[For Whom Are Clinical Practice Guidelines?-Is Minds the Imperial Standard?]

It has been more than 20 years since the first guidelines(GL)for cancer treatment were published, and the methodology used to create GL have changed over the years. The methodologies are becoming fairer and more objective, but the rules have become so important that some are difficult for the GL users to understand. In this issue, an author discussed the confusion in the field in GL methodology based on the discussion of postoperative adjuvant therapy of NSCLC. In addition, lung cancer is becoming more and more segmented, and there are many clinical questions(CQs)which the evidence is fragmented and insufficient in lung cancer treatment. Also, only prospective papers are currently adapted for the base of evidence. It is difficult to provide recommendations for CQs in areas where prospective studies are difficult, for example, meningitis cases. How can we provide direction for areas where the evidence is insufficient at such times? We are currently in a transitional period, which will be resolved through further discussions, but we need to be a little more flexible in our methodology to make GLs and be able to provide direction for CQs. One way to provide direction for CQs, even in a form other than CQ, would be to present expert opinions or employ retrospective studies.

Clinical utility of liquid biopsy for EGFR driver, T790M mutation and EGFR amplification in plasma in patients with acquired resistance to afatinib.

BACKGROUND: Cell-free DNA (cfDNA) genotyping in plasma using the cobas EGFR Mutation Test v2 (cobas) is the first liquid biopsy as a companion diagnosis to identify the EGFR T790M mutation (T790M) after the failure of treatment of EGFR-tyrosine kinase inhibitors (TKIs) (1st generation, gefitinib [G] and erlotinib [E] and 2nd generation, afatinib [A]). This study investigated the clinical utility of a liquid biopsy for patients who acquired resistance to afatinib. METHODS: We prospectively collected plasma from 51 patients who had acquired resistance to afatinib between April 2015 and November 2016 to evaluate the frequency of T790M by cobas and digital droplet PCR (UMIN000025112). Additionally, we retrospectively reviewed 38 patients who tested by cobas in plasma after G/E failure to compare for T790M detection between A and with G/E. RESULTS: The detection rate of EGFR-driver and T790M in plasma in patients treated with A (A group) as a first-line EGFR-TKI was lower than with G/E followed by A (G/E→A group), although the differences were not significant (EGFR-driver: 41% [A] vs. 67% [G/E→A], P=0.1867; and T790M: 8% [A] vs. 17% [G/E→A], P=0.5798). In first-line setting, the detection rate for EGFR-driver and T790M in plasma by cobas was lower in A group than in G/E group, although there was no significant difference (EGFR-driver: 34% [A] vs. 52% [G/E], P=0.2072; and T790M: 10% [A] vs. 27% [G/E], P=0.1161). CONCLUSION: The detection of EGFR-driver and T790M in plasma by cobas in patients treated with afatinib might be lower than with G/E in a real-world setting.

Efficacy of Xenon Light With Indocyanine Green for Intersegmental Visibility in Thoracoscopic Segmentectomy.

BACKGROUND: We previously reported useful methods that can be implemented to identify intersegmental boundary lines (IBLs) by using an intravenous indocyanine green (ICG) fluorescence imaging system (ICG-FS) during a thoracoscopic anatomical segmentectomy (TAS). The aim of this study was to evaluate the recently released third-generation ICG-FS that features an emphasizing xenon-light source for IBL identification. METHODS: We prospectively studied cases involving 106 consecutive patients who underwent TAS. Intraoperatively, we used the third-generation ICG-FS, the conventional ICG methods (CIM) emphasizing xenon-light (CIM-X), and the spectra-A method (SAM) emphasizing xenon-light (SAM-X), for IBL identification. Furthermore, 16 of the 106 patients (15%) could be simultaneously evaluated using old-generation ICG-FSs, CIM, and SAM. All images were completely quantified for illuminance and for three colors, red, green, and blue. RESULTS: IBLs were successfully identified in all the patients (100%) with no adverse events. The SAM-X significantly increased the illuminance, especially in the resecting segments, compared to the CIM (39.0 versus 22.2, P < 0.01) and SAM (39.0 versus 29.3, P < 0.01), with enhanced red color compared to the CIM (33.1 versus 21.9, P < 0.01) and SAM (33.1 versus 14.0, P < 0.01). Furthermore, the SAM-X significantly increased the illuminance contrast compared to the CIM-X (34.1 versus 15.3, P < 0.01). CONCLUSIONS: The present study suggests that the SAM-X potentially provided images with the highest visibility and colorfulness compared to the older generation ICG-FSs or CIM-X. Secure IBL identification can be more easily and safely performed using the SAM-X.

