Comparison of SP263 and 22C3 pharmDx assays to test programmed death ligand-1 (PD-L1) expression in surgically resected non-small cell lung cancer.

BACKGROUND: Atezolizumab, one of the immune checkpoint inhibitors, has been approved as an adjuvant treatment following resection and platinum-based chemotherapy in patients with stage II-IIIA non-small cell lung cancer with 1% or more programmed death ligand-1 (PD-L1) expression. The Food and Drug Administration (FDA) has approved SP263 as a companion diagnostic assay for adjuvant treatment with atezolizumab; however, in clinical practice, the 22C3 assay is most commonly used for advanced non-small cell lung cancer. Therefore, our study aimed to compare two PD-L1 assays, SP263 and 22C3, to evaluate whether 22C3 could replace SP263 when deciding whether to administer adjuvant atezolizumab. METHODS: We retrospectively and prospectively analyzed 98 patients who underwent surgical resection at Kanagawa Cancer Center (Japan). An immunohistochemistry assay was performed for all the cases with both SP263 and 22C3. We statistically analyzed the concordance of PD-L1 expression between SP263 and 22C3 assays. RESULTS: The concordance between the two assays using Cohen's kappa was κ = 0.670 (95% CI: 0.522-0.818) at the 1% cutoff and κ = 0.796 (95% CI: 0.639-0.954) at the 50% cutoff. The Spearman correlation coefficient of 0.874 (p < 0.01) indicated high concordance. PD-L1 expression with 22C3 resulted slightly higher than that with SP263. CONCLUSIONS: This study showed a high concordance of PD-L1 expression with the SP263 and 22C3 assays. Further studies examining the therapeutic effects of adjuvant atezolizumab are required.

Comparison between next-generation sequencing and multiplex polymerase chain reaction assays for nonsmall-cell lung cancer molecular diagnosis.

PURPOSE: Genetic mutation detection has become an important step in nonsmall-cell lung cancer (NSCLC) treatment because of the increasing number of drugs that target genomic rearrangements. A multiplex test that can detect multiple gene mutations prior to treatment is thus necessary. Currently, either next-generation sequencing (NGS)-based or polymerase chain reaction (PCR)-based tests are used. We evaluated the performance of the Oncomine Dx Target Test (ODxTT), an NGS-based multiplex biomarker panel test, and the AmoyDx Pan Lung Cancer PCR Panel (AmoyDx PLC panel), a real-time PCR-based multiplex biomarker panel test. MATERIALS AND METHODS: Patients with histologically diagnosed NSCLC and a sufficient sample volume to simultaneously perform the AmoyDx PLC panel and ODxTT-M were included in the study. The success and detection rates of both tests were evaluated. RESULTS: Biopsies revealed 116 cases of malignancies, 100 of which were NSCLC. Of these, 59 met the inclusion criteria and were eligible for analysis. The success rates were 100% and 98% for AmoyDx PLC panel and ODxTT-M, respectively. Nine driver mutations were detected in 35.9% and 37.3% of AmoyDx PLC and ODxTT-M panels, respectively. EGFR mutations were detected in 14% and 12% of samples using the AmoyDx PLC panel and ODxTT-M, respectively. Of the 58 cases in which both NGS and AmoyDx PLC panels were successful, discordant results were observed in seven cases. These differences were mainly due to different sensitivities of the detection methods used and the gene variants targeted in each test. DISCUSSION: The AmoyDx PLC panel, a PCR-based multiplex diagnostic test, exhibits a high success rate. The frequency of the nine genes targeted for treatment detected by the AmoyDx PLC panel was comparable to the frequency of mutations detected by ODxTT-M. Clinicians should understand and use the AmoyDx PLC panel and ODxTT-M with respect to their respective performances and limitations.

A single arm Phase I/II trial on the combination of carboplatin, nab-paclitaxel and avastin as first-line treatment for advanced non-squamous non-small cell lung cancer (TORG1424/OLCSG1402: CARNAVAL).

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.

Symptomatic Pneumonitis With Durvalumab After Concurrent Chemoradiotherapy in Unresectable Stage III NSCLC.

