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To evaluate the efficacy and safety of osimertinib plus bevacizumab for previously untreated patients with advanced nonsquamous NSCLC harboring EGFR-sensitizing mutations.We conducted a randomized, open-label, phase 2 study at 21 institutions in Japan. Previously untreated patients with advanced nonsquamous NSCLC harboring EGFR-sensitizing mutations received either osimertinib (80 mg, daily) plus bevacizumab (15 mg/kg, every 3 wk) or osimertinib monotherapy, and were stratified according to sex, stage, and EGFR mutation status. The primary end point was progression-free survival (PFS) in the intention-to-treat population, assessed by means of blinded, independent central radiologic review.Between January 2018 and September 2018, a total of 122 patients were enrolled (osimertinib + bevacizumab arm, 61 patients; osimertinib monotherapy arm, 61 patients). At a median follow-up duration of 19.8 months, the median PFS was 22.1 months for osimertinib plus bevacizumab and 20.2 months for osimertinib monotherapy, with a hazard ratio of 0.862 (60% confidence interval: 0.700-1.060, 95% confidence interval: 0.531-1.397, one-sided stratified log-rank p = 0.213). Adverse events of grade 3 or worse were observed in 34 patients (56%) in the osimertinib plus bevacizumab arm and 29 (48%) in the osimertinib monotherapy arm. In addition, two (3%) and 11 patients (18%) experienced any grade pneumonitis, respectively, and grade 3 pneumonitis was observed in one patient (2%) in each arm.This study failed to exhibit the efficacy of osimertinib plus bevacizumab for improving the PFS among patients with nonsquamous NSCLC harboring EGFR mutations as first-line treatment.

Supplementary Figure from Nivolumab Retreatment in Non–Small Cell Lung Cancer Patients Who Responded to Prior Immune Checkpoint Inhibitors and Had ICI-Free Intervals (WJOG9616L)

Supplementary Table from Nivolumab Retreatment in Non–Small Cell Lung Cancer Patients Who Responded to Prior Immune Checkpoint Inhibitors and Had ICI-Free Intervals (WJOG9616L)

Purpose:To explore the efficacy of retreatment with immune checkpoint inhibitors (ICI) in patients with advanced non–small cell lung cancer (NSCLC) who responded to prior ICI and had adequate ICI-free interval.Patients and Methods:Patients with advanced NSCLC who had achieved complete response (CR), partial response (PR), or stable disease for ≥6 months with prior ICI therapy preceding progression were prospectively enrolled. All patients should have had ICI-free interval ≥60 days before registration. Patients were treated with nivolumab (240 mg) every 2 weeks until progression. The primary endpoint was overall response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival, and safety (Trial Identifier, UMIN000028561).Results:Sixty-one patients were enrolled during October 2017 to February 2020, with 59 analyzed for efficacy. Regarding prior ICI, 41 patients had CR or PR. Median treatment on ICI and median ICI-free intervals were 8.1 months and 9.2 months, respectively. Twenty patients experienced immune-related adverse events (irAE) that required discontinuation of prior ICI. Nivolumab retreatment demonstrated ORR of 8.5% [95% confidence interval (CI), 2.8–18.7%] and median PFS of 2.6 months (95% CI, 1.6–2.8 months) while 5 responders had 11.1 months of median PFS. In the multivariate analysis, ICI-free interval was the only predictive factor of PFS (HR, 2.02; P = 0.02), while prior efficacy or history of irAE was not. Common adverse events were skin disorders (23%), malaise (20%), and hypoalbuminemia (15%).Conclusions:Even in patients who initially responded to prior ICI and had ICI-free interval, once resistance occurred, retreatment with nivolumab had limited efficacy.

Background: The efficacy and tolerability of high-flow nasal cannula (HFNC) for relieving dyspnea in advanced cancer patients with limited prognosis requires elucidation. Methods: Patients with advanced cancer who had dyspnea at rest (numeric rating scale, NRS≥3) and respiratory failure were enrolled. They were treated with HFNC for five days. Primary endpoint was change of mean modified Borg scale at 24 hours. Key secondary endpoints consisted of change in modified Borg scale during the study period and feasibility (Trial Identifier, UMIN000035738). Results: Between February 2019 and February 2022, 25 patients were enrolled and 21 were analyzed. Twenty patients used inspired oxygen and the mean fraction of inspired oxygen (FiO2) was 0.34 (range, 0.21–1.0). At baseline, mean NRS (dyspnea) was 5.9 (range, 3–10). Median survival time was 19 days (range, 3–657). The change of mean modified Borg scale was 1.4 (80% confidence interval [CI]: 0.8–1.9) at 24 hours, 11 patients showed 1.5 points improvement of modified Borg scale. Within 1 hour, nine patients showed 1.5 points improvement of modified Borg scale and such early responders were likely to maintain dyspnea improvement for 24 hours.­ Nineteen patients could continue HFNC for 24 hours and 11 patients completed five days of HFNC. Conclusion: To our knowledge, this trial is the first prospective study to show the efficacy and tolerability of HFNC regarding dyspnea for five days in patients under palliative care. HFNC can be a palliative treatment option in advanced cancer patients with dyspnea.

A multistep sorting method for enrichment of rare cells, such as circulating tumor cells, in the blood without cumbersome pretreatments required by most flow cytometry-based methods, which lead to high cost and decreased detection efficiency, was developed.After only hemolysis and cell staining, cancer cells are enriched by repetitive sorting (3×) based on nuclear-positive, cytokeratin-positive, and CD45-negative expression.Experiments using spikes of PC-9 cells showed a mean recovery of 65% and mean purity of 83%, which was retained up to 72 hours after blood draw using preservative tubes. Significant differences in expression level of programmed death-ligand 1 or vimentin were observed between high- and low-expressing cell lines, concurrently with enrichment. Next-generation sequencing analysis of recovered PC-9, A549, and MDA-MB231 cells successfully detected all known mutations.This novel isolation method applicable for preserved samples with sufficient recovery and purity may be substantially beneficial for recovering cells for subsequent molecular analysis.