Four Hours Postoperative Mobilization is Feasible After Thoracoscopic Anatomical Pulmonary Resection.

BACKGROUND: We aimed to analyze the feasibility and risk factors associated with early mobilization (EM) within 4 h after thoracoscopic lobectomy and segmentectomy. METHODS: This study retrospectively evaluated 214 consecutive patients who underwent thoracoscopic anatomical pulmonary resection using our EM protocol between October 2017 and February 2019. We compared the correlations of the patients' characteristics including the total number of drugs and perioperative parameters such as air leak, and orthostatic hypotension (OH) between the EM (E group) and failed EM (F group) groups. Second, we evaluated risk factors for OH, which often causes critical complications. RESULTS: A total of 198 patients (92.5%: E group) completed the EM protocol, whereas 16 patients did not (7.5%: F group). The primary causes of failure were severe pain, air leak, postoperative nausea and vomiting, and OH (n = 1, 3, 8, and 4). Upon univariate analysis, air leakage, OH, and non-hypertension were identified as risk factors for failed EM (all p <0.05). EM was associated with a shortened chest tube drainage period (p <0.01). Thirty patients (14%) experienced OH, and 20% of them failed EM. A total number of drugs ≥5 (p = 0.015) was an independent risk factor for OH. Operative and anesthetic variables were not associated with EM or OH. CONCLUSIONS: The EM protocol was safe and useful for tubeless management. Surgeons should be advised to actively prevent air leak. Our EM protocol achieved a low frequency of OH in mobilization. Due to its versatility, our mobilization protocol may be promising, especially in patients without severe comorbidities. Clinical registration number: The study protocol was approved by the Review Board of Aichi Cancer Center (approval number: 2020-1-067).

Comparison between Fluorimetry (Qubit) and Spectrophotometry (NanoDrop) in the Quantification of DNA and RNA Extracted from Frozen and FFPE Tissues from Lung Cancer Patients: A Real-World Use of Genomic Tests.

Background and Objectives: Panel-based next-generation sequencing (NGS) has been carried out in daily clinical settings for the diagnosis and treatment guidance of patients with non-small cell lung cancer (NSCLC). The success of genomic tests including NGS depends in large part on preparing better-quality DNA or RNA; however, there are no established operating methods for preparing genomic DNA and RNA samples. Materials and Methods: We compared the following two quantitative methods, the QubitTM and NanoDropTM, using 585 surgical specimens, 278 biopsy specimens, and 82 cell block specimens of lung cancer that were used for genetic tests, including NGS. We analyzed the success rate of the genomic tests, including NGS, which were performed with DNA and RNA with concentrations that were outliers for the Qubit Fluorometer. Results: The absolute value for DNA concentrations had a tendency to be higher when measured with NanoDropTM regardless of the type of specimen; however, this was not the case for RNA. The success rate of DNA-based genomic tests using specimens with a concentration below the lower limit of QubitTM detection was as high as approximately 96%. At less than 60%, the success rate of RNA-based genomic tests, including RT-PCR, was not as satisfactory. The success rates of the AmpliSeqTM DNA panel sequencing and RNA panel sequencing were 77.8% and 91.5%, respectively. If at least one PCR amplification product could be obtained, then all RNA-based sequencing was performed successfully. Conclusions: The concentration measurements with NanoDropTM are reliable. The success rate of NGS with samples at concentrations below the limit of detection of QubitTM was relatively higher than expected, and it is worth performing PCR-based panel sequencing, especially in cases where re-biopsy cannot be performed.

Propensity score analysis of overall survival between first- and second-generation EGFR-TKIs using real-world data.

