8081 Background: Concurrent chemoradiotherapy (CCRT) followed by prophylactic cranial irradiation (PCI) is potentially curative for limited-stage small-cell lung cancer (LS-SCLC), yet reliable markers for identifying long-term survivors remain undefined. The Enhanced Assessment for SCLC Treatment (EAST) score was originally derived from a retrospective, single-center training cohort for prognostic stratification of LS-SCLC patients receiving CCRT. This score integrates N3 status, serum lactate dehydrogenase (LDH), pro-gastrin-releasing peptide (ProGRP), and cytokeratin 19 fragment (CYFRA 21-1) levels measured at diagnosis. This study (JCOG2401A) validated its prognostic utility using data from two randomized controlled trials (RCTs) of LS-SCLC. Methods: The validation cohort comprised patients enrolled in JCOG0202 and JCOG1011: randomized phase 3 and 2 studies, respectively, that compared multiple consolidation chemotherapy regimens following CCRT. External validation of the dichotomized EAST score (low: score 0–1, high: 2–5) was performed by assessing discrimination and calibration for progression-free survival (PFS) and overall survival (OS). Exploratory subgroup analyses were conducted in an integrated cohort of the training cohort (N = 224; median follow-up, 64.5 months) and the validation cohort. Hazard ratios (HRs) for PCI were estimated using propensity score-weighted Cox models. Results: Out of 309 patients in these trials, 205 with complete data for EAST score components were included in the validation cohort. Median age was 62 years. Low- vs. high-risk groups showed stage (I-II/III) distributions of 28/72% vs. 11/89%, and tumor response (CR-PR/SD) distributions of 89/3% vs. 91/2%, respectively. The low-risk group (N = 114) showed better outcomes than the high-risk group (N = 91) for both PFS and OS (Table). Integrated cohort analysis revealed a numerical survival benefit from PCI in low-risk patients (N = 214), whereas the benefit was highly limited in the high-risk group (N = 202) (Table). Conclusions: The prognostic value of the EAST score was validated even in external RCT datasets. High-risk patients, characterized by early recurrence and inferior OS, derive minimal benefit from PCI. These findings provide a rationale for a planned risk-adapted RCT utilizing the EAST score. Median PFS, months PFS, HR (95% CI) Median OS, months OS, HR (95% CI) Low- vs. high-risk Training cohort (N=107/117) 20.6/9.4 0.48 (0.34-0.67) 53.0/34.2 0.67 (0.46-0.98) Validation cohort (N=114/91) 25.0/10.7 0.55 (0.40-0.77) 63.2/29.6 0.51 (0.36-0.73) PCI vs. no-PCI All (N=287/129) 14.5/12.9 0.91 (0.65-1.28) 50.0/35.5 0.78 (0.56-1.10) Low risk (N=152/62) 31.3/14.6 0.86 (0.49-1.48) 67.9/40.1 0.75 (0.43-1.31) High risk (N=135/67) 10.2/10.6 0.99 (0.71-1.39) 34.2/30.9 0.86 (0.59-1.28)