Considering the increasing number of identified driver oncogene alterations, additional genetic tests are required to determine the treatment for advanced non‐small‐cell lung cancer (NSCLC). Next‐generation sequencing can detect multiple driver oncogenes simultaneously, enabling the analysis of limited amounts of biopsied tissue samples. In this retrospective, multicenter study (UMIN ID000039523), we evaluated real‐world clinical data using the Oncomine Dx Target Test Multi‐CDx System (Oncomine DxTT) as a companion diagnostic system. Patients with NSCLC who were tested for a panel of 46 genes using the Oncomine DxTT between June 2019 and January 2020 were eligible for enrollment. Patients from 19 institutions affiliated to the West Japan Oncology Group were recruited. The primary endpoint of the study was the success rate of genetic alteration testing in four driver genes (EGFR, ALK, ROS1, and BRAF) using the Oncomine DxTT. In total, 533 patients were enrolled in the study. The success rate of genetic alteration testing for all four genes was 80.1% (95% CI 76.5%‐83.4%). Surgical resection was associated with the highest success rate (88.0%), which was significantly higher than that for bronchoscopic biopsy (76.8%, P = .005). Multivariate analysis revealed a significant difference for surgical resection alone (P = .006, 95% CI 1.36‐6.18, odds ratio 2.90). Although the success rate of genetic alteration testing immediately after Oncomine DxTT induction was not sufficient in this study, optimizing specimen quantity and quality may improve the use of driver gene testing in clinical settings., The mutation identification success rate for all four genes was 80.1%. Surgical resection was associated with the highest success rate. Multivariate analysis showed a significant difference for surgical resection alone.

Introduction Despite the extensive use of the combination of cytotoxic chemotherapy and programmed cell death protein 1/programmed death-ligand 1 checkpoint inhibitors for cancer treatment, the incidence and characteristics of pneumonitis caused by this combination therapy have not been examined in clinical settings. Methods We conducted a 36-centre, retrospective cohort study in patients with chemo-naive advanced non-squamous non-small cell lung cancer who received a combination of platinum, pemetrexed and pembrolizumab between December 2018 and June 2019. Results The study comprised 299 patients. The most frequent grade ≥3 non-hematologic adverse event was pneumonitis. There were 37 patients (12.4%, 95% CI 8.9–16.7) with all-grade pneumonitis and 10 (3.3%, 95% CI 1.6–6.1) with grade ≥3 pneumonitis. Of these, 21 (7.0%, 95% CI 4.4–10.5) and 9 patients (3.0%, 95% CI 1.4–5.6) developed all-grade and grade ≥3 pneumonitis within 90 days after initiating the combination therapy, respectively. The median time to treatment failure and progression-free survival was 5.9 (95% CI 5.0–6.8) and 7.5 (95% CI 6.5–8.7) months, respectively. In the survival analysis after adjusting for immortal time bias, pneumonitis was independently associated with shorter progression-free survival (HR 1.99, 95% CI 1.07–3.69, P = 0.03) and overall survival (HR 3.03, 95% CI 1.12–8.20, P = 0.03). Conclusions Treatment-related pneumonitis occurred at a higher rate in the real-world population than that reported previously; it led to worse survival outcomes. Pneumonitis requires more attention. Additional studies are required to improve the safety of this combination therapy. Trial registration number UMIN000038084

Background: Programmed cell death-ligand 1 (PD-L1) inhibitor durvalumab has been found to improve disease control in patients with unresectable stage III non-small cell lung cancer (NSCLC) treated with definitive concurrent chemoradiation therapy (dCCRT), but approximately a half of patients eventually experience disease progression within one year after the start of durvalumab. The mechanism of this resistance at such an early timing is poorly identified. Therefore, we conducted a prospective biomarker study to explore the resistance mechanisms to durvalumab after CCRT (Trial Identifier: UMIN000035916). Methods: A total of 139 patients with unresectable stage III NSCLC enrolled into this study after dCCRT were treated with durvalumab for up to 1 year. 135 patients who fulfilled the predetermined selection criteria were included for this primary biomarker analysis. Archival tumor tissues collected before the treatment were analyzed by immunohistochemistry for several key biomarkers such as PD-L1, CD8, and CD73, DNA sequencing for tumor-mutation burden (TMB) and genomic profile, as well as gene expression profiling (GEP). Peripheral blood mononuclear cells (PBMC) were also collected before and after durvalumab for flow-cytometry (FCM) analysis where available. Progression-free survival (PFS) was compared based on these biomarkers. Results: Median follow-up time was 14.4 months. Median PFS was 14.9 months (95% confidence interval [CI], 11.3-not reached), and 1-year PFS rate was 56.3% (95% CI, 47.3-64.3). CD8+ tumor-infiltrating lymphocytes (TILs), PD-L1 tumor proportion score (TPS), TMB, and CD73 on tumor cells were associated with PFS (hazard ratios [HRs], 0.40 [95% CI, 0.22-0.73] for CD8+TILs; 0.67 [95% CI, 0.40-1.11] for PD-L1-TPS ≥1%; 0.59 [95% CI, 0.34-1.02] for high TMB; 1.45 [95% CI, 0.86-2.43] for high CD73). Common pathogenic gene alterations such as EGFR, KRAS, and TP53 were not associated with PFS. Multivariable analysis including key clinical factors as covariables indicated that CD8+TILs and the CD73-expressing tumor cells were independently associated with durvalumab outcome (HRs, 0.26 [95% CI, 0.08-0.89] for CD8+TILs; 5.83 [95% CI, 1.33-25.62] for CD73). The significance of CD73-expressing tumor cells as a resistance factor was more obvious in patients with high CD8+TILs (HR, 2.35 [95% CI, 1.14-4.86]). GEP of tumor tissue and FCM of PBMC suggested that CD73-expressing tumor cells prevented effective reinvigoration of antigen-reactive CD8+ T cells by durvalumab due to the immunosuppressive activity. Conclusions: Low preexisting CD8+TILs or high CD73-expressing tumor cells were suggested to be primary resistance mechanism to durvalumab after CCRT in stage III NSCLC. Further development of next treatment approach will be prompted based on these findings. Citation Format: Koji Haratani, Atsushi Nakamura, Nobuaki Mamesaya, Kenji Sawa, Yasuto Yoneshima, Ryota Saito, Tomohiro Ozaki, Kenjiro Tsuruoka, Akito Hata, Kosuke Tsuruno, Tomohiro Sakamoto, Shunsuke Teraoka, Masahide Oki, Hiroshi Watanabe, Tomoyuki Otani, Kazuko Sakai, Shuta Tomida, Yasutaka Chiba, Akihiko Ito, Kazuto Nishio, Nobuyuki Yamamoto, Kazuhiko Nakagawa, Hidetoshi Hayashi. A multi-institutional prospective biomarker study of durvalumab after concurrent chemoradiation therapy in patients with unresectable stage III non-small cell lung cancer (WJOG11518L/SUBMARINE) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2173.

