ABSTRACT
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.
Subject(s)
Autoimmune Diseases , Carcinoma, Non-Small-Cell Lung , Immune Checkpoint Inhibitors , Lung Neoplasms , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/mortality , Lung Neoplasms/drug therapy , Lung Neoplasms/mortality , Retrospective Studies , Female , Immune Checkpoint Inhibitors/therapeutic use , Immune Checkpoint Inhibitors/adverse effects , Male , Aged , Autoimmune Diseases/mortality , Autoimmune Diseases/drug therapy , Autoimmune Diseases/complications , Middle Aged , Survival Analysis , Japan/epidemiology , Aged, 80 and over , Survival Rate , AdultABSTRACT
BACKGROUND: Evidence for use of second-line immunosuppressants for immune-related adverse events (irAEs) is inadequate. Therefore, a multicenter analysis should assess the efficacy of second-line immunosuppressants for severe irAEs associated with different malignant diseases. METHODS: This descriptive study aims to investigate the effects of second-line immunosuppressants on corticosteroid-refractory irAEs in patients with lung cancer. We analyzed the effects of second-line immunosuppressants on underlying lung cancer and associated adverse effects. RESULTS: Our study included 4589 patients who had received immune checkpoint inhibitor treatment, with 73 patients (1.6%) developing irAEs requiring second-line immunosuppressants. The most commonly observed irAE was pneumonitis (26 patients), followed by hepatobiliary disorders (15 patients) and enteritis (14 patients). We found a confirmed response rate of 42.3% for pneumonitis, which was lower than the response rates of 86.7% for hepatobiliary disorders and 92.9% for enteritis. The time from the start of corticosteroid therapy to the addition of a second-line immunosuppressant correlated significantly with the resolution of irAE to Grade 1 (correlation coefficients of r = 0.701, p < 0.005). The median progression-free survival and duration of response of underlying lung cancer from second-line immunosuppressant administration were 2.1 and 3.0 months, respectively. Of the patients with irAE, 27.4% developed infections and 5.5% might die due to infection. CONCLUSION: Second-line immunosuppressant response was confirmed in 72.2% of irAEs in patients with lung cancer, with lower response rates observed in irAE pneumonitis compared to other irAEs.
Subject(s)
Antineoplastic Agents, Immunological , Carcinoma, Non-Small-Cell Lung , Digestive System Diseases , Enteritis , Lung Neoplasms , Pneumonia , Humans , Adrenal Cortex Hormones/adverse effects , Antineoplastic Agents, Immunological/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Digestive System Diseases/chemically induced , Enteritis/chemically induced , Immunosuppressive Agents/therapeutic use , Lung Neoplasms/pathology , Nivolumab/therapeutic use , Pneumonia/etiology , Pneumonia/chemically induced , Retrospective Studies , SteroidsABSTRACT
BACKGROUND: The therapeutic efficacy of cytotoxic anticancer drugs has been reported to be enhanced after immune checkpoint inhibitors (ICI) in non-small cell lung cancer; however, it is unclear whether the same is applicable for small cell lung cancer (SCLC). We evaluated the efficacy of second-line amrubicin (AMR) following first-line platinum-based chemotherapy and ICI combination therapy (chemo-ICI) in SCLC. PATIENTS AND METHODS: We retrospectively enrolled consecutive patients with SCLC treated with AMR as a second-line following chemo-ICI as first-line between July 2019 and April 2021 from 16 institutions throughout Japan. We investigated the therapeutic effectiveness, safety, and efficacy-enhancing variables of AMR. RESULTS: Overall, 89 patients treated with AMR after first-line chemo-ICI were analyzed. The overall response rate (ORR) was 29.2% (95% confidence intervals [CI], 20.1-39.8) and median PFS (m PFS) was 2.99 months (95% CI, 2.27-3.65). Patients who relapsed more than 90 days after receiving first-line platinum combination therapy (sensitive relapse) exhibited greater ORR (58.3% vs. 24.7%, p = 0.035) and m PFS (5.03 vs. 2.56 months, p = 0.019) than patients who relapsed in <90 days (refractory relapse). Grade 3 or higher adverse events were mainly hematological toxicity. CONCLUSIONS: Our study suggested that the therapeutic effect of AMR was not enhanced after ICI on SCLC. However, AMR may be effective in cases of sensitive relapse after chemo-ICI. There was no increase in severe toxicity associated with AMR after ICI.
