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Background: Immune checkpoint inhibitors (ICIs) have been approved as first-line therapy for advanced non-small cell lung cancer (NSCLC). The probiotic MIYAIRI 588 can potentially improve the outcomes of patients with advanced NSCLC treated with ICI. However, the impact of other probiotics on ICI-treatment efficacy remains unclear. Thus, we aimed to clarify the association between BIO-three use and treatment outcomes in patients with advanced NSCLC treated with ICI. Methods: This retrospective study included patients aged ≥ 18 years with advanced or recurrent NSCLC who had received ICI monotherapy or ICI plus chemotherapy. Concomitant therapy with probiotic bacteria was defined as receiving it within 180 days before ICI therapy. Results: Here, 289 patients were enrolled, including 23 (8.0%) receiving BIO-three. In the multivariable analysis, the progression-free survival (PFS) and overall survival (OS) of patients receiving BIO-three tended to be longer than those of patients not receiving probiotic therapy (PFS, hazard ratio [HR] 0.75; 95% confidence interval [CI] 0.43–1.30; p = 0.33; OS, HR 0.69; 95% CI 0.37–1.28; p = 0.24). After propensity score matching with weighted adjustment, patients receiving BIO-three tended to have prolonged PFS (median PFS [range] 7.6 months [2.6–17.4] vs 3.2 months [1.6–7.0]; HR 0.53; 95% CI 0.25–1.12; p = 0.09) and OS (median OS [range] 25.6 months [10.8–not reached] vs 10.9 months [7.3–not reached]; HR 0.57; 95% CI 0.24–1.36; p = 0.20) than those not receiving probiotic therapy. Conclusion: This study suggests the prognostic impact of concomitant BIO-three use in patients with advanced NSCLC on ICI treatment. [ABSTRACT FROM AUTHOR]

The insulin-like growth factor 1 receptor (IGF1R) has been associated with growth and metastasis in various cancers. However, its role in postoperative recurrence and prognosis in lung cancer lacks clear consensus. Therefore, this study aimed to investigate the potential relationship between IGF1R and postoperative recurrence as well as long-term survival in a large cohort. Additionally, we assessed the relationship between IGF1R and programmed death ligand 1 (PD-L1) expression. Our study encompassed 782 patients with non-small cell lung cancer (NSCLC). Immunostaining of surgical specimens was performed to evaluate IGF1R and PD-L1 expression. Among the patients, 279 (35.8%) showed positive IGF1R expression, with significantly worse relapse-free survival (RFS) and overall survival (OS). Notably, no significant differences in RFS and OS were observed between IGF1R-positive and -negative groups in stages 2 and 3. However, in the early stages (0–1), the positive group displayed significantly worse RFS and OS. In addition, PD-L1 expression was detected in 100 (12.8%) patients, with a significant predominance in the IGF1R-positive. IGF1R may serve as a prognostic indicator and a guide for perioperative treatment strategies in early-stage lung cancer. In conclusion, our findings underscore an association between IGF1R expression and poor survival and PD-L1 expression in NSCLC. [ABSTRACT FROM AUTHOR]

The usefulness of the derived neutrophil-to-lymphocyte ratio (dNLR) and its dynamics before/after durvalumab consolidation therapy to predict safety or efficacy remains unclear. We retrospectively reviewed patients with locally advanced non-small cell lung cancer treated with durvalumab consolidation therapy after chemoradiotherapy (D group) or chemoradiotherapy alone (non-D group) at multiple institutions. We investigated the association between dNLR, or its dynamics, and pneumonitis, checkpoint inhibitor-related pneumonitis (CIP), irAEs, and efficacy. Ninety-eight and fifty-six patients were enrolled in the D and non-D groups, respectively. The dNLR at baseline was significantly lower in patients who experienced irAEs or CIP than in those who did not. The low dNLR group, 28 days following durvalumab consolidation therapy (dNLR28 ≤ 3), demonstrated longer progression-free survival (PFS) and overall survival (OS) than the high dNLR group (dNLR28 > 3) (PFS, hazard ratio [HR] 0.44, 95% confidence interval [CI] 0.22–0.88, p = 0.020; OS, HR 0.39, 95% CI 0.16–0.94, p = 0.037). Among patients with high dNLR at baseline (dNLR > 3), the dNLR28 ≤ 3 group showed longer PFS than the dNLR28 > 3 group (p = 0.010). The dNLR is a predictive factor for irAEs and CIP in patients receiving durvalumab consolidation therapy. The dNLR at 28 days after durvalumab consolidation therapy and its dynamics predict favorable outcomes. [ABSTRACT FROM AUTHOR]

