined as the duration from initial therapy to disease progression or death. PFS2 was defined as the duration from the first disease progression to the second disease progression or death. One hundred and eighty patients with ES-SCLC were included. We performed landmark analysis, which showed that compared to the second-line and subsequent-lines ICIs-combined therapy group (2SL-ICIs) and non-ICIs group, the first-line ICIs-combined therapy group (1L-ICIs) prolonged OS and PFS1. There was a trend toward prolonged OS in the 2SL-ICIs group than in the non-ICIs group, but the significance threshold was not met (median OS 11.94months vs. 11.10months, P = 0.14). A longer PFS2 was present in the 2SL-ICIs group than in the non-ICIs group (median PFS2 4.13months vs. 2.60months, P < 0.001). First-line ICIs plus chemotherapy should be applied in clinical practice. If patients did not use ICIs plus chemotherapy in first-line therapy, the use of ICIs in the second line or subsequent lines of treatment could prolong PFS2.

Abstract LB442: Novel antibodies against a KK-LC-1-derived peptide presented on HLA-A*01 on tumor cells

Abstract The prognostic benefit of immune checkpoint inhibitors (CPIs) is mainly restricted to specific cancers, such as melanoma and lung adenocarcinoma. For patients with cancers which are noninflamed (“cold”), or CPI-resistant, therapeutic options are currently limited. Recently, the US FDA approved the first bispecific molecule targeting a tumor peptide MHC. This highlights the potential of targeting MHC-presented tumor antigens to empower T cells to specifically recognize and eliminate solid tumors. While there is a growing number of agents targeting pMHCs, most of them are restricted to HLA-A*02. There is an urgent need to identify effective pMHC targeted therapies for solid tumors, especially on other alleles to increase the proportion of eligible patients. Kita-Kyushu lung cancer antigen-1 (KK-LC-1/CT83) peptide presented on HLA-A*01 is a promising tumor target as its expression is restricted to tumors and it is broadly expressed in many cancers including gastric, lung, breast, and cervical cancer. However, targeting the KK-LC-1/HLA-A*01 complex is challenging due to the high levels of similar off-target peptides presented in healthy tissues. Through in silico analysis we identified peptides within the human genome that share a high sequence identity to the target. These peptides were found in a database containing &amp;gt;1 million mass spectrometry (MS)-identified peptides presented by healthy tissues, cancer cell lines, and tumor tissue samples. A peptide derived from 6-pyruvoyltetrahydropterin synthase (PTS) was found to be abundantly presented in healthy tissues. MS confirmed that this peptide occurs at extremely high natural levels (620 - 3500 copies per cell) on HLA-A*01 cell lines and healthy tissue. Here, we describe a set of pMHC T-cell engager (TCE) antibodies with high specificity towards HLA-A*01 restricted KK-LC-1 epitope. ScFv phage display libraries were rigorously screened for binding to the pMHC target and counter-screened against predicted off-target peptides including PTS. Specific scFv hits were reformatted into TCEs using an anti-CD3 Fab effector arm. The TCEs showed efficient killing of KK-LC-1/HLA-A*01-positive human cell lines NCI-H1703 and EKVX in co-cultures with human PBMCs, while KK-LC-1-negative/HLA-A*01-positive cell lines SK-MEL-30 and PC-3 (known to present the risk peptides on the surface) were minimally affected. TCE-dependent T cell activation measured by IFNγ was significantly higher in presence of TAP-deficient, (empty) HLA-A*01-expressing T2 cells pulsed with the target peptide compared to the risk peptides. Alanine scans of isolated binders confirmed that at least 6 amino acids of the KK-LC-1 peptide are required for binding. Overall, the data show that these antibodies have promising anti-tumor activity and specificity for KK-LC-1/HLA-A*01 positive tumors. Future activities will focus on lead optimization for therapeutic development. Citation Format: Fabian Scheifele, Stephanie Jungmichel, Nagjie Alijaj, Athanasia Dasargyri, Romina Doerig, Philip Knobel, Hannes Merten, Philipp Richle, Thomas Schleier, Anna Sobieraj, Alessio Vantellini, Tim Fugmann, Rom Leidner, Swethajit Biswas, Leonardo Borras. Novel antibodies against a KK-LC-1-derived peptide presented on HLA-A*01 on tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB442.

