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8528 Background: The standard treatment for locally advanced non-small cell lung cancer (NSCLC) is chemoradiotherapy (CRT) followed by treatment of durvalumab, one of immune checkpoint inhibitors (ICI). Interstitial lung disease (ILD) is a clinically life-threatening toxicity of CRT or durvalumab. The patient-characteristics or dose-volume histogram parameters of radiotherapy have been reported to be the risk factors for radiation-induced pneumonitis. However, the risk factors for ILD during durvalumab therapy has not been established. Interstitial lung abnormalities (ILA) are generated by aging or smoking, and manifest as minor interstitial shadow on lung computed tomography (CT). We previously reported that ILA were risk factors for ICI-induced ILD in patients with advanced NSCLC, as well as non-lung cancer. Therefore, we investigated whether ILA could be risk factors for ILD during the durvalumab therapy. Methods: We retrospectively enrolled NSCLC patients who received durvalumab after CRT at 10 institutions from July 2018 to June 2021. Patient-information, patient-characteristics, dose-volume histogram parameters, chest CT findings, and laboratory data, were obtained. CT findings were examined using CT obtained after CRT and prior to durvalumab therapy. Results: A total of 153 patients were enrolled, and the prevalence of ILA was 37.8% (56 patients) before durvalumab treatment. Among the enrolled patients, 94 (63.5%) developed ILD during durvalumab therapy. The proportion of patients with grade 1, grade 2, or grade 3 ILD was observed to be 29.7% (44 patients), 25.7% (38 patients), and 8% (12 patients), respectively. Univariate logistic regression analysis revealed that higher age, higher dose volume histogram parameters (V5, V20, mean lung dose), and the presence of ILA were significant risk factors for grade 2 or more ILD. Multivariate logistic regression analysis showed that ILA, especially ground grass attenuation in ILA, was an independent risk factor for grade 2 or more ILD (odds ratio: 7.02, 95% CI: 2.95-16.69, p < 0.0001). Conclusions: Pre-existing ILA are risk factors for ILD during durvalumab treatment after CRT. This observation is consistent with previously reported findings in patients with advanced lung cancer and non-lung cancer. Therefore, we should pay more attention to the development of grade 2 or more ILD during durvalumab treatment in patients with ILA.

e21156 Background: Pembrolizumab is the recommended first-line therapy for patients with advanced non-small cell lung cancer (NSCLC) and a programmed death ligand-1 (PD-L1) tumor proportion score (TPS) of ≥50% without driver mutations. However, its efficacy and safety for patients ≥75 years has not been prospectively investigated; this was the aim of this study. Methods: This multi-center and open-label single-arm phase II study was conducted at 12 institutions. Chemotherapy-naïve patients with advanced NSCLC and a PD-L1 TPS of ≥50% without EGFR mutations or translocation of the ALK received pembrolizumab (200 mg) every 3 weeks. The primary endpoint was progression-free survival (PFS) with a threshold of 4.3 months. The secondary endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR), safety. Quality of life (QOL) was assessed using EORTC QLQ-C30 and EORTC QLQ-LC13. The patients completed the questionnaires immediately after providing informed consent, and also before the third, sixth, twelfth, eighteenth, and twenty-fourth treatment cycles. Results: Twenty-six patients were enrolled between October 2017 and March 2020. The median PFS was 9.6 (95% confidence interval [CI], 2.1–20.6) months. The lower limit of the 95% CI did not exceed the target. The median OS was 21.6 (95% CI, 15.1–not reached) months.The ORR and DCR were 41.7% (24.5–61.2) and 70.8% (50.8–85.1), respectively. The proportion of patients with Grade ≥3 treatment-related adverse events was 15.4%. The Score of Global Health Status/QOL, symptom scales and/or items, and functioning scales of EORTC QLQ-C30 and EORTC QLQ-LC13 did not change significantly during the treatment. Conclusions: This study showed pembrolizumab was tolerable treatment for the elderly patients. Although the primary endpoint, the median PFS (9.6 months) was slightly shorter than that (10.3 months) of the previous phase III study (KEYNOTE-024 study), the median PFS, did not achieve the expected value. Clinical trial information: UMIN000040474.