We constructed a data set of EGFR-mutant non-small-cell lung carcinoma (NSCLC) patients, and compared the overall survival of first-generation (1G), and second-generation (2G) EGFR-tyrosine kinase inhibitors (TKIs) in clinical practice using a propensity score. We reviewed the clinical data of consecutive EGFR-mutated NSCLC patients who received EGFR-TKI therapy between January 2008 and August 2017 at 11 institutions in Japan. The primary endpoint was overall survival (OS). When comparing OS between 1G and 2G EGFR-TKIs, propensity score analyses were performed using 2 methods: matching and inverse probability of treatment weighting (IPTW). (Clinical Trial information: UMIN000030121) In total, 1400 patients from 11 institutions were enrolled in this study, and the data from the 1366 patients who received only EGFR-TKI therapy were analyzed (gefitinib [GEF], N = 732; erlotinib [ERL], N = 416; afatinib, N = 218). Median OS times (months [95%CI]) were 29.7 [27.5-33.5] in the 1G group (gefitinib, 32.0 [28.1-35.8]; erlotinib, 27.5 [23.9-31.7]), and 38.6 [32.2-NR] in the 2G group (afatinib), respectively. The trend of longer OS for afatinib against 1G EGFR-TKIs remained, even after adjusted by propensity score. (unadjusted, hazard ratio [HR] 0.676, P = .0023; adjusted by IPTW, HR 0.685 P < .0001; adjusted by matching, HR 0.725, P = .0418). Exploratory analysis showed that OS using the 2G EGFR-TKI was superior to that of the 1G EGFR-TKIs, suggesting the potential of sequential therapy of 2G EGFR-TKI followed by osimertinib. (HR 0.419, P = .0519) Real-world data analysis using 1354 data records, using propensity scoring, indicated that 2G EGFR-TKI had a trend of longer OS compared with 1G EGFR-TKIs.

Efficacy of Immune Checkpoint Inhibitor Monotherapy for Advanced Non-Small-Cell Lung Cancer with ALK Rearrangement.

Programmed death-ligand 1 (PD-L1) expression is a predictor of immune checkpoint inhibitor (ICI) treatment efficacy. The clinical efficacy of ICIs for non-small-cell lung cancer (NSCLC) patients harboring major mutations, such as EGFR or ALK mutations, is limited. We genotyped 190 patients with advanced lung adenocarcinomas who received nivolumab or pembrolizumab monotherapy, and examined the efficacy in NSCLC patients with or without major mutations. Among the patients enrolled in the genotyping study, 47 patients harbored EGFR mutations, 25 patients had KRAS mutations, 5 patients had a HER2 mutation, 6 patients had a BRAF mutation, and 7 patients had ALK rearrangement. The status of PD-L1 expression was evaluated in 151 patients, and the rate of high PD-L1 expression (≥50%) was significantly higher in patients with ALK mutations. The progression-free survival was 0.6 (95% CI: 0.2-2.1) months for ALK-positive patients and 1.8 (95% CI: 1.2-2.1) months for EGFR-positive patients. All patients with ALK rearrangement showed disease progression within three months from the initiation of anti-PD-1 treatment. Our data suggested that ICI treatment was significantly less efficacious in patients with ALK rearrangement than in patients with EGFR mutations, and PD-L1 expression was not a critical biomarker for ICI treatment for patients with one of these mutations.

Unique prevalence of oncogenic genetic alterations in young patients with lung adenocarcinoma.

BACKGROUND: Lung adenocarcinoma in the young is a rare entity, and the oncogenic genetic alterations (GAs) and clinical characteristics associated with this disease are poorly understood. Conversely, it has been demonstrated that young age at diagnosis defines unique biology in other cancers. For this report, the effects of young age on lung adenocarcinoma are reported. METHODS: The authors retrospectively screened 1746 consecutive patients who were diagnosed with stage I through IV adenocarcinoma between 2009 and 2015 and identified 81 who were aged 40 years or younger at diagnosis. The clinical and genetic characteristics of this younger population were analyzed. RESULTS: Of the 81 younger patients identified, 36 (44%) were men, 36 (44%) were never smokers, and the median age was 36 years (range, 26-40 years). Thirty-three patients (41%) harbored anaplastic lymphoma kinase (ALK) translocations, 24 (30%) had epidermal growth factor receptor (EGFR) mutations, and 2 (2%) had v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations. Rare oncogenic GAs also were studied in patients who had wild-type ALK/EGFR/KRAS adenocarcinoma, including 4 patients with HER2 mutations, 2 with Ret proto-oncogene (RET) translocations, and 2 with ROS proto-oncogene 1 receptor tyrosine kinase (ROS1) translocations. Notably, oncogenic GAs (P < .001), ALK (P < .001) and ROS1 (P = .033) translocations, and HER2 mutations (P < .001) were associated with young age, and a similar trend was observed for RET translocations (P = .108). Younger patients who had adenocarcinoma without GAs had a significantly worse prognosis compared with older patients without GAs (overall survival, 8.9 vs 16.4 months; P < .001) and patients with GAs (24.9 months; P < .001). CONCLUSIONS: Younger patients with adenocarcinoma have a distinctly unique prevalence of oncogenic GAs. Comprehensive oncogenic GA screening is especially recommended for personalized medicine strategies in this population. Cancer 2017;123:1731-1740. © 2017 American Cancer Society.

