Anti-programmed Death-1 Therapy Research Articles

Contrast-enhanced CT-based radiomic analysis for determining the response to anti-programmed death-1 therapy in esophageal squamous cell carcinoma patients: A pilot study.

In view of the fact that radiomics features have been reported as predictors of immunotherapy to various cancers, this study aimed to develop a prediction model to determine the response to anti-programmed death-1 (anti-PD-1) therapy in esophageal squamous cell carcinoma (ESCC) patients from contrast-enhanced CT (CECT) radiomics features. Radiomic analysis of images was performed retrospectively for image samples before and after anti-PD-1 treatment, and efficacy analysis was performed for the results of two different time node evaluations. A total of 68 image samples were included in this study. Quantitative radiomic features were extracted from the images, and the least absolute shrinkage and selection operator method was applied to select radiomic features. After obtaining selected features, three classification models were used to establish a radiomics model to predict the ESCC status and efficacy of therapy. A cross-validation strategy utilizing three folds was employed to train and test the model. Performance evaluation of the model was done using the area under the curve (AUC) of receiver operating characteristic, sensitivity, specificity, and precision metric. Wavelet and area of gray level change (log-sigma) were the most significant radiomic features for predicting therapy efficacy. Fifteen radiomic features from the whole tumor and peritumoral regions were selected and comprised of the fusion radiomics score. A radiomics classification was developed with AUC of 0.82 and 0.884 in the before and after-therapy cohorts, respectively. The combined model incorporating radiomic features and clinical CECT predictors helps to predict the response to anti-PD-1therapy in patients with ESCC.

Phase 1b study of cobimetinib plus atezolizumab in patients with advanced BRAFV600 wild-type melanoma progressing on prior anti–programmed death-1 therapy

ObjectiveTo evaluate the efficacy and safety of cobimetinib plus atezolizumab in the treatment of patients with advanced BRAFV600 wild-type melanoma who had progressed on prior anti‒programmed death-1 (PD-1) therapy. Patients and methodsThis phase 1b, open-label, international multicentre study enrolled 3 cohorts. Herein, we report on patients in cohorts A and B who had progressed on prior anti‒PD-1 therapy. Patients in cohort A received cobimetinib 60 mg once daily for 21 days followed by a 7-day break and concurrent intravenous atezolizumab 840 mg every 2 weeks. Patients in cohort B received the same dosing regimen as cohort A except for cycle 1 in which patients received cobimetinib only for the first 14 days prior to initiation of atezolizumab on cycle 1 day 15. Coprimary end-points were objective response rate and disease control rate. Secondary end-points were duration of response, progression free survival and overall survival. ResultsBetween 19th June 2017 and 12th December 2018, 103 patients were enrolled. Median follow-up was 6.9 months (interquartile range, 4.8–10.1 months); objective response rate was 14.6% and disease control rate was 38.8% (95% confidence interval, 29.39–48.94). The median duration of response, progression-free survival and overall survival was 12.7 months, 3.8 months and 14.7 months, respectively. The most common adverse events were diarrhoea (75/103; 72.8%), dermatitis acneiform (57/103; 55.3%) and nausea (52/103; 50.5%). Thirty-four patients (33.0%) died: 33 (91.7%) due to progressive disease and one (1%) due to treatment-related oesophagitis. ConclusionsCombination therapy with cobimetinib and atezolizumab in patients with advanced BRAFV600 wild-type melanoma with disease progression on or after prior anti‒PD-1 therapy demonstrated limited activity. Clinical trial registrationThis study is registered with ClinicalTrials.gov; NCT03178851;

810P PRESERV MEL: Real-world outcomes and health-related quality of life (HRQoL) in patients receiving adjuvant nivolumab for melanoma in Belgium and Luxembourg

Based on CheckMate 238 results, nivolumab was the first anti-programmed death-1 therapy reimbursed in Belgium and Luxemburg as an adjuvant treatment for adults with resected melanoma. This study aimed to describe effectiveness, safety and HRQoL of patients (pts) treated with adjuvant nivolumab in the real-world.

KEYNOTE B68: Open-label phase 2 study of the efficacy and safety of pembrolizumab administered every six weeks in patients with relapsed or refractory classical Hodgkin lymphoma or primary mediastinal B-cell lymphoma.

