Comparative analysis of different response criteria at early phase after PD-1 blockade in non-small lung cancer.

PURPOSE: To compare different response criteria using computed tomography (CT) and positron emission tomography (PET) in measuring response and survival in the early phase after programmed death-1 (PD-1) blockade monotherapy in patients with advanced non-small cell lung cancer (NSCLC). METHODS: A total of 54 patients with advanced NSCLC who had 2-deoxy-2-[fluorine-18]-fluoro-D-glucose PET or CT at baseline, and 4 and 9 weeks after PD-1 blockade, were registered. Therapeutic response was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST), the immune-modified RECIST (irRECIST), the PET Response Criteria in Solid Tumors (PERCIST), the immune-modified PERCIST (iPERCIST), and the European Organization for Research and Treatment of Cancer (EORTC) criteria for dichotomous groups, such as responders vs. non-responders and controlled vs. uncontrolled diseases. Cohen's κ was used to evaluate the concordance among the different criteria. RESULTS: The concordance between CT and PET response criteria was fair or slight for responders vs. non-responders, but the agreement between iPERCIST and irRECIST was moderate for controlled vs. uncontrolled diseases. The agreement between EORTC and PERCIST or iPERCIST in detecting responders was higher in the application of metabolic tumor volume (MTV) and total lesion glycolysis (TLG) than in the standardized uptake value corrected for lean body mass (SUL)peak. To distinguish controlled from uncontrolled disease, RECIST, irRECIST, and PET criteria (PERCIST, iPERCIST, and EORTC) defined by MTV or TLG were found to be significant predictors of progression-free survival. To distinguish responders from non-responders, iPERCIST by SULpeak or EORTC by TLG were identified as significant indicators. The EORTC criteria using TLG for the detection of responders or uncontrolled diseases had a significantly higher predictive value for response assessment. CONCLUSIONS: The EORTC criteria based on TLG for the early detection of responders and uncontrolled disease were effective as a response assessment at 4 weeks after the PD-1 blockade. When SULpeak was not used but MTV or TLG was, the agreement between EORTC and PERCIST or iPERCIST was almost perfect.

Efficacy and safety of amrubicin therapy after chemoimmunotherapy in small cell lung cancer patients.

Background: Although the addition of immune checkpoint inhibitors (ICIs) to platinum-doublet chemotherapy has improved the efficacy of first-line therapy in extensive-disease small cell lung cancer (SCLC) patients, the best treatment option for patients with recurrent SCLC has not yet been determined. We conducted a retrospective study to evaluate the efficacy and safety of amrubicin (AMR) therapy after treatment with ICIs. Methods: We retrospectively assessed patients with recurrent SCLC who received AMR after chemoimmunotherapy at the Niigata Lung Cancer Treatment Group from August 2019 to February 2021. Results: This analysis included 30 patients. The median progression-free survival (PFS) and overall survival (OS) were 3.8 (95% CI: 2.7-4.2) and 10 (95% CI: 7.4-14.8) months, respectively. The median PFS and OS did not significantly differ between the sensitive and refractory groups [PFS; 3.1 (95% CI: 1.1-4.0) vs. 4.2 (95% CI: 2.3-4.8) months, P=0.1142, OS; 10.0 (95% CI: 5.2-14.8) vs. 10.4 (95% CI: 3.8-NE) months, P=0.5525]. The most common adverse event was grade ≥3 neutropenia, which occurred in 22 of 30 patients (73%), and 2 patients (7%) discontinued AMR due to adverse events. Conclusions: AMR after chemoimmunotherapy shows good clinical efficacy and safety in patients with recurrent SCLC.

Phase II study of nanoparticle albumin-bound paclitaxel monotherapy for relapsed non-small cell lung cancer with patient-reported outcomes (NLCTG1302).