8573 Background: Pembrolizumab is a standard 1st line treatment for advanced non–small cell lung cancer (NSCLC) with high PD-L1 expression (tumor proportion score [TPS] ≥50%); however, durable benefit is achieved in only a subset of patients. Prior pembrolizumab-based combination strategies (e.g., anti-TIGIT) have inconsistently improved outcomes over pembrolizumab monotherapy in this setting. Epidermal growth factor receptor (EGFR) signaling may promote immune evasion by stabilizing PD-L1 expression and shaping an immunosuppressive tumor microenvironment, providing a rationale for combining the anti-EGFR antibody necitumumab with pembrolizumab. We therefore evaluated the efficacy and safety of necitumumab plus pembrolizumab in treatment-naive patients with PD-L1–high advanced NSCLC. Methods: K-TAIL-202 (jRCT2031200248) was an open-label, multicenter, single-arm phase II study conducted in Japan. Eligible patients were aged ≥20 years with unresectable stage III/IV or recurrent NSCLC, PD-L1 TPS ≥50% (22C3), ECOG PS 0–1, and ≥1 measurable lesion. Patients received necitumumab 800 mg IV on days 1 and 8 plus pembrolizumab 200 mg IV on day 1 every 3 weeks for up to 35 cycles or until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed objective response rate (ORR) per RECIST v1.1; secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. The study assumed an expected ORR of 54.8% and a threshold ORR of 39.0% (one-sided α = 0.10; 80% power), requiring enrollment of 50 patients. Results: Between December 2020 and March 2023, 50 patients were enrolled (median age, 72 years). The ORR was 68.0% (95% CI, 53.3–80.5) and the disease control rate was 78.0% (95% CI, 64.0–88.5). Complete response, partial response, stable disease, progressive disease, and not evaluable status were observed in 2.0%, 66.0%, 10.0%, 12.0%, and 10.0% of patients, respectively, meeting the primary endpoint. Median PFS was 16.0 months (95% CI, 9.0–24.0), with a 24-month PFS rate of 35.9%. Median OS was not attained (95% CI, 38.0 months–not estimable), and the 24-month OS rate was 71.3%. The most treatment-emergent adverse events included acneiform dermatitis (66.0%), hypomagnesemia (60.0%), and pneumonitis (12.0%). One grade 5 cardiac arrest occurred in 1 patient (2.0%), for which a causal relationship to study treatment could not be ruled out. Conclusions: At final analysis, first-line necitumumab plus pembrolizumab demonstrated durable antitumor activity and encouraging long-term survival as a chemotherapy-free regimen in patients with PD-L1–high advanced NSCLC. Toxicities were consistent with the known profiles of EGFR-targeted antibodies and PD-1 inhibitor therapy, underscoring the need for careful monitoring. These findings warrant further confirmation in a randomized phase III clinical trial. Clinical trial information: jRCT2031200248.

BACKGROUND:Radiation-induced esophagitis (RE) is common during thoracic radiotherapy for NSCLC. We assessed its clinical impact and developed a model to predict grade ≥ 2 acute RE in patients with unresectable stage III NSCLC undergoing concurrent chemoradiotherapy, using the Japan Lung Cancer Society integrated phase II-III database. METHODS:We retrospectively analyzed clinical and laboratory data from 1288 patients across 8 randomized trials (1999-2016). We evaluated associations between RE and survival outcomes and identified predictors of grade ≥ 2 acute RE using LASSO regression. RESULTS:Grade 2 RE occurred in 15% and grade 3 in 2.0%. Grade ≥ 2 RE was not significantly associated with progression-free survival (PFS; HR 0.98, 95% confidence interval [CI] 0.72-1.34) or overall survival (OS; HR 1.20, 95% CI 0.82-1.75). Grade ≥ 3 RE was significantly associated with worse PFS (HR 1.62, 95% CI 1.12-2.35) but not with OS (HR 1.22, 95% CI 0.58-2.60). Eight variables independently predicted grade ≥ 2 RE: female sex, T stage < 4, N3 status, adenocarcinoma histology, primary tumor in the left upper lobe, cisplatin use, white-blood-cell count < 11 × 109/L, and hemoglobin ≤ 12 g/dL. The model achieved a c-statistic of 0.85 (95% CI, 0.81-0.88). CONCLUSION:In this national clinical-trial cohort, grade ≥ 2 RE was not associated with worse OS, but grade ≥ 3 RE was associated with worse PFS in patients receiving concurrent chemoradiotherapy for unresectable stage III NSCLC. The 8-variable model provides a practical tool for predicting grade ≥ 2 RE and may facilitate tailored supportive care.

