PET/CT-guided management of immune checkpoint blockade and multi-modal profiling following treatment in long-term responders with metastatic lung cancer in the National Network Genomic Medicine Lung Cancer Germany (nNGM).

Liver toxicity as a limiting factor to the increasing use of immune checkpoint inhibitors.

BackgroundNon-small cell lung cancer (NSCLC) patients bearing targetable oncogene alterations typically derive limited benefit from immune checkpoint blockade (ICB), which has been attributed to low tumor mutation burden (TMB) and/or...

BackgroundFive-year survival analyses of patients receiving immune checkpoint inhibitors (ICIs) for metastatic non-small cell lung cancer (NSCLC) have demonstrated continued clinical benefit compared to chemotherapy.1 2 Our study aims at...

9549 Background: Long-term response – the plateau of the survival curve – is the transcendent benefit from PD-1 blockade. However, only a subset of responses achieve substantial durability. The frequency, characteristics, and predictors of long-term responders (LTR) to PD-1 blockade are not well known and may differ from short-term responders (STR). Methods: Patients with advanced NSCLC treated with anti-PD-1/PD-L1 therapy from two institutions (MSK and DFCI) were examined. Responses were assessed by RECIST. LTR was defined as PR/CR lasting ≥ 24 months. STR was defined as PR/CR lasting < 12 months. Comparisons were also made to patients with progressive disease (PD). PD-L1 expression was assessed by IHC. TMB was assessed by targeted NGS; high TMB was defined as ≥ median of the cohort. A subset had detailed molecular profiling by MSK-IMPACT. Fisher’s exact and Mann-Whitney U tests were used to compare features, and the log-rank test was used to compare survival. Results: Of 2318 patients (MSK n = 1536, DFCI n = 782), 126 (5.4%, 95% CI 4.6-6.4%) achieved LTR, with similar rates in both cohorts. STR occurred in 139 (6%). Overall survival was longer in LTR compared to STR (median NR vs 19.6 months, HR 0.07, p < 0.001). LTR had deeper responses compared to STR (median best overall response -69% vs -46%, p < 0.001). Patients with LTR were younger ( < 65 years old) and had increased TMB (≥ median mut/Mb) compared to both STR and PD (p = 0.006, p = 0.03; p < 0.001, p < 0.001). The rate of LTR was enriched among patients with both high TMB/high PD-L1 compared to those with low TMB/low PD-L1 (9% vs 1%, OR 9.2, p < 0.001), while STR was similar in both groups (7% vs 6%). 2% of patients with sensitizing EGFR mutations (n = 243) achieved LTR. Loss of function variants in ARID1A (14% vs 2%), PTEN (8% vs 0%), and KEAP1 (12% vs 2%) were enriched in LTR compared to STR (p < 0.05 for each). Among patients with KRAS mutations, the rate of LTR was higher in those with co-mutation with TP53 compared to STK11 (11% vs 2%, p = 0.01). Conclusions: Long-term response (LTR, ongoing response ≥ 24 months) to PD-1 blockade is an uncommon but profound clinical outcome in metastatic lung cancers. Younger age and high TMB correlate with LTR; the combination of high TMB/high PD-L1 enriches for LTR but not STR. Features predicting long term response may be distinct from those predicting initial response.

Many decades in the making, immunotherapy has demonstrated its ability to produce durable responses in several cancer types. In the last decade, immunotherapy has shown itself to be a viable therapeutic approach for non-small cell lung cancer (NSCLC). Several clinical trials have established the efficacy of immune checkpoint blockade (ICB), particularly in the form of anti-programmed death 1 (PD-1) antibodies, anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibodies and anti-programmed death 1 ligand (PD-L1) antibodies. Many trials have shown progression free survival (PFS) and overall survival (OS) benefit with either ICB alone or in combination with chemotherapy when compared to chemotherapy alone. The identification of biomarkers to predict response to immunotherapy continues to be evaluated. The future of immunotherapy in lung cancer continues to hold promise with the development of combination therapies, cytokine modulating therapies and cellular therapies. Lastly, we expect that innovative advances in technology, such as artificial intelligence (AI) and machine learning, will begin to play a role in the future care of patients with lung cancer.

IA19: Immunotherapy in ovarian cancer: Challenges and novel opportunities

Cytoreduction and the Optimization Of Immune Checkpoint Inhibition with Radiation Therapy

Regional chemotherapy has been proposed as a treatment modality in a number of cancer settings. In primary or metastatic lung cancer, administration of chemotherapy via inhalation could increase exposure of lung tumor to the drug, while minimizing systemic side effects. Several proof of concept studies in animal models of metastatic or primary lung cancer have demonstrated the safety, pharmacokinetic advantage, and antitumor effect of aerosol administration of several chemotherapeutic agents including doxorubicin, gemcitabine and liposome-encapsulated formulations of paclitaxel and 9-nitrocamptothecin (9-NC). Recent phase I studies have demonstrated the feasibility of aerosol delivery of doxorubicin and liposomal formulations of 9-NC and cisplatin in patients with primary and metastatic lung cancer with a limited pharmacokinetic profile consistent with the observed low systemic toxicity. Further studies integrating safety, pharmacokinetic, and efficacy considerations are required to determine whether there is a place for local administration of chemotherapy via inhalation in lung cancer.

