Risk and survival of patients with non-small cell lung cancer and pre-existing autoimmune disorders receiving immune checkpoint blockade therapy: Survival analysis with inverse probability weighting from a nationwide, multi-institutional, retrospective study (NEJ047).

BACKGROUND: The risk and survival of patients with non-small cell lung cancer (NSCLC) with pre-existing autoimmune disorders (AIDs) receiving immune checkpoint blockade (ICB) therapy have not been clearly established. PATIENTS AND METHODS: This multi-institutional, retrospective cohort study was conducted in collaboration with 20 centers in Japan. RESULTS: In total, 229 patients with advanced or recurrent NSCLC and pre-existing AID, with or without ICB treatment from January 2010-February 2020, were included and analyzed. Among 69 patients who received ICB, 2 received two lines of ICBs with a total of 71 ICB treatments; 57 (80.3 %) and 14 (19.7 %) patients received ICB monotherapy and combination therapy, respectively. AID flares were observed in 18 patients (25.4 %, 95 % confidence interval [CI], 15.8-37.1 %) receiving ICB. AID exacerbations were more likely when NSCLC was diagnosed less than 1 year after the AID diagnosis (odds ratio 5.26 [95 % CI, 1.40-21.61]; P = 0.016). Immune-related adverse events were observed in 32 patients (45.1 %, 95 % CI, 33.2-57.3 %); 17 had grade 3 or higher. The safety profile of combination immunotherapy was not significantly different from that of the monotherapy. After inverse probability weighting, the use of ICB prolonged survival (hazard ratio 0.43 [95 % CI, 0.26-0.70]; P = 0.0006). CONCLUSIONS: These findings revealed a novel risk factor for AID flares following ICB treatment, that is the diagnosis of NSCLC within 1 year of AID diagnosis, and showed that ICBs may improve survival in this population. These results support the utilization of ICB in patients with NSCLC and pre-existing AID.

Extended ICI treatment after first-line chemoimmunotherapy could predict the clinical benefit of ramucirumab plus docetaxel in advanced non-small lung cancer: Post hoc analysis from NEJ051 (REACTIVE study).

BACKGROUND: The factors that predict the clinical response to ramucirumab plus docetaxel (RD) after first-line chemoimmunotherapy are unresolved. We explored whether the therapeutic efficacy of prior chemoimmunotherapy could predict the outcome of RD as sequential therapy in patients with advanced non-small cell lung cancer (NSCLC). METHODS: Our study comprised 288 patients with advanced NSCLC who received RD as the second-line treatment after first-line chemoimmunotherapy at 62 Japanese institutions. Chemoimmunotherapy consisted of a platinum-based regimen and immune checkpoint inhibitors (ICIs). The association between several variables and the therapeutic outcome of RD was determined via logistic regression analysis. RESULTS: Of the 288 patients, 225 (78.1%) received maintenance therapy and 108 (37.5%) received both ICI treatment for >180 days and maintenance therapy. All of 108 patients having ICIs for >180 days received maintenance therapy. Univariate analysis identified performance status, histology (adenocarcinoma), maintenance therapy, and ICI treatment >180 days as significant predictors of better progression-free survival (PFS) and overall survival (OS) after RD administration. Multivariate analysis confirmed that these factors independently predicted favorable PFS and OS. The therapeutic response and PD-L1 expression were not closely associated with outcome after RD treatment. In particular, maintenance therapy >4 cycles was more predictive of the better prognosis for RD treatment. CONCLUSION: Extended ICI treatment after chemoimmunotherapy and maintenance therapy enhanced the efficacy of second-line RD treatment in patients with advanced NSCLC.

A Prospective Cohort Study Assessing the Relationship between Plasma Levels of Osimertinib and Treatment Efficacy and Safety.