Purpose: Krebs von den Lungen-6 (KL-6) functions as a tumor marker, as well as a diagnostic tool for interstitial pneumonia (IP). However, the significance of KL-6 in the immune-checkpoint inhibitor (ICI) treatment of non-small cell lung cancer (NSCLC), especially in patients without IP, is unknown. Methods: This multicenter, retrospective study, which included patients with advanced NSCLC who received ICI therapy, analyzed the association between serum KL-6 values and ICI efficacy and the association between serum KL-6 values and ICI-induced interstitial lung disease (ILD) occurrence, focusing primarily on patients without IP. Results: In total, 322 patients had available KL-6 values before ICI therapy. Among 202 patients without IP who received ICI monotherapy, the high-KL-6 group (≥ 500 U/mL) showed significantly shorter progression-free survival (PFS) and overall survival (OS) than the low-KL-6 group (< 500 U/mL) (median: 2.1 vs. 3.6 months, p = 0.048; median: 9.2 vs. 14.5 months, p = 0.035). There was no significant difference in response rate between the KL-6 high and low groups (19% vs. 29%, p = 0.14). In the multivariate analysis, high KL-6 was a significant predictor of poor PFS (hazard ratio [HR], 1.52; 95% confidence interval [CI] 1.10–2.11, p = 0.012) and OS (HR, 1.51; 95% CI 1.07 − 2.13, p = 0.019) for patients treated with ICI monotherapy. There was no significant difference in the occurrence rate of ILD between the high KL-6 and low KL-6 groups in patients with (20% vs. 15%, p = 1.00) or without IP (12% vs. 12%, p = 1.00). Conclusion: In ICI monotherapy for NSCLC without IP, elevated serum KL-6 levels were associated with poorer outcomes. [ABSTRACT FROM AUTHOR]

Background: Although vimentin is often expressed in non–small cell lung cancer (NSCLC), the association between vimentin expression and immune‐checkpoint inhibitor (ICI) efficacy remains unclear. Methods: This retrospective multicenter study enrolled patients with NSCLC who received ICI treatment between December 2015 and July 2020. The authors constructed tissue microarrays and performed immunohistochemical staining with vimentin. They analyzed the relationship between vimentin expression rate and objective response rate (ORR), progression‐free survival (PFS), and overall survival (OS). Results: Immunohistochemically evaluable specimens on microarray blocks were available for 397 patients, of whom 343 (86%) were negative (<10%), 30 (8%) were positive (10%−49%), and 24 (6%) were highly positive (≥50%) for vimentin expression. Both rates of programmed death‐ligand 1 (PD‐L1) tumor proportion score ≥1% and ≥50% were significantly higher in the vimentin‐positive group (≥10%) than the vimentin‐negative group (<10%) (96% vs. 78%, p =.004; 64% vs. 42%, p =.006, respectively). In patients treated with ICI monotherapy, ORR, PFS, and OS were significantly better in the vimentin‐positive group (10%−49%) than in the vimentin‐negative group (<10%) (54% vs. 25%, p =.003, median = 7.9 vs. 3.2 months, p =.011; median = 27.0 vs. 13.6 months, p =.015, respectively), whereas there was no significant difference in PFS and OS between the vimentin highly positive group (≥50%) and the vimentin‐negative group (<10%) (median = 3.4 vs. 3.2 months, p =.57; median = 7.2 vs. 13.6 months, p =.086, respectively). Conclusions: Vimentin expression correlated with PD‐L1 expression and ICI efficacy. Plain Language Summary: We constructed tissue microarrays and performed immunohistochemical staining with vimentin on 397 patients with advanced non–small cell lung cancer who were treated with immune‐checkpoint inhibitor (ICI).The vimentin‐positive group who were treated with ICI monotherapy showed significantly better objective response rate, progression‐free survival, and overall survival than the vimentin negative group.The measurement of vimentin expression will aid in determining appropriate immunotherapy strategies. Vimentin expression correlated with programmed death‐ligand 1 expression and immune checkpoint inhibitor efficacy. The measurement of vimentin expression will aid in determining appropriate immunotherapy strategies. [ABSTRACT FROM AUTHOR]