Noninvasive diagnostics using circulating tumor cells (CTCs) are expected to be useful for decision making in precision cancer therapy. AXL, a receptor tyrosine kinase is associated with tumor progression, epithelial‐to‐mesenchymal transition (EMT), and drug resistance, and is a potential therapeutic target. However, the epithelial markers generally used for CTC detection may be not enough to detect AXL‐expressing CTCs due to EMT. Here, we evaluated the detection of AXL‐expressing CTCs using the mesenchymal marker vimentin with a microcavity array system. To evaluate the recovery of cancer cells, spike‐in experiments were performed using cell lines with varying cytokeratin (CK) or vimentin (VM) expression levels. With high CK and low VM‐expressing cell lines, PC‐9 and HCC827, the recovery rate of AXL‐expressing cancer cells was 1%‐17% using either CK or VM as markers. Whereas, with low CK and high VM‐expressing cell lines, MDA‐MB231 and H1299, it was 52%‐75% using CK and 72%‐88% using VM as a marker. For clinical evaluation, peripheral blood was collected from 20 non–small cell lung cancer patients and CTCs were detected using CK or VM as markers in parallel. Significantly more AXL‐expressing single CTCs were detected in VM‐positive than CK‐positive CTCs (P, We established the detection of AXL‐expressing in circulating tumor cells of lung cancer patients incorporating vimentin as a CTC marker in addition to cytokeratin. Significantly more AXL‐expressing CTCs were detected in patients who had prior treatment history than those did not, suggesting the involvement of AXL in drug resistance.

Motoko Tachihara,1 Kayoko Tsujino,2 Takeaki Ishihara,3 Hidetoshi Hayashi,4 Yuki Sato,5 Takayasu Kurata,6 Shunichi Sugawara,7 Isamu Okamoto,8 Shunsuke Teraoka,9 Koichi Azuma,10 Haruko Daga,11 Masafumi Yamaguchi,12 Takeshi Kodaira,13 Miyako Satouchi,14 Mototsugu Shimokawa,15 Nobuyuki Yamamoto,9 Kazuhiko Nakagawa4 On behalf of members of the West Japan Oncology Group (WJOG)1Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe City, Japan; 2Department of Radiation Oncology, Hyogo Cancer Center, Akashi City, Japan; 3Division of Radiation Oncology, Kobe University Graduate School of Medicine, Kobe City, Japan; 4Department of Medical Oncology, Kindai University, Osakasayama City, Japan; 5Department of Respiratory Medicine, Kobe City Medical Center General Hospital, Kobe City, Japan; 6Department of Thoracic Oncology, Kansai Medical University Hospital, Hirakata City, Japan; 7Department of Pulmonary Medicine, Sendai Kousei Hospital, Sendai City, Japan; 8Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka City, Japan; 9Internal Medicine III, Wakayama Medical University, Wakayama, Japan; 10Division of Respirology, Neurology, and Rheumatology, Department of Internal Medicine, Kurume University School of Medicine, Fukuoka City, Japan; 11Department of Medical Oncology, Osaka City General Hospital, Osaka, Japan; 12Department of Thoracic Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka City, Japan; 13Departments of Radiation Oncology, Aichi Cancer Center Hospital, Nagoya City, Aichi, Japan; 14Department of Thoracic Oncology, Hyogo Cancer Center, Akashi City, Japan; 15Department of Biostatistics, Yamaguchi University Graduate School of Medicine Yamaguchi, Ube City, JapanCorrespondence: Motoko TachiharaDivision of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe City, 650-0017, JapanTel +81-78-382-5660Fax +81-78-382-5661Email mt0318@med.kobe-u.ac.jpAbstract: Durvalumab (anti-programmed cell death ligand-1) administration after concurrent chemoradiotherapy (cCRT) has improved the survival of patients with unresectable, locally advanced (LA) stage III non-small cell lung cancer (NSCLC). Some patients are unable to complete cCRT and cannot receive immunotherapy due to poor performance status based on adverse events after cCRT. Immunotherapy plays an important role in anti-programmed cell death ligand-1 (PD-L1)-positive advanced NSCLC and is replacing chemotherapy. In addition, radiotherapy and immunotherapy have been reported to have a synergistic effect. This Phase II, multicenter study (DOLPHIN, WJOG11619L, JapicCTI-194840) is designed to assess the efficacy and safety of durvalumab plus concurrent curative radiation therapy for PD-L1-positive unresectable LA-NSCLC without chemotherapy. Unresectable LA stage III NSCLC patients aged 20 years or older with a World Health Organization/Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 and PD-L1 positivity are enrolled. The patients will receive curative radiation therapy (60 Gy) plus durvalumab 10 mg/kg every 2 weeks (q2w) for up to 12 months until there is evidence of disease progression (PD) or unacceptable toxicity. The primary endpoint is the 12-month progression-free survival rate as assessed by an independent central review. The secondary endpoints are progression-free survival, overall survival, objective response rate, treatment completion rate, and safety. Recruitment began in September 2019.Keywords: clinical study, locally advanced non-small cell lung cancer, immunotherapy, programmed cell death ligand-1, durvalumab, radiation

The incidence of real-world pneumonitis and durvalumab rechallenge during chemoradiotherapy and durvalumab consolidation for non-small cell lung cancer is unknown.We retrospectively evaluated the medical records of 302 consecutive patients diagnosed with non-small cell lung cancer who started chemoradiotherapy between May 2018 and May 2019.Median age was 70 (range: 40-87) years. Volume of lung parenchyma that received 20 Gy (V20) exceeded 35% in 2% and mean lung dose exceeded 20 Gy in 1% of patients. Durvalumab consolidation was delivered to 225 patients (75%). Overall, 83% (n = 251), 34% (n = 103), 7% (n = 21), and 1% (n = 4) of the patients developed any grade of pneumonitis, symptomatic pneumonitis, ≥grade 3 pneumonitis, and fatal (grade 5) pneumonitis, respectively. Corticosteroids were administered to 25% of the patients to treat pneumonitis. Multivariate analysis identified the predictive factors for the development of symptomatic pneumonitis: V20 Gy or more ≥ 25% (odds ratio [OR]: 2.37, P = 0.008) and mean lung dose (MLD) ≥ 10 Gy (OR: 1.93, P 0.0047). Of the 52 patients who received corticosteroids for pneumonitis after durvalumab initiation, 21 were rechallenged with durvalumab. Overall, 81% of patients met the PACIFIC study's rechallenge criteria and did not experience a severe pneumonitis relapse.High V20 and MLD were independent risk factors of symptomatic pneumonitis. More than 80% of the patients who were rechallenged with durvalumab after pneumonitis met the PACIFIC study's rechallenge criteria. Consequently, severe relapse did not occur. Cooperation between radiation and medical oncologists is important for safe chemoradiotherapy and the safe completion of durvalumab consolidation therapy.