The next-generation KRAS inhibitors What comes after sotorasib and adagrasib?

The Kirsten rat sarcoma viral oncogene homolog (KRAS) is one of the first driver oncogenes identified in human cancer in the early 1980s. However, it has been deemed 'undruggable' for nearly four decades until the discovery of KRAS G12C covalent inhibitors, which marked a pivotal breakthrough. Currently, sotorasib and adagrasib have been approved by the US FDA to treat patients with non-small cell lung cancer (NSCLC) harboring KRAS G12C mutation. However, their efficacy is somewhat limited compared to that of other targeted therapies owing to intrinsic resistance or early acquisition of resistance. While G12C is the predominant subtype of KRAS mutations in NSCLC, G12D/V is prevalent in colorectal and pancreatic cancers. These facts have spurred active research to develop more potent KRAS G12C inhibitors as well as inhibitors targeting non-G12C KRAS mutations. Novel approaches, such as molecular shielding or targeted protein degradation, are also under development. Combining KRAS inhibitors with inhibitors of the receptor-tyrosine kinase-RAS-mitogen-activated protein kinase (MAPK) pathway is underway to counteract redundant feedback mechanisms. Additionally, immunological approaches utilizing T-cell receptor (TCR)-engineered T cell therapy or vaccines, and Hapimmune antibodies are ongoing. This review delineates the recent advancements in KRAS inhibitor development in the post-sotorasib/adagrasib era, with a focus on NSCLC.

Path Less Traveled: Targeting Rare Driver Oncogenes in Non-Small-Cell Lung Cancer.

Over the past decade, tremendous efforts have been made in the development of targeted agents in non-small-cell lung cancer (NSCLC) with nonsquamous histology. Pivotal studies have used next-generation sequencing to select the patient population harboring oncogenic driver alterations that are targetable with targeted therapies. As treatment paradigm rapidly evolves for patients with rare oncogene-driven NSCLC, updated comprehensive overview of diagnostic approach and treatment options is paramount in clinical settings. In this review article, we discuss the epidemiology, molecular testing, and landmark clinical trials addressing the targeted agents for ROS1 rearrangement, METex14 skipping mutation, EGFR exon 20 insertion, KRAS G12C mutation, HER2 mutation, RET fusion, NTRK fusion, and BRAF mutations.

Modulating the gut microbiome in non-small cell lung cancer: Challenges and opportunities.

Despite the efficacy of immunotherapy in non-small cell lung cancer (NSCLC), the majority of the patients experience relapse with limited subsequent treatment options. Preclinical studies of various epithelial tumors, such as melanoma and NSCLC, have shown that harnessing the gut microbiome resulted in improvement of therapeutic responses to immunotherapy. Is this review, we summarize the role of microbiome, including lung and gut microbiome in the context of NSCLC, provide overview of the mechanisms of microbiome in efficacy and toxicity of chemotherapies and immunotherapies, and address current ongoing clinical trials for NSCLC including fecal microbiota transplantation (FMT) and live biotherapeutic products (LBPs).

It might be a dead end: immune checkpoint inhibitor therapy in EGFR-mutated NSCLC.

Despite innovative advances in molecular targeted therapy, treatment strategies using immune checkpoint inhibitors (ICIs) for epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) have not progressed significantly. Accumulating evidence suggests that ICI chemotherapy is inadequate in this population. Biomarkers of ICI therapy, such as programmed cell death ligand 1 (PD-L1) and tumor-infiltrating lymphocytes (TILs), are not biomarkers in patients with EGFR mutations, and the specificity of the tumor microenvironment has been suggested as the reason for this. Combination therapy with PD-L1 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors is a concern because of its severe toxicity and limited efficacy. However, early-stage NSCLC may differ from advanced-stage NSCLC. In this review, we comprehensively review the current evidence and summarize the potential of ICI therapy in patients with EGFR mutations after acquiring resistance to treatment with EGFR-tyrosine kinase inhibitors (TKIs) with no T790M mutation or whose disease has progressed on osimertinib.

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.

Real-World Outcomes of Subsequent Chemotherapy after Progression Following Chemoradiation and Consolidative Durvalumab Therapy in Locally Advanced Non-small Cell Lung Cancer: An Exploratory Analysis from the CRIMSON Study (HOPE-005).