Background: Many previous studies have demonstrated that minor-frequency pretreatment T790M mutation (preT790M) could be detected by ultrasensitive methods in a considerable number of treatment-naïve, epidermal growth factor receptor (EGFR)-mutated, non-small cell lung cancer (NSCLC) cases. However, the impact of preT790M in resected cases on prognosis remains unclear.Methods: We previously reported that preT790M could be detected in 298 (79.9%) of 373 surgically resected, EGFR-mutated NSCLC patients. Therefore, we investigated the impact of preT790M on recurrence-free survival (RFS) and overall survival (OS) in this cohort by multivariate analysis. All patients were enrolled from July 2012 to December 2013, with follow-up until November 30, 2017.Results: The median follow-up time was 48.6 months. Using a cutoff value of the median preT790M allele frequency, the high-preT790M group (n = 151) had significantly shorter RFS (hazard ratio [HR] = 1.51, 95% confidence interval [CI]: 1.01-2.25, P = 0.045) and a tendency for a shorter OS (HR = 1.87, 95% CI: 0.99-3.55, P = 0.055) than the low-preT790M group (n = 222). On multivariate analysis, higher preT790M was independently associated with shorter RFS (high vs low, HR = 1.56, 95% CI: 1.03-2.36, P = 0.035), irrespective of advanced stage, older age, and male sex, and was also associated with shorter OS (high vs low, HR = 2.16, 95% CI: 1.11-4.20, P = 0.024) irrespective of advanced stage, older age, EGFR mutation subtype, and history of adjuvant chemotherapy.Conclusions: Minor-frequency, especially high-abundance of, preT790M was an independent factor associated with a poor prognosis in patients with surgically resected, EGFR-mutated NSCLC. [ABSTRACT FROM AUTHOR]

Background: Platinum-based chemoradiotherapy is the standard treatment for unresectable stage III non-small-cell lung cancer (NSCLC). However, few studies have evaluated the efficacy of subsequent chemotherapy for relapsed NSCLC following platinum-based chemoradiotherapy. This study aimed to evaluate the efficacy of platinum-doublet chemotherapy as a second-line treatment for patients with unresectable stage III NSCLC.Methods: We retrospectively evaluated patients with unresectable stage III NSCLC treated with cytotoxic chemotherapy following platinum-based chemoradiotherapy who were registered in a nationwide registry NSCLC database. Patients were divided into the platinum-doublet chemotherapy (platinum) group and single-agent chemotherapy (non-platinum) group based on the type of second-line chemotherapy.Results: The platinum group (n = 119) showed significantly better overall survival (OS) than the non-platinum group (n = 201) (median OS: 21.5 vs. 10.5 months, hazard ratio [HR]: 0.54, 95% confidence interval [CI]: 0.40-0.73, p < 0.001). OS from the beginning of chemoradiotherapy was also significantly better in the platinum group than in the non-platinum group (median OS: 34.9 vs. 21.8 months, HR: 0.58, 95% CI: 0.43-0.79, p = 0.001). In the multivariate analysis, platinum-doublet chemotherapy as second-line therapy, female sex, clinical stage IIIA, and duration of ≥ 8.6 months from the beginning of first-line therapy to the beginning of second-line therapy were associated with significantly better OS.Conclusion: Platinum-doublet chemotherapy as a second-line therapy may prolong survival in unresectable stage III NSCLC patients following platinum-based chemoradiotherapy. Thus, re-administration of platinum agents may be a promising treatment for unresectable stage III NSCLC treated with platinum-based chemoradiotherapy. [ABSTRACT FROM AUTHOR]