Osimertinib is a standard treatment for patients with EGFR-mutated non-small cell lung carcinoma (NSCLC). We evaluated the relationship between plasma osimertinib concentrations and treatment outcome in patients with NSCLC for this cohort study. The plasma levels of osimertinib and its metabolite AZ5104 were measured a week after the start of treatment (P1). The primary endpoint was to evaluate the correlation between plasma concentration and adverse events (AEs). The correlation with treatment efficacy was one of the secondary endpoints. In patients with CNS metastases, the concentration in the cerebrospinal fluid was also measured. Forty-one patients were enrolled. The frequency of AEs was highest for rash, followed by anorexia and thrombocytopenia. Thirty-eight cases provided measurements for P1. The median plasma concentration of osimertinib was 227 ng/mL, and that of AZ5104 was 16.5 ng/mL. The mean CNS penetration rate of two cases was 3.8%. The P1 in the group with anorexia was significantly higher than that in the group without anorexia (385.0 ng/mL vs. 231.5 ng/mL, p = 0.009). Divided into quartiles by P1 trough level, Q2 + Q3 (164-338 ng/mL) had longer PFS, while Q1 and Q4 had shorter PFS. An appropriate plasma level of osimertinib may avoid some adverse events and induce long PFS. Further large-scale trials are warranted.

A Large-Scale Prospective Concordance Study of Plasma- and Tissue-Based Next-Generation Targeted Sequencing for Advanced Non-Small Cell Lung Cancer (LC-SCRUM-Liquid).

PURPOSE: We evaluated plasma cell-free DNA (cfDNA) and tissue-based sequencing concordance for comprehensive oncogenic driver detection in non-small cell lung cancer (NSCLC) using a large-scale prospective screening cohort (LC-SCRUM-Liquid). EXPERIMENTAL DESIGN: Blood samples were prospectively collected within 4 weeks of corresponding tumor tissue sampling from patients with advanced NSCLC to investigate plasma cfDNA sequencing concordance for alterations in 8 oncogenes (EGFR, KRAS, BRAF, HER2, MET, ALK, RET, and ROS1) compared with tissue-based next-generation targeted sequencing. RESULTS: Paired blood and tissue samples were obtained in 1,062/1,112 enrolled patients with NSCLC. Oncogenic alteration was detected by plasma cfDNA sequencing and tissue assay in 455 (42.8%) and 537 (50.5%) patients, respectively. The positive percent agreement of plasma cfDNA sequencing compared with tissue DNA and RNA assays were 77% (EGFR, 78%; KRAS, 75%; BRAF, 85%; HER2, 72%) and 47% (ALK, 46%; RET, 57%; ROS1, 18%; MET, 66%), respectively. Oncogenic drivers were positive for plasma cfDNA and negative for tissue due to unsuccessful genomic analysis from poor-quality tissue samples (70%), and were negative for plasma cfDNA and positive for tissue due to low sensitivity of cfDNA analysis (61%). In patients with positive oncogenic drivers by plasma cfDNA sequencing but negative by tissue assay, the response rate of genotype-matched therapy was 85% and median progression-free survival was 12.7 months. CONCLUSIONS: Plasma cfDNA sequencing in patients with advanced NSCLC showed relatively high sensitivity for detecting gene mutations but low sensitivity for gene fusions and MET exon 14 skipping. This may be an alternative only when tissue assay is unavailable due to insufficient DNA and RNA. See related commentary by Jacobsen Skanderup et al., p. 1381.

Real-world outcomes of chemotherapy for lung cancer patients undergoing hemodialysis: A multicenter retrospective cohort study (NEJ-042).

INTRODUCTION: Malignant tumors are the major cause of death in hemodialysis patients. Management of these patients remains challenging as there is no evidence that chemotherapy is beneficial, and a lack of information about actual clinical practice. METHODS: This multicenter retrospective study included hemodialysis patients who were diagnosed with lung cancer from January 2002 to June 2018. We reviewed their clinical information including patient characteristics associated with lung cancer and end-stage renal disease, regimen, efficacy and safety of chemotherapy, and outcomes. RESULTS: A total of 162 patients from 22 institutions in Japan were registered. Of 158 eligible patients, 91 received chemotherapy (80 as palliative chemotherapy and 11 as chemoradiotherapy) and 67 received best supportive care only regardless of cancer stage. In small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) patients who received cytotoxic chemotherapy, the objective response rates (ORR) and median overall survival (OS) were 68.1 %, 12.3 months and 37.0 %, 8.5 months, respectively. The ORR and median OS in patients with EGFR-mutant NSCLC treated with EGFR-tyrosine kinase inhibitors (TKI) were 44.4 % and 38.6 months. The treatment-related adverse events (Grade 3 or higher) induced by cytotoxic chemotherapy were myelosuppression and febrile neutropenia; treatment-related death (TRD) was observed in one patient. TRD occurred in 3 of 18 patients who received EGFR-TKI. CONCLUSION: Chemotherapy should be considered for hemodialysis patients with EGFR-mutant NSCLC and SCLC. However, the survival benefits of chemotherapy for NSCLC patients with EGFR-wild type are unclear; physicians should carefully consider whether to offer chemotherapy to this patient subset.