Background: This multicenter, open-label, single-arm phase II study [Niigata Lung Cancer Treatment Group (NLCTG) 1302] was conducted to evaluate the efficacy and safety of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) monotherapy for previously treated patients with advanced non-small cell lung cancer (NSCLC). We also investigated chemotherapy-induced peripheral neuropathy (CIPN) to evaluate the quality of life (QOL). Methods: Sixty-five patients with advanced NSCLC from 14 participating institutions who had previously undergone one or two cytotoxic chemotherapy regimens were enrolled in this study. The patients received 100 mg/m2 nab-paclitaxel intravenously on days 1, 8, and 15, every 4 weeks. The primary endpoint was overall objective response rate. CIPN symptoms were prospectively assessed using the Patient Neurotoxicity Questionnaire (PNQ) and Common Terminology Criteria for Adverse Events (CTCAE). Results: The overall response rate (ORR) was 18.5% [95% confidence interval (CI): 10.9-29.6%], and the median progression-free survival (PFS) was 3.4 (95% CI: 2.5-4.3) months. Median overall survival (OS) was 8.6 (95% CI: 7.1-10.2) months. The most common non-hematologic grade ≥3 adverse events were infection (7.7%) and hyponatremia (4.6%). Neutropenia was the most common grade 3 or 4 adverse event (30.8%), and febrile neutropenia developed in 6.2% patients. The PNQ and CTCAE scores for motor peripheral neuropathy were low (kappa =0.10). Conclusions: The primary endpoint was achieved. Nab-paclitaxel was well tolerated and showed anti-tumor activity in patients with previously treated NSCLC. This study demonstrates a low degree of concordance in CIPN grading between physicians and patients. Trial Registration: University hospital Medical Information Network Clinical Trial Registry (ID: UMIN000012343).

Prospective assessment using 18F-FDG PET/CT as a novel predictor for early response to PD-1 blockade in non-small-cell lung cancer.

Anti-programmed death-1 (PD-1) blockade is a standard treatment for advanced non-small-cell lung cancer (NSCLC). However, no appropriate modality exists for monitoring its therapeutic response immediately after initiation. Therefore, we aimed to elucidate the clinical relevance of 18F-FDG PET/CT versus CT in predicting the response to PD-1 blockade in the early phase. This prospective study included a total of 54 NSCLC patients. 18F-FDG PET/CT was performed at 4 weeks and 9 weeks after PD-1 blockade monotherapy. Maximum standardized uptake values (SULmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were evaluated. Among all patients, partial metabolic response and progressive metabolic disease after PD-1 blockade were observed in 35.2% and 11.1% on SULmax, 22.2% and 51.8% on MTV, and 27.8% and 46.3% on TLG, respectively, whereas a partial response (PR) and progressive disease (PD), respectively, based on RECIST v1.1 were recognized in 35.2% and 35.2%, respectively. The predictive probability of PR (MTV: 57.9% vs. 21.1%, p = 0.044; TLG: 63.2% vs. 21.1%, p = 0.020) and PD (MTV: 78.9% vs. 47.3%, p = 0.002; TLG: 73.7% vs. 21.1%, p = 0.007) detected based on RECIST at 4 weeks after PD-1 blockade initiation was significantly higher using MTV or TLG on 18F-FDG uptake than on CT. Multivariate analysis revealed that metabolic response by MTV or TLG at 4 weeks was an independent factor for response to PD-1 blockade treatment. Metabolic assessment by MTV or TLG was superior to morphological changes on CT for predicting the therapeutic response and survival at 4 weeks after PD-1 blockade.

Observational study of rebiopsy in EGFR-TKI-resistant patients with EGFR mutation-positive advanced NSCLC.