Background: To report the follow up data and clinical outcomes of the JME study (UMIN 000008177), a prospective, multicenter, molecular epidemiology examination of 876 surgically resected non‐small‐cell lung cancer (NSCLC) cases, and the impact of somatic mutations (72 cancer‐associated genes) on recurrence‐free survival (RFS) and overall survival (OS). Methods: Patients were enrolled between July 2012 and December 2013, with follow up to 30th November 2017. A Cox proportional hazards model was used to assess the impact of gene mutations on RFS and OS, considering sex, smoking history, age, stage, histology, EGFR, KRAS, TP53, and number of coexisting mutations. Results: Of 876 patients, 172 had ≥2 somatic mutations. Median follow‐up was 48.4 months. On multivariate analysis, number of coexisting mutations (≥2 vs 0 or 1, HR = 2.012, 95% CI: 1.488‐2.695), age (≥70 vs <70 years, HR = 1.583, 95% CI: 1.229‐2.049), gender (male vs female, HR = 1.503, 95% CI: 1.045‐2.170) and pathological stage (II vs I, HR = 3.386, 95% CI: 2.447‐4.646; ≥III vs I, HR = 6.307, 95% CI: 4.680‐8.476) were significantly associated with RFS, while EGFR mutation (yes vs no, HR = 0.482, 95% CI: 0.309‐0.736), number of coexisting mutations (≥2 vs 0 or 1, HR = 1.695, 95% CI: 1.143‐2.467), age (≥70 vs <70 years, HR = 1.932, 95% CI: 1.385‐2.726), and pathological stage (II vs I, HR = 2.209, 95% CI: 1.431‐3.347; ≥III vs I, HR = 5.286, 95% CI: 3.682‐7.566) were also significant for OS. Conclusion: A smaller number of coexisting mutations, earlier stage, and younger age were associated with longer RFS and OS, while EGFR mutations were significantly associated with improved OS. [ABSTRACT FROM AUTHOR]

Objectives Non-small cell lung cancer (NSCLC) and chronic obstructive pulmonary disease (COPD) have been proposed to have a mutual developmental mechanism, but their association has not been fully understood. We aimed to examine the association of the mutational landscape of NSCLC with co-morbid COPD. Materials and methods A total of 197 surgical specimens of early stage NSCLC were retrospectively collected from two independent sources, namely, the Japan Molecular Epidemiology for Lung Cancer Study and the Osaka City University Hospital cohort from 2010 to 2013. COPD and its severity were defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines and grading system. For molecular profiling of NSCLC patients with COPD, the extracted DNAs were deep-sequenced using next generation sequence technologies for somatic mutations in a maximum 72 cancer-associated genes. Logistic regression analysis was performed to evaluate the impact of COPD on the somatic mutations. Results The COPD group (n = 77), including 56 GOLD 1 and 21 GOLD 2 or 3 patients, had 58 squamous cell lung carcinoma (SCC) cases and 19 adenocarcinoma cases. The non-COPD group (n = 120) had 53 SCC cases, 64 adenocarcinoma cases, and three cases with other histology. The frequency of PIK3CA mutation was significantly higher in the COPD group than in the non-COPD group (10.4% vs. 1.7%, p = 0.015). Meanwhile, NFE2L2 mutation was observed only in SCC cases, with no difference in the frequency between the two groups (17.2% vs. 17.0%). In the multivariate logistic regression model with consideration for COPD status, age, smoking dose, pathological stage, and histology, significantly more PIK3CA mutation was observed in the presence of COPD (odds ratio = 5.31, 95% CI: 1.03–27.29, p = 0.046). Conclusions PIK3CA mutation is a distinctive genetic feature of NSCLC with COPD, regardless of age, smoking dose, pathological stage, and histology. [ABSTRACT FROM AUTHOR]