Abstract 3736: Bridging the gaps: A cross-species approach to PD-1 and OX40 combination immunotherapy

Abstract Monoclonal antibodies (mAbs) targeting immune checkpoints, such as PD-1, PD-L1, and CTLA4, have provided unprecedented clinical benefits to human cancer patients. Novel strategies such as combination therapy with OX40 or 4-1BB agonists are currently under investigation in various pre-clinical studies to enhance the therapeutic benefits of immune checkpoint inhibitors. While syngeneic mouse tumor xenograft models offer valuable insights in pre-clinical testing, they fall short in capturing the nuanced heterogeneity within and between tumors and the dynamic tumor-immune interface. In contrast, canine patients with spontaneous neoplasms possess a closely analogous and intact immune system. These canine patients, who receive sophisticated and advanced medical therapy like their human counterparts, can serve as a vital intermediate pre-clinical model system between rodent studies and human clinical trials, potentially reducing clinical trial failures. In this study, we have developed a novel bispecific fusion protein, denoted BsOXPD, that combines OX40 agonism and PD-1 blockade into a single therapeutic. Our bispecific fusion protein employs an anti-PD-1 nanobody (Nb) to bind and block the PD1 pathway and the extracellular domain (ECD) of the OX40 ligand to stimulate the OX40 receptor. We have developed murinized, caninized, and humanized versions of this protein. All versions of the bispecific fusion protein retain their biochemical and functional properties following the murinization, caninization, and humanization processes. Importantly, all versions effectively disrupt the PD-1/PD-L1 axis in murine, canine, and human systems while concurrently acting as potent OX40 agonists. To further improve the humanized version of the BsOXPD, we partially humanized the anti-PD1 Nb by introducing amino acid substitutions in various framework regions. The humanized anti-PD1 Nb still completely inhibited the binding of human PD-L1 to the PD-1 receptor. The caninized version of BsOXPD exhibits no toxicities or immune-related adverse events (irAEs) following intravenous injection at doses of 1 mg/kg or 3 mg/kg body weight in healthy beagle dogs. In summary, we have designed a cross-species Nb-based fusion protein for PD1 blockade and OX40 agonism. Our next goal is to evaluate the therapeutic efficacy of caninized BsOXPD in pet dogs with oral melanoma in neoadjuvant settings. Therefore, our cross-species approach will offer comprehensive insights into the safety, pharmacokinetic (PK) profile, and clinical benefits associated with the concurrent application of PD1 blockade and OX40 agonism. Citation Format: Maninder Sandey, Damien Ruiz, Jonathan Marable, Deepa Bedi, Payal Agarwal. Bridging the gaps: A cross-species approach to PD-1 and OX40 combination 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 3736.

Abstract 912: CheckpointPx, an interpretable radiology AI tool, predicts checkpoint blockade benefit independent of PDL1 status in non-small cell lung cancers (NSCLC): A multi-institutional validation study

Abstract Background: Immune Checkpoint Inhibitors (ICIs) are a cornerstone in the treatment of cancers such as Non-Small Cell Lung Cancer (NSCLC). Despite the standard use of biomarkers such as PD-L1 expression for selecting ICI regimens, recent studies suggest missed opportunities for benefit in PD-L1 low/negative patients. Therefore, there is an urgent need for new biomarker strategies capable of guiding the use of ICIs in NSCLC. We introduce and validate an AI-powered radiology tool for ICI patient selection that provides interpretable predictions by quantifying aspects of tumor biology on baseline CT scans directly associated with ICI efficacy, such as tumor heterogeneity and twistedness of the tumor-associated vasculature. Methods: We analyzed CT scans of 439 patients treated with ICI at 4 institutions (D1-D4) using the Picture Health Px platform. Experienced radiologists and physicians across institutions delineated target lesions on baseline CT scans. A deep learning model was used to segment pulmonary vessels. CheckpointPx v1.11, an interpretable neural network incorporating quantitative features extracted from within the tumor and its vasculature, was trained to predict ICI response (defined as disease control per RECIST best overall response) on n=247 patients (D1-D3). It was assessed with respect to response and progression free-survival (PFS) on 192 patients (D2-D4), with D4 (n=105) being an external validation set. CheckpointPx was also evaluated within PDL1 subsets among testing set patients where available (n=138). Results: The cohort was predominantly late stage (Stage 3/4) (&amp;gt;85%) and was mixed with respect to ICI line of treatment (1st-4th). 122 of 247 (49%) and 119 of 192 (62%) were responders in training and test cohorts respectively. CheckpointPx included 16 features, such as entropy-based heterogeneity and quantitative vessel tortuosity (twistedness). The model predicted response to ICI with an AUC=0.65 on the test set. The CheckpointPx High Risk group significantly stratified patients by PFS (HR=1.67 [1.22-2.28], p=0.001). This separation remained significant within the subset of PDL1-negative (HR=2.71 [1.35-5.44], p=0.005) and PDL1-positive patients (HR=2.05 [1.22-3.46], p=0.007). Conclusions: From baseline radiology, CheckpointPx was shown to strongly predict ICI outcomes across multiple institutions, NSCLC stages, and lines of ICI. Furthermore, the tool stratified patients by ICI benefit within both PDL1-positive and negative subsets - suggesting the potential of CheckpointPx to address critical gaps in the NSCLC biomarker landscape. CheckpointPx is driven by interpretable imaging biomarkers, and thus its predictions are tied to specific and quantifiable phenotypic attributes of the tumor and its microenvironment. Citation Format: Amogh Hiremath, Seyoung Lee, Jeeyeon Lee, Peter Haseok Kim, Kai Zhang, Salie Lee, Monica Yadav, Maria Jose Aguilera Chuchuca, Taegyu Um, Myungwoo Nam, Liam Il-Young Chung, Hye Sung Kim, Jisang Yu, Trie Arni Djunadi, Leeseul Kim, Youjin Oh, Sungmi Yoon, Zunairah Shah, Yuchan Kim, Ilene Hong, Grace Kang, Jessica Jang, Amy Cho, Soowon Lee, Cecilia Nam, Timothy Hong, Yury S. Velichko, Amit Gupta, Vamsidhar Velcheti, Anant Madabhushi, Nathaniel Braman, Young Kwang Chae. CheckpointPx, an interpretable radiology AI tool, predicts checkpoint blockade benefit independent of PDL1 status in non-small cell lung cancers (NSCLC): A multi-institutional validation study [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 912.