Osimertinib in poor performance status patients with T790M-positive advanced non-small-cell lung cancer after progression of first- and second-generation EGFR-TKI treatments (NEJ032B).

BACKGROUND: Osimertinib is effective in patients with T790M mutation-positive advanced non-small-cell lung cancer (NSCLC) resistant to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). However, its effectiveness and safety in patients with poor performance status (PS) are unknown. METHODS: Enrolled patients showed disease progression after treatment with gefitinib, erlotinib, or afatinib; T790M mutation; stage IIIB, IV, or recurrent disease; and PS of 2-4. Osimertinib was orally administered at a dose of 80 mg/day. The primary endpoint of this phase II study (registration, jRCTs061180018) was response rate and the secondary endpoints were progression-free survival (PFS), overall survival (OS), disease control rate, and safety. RESULTS: Thirty-three patients were enrolled, of which 69.7% and 24.2% had PS of 2 and 3, respectively. One patient was excluded due to protocol violation; in the remaining 32 patients, the response rate was 53.1%; disease control rate was 75.0%; PFS was 5.1 months; and OS was 10.0 months. The most frequent adverse event of grade 3 or higher severity was lymphopenia (12.1%). Interstitial lung disease (ILD) was observed at all grades and at grades 3-5 in 15.2% (5/33) and 6.1% (2/33) of patients, respectively. Treatment-related death due to ILD occurred in one patient. Patients negative for activating EGFR mutations after osimertinib administration had longer median PFS than those positive for these mutations. CONCLUSION: Osimertinib was sufficiently effective in EGFR-TKI-resistant, poor PS patients with T790M mutation-positive advanced NSCLC. Plasma EGFR mutation clearance after TKI treatment could predict the response to EGFR-TKIs.

Phase I/II study of biweekly nab-paclitaxel in patients with platinum-pretreated non-small cell lung cancer: NJLCG1402.

BACKGROUND: NJLCG1402 was a phase I/II trial investigating biweekly nanoparticle albumin-bound paclitaxel (nab-PTX) in patients with advanced non-small cell lung cancer (NSCLC). METHODS: The study included patients aged ≥20 years with previously treated NSCLC. Nab-PTX (100-150 mg/m2 ) was administered biweekly in a 28-day cycle. The phase I portion was performed to determine the recommended phase II dose of nab-PTX. In the phase II portion, the primary endpoint was the objective response rate. Secondary endpoints were disease control rate, progression-free survival, overall survival, and safety. RESULTS: A total of 15 patients received biweekly nab-PTX (100-150 mg/m2 ) and 12 patients in phase II were treated with 150 mg/m2 . In the phase I portion, 150 mg/m2 was determined as the recommended dose. Among those treated with 150 mg/m2 , the objective response rate was 22%, and the median progression-free and overall survival was 3.6 and 11.2 months, respectively. Adverse events grade ≥3 were observed in 39% of patients. CONCLUSIONS: Biweekly nab-PTX monotherapy was well tolerated and exhibited favorable antitumor activity in patients with previously treated NSCLC.

Prospective Multicenter Study of Chemotherapy-Induced Clostridium (Clostridioides) difficile Infection in Patients With Lung Cancer: North Japan Lung Cancer Study Group Trial 1204.