Background Although predictive value of immune‐related adverse events (irAEs) induced by immune checkpoint inhibitors (ICIs) have been suggested by several studies, their assessments were insufficient because patients were categorized only by the occurrence of irAEs. It has not been elucidated whether irAEs also play a significant role even in responders. Materials and Methods Between December 2015 and September 2018, 106 patients with advanced non‐small cell lung cancer treated with ICIs were enrolled in our prospective biomarker study. Twenty‐three of these were responders, defined as those with complete or partial response. We investigated the proportion of irAEs among overall and responders. For responders, progression‐free survival (PFS) and overall survival of ICIs were compared between those with and without irAEs. As an exploratory analysis, we measured 41 proteins from peripheral blood before and after ICI treatment. Results The proportion of irAEs was significantly higher in responders than nonresponders (65.2% vs. 19.3%, p < .01). Among responders, clinical characteristics did not differ regardless of the occurrence of irAEs. However, there was a significant difference in PFS among responders (irAE group 19.1 months vs. non‐irAE group 5.6 months; hazard ratio: 0.30 [95% confidence interval: 0.10–0.85]; p = .02). Of 41 protein analyses, fibroblast growth factor‐2 at baseline and monocyte chemoattractant protein fold change showed significant differences between them (p < .04). Conclusion Although this is a small sample–sized study, irAE might be a predictive factor of durable efficacy, even in patients who responded to ICIs. Investigation into the significance of irAEs in responders will contribute to the establishment of optimal administration of ICI. Implications for Practice Although the predictive value of immune‐related adverse events (irAEs) induced by immune checkpoint inhibitors (ICIs) has been suggested by several studies, it has not been elucidated whether irAEs also play a significant role even in responders. This study showed that more than 60% of responders had irAEs. It demonstrated the strong correlation between irAEs and efficacy even in responders. Investigation into the significance of irAEs in responders will contribute to the establishment of optimal administration of ICI., Immune‐related adverse events might be a predictive factor of efficacy, even I patients who respond to immune checkpoint inhibitor therapy. This study investigated the significance of immune‐related adverse events in patients with non‐small cell lung cancer who had complete or partial response after treatment with immune checkpoint inhibitors.

According to rapid development of chemotherapy in advanced non-small cell lung cancer (NSCLC), the Japan Lung Cancer Society has been updated its own guideline annually since 2010. In this latest version, all of the procedure was carried out in accordance with grading of recommendations assessment, development and evaluation (GRADE) system. It includes comprehensive literature search, systematic review, and determination of the recommendation by multidisciplinary expert panel which consisted of medical doctors, pharmacists, nurses, statisticians, and patients from patient advocacy group. Recently, we have had various types of chemotherapeutic drugs like kinase inhibitors or immune-checkpoint inhibitors. Thus, the guideline proposes to categorize patients into three entities: (1) driver oncogene-positive, (2) PD-L1 ≥ 50%, and (3) others. Based on this subgroup, 31 clinical questions were described. We believe that this attempt enables clinicians to choose appropriate treatment easier. Here, we report an English version of the Japan Lung Cancer Society Guidelines 2018 for NSCLC, stages IV.

Although programmed cell death-ligand-1 (PD-L1) expression in tumor tissue has been established as predictive biomarker for the anti-programmed cell death-1 (PD-1) antibody treatment of non-small-cell lung cancer (NSCLC), additional biomarkers are critically needed. We evaluated serum proteins relevant to immune checkpoint blockade in patients with NSCLC treated with nivolumab to identify novel non-invasive predictive biomarkers.Patients with advanced NSCLC, who had failed at least one prior chemotherapy regimen, received nivolumab monotherapy (3 mg/kg, Q2W) until progressive disease (PD) or unacceptable toxicity was observed. Blood samples were collected at baseline and week 4. Fifty-seven serum protein levels were quantified with a Milliplex MAP assay. The associations of both clinical benefit (CB) and the onset of immune related adverse events (irAEs) with serum proteins levels were evaluated.Thirty-eight patients with advanced NSCLC were enrolled in the study, with 38 and 32 paired serum samples at baseline and week 4 being available for efficacy analysis and irAE analysis, respectively. In durable CB (DCB) patients compared with non-DCB patients, the baseline serum levels of BMP-9 were significantly higher, whereas the follistatin, IL-8, IP-10, and TNF-α levels were significantly lower. In irAE patients compared with non-irAE patients the serum levels of G-CSF and RANTES at week 4 were significantly higher, whereas the levels of leptin were significantly lower. A multivariate analysis revealed that follistatin and IP-10 were statistically associated with DCB (p 0.05) and RANTES was associated with irAE onset (p 0.05). In a subset of irAE-developed patients, RANTES levels decreased after steroid administration, supporting its involvement in irAE.Serum proteins have the potential to be predictive markers for DCB and irAEs onset in patients with NSCLC treated with nivolumab. In addition, antitumor activity and irAEs may not be regulated by the same mechanisms.

While PD-1/L1 inhibitors are characterized by durable tumor control, they also prolong survival without prolongation of progression-free survival (PFS) in part of patients. However, little is known about the factors and mechanisms involved in this. Between December 2015 and September 2018, 106 patients with advanced non-small cell lung cancer treated with ICI monotherapy were enrolled in a prospective-observational study. Sixty-nine of whom progressed or died within 6 months after ICI initiation were defined as patients without durable clinical benefit (NDBs). Clinical factors and 39 serum proteins before ICI initiation and at the time of progressive disease (PD) were explored for an association with overall survival (OS) and OS after PD (OS-PD). As a result, median PFS, OS, and OS-PD were 44 days [95% confidence interval (CI): 39-56), 211 days (95% CI: 158-425), and 193 days (95% CI: 118-349), respectively. By multivariate analysis for OS, CRP ( 1.44 mg/dl) [HR 2.59 (95% CI:1.33-5.04), P = 0.005] and follistatin ( 685 pg/ml) [HR 2.29 (95% CI:1.12-4.69), P = 0.023] before ICI initiation were significantly predictive. Notably, no serum protein at the time of PD was predictive for OS-PD. There were also no serum predictive factors of OS in the 33 patients with durable clinical benefit. In conclusion, serum levels of CRP and follistatin before ICI initiation, not at the time of PD, are predictive for OS in NDBs, suggesting long-term survivor in NDBs are predetermined by the immune status before ICI initiation.