Abstract 3856: Nodal metastasis as an immune indicator in cancer (ca) therapy

Abstract Introduction: Nodal Metastasis as an Immune Indicator in Cancer (Ca) Therapy Staging (sg) is widely used to identify appropriate treatment options &amp; implement therapy. Tumor-Node-Metastasis (TNM) is the most utilized sg system. In it, nodal involvement is viewed simply as an adverse metric without biologic connotation, and gross metastasis (M1) eclipses other variables and denotes the least favorable sg. Ca’s ability to thrive within the lymph node itself was intriguing to us in the immune-oncology (IO) era. Failure to overcome an immunogenic ca (e.g., dysfunctional apoptosis) leads to T-cell exhaustion (TCE) typified by PD-1 expression. Immune Checkpoint Inhibitors (ICI) address TCE by intercepting the PD-1:PDL-1 synapse. We reasoned that immune actions are distinct in tumor beds vs nodes &amp; hypothesized that immunogenic N(+), implies ca’s ability to defend itself (e.g., PDL-1 expression); N(0), reflects immune susceptibility and effective clearance outside the tumor bed. In the latter scenario, TCE is nonexistent; ICIs are less beneficial. Tumor beds (T, M) are sanctuaries exempt from immune action due to factors such as hypoxia, acidity, and poor tumor vasculature which lead to poor T-cell trafficking, to name a few. M1 develop from circulating ca stem cells, an immune-exempt entity. Methods: We examined the interaction between ICIs &amp; nodal involvement dichotomizing surveillance, epidemiology and end results SEER cases into N(0) or N(+) within M1 melanoma &amp; lung cancer. 2005, 2015-17 denote pre-, and post ICI, respectively to provide mature survival data. Results: Table 1 depicts the 4- or 5-year overall survival in the specified subsets. Conclusions: ICI benefit is more prominent in N(+) ca, where TCE is likely. N(0) ca represents immune-prone ca with less TCE &amp; need to be viewed as a biologically distinct subset. Agents influencing T-cell access (angiogenic)/functionality should be considered in these cases. Finally, we suggest that PDL-1 testing should specify testing sites as nodal vs tumor bed expression. Expectations SEER results: % Overall Survival at 5-y (melanoma) or 4-y (Lung ca) Pre-ICI Post ICI Metric Melanoma Mechanism 2005 2015 Increment in 5yr OS N(0) favorable prognosis Immunogenic tumor N(0): 302 cases 20 29 8 (20 -12) N+ Predicts benefit to ICI T-cell exhaustion in N(+) only N(+): 210 cases 12 37 N(+): +25 &amp;gt; N(0): +9 2005 2017 Increment in 4yr OS Lung Cancer N(0) similar to N(+) Less immunogenic tumor N(0) 9,583 cases 18 18 4 (18 -14) N+ Predicts benefit to ICI T-cell exhaustion in N(+) only N(+): 17,887 cases 14 20 +6 Citation Format: Bradley Fugere, Jim Chen, Tyler C. Fugere, Farah Mazahreh, Nishanth Thalambadu, A Mazin Safar. Nodal metastasis as an immune indicator in cancer (ca) therapy [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 3856.

Abstract 1213: Tissue-specific thresholds and microenvironment correlates of tumor mutation burden associated with immunotherapy benefit and prognosis in microsatellite stable cancers