BACKGROUND: Diarrhea post-antibiotic use is primarily attributed to mucosal lesions induced by Clostridium (Clostridioides) difficile (C. difficile) infection (CDI). Cancer patients undergoing chemotherapy might have a higher risk of CDI even when prior antibiotics are not used. Thus far, the relationship between lung cancer chemotherapy and the incidence of diarrhea remains unclear. This prospective multicenter study aimed to determine the incidence of CDI in lung cancer patients undergoing chemotherapy. METHODS: The presence of C. difficile and its toxins was investigated in lung cancer patients experiencing diarrhea during chemotherapy including paclitaxel (PTX), nanoparticle albumin-bound paclitaxel (nab-PTX), docetaxel (DOC), tegafur-gimeracil-oteracil (S-1), or irinotecan (CPT-11). If grade 2 or higher diarrhea occurred, then a stool culture was performed to detect anaerobic organisms and C. difficile toxins A and B. Additional data were collected through patient interviews and medical chart review. RESULTS: A total of 263 consecutive patients were enrolled in the study; grade 2 or higher diarrhea was observed in 22 patients (8.4%); CDI was confirmed in five of them (1.9%). The incidence of CDI was 22.7% of all diarrhea cases, and 50% of patients treated with PTX were CDI positive; the incidence of CDI was significantly higher in patients treated with PTX (P=0.039). Among the diarrhea cases, CDI patients had significantly worse ECOG performance status (PS) (P=0.043) and a significantly higher neutrophil count (P=0.028) than non-CDI patients. No CDI patients received antibiotics before cancer chemotherapy. CONCLUSIONS: Although diarrhea does not always affect a large portion of lung cancer chemotherapy recipients, clinicians should consider the possibility of CDI occurrence in lung cancer patients receiving chemotherapy, particularly PTX, without prior antibiotic exposure.

Randomized phase II trial of uracil/tegafur and cisplatin versus pemetrexed and cisplatin with concurrent thoracic radiotherapy for locally advanced unresectable stage III non-squamous non-small cell lung cancer: NJLCG1001.

BACKGROUND: The optimal regimen for concurrent chemoradiotherapy (CCRT) of locally advanced non-squamous non-small cell lung cancer (NSCLC) was not definitive. We conducted randomized phase II study, NJLCG0601, and chemoradiotherapy with uracil/tegafur (UFT) and cisplatin achieved promising efficacy without severe toxicities. Here, we evaluated between this regimen and pemetrexed plus cisplatin in chemoradiotherapy for stage III non-squamous NSCLC. METHODS: Patients with inoperable stage III non-squamous NSCLC were randomly assigned in a 1:1 ratio to UFT 400 mg/m2 on days 1-14 and 29-42, and cisplatin 80 mg/m2 on days 8 and 36 (UP), or cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 on days 1, 22, and 43 (PP). Involved-field radiotherapy (IFRT) underwent from day 1 to a total dose of 66 Gy in 33 fractions. Consolidation chemotherapy after CCRT was prohibited for this study. The primary endpoint was defined as 2-year overall survival (OS). This trial was registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN000003948). RESULTS: From November 2010 to June 2017, 86 patients were entered from 11 institutions. Median follow-up was 54 months. Of the 85 eligible patients, the 2-year OS rate was 78.6% (95% CI, 62.8-88.3%) in UP and 85.5% (95% CI, 70.5-93.2%) in PP. Median PFS and OS was 12.3 and 64.2 months in UP, 26.2 months and not reached in PP, respectively. Grade 3/4 febrile neutropenia was more frequent in the UP group (14.0% vs. 2.0%). CONCLUSIONS: Both UP and PP with IFRT achieved the expected 2-year OS. PP engendered more favorable OS and PFS compared to UP in terms.

Extensive Lung Resection for Nontuberculous Mycobacterial Lung Disease With Multilobar Lesions.