Introduction Pulmonary sarcomatoid carcinoma (PSC) is a rare, aggressive variant of non-small cell lung cancer (NSCLC) related to emerging evidence of high programmed death-ligand 1 (PD-L1) expression, although its reported prevalence varies widely. We conducted a systematic review and meta-analysis to quantify the pooled prevalence of PD-L1 expression in PSC and identify factors associated with its variability. Methods We searched PubMed, Web of Science, and the Cochrane Library up to November 2025. Studies reporting PD-L1 expression via the tumor proportion score (TPS) in confirmed PSC (≥10 patients) were included. Random-effects meta-analysis was performed at TPS ≥ 50% and TPS ≥ 1% thresholds. Subgroup analyses and meta-regression explored sources of heterogeneity. This study was registered with PROSPERO (CRD420251243606). Results Thirty-four studies encompassing up to 1,789 patients were included. The pooled prevalence of high PD-L1 expression (TPS ≥ 50%) was 57.33%, and PD-L1 positivity (TPS ≥ 1%) was 79.61%. At TPS ≥ 50%, non-Asian studies showed a numerically higher prevalence than Asian studies, although this difference was not statistically significant. Higher ever-smoker proportion and 100% pleomorphic carcinoma composition were each associated with significantly higher prevalence at TPS ≥ 1%. In meta-regression, no covariate reached statistical significance at TPS ≥ 50%, whereas the proportion of pleomorphic carcinoma, ever-smokers, and median age were significant predictors at TPS ≥ 1%. Conclusions PD-L1 expression is remarkably prevalent in PSC, substantially exceeding conventional NSCLC. These findings may inform immunotherapy decision-making for advanced PSC.

8541 Background: Concomitant medications that alter gut microbiome composition, such as proton pump inhibitors (PPIs) and antibiotics, have been suggested as possible modifiers of immune checkpoint inhibitor outcomes; however, there is a paucity of prospective data with pre-specified exposure windows during atezolizumab-bevacizumab-carboplatin-paclitaxel (ABCP) treatment. This study investigated the associations between peri-initiation PPI/antibiotic exposure and gut microbiota with clinical outcomes. Methods: K-TAIL-201 is a prospective, single-arm, phase II study (jRCT031200088) that enrolled Japanese patients with previously untreated advanced non-squamous non-small cell lung cancer (NSCLC) who received an induction ABCP regimen, followed by maintenance with atezolizumab plus bevacizumab. The primary endpoint was six-month progression-free survival (PFS) rate. PPI/antibiotic exposure was evaluated in two pre-specified windows: pre-treatment (up to 21 days before ABCP) and early on-treatment (the first 21 days of treatment). Longitudinal fecal samples were collected and analyzed using 16S rRNA gene sequencing. Exploratory analyses were conducted to investigate the relationships between exposure/microbiota features and outcomes. Results: Thirty-two patients were enrolled, with a median follow-up period of 20.6 months. The 6-month PFS rate was 59.4% (95% confidence interval (CI), 40.6–76.3), objective response rate was 50.0% (95% CI, 31.9–68.2), median PFS was 7.1 months (95% CI, 5.9–9.6), and the median overall survival (OS) was 24.3 months (95% CI, 18.7–not reached). Early on-treatment PPI exposure was associated with poorer outcomes, including shorter PFS (hazard ratio [HR] 7.07, p < 0.001) and OS (HR 5.66, p = 0.009), whereas pre-treatment PPI exposure was not associated with PFS of at least six months. Early on-treatment antibiotic exposure was associated with a lower 6-month PFS rate (21% versus 89%, p < 0.001), but showed no association with time-to-event PFS (HR 1.62, p = 0.41). Microbiota analyses revealed no significant differences in alpha or beta diversity by outcome or exposure group. However, Bifidobacterium was more frequently detected among responders. Conclusions: Early on-treatment (but not pre-treatment) PPI exposure is strongly associated with inferior PFS and OS in patients with advanced non-squamous NSCLC on ABCP regimen, supporting the clinical relevance of exposure timing. These findings suggest careful PPI use during the induction phase and warrant validation in larger prospective cohorts. Clinical trial information: 031200088.