BACKGROUND: The optimal subsequent treatment strategy for locally advanced non-small cell lung cancer (LA-NSCLC) after chemoradiotherapy (CRT) and consolidative durvalumab therapy remains unknown. We aimed to determine the optimal subsequent treatment strategy for this clinical population. MATERIALS AND METHODS: We retrospectively enrolled 523 consecutive patients with LA-NSCLC treated with CRT and analyzed the treatment outcomes of subsequent therapy after progression following CRT and consolidative durvalumab therapy. Patients who received tyrosine kinase inhibitors as subsequent therapy were excluded. RESULTS: Out of 122 patients who received subsequent chemotherapy, 55% underwent platinum-based, 25% non-platinum-based, and 20% immune checkpoint inhibitor (ICI)-containing therapies. In the platinum-based group, patients with a durvalumab-progression-free survival (Dur-PFS) ≥ 1 year had a significantly longer median subsequent therapy-PFS (SubTx-PFS) than those with Dur-PFS < 1 year (13.2 months vs. 4.7 months; hazard ratio, 0.45; 95% confidence interval, 0.21-0.97; P = .04). Furthermore, among patients receiving non-platinum-based chemotherapy, the median SubTx-PFS was longer in the combined with angiogenesis inhibitor group than in the without group, although the difference was not statistically significant. No significant difference of SubTx-PFS was observed between the reason for durvalumab discontinuation and the outcomes of ICI-containing therapy. CONCLUSION: In clinical practice, platinum-based chemotherapy rechallenge is frequently employed following progression subsequent to CRT and consolidative durvalumab therapy for LA-NSCLC. Optimal treatment strategies may consider Dur-PFS and angiogenesis inhibitor feasibility. Further research is warranted to identify clinical biomarkers that can help identify patients who would benefit from ICI rechallenge.

Osimertinib as first-line treatment for elderly patients with advanced EGFR mutation-positive non-small cell lung cancer in a real-world setting (OSI-FACT-EP).

OBJECTIVES: Osimertinib is the primary treatment for patients with epidermal growth factor receptor (EGFR) mutation-positive advanced non-small cell lung cancer. However, evidence of the outcomes of osimertinib treatment in patients over 75 years of age in the real-world setting is limited. MATERIALS AND METHODS: This retrospective study analyzed the data of 538 patients (203 elderly and 335 non-elderly) with EGFR mutation-positive lung cancer in whom osimertinib was initiated as first-line treatment between August 2018 and December 2019. Patients over 75 years of age were classified as elderly. The data cut-off date was February 28, 2022. RESULTS: The progression-free survival (PFS) did not significantly differ between the elderly and non-elderly groups [elderly group: median PFS, 16.9 months (95 % confidence interval (CI), 14.3-20.2); non-elderly group: median PFS, 22.1 months (95 % CI: 19.5-26.3); hazard ratio (HR) for the elderly against the non-elderly: 1.21 (95 % CI: 0.98-1.50), p = 0.079]. However, the time to treatment failure (TTF) was significantly shorter in the elderly than in the non-elderly [elderly group: median TTF, 14.0 months (95 % CI: 0.98-1.50); non-elderly group: median TTF, 21.8 months (95 % CI: 18.2-24.6); HR for the elderly against the non-elderly: 1.46 (95 % CI: 1.20-1.77), p < 0.001]. Furthermore, the rate of treatment discontinuation because of adverse events was 28.6 % in the elderly and 14.9 % in the non-elderly (p < 0.001). Among patients who discontinued treatment, the conversion rate to second-line treatment was 39.6 % in the elderly and 72.8 % in the non-elderly. In addition, the median overall survival was 30 months (95 % CI: 25.8-37.7) in the elderly and not reached (NR) (95 % CI: NR-NR) in the non-elderly (p < 0.001). CONCLUSION: In a real-world clinical setting, elderly patients receiving osimertinib as first-line treatment should be aware of the frequent inability to transition to second-line treatment due to adverse events.

Safety and efficacy of osimertinib rechallenge or continuation after pneumonitis: A multicentre retrospective cohort study.