The identification of acquired resistance mutations has been essential in non-small-cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) active mutations. Rebiopsy plays a pivotal role in selecting the optimal treatment for patients who develop resistance to initial EGFR-tyrosine kinase inhibitors (EGFR-TKIs). This multicenter, observational study was conducted to investigate the details of rebiopsy in Japanese clinical practice. The primary endpoints were the implementation rate of rebiopsy and the concordance rate for T790M mutation detection between histological and cytological specimens using the cobas EGFR Mutation Test, version 2. One hundred ninety-four patients with EGFR-mutant NSCLC were enrolled, and 120 patients developed acquired resistance to EGFR-TKIs. The median age was 68 years (range 20-87), and 52.5% of the patients were women. Rebiopsy was performed in 109 patients, and the implementation rate of rebiopsy was 90.8%. The success rates of rebiopsy in the total, histology, cytology and liquid biopsy populations were 67.9%, 81.3%, 66.7% and 43.8%, respectively. The positive percent agreement and the negative percent agreement in the detection of the T790M mutation between the histological and cytological specimens were both 90.9%. Obtaining histological or cytological tissue samples at rebiopsy may contribute to improving the detection rate of the T790M mutation (trial registration number: UMIN000026019).

Prognostic significance of procalcitonin in small cell lung cancer.

BACKGROUND: Procalcitonin (PCT) is a serological marker whose utility has been established in infectious disease areas. Although serum calcitonin is a prognostic predictor in patients with medullary thyroid carcinoma, the clinical usefulness of PCT remains unclear in lung cancer patients. METHODS: As a discovery cohort, we retrospectively analyzed consecutive patients with non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) who received first-line chemotherapy at our institution, and PCT blood levels were measured. As the validation cohort, PCT blood levels were prospectively evaluated in SCLC patients before first-line chemotherapy. The correlation between a PCT increase and prognosis was examined in the discovery and validation cohorts. RESULTS: Twenty-three SCLC patients and 26 NSCLC patients were enrolled as the discovery cohort, and 30 SCLC patients were enrolled as the validation cohort. The PCT level in SCLC patients was significantly higher than that in NSCLC patients. The PCT level was not associated with WBC count and weakly associated with the CRP level. In both the discovery and validation cohorts, the median survival time was significantly shorter in SCLC patients with PCT-high than in SCLC patients with PCT-normal (discovery; 11.7 vs. 89.7 months, P<0.005, validation; 9.6 vs. 22.6 months, P<0.005). CONCLUSIONS: It may be difficult to differentiate bacterial infections in SCLC patients by PCT, as PCT is elevated even in SCLC patients without infectious diseases. This is the first study to prospectively verify that pretreatment PCT levels have a significant negative correlation with prognosis in SCLC patients.

HER3 activation contributes toward the emergence of ALK inhibitor-tolerant cells in ALK-rearranged lung cancer with mesenchymal features.

Anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs) have shown dramatic efficacy in patients with ALK-rearranged lung cancer; however, complete response in these patients is rare. Here, we investigated the molecular mechanisms underlying the emergence and maintenance of drug-tolerant cells in ALK-rearranged lung cancer. Cell based-assays demonstrated that HER3 activation and mesenchymal-to-epithelial transition, mediated through ZEB1 proteins, help maintain cell survival and induce the emergence of ALK-TKI-tolerant cells. Compared with ALK-TKIs alone, cotreatment with pan-HER inhibitor afatinib and ALK-TKIs prevented tumor regrowth, leading to the eradication of tumors in ALK-rearranged tumors with mesenchymal features. Moreover, pre-treatment vimentin expression in clinical specimens obtained from patients with ALK-rearranged lung cancer was associated with poor ALK-TKI treatment outcomes. These results demonstrated that HER3 activation plays a pivotal role in the emergence of ALK-TKI-tolerant cells. Furthermore, the inhibition of HER3 signals combined with ALK-TKIs dramatically improves treatment outcomes for ALK-rearranged lung cancer with mesenchymal features.

PD-1 blockade therapy augments the antitumor effects of lymphodepletion and adoptive T cell transfer.