TPS7585 Background: Classical Hodgkin lymphoma (cHL) and primary mediastinal B-cell lymphoma (PMBCL) frequently harbor amplifications at 9p24.1, leading to overexpression of PD-L1 and PD-L2, suggesting a genetically driven vulnerability to programmed death 1 (PD-1) blockade. The PD-1 inhibitor pembrolizumab, dosed at 200 mg every 3 weeks (Q3W), demonstrated strong antitumor activity and acceptable safety that led to approvals for adult and pediatric patients with relapsed or refractory (R/R) cHL and R/R PMBCL. Efficacy, safety, and pharmacokinetic (PK) results from studies in solid tumors have since led to accelerated approval for the pembrolizumab 400 mg Q6W regimen for all indications in adults; however, further efficacy and safety data are needed for hematologic indications. The open-label, single-arm, multisite, global, phase 2 KEYNOTE-B68 study (NCT04875195) evaluates the safety, efficacy, and PK profile of pembrolizumab 400 mg Q6W in patients with R/R cHL or PMBCL. Methods: Patients must have histologically confirmed R/R cHL (cohort 1) or R/R PMBCL (cohort 2) per WHO classification and radiographically measurable disease per the Lugano 2014 classification criteria and must not have previously received treatment with anti–PD-1 therapy. Eligible patients must have failed to respond to or relapsed after receiving an autologous stem cell transplant (ASCT) or must be ineligible for ASCT and must have failed to respond or relapsed after ≥1 (cHL) or ≥2 (PMBCL) prior lines of therapy; patients with PMBCL must have received ≥1 line of therapy containing rituximab. Approximately 60 patients will be enrolled. They will receive pembrolizumab 400 mg IV Q6W for up to 18 cycles. Disease assessments will occur Q12W by investigator per the Lugano 2014 response criteria. Local radiographic assessments will be collected by computed tomography Q12W and by positron emission tomography at weeks 12 and 24 and to confirm complete response. Adverse events will be monitored and assessed by investigators throughout the study, and their severity will be graded per NCI Common Terminology Criteria for Adverse Events, version 5.0 guidelines. Patients who receive an allogeneic SCT within 2 years of the last dose of study treatment will be monitored for 18 months after SCT for events of clinical interest. The primary end point (assessed per cohort) is objective response rate by investigator per the Lugano 2014 classification criteria. Secondary end points (assessed per cohort) include duration of response by investigator assessment, characterization of the PK profile and immunogenicity for pembrolizumab 400 mg Q6W, and safety. Exploratory end points assessed per cohort include overall survival, progression-free survival per the Lugano 2014 criteria, and molecular biomarker analyses. Clinical trial information: NCT04875195.

Predictive value of 3′-deoxy-3′-18F-fluorothymidine PET in the early response to anti-programmed death-1 therapy in patients with advanced non-small cell lung cancer

BackgroundAnti-programmed death-1 (anti-PD-1) therapy has shown clinical success in patients with advanced non-small cell lung cancer (NSCLC). However, it is difficult to evaluate the early response to anti-PD-1 therapy. We...

Clinical decision support algorithm based on machine learning to assess the clinical response to anti–programmed death-1 therapy in patients with non–small-cell lung cancer

ObjectiveAnti–programmed death (PD)-1 therapy confers sustainable clinical benefits for patients with non–small-cell lung cancer (NSCLC), but only some patients respond to the treatment. Various clinical characteristics, including the PD-ligand 1 (PD-L1) level, are related to the anti–PD-1 response; however, none of these can independently serve as predictive biomarkers. Herein, we established a machine learning (ML)–based clinical decision support algorithm to predict the anti–PD-1 response by comprehensively combining the clinical information. Materials and methodsWe collected clinical data, including patient characteristics, mutations and laboratory findings, from the electronic medical records of 142 patients with NSCLC treated with anti–PD-1 therapy; these were analysed for the clinical outcome as the discovery set. Nineteen clinically meaningful features were used in supervised ML algorithms, including LightGBM, XGBoost, multilayer neural network, ridge regression and linear discriminant analysis, to predict anti–PD-1 responses. Based on each ML algorithm's prediction performance, the optimal ML was selected and validated in an independent validation set of PD-1 inhibitor–treated patients. ResultsSeveral factors, including PD-L1 expression, tumour burden and neutrophil-to-lymphocyte ratio, could independently predict the anti–PD-1 response in the discovery set. ML platforms based on the LightGBM algorithm using 19 clinical features showed more significant prediction performance (area under the curve [AUC] 0.788) than on individual clinical features and traditional multivariate logistic regression (AUC 0.759). ConclusionCollectively, our LightGBM algorithm offers a clinical decision support model to predict the anti–PD-1 response in patients with NSCLC.