e21177 Background: The significance of micro-pretreatment EGFR T790M mutation on EGFR-tyrosine kinase inhibitor (TKI) efficacy in patients with non-small cell lung cancer (NSCLC) remains uncertain. In addition, there has been no method to examine the micro-T790M mutation after excluding formalin-fixed and paraffin-embedded (FFPE)-derived artificial mutations. Therefore, we used a novel method to examine the variant allele frequency (VAF) of T790M mutation in the FFPE samples after excluding the artificial mutations. Subsequently, we retrospectively investigated the association between micro-T790M mutations and time to treatment failure (TTF) in patients treated with 1st, 2nd, or 3rd generation (1G, 2G, 3G) EGFR-TKIs. Methods: We enrolled patients with NSCLC who harbored EGFR exon 19 deletion (Del19) or L858R without T790M mutation using conventional methods. Patients who received 1G or 2G EGFR-TKIs until June 2018 or 3G EGFR-TKI until June 2019 from 31 institutions were included. Droplet digital PCR was performed using pretreatment FFPE tumor samples. We defined cases as micro-T790M positive when the VAF of T790M was higher than that of F795F, owing to the FFPE-derived artificial mutations. The ratio of micro-T790M mutation was calculated as follows: {(VAF of T790M) – (VAF of F795F)} /VAF of (Del19 or L858R). The lowest value was set as 0. Results: A total of 110, 102, and 103 patients received 1G, 2G, and 3G EGFR-TKIs, respectively. Of these patients, 48.1%, 47.0%, and 47.6% were classified as micro-T790M positive, respectively. The ratios of micro-T790M mutation, represented as median (%) (interquartile range), in 1G, 2G, and 3G EGFR-TKI groups were 0.27 (0.12-0.87), 0.28 (0.13-0.47), and 0.42 (0.20-0.68), respectively. The VAF of T790M or F795F in all patients, represented as median (%) (interquartile range), was 0.26 (0.19-0.35) or 0.25 (0.19-0.33), respectively. The TTF was not significantly different between the T790M-positive and negative groups in analysis based on each generation TKIs. In the Del19 group, the TTF of the 1G EGFR-TKI was significantly shorter, while that of the 3G EGFR-TKI was significantly longer in the T790M-positive group than in the negative group ( p= 0.02, 0.04, respectively). In the T790M-positive group, the TTF of the 2G or 3G EGFR-TKI group was significantly longer than that of the 1G EGFR-TKI group ( p= 0.04, 0.01, respectively). This result was observed in the Del19 group but not in the L858 group. Furthermore, TTF did not significantly differ between the 1G, 2G, and 3G EGFR-TKIs in the T790M-negative group. Conclusions: This study showed that micro- EGFR T790M mutations influence the EGFR-TKI efficacy. Detection of micro-T790M mutations will facilitate selection of the optimal EGFR-TKI for patients with EGFR mutated NSCLC.

e21736 Background: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), are less toxic than conventional chemotherapy drugs, and benefit patients with EGFR-mutated non-small cell lung (NSCLC) cancer. However, there are a few patients who are not able to receive EGFR-TKI due to poor performance status, older age, or sever comorbidities. Here, we aimed to determine the prognostic significance of EGFR mutation in NSCLC patients who received best supportive care (BSC) alone, and compare the anti-tumor outcomes of only EGFR-TKI-treated patients vs. BSC patients. Methods: We retrospectively reviewed the medical records of patients diagnosed with NSCLC at Higashihiroshima Medical Center during April 1991–January 2019 and Hiroshima University Hospital during April 2008–August 2018. Results: A total of 1163 patients diagnosed with unresectable NSCLC were included in this analysis. Of these 1163 patients, 234 patients received BSC alone.Among 196 patients who underwent EGFR mutation analysis, 38 and 158 did and did not harbor an EGFR mutation, respectively, and the mean survival times (MST) did not differ significantly between these groups (121 vs. 85 days, p = 0.789). Consistent with the survival analysis, the multivariate Cox regression analyses showed EGFR mutation was not an independent prognostic factor. After propensity score matching, a comparison of only EGFR-TKI-treated (n = 35) and BSC patients (n = 35) with EGFR mutation revealed that the former had a significantly longer MST than the latter (372 vs. 121, p < 0.001). Conclusions: EGFR mutation itself was not a significant prognostic factor in untreated NSCLC patients. The patients who received EGFR-TKI had a significantly longer MST than their untreated counterparts. Our results may help to explain the benefit of EGFR-TKI, particularly for patients who would be directed towards treatment with BSC.

e21536 Background: The standard treatment for locally advanced non-small cell lung cancer (NSCLC) is chemoradiotherapy (CRT) followed by anti-programmed cell death-ligand 1 (PD-L1) drug therapy. BIM deletion induces apoptosis suppression and the effect of epidermal growth factor-tyrosine kinase inhibitor is reportedly attenuated in EGFR-mutated NSCLC patients with BIM deletion. This study retrospectively examined the effects of BIM deletion on CRT or PD-1 treatment in patients with NSCLC. Methods: Among patients with unresectable NSCLC at Higashi-Hiroshima Medical Center and Hiroshima University Hospital between April 1994 and April 2018, we enrolled those treated with CRT or chemotherapy using carboplatin + paclitaxel or cisplatin + vinorelbine, or PD-1 antibody treatment. Results: Of 1,224 patients with unresectable NSCLC, 88, 80, and 79 underwent CRT, chemotherapy, or PD-1 antibody treatments, respectively. Within these treatment groups, 15 (17%), 15 (19%) and 11 (14%) patients, respectively, had BIM deletion. Among patients receiving CRT, the progression-free survival and overall survival were significantly shorter in those with BIM deletion than in those without (150 vs. 254 days, p = 0.003; 429 vs. 710 days, p = 0.03). Moreover, multivariate Cox regression analysis showed BIM deletion to be an independent factor for anti-tumor effect or prognosis (hazard ratio [95% confidence interval] 2.042, [1.112–4.039], p = 0.029; 2.414, [1.063–4.984], p = 0.036). These results were not observed in the chemotherapy and PD-1 treatment groups. To confirm the association between radiation therapy effect and BIM deletion, we performed in vitro experiments using two NSCLC cell lines (A549 and EBC-1). Suppressed BIM expression using siRNA (instead of BIM deletion) in these cells showed significantly suppressed antitumor effect and apoptosis 48 hours after 30-Gy irradiation but not chemotherapy. Conclusions: We showed that BIM deletion is an independent anti-tumor effect or prognostic factor for CRT. The results also indicated that BIM deletion was associated with the effects of radiation but not chemotherapy or PD-1 antibody treatment.