Lymphodepleting cytotoxic regimens enhance the antitumor effects of adoptively transferred effector and naïve T cells. Although the mechanisms of antitumor immunity augmentation by lymphodepletion have been intensively investigated, the effects of lymphodepletion followed by T cell transfer on immune checkpoints in the tumor microenvironment remain unclear. The current study demonstrated that the expression of immune checkpoint molecules on transferred donor CD4+ and CD8+ T cells was significantly decreased in lymphodepleted tumor-bearing mice. In contrast, lymphodepletion did not reduce immune checkpoint molecule levels on recipient CD4+ and CD8+ T cells. Administration of anti-PD-1 antibodies after lymphodepletion and adoptive transfer of T cells significantly inhibited tumor progression. Further analysis revealed that transfer of both donor CD4+ and CD8+ T cells was responsible for the antitumor effects of a combination therapy consisting of lymphodepletion, T cell transfer and anti-PD-1 treatment. Our findings indicate that a possible mechanism underlying the antitumor effects of lymphodepletion followed by T cell transfer is the prevention of donor T cell exhaustion and dysfunction. PD-1 blockade may reinvigorate exhausted recipient T cells and augment the antitumor effects of lymphodepletion and adoptive T cell transfer.

The Prognostic Significance of the Continuous Administration of Anti-PD-1 Antibody via Continuation or Rechallenge After the Occurrence of Immune-Related Adverse Events.

OBJECTIVES: Although immune checkpoint inhibitors (ICIs) have been shown to improve overall survival (OS) in advanced non-small-cell lung cancer (NSCLC) patients, ICIs sometimes cause various types of immune-related adverse events (irAEs), which lead to the interruption of ICI treatment. This study aims to evaluate the clinical significance of the continuation of ICIs in NSCLC patients with irAEs and to assess the safety and efficacy of the readministration of ICIs after their discontinuation due to irAEs. METHODS: We retrospectively identified patients with advanced NSCLC who were treated with first- to third-line anti-programmed cell death-1 (PD-1) therapy from January 2016 through October 2017 at multiple institutions belonging to the Niigata Lung Cancer Treatment Group. Progression-free survival (PFS) and OS from the initiation of ICI treatment were analyzed in patients with and without irAEs, with and without ICI interruption, and with and without ICI readministration. A 6-week landmark analysis of PFS and OS was performed to minimize the lead-time bias associated with time-dependent factors. RESULTS: Of 231 patients who received anti-PD-1 antibodies, 93 patients (40%) developed irAEs. Of 84 eligible patients with irAEs, 32 patients (14%) continued ICIs, and OS was significantly longer in patients who continued ICIs than that in patients who discontinued ICIs [not reached (95% CI: NE-NE) vs. not reached (95% CI: 22.4-NE); p = 0.025]. Of 52 patients who discontinued ICIs, 14 patients (6.1%) readministered ICIs, and OS in patients with ICI readministration was significantly longer than that in patients without ICI readministration [not reached (95% CI: NE-NE) vs. not reached (95% CI: 8.4-NE); p = 0.031]. CONCLUSION: The current study demonstrated that both the continuation and readministration of ICIs after irAE occurrence improved OS compared to the permanent interruption of ICIs in NSCLC patients with ICI-related irAEs.

Subsequent systemic therapy for non-small cell lung cancer patients with immune checkpoint inhibitor-related interstitial lung disease.

BACKGROUND: Although immune checkpoint inhibitors (ICIs) are effective for advanced non-small cell lung cancer (NSCLC), ICIs may cause interstitial lung disease (ILD), which results in treatment discontinuation and is sometimes fatal. Despite the high incidence of ICI-related ILD, there are few cancer treatment options for patients. This study aimed to evaluate the safety and efficacy of subsequent systemic cancer therapy in NSCLC patients with ICI-related ILD. METHODS: We retrospectively assessed NSCLC patients who received programmed cell death-1 (PD-1) inhibitors as first- to third-line therapy at participating institutions of the Niigata Lung Cancer Treatment Group from January 2016 to October 2017. RESULTS: This analysis included 231 patients, 32 (14%) of whom developed ICI-related ILD. Of these patients, 16 (7%) received subsequent systemic cancer treatments. The median overall survival (OS) tended to be longer in the systemic cancer therapy group than in the no systemic cancer therapy group [22.2 months (95% CI: 1-NE) vs. 4.5 months (95% CI: 1-NE); P=0.067]. ICI-related ILD recurred in half of the patients who received systemic cancer therapy, and the median OS tended to be shorter in patients with recurrent ICI-related ILD [22.0 months (95% CI: 1-NE) vs. 7.0 months (95% CI: 1-NE); P=0.3154]. CONCLUSIONS: According to the current study, systemic cancer treatment is effective in patients with ICI-related ILD; however, its safety is uncertain because of the high risk of ICI-related ILD recurrence and poor survival outcome following ILD recurrence.