PURPOSE:This study investigated the efficacy and safety of pembrolizumab and necitumumab as first-line therapy for patients with advanced non-small-cell lung cancer (NSCLC) who had ≥50% programmed death-ligand 1 (PD-L1) expression. PATIENTS AND METHODS:This nonrandomized, multicenter, open-label, single-arm phase II trial included patients with previously untreated advanced NSCLC who had a PD-L1 tumor proportion score of ≥50%. Patients received pembrolizumab and necitumumab every 3 weeks for up to 35 cycles. The primary endpoint was the investigator-assessed objective response rate (ORR). The secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. RESULTS:The sample comprised 50 patients (38 men, 12 women; median age: 72 years, range: 51-90 years). The ORR was 76.0% (95% confidence intervals: 61.9-86.9; P < 0.0001), with complete and partial response rates of 2.0% and 74.0%, respectively. Moreover, 10.0% and 8.0% of the patients had stable and progressive disease, respectively, whereas 6.0% could not be evaluated. The median PFS was 15.7 months, whereas the median OS was not reached at the time of analysis. The most common treatment-related adverse events were rash (64.0%) and hypomagnesemia (60.0%). Grade 3 interstitial lung disease occurred in five patients (10.0%), and grade 5 cardiac arrest occurred in one patient (2.0%). CONCLUSIONS:The pembrolizumab and necitumumab combination exhibited a promising ORR of 76.0% with a manageable safety profile in patients with NSCLC who had high PD-L1 expression. These findings highlight the need for further research on this regimen for patients with advanced NSCLC who have high PD-L1 expression.

Abstract Introduction The systemic immune-inflammation index (SII) has emerged as a promising prognostic marker in various malignancies. However, its prognostic significance in patients with small-cell lung cancer (SCLC) treated with immune checkpoint inhibitors (ICIs) remains unclear. In this study, we evaluated the prognostic impact of the SII in patients with SCLC after ICI use. Methods Of 62 patients with SCLC who received chemoimmunotherapy at our institution between September 2019 and July 2024, we retrospectively analyzed 36 patients who subsequently received ICI maintenance therapy following the initial chemoimmunotherapy treatment. The SII was calculated at the start of the second cycle of the ICI maintenance therapy. Patients were stratified into high (≥ 570) and low (< 570) SII groups. Overall survival (OS) and progression-free survival (PFS) were compared between the groups using the Kaplan–Meier method and log-rank test. Multivariate analysis using the Cox proportional hazards model was performed to identify independent prognostic factors. Results The high SII group exhibited a significantly shorter OS (median 12.1 vs. 24.1 months, P = 0.010) and PFS (median 5.2 vs. 8.1 months, P = 0.026) than those in the low SII group. A multivariate analysis identified SII ≥ 570 as an independent negative prognostic factor for OS (hazard ratio 3.83, 95% confidence interval 1.38–10.6, P = 0.010). Conclusions Elevated SII in the initial phase of ICI maintenance therapy was associated a with poor prognosis in patients with SCLC, supporting its utility as a prognostic biomarker in this setting. Therefore, prospective validation is required to confirm these findings.

No study has directly compared the outcomes of surgery and concurrent chemoradiotherapy (cCRT) in patients with stage III non-small cell lung cancer (NSCLC) to date. This study aimed to compare the treatment efficacy of complete resection and definitive cCRT. Patients were recruited in this retrospective study from Yokohama Municipal Citizens’ Hospital between January 2013 and December 2022. We analyzed patients with pathological stage III NSCLC who underwent complete surgical resection and those with clinical stage III NSCLC who underwent definitive cCRT. Propensity score matching was performed to balance baseline clinicopathological factors, and the prognoses of patients in each treatment group were examined using Cox proportional hazards regression. Of the 923 patients with NSCLC who underwent surgery, 97 with pathologic stage III NSCLC underwent complete resection (surgery group) and 125 with clinical stage III NSCLC underwent cCRT (cCRT group), of whom 54 (43.2

Aspiration pneumonia is one of the most severe complications associated with near-drowning and is referred to as drowning-associated pneumonia (DAP). Inhaled water may be contaminated by various pathogens, thereby facilitating DAP development. The causative organisms of DAP differ from those of community-acquired pneumonia, with Gram-negative bacilli being predominant. We herein report an 83-year-old Japanese man with chronic kidney disease who presented to the emergency department after a near-drowning episode. His oxygen saturation level was 86% despite receiving oxygen via a 10 L/min reservoir mask. He was admitted to the intensive-care unit, where high-flow nasal cannula therapy (50 L/min with an FiO2 of 1.0) was initiated. His respiratory condition gradually improved, and he was transferred to the general ward. However, on day 10 of hospitalization, the patient developed a fever. Chest computed tomography (CT) revealed a new cavity in the right upper lobe, which was suggestive of a lung abscess. Ceftriaxone was initiated but was ineffective. Sputum culture on day 10 revealed Pseudomonas aeruginosa, and cefepime was subsequently administered. His fever resolved, and follow-up CT on day 23 showed marked improvement in the cavity and surrounding consolidation. Due to suspected cefepime-induced acute kidney injury, the antibiotics were switched to moxifloxacin, and the patient was discharged on hospital day 28. Following macroaspiration events, clinicians should evaluate the risk of pneumonia and likely pathogens. In patients who develop pneumonia after near-drowning, empirical coverage of Gram-negative organisms, including P. aeruginosa, should be considered.

