Efficacy of chemotherapy plus immune checkpoint inhibitors in patients with non-small cell lung cancer who have rare oncogenic driver mutations: a retrospective analysis.

BACKGROUND: Targeted therapy is now the standard of care in driver-oncogene-positive non-small cell lung cancer (NSCLC). Its initial clinical effects are remarkable. However, almost all patients experience treatment resistance to targeted therapy. Hence, chemotherapy is considered a subsequent treatment option. In patients with driver-oncogene-negative NSCLC, combined immune checkpoint inhibitors (ICIs) and chemotherapy as the first-line therapy has been found to be beneficial. However, the efficacy of ICI plus chemotherapy against driver-oncogene-positive NSCLC other than epidermal growth factor receptor mutation and anaplastic lymphoma kinase fusion is unclear. METHODS: Using the hospital medical records, we retrospectively reviewed advanced or recurrent NSCLC patients who were treated with chemotherapy with or without ICIs at Aichi Cancer Center Hospital between January 2014 and January 2023. Patients with druggable rare mutations such as KRAS-G12C, MET exon 14 skipping, HER2 20 insertion, BRAF-V600E mutations, and ROS1 and RET rearrangements were analyzed. RESULTS: In total, 61 patients were included in this analysis. ICI plus chemotherapy was administered in 36 patients (the ICI-chemo group) and chemotherapy in 25 patients (the chemo group). The median progression-free survival (PFS) rates were 14.0 months in the ICI-chemo group and 4.8 months in the chemo group (hazard ratio [HR] = 0.54, 95% confidence interval [CI] = 0.28-1.01). The median overall survival rates were 31.3 and 21.7 months in the ICI-chemo and chemo groups, respectively (HR = 0.70, 95% CI = 0.33-1.50). Multivariate Cox regression analysis of PFS revealed that HER2 exon 20 insertion mutation was significantly associated with a poorer PFS (HR: 2.39, 95% CI: 1.19-4.77, P = 0.014). Further, ICI-chemo treatment was significantly associated with a better PFS (HR: 0.48, 95% CI: 0.25-0.91, P = 0.025). CONCLUSION: ICI plus chemotherapy improves treatment efficacy in rare driver-oncogene-positive NSCLC.

Feasibility and utility of transbronchial cryobiopsy in precision medicine for lung cancer: Prospective single-arm study.

Cryoprobe is a novel transbronchial biopsy (TBB) tool that yields larger tissue samples than forceps. Pathological diagnosis and biomarker analysis, such as genetic alterations and programmed death-ligand 1 (PD-L1) expression, are paramount for precision medicine against lung cancer. We evaluated the safety and usefulness of cryoprobe TBB for lung cancer diagnosis and biomarker analysis. In this single-center, prospective single-arm study, patients suspected of having or diagnosed with primary lung cancer underwent cryoprobe TBB using flexible bronchoscopy after conventional forceps TBB from the same lesion. Cryoprobe TBB was performed in 121 patients. The incidence rate of severe bleeding and serious adverse events (4% [90% confidence interval: 2%-9%]) was significantly lower than the expected rate (20% with 30% threshold, P < 0.01). Combining both central and peripheral lesions, the diagnostic yield rate of cryoprobe samples was 76% and that of forceps samples was 84%. Compared with forceps TBB samples, cryoprobe TBB samples were larger (cryoprobe 15 mm2 vs forceps 2 mm2 ) and resulted in a larger proportion of definite histomorphological diagnosis (cryoprobe 86% vs forceps 74%, P < 0.01), larger amounts of DNA extracted from samples (median: cryoprobe, 1.60 µg vs forceps, 0.58 µg, P = 0.02) and RNA (median: cryoprobe, 0.62 µg vs forceps, 0.17 µg, P < 0.01) extracted from samples, and tended to yield greater rates of PD-L1 expression >1% (51% vs 42%). In conclusion, cryoprobe is a safe and useful tool for obtaining lung cancer tissue samples of adequate size and quality, which allow morphological diagnosis and biomarker analysis for precision medicine against lung cancer.

Primary Prophylaxis Indication for Docetaxel Induced Febrile Neutropenia in Elderly Patients with Non-Small Cell Lung Cancer.