A prospective phase II study of multimodal prophylactic treatment for afatinib-induced adverse events in advanced non-small cell lung cancer (Niigata Lung Cancer Treatment Group 1401).

BACKGROUND: Afatinib has shown clinical benefits in patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations. Many patients treated with afatinib experience skin or gastrointestinal toxicity. However, an effective management strategy has not been established. This prospective study was conducted to evaluate the efficacy of multimodal prophylactic treatment for afatinib-induced toxicity. METHODS: This single-arm prospective study was conducted to evaluate the efficacy of multimodal prophylactic treatment for afatinib-induced toxicity in patients with EGFR mutation positive advanced NSCLC who planned to receive a 40 mg dose of afatinib. Eligible patients were treated with oral loperamide (2 mg twice per day), prophylactic minocycline (100 mg once per day), topical medium-class steroids, and gargling with sodium azulene. The primary endpoint was the ability of prophylactic loperamide to prevent severe or intolerable diarrhea during the 4 weeks after the initial administration of afatinib. The incidence, severity and time to occurrence of diarrhea, rash, oral mucositis and paronychia were evaluated based on a daily patient questionnaire. RESULTS: Forty-six patients were enrolled. The primary endpoint analysis was performed in 35 patients as the per-protocol (PP) population. The 4-week successful prophylaxis rate for severe or intolerable diarrhea was 82.9% (90% confidence interval: 70.1-91.9%). In the total population, the incidences of grade 3 or higher rash, oral mucositis and paronychia within 4 weeks were 4%, 2% and 4%, respectively. CONCLUSIONS: Prophylactic loperamide administration was not effective in preventing severe or intolerable diarrhea during afatinib treatment. Adequate dose reduction will be a better approach to manage afatinib-induced diarrhea. Multimodal prevention using minocycline, topical steroids and gargling with sodium azulene may be helpful to maintain compliance with afatinib treatment (UMIN000016167).

Combination therapy of cisplatin with cilastatin enables an increased dose of cisplatin, enhancing its antitumor effect by suppression of nephrotoxicity.

Cisplatin, one of the most active anticancer agents, is widely used in standard chemotherapy for various cancers. Cisplatin is more poorly tolerated than other chemotherapeutic drugs, and the main dose-limiting toxicity of cisplatin is its nephrotoxicity, which is dose-dependent. Although less toxic methods of cisplatin administration have been established, cisplatin-induced nephrotoxicity remains an unsolved problem. Megalin is an endocytic receptor expressed at the apical membrane of proximal tubules. We previously demonstrated that nephrotoxic drugs, including cisplatin, are reabsorbed through megalin and cause proximal tubular cell injury. We further found that cilastatin blocked the binding of cisplatin to megalin in vitro. In this study, we investigated whether cilastatin could reduce cisplatin-induced nephrotoxicity without influencing the antitumor effects of cisplatin. Nephrotoxicity was decreased or absent in mice treated with cisplatin and cilastatin, as determined by kidney injury molecule-1 staining and the blood urea nitrogen content. Combined with cilastatin, a twofold dose of cisplatin was used to successfully treat the mice, which enhanced the antitumor effects of cisplatin but reduced its nephrotoxicity. These findings suggest that we can increase the dose of cisplatin when combined with cilastatin and improve the outcome of cancer patients.