Aim The emergency department requires simple and useful clinical indicators to identify bacteremia. This retrospective study explored the Systemic Inflammatory Response Syndrome (SIRS) and quick Sequential Organ Failure Assessment (qSOFA) scores for predicting bacteremia. Methods Between April and September 2017, we assessed blood cultures of 307 patients in our emergency department. We calculated the SIRS and qSOFA scores for these patients and evaluated their correlation with bacteremia. Results Of 307 patients, 66 (21.5%) had bacteremia, 237 (77.2%) were SIRS‐positive, and 123 (40.0%) were qSOFA‐positive. The sensitivity and specificity of the SIRS score for predicting bacteremia were 87.9% and 25.7%, respectively. The sensitivity and specificity of the qSOFA score were 47.0% and 61.8%, respectively. Multivariate analysis revealed that body temperature (odds ratio, 2.16; 95% confidence interval, 1.22–3.84; P = 0.009) and blood pressure (odds ratio, 2.72; 95% confidence interval, 1.39–5.35; P = 0.004) significantly associated with bacteremia. Conclusions The SIRS score was a more sensitive indicator than the qSOFA score for predicting bacteremia., We compared the Systemic Inflammatory Response Syndrome (SIRS) and quick Sequential Organ Failure Assessment (qSOFA) scores in predicting bacteremia. SIRS had higher sensitivity (87.9%) than qSOFA (47.0%). Body temperature significantly correlated with bacteremia and SIRS sensitivity in predicting bacteremia was lower in the antipyretic group.

Introduction In patients with relapsed SCLC, amrubicin (AMR) is the current standard treatment in Japan. Nevertheless, its efficacy is not satisfactory and prognosis is poor. Preclinical study suggested that anthracycline agent might induce immunogenic cell death and work synergistically with immune checkpoint inhibitors. Methods Patients with relapsed SCLC who relapsed after completion of platinum-containing regimen were registered. Patients were treated with pembrolizumab (200 mg, flat dose on d 1, every 3 wk for 2 y) plus AMR (40 mg/m2 on d 1–3, every 3 wk until progression). Primary end point was overall response rate (ORR). Secondary end points consisted of progression-free survival (PFS), overall survival, and safety. On the basis of the hypothesis that this treatment will improve ORR from 20% to 40% (0.1 of one-sided α and power of 0.8), 25 patients are required (trial identifier: NCT03253068). Results Between November 2017 and October 2019, a total of 25 patients were enrolled. Most participants (88%) relapsed within 90 days after platinum-containing therapy and all patients were immune checkpoint inhibitor-naive. ORR, the primary end point, was 52.0% (95% confidence interval [CI]: 31.3%–72.2%). Median PFS was 4.0 months (95% CI: 2.8–7.0 mo), and PFS rate at 1 year was 14.4%. Median overall survival was 10.6 months (95% CI: 7.3–21.3 mo). Common adverse events greater than or equal to grade 3 were neutropenia (64%), leukopenia (40%), and febrile neutropenia (16%). No treatment-related deaths occurred. Conclusions Among patients with relapsed SCLC, pembrolizumab plus AMR was effective and tolerable.

BACKGROUND Programmed cell death ligand 1 is a biomarker of immune checkpoint inhibitors (ICIs) for treating advanced non-small-cell lung cancer (NSCLC). Here, we evaluated serum proteins from patients with advanced NSCLC treated with ICIs to determine their potential as noninvasive predictive biomarkers for efficacy and immune-related adverse events (irAEs). PATIENTS AND METHODS Patients with advanced NSCLC who received nivolumab or pembrolizumab monotherapy until disease progression or unacceptable toxicity were integrated with previously reported nivolumab-treated patients. Blood samples were collected serially from baseline until the disease progressed. Serum protein levels were quantified using the Luminex assay. Associations of clinical benefit (CB) and onset of irAEs with serum protein levels were evaluated. RESULTS Sixty-three patients with advanced NSCLC were studied, and we used 63 and 47 paired serum samples at baseline and the second sampling point, respectively, for efficacy analysis. Baseline growth-regulated oncogene 1 (GRO-1) levels were significantly lower in durable CB (DCB) patients than in non-DCB patients (P < .05). Changes in monocyte chemoattractant protein 1 (MCP-1) levels significantly decreased between baseline and the second sampling point (P < .05). Patients with the low GRO-1/decreased MCP-1 subtype showed significantly longer progression-free survival (PFS) and overall survival (OS) than the high GRO-1/increased MCP-1 subgroup did (median PFS, not reached vs. 47 days, P < .0001; median OS, 985 days vs. 148 days, P = .0002, respectively). Elevated GRO-1 levels were associated with immune-related adverse event onset. CONCLUSIONS Serum GRO-1 and MCP-1 levels can identify patients with advanced NSCLC who are likely to benefit from ICI treatment. Time-course tracing of these protein levels might be valuable in ICI treatment.

Importance Although treatment with first-generation epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitor (TKI) plus antiangiogenic inhibitor has shown promising efficacies in patients withEGFR-mutated lung adenocarcinoma, recent single-arm studies have suggested that osimertinib plus antiangiogenic inhibitor might not work synergistically. Objective To explore the efficacy and safety of osimertinib plus bevacizumab compared with osimertinib alone in patients with lung adenocarcinoma withEGFRT790M mutation. Design, Setting, and Participants Patients with advanced lung adenocarcinoma that progressed with prior EGFR-TKI treatment (other than third-generation TKI) and acquiredEGFR T790M mutation were enrolled. This study comprises a lead-in part with 6 patients and a subsequent phase 2 part. In phase 2, patients were randomized to osimertinib plus bevacizumab or osimertinib alone in a 1:1 ratio. Interventions The combination arm received oral osimertinib (80 mg, every day) plus intravenous bevacizumab (15 mg/kg, every 3 weeks) until progression or unacceptable toxic effects. The control arm received osimertinib monotherapy. Main Outcomes and Measures The primary end point was progression-free survival (PFS) assessed by investigators. Secondary end points consisted of overall response rate, time to treatment failure, overall survival, and safety. Results From August 2017 through September 2018, a total of 87 patients were registered (6 in the lead-in part and 81 in the phase 2 part [intention-to-treat population]). Among those randomized, the median (range) age was 68 (41-82) years; 33 (41%) were male; 37 (46%) had an Eastern Cooperative Oncology Group performance status of 0; and 21 (26%) had brain metastasis. Although the overall response rate was better with osimertinib plus bevacizumab than osimertinib alone (68% vs 54%), median PFS was not longer with osimertinib plus bevacizumab (9.4 months vs 13.5 months; adjusted hazard ratio, 1.44; 80% CI, 1.00 to 2.08;P = .20). Median time to treatment failure was also shorter in the combination arm vs the osimertinib arm (8.4 months vs 11.2 months;P = .12). Median overall survival was not different in the combination arm vs osimertinib arm (not reached vs 22.1 months;P = .96). In the combination arm, common adverse events of grade 3 or higher were proteinuria (n = 9; 23%), hypertension (n = 8; 20%). Conclusions and Relevance In this randomized clinical trial comparing osimertinib plus bevacizumab vs osimertinib alone, the combination arm failed to show prolongation of PFS in patients with advanced lung adenocarcinoma withEGFR T790M mutation. Trial Registration UMIN Clinical Trials Registry Identifier:UMIN000023761