BACKGROUND: Nontuberculous mycobacterial lung disease often spreads to multiple lobes, and extensive lung resection (ELR) is sometimes required to control the disease. The safety and feasibility of ELR for nontuberculous mycobacterial lung disease remain unclear, however. METHODS: This retrospective study included patients with nontuberculous mycobacterial lung disease who underwent adjuvant lung resection. Characteristics were compared between patients who underwent ELR and those who underwent simple anatomic lung resection (SALR). The outcome data were analyzed by a Cox regression analysis. RESULTS: A total of 146 patients underwent ELR (n = 54) or SALR (n = 92). ELR was associated with a longer operative time (306 vs 237 minutes; P < .001) and higher incidence of prolonged air leak (17% vs 3.3%; P = .016) than SALR. Rates of mortality, sputum culture conversion (positive to negative), and microbiological recurrence did not differ markedly between the groups. In the multivariate analysis, ELR was not a significant risk factor for an unfavorable outcome after nontuberculous mycobacterial lung disease surgery (hazard ratio, 2.23; 95% confidence interval, 0.82-6.03; P= .11). CONCLUSIONS: ELR for nontuberculous mycobacterial lung disease has some drawbacks compared with SALR but seems as safe and feasible as SALR. ELR may provide improved disease control in some cases of nontuberculous mycobacterial lung disease with multilobar lesions.

Randomized phase II trial of carboplatin + nab-paclitaxel versus cisplatin + gemcitabine for chemotherapy-naïve squamous cell carcinoma: North Japan lung cancer study group 1302.

BACKGROUND: A subset analysis of the CA031 trial showed significant improvement in the overall response rate after administration of carboplatin plus weekly albumin-bound paclitaxel compared to carboplatin plus paclitaxel for squamous cell carcinoma of the lung (SQ). We conducted this phase II study to compare carboplatin plus weekly albumin-bound paclitaxel (CnP) to cisplatin plus gemcitabine (CG), a standard regimen for SQ. METHODS: Chemotherapy-naïve patients with SQ were randomly assigned to receive cisplatin (80 mg/m2) on day 1 plus gemcitabine (1000 mg/m2) on days 1 and 8 every 3 weeks or carboplatin (area under the curve: 6 mg/mL/min) on day 1 plus nab-paclitaxel (75 mg/m2) on days 1, 8, and 15 every 3 weeks. The primary endpoint was overall response rate. The secondary endpoints were progression-free survival, overall survival, disease control rate, and toxicity. RESULTS: Between June 2013 and October 2018, 71 patients were enrolled and assigned to either the CG arm (n = 35) or the CnP arm (n = 36) of the study. The overall response rate was 43% [95% confidence interval (CI) 27.3-58.5] in the CG arm and 47% (95% CI 31.7-62.7) in the CnP arm. Although drug combination efficacies did not differ, there were differences in toxicity: hematologic toxicities (leukopenia, neutropenia, and thrombocytopenia) were found mostly in the CG arm, whereas anemia and sensory neuropathy were more common in the CnP arm. CONCLUSIONS: CnP had similar response as CG despite being a carboplatin-based regimen and toxicities differed between arms. Regarding ORR, CnP was comparable to CG for SQ.

Phase II Study of Low-Dose Afatinib Maintenance Treatment Among Patients with EGFR-Mutated Non-Small Cell Lung Cancer: North Japan Lung Cancer Study Group Trial 1601 (NJLCG1601).

LESSONS LEARNED: Low-dose afatinib maintenance treatment among patients with EGFR-mutated NSCLC achieved long-time to treatment failure with fewer treatment-related AEs without detracting from the therapeutic efficacy. This modified regimen represents a practical usage that balances effectiveness and safety. BACKGROUND: Although afatinib is an effective therapy for patients with EGFR-mutated non-small cell lung cancer (NSCLC), drug-related adverse events (AEs) have often necessitated dose reductions. In a post hoc analysis of the LUX-Lung 3 and 6 trials, there was no difference in median progression-free survival (PFS) between patients who had the dose of afatinib reduced and those who did not. We thus evaluated the efficacy and tolerability of low-dose afatinib maintenance treatment among patients with NSCLC harboring EGFR mutations who had not been previously treated. METHODS: Eligible patients received afatinib 40 mg orally once daily. When prescribed grade ≥ 2 AEs, rash of grade ≥ 3, or unacceptable toxicity occurred, the afatinib dose was reduced from 40 to 30 mg and if needed from 30 to 20 mg. The primary endpoint was the 1-year PFS rate. Secondary endpoints were PFS, overall response rate (ORR), and toxicity. RESULTS: Among 30 patients, 93% had adenocarcinoma, 53% had exon 19 deletion, 37% had L858R, and 10% had minor mutations. The 1-year PFS rate was 50% (95% confidence interval [CI], 31.3-66.1) and the median PFS was 11.8 months (95% CI, 7.1-21.4). The incidence rate of grade ≥ 3 toxicities was 57%, including elevated aspartate aminotransferase/alanine aminotransferase level (13%), diarrhea (10%), and paronychia (10%). CONCLUSION: Low-dose afatinib maintenance treatment reduced treatment-related AEs without detracting from the therapeutic efficacy.