Background/Aim: Survival outcomes in patients with successfully resected non-small-cell lung cancer (NSCLC) are not well understood. Furthermore, the best treatment strategy for postoperative locoregional recurrence has not been established. Patients and Methods: Patients who underwent R0 resection of NSCLC between 2013 and 2022 were retrospectively reviewed. The survival after recurrence was analyzed by categorizing patients into locoregional and distant recurrence groups. Moreover, the efficacy of salvage local therapy including radiotherapy (RT) and concurrent chemoradiotherapy (cCRT) was evaluated in terms of progression-free-survival (PFS), overall survival (OS), and safety. Results: Of the 694 patients who underwent R0 surgery, 150 were diagnosed with postoperative recurrence consisting of 54 cases of locoregional and 96 of distant recurrence. The median OS was 55.9 and 22.3 months in the locoregional and distant recurrence groups, respectively [hazard ratio (HR)=0.52; 95% confidence interval (CI)=0.32-0.84; p<0.001]. In the multivariate analysis, distant recurrence, negative oncogenic driver-mutation, and male sex were identified as independent predictors of a poor prognosis. Of the 54 patients with locoregional recurrence, local therapy was administered to 48 comprising 30 cases of cCRT and 18 of RT alone. The median PFS and OS were 13.3 and 60.4 months, respectively. Regarding adverse events, two cases (4.2%) of grade >= 3 radiation pneumonitis occurred. Conclusion: The OS of patients with locoregional recurrence of NSCLC was significantly better than that of patients with distant recurrence. Salvage local therapy, including cCRT and RT, may be an effective option for the treatment of locoregional recurrence due to its superior PFS, OS, and tolerability.

Abstract Background Cold agglutination syndrome is a subtype of autoimmune hemolytic anemia. The condition is referred to as “cold” because the antibodies become active and induce hemolysis at cold temperatures, typically 3–4 °C, which is not always the case in other kinds of autoimmune hemolytic anemia. Whereas primary cold agglutination syndrome may occur in the absence of underlying conditions, secondary cold agglutination syndrome is associated with the presence of underlying infections, including coronavirus disease 2019. Case presentation We report the case of a 69-year-old Japanese woman with periodontitis who was referred to our hospital with complaints of brown-colored urine and chest pain. Her hemoglobin level was 6.1 g/dL. Computed tomography revealed multiple lung abscesses. Her direct antibody test results were positive (2+) for anti-complement direct antiglobulin and negative for immunoglobulin G, and her cold agglutinin titer was elevated at 1:4096. Workup for anemia revealed a positive result for cold agglutination syndrome. The patient had received the fourth dose of coronavirus disease 2019 vaccination. Nasopharyngeal swab test for detecting severe acute respiratory syndrome coronavirus 2 using a real-time reverse-transcription polymerase chain reaction gave a cycle threshold value of 42.3, and the level of virus-specific immunoglobulin G was elevated at 7.71 S/C (normal range −1.4 S/C). Conclusion A decrease in hemoglobin in patients with coronavirus disease 2019 may be associated with secondary cold agglutination syndrome. The patient was hypothesized to have developed multiple lung abscesses with secondary cold agglutination syndrome following coronavirus disease 2019. Thus, following coronavirus disease 2019, patients can develop secondary cold agglutination syndrome, which could worsen owing to associated bloodstream bacterial infections.