e15171 Background: Immune check point inhibitor (ICI) induced interstitial lung disease (ICI-ILD) is a clinically serious and life-threatening toxicity. Pre-existing ILD has been reported to be a risk factor for ICI-ILD in patients with non-small cell lung cancer (NSCLC). In addition, we have previously reported that interstitial lung abnormality (ILA) is also a risk factor for the ICI-ILD. Therefore, we investigated whether any patient characteristics, including ILA, were risk factors for ICI-ILD in patients with non-NSCLC cancers. Methods: Head and neck cancer, malignant melanoma, oral cavity cancer, renal cell carcinoma or gastric cancer patients who received anti PD-1 antibody (Nivolumab or Pembrolizumab) at Hiroshima University Hospital from December 2015 to May 2019 were enrolled. Information on patient characteristics before anti-PD-1 antibody administration, including chest CT findings and laboratory data, were obtained. Results: Two hundred patients were enrolled, and 20 (10%) developed ICI-ILD. Grade1 was observed in 15 patients, grade2 in 3, and grade3 and 5 in 1. There was no significant difference in the background factors between patients with and without ICI-ILD. On the other hand, the proportion of patients with ILA was significantly higher in the patients with ICI-ILD than those without (P < 0.01). Furthermore, univariate logistic regression analysis revealed ILA was the risk factor for ICI-ILD (p < 0.01), and multivariate logistic regression analysis showed that GGA or reticulation in ILA was an independent risk factor for ICI-ILD (p = 0.016, 0.011). Conclusions: Pre-existing ILA is a risk factor for ICI-ILD, and GGA or reticulation in ILA is an independent risk factor for ICI-ILD in patients with non-NSCLC cancers. Therefore, we should pay more attention to the development of ICI-ILD in patients with ILA, especially GGA or reticulation.

106 Background: Programmed death-1 (PD-1) inhibitors effectively treat non-small-cell lung cancer (NSCLC) and prolong survival, but the clinical benefits are limited in a small population. However, robust biomarkers for predicting clinical benefits with anti-PD-1 therapy have yet to be identified, therefore, predictive biomarkers are needed to select patients with benefits. On the other hand, NSCLC expresses NY-ESO-1 and XAGE1 cancer-testis antigens, which elicit spontaneous immune responses in NSCLC patients. Methods: We conducted a prospective multicenter study to investigate whether serum antibody against NY-ESO-1 and/or XAGE1 antigens was a predictive biomarker in anti-PD-1 therapy for NSCLC. Serum antibody was serially detected by ELISA, and antibody titers were monitored during anti-PD-1 therapy. Tumor tissues were analyzed by immunohistochemistry and whole exome sequencing. Objective response rate (ORR) and survival were the primary and secondary endpoint, respectively. Results: In the discovery cohort (n = 13), six antibody-positive NSCLC responded to anti-PD-1 therapy (two complete and four partial responses), whereas seven antibody-negative NSCLC did not. Antibody positivity was associated with good response and survival, regardless of tumor PD-ligand1 expression, mutation burden, and CD8 T-cell infiltration. In the independent validation cohort (n = 40), ten antibody-positive NSCLC obtained the significant clinical benefits with anti-PD-1 therapy as compared with 30 negative NSCLC (ORR 50% vs 6.7%, P = 0.006). In the multivariate analysis, only antibody positivity was a significantly better predictive biomarker of progression free survival (HR 0.04, 95% CI 0.0 to 0.3) and overall survival (HR 0.2, 95% CI 0.0 to 0.9) after anti-PD-1 therapy. Antibody titers in responders transiently increased with spikes and gradually decreased with tumor shrinkage after anti-PD-1 therapy, and strongly correlated with tumor reduction rates and tumor burden. Conclusions: Our results suggest that NY-ESO-1 and/or XAGE1 serum antibodies are useful biomarkers for predicting clinical benefits and monitoring tumor burden in anti-PD-1 therapy for NSCLC.