Disseminated Varicella-zoster Virus Infection Causing Fatal Pneumonia in an Immunocompromised Patient with Chronic Interstitial Pneumonia.

Viral pneumonia caused by varicella-zoster virus (VZV) infection is a rare but important complication, especially regarding varicella infections. Although disseminated cutaneous herpes zoster (DCHZ) is often associated with visceral diseases, there have been few reports of DCHZ-related pneumonia. We herein report a rare case of a lethal disseminated VZV infection that caused severe pneumonia in a Japanese patient who had chronic interstitial pneumonia. Physicians should consider the possibility of VZV-related pneumonia, especially in patients with a medical history of hematopoietic stem cell transplantation and immunosuppressive therapy.

Frequent Germline and Somatic Single Nucleotide Variants in the Promoter Region of the Ribosomal RNA Gene in Japanese Lung Adenocarcinoma Patients.

Ribosomal RNA (rRNA), the most abundant non-coding RNA species, is a major component of the ribosome. Impaired ribosome biogenesis causes the dysfunction of protein synthesis and diseases called "ribosomopathies," including genetic disorders with cancer risk. However, the potential role of rRNA gene (rDNA) alterations in cancer is unknown. We investigated germline and somatic single-nucleotide variants (SNVs) in the rDNA promoter region (positions -248 to +100, relative to the transcription start site) in 82 lung adenocarcinomas (LUAC). Twenty-nine tumors (35.4%) carried germline SNVs, and eight tumors (9.8%) harbored somatic SNVs. Interestingly, the presence of germline SNVs between positions +1 and +100 (n = 12; 14.6%) was associated with significantly shorter recurrence-free survival (RFS) and overall survival (OS) by univariate analysis (p < 0.05, respectively), and was an independent prognostic factor for RFS and OS by multivariate analysis. LUAC cell line PC9, carrying rDNA promoter SNV at position +49, showed significantly higher ribosome biogenesis than H1650 cells without SNV. Upon nucleolar stress induced by actinomycin D, PC9 retained significantly higher ribosome biogenesis than H1650. These results highlight the possible functional role of SNVs at specific sites of the rDNA promoter region in ribosome biogenesis, the progression of LUAC, and their potential prognostic value.

Prognostic significance of the radiologic features of pneumonitis induced by anti-PD-1 therapy.

BACKGROUND: Interstitial lung disease (ILD) induced by anti-programmed-cell death-1 (PD-1) and anti-PD-ligand 1 (PD-L1) is potentially life-threatening and is a common reason of the discontinuation of therapy. In contrast, an enhancement in antitumor effects was reported in patients who developed immune-related adverse events, including ILD. Although recent evidence suggests that radiologic patterns of ILD may reflect the severity of ILD and the antitumor immune responses to anti-PD-1/PD-L1 therapies, the association between radiologic features and clinical outcomes remains unclear. METHODS: Patients with advanced non-small-cell lung cancer who were treated with 1st to 3rd line anti-PD-1 therapy from January 2016 through October 2017 were identified at multiple institutions belonging to the Niigata Lung Cancer Treatment Group. ILD was diagnosed by the treating physicians, and chest computed tomography scans were independently reviewed to assess the radiologic features of ILD. RESULTS: A total of 231 patients who received anti-PD-1 therapy were enrolled. Thirty-one patients (14%) developed ILD. Sixteen patients were classified as having ground glass opacities (GGO), 16 were classified as having cryptogenic organizing pneumonia (COP), and one was classified as having pneumonitis not otherwise specified. Patients with GGO had significantly worse overall survival time compared to patients with COP (7.8 months (95% CI: 2.2-NE) versus not reached (95% CI: 13.2-NE); P = 0.0175). Multivariate analysis of all 231 patients also revealed that PS = 1 and ≥2 and GGO were significant predictors of a worse overall survival. CONCLUSIONS: This study demonstrated that patients who developed GGO exhibited worse outcomes among non-small-cell lung cancer patients receiving anti-PD-1 therapies.