Introduction: In the placebo-controlled, phase 3 PACIFIC trial, durvalumab significantly prolonged progression-free survival (PFS) (p < 0.0001) and overall survival (OS) (p = 0.00251) in patients with unresectable stage III NSCLC and no progression after platinum-based concurrent chemoradiotherapy (cCRT). Pneumonitis or radiation pneumonitis (PRP) was common in both arms. We report exploratory analyses evaluating the association of symptomatic (grade ≥2) PRP (G2+PRP) with baseline factors and clinical outcomes. Methods: Patients with WHO performance status of 0 or 1 were randomized (2:1) to 12 months of durvalumab or placebo, 1 to 42 days after cCRT. Associations between baseline factors and on-study G2+PRP in durvalumab-treated patients were investigated using univariate and multivariate logistic regression. PFS and OS were analyzed using Cox proportional hazards models adjusted for time-dependent G2+PRP plus covariates for randomization stratification factors without and with additional baseline factors. Results: On-study G2+PRP occurred in 94 of 475 (19.8%) and 33 of 234 patients (14.1%) on durvalumab and placebo, respectively (median follow-up, 25.2 mo); grade greater than or equal to 3 PRP was uncommon (4.6% and 4.7%, respectively). Time to onset and resolution of G2+PRP was similar with durvalumab and placebo. Univariate and multivariate analyses identified patients treated in Asia, those with stage IIIA disease, those with performance status of 1, and those who had not received induction chemotherapy as having a higher risk of G2+PRP. PFS and OS benefit favoring durvalumab versus placebo was maintained regardless of time-dependent G2+PRP. Conclusions: Factors associated with higher risk of G2+PRP with durvalumab after cCRT were identified. Clinical benefit was maintained regardless of on-study G2+PRP, suggesting the risk of this event should not deter the use of durvalumab in eligible patients with unresectable stage III NSCLC.

Artemis: A Multicenter, Open-Label, Single-Arm, Phase II Study to Evaluate the Efficacy and Safety of First-Line Carboplatin/Paclitaxel/Lenvatinib/Pembrolizumab Combination for Previously Untreated Advanced or Recurrent Thymic Carcinomas.

BACKGROUND: Thymic carcinoma is a rare cancer with an aggressive clinical presentation and no organotypic symptoms. Despite using platinum-based chemotherapy as first-line treatment, the prognosis remains poor, necessitating a novel therapeutic strategy. METHODS: The artemis trial is a Phase II, single-arm, multicenter study designed to evaluate the efficacy and safety of carboplatin, paclitaxel, lenvatinib, and pembrolizumab as first-line chemotherapy for patients with advanced or recurrent thymic carcinoma. A total of 35 patients will be enrolled in this study and will receive induction therapy every 3 weeks for up to 4 cycles, followed by pembrolizumab every 3 weeks, and daily lenvatinib as maintenance therapy for up to 31 cycles (for 2 years). Lenvatinib will be continued until disease progression or unacceptable toxicity based on the discretion of the attending physician. CONCLUSION: The primary endpoint of the study is the objective response rate, with secondary endpoints including progression-free survival, overall survival, duration of response, disease control rate, and safety profile. TRIAL REGISTRATION: ClinicalTrials.gov NCT05832827 Registered on April 27, 2023, https://classic. CLINICALTRIALS: gov/ct2/show/NCT05832827. Japan Registry of Clinical Trials (jRCT), jRCT2031230114. Registered on May 22, 2023, https://jrct.niph.go.jp/latest-detail/jRCT2031230114.

Phase II Study of the Liposomal Formulation of Eribulin (E7389-LF) in Combination with Nivolumab: Results from the Small Cell Lung Cancer Cohort.