Phase II study of S-1 in patients with previously-treated invasive thymoma and thymic carcinoma: North Japan lung cancer study group trial 1203.

OBJECTIVES: Invasive thymoma (IT) and thymic carcinoma (TC) are rare epithelial neoplasms arising in the anterior mediastinum. Platinum-based chemotherapies are widely used for first-line treatment of unresectable IT and TC, but no standard treatment has been established for previously-treated IT and TC thus far. Because promising efficacy of S-1 (tegafur, gimeracil and oteracil combination) has been reported in some retrospective studies, we conducted the first prospective phase II trial to evaluate its efficacy in previously-treated patients with advanced IT and TC. MATERIALS AND METHODS: Patients progressing after at least one regimen of systemic chemotherapy received S-1 orally at a dose based on body surface area for 2 weeks followed by one week of rest until tumor progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR) and secondary endpoints were progression-free survival (PFS), overall survival (OS), and toxicity profile. We defined an ORR of 25% as indicating potential usefulness while ORR of 10% was the lower limit of interest. RESULTS: Forty patients were enrolled (IT, n = 20; TC, n = 20). ORR was 17.5% (95% CI 7.3-32.8; IT, 10%; TC, 25%), disease control rate was 85% (IT, 95%; TC, 75%). Median PFS was 7.0 months (IT, 11.3 months; TC, 5.4 months), and median OS was 40.3 months (IT, 58.5 months; TC, 22.7 months) with a median follow-up of 51.9 months. Major toxicities (grade 3-4) were anorexia (10%), neutropenia (7.5%) and pneumonitis (5%). No treatment-related death was observed. CONCLUSION: Although the primary endpoint was not met, S-1 monotherapy did have effects similar to recently reported immunotherapies for TC but at much lower cost. S-1 could represent a treatment option for previously-treated advanced TC. This trial was registered as UMIN 000008174.

Clinical Outcomes of Second-Line Chemotherapy in Patients with Previously Treated Advanced Thymic Carcinoma: A Retrospective Analysis of 191 Patients from the NEJ023 Study.

BACKGROUND: Owing to the rarity of this tumor, there is limited information about second-line chemotherapy for patients with previously treated advanced thymic carcinoma. MATERIAL AND METHODS: We performed a multi-institutional, retrospective study named NEJ023 for patients with advanced thymic carcinoma. Patients without indications for curative treatment were treated with chemotherapy from 1995 to 2014 at 40 institutions in the North East Japan Study Group. Demographic and clinicopathologic characteristics, data on treatment methods, and outcomes of second-line chemotherapy were obtained from medical records. RESULTS: In total, 191 patients were enrolled in this study. Second-line chemotherapy included platinum-based doublets in 57.6% of patients, other multidrug chemotherapy (e.g., cisplatin, doxorubicin, vincristine, and cyclophosphamide) in 13.6%, and monotherapy in 28.8%. The median follow-up time was 50.5 months, and the median overall survival (OS) from the start of second-line chemotherapy was 22.4 (95% confidence interval, 17.5-26.7) months. The average response rate (RR) was 20.0% overall; it was 21.6% for patients treated with platinum-based doublet chemotherapy, 13.6% for those treated with other multidrug chemotherapy, and 19.6% for those treated with single agent chemotherapy. There was no significant difference in OS between platinum-based doublet chemotherapy, other multidrug chemotherapy, and monotherapy (the median OS was 22.4, 25.7, and 21.4 months, respectively). CONCLUSION: The median OS was 22.4 months in patients with advanced thymic carcinoma treated with second-line chemotherapy. There were no significant differences in RR and OS between monotherapy and multidrug chemotherapy in this study. IMPLICATIONS FOR PRACTICE: Owing to the rarity of this tumor, there is limited information about second-line chemotherapy for patients with previously treated advanced thymic carcinoma. This is the largest data for those patients treated with second-line chemotherapy. This study suggests there is no significant difference in efficacy between monotherapy and multidrug chemotherapy for previously treated advanced thymic carcinoma. This result can support the adequacy to select monotherapy as treatment of those patients.

