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3046 Background: Osimertinib, a highly selective third generation EGFR tyrosine kinase inhibitor (TKI) became the standard front-line therapy for EGFR-mutant NSCLC. However, therapeutic options are limited for TKI resistance which commonly occurs. Therefore, overcoming acquired resistance to osimertinib remains an important high unmet need in the field of precision oncology. Herein, we present the first case of advanced adenocarcinoma of the lung that showed notable response with the addition of selpercatinib after acquired resistance to osimertinib monotherapy. Methods: Case presentation. Results: A 37-year-old woman with stage IVB adenocarcinoma of lung with osseous, hepatic and brain metastases initially received one cycle of carboplatin, pemetrexed and pembrolizumab. Based on the EGFR exon19 deletion detected from ctDNA NGS assay (Guardant 360) [variant allele frequency (VAF) 62.7%], the treatment regimen was changed to osimertinib monotherapy (80mg PO daily). Bevacizumab was empirically added given CNS involvement. She maintained overall stable disease for 10 months before subsequent CT showed disease progression. The treatment regimen was switched to atezolizumab, bevacizumab, paclitaxel and carboplatin combination therapy. She tolerated 6 cycles of the regimen in 4 month before a subsequent brain MRI revealed progression of the metastatic brain disease with new leptomeningeal disease. Whole brain radiotherapy was performed and decision was made to start combination TKI treatment of selpercatinib (120mg BID) added to the osimertinib (80mg daily) monotherapy based on her repeat ctDNA NGS assay result showing concurrent acquired CCDC6RET fusion (VAF 0.05%) and EGFR exon 19 deletion (VAF 10.0%). The 6 week follow-up CT demonstrated significant decrease in the largest lung mass (33.95*24.22mm->32.50*16.07mm). Repeat ctDNA NGS assay at one week after selpercatinib use showed disappearance of RET fusion and significant decrease in EGFR clone (VAF 10.0% to 0.05%). Conclusions: It has been reported that co-occurring RET fusions in NSCLC patients with EGFR mutations may contribute to acquired resistance to EGFR inhibitors. Several successful cases of cabozantinib, a non-selective RET inhibitor, or pralsetinib, a selective RET inhibitor combined with EGFR inhibitor, have been reported to aid in overcoming the acquired resistance to EGFR inhibitors. To date, there has been no report of clinical benefit in adding a RET inhibitor based on ctDNA detection of RET fusion with minute variant allele frequency. We for the first time report the case of overcoming acquired resistance to osimertinib by adding selpercatinib, a selective RET inhibitor in NSCLC patients with acquired RET fusion detected in ctDNA at VAF of 0.05%.

e21218 Background: Early recognition of immune-related adverse events (irAEs) of immune checkpoint inhibitors(ICI) is important. Circulating proteome reflects host response to diseases and is being explored as a marker for response to immunotherapy. We previously have reported that a serum-based proteomics test, Primary Immune Response (PIR) demonstrated a trend that PIR-sensitive patients are more likely to tolerate ICI treatment longer without developing irAEs in non-small cell lung cancer (NSCLC) patients. The VeriStrat test is another serum-based proteomic assay, which was reported to be predictive of survival outcomes for all treatment regimens and lines of therapy including ICI in NSCLC. We explored the associations between the VeriStrat test and developing irAEs in NSCLC patients treated with ICI. Methods: Data of 70 consented NSCLC patients treated with any regimens and lines of therapy including ICI were collected. Samples were grouped into either VeriStrat ‘Good’(VS-G) or VeriStrat ‘Poor’(VS-P). We analyzed the durations from the immunotherapy initiation to each episode of irAE and each irAE above grade 2 using log-rank test. IrAEs were graded according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Results: Among the 70 patients, 18 patients (25%) experienced one or more irAEs. There was no significant difference in ‘Time to first irAE’ between VS-G and VS-P (p = 0.72, HR = 0.82, 95% CI = 0.29-2.32). Among 48 VS-G patients, 12(25%) had one or more irAE and 5(10%)had irAE graded over 2. Among 22 VS-P patients, 6(27%) had one or more irAE and 2(9%) had irAE graded over 2. There was no significant difference between VS-G and VS-P groups in the development of irAE and irAE graded over 2. Conclusions: There was no statistically significant association between the VeriStrat test and the development of irAEs. Further studies are warranted to investigate proper serum based proteomic assay to predict the development of irAE.