Abstract Background: Immune checkpoint inhibitors (ICIs) targeting anti-PD-1/L1 have expanded the treatment landscape against cancers, but are only effective in a subset of patients across all cancer types. Tumor mutation burden (TMB) is postulated to be a generic determinant of ICI dependent-tumor rejection. Here, we clarify the association between TMB and survival outcomes among microsatellite-stable cancers in a real-world clinicogenomic cohort including 70,698 patients distributed across 27 histologies. Methods: Patients were segregated into mutually exclusive anti-PD-1/L1 (N=14,736, immune checkpoint inhibitor, ICI) and non-ICI cohorts (N=55,962) if they had received pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, or cemiplimab, and non-ICI therapies, respectively, during the course of treatment for individual cancer types. Patients treated with chemo-immunotherapy combination regimens were included in the ICI cohorts, but anti-CTLA-4 agents were excluded from both cohorts. For both ICI and non-ICI cohorts, patients were reiteratively categorized as TMB-high or -low using increasing TMB thresholds up to the 90th percentile TMB for individual cancer types. Outcomes were then assessed using Cox regression analyses of overall survival (OS). Results: Across 27 histologies, 12 cancer types had at least one TMB cutoff associated with survival benefit upon ICIs (melanoma, NSCLC, SCLC, bladder, cervical, colorectal, gastric, ovarian, head and neck, vulvar cancers, as well as carcinoma of unknown primary, and sarcoma), and these associations were generally conserved across sex and age groups, although not necessarily significant in all cases. In two cancer types (cholangiocarcinoma and neuroendocrine tumors), TMB cutoffs were associated with worse OS with ICIs. The lowest TMB cutoff in which a survival benefit could be detected with ICIs ranged from 2 mut/Mb in melanoma to 9 mut/Mb in colorectal cancer. TMB thresholds with the greatest predictive value (defined as the lowest survival hazard ratio) were frequently near the highest TMB examined for individual cancer types, suggesting that TMB may scale with ICI benefit. Conclusion: TMB was associated with survival benefit or detriment depending on tissue and treatment context. Detectable survival benefits were noted over a broad range of TMB cutoffs across cancer types, and a dose-dependent relationship between TMB and outcomes was observed in a subset of cancers. These results may have implications for cancer-agnostic and universal TMB cutoffs to guide the use of anti-PD-1/L1 therapies, and underline the importance of tissue context in the clinical development of ICI biomarkers. Citation Format: Maishara Muquith, Magdalena Espinoza, Andrew Elliott, Joanne Xiu, Andreas Seeber, Wafik El-Deiry, Emmanuel S. Antonarakis, Stephanie Graff, Michael J. Hall, Hossein Borghaei, Dave S. Hoon, Stephen V. Liu, Patrick C. Ma, Rana R. McKay, Trisha Wise-Draper, John Marshall, George W. Sledge, David Spetzler, Hao Zhu, David Hsieh. Tissue-specific thresholds and microenvironment correlates of tumor mutation burden associated with immunotherapy benefit and prognosis in microsatellite stable cancers [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 1213.

Abstract 1541: Heterogeneity of the hormone receptor-positive breast tumor immune microenvironment according to patient’s body mass index

Abstract Background: Obesity is a risk factor for postmenopausal hormone receptor-positive (HR+) breast cancer (BC) and is associated with poorer outcomes. “Obesity-paradox”, a phenomenon where obesity (BMI ≥ 30) is associated with better outcomes in patients treated with immune checkpoint inhibitors (ICI), has been observed in several cancer types. It is however under-explored in BC, especially HR+ BC. Emerging data from recent trials (KEYNOTE-756 and CheckMate 7FL) have shown the potential benefits of ICI for treating early HR+ BC. This prompted the need for better insights into the biological link between obesity and HR+ BC, particularly its tumor immune microenvironment (TIME). Patients &amp; Methods: A monocentric cohort of 33 patients (11 lean, 11 overweight, 11 obese) with early HR+ BC was selected for the study, whose tumor tissues were collected and subjected to snRNA-seq. Unsupervised clustering and cluster annotation were performed on the processed data leading to identification of cell types and subtypes. We then performed differential gene expression (DGEA) and gene set enrichment analyses (GSEA) according to BMI category for each of the immune cell types. Results: We identified a total of 76,773 immune cells belonging to six major cell types, namely B/plasma cell, dendritic cell (DC), mast cell, monocyte/macrophage (mono/macro), T cell, and natural killer (NK) cell. Their proportions varied between patients, however immune cellular composition was not associated with BMI. DGEA and GSEA revealed highly cell type-specific obesity-associated differences in the expression profile of immune cells. Notably, an enrichment of B cell-mediated immune activities, substantiated by the upregulation of Ig genes, was observed in B cells and plasma cells. This was however coupled with an overexpression of the checkpoint BTLA in B cells. CD8+ and CD4+ T cells showed a lower level of activation (higher LEF1, TCF7, lower ANXA1, IL4R), and NK cells a decreased cytokine production (CD96, CD226) and conflicting differential expression of cytotoxic molecules (lower NKG7, higher granzymes). Checkpoint genes such as PDCD1, CTLA4, TIGIT, LAG3, HAVCR2 did not show significant changes in their expression in T/NK cells. Mast cells displayed a downregulation of antigen presenting genes (CD74, HLA-A/B/E). DC and mono/macro populations also exhibited both up- and down-regulation of genes involved in different immune pathways. Conclusion: Our current data suggested that obesity was associated with multi-directional changes in the immune activities, possibly implying an unresolved inflammation in the HR+ BC tissue. Further investigation incorporating other cell types and their interaction with immune cells in both tumor and matched normal mammary tissues is warranted and on-going, which could provide more understanding of HR+ breast TIME and lead to speculation on therapeutic implications. Citation Format: Ha-Linh Nguyen, Tatjana Geukens, Maxim De Schepper, Karen Van Baelen, Marion Maetens, Gitte Zels, Amena Mahdami, Edoardo Isnaldi, Sigrid Hatse, Joke Verbeke, Christophe Matthys, Bernard Thienpont, Evy Vanderheyden, Thomas Van Brussel, Rogier Schepers, Gino Philips, Bram Boeckx, Diether Lambrechts, Giuseppe Floris, François Richard, Christine Desmedt. Heterogeneity of the hormone receptor-positive breast tumor immune microenvironment according to patient’s body mass index [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 1541.