Subject(s)
Antineoplastic Agents , Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Small Cell Lung Carcinoma , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/chemically induced , Immune Checkpoint Inhibitors/pharmacology , Immune Checkpoint Inhibitors/therapeutic use , Retrospective Studies , Carcinoma, Non-Small-Cell Lung/drug therapy , Neoplasm Recurrence, Local/drug therapy , Small Cell Lung Carcinoma/drug therapy , Antineoplastic Agents/therapeutic use , Treatment Outcome , RecurrenceABSTRACT
Introduction: Despite a considerable benefit of adding immune checkpoint inhibitors (ICIs) to platinum-based chemotherapy for patients with extensive-stage SCLC (ES-SCLC), a durable response to ICIs occurs in only a small minority of such patients. Methods: A total of 135 patients with ES-SCLC treated with chemotherapy either alone (chemo-cohort, n = 71) or together with an ICI (ICI combo-cohort, n = 64) was included in this retrospective study. Tumors were classified pathologically as inflamed or noninflamed on the basis of programmed death-ligand 1 expression and CD8+ tumor-infiltrating lymphocyte density. Immune-related gene expression profiling was performed, and predicted neoantigen load was determined by whole-exome sequencing. Results: Among patients in the ICI combo-cohort, median progression-free survival was 10.8 and 5.1 months for those with inflamed (n = 7) or noninflamed (n = 56) tumors, respectively (log-rank test p = 0.002; hazard ratio of 0.26). Among the 89 patients with immune-related gene expression profiling data available, inflamed tumors had a higher T cell-inflamed GEP score than did noninflamed tumors (-0.18 versus -0.58, p < 0.001). The 12-month progression-free survival rate was 16.1% and 0% for patients in the ICI combo-cohort harboring tumors with a high (n = 26) or low (n = 18) frameshift neoantigen load, respectively. A high-frameshift neoantigen load was associated with up-regulation of gene signatures related to antigen presentation and costimulatory signaling. A durable clinical benefit of ICI therapy was observed only in patients with inflamed tumors and a high-frameshift neoantigen load. Conclusions: Expression of programmed death-ligand 1, CD8+ T cell infiltration, and a high-frameshift neoantigen load are associated with clinical benefit of ICI therapy in ES-SCLC. Clinical trial registration: UMIN000041056.
ABSTRACT
BACKGROUND: A cisplatin plus irinotecan (CPT-11) regimen is used for patients with extensive disease small cell lung cancer (ED-SCLC). Amrubicin (AMR) is primarily used for relapsed SCLC. The HOT1401/NJLCG1401 trial, an open-label randomized phase II trial, was designed to assess the benefit of maintenance therapy in patients with ED-SCLC who responded to induction therapy. METHODS: Patients with histologically- or cytologically-confirmed ED-SCLC were included and were treated with an induction therapy of four cycles of cisplatin (60 mg/m2 on day 1) plus CPT-11 (60 mg/m2 on days 1, 8, and 15) every four weeks. After induction therapy, patients who had nonprogressive disease were randomized to receive either maintenance CPT-11 (60 mg/m2 on days 1 and 8) every three weeks, or AMR (35 mg/m2 on days 1-3) every three weeks. RESULTS: A total of 34 patients were enrolled; 20 patients had progressive disease or received incomplete induction chemotherapy. Finally, 14 patients were randomly assigned to receive CPT-11 (n = 7) or AMR (n = 7). This study was terminated prematurely because of low patient accrual. The overall objective response rate was 73%, the median PFS was 5.7 months (95% confidence interval [CI]: 3.6-11.8), and the median overall survival was 20.1 months (95% CI: 13.7-not reached). No statistically significant difference in progression-free survival (PFS) were noted between patients treated with CPT-11 and those treated with AMR. There were no treatment-related deaths in this study. CONCLUSIONS: Maintenance therapy with CPT-11 or AMR after induction therapy might be effective in some patients.