PURPOSE: E7389-LF is a liposomal formulation of eribulin that contributes to tumor vascular remodeling. The phase II part of this phase Ib/II study assessed the efficacy/safety of E7389-LF in combination with nivolumab in several disease cohorts; herein, we report results from the small cell lung cancer (SCLC) cohort. EXPERIMENTAL DESIGN: Patients with unresectable/measurable SCLC and disease progression with first-line platinum-based chemotherapy with/without an immune checkpoint inhibitor (ICI) were enrolled to receive E7389-LF 2.1 mg/m2 plus nivolumab 360 mg intravenously every 3 weeks. The primary objective of this part was to assess the objective response rate (ORR). Secondary objectives included assessments of safety and progression-free survival (PFS); exploratory assessments included overall survival (OS) and biomarkers. RESULTS: Thirty-four patients were enrolled. By the data cut-off date (May 31, 2022), 29 (85.3%) had discontinued. Efficacy/biomarker analyses included 33 patients (1 had their diagnosis changed postenrollment); the ORR of E7389-LF plus nivolumab was 24.2% [95% confidence interval (CI): 11.1-42.3], the median PFS was 3.98 months (95% CI: 2.63-4.40), and, at a median follow-up of 10.6 months, the median OS was not reached (95% CI: not estimable). Notably, 27 of 33 patients (81.8%) had received an ICI as their prior first-line therapy. Treatment-related, treatment-emergent adverse events occurred in 97.1% (any grade) and 82.4% (grade ≥3) of enrolled patients; the most common event was neutropenia. Changes in vascular and immune-related plasma markers were observed. CONCLUSIONS: E7389-LF 2.1 mg/m2 in combination with nivolumab 360 mg every 3 weeks showed notable antitumor activity as second-line therapy for SCLC; no new safety signals were observed compared with either agent as monotherapy. SIGNIFICANCE: This phase II part of a phase Ib/II study assessed liposomal eribulin (E7389-LF) plus nivolumab in 34 patients with pretreated SCLC; 8 of 33 evaluable patients (including 6/27 pretreated with ICIs) had objective responses. The combination was tolerable; increases in vasculature-related biomarkers tended to correlate with responses.

Phase II Study of Durvalumab Immediately after Completion of Chemoradiotherapy in Unresectable Stage III Non-small Cell Lung Cancer: TORG1937 (DATE Study).

PURPOSE: Concurrent chemoradiotherapy (CCRT) followed by durvalumab consolidation for up to 12 months is the standard of care for patients with unresectable stage III non-small cell lung cancer (NSCLC). However, exactly when to initiate durvalumab therapy after chemoradiation completion remains unknown. We evaluated the efficacy and safety of durvalumab, administered immediately after CCRT completion, for patients with unresectable stage III NSCLC. PATIENTS AND METHODS: This study was a prospective, single-arm, open-label phase II clinical trial. Patients without disease progression after definitive CCRT (two cycles of platinum-based doublet chemotherapy with 60 Gy/30 Fr radiotherapy) received durvalumab (every 2 weeks for up to 12 months) from the next day (up to 5 days) after the final radiation dose. The primary endpoint was the 1-year progression-free survival (PFS) from registration before the start of CCRT. RESULTS: From January 2020 to August 2020, 47 of 50 enrolled patients were evaluable for treatment efficacy and safety. The 1-year PFS from registration was 75.0% [60% confidence interval (CI), 69.0-80.0 and 95% CI, 59.4-85.3]. The objective response rate throughout the study treatment and median PFS from registration were 78.7% and 14.2 months (95% CI, 13.4 to not reached), respectively. Grade 3/4 pneumonitis and febrile neutropenia were each 4.3%. CONCLUSIONS: Our study met the primary endpoint. The incidence of pneumonitis was similar to that of a Japanese subset in the PACIFIC study. Our data support the efficacy and safety of durvalumab administered immediately after the completion of CCRT for patients with unresectable stage III NSCLC.

Mutation profile and programmed death ligand 1 status of patients with non-small cell lung cancer diagnosed with "adenocarcinoma" and "non-small cell carcinoma favor adenocarcinoma".