Inflammatory Markers Predict Survival in Patients With Advanced Gastric and Colorectal Cancers Receiving Anti–PD-1 Therapy

There is a lack of useful biomarkers for predicting the efficacy of anti–programmed death-1 (PD-1) therapy for advanced gastric and colorectal cancer. To address this issue, in this study we investigated the correlation between inflammatory marker expression and survival in patients with advanced gastric and colorectal cancer. Data for 111 patients with advanced gastric and colorectal cancer treated with anti–PD-1 regimens were retrospectively analyzed. Neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), and clinical characteristics of each patient were selected as the main variables. Overall response rate, disease control rate, and progression-free survival were primary endpoints, and overall survival and immune-related adverse events (irAEs) were secondary endpoints. The chi-squared test and Fisher’s exact test were used to evaluate relationships between categorical variables. Uni- and multivariate Cox regression analyses were performed, and median progression-free survival and overall survival were estimated with the Kaplan–Meier method. The overall response rate and disease control rate of anti–PD-1therapy in advanced gastric and colorectal tumors were 12.61 and 66.66%, respectively. The patients with MLR < 0.31, NLR < 5, and PLR < 135 had a significantly higher disease control rate than those with MLR > 0.31, NLR > 5, and PLR > 135 (P < 0.05). The multivariate analysis revealed that MLR < 0.31, BMI > 18.5, and anti–PD-1 therapy in first-line were associated with prolonged PFS. MLR < 0.31 and BMI > 18.5 were associated with prolonged overall survival. The irAE rate differed significantly between PLR groups, and PLR < 135 was associated with an increased rate of irAEs (P = 0.028). These results indicate that the inflammatory markers NLR, MLR, and PLR have clinical utility for predicting survival or risk of irAEs in patients with advanced gastric cancer and colorectal cancer.

PD-1 blockade carries perils

Immunotherapy The potentiation of T cell–mediated antitumor responses achieved in multiple types of cancer through inhibition of the programmed death-1 (PD-1) checkpoint pathway has led to suggestions that anti–PD-1 therapy might also boost T cell immunity in chronic infections, including tuberculosis. Kauffman et al. examined the effect of anti–PD-1 antibody treatment on the clinical course of Mycobacterium tuberculosis (Mtb) infection in rhesus macaques. CD8 T cell responses were boosted in monkeys receiving anti–PD-1 infusions, but the stronger CD8 T cell responses were coupled with increases in proinflammatory cytokines, impaired CD4 T cell function, and higher bacterial loads in lung granulomas. These findings in a nonhuman primate model signal that anti–PD-1–based therapy needs to be used cautiously in cancer patients with a history of Mtb exposure. Sci. Immunol. 6 , eabf3861 (2021).

Clinicopathologic characterization of enfortumab vedotin-associated cutaneous toxicity in patients with urothelial carcinoma

Clinicopathologic characterization of enfortumab vedotin-associated cutaneous toxicity in patients with urothelial carcinoma

Outcomes with anti-EGFR monoclonal antibodies in metastatic and recurrent anal squamous cell carcinoma