Phase II trial of induction chemotherapy with carboplatin and paclitaxel plus bevacizumab in patients with stage IIIA to IV nonsquamous non-small cell lung cancer.

PURPOSE: Surgery remains the best curative treatment option for non-small cell lung cancer (NSCLC), but is of benefit only to patients with localized disease. A meta-analysis showed a significant beneficial effect of induction chemotherapy on survival, but there is still no clear evidence. This phase II study was conducted to establish whether induction chemotherapy with carboplatin (CBDCA) and paclitaxel (PTX) plus bevacizumab prior to surgery reduces the risk of progression. METHODS: The subjects of this study were 29 patients with treatment-naive nonsquamous NSCLC (clinical stages IIIA to IV). Patients received PTX (200 mg/m2), CBDCA (area under the curve, 5), and bevacizumab (15 mg/kg) followed by surgery. Chemotherapy was repeated every 3 weeks for up to six cycles. RESULTS: The overall response rate was 72.4%. Of the 29 patients, ten underwent surgery after the induction chemotherapy and complete resection was achieved in 7 (70%). The median progression-free-survival (PFS) time and the 3-year PFS rate were 0.92 years and 16.2%, respectively. The median overall survival (OS) time and the 3-year OS rate were 1.96 years and 44.9%, respectively. CONCLUSION: Combined modality therapy with surgery after induction chemotherapy with CBDCA and PTX plus bevacizumab is clinically feasible and tolerable for patients with unknown or negative molecular profiles.

Outcomes and risk factors after adjuvant surgical treatments for Mycobacterium avium complex lung disease.

BACKGROUND: Limited information is currently available on the postoperative outcomes of Mycobacterium avium complex lung disease (MAC-LD). OBJECTIVE: To show the outcomes of pulmonary resection and identify risk factors after adjuvant surgical treatments for MAC-LD. METHODS: One hundred and eight patients underwent adjuvant lung resection for MAC-LD at two hospitals between January 2008 and July 2016. We retrospectively evaluated outcomes and risk factors. RESULTS: Postoperative complications occurred in 14 patients (13%). After lung resection, 98 out of 108 patients (91%) achieved sputum culture conversion, eight (8.2%) of whom developed microbiological recurrence during the follow-up period. As a result, the success rate of adjuvant surgical treatments for MAC-LD with drug resistance was 83%. A multivariable analysis showed that a longer period from the initial medical treatment to surgery (hazard ratio, 1.01; 95% confidence interval, 1.00-1.02; p = 0.008) was independently associated with an increased risk of unfavorable outcomes after adjuvant surgery. CONCLUSIONS: Adjuvant surgical treatments for MAC-LD have acceptable outcomes. Better control of the disease may be achieved in some patients with drug resistance and indications for surgery through surgical treatments, and pulmonary resection needs to be performed earlier rather than continuing chemotherapy in these patients because it reduces unfavorable outcomes.

Successful Treatment of Transplantation-associated Atypical Hemolytic Uremic Syndrome With Eculizumab.

We herein reported a 4-month-old boy with transplantation-associated atypical hemolytic uremic syndrome (TA-aHUS) who was successfully treated with eculizumab. The patient diagnosed with type 3 of familial hemophagocytic lymphohistiocytosis underwent cord blood transplantation. After transplantation, he developed TA-aHUS, but plasma exchanges were unsuccessful. We identified deletions in CFH-related gene 1 (del-CFHR1) by the multiplex ligation-dependent probe amplification testing procedure and CFH autoantibodies. Eculizumab has been administered to the patient, with a marked improvement being achieved in thrombocytopenia. He has been well except for the persistent microhematuria for a year after transplantation. Uncontrolled complement activation might be involved in the pathophysiology of TA-aHUS.