BACKGROUND: The terminology for lung cancer diagnosis in small biopsies was adopted in the 2015 World Health Organization classification. If non-small cell lung cancer (NSCLC) has no clear adenocarcinoma (AD) or squamous cell carcinoma morphology, the tumor is further classified based on mucin or immunohistochemical staining as NSCLC favor AD (NFAD), NSCLC favor squamous cell carcinoma, or NSCLC not otherwise specified. Since this new term was defined, the difference between AD and NFAD has not yet been fully explored. This study aimed to examine the differences in clinical background, gene alteration frequency, and programmed death ligand 1 (PD-L1) expression. METHODS: We included patients diagnosed with AD or NFAD with small samples, and who underwent testing with the Oncomine Dx target test between August 2019 and April 2023 in Kanagawa Cancer Center. RESULTS: This study comprised 268 patients. A total of 96 patients underwent surgery after AD or NFAD diagnosis. The clinical stage was more advanced and pathological N0 was lower in NFAD than in AD. The pathology of the surgical specimens revealed that solid predominant AD was significantly more common in NFAD than in AD (p < 0.001). In both AD and NFAD, EGFR mutation was the most frequent gene alteration, followed by KRAS mutation. The frequency of EGFR mutations was significantly higher in AD than in NFAD. PD-L1 expression was significantly higher in NFAD than in AD (p < 0.001). CONCLUSION: This study shows a clear difference between AD and NFAD in terms of cancer progression, pathological features of the main tumor, genetic characteristics, and PD-L1 expression.

Prospective observational study to explore genes and proteins predicting efficacy and safety of brigatinib for ALK-gene rearranged non-small-cell lung cancer: study protocol for ABRAID study (WJOG11919L).

Background: ALK-tyrosine kinase inhibitors (ALK-TKIs) are effective for treating non-small-cell lung cancer with ALK gene rearrangement; however, resistance is inevitable. Brigatinib is a unique ALK-TKI that is effective against many resistance mutations. However, data on factors associated with its efficacy and resistance mechanisms are limited. Objectives: This study will evaluate the efficacy and safety of brigatinib in the real world and explore factors related to its efficacy, safety, and resistance mechanisms. Design: Prospective observational study. Ethics: This study is approved by the Ethics Committee of Wakayama Medical University. Written informed consent will be obtained from all patients before study-related procedures. Methods and analysis: This study comprises three cohorts. Cohorts A, B, and 0 will enroll patients receiving alectinib as the first ALK-TKI, receiving alectinib as the first ALK-TKI and subsequently cytotoxic agents and/or lorlatinib after alectinib, and without a history of ALK-TKI, respectively. Overall, 100, 30, and 50 patients will be enrolled in Cohorts A, B, and 0, respectively. Circulating tumor DNA before starting brigatinib and at disease progression will be analyzed in all cohorts using a hypersensitive next-generation sequencing (NGS) PGDx Elio plasma resolve panel. Serum protein levels will be analyzed using the Milliplex xMAP assay system with a Luminex 200 (Luminex, Austin, USA). The enrollment period is 31 months and the patients will be observed for 2 years after enrollment. Archived tissues will be collected for NGS analysis, gene expression analysis, and immunohistochemistry staining 1 year after completion of registration. Quality of life and safety evaluation using electronic patient-reported outcomes will be investigated. Discussion: This study will elucidate predictors of ALK-TKI efficacy and resistance mechanisms and evaluate the efficacy and safety of brigatinib in a real-world setting. The results will provide crucial information for establishing treatment strategies, discovering novel biomarkers, and developing new therapeutic agents. Trial registration: UMIN000042439.

First-Line Osimertinib for Previously Untreated Patients With NSCLC and Uncommon EGFR Mutations: The UNICORN Phase 2 Nonrandomized Clinical Trial.