Abstract Background: Pembrolizumab is the standard of care for advanced non-small cell lung cancer (NSCLC) with high programmed death-1 ligand 1 (PD-L1) expression. However, combination therapies comprising pembrolizumab and ipilimumab, tiragolumab, or lenvatinib have not demonstrated superior efficacy in this patient group. This study explored the effectiveness of the novel combination of pembrolizumab and necitumumab as first-line therapy in patients having advanced NSCLC with PD-L1 expression of 50% or higher. Methods: Patients with untreated advanced NSCLC with PD-L1 expression of 50% or higher received pembrolizumab and necitumumab every 3 weeks up to 35 cycles. The primary endpoint was investigator-assessed objective response rate (ORR), and the secondary endpoints were progression-free survival (PFS), overall survival (OS), and adverse events. The sample size was calculated using 80% power with a one-sided alpha error of 10%, a threshold ORR of 39.0%, and an expected ORR of 54.8%. Results: From December 2020 to March 2023, 50 patients were enrolled. Patient characteristics were as follows: male/female patients: 38/12; median age: 72 years (range: 51-90 years); histology, adenocarcinoma/squamous cell carcinoma/other: 35/15/5; and PS, 0/1: 20/30. At the time of the primary analysis, the ORR was 76.0% (95% CI: 61.9%-86.9%), with 2.0%, 74.0%, 10.0%, and 8.0% of the patients showing complete response, partial response, stable disease, and progressive disease, respectively. The median PFS was 15.7 months (95% CI, 10.3 to not reached) and the median OS was not reached. Common toxicities included rash (86%) and hypomagnesemia (60%). Grade 3 interstitial lung disease was noted in 5 patients (10%) and grade 5 cardiac arrest in 1 patient (2%). Conclusion: Combination therapy comprising pembrolizumab and necitumumab demonstrated a 76.0% ORR, meeting the primary endpoint, with manageable toxicities. The regimen showed promising clinical activity in patients with NSCLC and high PD-L1 expression, warranting further investigation. Clinical trial ID: jRCT2031200248. Citation Format: Atsushi Horiike, Hiroshi Wakui, Shunichi Sugawara, Yuji Minegishi, Sadatomo Tasaka, Sojiro Kusumoto, Toshio Sakatani, Hiroyuki Suzuki, Yukio Hosomi, Yuichi Tambo, Tsuneo Shimokawa, Hiroo Ishida, Eisaku Miyauchi, Katsuhiko Naoki, Tatsuro Fukuhara, Emiko Mura, Toshiaki Tsurui, Risako Suzuki, Nana Iriguchi, Tomoyuki Ishiguro, Yuya Hirasawa, Ryo Manabe, Masahiro Shimokawa, Ryotaro Ohkuma, Hirotsugu Ariizumi, Yutaro Kubota, Kazuyuki Hamada, Sachiko Takenoshita, Kakei Ryu, Takehiko Sambe, Eisuke Inoue, Satoshi Wada, Kiyoshi Yoshimura, Hironori Sagara, Shinichi Kobayashi, Takuya Tsunoda. Promotive clinical effects of pembrolizumab with necitumumab in patients having advanced non-small cell lung cancer with PD-L1 expression of 50% or higher in a phase II study (K-TAIL-202) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT032.

Durvalumab consolidation after chemoradiotherapy for stage III non-small cell lung cancer (NSCLC) has become the standard of care. Single-center results were examined for treatment outcomes and patterns of pneumonitis in clinical practice. Patients with stage III NSCLC who underwent chemoradiotherapy at our institution (n = 150) were included. The patients were treated with chemoradiotherapy and durvalumab consolidation (Group D, n = 69) or chemoradiotherapy alone (Group N, n = 81). The overall survival (OS), progression-free survival (PFS), and the incidence of and risk factors for 12-month pneumonitis grade ≥ 2 (G2) were investigated. Two-year OS rates were 71.6% in Group D and 52.7% in Group N (p = 0.052). Two-year PFS rates were 43.0% in Group D and 26.5% in Group N (p = 0.010), although a propensity score matched analysis showed no significant difference. The incidence of 12-month pneumonitis ≥ G2 tended to be higher in Group D than in Group N (41.9% vs. 26.3%, p = 0.080). However, there was no difference in pneumonitis ≥ G3 rates (10.5% vs. 12.6%, p = 0.657). A multivariate analysis showed that the lung volume spared from 5 Gy (VS5) < 1800 cm3 was a risk factor for pneumonitis ≥ G2 in Group D. Durvalumab consolidation showed the potential to prolong PFS without increasing the severity of pneumonitis.