Efficacy and predictors of immune checkpoint inhibitors in patients with gallbladder cancer.

Immune checkpoint inhibitors (ICIs) have shown promising efficacy in multiple cancers including biliary tract cancers (BTCs). However, the data focusing on the efficacy of ICIs in patients with gallbladder cancer (GBC) is still limited. In this study, we aim to assess the efficacy of ICIs in GBC and explore the clinicopathologic and molecular markers associated with ICI benefit. We retrospective analyzed 69 GBC patients who had received ICI therapy between January 2016 and December 2020. Tumor samples were obtained for genomic sequencing and immunohistochemical analysis. The median progression-free survival (PFS) and overall survival (OS) was 4.4 months and 8.5 months, respectively. Multivariate analysis indicated that alcohol intake history, carcinoma embryonic antigen (CEA) level ≥100 U/mL, and cutaneous immune-related adverse events (irAEs) were independent prognostic factors for PFS. CEA level ≥100 U/mL and cutaneous irAEs were independent prognostic factors for OS. The objective response rate and disease control rate (DCR) were 15.9% and 37.7%, respectively. Patients with cutaneous irAEs, high CD8+ T cell infiltrated or immune inflamed GBCs had higher DCR. Patients with high CD8+ T cell infiltrated or immune inflamed GBCs also had a notably improved prognosis. These results suggest that ICIs were effective in patients with GBC. High CEA level, cutaneous irAEs, high CD8+ T cell infiltration, and immune inflamed phenotype could be useful for predicting the efficacy of ICIs in GBC.

The role of androgen response pathway in association with tumor biology and response to neoadjuvant immune-checkpoint inhibitors (ICI) in muscle-invasive urothelial bladder carcinoma (MIBC).

662 Background: Emerging findings from ICI trials are suggestive of differential outcomes in females compared with males. Sex-specific differences in tumor biology, microbiome, and outcomes in MIBC are well-established. Conversely, limited data are available regarding the role of the androgen response pathway in explaining subtype differences between males and females and, most importantly, response to ICI. Methods: We retrospectively evaluated the biomarker findings of the transurethral resection of the bladder tumors (TURBT) and baseline clinical characteristics of patients (pts) with cT2-4N0M0 MIBC who received neoadjuvant pembrolizumab and radical cystectomy (RC) in the PURE-01 study. Transcriptome-wide expression profiling was performed on 102 TURBT samples. We focused on androgen receptor (AR) gene expression and the hallmark androgen response pathway expression quantifying 117 different genes related to the androgen response pathway as previously reported (PMID: 26771021). Pt and tumor characteristics were compared between subgroups using χ2 tests and two-sided Wilcoxon rank-sum tests. Kaplan-Meier curves and log rank tests evaluated gene expression and signature scores in association with the event-free survival (EFS), calculated from start of pembrolizumab treatment. Signature scores were analyzed as continuous values and were split by median and quartile values. Results: Pts received pembrolizumab and RC from 2017 to 2022. There were 87 (85.3%) males and 15 (14.7%) females. AR gene expression was not significantly different between males and females (p = 0.5), whereas androgen response signature was significantly higher in male (p = 0.03). The AR gene expression and androgen response signature scores were more highly expressed in luminal tumors vs rest of molecular subtypes (p = 0.005 and p &lt; 0.001). Despite AR gene expression was not associated with ypT0N0 response (p = 0.425), hallmark androgen response signature scores were significantly lower in ypT0N0 responders (p = 0.033). Higher hallmark androgen response signature scores were statistically significantly associated with shorter EFS (p = 0.028), whereas AR gene expression was not (p = 0.152). Conclusions: For the first time to our knowledge, we reported the androgen response pathway expression to be a potential biomarker of ICI benefit in MIBC. This signature was also associated with a luminal subtype, linked to inferior responsiveness to ICI. If confirmed at a larger scale these analyses will strengthen the need for sex-specific approaches and potentially new combination therapies in MIBC.

Benefit of immune checkpoint inhibitors (ICI) for patients with advanced esophageal squamous cell carcinoma and low PD-L1 expression: A systematic review and meta-analysis.