Phase II Study of Modified Carboplatin Plus Weekly Nab-Paclitaxel in Elderly Patients with Non-Small Cell Lung Cancer: North Japan Lung Cancer Study Group Trial 1301.

LESSONS LEARNED: Weekly nanoparticle albumin-bound-paclitaxel (75 mg/m2) in combination with carboplatin (area under the curve 6 mg/mL/min) in elderly patients with previously untreated, advanced non-small cell lung cancer showed favorable efficacy, was well tolerated, and showed less neuropathic toxicity.This modified regimen offers potential for the treatment of elderly patients. BACKGROUND: The CA031 trial suggested weekly nanoparticle albumin-bound-paclitaxel (nab-PTX) was superior in efficacy to paclitaxel (PTX) once every 3 weeks when combined with carboplatin (CBDCA) for advanced non-small cell lung cancer (NSCLC) patients; a subgroup analysis of elderly patients looked promising. In a multicenter phase II trial, we prospectively evaluated the efficacy and tolerability of modified CBDCA plus weekly nab-PTX for elderly patients with untreated advanced NSCLC. METHODS: Eligible patients received CBDCA (area under the curve [AUC] 6 mg/mL/min) on day 1 and nab-PTX (75 mg/m2) on days 1, 8, and 15 every 4 weeks. The primary endpoint was an overall response rate (ORR), and secondary endpoints were progression-free survival (PFS), overall survival (OS), and toxicity. RESULTS: Of 32 patients (median age of 78 years), 84% were male, 56% had stage IV NSCLC, and 56% had squamous cell carcinoma. ORR and disease control rates were 50% (95% confidence interval (CI): 33-67) and 94% (95% CI: 85-100), respectively. Median PFS and OS were 6.4 months (95% CI: 4.8-8.0) and 17.5 months (95% CI: 11.9-23.1), respectively. Grade ≥3 toxicities were neutropenia (47%), leukopenia (38%), anemia (34%), thrombocytopenia (25%), and anorexia (9%). Febrile neutropenia and treatment-related deaths were not observed. CONCLUSION: Modified CBDCA plus weekly nab-PTX demonstrated significant efficacy and acceptable toxicities in elderly patients with advanced NSCLC.

A phase II study of carboplatin plus weekly paclitaxel with bevacizumab for elderly patients with non-squamous non-small-cell lung cancer (NEJ016).

Background The efficacy and safety of bevacizumab in elderly patients with non-small cell lung cancer remain controversial. This study focused on both selecting fit elderly patients and overcoming interpatient variability with respect to pharmacodynamics. Methods Elderly (age: ≥70 years) patients with advanced non-squamous non-small cell lung cancer were enrolled. Patients with uncontrolled congestive heart failure and uncontrolled diabetes were excluded. The treatment regimen comprised carboplatin at an area under the curve of 5 mg/ml/min on day 1, paclitaxel at 90 mg/m2 on days 1 and 8, and bevacizumab at 15 mg/kg on day 1 every 21 days for up to 4 cycles, followed by maintenance bevacizumab. Dose reduction due to side effects was performed, with a wide range of doses of paclitaxel from 23 mg/m2/week to 60 mg/m2/week. Results Of the 36 patients entered, 38.9% required a dose reduction or cancellation of paclitaxel administration on day 8, and 75% patients were able to complete 4 cycles of triplet therapy. The response rate, primary endpoint, was 69.4% (95% confidence interval [CI]: 51.9-83.7). The median progression free survival and overall survival were 8.4 months and 29.2 months, respectively. The most common adverse events included neutropenia, hypertension, anemia, and infection. Although Grade ≥ 3 adverse events were observed in 24 patients (66.7%), there were no deaths due to toxicity. Conclusion Carboplatin plus weekly paclitaxel with bevacizumab is a feasible, effective first-line regimen for elderly non-small cell lung cancer patients. (UMIN00006622).