Le nivolumab peut-il être utilisé dans les fibroses pulmonaires idiopathiques ?

Prognostic Value of Pretreatment FDG-PET Parameter for Early Stage Non-small Cell Lung Cancer Treated With Stereotactic Ablative Radiation Therapy

The present study was conducted to characterize the clinicopathologic characteristics, immunohistochemical staining results, and immune checkpoint inhibitors (ICIs) efficacy in patients with SMARCA4-deficient/TP53 mutant lung cancer. Patients diagnosed with advanced or metastatic undifferentiated lung cancer harboring SMARCA4-deficient and TP53 mutations, however, without targetable sensitive mutations were retrieved from the electronic medical record system. Descriptive statistics were used to describe the baseline characteristics and clinical features including age, gender, eastern cooperative oncology group performance status, disease stage, smoking status, chief complaint, site of the primary mass, tumor size, gross type, symptoms, local invasion, and metastatic sizes. Immunological markers and potential drive genes were detected by immunohistochemical staining and next generation sequencing. Efficacy and safety profile of ICIs in included patients was evaluated with progression-free survival and overall survival. Between January 2019 and September 2022, there were 4 patients included within the inclusion criteria in the present study. Biomarkers including CK, CK7, and integrase interactor 1 were detected positive, however, other immunological markers including CK20, CD56, P63, P40, NapsinA, TTF-1, CgA, Syn, BRG1, or PD-L1 were detected negative among them. Results of next generation sequencing panel were failed to discover any targetable sensitive mutations. A total of 4 mutation types of TP53, including p.C141Y, p.S240G, p.E339X (terminator acquired), and p.L130F detected for the patients, respectively. Microsatellite stability status, as well as low tumor mutation burden was identified among all the patients. Median progression-free survival for ICIs as first line treatment and median overall survival were 3.25 months (range from 1.3 to 6.8 months), and 6.0 months (range from 2.7 to 9.6 months), respectively. Our results indicated that advanced lung cancer patients harboring co-occurring SMARCA4-deficient/TP53 mutations might respond to ICIs treatment, though within negative programmed cell death-ligand 1 expression or low tumor mutation burden. However, hyperprogressive disease by ICIs may also happen for such patients. The mutation types of TP53 might play a role during the exposure of ICIs, however, need further identification in basic experiments.

238 Meta-analysis on the incidence of hyperprogressive disease during immune checkpoint inhibitor therapy

BackgroundLung cancer remains one of the most prevalent cancer types worldwide, with a high mortality rate. Upregulation of programmed cell death protein 1 (PD-1) and its ligand (PD-L1) may represent a key mechanism for evading immune surveillance. Immune checkpoint blockade (ICB) antibodies against PD-1 or PD-L1 are therefore widely used to treat patients with lung cancer. However, the mechanisms by which lung cancer and neutrophils in the microenvironment sustain PD-L1 expression and impart stronger inhibition of CD8+ T cell function remain unclear.MethodsWe investigated the role and underlying mechanism by which PD-L1+ lung cancer and PD-L1+ neutrophils impede the function of CD8+ T cells through magnetic bead cell sorting, quantitative real-time polymerase chain reaction (RT-PCR), western blotting, enzyme-linked immunosorbent assays, confocal immunofluorescence, gene silencing, flow cytometry, etc. In vivo efficacy and safety studies were conducted using (Non-obeseDiabetes/severe combined immune deficiency) SCID/NOD mice. Additionally, we collected clinical and prognostic data from 208 patients who underwent curative lung cancer resection between 2017 and 2018.ResultsWe demonstrated that C-X-C motif chemokine ligand 5 (CXCL5) is markedly overexpressed in lung cancer cells and is positively correlated with a poor prognosis in patients with lung cancer. Mechanistically, CXCL5 activates the phosphorylation of the Paxillin/AKT signaling cascade, leading to upregulation of PD-L1 expression and the formation of a positive feedback loop. Moreover, CXCL5 attracts neutrophils, compromising CD8+ T cell-dependent antitumor immunity. These PD-L1+ neutrophils aggravate CD8+ T cell exhaustion following lung cancer domestication. Combined treatment with anti-CXCL5 and anti-PD-L1 antibodies significantly inhibits tumor growth in vivo.ConclusionsOur findings collectively demonstrate that CXCL5 promotes immune escape through PD-L1 upregulation in lung cancer and neutrophils chemotaxis through autocrine and paracrine mechanisms. CXCL5 may serve as a potential therapeutic target in synergy with ICBs in lung cancer immunotherapy.