ABSTRACT Objectives Metastatic squamous cell carcinoma anal cancer (SCCA) is rare. Prospective data recommends front-line platinum doublet combinations and second-line anti-programmed death-1 therapy. Standard therapy beyond these treatments are currently unknown. We evaluated anti-EGFR monoclonal antibody (mAb) outcomes in metastatic SCCA. Methods Metastatic SCCA patients given anti-EGFR mAb from Oct 2011-May 2018 were included. Primary endpoints included best response, progression-free survival, and overall survival. Results 56 patients were evaluated with a median of one prior therapy. Most patients (~90%) received anti-EGFR mAbs with chemotherapy. Response rate (any response) was 41%. Median PFS was 4.3 months with a median OS of 16 M. Seven patients with disease control proceeded onto maintenance therapy (anti-EGFR mAb ± a fluoropyrimidine) with a median PFS of 13.8 M. Next generation sequencing of 16 pts (28%) showed 4 pts had a PIK3CA mutation with 3 of these 4 patients demonstrating progression on initial restaging. Conclusion Our analysis suggests anti-EGFR mAb therapy with chemotherapy provides clinical benefit in previously treated metastatic SCCA. Our maintenance therapy and the role of PIK3CA MT outcomes were thought-provoking. Expert Opinion Metastatic SCCA patients have limited options; therefore, anti-EGFR mAbs may provide benefit in the treatment armamentarium and should be further explored.

Neurological adverse effects due to programmed death 1 (PD-1) inhibitors

PD-1 Immunotherapy is integral in treating multiple cancers, but has been associated with neurological adverse events (nAEs). Our study was aimed at identifying the clinical spectrum of nAEs associated with pembrolizumab and nivolumab. We performed an IRB approved single-center retrospective cohort study on patients receiving either pembrolizumab or nivolumab. Patients that developed nAEs within 12months of treatment were identified. Descriptive statistics were conducted, and differences between groups were analyzed by the Chi-square or t test method. In total, 649 patients were identified. Seventeen patients (2.6%) developed nAEs. Eight of those were on pembrolizumab and nine were on nivolumab. Average age was 62.1years. Ten were males and 7 were females. Most patients had melanoma (6, 35.3%). Patients who developed nAEs more frequently had intracranial lesions at initiation of anti PD-1 therapy compared to those who did not develop nAEs (76.5% vs 27.8%; p-value < 0.001). Fifteen patients (88.2%) permanently stopped PD-1 therapy. In 8 patients, treatment termination resolved symptoms attributed to immune checkpoint blockade. The majority of patients developed grade 3 or 4 nAEs (10 patients, 58.8%), and required hospitalization (11 patients, 64.7%). Eight patients died for nAEs referable causes. Pembrolizumab and nivolumab are associated with the development of nAEs associated with increased risk of permanent discontinuation of treatment, hospitalization, and death. Melanoma patients might be at a particularly high risk of such side effects. Future studies are still required to better assess which patients benefit most from such therapies, while minimizing the risk of complications.

Bullous pemphigoid after anti–programmed death-1 therapy: A retrospective case-control study evaluating impact on tumor response and survival outcomes

To the Editor: Dermatologic adverse events (dAEs) such as lichenoid dermatitis, spongiotic dermatitis, and vitiligo have been associated with improved tumor response and survival outcomes after programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) inhibitors.1-3 Such associations have not been well established for bullous pemphigoid (BP), an antibody-mediated dAE.4 This study evaluated the impact of BP development on overall response rate (ORR), progression-free survival (PFS), and overall survival (OS).

Targeting EZH2 Enhances Antigen Presentation, Antitumor Immunity, and Circumvents Anti–PD-1 Resistance in Head and Neck Cancer

Anti-programmed death-1 (PD-1) receptor-based therapeutics improve survival in patients with recurrent head and neck squamous cell carcinoma (HNSCC), but many do not benefit due to a low response rate. Herein, we identified EZH2 as a therapeutic target that enhanced tumor cell antigen presentation and subsequently sensitized resistant tumors to anti-PD-1 therapy. EZH2 regulation of antigen presentation was defined using EZH2 inhibitors (GSK126 and EPZ6438) in human and mouse HNSCC cell lines. Mechanistic dissection of EZH2 in regulation of antigen presentation was investigated using flow cytometry, qRT-PCR, ELISA, and chromatin-immunoprecipitation assays. EZH2-deficient cell lines were generated using CRISPR-CAS9. GSK126 and anti-PD-1-blocking antibody were used in testing combinatorial therapy in vivo. EZH2 expression was negatively correlated with antigen-processing machinery pathway components in HNSCC data sets in The Cancer Genome Atlas. EZH2 inhibition resulted in significant upregulation of MHC class I expression in human and mouse human papillomavirus-negative HNSCC lines in vitro and in mouse models in vivo. Enhanced antigen presentation on the tumor cells by EZH2 inhibitors or CRISPR-mediated EZH2 deficiency increased antigen-specific CD8+ T-cell proliferation, IFNγ production, and tumor cell cytotoxicity. Mechanistically, EZH2 inhibition reduced the histone H3K27me3 modification on the β-2-microglobulin promoter. Finally, in an anti-PD-1-resistant model of HNSCC, tumor growth was suppressed with combination therapy. Our results demonstrated that targeting EZH2 enhanced antigen presentation and was able to circumvent anti-PD-1 resistance. Thus, combining EZH2 targeting with anti-PD-1 may increase therapeutic susceptibility in HNSCC.