In advanced non-small cell lung cancer (NSCLC), the reported incidence of febrile neutropenia (FN) caused by docetaxel (DTX) is 10-20% in clinical trial data. However, FN incidence caused by DTX in real-world setting remains unclear. We evaluated FN incidence caused by DTX and identify risk factors of FN in real-world setting. One hundred and seventy-one NSCLC patients treated with DTX were retrospectively analyzed and 44 (26%) developed FN. Multivariate analysis identified higher age (≥65 years) and prior history of FN as independent risk factors for FN. Primary prophylaxis for FN might be recommended in elderly patients with/without prior history of FN.

The incidence of drug-induced interstitial lung disease caused by epidermal growth factor receptor tyrosine kinase inhibitors or immune checkpoint inhibitors in patients with non-small cell lung cancer in presence and absence of vascular endothelial growth factor inhibitors: a systematic review.

Interstitial lung disease (ILD) or pneumonitis caused by epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) or immune checkpoint inhibitors (ICI) is a major concern in the treatment of non-small cell lung cancer (NSCLC). Whether the addition of vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) inhibitors can reduce the incidence of drug-induced ILD remains unclear. We conducted a systematic review to assess the incidence of ILD induced by EGFR-TKIs or ICIs in the presence or absence of VEGF/VEGFR inhibitors in relevant randomized trials between January 2009 and October 2023. The primary outcome was the odds ratio for the incidence of ILD in all patients worldwide and Asians. Secondary outcomes were the odds ratios (ORs) of the incidence at grade-3 or higher ILD in all patients worldwide and Asians. We identified 13 randomized studies, one sub-analysis in the EGFR-TKI group, and three randomized studies in the ICI group. In the EGFR-TKI group, the OR of ILD incidence at any grade with VEGF/VEGFR inhibitors was 0.54 (95% CI, 0.32-0.90; p = 0.02), which represented a significantly lower incidence than that without VEGF/VEGFR inhibitors. Contrarily, the OR of ILD incidence at grade ≥ 3 with VEGF/VEGFR inhibitors was 1.00 (95% CI, 0.43-2.36; p = 0.99). In all subjects in the ICI group, the OR of ILD incidence at any grade with VEGF/VEGFR inhibitors was 0.78 (95% CI, 0.51-1.21; p = 0.27). The systematic review demonstrated that the addition of VEGF/VEGFR inhibitors could reduce the incidence of drug-induced ILD at any grade caused by EGFR-TKI in patients with NSCLC but could not reduce that at grade ≥ 3. The ILD induced by ICIs remains undetermined owing to the limited number of randomized trials for which ILD data are available. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=409534, identifier CRD42023409534.

Long-Term Response of Lorlatinib to Leptomeningeal Metastasis in Patients with Anaplastic Lymphoma Kinase Fusion Positive Non-Small Lung Cancer: A Case Report.

Introduction: Patients with anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) are at increased risk of central nervous system (CNS) metastasis at initial diagnosis and throughout treatment. In a phase 3 trial, lorlatinib, a third-generation ALK tyrosine kinase inhibitor, significantly improved progression-free survival. In further analysis, lorlatinib revealed superior intracranial efficacy and prolonged time to intracranial progression compared with crizotinib. Case Presentation: Herein, we report a case of ALK-positive NSCLC with leptomeningeal metastasis that was successfully treated with lorlatinib after progression to brigatinib and alectinib. This case demonstrates the potential of lorlatinib in managing leptomeningeal metastasis in ALK-positive NSCLC. Conclusion: The case suggests a paradigm shift in therapeutic approaches for CNS metastasis, including brain and leptomeningeal metastases.

Efficacy and safety of second-line therapy of docetaxel plus ramucirumab after first-line platinum-based chemotherapy plus immune checkpoint inhibitors in non-small cell lung cancer (SCORPION): a multicenter, open-label, single-arm, phase 2 trial.