Micro-RNAs are approximately 21-25-nucleotide-long noncoding RNAs that regulate gene expression primarily at the post-transcriptional level in animals. Here, we report that micro-RNA-1 (miR-1), abundant in the cardiac and smooth muscles, is expressed in the lung and is down-regulated in human primary lung cancer tissues and cell lines. In situ hybridization demonstrated localization of miR-1 in bronchial epithelial cells. The tumor suppressor C/EBPalpha, frequently suppressed in lung cancer, reactivated miR-1 expression in the lung cancer cells. Repressed miR-1 was also activated in lung cancer cells upon treatment with a histone deacetylase inhibitor. These observations led us to examine the antitumorigenic potential of miR-1 in lung cancer cells. Expression of miR-1 in nonexpressing A549 and H1299 cells reversed their tumorigenic properties, such as growth, replication potential, motility/migration, clonogenic survival, and tumor formation in nude mice. Exogenous miR-1 significantly reduced expression of oncogenic targets, such as MET, a receptor tyrosine kinase, and Pim-1, a Ser/Thr kinase, frequently up-regulated in lung cancer. Similarly, the levels of two additional targets, FoxP1, a transcription factor with oncogeneic property, and HDAC4 that represses differentiation-promoting genes, were reduced in miR-1-expressing cells. Conversely, depletion of miR-1 facilitated N417 cell growth with concomitant elevation of these targets. Further, ectopic miR-1 induced apoptosis in A549 cells in response to the potent anticancer drug doxorubicin. Enhanced activation of caspases 3 and 7, cleavage of their substrate PARP-1, and depletion of anti-apoptotic Mcl-1 contributed to the sensitivity of miR-1-expressing cells to doxorubicin. Thus, miR-1 has potential therapeutic application against lung cancers.

Background: The distinction of primary lung cancer from metastatic breast cancer is crucial in patients presenting with a solitary pulmonary nodule after breast surgery. However definitive diagnosis of these nodules is often difficult due to similar radiological and pathological features in primary lung and metastatic breast cancer nodules. We assessed the feasibility of our diagnostic approach for these nodules by morphopathological and immunohistochemical examination, and estimated the frequency of primary lung cancer occurrence in breast cancer patients. Material and Methods: We evaluated solitary pulmonary nodules appearing in 24 patients (0.62% : 24/3851) after breast surgery between 1994 and 2006. Patients with metastases to organs other than lungs were not included. For histological examination, CT-guided core needle biopsy (CT-CNB), trans-bronchial lung biopsy (TBLB), or surgical resection was performed. Besides conventional morphopathological examination using HE staining, differential diagnosis was performed by immunohistochemical examination (thyroid transcription factor-1: TTF-1, surfactant pro-protein B: SPPB, estrogen receptor: ER, mammaglobin1: MGB1). The immunopositive results for TTF-1 and SPPB support the specimen diagnosis of primary lung cancer. The immunopositive and immunonegative results for ER and both TTF-1 and SPPB, respectively, suggest that the specimen has a high probability of being metastatic breast cancer. And for cases in which differential diagnosis failed in the morpopathological and TTF-1, SPPB, and ER examination, MGB1 examination was conducted. Several patient and tumor characteristics were evaluated according to the definitive diagnosis of pulmonary nodules in both metastatic breast and primary lung cancer groups, which were then compared using Student's t-test. Results: Biopsy specimens were obtained using minimally invasive methods (CT-CNB and TBLB) in 21 patients (87.5%). Surgical resection was performed for diagnosis and treatment in three patients. Differential diagnosis was obtained by morphopathological methods alone in 18 patients (75.0%, primary lung cancer: 6 cases, metastaic breast cancer: 12 cases) and by immunohistochemical examination in the remaining 6 (25.0%, primary lung cancer: 1 case, metastaic breast cancer: 5 cases). Final diagnosis was metastatic breast and primary lung cancer in 17 (70. 8%) and 7 patients (29.2%), respectively. The mean age was significantly higher in the primary lung than metastatic breast cancer patients group (67 years vs. 57 years: p=0.036). No significant difference in the average diameter of pulmonary nodules was observed between metastatic breast and primary lung cancer patients (2.32cm vs. 2.29 cm). Furthermore, there were no clinical findings between metastatic breast cancer patients group and primary lung cancer group. Conclusions: Our results show the clinical feasibility of our approach to the differential diagnosis of breast cancer relapse and primary lung cancer presenting as a solitary nodule in patients after breast surgery. Further, replication of our findings under independent setting is recommended. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-03-05.