Induction of natural killer antibody-dependent cell cytotoxicity and of clinical activity of cetuximab plus avelumab in non-small cell lung cancer

BackgroundAntibody-dependent cell-mediated cytotoxicity (ADCC) may mediate antitumour activity of IgG1-isotype monoclonal antibody (mAb), suggesting as potential treatment combination of IgG1-mAbs, anti-epidermal growth factor receptor cetuximab and anti-programmed death-ligand-1 avelumab.MethodsWe evaluated ADCC induction in lung cancer cells by lactate dehydrogenase (LDH) release assay. Antitumour activity and safety of cetuximab plus avelumab were explored in a single-arm proof-of-concept study in pre-treated non-small cell lung cancer (NSCLC) patients (pt) (Cetuximab-AVElumab-lung, CAVE-Lung). Search for predictive biomarkers of response was done.ResultsAvelumab plus cetuximab induced ADCC in NSCLC cells in vitro in presence of natural killers (NK) from healthy donors (HD) or NSCLC pt, as effectors. Sixteen relapsed NSCLC pt were treated with avelumab plus cetuximab. Antitumour activity was observed in 6/16 pt, defined by progression free survival (PFS) ≥8 months, with 4 of them still on treatment at data lock time (range, 14–19 months). Of note, 3/6 responders had received as previous line anti-programmed death-1 therapy. In responders, clinical benefit was accompanied by significant increase in LDH release over baseline at the first radiological evaluation (8 weeks) (p=0.01) and by early skin toxicity; while in the 10 non-responders, that had PFS ≤5 months, LDH release tends to reduce. Baseline circulating DNA levels were higher in non-responders compared with responders and HD (p=0.026) and decrease in responders during therapy. Mutations in DNA damage responsive family genes were found in responders.ConclusionCetuximab and avelumab activates NSCLC pt NK cells. Ex vivo evaluation of ADCC, circulating DNA levels and early skin toxicity may predict response to cetuximab plus avelumab in NSCLC.EUDRACT 2017-004195-58

The Diversity of Gut Microbiome is Associated With Favorable Responses to Anti–Programmed Death 1 Immunotherapy in Chinese Patients With NSCLC

IntroductionGut microbiome affecting the responses to immune checkpoint inhibitors against advanced NSCLC has been investigated in the Western population. However, considering pre-existing genetic and gut microbiota variation, the relevance remains unknown in the East-Asian NSCLC population. This study is designed to explore the relationship between gut microbiome and clinical outcomes in Chinese patients with NSCLC who have received treatment using an anti–programmed death 1 (PD-1) blockade. MethodsThirty-seven patients with advanced NSCLC receiving treatment with nivolumab were enrolled in CheckMate 078 (NCT02613507) and CheckMate 870 (NCT03195491). Fecal samples were collected at the starting point, when patients received nivolumab, at clinical evaluation, and when disease progression was noted. 16S ribosome RNA gene sequencing was applied to assess gut microbiota profiles. Peripheral immune signatures were determined by multicolor flow cytometry in parallel. ResultsWhen subgrouping patients into responder (R) and nonresponder according to the clinical response assessed using Response Evaluation Criteria in Solid Tumor version 1.1, R patients harbored higher diversity of gut microbiome at the starting point with stable composition during the treatment. Patients with high microbiome diversity had significantly prolonged progression-free survival when compared to those with low diversity. Compositional difference was observed between the two groups as well with the enrichment of Alistipes putredinis, Bifidobacterium longum, and Prevotella copri in R whereas Ruminococcus_unclassified enriched in nonresponding patients. Analysis of systemic immune responses using multicolor flow cytometry revealed that patients with a high abundance of microbiome diversity in the gut had a greater frequency of unique memory CD8+ T cell and natural killer cell subsets in the periphery in response to anti–PD-1 therapy. ConclusionsOur results reveal strong correlation between gut microbiome diversity and the responses to anti–PD-1 immunotherapy in Chinese patients with advanced NSCLC. Patients with favorable gut microbiome (such as those with high diversity) exhibit enhanced memory T cell and natural killer cell signatures in the periphery. These findings provide important implications for the prediction and the evaluation of anti–PD-1 immunotherapy against NSCLC in the Chinese population.