Efficacy of EGFR-TKIs with or without upfront brain radiotherapy for EGFR-mutant NSCLC patients with central nervous system metastases.

BACKGROUND: Although the clinical efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in EGFR-mutant non-small cell lung cancer (NSCLC) patients has been demonstrated, their efficacy in EGFR-mutant NSCLCs with central nervous system (CNS) metastases and the role of radiotherapy remain unclear. This study aimed to determine if it is preferable to add upfront cranial radiotherapy to EGFR-TKIs in patients with EGFR-mutant NSCLC with newly diagnosed brain metastases. METHODS: We retrospectively analyzed the data of EGFR-mutant NSCLC patients with CNS metastases who received EGFR-TKIs as a first-line therapy. RESULTS: A total of 104 patients were enrolled and 39 patients received upfront brain radiotherapy, while 65 patients received first and second generation EGFR-TKIs first. The median time to treatment failure (TTF) was 7.8 months (95% confidence interval [CI]: 6.3-9.4). The median survival time (MST) was 24.0 months (95% CI: 20.1-30.1). The overall response rate of the CNS was 37%. The median CNS progression-free survival (PFS) was 13.2 months (95% CI: 10.0-16.2). Brain radiotherapy prior to EGFR-TKI prolonged TTF (11.2 vs. 6.8 months, P = 0.038) and tended to prolong CNS-PFS (15.6 vs. 11.1 months, P = 0.096) but was not significantly associated with overall survival (MST 26.1 vs. 24.0 months, P = 0.525). Univariate and multivariate analyses indicated that poor performance status and the presence of extracranial metastases were poor prognostic factors related to overall survival. CONCLUSION: EGFR-TKI showed a favorable effect for EGFR-mutant NSCLC patients with CNS metastases. Prolonged TTF and CNS-PFS were observed with upfront brain radiotherapy.

Retrospective analysis of antitumor effects and biomarkers for nivolumab in NSCLC patients with EGFR mutations.

Although the blockade of programmed cell death 1 (PD-1)/PD-ligand (L) 1 has demonstrated promising and durable clinical responses for non-small-cell lung cancers (NSCLCs), NSCLC patients with epidermal growth factor receptor (EGFR) mutations responded poorly to PD-1/PD-L1 inhibitors. Previous studies have identified several predictive biomarkers, including the expression of PD-L1 on tumor cells, for PD-1/PD-L1 blockade therapies in NSCLC patients; however, the usefulness of these biomarkers in NSCLCs with EGFR mutations has not been elucidated. The present study was conducted to evaluate the predictive biomarkers for PD-1/PD-L1 inhibitors in EGFR-mutated NSCLCs. We retrospectively analyzed 9 patients treated with nivolumab for EGFR-mutated NSCLCs. All but one patient received EGFR-tyrosine kinase inhibitors before nivolumab treatment. The overall response rate and median progression-free survival were 11% and 33 days (95% confidence interval (CI); 7 to 51), respectively. Univariate analysis revealed that patients with a good performance status (P = 0.11; hazard ratio (HR) 0.183, 95% CI 0.0217 to 1.549), a high density of CD4+ T cells (P = 0.136; HR 0.313, 95% CI 0.045 to 1.417) and a high density of Foxp3+ cells (P = 0.09; HR 0.264, 95% CI 0.0372 to 1.222) in the tumor microenvironment tended to have longer progression-free survival with nivolumab. Multivariate analysis revealed that a high density of CD4+ T cells (P = 0.005; HR<0.001, 95% CI <0.001 to 0.28) and a high density of Foxp3+ cells (P = 0.003; HR<0.001, 95% CI NA) in tumor tissues were strongly correlated with better progression-free survival. In contrast to previous studies in wild type EGFR NSCLCs, PD-L1 expression was not associated with the clinical benefit of anti-PD-1 treatment in EGFR-mutated NSCLCs. The current study indicated that immune status in the tumor microenvironment may be important for the effectiveness of nivolumab in NSCLC patients with EGFR mutations.