Background: Immune checkpoint inhibitors (ICI) plus platinum-based chemotherapy has been recognized as a standard first-line therapy in non-small cell lung cancer (NSCLC); however, no prospective clinical trials of docetaxel (DTX) plus ramucirumab (RAM) following first-line ICI plus platinum-based chemotherapy has been reported. Methods: In this multicentre, open-label, single-arm, phase 2 trial, we enrolled patients with NSCLC from eight centres in Japan. Patients with metastatic NSCLC with disease progression after platinum-based chemotherapy plus ICI were eligible for the study. Patients were intravenously treated with 60 mg/m2 of DTX and 10 mg/kg of RAM on day 1 with a strong recommendation of pegfilgrastim administration on day 2 every 3 weeks. The primary end point was objective response rate (ORR) in efficacy analysis population. Safety was assessed in all patients treated at least one dose. The ORR of the null and alternative hypotheses were 10% and 30%, with α error of 0.1 and ß error of 0.1. This trial is registered with the Japan Registry for Clinical Trials, jCRTs041190077. Findings: Between 16 January, 2020, and 24 August, 2021, 33 patients (median age 66 [range 42-79] years) were enrolled. Thirteen patients (41%) had Eastern Cooperative Oncology Group performance status of 1. Twenty-five patients (78%) had an interval of <60 days after the last administration of ICI. In the efficacy analysis population (n = 32), the primary endpoint was met as 11 patients achieved partial response (PR), with ORR of 34.4% (80% CI, 23.1-47.2). Grade ≥3 anaemia and febrile neutropenia were observed in 2 (6%) and 3 (9%) patients, respectively. No treatment-related deaths and no new safety signals were observed. Interpretation: DTX plus RAM demonstrated encouraging antitumor activity with a manageable safety profile in patients who have progressed on front-line ICIs plus platinum-based chemotherapy. The results of this trial can be a helpful reference in conducting further phase III trials of new second-line treatment options. Funding: Eli Lilly Japan K.K.

Non-invasive early prediction of immune checkpoint inhibitor efficacy in non-small-cell lung cancer patients using on-treatment serum CRP and NLR.

PURPOSE: We determined the clinical relevance of early C-reactive protein (CRP) and neutrophil-lymphocyte ratio (NLR) change in blood as surrogate markers of pro-tumor inflammation (PTI) for predicting clinical outcome of programmed cell death (PD)-1/programmed cell death ligand (PD-L) 1 inhibitor treatment in non-small-cell lung carcinoma (NSCLC). METHODS: We retrospectively reviewed NSCLC patients treated with anti-PD-1 or PD-L1 inhibitors. Early CRP change was defined as the ratio of 6 weeks CRP to baseline CRP, and early NLR change was defined as that of the 6 weeks NLR to baseline NLR. PTI index was determined by combinatorial evaluation of early CRP change and early NLR change, PTI index low: both of these were low, intermediate: either of these was low, high; both of these were high. RESULTS: The study included 217 patients. Early CRP change and early NLR change were both associated with PFS and OS. The combinatorial evaluation using these two markers enabled the clear stratification of PFS and OS. The median PFS in patient with PTI index low was 13.9 months, while the median PFS in those with PTI index high was 2.5 months (p < 0.01, log-rank test). The median OS in patients with PTI index low was not reached; the median OS in those with PTI index high was only 15.4 months (p < 0.01, log-rank test). CONCLUSIONS: The combinatorial early CRP change and early NLR change as PTI biomarkers have clinical potential in identifying NSCLC patients who can achieve a durable response and long-term survival using PD-1/PD-L1 inhibitors.

Amelanotic Malignant Melanoma with a BRAF V600E Mutation Mimicking Primary Lung Cancer.

Amelanotic melanoma is a rare type of melanoma that shows little or no melanin pigmentation. When tumor lesions are not detected in cutaneous sites, the presence of melanin is the hallmark sign of malignant melanoma. We herein report a case of amelanotic melanoma with a BRAF V600E mutation mimicking primary lung cancer that was finally diagnosed on an autopsy. The current case suggests important caveats for the differential diagnosis of patients with BRAF V600E mutation-positive poorly differentiated lung tumors. In terms of the pathological diagnosis, routine immunohistochemical staining may be useful, especially in patients with a poorly differentiated lung tumor without TTF-1 expression.

Is area under the curve the best parameter for carboplatin induced emetic risk stratification?

Carboplatin (CBDCA)-induced emetic risk is currently classified on the basis of CBDCA-area under the curve (CBDCA-AUC). We investigated the utility of three CBDCA dosage parameters for predicting emesis by CBDCA. Patients with thoracic cancer treated with CBDCA were included. The endpoints were complete response (CR) and total control (TC). CR was defined as no vomiting and no use of rescue medication during the overall assessment period, whereas TC was defined as no vomiting, nausea, nor use of rescue medication during the overall assessment period. The parameters of CBDCA were defined as follows: (1) CBDCA-AUC; (2) CBDCA/body surface area (BSA): the administered dose of CBDCA per body surface area (mg/m2); and (3) total CBDCA/body: the total administered dose of CBDCA (mg). Eighty-five patients were evaluated. The median CBDCA/BSA but not CBDCA-AUC was higher in patients with non-CR compared to those with CR. Receiver operating characteristic curve analysis revealed that the AUC of CBDCA/BSA for predicting non-CR was higher than that of CBDCA-AUC. CBDCA/BSA shows greater potential for predicting CBDCA-induced emetic risk compared with CBDCA-AUC, which is the parameter in current antiemetic guidelines.