Importance: Non-small cell lung cancer (NSCLC) with uncommon EGFR mutations is a rare subgroup, composing 14% of all EGFR mutations. Objective: To determine the usefulness of osimertinib in previously untreated patients with metastatic NSCLC harboring uncommon EGFR mutations, excluding exon 20 insertion mutations. Design, Setting, and Participants: This multicenter, open-label, single-group, phase 2 nonrandomized clinical trial enrolled patients from April 10, 2020, to May 31, 2022, with a follow-up of 6 months from the date the last patient was enrolled. The study enrolled 42 patients with uncommon EGFR mutations, of whom 40 were eligible. Intervention: Osimertinib, 80 mg once daily, was administered orally to patients. Main Outcomes and Measures: The primary end point was the overall response rate (ORR). The secondary end points were disease control rate (DCR), progression-free survival (PFS), time to treatment failure (TTF), overall survival (OS), duration of response (DoR), and safety of osimertinib. Patients were included in the study on an intention-to-treat basis. Results: Of the 40 eligible patients, 22 were men (55.0%) and the median age was 72 years (range, 39.0-88.0 years). The most common mutations were G719X (20 [50.0%]), S768I (10 [25.0%]), and L861Q (8 [20.0%]). The ORR was 55.0% (90% CI, 40.9%-68.5%) and the DCR was 90.0% (95% CI, 76.3%-97.2%). The median PFS was 9.4 months (95% CI, 3.7-15.2 months) after a median follow-up of 12.7 months (range, 2.7-30.7 months). The median TTF was 9.5 months (95% CI, 5.6-30.3 months), median OS was not reached (NR; 95% CI, 19.3 months to NR), and median DoR was 22.7 months (95% CI, 9.5 months to NR). The ORR for patients with solitary or compound uncommon EGFR mutations was 45.5% (90% CI, 26.9%-65.3%) and 66.7% (90% CI, 43.7%-83.7%), respectively. Median PFS for patients with solitary or compound uncommon EGFR mutations was 5.4 months (95% CI, 3.6-22.7 months) and 9.8 months (95% CI, 5.1 months to NR), respectively. Median OS for patients with solitary or compound uncommon EGFR mutations was 23.0 months (95% CI, 12.3 months to NR) and NR, respectively. Median DoR for patients with solitary or compound uncommon EGFR mutations was 22.7 months (95% CI, 3.6-22.7 months) or NR (95% CI, 5.7 months to NR), respectively. Grade 3 or 4 adverse events were reported by 11 patients (27.5%), and 5 patients (12.5%) developed interstitial lung disease. All adverse events were manageable, and there were no treatment-related deaths. Conclusions and Relevance: Osimertinib showed clinical activity with manageable toxic effects among previously untreated patients with metastatic NSCLC harboring uncommon EGFR mutations other than exon 20 insertion mutations. The results support the use of osimertinib as a treatment option for this patient population. Trial Registration: Japan Registry of Clinical Trials Identifier: jRCTs071200002.

Continuation of osimertinib in EGFR-mutant non-small-cell lung cancer patients bearing CNS metastasis (EPONA study).

The patients harboring EGFR-mutated non-small-cell lung cancer, treated with EGFR tyrosine kinase inhibitor will lead to longer survival than those having non-small-cell lung cancer (NSCLC) patient who do not harbor EGFR mutations. This ongoing clinical trial is to investigate the secondary chemoprevention effect of osimertinib from CNS with platinum doublets chemotherapy in patients who had progressive disease outside of CNS lesions. The aim of this randomized, phase II trial is to evaluate platinum and pemetrexed chemotherapy followed by pemetrexed maintenance with or without continuation of osimertinib for secondary CNS prevention in patients with brain metastatic NSCLC with EGFR mutation, with other than CNS lesions, but no progressive disease in the CNS lesion after osimertinib. The primary end point is to assess progression-free survival by investigator assessment. The key secondary end points are overall survival, response rate, time to CNS controlling, time to whole-brain irradiation and safety. Clinical trial registration: Japan Registry of Clinical Trials (jRCT), Japan (jRCTs071200029).

The authors are conducting a clinical trial aimed at improving treatment for individuals diagnosed with non-small-cell lung cancer, a specific type of lung cancer. In some cases, this cancer can spread to the brain. This study focuses on patients whose cancer is stable in the brain but progressing in other parts of the body. The study is comparing two different treatment approaches. One involves a combination of two drugs, platinum and pemetrexed, while the other combines these drugs with a third one called osimertinib. The main objective is to determine if continuing osimertinib treatment benefits these patients. The authors are evaluating the time it takes for the cancer to start growing again, known as progression-free survival, to identify the most effective treatment. Progression-free survival represents the duration that patients live without their disease worsening. This study, the EPONA study, will provide valuable insights into optimizing the treatment of this type of cancer.