BACKGROUND:Bevacizumab with platinum doublet therapy including paclitaxel + carboplatin improves the survival of patients with non-squamous non-small cell lung cancer. However, in a previous trial (CA031), paclitaxel + carboplatin led to Grade > 3 neutropenia in a Japanese population. Nanoparticle albumin-bound paclitaxel exhibits an improved toxicity profile. We evaluated the safety, dosage and response rate of the nanoparticle albumin-bound paclitaxel + carboplatin + bevacizumab combination in a Japanese population. METHODS:Chemotherapy-naive patients with advanced non-squamous non-small cell lung cancer were included. The dosage schedule was established in the Phase I trial as follows: 4-6 cycles of carboplatin (area under the concentration-time curve = 6 on Day 1) + nanoparticle albumin-bound paclitaxel (100 mg/m2 on Days 1, 8 and 15) + bevacizumab (15 mg/kg on Day 1), followed by maintenance therapy (nanoparticle albumin-bound paclitaxel + bevacizumab). The response rate and presence of adverse effects were evaluated in the Phase II trial. RESULTS:The overall response rate was 56.5% (90% confidence interval: 44.5-68.5), and 93% of patients (43/46) showed tumor shrinkage or maintained a stable disease course. The primary endpoint was achieved. At the median follow-up duration of 42 months, the median overall survival was 18.9 (range: 10.5-32.4) months. The most frequently observed Grade ≥ 3 adverse effects were neutropenia (72%), leukopenia (50%) and anemia (30%). CONCLUSIONS:All adverse effects were manageable and none resulted in patient death. In conclusion, the nanoparticle albumin-bound paclitaxel + carboplatin + bevacizumab combination is favorable and well tolerated in Japanese patients as first-line treatment for advanced non-squamous non-small cell lung cancer.

Abstract Background The relationship between epidermal growth factor receptor tyrosine kinase inhibitor (EGFR‐TKI) resistance, including osimertinib, and programmed cell death‐ligand 1 (PD‐L1) expression status in EGFR‐mutated non‐small cell lung carcinoma (NSCLC) remains unclear. Patients and Methods We retrospectively analyzed 64 patients with unresectable advanced or metastatic NSCLC carrying EGFR exon 19 deletions (ex19del) or EGFR exon 21 L858R substitutions (L858R) who received osimertinib as the first‐line treatment. We compared progression‐free survival (PFS) between eligible patients with PD‐L1 tumor proportion scores (TPS) ≥20% and PD‐L1 TPS <20% using the Kaplan–Meier survival plots with a log‐rank test. Multivariate analysis was performed to examine the poor prognostic factors of PFS. Results The PD‐L1 TPS ≥20% group included 22 cases (median [range] age: 70.5 [33–86] years; 10 women [45.5%]; 11 current or ex‐smokers [50%]); ECOG performance status (PS) of 0–1/2/3/4 was noted in 16/4/1/1 patients, respectively. The PD‐L1 TPS <20% group included 42 patients (median [range] age 73 [43–88] years; 29 women [69%]; 12 current or ex‐smokers [28.6%]); ECOG PS of 0–1/2/3/4 was noted in 33/6/3/0 cases, respectively. The median PFS was 9.1 and 28.1 months in the PD‐L1 TPS ≥20% and PD‐L1 TPS <20% groups, respectively (log‐rank p = 0.013). Multivariate analysis revealed that PD‐L1 TPS ≥20% was associated with PFS (hazard ratio: 2.35, 95% confidence interval: 1.09–5.08, p = 0.030). Conclusion PD‐L1 TPS ≥20% in patients with EGFR‐mutated NSCLC may be associated with early resistance to osimertinib.