Risk factors for pneumonitis in solid tumors treated with anti-programmed death-1 therapy: A case-control study.

e15132Background: Despite its great efficacy in patients with solid tumors, immune checkpoint blockade (ICB) might also lead to a series of inflammatory effects known as immune-related adverse even...

Granulomatous myositis induced by anti–PD-1 monoclonal antibodies

With the expanding use of immune checkpoint blockers typified by anti–programmed death-1 (PD-1) and anti–cytotoxic T-lymphocyte-associated protein 4 monoclonal antibodies (Abs) for antitumor therapy, the number of patients showing immune-related adverse events (irAEs) is increasing. Skeletal muscle is one of the target tissues of irAEs and several features of myopathy as irAEs have been reported: myasthenia gravis (MG) overlap, cardiac involvement, necrotizing myopathy, and inflammatory myopathy with T-cell and B-cell infiltration.1–4 However, the immunopathogenesis of muscle destruction remains unclear. Here, we report 2 cases of granulomatous myositis after anti–PD-1 therapy. The authors thank Drs. Ryo Usui, Keiichi Hokkoku (Teikyo University School of Medicine), Tatsuhiko Naito, Masao Osaki, and Yoshikazu Uesaka (Toranomon Hospital) for help in the acquisition of clinical data of the patients.

Risk factors for and characteristics of pneumonitis in patients treated with anti-programmed death-1 therapy.

128 Background: Pneumonitis is an uncommon but potentially fatal toxicity of anti–programmed death-1 (PD-1) monoclonal antibodies (mAbs), but its prevalence, risk factors and clinical features are poorly described. Methods: The medical records of 234 patients with advanced cancer who underwent anti–PD-1mAbs therapies between September 2015 and September 2017 at the Cancer Center of the Chinese PLA (People’s Liberation Army) General Hospital were analyzed with regard to patient background and clinical features. Pneumonitis was diagnosed by the treating investigator; cases with confirmed malignant lung infiltration or infection were excluded. Univariate and multivariate analyses were performed to identify independent predictive factors for pneumonitis. Clinical features, management and prognosis of pneumonitis were also collected. Results: A total of 55 patients (23.5%) developed pneumonitis. Anti–PD-1mAbs induced pneumonitis was significantly associated with male sex, a history of prior thoracic radiotherapy, combination therapy and underlying lung condition (odds ratios 3.380, 3.081, 2.538 and 2.559, respectively). Time to onset of pneumonitis ranged from 2 days to 277days (median time was 85days). 85.4% (47 of 55) of cases were grade 1 to 2, 25.5% (14 of 55) were treated with steroid therapy, of which 85.7% (12 of 14) resolved/ improved. Nine (16.4%) patients worsened clinically and one died during the course of pneumonitis treatment. Conclusions: Pneumonitis associated with anti–PD-1 mAbs is a serious adverse effect in the clinical setting that cannot be ignored. However, patient selection based on sex, history of prior thoracic radiotherapy, combination therapy and underlying lung condition can minimize pneumonitis risk. Most events are low grade and resolved/ improved with steroid therapy. Rarely, pneumonitis worsens despite steroid therapy, and may result in death.

Duration of Anti-Programmed Death-1 Therapy in Advanced Melanoma: How Much of a Good Thing Is Enough?