As the use of immune checkpoint inhibitors (ICIs) in treating a variety of cancer types has increased in recent years, so too have the number of reports on patients acquiring resistance to these therapies. Overcoming acquired resistance to immunotherapy remains an important need in the field of immuno-oncology. Herein, we present a case that suggests sequential administration of combination immunotherapy may be beneficial to advanced cervical cancer patients exhibiting acquired resistance to mono-immunotherapy. The patient’s tumor is microsatellite instability-high (MSI-H), which is an important biomarker in predicting ICI response. Results from recent interim prospective studies using combination immunotherapy (eg, nivolumab and ipilimumab) with anti-PD-1 plus anti-CTLA-4 inhibitor following progression on anti-PD-1 inhibitors (eg, nivolumab) have shown anti-tumor activity in patients with advanced melanoma and metastatic urothelial carcinoma. We also introduce retrospective studies and case reports/case series of dual checkpoint inhibition with anti-PD-1 inhibitor plus anti-CTLA-4 inhibitor after progression on prior anti-PD/PD-L1 monotherapy. To date, there has been no prospective study on the use of combined anti-PD-1 and anti-CTLA-4 therapy at the time of progression on anti-PD-1 therapy in patients with MSI-H tumors or advanced cervical cancer. In this report, we provide evidence that supports future investigations into such treatments.

BackgroundTumors with high tumor mutational burden (TMB) or defects in mismatch repair (dMMR) respond well to immune checkpoint inhibitors (ICIs).1 2 TMB and DNA repair gene mutations including dMMR are closely related to the increase of neoantigens, which are recognized by immune cells to trigger an immune response.1 3 Although not a standard of care in thyroid cancer treatment, there are ongoing clinical trials for ICI use in differentiated thyroid carcinoma. However, not much has been explored concerning the neoantigen landscape and its association with immune traits in papillary thyroid cancer (PTC). We aim to analyze the immune landscape of PTC in association with neoantigen burden, TMB, and DNA repair gene mutations.MethodsWe used the PTC cohort data from The Cancer Genome Atlas (TCGA). The mutation counts and data for neoantigen prediction were acquired from TCGA mutation calling. CloudNeo pipeline was used for neoantigen prediction. TMB was calculated as the sum of missense and indel mutation counts per megabase pairs covered by whole-exome sequencing. Tumor-infiltrating immune cells were estimated using CIBERSORT.ResultsOut of the 496 PTC patients from cBioPortal, a subset of 400 patients with available mutation counts and predicted neoantigen burden was included in the study. Immune cell infiltration estimated by CIBERSORT showed macrophage M2 as the most abundant, followed by macrophage M0 and other T cells (figure 1). The TMB ranged from 0.03 to 2.05 with a median value of 0.2. Neoantigen burden ranged from 0 to 18 with a median value of 1, which is relatively low compared to the median value of 18 in non-small cell lung cancer (NSCLC)1 (figure 2). One or more DNA repair gene mutations were discovered in 32 patients (8%). The mutation status of repair genes was not related to TMB or neoantigen burden. TMB or neoantigen burden was not related to immune traits such as infiltration of CD8+ T cells or regulatory T cells, cytolytic activity score, and PD-L1 expression.Abstract 753 Figure 1Immune cell infiltration estimated by CIBERSORTAbstract 753 Figure 2Histogram of neoantigen burdenConclusionsThis is the first study to report the immune landscape of PTC in the context of neoantigen. The lack of association between TMB or neoantigen burden with immune traits may be due to the relatively low number of neoantigens in PTC compared to other immunogenic cancers such as NSCLC. Our results suggest that mutations in DNA repair genes or TMB are likely to have limited value in predicting response to ICI treatment in PTC.ReferencesChae YK, et al., Mutations in DNA repair genes are associated with increased neoantigen burden and a distinct immunophenotype in lung squamous cell carcinoma. Sci Rep 2019; 9:3235.Rizvi NA, et al., Cancer immunology. mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 2015; 348:124–128.Schumacher TN, Schreiber RD, Neoantigens in cancer immunotherapy. Science 2015; 348:69–74.