Efficacy of osimertinib for lung squamous cell carcinoma with de novo EGFR T790M-positive: Case report and literature review.

Among epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancers, squamous cell carcinoma is less common and shows lower responsiveness to first-generation EGFR tyrosine kinase inhibitors (TKIs) compared to adenocarcinoma. However, the efficacy of osimertinib for squamous cell carcinoma with EGFR mutations is not well known. This study reports the case of a 57-year-old male diagnosed as having stage IIIC squamous cell lung cancer. Oncomine Dx Target Test identified EGFR exon19 deletion and de novo EGFR T790M mutation with variant allele frequencies (VAF) of 21.6% and 25.2%, respectively. The patient was treated with osimertinib after progression on chemoradiotherapy followed by durvalumab, and a partial response was maintained for more than 20 months. To predict EGFR-TKI efficacy, confirmation of gene mutations and VAF using next-generation sequencing is helpful.

Machine learning for prediction of immunotherapeutic outcome in non-small-cell lung cancer based on circulating cytokine signatures.

BACKGROUND: Immune checkpoint inhibitor (ICI) therapy has substantially improved the overall survival (OS) in patients with non-small-cell lung cancer (NSCLC); however, its response rate is still modest. In this study, we developed a machine learning-based platform, namely the Cytokine-based ICI Response Index (CIRI), to predict the ICI response of patients with NSCLC based on the peripheral blood cytokine profiles. METHODS: We enrolled 123 and 99 patients with NSCLC who received anti-PD-1/PD-L1 monotherapy or combined chemotherapy in the training and validation cohorts, respectively. The plasma concentrations of 93 cytokines were examined in the peripheral blood obtained from patients at baseline (pre) and 6 weeks after treatment (early during treatment: edt). Ensemble learning random survival forest classifiers were developed to select feature cytokines and predict the OS of patients undergoing ICI therapy. RESULTS: Fourteen and 19 cytokines at baseline and on treatment, respectively, were selected to generate CIRI models (namely preCIRI14 and edtCIRI19), both of which successfully identified patients with worse OS in two completely independent cohorts. At the population level, the prediction accuracies of preCIRI14 and edtCIRI19, as indicated by the concordance indices (C-indices), were 0.700 and 0.751 in the validation cohort, respectively. At the individual level, patients with higher CIRI scores demonstrated worse OS [hazard ratio (HR): 0.274 and 0.163, and p<0.0001 and p=0.0044 in preCIRI14 and edtCIRI19, respectively]. By including other circulating and clinical features, improved prediction efficacy was observed in advanced models (preCIRI21 and edtCIRI27). The C-indices in the validation cohort were 0.764 and 0.757, respectively, whereas the HRs of preCIRI21 and edtCIRI27 were 0.141 (p<0.0001) and 0.158 (p=0.038), respectively. CONCLUSIONS: The CIRI model is highly accurate and reproducible in determining the patients with NSCLC who would benefit from anti-PD-1/PD-L1 therapy with prolonged OS and may aid in clinical decision-making before and/or at the early stage of treatment.

Clinical roles of soluble PD-1 and PD-L1 in plasma of NSCLC patients treated with immune checkpoint inhibitors.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) have significantly improved the prognosis of non-small cell lung cancer (NSCLC). However, only a limited proportion of patients can benefit from this therapy, and clinically useful predictive biomarkers remain to be elucidated. METHODS: Blood was collected from 189 patients with NSCLC before and six weeks after the initiation of ICI treatment (anti-PD-1 or anti-PD-L1 antibody). Soluble PD-1 (sPD-1) and PD-L1 (sPD-L1) in plasma before and after treatment were analyzed to evaluate their clinical significance. RESULTS: Cox regression analysis demonstrated that higher sPD-L1 levels before treatment significantly predicted unfavorable progression-free survival (PFS; HR 15.4, 95% CI 1.10-86.7, P = 0.009) and overall survival (OS; HR 11.4, 95% CI 1.19-52.3, P = 0.007) in NSCLC patients treated with ICI monotherapy (n = 122) but not in those treated with ICIs combined with chemotherapy (n = 67: P = 0.729 and P = 0.155, respectively). In addition, higher sPD-1 levels after treatment were significantly associated with better OS (HR 0.24, 95% CI 0.06-0.91, P = 0.037) in patients treated with anti-PD-1 monotherapy, whereas higher sPD-L1 levels after treatment were significantly associated with worse PFS (HR 6.09, 95% CI 1.42-21.0, P = 0.008) and OS (HR 42.6, 95% CI 6.83-226, P < 0.001). The levels of sPD-L1 at baseline closely correlated with those of other soluble factors, such as sCD30, IL-2Ra, sTNF-R1, and sTNF-R2, which are known to be released from the cell surface by zinc-binding proteases ADAM10/17. CONCLUSIONS: These findings suggest the clinical significance of pretreatment sPD-L1 as well as posttreatment sPD-1 and sPD-L1 in NSCLC patients treated with ICI monotherapy.