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice. A 53-year-old healthy man presented with recurrent in-transit melanoma of the right lower extremity. Eight years prior he had undergone wide local excision and sentinel lymph node biopsy for invasive melanoma of the anteromedial aspect of the distal right thigh. Pathology revealed an ulcerated melanoma, Breslow depth 3.5 mm, and with one involved micrometastatic inguinal lymph node. Staging studies did not demonstrate distant metastases. Superficial inguinal node dissection was performed and did not identify any additional metastatic nodes of 14 retrieved for a final pathologic staging of T3bN1aM0 (stage IIIB) cutaneous melanoma. He received 12 months of adjuvant high-dose interferon alfa-2b. Two years later, he developed a 1.2-cm subcutaneous focus of in-transit recurrence approximately 4 cm proximal to the original melanoma site in the right thigh, which was treated with surgical resection followed by adjuvant radiotherapy. Over the next 4 years, he underwent six additional surgeries for isolated in-transit recurrences affecting the same limb. He was referred for therapeutic options at the time of his latest in-transit recurrence. Examination revealed three palpable subcutaneous nodules in the right thigh in the setting of lymphedema. A core biopsy confirmed recurrent melanoma (Fig 1). Whole-body fluorodeoxyglucose positron emission tomography imaging revealed at least 17 hypermetabolic cutaneous and subcutaneous nodules in the right thigh, four fluorodeoxyglucose-avid nodules below the right knee, but no distant metastases (Fig 2A). Brain magnetic resonance imaging was normal. His serum chemistry profile, including lactate dehydrogenase, was normal. Molecular analysis demonstrated presence of BRAF V600E mutation in the tumor. After multidisciplinary evaluation, an isolated limb infusion procedure of the right lower extremity was not believed to be feasible, secondary to the proximal extent of the recurrence. Therapy was initiated with pembrolizumab at 2 mg/kg intravenously every 3 weeks.

Abstract B195: Immune microenvironment change after acquiring resistance to EGFR TKI therapy in EGFR mutant non-small cell lung cancer

Abstract Introduction: The efficacy of anti-programmed death-1 therapy in EGFR mutant NSCLC is limited. We hypothesized that immune microenvironment was different before and after developing acquired resistance to EGFR-TKI (tyrosine kinase inhibitor) therapy. We evaluated the change of the tumor proportion score (TPS) of programmed death-ligand 1 (PD-L1) and intratumoral CD8+ tumor-infiltrating lymphocyte (TIL) in EGFR mutant NSCLC. Materials and Methods: We identified 44 patients with sufficient paired tumor tissues before and after EGFR-TKI therapy available for analysis. PD-L1 expression on tumor cells was defined by immunohistochemical (IHC) stain with 22C3 pharmDx assay. Intratumoral CD8+ TIL score was also defined by IHC stain. Results: According to paired pre- and post-TKI biopsies comparison, the degree of PD-L1 expression was consistent in both biopsies in 26 (59.1%) patients, but varied upon the development of resistance in 18 (40.9%), with 10 showing higher levels of PD-L1 expression in the resistant biopsy. The score of CD8+ TIL was consistent in both biopsies in 15 (34.1%) patients, but varied upon the development of resistance in 29 (65.9%), with 11 (25%) showing higher levels CD8+ TIL score in the resistant biopsy. Regarding exon 20T790M acquired mutation, only 2 (14.2%) of 14 specimens observed higher TPS of PD-L1 in post-TKI biopsies. We defined high post-TKI TPS of PD-L1 group who observed high TPS of PD-L1 in post-TKI compared to paired pre-TKI biopsies or post- TKI TPS of PD-L1 ≥50%. The post-TKI high TPS of PD-L1 group tended to decrease CD8+ TIL score . 8 observed post-TKI TPS of PD-L1 ≥50% and 7 of 8 observed low CD8+ TIL score. The median progression-free survival of first-generation EGFR-TKI in these 7 patients was statistically significantly lower than the others (6.6 months vs 14.0 months, respectively; P=0.0105). Conclusions: The TPS of PD-L1 and CD8+ TIL score changed after EGFR-TKI therapy. High TPS of PD-L1 and low CD8+ TIL in post-TKI EGFR mutant NSCLC could be related to EGFR-TKI resistance. Before considering anti-PD-1 therapy, reevaluation of PD-L1 should be considered. Citation Format: Tae-Jung Kim, Jin-Hyoung Kang, Sook-hee Hong. Immune microenvironment change after acquiring resistance to EGFR TKI therapy in EGFR mutant non-small cell lung cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B195.