Supplementary Figure from A Randomized Comparison of Nivolumab versus Nivolumab + Docetaxel for Previously Treated Advanced or Recurrent ICI-Naïve Non–Small Cell Lung Cancer: TORG1630

Objectives: Cisplatin plus irinotecan has been considered as the standard therapy in younger (<70 years old) patients for extensive-disease small-cell lung cancer (ED-SCLC) in Japan. However, there is a lack of high-quality evidence for the use of irinotecan in elderly patients with ED-SCLC. This study aimed to demonstrate that car-boplatin plus irinotecan (CI) improves overall survival (OS) in elderly patients with ED-SCLC.Materials and methods: This was a randomized Phase II/III trial which enrolled elderly patients with ED-SCLC. Patients were randomized to the CI or carboplatin plus etoposide (CE) arm in a 1:1 ratio. The CE group intra-venously received carboplatin (AUC 5 mg/ml/min on day 1) and etoposide (80 mg/m2 on days 1-3) every 3 weeks for four cycles. The CI group received carboplatin (AUC 4 mg/ml/min on day 1) and irinotecan (50 mg/m2 on days 1 and 8) intravenously every 3 weeks for 4 cycles.Results: In total, 258 patients were enrolled and randomized (CE arm, 129 patients; CI arm, 129 patients). The median overall survival, progression-free survival, and objective response rate of the CE vs. CI arms were 12.0 (95% CI, 9.3-13.7) vs. 13.2 (95% CI, 11.1-14.6) months (HR, 0.85 (95% CI, 0.65-1.11)) (one-sided P = 0.11), 4.4 (95% CI, 4.0-4.7) vs. 4.9 (95% CI, 4.5-5.2) months (HR, 0.85 (95% CI, 0.66-1.09)), and 59.5% vs. 63.2%, respectively. A higher incidence of myelosuppression was observed in the CE group, whereas a higher incidence of gastrointestinal toxicity was observed in the CI group. Three treatment-related deaths occurred (one due to lung infection in the CE arm, and one due to lung infection and sepsis each in the CI arm).Conclusions: The CI treatment showed favorable efficacy; however, the difference was not statistically significant. These results suggest that CE should remain as the standard chemotherapy regimen for elderly patients with ED-SCLC.

Platinum and etoposide (ETP) combined with PD-L1 inhibitor is considered the first-line treatment for extensive-stage small cell lung cancer (ES-SCLC). However, reports on this regimen in combination with immune checkpoint inhibitors (ICIs) in the elderly are lacking. We evaluated the efficacy and safety of carboplatin (CBDCA)/ETP/ICI combination therapy for patients with ES-SCLC aged ≥ 71, in our hospital.

Introduction C-ros oncogene 1 (ROS1) translocation is an oncogenic driver-mutation identified in 1% to 2% of non-small-cell lung cancer (NSCLC) cases. Although crizotinib, a tyrosine kinase inhibitor (TKI) against ALK/ROS1, is known to be effective against ROS1-fusion-positive NSCLC, such cases sometimes progress with brain metastases. The most frequently reported crizotinib-resistance mutation is ROS1 G2032R, and some studies have found that even newly developed ROS1 TKIs, such as entrectinib and lorlatinib, show a decreased efficacy against it. The optimal therapies for ROS1-fusion-positive NSCLC and how such cases can be sequenced have not yet been established. Case Presentation We herein report a patient with ROS1-fusion-positive NSCLC diagnosed at 34 years old. Crizotinib was started at the diagnosis and switched after 25 months to cisplatin/pemetrexed/bevacizumab once the disease progressed with multiple brain metastases that were resistant to stereotactic radiation therapy. The cytotoxic chemotherapy stabilized the patient’s condition for 17 months until he developed leptomeningeal metastasis (LM). He underwent lumboperitoneal shunting and whole-brain radiotherapy, followed by crizotinib re-administration. Despite crizotinib treatment, his neurologic symptoms, such as double vision, headache, weakness in the legs, and walking difficulties, progressed. Eventually, subsequent entrectinib treatment was initiated, which resolved all of the symptoms mentioned above. Regrettably, liquid next-generation sequencing (NGS) had failed to detect the resistance mechanism due to minimal ctDNA in this case. Conclusion These findings imply that sequential entrectinib administration may be effective in patients with disease progression limited to central nervous system metastases during crizotinib administration.