346 Background: Immunotherapy has improved survival for patients with advanced esophageal squamous cell carcinoma (aESCC) and currently is the standard of care for patients with a positive PD-L1 status (CPS ≥10; TPS ≥1%) in the first-line setting. For PD-L1 negative/low, treatment options are limited, and chemotherapy is usually the first choice and associated with adverse events that may impair quality of life. Immunotherapy trials harbor conflicting results in this subgroup of patients, therefore, we performed a systematic review and meta-analysis to evaluate the potential benefit of ICI as single treatment for patients with aESCC and a PD-L1 expression negative/low. Methods: Studies that enrolled patients with aESCC treated with ICI versus chemotherapy in first and second-line settings and provided separate outcomes for patients with PD-L1 negative/low were identified by searching the EMBASE, PubMed and Cochrane databases. The outcomes evaluated were Overall Survival (OS), Progression Free-Survival (PFS) and Treatment-Emergent Adverse Events (TEAE). We pooled hazard ratio (HR) for PFS and OS endpoints and odds ratio (OR) with 95% confidence intervals (CI) for TEAE. Statistical analyses were performed using Revman 5.4 and a random-effects model. I² analysis was used to assess heterogeneity. This meta-analysis was recorded on Prospero ID CRD42023411251. Results: We included 6 randomized clinical trials with a total of 674 individuals in the final analysis. Most studies (5/6) included previously treated patients. ICI monotherapy in aESCC patients and PD-L1 expression negative/low was associated with a better OS (HR 0.86; 95% CI 0.76-0.97; p = 0.02; I² = 0%) and worse PFS (HR 1.37; 95% CI 1.10-1.71; p = 0.005; I² = 0%). Regarding the safety profile, it showed higher grade 3-5 toxicity rates (OR 1.8; 95% CI 1.17-2.78; p = 0.007; I² = 85%) for chemotherapy. Conclusions: ICI is effective for patients with aESCC and low/negative PD-L1 expression with an improvement in OS and a favorable safety profile.

Updated pooled analyses of first-line anti-PD1/PD-L1 inhibitors plus chemotherapy in advanced esophageal squamous cell carcinoma.

366 Background: Advanced and metastatic esophageal squamous cell carcinoma (ESCC) patients have limited treatment options and poor prognosis. Recently, several studies demonstrated the clinical benefit of combining immune checkpoint inhibitors (ICI) and chemotherapy (CT), leading to its approval in the first-line setting. Since then, efforts have been made to identify the patients who may benefit the most or not from the combination of ICI plus CT. Methods: We searched PubMed, Scopus, and the Cochrane Library for randomized clinical trials investigating first-line ICI plus chemotherapy (CT) for advanced or metastatic ESCC patients. Outcomes of interest included: overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and OS according to gender, PD-L1 expression (&lt;1% / ≥1%), and PD-L1 CPS (&lt;10 / ≥10). We used I2 statistics to assess heterogeneity, and the fixed-effect model was used to pool studies. Results: Eight studies were included with 4,702 patients. Of them, most had an ECOG 0 or 1, and were younger than 65 years (62%), male (77%), and Asian (78%). Metastatic disease was diagnosed in 75% of patients. ICI plus CT was administered to 58%, and 43% received CT +/- placebo. Median follow-up ranged from 7.1 to 22.6 months. ICI plus CT significantly improved all efficacy outcomes compared to CT alone: decreasing the risk of death by 32% (HR for OS: 0.68; 95%CI 0.63-0.74; p&lt;0.00001); reducing the risk of progression or death by 38% (HR for PFS: 0.62; 95%CI 0.58-0.67; p&lt;0.00001); and increasing the objective response rate (risk difference: 0.17; 95%CI 0.14-0.20; p&lt;0.00001). A survival benefit was seen across all subgroup analyses, but it was significantly higher in patients with PD-L1 ≥1% compared to those with PD-L1 &lt;1% (reduction in the risk of death of 38% versus 23% respectively, p=0.03). OS was not significantly different between males versus females, or PD-L1 CPS≥10 versus CPS&lt;10. Conclusions: Our large systematic review and meta-analysis support the efficacy and survival benefit of ICI plus CT as first-line therapy for all ESCC patients, regardless of gender or PD-L1 expression.