Background: Although it has been known that N-glycan moiety in immunoglobulin G (IgG) fragment crystallizable (Fc) region, which affects antigen dependent cellular cytotoxicity (ADCC) activity is different between healthy individuals and cancer patients, the impact of N-glycan structure on cancer treatment is unknown. Here, we evaluated the putative ADCC activity by the N-glycan moiety of IgG-Fc using serum samples and analyzed its association with clinical benefits from immune checkpoint inhibitors (ICIs) in patients with advanced non-small cell lung cancer (NSCLC). Patients and Methods: Serum samples from healthy volunteers (HVs) were obtained from Tohoku Medical Megabank and chronic obstructive pulmonary disease (COPD) patients were enrolled as a smoking-related non-cancer disease cohort. Serum samples from advanced NSCLC patients receiving ICIs until disease progression or unacceptable toxicity were collected prior treatment. Three IgG fractions (area 1, 2 and 3) corresponding to three peaks identified by affinity chromatography using TSKgel FcR-IIIA-NPR column (Tosoh, Japan) were quantified and the putative ADCC activity was estimated based on the ratio of area 3, which associates with highest ADCC activity, to the whole area (area 3 (%)). Mann-Whitney U-test, Kaplan-Meier methods and the log-rank test were conducted for statistical analyses using JMP Pro software (ver. 14.0). Results: Forty-two COPD and ninty-six NSCLC patients were registered in the study between Jan 2016 and May 2021 at Wakayama Medical University. Characteristics of the patients were as follows: median age, 70 (range, 49-91); male. 78%; smoker, 79%; previous treatment ≥1, 77%; performance status 0-1, 82%; stage IV, 69%; squamous/non-squamous/unknown, 29/69/2%; nivolumab/pembrolizumab/atezolizumab, 46/42/12%. The objective response rate was 25.0% (24/96). The median progression free survival (PFS) and median overall survival (OS) was 72 days (95%CI, 49 to 127) and 310 days (95% CI, 216 to 453), respectively. The area 3 (%) was significantly lower in NSCLC patients than both HVs and COPD patients (P=0.0002 and p Conclusion: Our results suggest that evaluation of the N-glycan moiety of IgG-Fc in peripheral blood has a potential as a prognostic biomarker in advanced NSCLC patients treated with ICIs. Citation Format: Jun Oyanagi, Yasuhiro Koh, Yasuyuki Akiyama, Atsushi Morimoto, Koichi Sato, Shunsuke Teraoka, Daichi Fujimoto, Nahomi Tokudome, Atsushi Hayata, Yuichi Ozawa, Hiroaki Akamatsu, Masanori Nakanishi, Hiroki Ueda, Nobuyuki Yamamoto. N-glycan moiety of IgG-Fc region is a prognostic biomarker for advancednon-small cell lung cancertreated with immune checkpoint inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 516.

Background: To overcome resistance to EGFR TKI osimertinib in EGFR-mutated lung cancer is critically needed. We performed a biomarker study utilizing serially collected plasma samples in a phase I study to investigate the safety and efficacy of the combination of osimertinib and afatinib in patients who failed osimertinib (jRCTs051180008), in which a total of 13 patients were enrolled and the overall response rate and the median progression-free survival were 7.7% and 2.4 months, respectively, to access the trajectory of the mutational landscape and its association with the efficacy. Methods: Peripheral blood samples were collected from the patients in K2 EDTA vacutainers (Becton Dickinson) before and four weeks after administration of the combination therapy and upon disease progression. Plasma was isolated immediately after the blood draw and stored at -80℃ until use. Cell-free DNA (cfDNA) was extracted from the plasma and used for next-generation sequencing library construction using AVENIO ctDNA Surveillance Kit (Roche Diagnostics) to assess genetic alterations in 197 cancer-related genes. Sequencing was performed on Nextseq500 system (Illumina) followed by mutation analyses using an Avenio Oncology Analysis Server (Roche Diagnostics). Results: Mutations in EGFR gene were detected in 10 out of 13 cfDNA samples (77%) including T790M/cis-C797S mutations before treatment and among those harboring T790M/cis-C797S mutations, 2 patients had progressive disease (PD) and 1 had stable disease (SD), indicating little benefit from the combination therapy in this genotype. Although other mutations in genes such as TP53 and/or KRAS were detected before treatment, no relevant associations were observed between tumor response or progression-free survival. One patient who had SD harbored CNTN5 mutation at PD, suggesting the potential involvement with the acquired resistance. Early emergence of EGFR G796S mutation observed in one patient after the initiation of the treatment along with basal L858R/T790M mutations may confer early resistance to the treatment. We also observed the emergence of MET amplification in 2 patients and ERBB2 amplification in 1 patient at PD, strongly suggesting the potential mechanisms responsible for resistance. Conclusions: This signal seeking biomarker study using cfDNA to better understand the association of mutational status and the treatment efficacy of the combined treatment was feasible and informative despite the small-scale study, supporting the advantage of further implementation. Citation Format: Yasuhiro Koh, Satoru Miura, Jun Oyanagi, Hiroshige Yoshioka, Koichi Azuma, Hidenobu Ishii, Kayoko Kibata, Kenichi Koyama, Shunsuke Teraoka, Yuichi Ozawa, Takaaki Tokito, Toshio Shimokawa, Takayasu Kurata, Nobuyuki Yamamoto, Hiroshi Tanaka. Longitudinal cell-free DNA analysis in phase I study evaluating afatinib in combination with osimertinib in patients who failed prior osimertinib treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5153.