Subject(s)
Anthracyclines/administration & dosage , Induction Chemotherapy , Irinotecan/administration & dosage , Lung Neoplasms/drug therapy , Small Cell Lung Carcinoma/drug therapy , Adult , Aged , Antineoplastic Agents/administration & dosage , Cisplatin/administration & dosage , Drug Therapy, Combination , Female , Humans , Male , Middle Aged , Prospective Studies , Topoisomerase I Inhibitors/administration & dosage , Young AdultABSTRACT
BACKGROUND: We assessed the efficacy and safety of bevacizumab and S-1 chemotherapy for patients with previously treated advanced non-squamous non-small-cell lung cancer (NSCLC). METHODS: This was a prospective single-arm study, including patients with non-squamous NSCLC who had received at least one chemotherapy regimen along with a platinum-based regimen. Bevacizumab 15 mg/kg was intravenously administered every 3 weeks, and S-1 40 mg/m2 was orally administered twice daily from day 1 (evening) through day 15 (morning). The treatment continued for 3 weeks/cycle until disease progression or until unacceptable toxicities occurred. During the lead-in part, six patients were evaluated for dose-limiting toxicity (DLT) rate. In phase II, the primary endpoint was objective response rate (ORR). Secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. RESULTS: In the lead-in part, we evaluated the safety in the first six patients and observed no DLT. In phase II, a total of 46 patients were enrolled from September 2012 to December 2018. The median follow-up duration was 13.7 months [95% confidence interval (CI) 1.4-72.0]. The ORR was 28.3%. The median PFS and OS were 4.3 (95% CI 2.9-5.9) and 15.0 months (95% CI 9.8-30.3), respectively. The most common adverse events were hypertension (65.2%), diarrhea (47.8%), mucositis oral (45.7%), and proteinuria (43.5%), and the most common grade 3 adverse events were hypertension (23.9%) and proteinuria (6.5%). Grade 4/5 adverse events were not observed. CONCLUSION: Bevacizumab and S-1 combination chemotherapy showed high activity and were well tolerated in patients with previously treated advanced non-squamous NSCLC.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Bevacizumab/adverse effects , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/pathology , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Neoplasm Staging , Prospective StudiesABSTRACT
LESSONS LEARNED: The combination of cisplatin plus nab-paclitaxel with concurrent thoracic radiotherapy in unresectable stage III non-small cell lung cancer is a promising therapeutic strategy. Further investigation is warranted. BACKGROUND: We conducted a phase I/II trial of cisplatin plus nab-paclitaxel with concurrent thoracic radiotherapy for locally advanced non-small cell lung cancer (NSCLC) to determine the recommended dose (RD) of nab-paclitaxel and to evaluate the safety and efficacy of this regimen. METHODS: In the phase I study, escalating doses of weekly nab-paclitaxel were administered together with cisplatin at 75 mg/m2 every 3 weeks and concurrent radiotherapy. In the phase II study, nab-paclitaxel was administered at the RD. RESULTS: In the phase I study, whereas no dose-limiting toxicity (DLT) was observed with nab-paclitaxel at 50 or 60 mg/m2 , one of six patients experienced DLT (esophagitis of grade 3) at 70 mg/m2 , determined as the RD. Twenty-four patients at RD were evaluable for safety and efficacy in phase II. Common toxicities included esophagitis (87.5%) and leukopenia (79.2%). Pneumonitis and treatment-related deaths were not observed, but 20 patients (83.3%) experienced radiation pneumonitis, with one case of grade 3 and four of grade 2, after completion of concurrent chemoradiotherapy. The 2-year overall survival and progression-free survival rates were 73.9% and 56.5% (95% confidence interval [CI], 34.3%-74.7%), respectively. CONCLUSION: Concurrent chemoradiation with nab-paclitaxel at 70 mg/m2 and cisplatin at 75 mg/m2 every 3 weeks showed encouraging feasibility and activity for locally advanced NSCLC.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Albumins , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/radiotherapy , Chemoradiotherapy , Cisplatin/therapeutic use , Combined Modality Therapy , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/radiotherapy , Paclitaxel/therapeutic useABSTRACT
BACKGROUND: Currently used biomarkers for immunotherapy are inadequate because they are only based on tumor properties. In view of microenvironment changes by tumors, host immunity should be considered, which may result in identifying more accurate and easily detectable biomarkers for daily clinical practice. Here, we assessed serum immune-modulating factor levels for the response to anti-PD-1 antibodies during the first cycle in non-small cell lung cancer (NSCLC) patients. METHODS: Serum was collected from patients with advanced NSCLC treated with nivolumab or pembrolizumab at several time points during the first cycle. We applied the enzyme-linked immunosorbent assays (ELISAs) and multiplex assays to measure the levels of immune modulators. RESULTS: A total of 40 patients treated with nivolumab and 26 patients treated with pembrolizumab were studied. By ELISA, serum perforin, but not granzyme B, was measured in all samples. By multiplex assay, 10 immune modulators, including granzyme B, were measured in some, but not all, samples. Serum baseline perforin levels were strongly associated with increased progression-free survival (PFS) and overall survival (OS) times. Sequential changes in perforin levels during the first cycle were weakly associated with the clinical outcome. CONCLUSIONS: Serum baseline perforin levels may be used to predict the prognosis of NSCLC patients treated with anti-PD-1 antibody therapy. KEY POINTS: To identify a useful predictive marker for anti-PD-1 antibody therapy, using blood samples might be helpful. Serum baseline perforin levels were closely associated with prognosis with anti-PD-1 antibody therapy in non-small cell lung cancer.