Abstract B087: Mutant-p53 amplifies Cxcl1 expression from distal enhancers blunting immune checkpoint inhibition efficacy in pancreatic cancer

Abstract Pancreatic ductal Adenocarcinoma (PDAC) is an aggressive malignancy complicated by poor early diagnosis and a lack of response to traditional treatments. It is characterized by a desmoplastic stroma, a lack of infiltration and activation of T cells, and a low mutational burden. The genetic landscape of PDAC is defined by activating KRAS mutations (~90%) and p53 alterations (~70%), but the molecular switches perturbed by these genetic aberrations remain unclear. p53 missense mutations, unlike mutations resulting in the loss of p53, are considered to acquire tumor-supporting functions. But these novel functions remain uncharacterized. The ambiguity in the molecular mechanism of mutant-p53 is further exacerbated by the existence of various types of p53 mutations. The majority of p53 mutations are missense mutations in the DNA binding domain. The repertoire of transcription factors (TFs) it can interact with and the vast regulatory landscape of each TF—composed of gene promoters and distal enhancers—present obstacles in understanding the molecular mechanisms promoting PDAC. In this study, we examined how a common p53 missense mutation in PDAC plays a role in weakening the Immune checkpoint Inhibitors (ICIs) efficacy. Using cells derived from a genetically engineered mouse model (GEMM) of PDAC with activating KRAS mutation (KrasG12D/+) and a p53 missense mutation (p53R172H/-), we found that the PDAC tumorigenesis and resistance to ICIs are dependent on the mutant-p53. We used isogenic p53-null PDAC cells and the restoration of p53R172H in p53-null cells to demonstrate the role of p53R172H in controlling the expression of immunosuppressive chemokine genes such as Cxcl1. p53R172H deletion attenuated PDAC tumor growth, increased the influx of cytotoxic T-cells, and sensitized the tumor to ICIs. The p53R172H-mediated TME reprogramming was replicated by the deletion of the Cxcl1 gene, suggesting the anti-tumorigenic effect of p53R172H was mediated by the Cxcl1 gene. We probed the mechanism of Cxcl1 expression dependence on p53R172H. We found that in conjunction with NF-kB, p53R172H occupies the distal transcription regulatory elements (dTREs) of the Cxcl1 gene harboring NF-kB binding sites. Strikingly, deletion of the Cxcl1 dTREs in PDAC cells recapitulates the phenotypes of p53R172H deletion and Cxcl1 deletion in terms of tumor size, immune landscape of the TME, and ICI responsiveness. Furthermore, we examined the interplay between p53R172H and NF-kB and found that the p53R172H physically interacts with the NF-kB subunit RelA and facilitates its nuclear translocation. Overall, we characterize how a common p53 mutation in PDAC co-opts non-coding regulatory DNA to augment the expression of selective chemokine genes and establishes an immunosuppressive TME to shield the therapeutic benefits of ICIs. Citation Format: Dig B. Mahat, Heena Kumra, Emily Metcalf, Sarah Castro, Kim Nguyen1, Arundeep Singh, William W. Ho, Ivy Chen, Brandon Sullivan, Leon Yim, Enrico Moiso, Vikash Chauhan, Hernandez Moura Silva, Stefani Spranger, Rakesh Jain, Phillip A. Sharp. Mutant-p53 amplifies Cxcl1 expression from distal enhancers blunting immune checkpoint inhibition efficacy in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B087.

The efficacy of immune checkpoint inhibitors is limited in elderly NSCLC: a retrospective efficacy study and meta-analysis.

Immune checkpoint inhibitors (ICIs) have improved the long-term survival of NSCLC patients. However, the efficacy of ICIs in elderly NSCLC patients remains controversial. We conducted a retrospective study and meta-analysis exploring the efficacy of ICIs in those patients using public databases and RCTs. NSCLC patients were identified into elderly and non-elderly groups by age 75 years. The retrospective study showed significant differences in OS and PFS between non-elderly and elderly patients treated with ICIs (P= 0.029 and 0.027), with reduced efficacy in elderly NSCLC patients. ECOG PS also negatively affected OS in elderly NSCLC patients (P= 0.007). In meta-analysis, the HR for OS in the non-elderly and elderly groups were 0.74 and 0.90, respectively, and the difference between the two age groups was statistically significant (P= 0.025). ICIs resulted in a lower incidence of all-grade (OR= 0.47) and high-grade TRAEs (OR= 0.38) than chemotherapy. Our findings revealed that the survival benefit of ICIs in elderly patients (≥ 75 years) may be lower than in non-elderly patients. In addition, the incidence of TRAEs induced by ICIs was lower than chemotherapy.

Clinical Application of ImmunoPET Targeting Checkpoint Inhibitors

In the last decade, monoclonal antibodies (mAbs) targeting CTLA-4, PD-1, or PD-L1 have been developed and immune checkpoint inhibitors (ICIs) have become the main approach in cancer immunotherapy. However, not all patients benefit from ICI therapy and some are at risk of developing treatment-induced side-effects. These aspects, in parallel with the imaging challenges related to response assessments during immunotherapy, have driven scientific research to the discovery of new predictive biomarkers to individualize patients who could benefit from ICIs. In this context, molecular imaging using PET (positron emission tomography), which allows for whole-body tumor visualization, may be a promising non-invasive method for the determination of patients’ sensitivity to antibody drugs. Several PET tracers, diverse from 2-[18F]FDG (or 2-Deoxy-2-[18F]fluoroglucose), have been developed to image immune checkpoints (ICs) or key elements of the immune system, although most of them are still in preclinical phases. Herein, we present the current state of the ImmunoPET-targeting of IC proteins with mAbs and antibody fragments, with a main focus on the latest developments in clinical molecular imaging studies of solid tumors. Moreover, given the relevance of the immune system and of tumor-infiltrating lymphocytes in particular in the prediction of the benefit of ICIs, we dedicate a portion of this review to ImmunoPET-targeting T cells.