Patients with NSCLC in East Asia, including Japan, frequently contain EGFR mutations. In 2018, we published the latest full clinical practice guidelines on the basis of those provided by the Japanese Lung Cancer Society Guidelines Committee. The purpose of this study was to update those recommendations, especially for the treatment of metastatic or recurrent EGFR-mutated NSCLC. We conducted a literature search of systematic reviews of randomized controlled and nonrandomized trials published between 2018 and 2019 that multiple physicians had reviewed independently. On the basis of those studies and the advice from the Japanese Society of Lung Cancer Expert Panel, we developed updated guidelines according to the Grading of Recommendations, Assessment, Development, and Evaluation system. We also evaluated the benefits of overall and progression-free survival, end points, toxicities, and patients' reported outcomes. For patients with NSCLC harboring EGFR-activating mutations, the use of EGFR tyrosine kinase inhibitors (EGFR TKIs), especially osimertinib, had the best recommendation as to first-line treatment. We also recommended the combination of EGFR TKI with other agents (platinum-based chemotherapy or antiangiogenic agents); however, it can lead to toxicity. In the presence of EGFR uncommon mutations, except for an exon 20 insertion, we also recommended the EGFR TKI treatment. However, we could not provide recommendations for the treatment of EGFR mutations with immune checkpoint inhibitors, including monotherapy, and its combination with cytotoxic chemotherapy, because of the limited evidence present in the literature. The 2020 Japanese Lung Cancer Society Guidelines can help community-based physicians to determine the most appropriate treatments and adequately provide medical care to their patients.

CD24, a heavily glycosylated glycosylphosphatidylinositol–anchored surface protein, inhibits phagocytosis as potently as CD47. The relationship between such anti‐phagocytic factors and the immune response with immune–checkpoint inhibitors (ICI) remains unexplored. We evaluated CD24 and CD47 tumor proportion scores (TPS) in 68 of the 106 patients with advanced non–small‐cell lung cancer who participated in a prospective observational study of ICI treatment. We also explored the impact of CD24 TPS and CD47 TPS on ICI efficacy and serum cytokine changes. CD24 positivity (TPS ≥ 1) was negatively associated with progression–free survival (PFS) of ICI when PD‐L1 TPS was, We evaluated tumor proportion score (TPS) of CD24 and CD47 in 68 patients with advanced, non–small‐cell lung cancer who participated in a prospective observational study for treatment with ICI, and we also explored the impact of CD24 TPS and CD47 TPS on the efficacy of ICI and serum cytokine alterations. CD24 positivity (TPS ≥ 1) was negatively associated with progression–free survival of ICI when PD‐L1 TPS

In the WJOG8815L phase II clinical study, we monitored EGFR mutation fractions (MFs) in the circulating tumor DNA (ctDNA) of EGFR T790M mutation‐positive patients with non‐small cell lung cancer (NSCLC) that received treatment with the tyrosine kinase inhibitor (TKI) osimertinib. The MF values of TKI‐sensitizing EGFR mutations in ctDNA at day 1 of cycle 4 of osimertinib treatment could predict osimertinib treatment outcomes., The WJOG8815L phase II clinical study involves patients with non‐small cell lung cancer (NSCLC) that harbored the EGFR T790M mutation, which confers resistance to EGFR tyrosine kinase inhibitors (TKIs). The purpose of this study was to assess the predictive value of monitoring EGFR genomic alterations in circulating tumor DNA (ctDNA) from patients with NSCLC that undergo treatment with the third‐generation EGFR‐TKI osimertinib. Plasma samples of 52 patients harboring the EGFR T790M mutation were obtained pretreatment (Pre), on day 1 of treatment cycle 4 (C4) or cycle 9 (C9), and at diagnosis of disease progression or treatment discontinuation (PD/stop). CtDNA was screened for EGFR‐TKI‐sensitizing mutations, the EGFR T790M mutation, and other genomic alterations using the cobas EGFR Mutation Test v2 (cobas), droplet digital PCR (ddPCR), and targeted deep sequencing. Analysis of the sensitizing—and T790M—EGFR mutant fractions (MFs) was used to determine tumor mutational burden. Both MFs were found to decrease during treatment, whereas rebound of the sensitizing EGFR MF was observed at PD/stop, suggesting that osimertinib targeted both T790M mutation‐positive tumors and tumors with sensitizing EGFR mutations. Significant differences in the response rates and progression‐free survival were observed between the sensitizing EGFR MF‐high and sensitizing EGFR MF‐low groups (cutoff: median) at C4. In conclusion, ctDNA monitoring for sensitizing EGFR mutations at C4 is suitable for predicting the treatment outcomes in NSCLC patients receiving osimertinib (Clinical Trial Registration No.: UMIN000022076).

BackgroundStudies have suggested that chemotherapy after immune checkpoint inhibitors may confer an improved response for non–small cell lung cancer (NSCLC). However, potential selection bias in such studies has not been addressed. We therefore applied propensity score analysis to investigate the efficacy of chemotherapy after PD-1 inhibitor treatment (CAP) compared with chemotherapy alone.MethodsWe conducted a retrospective observational cohort study for patients treated at 47 institutions across Japan between April 1, 2014 and July 31, 2017. Eligible patients had advanced or recurrent NSCLC who have undergone chemotherapy. Patients subsequently treated with chemotherapy (docetaxel with or without ramucirumab, S-1 or pemetrexed) either after PD-1 inhibitor therapy (CAP cohort) or alone (control cohort) were included. The primary end point was objective response rate (ORR). Inverse probability weighting (IPW) was applied to adjust for potential confounding factors.ResultsA total of 1439 patients (243 and 1196 in the CAP and control cohorts, respectively) was available for unadjusted analysis. Several baseline characteristics—including age, histology,EGFRorALKgenetic alterations, and brain metastasis—differed significantly between the two cohorts. After adjustment for patient characteristics with the IPW method, ORR was 18.9% for the CAP cohort and 11.0% for the control cohort (ORR ratio 1.71; 95% CI 1.19 to 2.46; p=0.004). IPW-adjusted Kaplan-Meier curves showed that median progression-free survival (PFS) for the CAP and control cohorts was 2.8 and 2.7 months (IPW-adjusted HR 0.95; 95% CI 0.80 to 1.12; p=0.55), and median overall survival (OS) was 9.2 and 10.4 months (IPW-adjusted HR 1.05; 95% CI 0.86 to 1.28; p=0.63), respectively.ConclusionsAfter accounting for selection bias by propensity score analysis, CAP showed a significantly higher ORR compared with chemotherapy alone, with the primary end point of ORR being achieved. However, these results did not translate into a PFS or OS advantage, suggesting that prior administration of PD-1 inhibitors may result in a synergistic antitumor effect with subsequent chemotherapy, but that such an effect is transient. CAP therefore does not appear to achieve durable tumor control or confer a lasting survival benefit.