A phase I/II study of osimertinib in EGFR exon 20 insertion mutation-positive non-small cell lung cancer.

OBJECTIVES: Several preclinical data proposed a potential efficacy of osimertinib, a third-generation EGFR tyrosine kinase inhibitor, for EGFR exon 20 insertion (EGFR ex20ins)-positive non-small cell lung cancer (NSCLC). However, reported case series and a retrospective study proposed controversial efficacy. The efficacy of osimertinib in EGFR ex20ins-positive NSCLC have not been well evaluated in prospective clinical trials. In this study, we performed a prospective, single-arm, multi-center, open-label, non-randomized phase I/II study to evaluate efficacy of osimertinib for EGFR ex20ins-positive NSCLC. MATERIALS AND METHODS: From August 2018 to January 2020, 14 NSCLC patients with EGFR ex20ins were enrolled, of whom 2 were excluded because they did not meet the inclusion criteria. Efficacy and safety of 80 mg osimertinib were evaluated. In addition, we performed a translational exploratory study to clarify the association of mutation type-specific drug sensitivity, osimertinib pharmacokinetic data, and clinical efficacy. RESULTS: Of the evaluated patients, none experienced objective response, 7 experienced stable disease (58.3%), and 5 experienced disease progression (41.7%). The median progression free survival (PFS) was 3.8 months, and the median overall survival was 15.8 months. Interestingly, the exploratory study demonstrated statistically significant positive correlation between plasma osimertinib concentration/in vitro IC50 ratio and PFS (R = 0.9912, P = 0.0001), highlighting the mutation type-specific concentration-dependent efficacy of osimertinib for EGFR ex20ins-positive NSCLC. CONCLUSIONS: Regular dose, 80 mg/day, of osimertinib has limited clinical activity in NSCLC patients with EGFR ex20ins. The translational study proposed the potential efficacy of higher dose osimertinib in a subgroup of EGFR ex20ins-positive NSCLC.

Validity of using immunohistochemistry to predict treatment outcome in patients with non-small cell lung cancer not otherwise specified.

PURPOSE: Histology samples are important for the appropriate administration of tumor type-specific cytotoxic and molecular-targeted therapies for the treatment of non-small cell lung cancer (NSCLC). When biopsy samples lack a definite morphology, a diagnosis can be selected from three subtypes based on immunohistochemistry (IHC) results, as follows: favor adenocarcinoma (ADC), favor squamous cell carcinoma (SQC), or not otherwise specified (NOS)-null. In terms of patient outcome, however, the validity of IHC-based classifications remains unknown. METHODS: A large series of 152 patients with advanced NSCLC whose diagnoses had been made based on morphological findings and who had been homogeneously treated were enrolled. We used IHC staining (TTF-1, SP-A, p40, and CK5/6) to examine tumor samples and refined the diagnoses. We then analyzed the pathological subgroups according to the IHC staining results. RESULTS: IHC profiling resulted in 50% of the cases being classified as favor ADC, 31% being classified as favor SQC, and 19% being classified as NOS-null groups. Compared with the favor ADC and favor SQC groups, the NOS-null group had a significantly poorer outcome. Pemetrexed-containing platinum regimens produced a response rate similar to that of other platinum doublet regimens in the favor ADC group (44% vs. 46%), whereas it produced a poorer response in the favor SQC group (0% vs. 52%) and the NOS-null group (0% vs. 24%). The favor ADC group tended to have a higher percentage of EGFR positivity and ALK positivity than the favor SQC group (25% vs. 11% and 7% vs. 0%, respectively). CONCLUSIONS: These findings support the use of immunohistological subtyping of NSCLC biopsy specimens to select patient-appropriate treatments.

DISC1 regulates neurotrophin-induced axon elongation via interaction with Grb2.