Insights from a Veterans Health Administration Database Analysis: Immune-Related Adverse Effects of Immunotherapy in Relapsed/Refractory Classical Hodgkin Lymphoma

Introduction: Despite the high success rates in treating Classical Hodgkin lymphoma (cHL), a specific group of patients still experience relapsed or refractory (R/R) disease, affecting approximately 10-20% of cases. The use of immunotherapy with checkpoint inhibitors (CPIs) has emerged as a promising approach, demonstrating impressive efficacy in R/R cHL patients [2,3]. However, there is a lack of real-world evidence regarding the immune-related adverse effects (irAEs) associated with immunotherapy in this relatively rare patient population. To address this gap, this study leverages the Veterans Health Administration (VHA) database to investigate irAEs, providing valuable insights to optimize treatment decisions. Methods: A retrospective analysis was conducted on Hodgkin lymphoma patients who received immunotherapy from the VHA Corporate Data Warehouse from 2014-2022. Patients came from all 18 Veterans Integrated Service Networks, spanning all 50 states and US territories. Data was collected to determine the baseline characteristics, disease factors, detailed AE occurrence as well as outcomes in this cohort. Results: The analysis included 68 cHL patients who received immunotherapy. The cohort had a mean age of 62.2 years (SD=15.9) and a median age of 66 years (IQR 54-72). The majority of the patients were male (97%) and White (80%) and only 6% of patients had a history of autoimmune disease. The distribution of patients across stages was as follows: Stage 1 (5%), Stage 2 (15%), Stage 3 (40%), and Stage 4 (40%). Additionally, 20% of patients underwent autologous stem cell transplantation (ASCT), with 10% receiving immunotherapy before transplantation and the remaining 10% receiving it post-transplant. In our cohort, 31% had documented adverse effects related to immunotherapy. The most common adverse events observed were hematological/cytopenias (8%), dermatologic/rash (6%), endocrine-related (6%), pneumonitis (5%), hepatitis (2%), myocarditis (2%), and other adverse events (8%). Discontinuation of therapy due to irAEs occurred in 12% of patients. These findings align with prior literature, which has consistently reported thyroid gland dysfunction (such as hypothyroidism and thyroiditis) and rash as the most frequently observed immune-related adverse events [2]. The most common management of irAEs were holding therapy followed by use of corticosteroids. Kaplan-Meier survival analysis revealed a median overall survival of 55.4 months (IQR=37.2-59.2), with a median follow-up time of 36.4 months (IQR=21.6 -58.6). Conclusion: This study, utilizing the VA database, provides a distinctive and valuable perspective on irAEs associated with immunotherapy in cHL patients. By leveraging a comprehensive database on a large scale, this study significantly enhances our comprehension of immunotherapy in the context of cHL, thereby offering crucial guidance for treatment decisions concerning relapsed/refractory Hodgkin lymphoma patients. The findings of this study strongly indicate the sustained benefits of immune checkpoint inhibitors (ICI) in this population, emphasizing the importance of close patient monitoring to detect and manage immune-related adverse events at an early stage, thereby preventing life-threatening complications.

Real-World Outcomes of Immunotherapy in Second- or Later-Line Non-Small Cell Lung Cancer with Actionable Genetic Alterations.

While the efficacy of immune checkpoint inhibitors (ICIs) in treating non-small cell lung cancer (NSCLC) patients with actionable genetic alterations (AGAs) is modest, certain patients demonstrate improved survival. Thus, this study aimed to evaluate the benefits of ICIs in NSCLC patients with diverse AGAs and verify the predictive biomarkers of ICI efficacy. From January 2018 to July 2022, this study compared the progression-free survival (PFS) of NSCLC patients with different AGAs treated with ICI monotherapy as second- or later-line therapy at Samsung Medical Center. To ascertain the predictors of ICIs efficacy, we adjusted ICIs' effects on PFS in terms of clinical and molecular biomarkers. EGFR (46.0%) was the most prevalent mutation in 324 patients. In multivariate analysis, PD-L1 positivity (tumor proportion score (TPS) ≥ 1%) (HR = 0.41) and the use of steroids for immune-related adverse events (HR = 0.46) were positive factors for ICI therapy in the AGAs group. Co-existing mutation of STK11 with KRAS mutation (HR = 4.53) and TP53 with MET mutation (HR = 9.78) was negatively associated with survival. The efficacy of ICI treatment varied across AGA subtypes, but patients with KRAS, MET, and BRAF mutations demonstrated relatively long-duration benefits of ICI therapy. PD-L1 was a significant positive predictive biomarker in all AGA groups.