Subject(s)
Biomarkers, Tumor/blood , Carcinoma, Non-Small-Cell Lung/drug therapy , Cytotoxins/therapeutic use , Immunotherapy/methods , Lung Neoplasms/drug therapy , Perforin/therapeutic use , Adult , Aged , Aged, 80 and over , Carcinoma, Non-Small-Cell Lung/pathology , Cytotoxins/pharmacology , Female , Humans , Lung Neoplasms/pathology , Male , Middle Aged , Perforin/pharmacologyABSTRACT
Thymic carcinoma (TC) is a rare cancer with minimal evidence of survival following palliative-intent chemotherapy. Sunitinib, everolimus, and pembrolizumab have been proposed as active agents based on previous phase II trials. In this phase II study, TC patients previously treated with platinum-based chemotherapy were enrolled. The patients received S-1 orally twice daily at a dose of 40-60 mg/m2 for 4 weeks, followed by 2 weeks off until the progression of the disease or the presence of unacceptable toxicities. The primary endpoint was the objective response rate (ORR), and secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. The sample size of 26 patients was planned to reject the ORR of 10% under the expectation of 30% with a power of 0.80 and a type I error of 0.05 (one-sided). Twenty-six patients were recruited between 2013 and 2016; 23 patients had squamous cell carcinoma and 10 had an ECOG performance status of 0. One patient showed complete response and seven patients showed partial responses, resulting in a 30.8% response rate (90% confidence interval [CI], 18.3-46.9) and an 80.8% disease control rate (90% CI, 65.4-90.3). The median PFS was 4.3 months (95% CI, 2.3-10.3 months) and median OS was 27.4 months (95% CI, 16.6-34.3). Adverse events of grade ≥ 3 included neutropenia (12%), skin rash (8%), elevated alanine aminotransferase, and fatigue (4%). No treatment-related death was observed. S-1 confirmed clinical activity with tolerability in patients with previously treated TC. (UMIN000010736).
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Oxonic Acid/therapeutic use , Palliative Care , Tegafur/therapeutic use , Thymus Neoplasms/drug therapy , Thymus Neoplasms/pathology , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Drug Combinations , Female , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Neoplasm Metastasis , Neoplasm Staging , Oxonic Acid/adverse effects , Palliative Care/methods , Retreatment , Tegafur/adverse effects , Thymus Neoplasms/mortality , Treatment OutcomeABSTRACT
Purpose: Anti-programmed-death-1 (PD-1) immunotherapy improves survival in non-small cell lung cancer (NSCLC), but some cases are refractory to treatment, thereby requiring alternative strategies. B7-H3, an immune-checkpoint molecule, is expressed in various malignancies. To our knowledge, this study is the first to evaluate B7-H3 expression in NSCLCs treated with anti-PD-1 therapy and the therapeutic potential of a combination of anti-PD-1 therapy and B7-H3 targeting.Experimental Design: B7-H3 expression was evaluated immunohistochemically in patients with NSCLC (n = 82), and its relationship with responsiveness to anti-PD-1 therapy and CD8+ tumor-infiltrating lymphocytes (TILs) was analyzed. The antitumor efficacy of dual anti-B7-H3 and anti-programmed death ligand-1 (PD-L1) antibody therapy was evaluated using a syngeneic murine cancer model. T-cell numbers and functions were analyzed by flow cytometry.Results: B7-H3 expression was evident in 74% of NSCLCs and was correlated critically with nonresponsiveness to anti-PD-1 immunotherapy. A small number of CD8+ TILs was observed as a subpopulation with PD-L1 tumor proportion score less than 50%, whereas CD8+ TILs were still abundant in tumors not expressing B7-H3. Anti-B7-H3 blockade showed antitumor efficacy accompanied with an increased number of CD8+ TILs and recovery of effector function. CD8+ T-cell depletion negated antitumor efficacy induced by B7-H3 blockade, indicating that improved antitumor immunity is mediated by CD8+ T cells. Compared with a single blocking antibody, dual blockade of B7-H3 and PD-L1 enhanced the antitumor reaction.Conclusions: B7-H3 expressed on tumor cells potentially circumvents CD8+-T-cell-mediated immune surveillance. Anti-B7-H3 immunotherapy combined with anti-PD-1/PD-L1 antibody therapy is a promising approach for B7-H3-expressing NSCLCs. Clin Cancer Res; 24(11); 2653-64. ©2018 AACR.