• Droplet digital polymerase chain reaction was able to detect low-frequency pretreatment T790M. • There existed a threshold of pretreatment T790M having impact on EGFR-TKIs efficacy. • High abundance of pretreatment T790M correlated to shorter PFS on EGFR-TKIs. • Pre-existing T790M may not necessarily confer T790M-mediated resistance to EGFR-TKIs. Low-frequency epidermal growth factor receptor (EGFR) T790M mutation could be detected by ultrasensitive methods in EGFR tyrosine kinase inhibitor (TKI)-naïve non-small cell lung cancer (NSCLC). However, the impact of pretreatment T790M (preT790M) on the efficacy of EGFR-TKIs and on resistance remains unclear. Two independent cohorts consisting of advanced EGFR-mutated NSCLC patients treated with first-line EGFR-TKIs, a derivation cohort that started treatment between August 2013 and July 2016 (cohort A, n = 44) and a validation cohort between August 2016 and December 2017 (cohort B, n = 22), were examined in this study. Among these, 28 patients underwent re-biopsy at disease progression. DNAs from pretreatment tumor biopsy samples and re-biopsy samples were assessed to detect T790M by the Cobas EGFR Mutation Test v2 (Cobas) and for quantitating T790M by droplet digital polymerase chain reaction (ddPCR). Detection rates of preT790M were 40.9% (18/44) in cohort A and 45.5% (10/22) in cohort B by ddPCR, and none by Cobas. A cutoff value of 0.3% for dividing into high- vs. low-preT790M allele frequency was determined by receiver operating characteristic curve analysis in cohort A. Progression-free survival (PFS) was significantly shorter in the high- preT790M group (n = 12) than in the low-preT790M (n = 6) and negative (n = 26) groups (combined low-preT790M) (median: 6.9 vs. 13.8 months, P = 0.00073). These observations were validated in cohort B [median: 6.2 (n = 5) vs. 15.3 months (n = 17), P = 0.0029]. In 28 paired biopsies, Cobas detected post-progression T790M in 60% (3/5) of the high-preT790M, in 57% (4/7) of the low-preT790M, and in 56% (9/16) of the negative-preT790M groups. EGFR -mutated NSCLC with high preT790M had significantly shorter PFS on EGFR-TKIs. However, preT790M abundance may not necessarily confer post-TKI T790M resistance. [ABSTRACT FROM AUTHOR]

Purpose Patients with advanced non-small cell lung cancer (NSCLC) harboring a sensitive epidermal growth factor receptor (EGFR) mutation have been shown to exhibit a marked response to EGFR-tyrosine kinase inhibitor (TKI) treatment. Pemetrexed and gefitinib were reported to have a schedule-dependent cytotoxic synergism. We evaluated the efficacy and safety of a combination regimen of gefitinib and pemetrexed as first-line chemotherapy in EGFR-mutated NSCLC patients. Patients and methods Systemic therapy-naïve patients with advanced non-squamous NSCLC harboring a sensitive EGFR mutation were included in this study. Pemetrexed was administered on day 1 at a dose of 500 mg/m 2 , and gefitinib was sequentially administered on days 2–16. This treatment regimen was repeated every 3 weeks until disease progression. Results Twenty-six patients were enrolled in this study. The median number of treatment cycles was 16 (range, 1–35). The overall response rate (ORR) was 84.6% (95% confidence interval [CI], 70.7–98.5%), and the disease control rate (DCR) was 96.2% (95% CI, 88.9–100%). Grade 3/4 hematological toxicities included neutropenia (15.4%), leukopenia (7.7%), and anemia (3.8%). No grade 4 non-hematological toxicities were observed. The main grade 3 non-hematological toxicities were infection (11.5%), increased alanine aminotransferase (11.5%) and aspartate aminotransferase (7.7%) levels, fatigue (3.8%), diarrhea (3.8%), and pneumonitis (3.8%). We observed a median progression-free survival (PFS) of 18.0 months (95% CI, 15.0–21.0 months) and a median survival time (MST) of 32.0 months (95% CI, 28.5–35.5 months). There were no treatment-related deaths. Conclusions The combination regimen used in this study showed a high ORR, long median PFS, and acceptable toxicity. A future randomized trial on pemetrexed plus gefitinib compared with gefitinib alone is warranted. [ABSTRACT FROM AUTHOR]