INTRODUCTION: Although osimertinib is a standard first-line treatment for patients with advanced-stage non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations, the incidence rate of pneumonitis associated with osimertinib is high. However, there are few reports about the safety and efficacy of osimertinib rechallenge after the development of pneumonitis. METHODS: We conducted a retrospective multicentre cohort study of consecutive patients who developed pneumonitis associated with osimertinib as a first-line and received osimertinib rechallenge. The primary outcome was the incidence rate of any grade pneumonitis after osimertinib rechallenge. The secondary outcome was treatment efficacy in patients after osimertinib rechallenge. RESULTS: In total, 33 patients who received osimertinib rechallenge were included. Of them, 26 patients had grade 1, 6 patients had grade 2, and 1 patient had grade 3 initial pneumonitis. The median follow-up period after the osimertinib rechallenge was 16.9 months (interquartile range, 11.1-21.3 months). After the start of osimertinib rechallenge, five patients (15%) experienced mild relapsed pneumonitis. Three of the five patients had similar imaging patterns for initial and relapsed pneumonitis. No significant differences in characteristics were observed between patients with and without relapsed pneumonitis. The median progression-free survival after osimertinib rechallenge was not achieved (95% confidence interval: 10.3 months - not reached). CONCLUSION: Osimertinib rechallenge was feasible and effective for patients who developed initial pneumonitis associated with first-line osimertinib therapy. Osimertinib might be considered a treatment option even after the development of mild initial pneumonitis.

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.

Impact of Corticosteroids for IrAEs on the Clinical Outcome of Immunotherapy in Patients With NSCLC.

BACKGROUND/AIM: The impact of corticosteroids for the treatment of immune-related adverse events (irAEs) on the antitumor effect of programmed cell death-1 (PD-1) inhibitor is unclear. PATIENTS AND METHODS: A total of 172 patients with non-small cell lung cancer (NSCLC) treated with PD-1 inhibitors were retrospectively reviewed. Patients were divided into four groups: those who did not develop irAEs [1] and those who developed irAE and were either not treated with corticosteroids [2] or treated with low [3] or high doses [4], and overall survival (OS) was analyzed by the time of corticosteroid treatment. Landmark analysis was performed using Cox proportional hazard model with time-dependent covariates. RESULTS: A high-dose steroid treatment within 60 days correlated with a significantly worse OS than that of the group with irAEs without steroids (p=0.004). Moreover, there was no significant difference in OS between the irAE without steroid and low-dose steroid groups. CONCLUSION: Early severe irAEs and high-dose corticosteroid treatment were poor prognostic factors in patients with NSCLC treated with PD-1 inhibitors.

Synchronous driver gene alterations (EGFR L858R, T790M, and ROS1) rearrangements in a patient with early-stage lung adenocarcinoma.

Concurrent EGFR mutation and ROS1 rearrangement is a rare event in early-stage non-small-cell lung cancer. In addition, a co-occurring de novo EGFR T790M mutation in such a case is extremely rare. We encountered a 72-year-old woman who developed 3 early-stage lung lesions synchronously, one each harboring EGFR L858R, ROS1 rearrangement, and EGFR L858R and de novo T790M. These three nodules were pathologically time-matched lepidic predominant adenocarcinoma with small invasive lesions, which may reflect the concept of field cancerization with driver mutations.

Risk factors for pneumonitis in patients with non-small cell lung cancer treated with immune checkpoint inhibitors plus chemotherapy: A retrospective analysis.

BACKGROUND: Immune checkpoint inhibitor (ICI) therapy plus chemotherapy has become a standard of care for patients with advanced non-small cell lung cancer (NSCLC). Pre-existing interstitial lung disease (ILD) is a risk factor for drug-induced pneumonitis caused by chemotherapy or ICI monotherapy. However, clinical data in patients with pre-existing ILD who received ICI therapy plus chemotherapy are limited. This study aimed to identify the risk factors for drug-induced pneumonitis in patients with NSCLC treated with ICIs plus chemotherapy. METHODS: We retrospectively reviewed the medical records of 160 consecutive patients who were diagnosed with NSCLC and treated with ICIs plus chemotherapy at Aichi Cancer Center Hospital between December 2018 and November 2020. Patients with a prior history of ICI treatment or thoracic radiotherapy were excluded from the analysis. RESULTS: Among 125 patients, pre-existing ILD was observed in 20 patients (16.0%). Drug-induced pneumonitis developed in 17 patients (13.6%), with a median time to onset of 19.3 weeks (range, 1.6-108.9 weeks). In multivariate logistic analysis, pre-existing ILD (odds ratio = 19.07, p = 0.0001) and PEM exposure (odds ratio = 5.67, p = 0.022) were identified as risk factors for the development of drug-induced pneumonitis. CONCLUSIONS: Pre-existing ILD and pemetrexed exposure are risk factors for drug-induced pneumonitis in patients with NSCLC.