Background Most patients with non–small-cell lung cancer (NSCLC) are ineligible for clinical trials. However, few studies have reported on the profiles and treatment outcomes for these patients. Therefore, we investigated the characteristics, outcomes, and survival of patients with advanced NSCLC who were ineligible for clinical trials. Materials and Methods We analyzed the data from a retrospective cohort of 786 consecutive patients with a diagnosis of advanced NSCLC. We reviewed the criteria of phase 1 to 3 clinical trials and classified patients according to the common first-line eligibility criteria for lung cancer. Results Of the 786 patients, 469 (60%) were ineligible for clinical trials. The main reasons for ineligibility were brain metastasis (41%), poor performance status (25%), and respiratory disease (24%). For all patients, ineligibility was identified as an independent predictor of overall survival (hazard ratio, 0.78; 95.0% confidence interval, 0.65-0.93; P = .008), even in those with a good performance status who had received chemotherapy (hazard ratio, 0.80; 95.0% confidence interval, 0.65-0.99; P = .037). In the subgroup analysis of ineligible patients, survival varied depending on the reasons for ineligibility. In particular, a history of cancer was not associated with a poor outcome, although this was a common reason for ineligibility. Conclusion Most patients were ineligible for clinical trials and had a shorter overall survival, although this varied depending on the reason for their ineligibility. These results should be considered when applying clinical trial outcomes to real-world patients. Further studies of ineligible patients are needed to improve the treatment decisions in clinical settings.

Introduction Nivolumab has demonstrated efficacy against metastatic NSCLC. Four programmed cell death ligand 1 (PD-L1) immunohistochemistry (IHC) assay systems are available for identification of responders among patients with NSCLC, and these assays show some differing characteristics. Accordingly, in this study, we evaluated the ability of these assays to identify responders to nivolumab therapy. Methods We retrospectively analyzed patients with previously treated advanced NSCLC, who received nivolumab between January 2016 and September 2016. Specimens were stained using four PD-L1 IHC assays (28-8, 22C3, SP142, and SP263). We classified patients as having test results that were strongly positive (tumor proportion score [TPS] ≥50%), weakly positive (TPS 1%–49%), or negative (TPS Results A total of 40 patients with NSCLC and their specimens were analyzed. Analytical comparisons demonstrated good concordance of PD-L1–stained tumor cells among the 28-8, 22C3, and SP263 assays (weighted κ coefficient 0.64–0.71), whereas the SP142 assay showed lower concordance with other assays (weighted κ coefficient 0.39–0.55). Progression-free survival in patients showing strongly positive PD-L1 staining classified by 28-8, 22C3, and SP263 assays was significantly longer than that in patients with a negative result for PD-L1 staining. Predictive performance of response to nivolumab, as assessed by receiver operating characteristic analysis, was also equivalent among the 28-8, 22C3, and SP263 assays (area under the curve 0.75–0.82), whereas the SP142 assay exhibited lower predictive performance (area under the curve 0.68). Conclusions The 28-8, 22C3, and SP263 PD-L1 IHC assays showed equivalent predictive performance, whereas the SP142 assay showed lower predictive performance.

Background: Structure of N-linked glycan in immunoglobulin G (IgG) fragment crystallizable (Fc) region is associated with antigen-dependent cellular cytotoxicity (ADCC) activity. Although it has been known that N-glycan moiety is different between healthy individuals and cancer patients, the relationship between the N-glycan structure and treatment response in cancer patients is unknown. Here, we evaluated the putative ADCC activity by the N-glycan moiety of IgG-Fc using peripheral blood and analyzed its association with clinical benefits from immune checkpoint inhibitors (ICIs) in patients with advanced non-small cell lung cancer (NSCLC). Patients and Methods: Advanced NSCLC patients received nivolumab, pembrolizumab or atezolizumab treatment until disease progression or unacceptable toxicity. Serum samples were collected at baseline. Tumor responses were classified into complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) based on RECIST v1.1. Durable clinical benefit (DCB) was defined as patients whose response was lasting over 6 months. Three IgG fractions (area 1, 2 and 3) corresponding to three peaks identified by affinity chromatography using TSKgel FcR-IIIA-NPR column (Tosoh, Japan) were quantified and the putative ADCC activity was estimated based on the ratio of area 3, which associates with highest ADCC activity, to the whole area. All statistical analyses were carried out using JMP Pro software (ver. 14.0). Mann-Whitney U-test was conducted. Time to event analysis was conducted using Kaplan-Meier methods and the log-rank test. Results: Ninety-seven patients were registered in the study between Jan 2016 and Nov 2018 at Wakayama Medical University. Characteristics of the patients were as follows: median age, 70 (range, 49-91); male. 78%; smoker, 79%; previous treatment ≥1, 77%; performance status 0-1, 82%; stage III/IV, 31/69%; squamous/non-squamous/unknown, 29/69/2%; nivolumab/pembrolizumab/atezolizumab, 46/42/12%. The objective response rate was 25.0% (24/96) and the disease control rate was 55.2% (53/96). The DCB rate was 45.4% (44/96). The median progression free survival (PFS) was 72 days (95%CI, 49 to 127) and median overall survival (OS) was 310 days (95% CI, 229 to 475). When time-to-event analysis was conducted by dividing into two groups at the median of the ratio of area 3 to the whole area, OS was significantly longer in patient with higher ratio than those with lower one in both entire cohort (median OS, 952 vs 482; 95% CI, 482 days-not reached and 233-744 days; log rank p=0.0292) and 2nd line cohort (median OS, 952 vs 292; 95% CI, 453 days-not reached and 120-692 days; log rank p=0.0010). Evaluation of IgG fraction was not associated with tumor response or PFS in this study cohort. Conclusion: Our results suggest that evaluation of the N-glycan moiety of IgG-Fc in peripheral blood has a potential as a prognostic biomarker in advanced NSCLC patients treated with ICIs. Citation Format: Jun Oyanagi, Yasuhiro Koh, Yasuyuki Akiyama, Atsushi Morimoto, Koichi Sato, Shunsuke Teraoka, Daichi Fujimoto, Nahomi Tokudome, Atsushi Hayata, Yuichi Ozawa, Hiroaki Akamatsu, Masanori Nakanishi, Hiroki Ueda, Nobuyuki Yamamoto. Clinical impact of evaluating serum IgG fractions in advanced non-small cell lung cancer treated with immune checkpoint inhibitors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P014.