Disrupted-in-Schizophrenia-1 (DISC1) is a candidate gene for susceptibility of schizophrenia. In the accompanying paper (Taya et al., 2006), we report that DISC1 acts as a linker between Kinesin-1 and DISC1-interacting molecules, such as NudE-like, lissencephaly-1, and 14-3-3epsilon. Here we identified growth factor receptor bound protein 2 (Grb2) as a novel DISC1-interacting molecule. Grb2 acts as an adaptor molecule that links receptor tyrosine kinases and the Ras-extracellular signal-regulated kinase (ERK) pathway. DISC1 formed a ternary complex with Grb2 and kinesin heavy chain KIF5A of Kinesin-1. In cultured rat hippocampal neurons, both DISC1 and Grb2 partially colocalized at the distal part of axons. Knockdown of DISC1 or kinesin light chains of Kinesin-1 by RNA interference inhibited the accumulation of Grb2 from the distal part of axons. Knockdown of DISC1 also inhibited the neurotrophin-3 (NT-3)-induced phosphorylation of ERK-1/2 at the distal part of axons and inhibited NT-3-induced axon elongation. These results suggest that DISC1 is required for NT-3-induced axon elongation and ERK activation at the distal part of axons by recruiting Grb2 to axonal tips.

Long-term survival outcome after postoperative recurrence of non-small-cell lung cancer: who is 'cured' from postoperative recurrence?

OBJECTIVES: Since survival after postoperative non-small-cell lung cancer (NSCLC) recurrence is extremely poor, the long-term post-recurrence outcomes are not well understood. The purpose of this study was to evaluate the long-term post-recurrence outcomes and clarify who are possibly 'cured' in recent clinical practice. METHODS: We reviewed the medical records of 635 patients who developed postoperative recurrence until 2012 after R0 resection for pathological Stage IA-IIIA NSCLC between 1993 and 2006. Factors associated with post-recurrence survival (PRS) and the characteristics of the long-term (≥5 years) survivors were analysed retrospectively. RESULTS: The 5-year PRS rate of all 635 patients was 13%. Multivariable analysis revealed that female [hazard ratio (HR) = 0.78], adenocarcinoma (HR = 0.77), locoregional (only) recurrence (HR = 0.59) and longer recurrence-free survival (HR = 0.99) were favourably associated with PRS. A total of 51 patients achieved 5-year PRS; however, 32 (63%) were cancer-bearing patients in their fifth post-recurrent year who were mainly treated by epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI). Subsequent PRS curves for cancer-controlled and cancer-bearing groups were different (8-year PRS: 94% vs 31%, P = 0.003). Among 19 cancer-controlled patients in their fifth post-recurrent year, 17 (89%) patients initially received radical local therapy for their recurrence. CONCLUSIONS: Two-thirds of 5-year survivors after postoperative NSCLC recurrence had a cancer-bearing status and showed deteriorated subsequent survival. Curability of postoperative NSCLC recurrence should be evaluated in terms of the 'cancer-controlled' status, and 'cured' population is included in the patients who are 'cancer controlled' at the fifth post-recurrent year.

Factors influencing the concordance of histological subtype diagnosis from biopsy and resected specimens of lung adenocarcinoma.

OBJECTIVES: Lung adenocarcinoma is heterogeneous, characterized by various histological subtypes. Determination of the predominant histological subtype (lepidic, papillary, acinar or solid-predominant) has been shown to correlate with genetic abnormalities and clinicopathological features. Although subtyping using small biopsy samples is important for tailored approaches to clinical management, limited data exist on the concordance of predominant subtype between resected specimens and biopsy specimens. MATERIALS AND METHODS: We compared the diagnosed predominant subtypes in resected specimens and matched biopsy specimens in a series of 327 lung adenocarcinomas. The accuracy of preoperative diagnosis by biopsy and the factors that influence concordance with resected specimen analysis were examined. RESULTS: In 211 of the 326 patients (66.0%), the predominant adenocarcinoma subtype diagnosed from biopsy matched the findings of resection analysis. Overall, the concordance rate in biopsy samples with larger tumor areas (≥ 0.7 mm(2)) was significantly higher than in those with smaller tumor area (<0.7 mm(2); 71.2% vs 60.7%, respectively; p=0.015). In the biopsy samples with smaller tumor areas, the concordance rate was 77% in lepidic subtype, 71% in papillary subtype, 60% in solid subtype, and 40% in acinar subtype. Concordance rate in the biopsy samples with larger tumor area was higher in papillary and solid subtypes (88% and 76%, respectively), but remained low in acinar subtype (37%). CONCLUSION: The current results indicate that accuracy of adenocarcinoma subtyping based on small biopsy samples is influenced by tumor area. Our study also suggests that subtyping of acinar histology using biopsy specimen is particularly error-prone.