A Retrospective, Multicenter, Observational Study to Evaluate Clinical Outcomes of Lorlatinib After Alectinib in Patients With ALK-Positive NSCLC in Japan.

Introduction: Lorlatinib is an ALK tyrosine kinase inhibitor approved in Japan for the treatment of advanced ALK+ NSCLC. There has been little evidence about lorlatinib efficacy after first-line (1L) alectinib in clinical practice in Japan. Methods: We retrospectively analyzed patients with advanced ALK+ NSCLC previously treated with 1L alectinib at multiple sites in Japan. Primary objectives were to collect patient demographics at baseline and estimate time to treatment failure (TTF) with second-line (2L) or third-line (3L) or later line (≥3L) lorlatinib treatment. Secondary objectives included objective response rate (ORR) with lorlatinib, reason for discontinuation and time to last treatment failure with lorlatinib, TTF and ORR of alectinib, and combined TTF. Results: Among the 51 patients included in the study, 29 (56.9%) received 2L and 22 (43.1%) received ≥3L lorlatinib treatment. At lorlatinib initiation, brain metastases were reported in 25 patients (49.0%), and 32 (62.7%) had an Eastern Cooperative Oncology Group performance status of 0 or 1. Median TTF with lorlatinib was 11.1 months (95% confidence interval [CI]: 4.6-13.8) in any line, 10.8 months (95% CI: 3.9-13.8) in 2L, and 11.5 months (95% CI: 2.9-not reached) in ≥3L. Median TTF was 11.5 months (95% CI: 3.9-not reached) in patients with brain metastases at lorlatinib initiation and 9.9 months (95% CI: 4.3-13.8) in patients without brain metastases. ORR was 35.7% with any-line lorlatinib treatment. Conclusions: Patient characteristics and efficacy were comparable with previous reports when lorlatinib was given after 1L alectinib in patients with ALK+ NSCLC.

Case report: anaplastic lymphoma kinase (ALK) rearranged adenocarcinoma with high level of microsatellite instability response to pembrolizumab.

The presence of anaplastic lymphoma kinase (ALK) rearrangement is reported to be related to the lack of efficacy of immune checkpoint inhibitors (ICIs). High levels of microsatellite instability (MSI-high) are important biomarkers of ICIs, particularly in colorectal cancer. The therapeutic effect of ICIs for MSI-high NSCLC is uncertain because of the rarity of these tumors. Here we report a case of ALK rearranged NSCLC with MSI-high. A 48-year-old male was diagnosed with lung adenocarcinoma, cT4N3M1a, stage IVA with ALK rearrangement, high PD-L1 expression with a tumor proportion score (TPS) of 100%, and MSI-high. The patient was treated with alectinib as the first-line therapy but progressed at five months with left atrial invasion re-expansion. The patient discontinued alectinib and was switched to pembrolizumab monotherapy. After two months, left atrial invasion significantly decreased. The patient continued pembrolizumab for a year without noticeable adverse events, and tumor shrinkage persisted. This case supports the efficacy of ICIs for MSI-high NSCLC, even in the presence of ALK rearrangement.

Pneumonitis associated with pembrolizumab plus chemotherapy for non-squamous non-small cell lung cancer.