A Phase II Study of Irinotecan for Patients with Previously Treated Small-Cell Lung Cancer.

OBJECTIVE: Chemotherapy with irinotecan plus cisplatin has shown promise in chemo-naïve small-cell lung cancer (SCLC) patients. However, irinotecan treatment for relapsed or refractory SCLC has not been adequately evaluated. This phase II study evaluated the appropriate treatment schedule of irinotecan as a single agent. This study was designed to determine the antitumor activity, toxicity, and survival in previously treated SCLC patients. METHODS: Previously treated SCLC patients with at least one platinum-based regimen received irinotecan (100 mg/m2) on days 1 and 8, every 3 weeks, until disease progression. The assessment of the response rate was the primary endpoint. RESULTS: Thirty patients were enrolled, with an objective response rate of 41.3% (95% confidence interval [CI] 25.5-59.3), and a disease control rate of 69%. Median progression-free and overall survival was 4.1 months (95% CI, 2.2-5.4) and 10.4 months (95% CI, 8.1-14), respectively. The grade 3/4 hematological toxicities were neutropenia (36.7%), thrombocytopenia (3.3%), anemia (13.3%), and febrile neutropenia (6.6%). There were no grade 4 nonhematological toxicities. Frequent grade 3 nonhematological toxicities included diarrhea (10%), anorexia (6.6%), and hyponatremia (6.6%). CONCLUSIONS: This phase II study showed a high objective response rate and long survival. Irinotecan monotherapy schedule used was well tolerated, and could be an active treatment option for these patients.

Transfer of in vitro-expanded naïve T cells after lymphodepletion enhances antitumor immunity through the induction of polyclonal antitumor effector T cells.

The adoptive transfer of effector T cells combined with lymphodepletion has demonstrated promising antitumor effects in mice and humans, although the availability of tumor-specific T cells is limited. We and others have also demonstrated that the transfer of polyclonal naïve T cells induces tumor-specific effector T cells and enhances antitumor immunity after lymphodepletion. Because tumors have been demonstrated to induce immunosuppressive networks and regulate the function of T cells, obtaining a sufficient number of fully functional naïve T cells that are able to differentiate into tumor-specific effector T cells remains difficult. To establish culture methods to obtain a large number of polyclonal T cells that are capable of differentiating into tumor-specific effector T cells, naïve T cells were activated with anti-CD3 mAbs in vitro. These cells were stimulated with IL-2 and IL-7 for the CD8 subset or with IL-7 and IL-23 for the CD4 subset. Transfer of these hyperexpanded T cells after lymphodepletion showed significant antitumor efficacy, and tumor-specific effector T cells were primed from these expanded T cells in tumor-bearing hosts. Moreover, these ex vivo-expanded T cells maintained T cell receptor diversity and showed long-term persistence of memory against specific tumors. Further analyses revealed that combination therapy consisting of vaccination with dendritic cells that were co-cultured with irradiated whole tumor cells and the transfer of ex vivo-expanded T cells significantly enhanced antitumor immunity. These results indicate that the transfer of ex vivo-expanded polyclonal T cells can be combined with other immunotherapies and augment antitumor effects.

Hypertrophic Pulmonary Osteoarthropathy in Anaplastic Lymphoma Kinase (ALK)-positive Lung Cancer.

A 49-year-old man was admitted to a hospital with chest pain and polyarthralgia. Chest radiography showed abnormal findings, and chest computed tomography showed a mass in the right lung. A transbronchial lung biopsy led to a diagnosis of anaplastic lymphoma kinase (ALK)-positive adenocarcinoma. Bone scintigraphy revealed bilateral symmetrical accumulations of (99m)Technetium complexes in the long bones, suggesting co-existing hypertrophic pulmonary osteoarthropathy (HPO). The patient underwent four courses of chemotherapy with cisplatin plus pemetrexed, which led to decreased (99m)Technetium accumulations in the long bones. To the best of our knowledge, this is the first reported case of HPO associated with ALK-positive lung cancer.