Studies elucidating detailed characteristics of pneumonitis in association with chemo-immunotherapy are limited. We aimed to investigate the characteristics of images, prognostic factors, and clinical course of combination therapy associated with pneumonitis. A multicenter, retrospective cohort study of patients with non-squamous non-small cell lung cancer who received a combination of platinum, pemetrexed, and pembrolizumab was conducted. Patients with confirmed pneumonitis established by an independent multidisciplinary team were enrolled. For 53 patients with pneumonitis, radiographic features at diagnosis predominantly comprised an organizing pneumonia pattern (62%, 33/53). Twelve (23%) patients experienced a worsening respiratory status during pneumonitis management, which was associated with a high mortality rate (58%, 7/12) during treatment. Severe grade at pneumonitis diagnosis (p < 0.001), diffuse alveolar damage (DAD) pattern (p = 0.002), and disease extent ≥ 25% in the lungs (p = 0.009) were significantly associated with worsening respiratory status. Furthermore, post-diagnosis survival was significantly worse in severe pneumonitis (p = 0.02) than in mild and in patients with the DAD pattern than in those without (p < 0.0001). We showed detailed clinical course of patients with pneumonitis and reported several important influencing factors. Given the small number of trials on pneumonitis, our findings provide valuable information to guide the development of appropriate management guidelines and improve pneumonitis treatment.

Neoadjuvant PD-1 Blockade in Non-Small Cell Lung Cancer: Current perspectives and Moving Forward.

Perioperative therapy for non-small cell lung cancer has been studied extensively in a bid to improve overall survival, as approximately half of the patients with surgically resectable tumors at the time of diagnosis relapse. In recent years, immune checkpoint inhibitor therapies, such as the anti-programmed death 1/programmed death-ligand 1 (PD-1/PD-L1) blockade, have contributed to achieving an improved overall survival of patients with advanced stage lung cancer. Thus, the development of this treatment strategy has considerable potential to precipitate a breakthrough in cancer immunotherapy. PD-1/PD-L1 blockade has several potential immunological benefits when used as a neoadjuvant therapy. However, there are concerns associated with this neoadjuvant therapy. Many studies have reported its efficacy, but there is limited evidence regarding the long-term survival of patients. Similarly, it is unclear whether existing biomarkers are adequate for monitoring the prognosis of patients, or if new biomarkers are required. In this article, we present recent reports on neoadjuvant PD-1/PD-L1 blockade therapy and discuss its future challenges.

Non-specific symptoms as a prodrome of immune-related adverse events in patients with non-small cell lung cancer receiving nivolumab: a consecutive analysis of 200 patients.

PURPOSE: Immune checkpoint blockade therapy is the standard treatment for metastatic or refractory non-small cell lung cancer (NSCLC). However, it is associated with immune-related adverse events (irAEs). irAEs are sometimes fatal; however, an efficient method for early irAEs detection has not been developed because their onset timing varies. We examined the significance of non-specific symptoms as a prodrome of irAEs in patients with NSCLC. METHODS: We reviewed consecutive patients who received nivolumab at a dosage of 3 mg/kg every 2 weeks for metastatic NSCLC between December 2015 and August 2017. Patient demographics, irAEs and signal symptoms were recorded. Non-specific symptoms (fever and fatigue) occurred 7 days or earlier before the onset of irAEs were considered signal symptoms. For statistical analyses, the association between irAEs and clinical information, including signal symptoms, was evaluated using Fisher's exact test and logistic regression. RESULTS: A total of 200 patients received nivolumab; 131 (65.5%) were male, their median age was 63 years (range 30-83), 174 (87.0%) had performance status of 0-1. Signal symptoms occurred in 38 (19.0%) of the 77 patients (38.5%) who experienced irAEs, and were positively associated with the occurrence of irAEs (P < 0.01). Multivariate analysis showed that the occurrence of irAEs was significantly higher in patients with PS 0-1 [odds ratio (OR) 7.01; 95% confidence intervals (CI), 1.69-29.13] and patients experienced signal symptoms (OR 17.30; 95% CI, 6.51-45.99). CONCLUSION: The occurrence of signal symptoms could be used in the early detection and management of irAEs in patients during immune checkpoint blockade therapy.