Subject(s)
B7 Antigens/metabolism , Immunomodulation , Neoplasms/immunology , Neoplasms/metabolism , T-Lymphocytes, Cytotoxic/immunology , T-Lymphocytes, Cytotoxic/metabolism , Aged , Aged, 80 and over , Animals , Antineoplastic Agents, Immunological/pharmacology , Antineoplastic Agents, Immunological/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , B7-H1 Antigen/antagonists & inhibitors , B7-H1 Antigen/metabolism , Biomarkers, Tumor , Disease Models, Animal , Drug Resistance, Neoplasm , Female , Humans , Male , Mice , Middle Aged , Molecular Targeted Therapy , Mutation , Neoplasms/pathology , Neoplasms/therapy , Prognosis , Treatment Outcome , Xenograft Model Antitumor AssaysABSTRACT
OBJECTIVE: The aim of this study was to identify baseline peripheral blood biomarkers associated with clinical outcome in patients with NSCLC treated with nivolumab. METHODS: Univariable and multivariable analyses were performed retrospectively for 134 patients with advanced or recurrent NSCLC treated with nivolumab to evaluate the relationship between survival and peripheral blood parameters measured before treatment initiation, including absolute neutrophil count (ANC), absolute lymphocyte count (ALC), absolute monocyte count, and absolute eosinophil count (AEC), as well as serum C-reactive protein and lactate dehydrogenase levels. Progression-free survival, overall survival, and response rate were determined. RESULTS: Among the variables selected by univariable analysis, a low ANC, high ALC, and high AEC were significantly and independently associated with both better progression-free survival (p = 0.001, p = 0.04, and p = 0.02, respectively) and better overall survival (p = 0.03, p = 0.03, and p = 0.003, respectively) in multivariable analysis. Categorization of patients according to the number of favorable factors revealed that those with only one factor had a significantly worse outcome than those with two or three factors. A similar trend was apparent for patients with a programmed death 1 ligand tumor proportion score less than 50%, whereas all patients with a score of 50% or higher had at least two favorable factors. CONCLUSIONS: A baseline signature of a low ANC, high ALC, and high AEC was associated with a better outcome of nivolumab treatment, with the number of favorable factors identifying subgroups of patients differing in survival and response rate.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Carcinoma, Non-Small-Cell Lung/pathology , Leukocytes/pathology , Lung Neoplasms/pathology , Lymphocytes/pathology , Neutrophils/pathology , Adenocarcinoma/blood , Adenocarcinoma/drug therapy , Adenocarcinoma/pathology , Aged , Antineoplastic Agents/therapeutic use , Carcinoma, Non-Small-Cell Lung/blood , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Squamous Cell/blood , Carcinoma, Squamous Cell/drug therapy , Carcinoma, Squamous Cell/pathology , Female , Follow-Up Studies , Humans , Lung Neoplasms/blood , Lung Neoplasms/drug therapy , Male , Nivolumab , Prognosis , Retrospective Studies , Survival RateABSTRACT
IMPORTANCE: Immune-related adverse events (irAEs) have been associated with the efficacy of PD-1 (programmed cell death protein 1) inhibitors in patients with melanoma, but whether such an association exists for non-small-cell lung cancer (NSCLC) has remained unknown. OBJECTIVE: To evaluate the relation of irAEs to nivolumab efficacy in NSCLC. DESIGN, SETTING, AND PARTICIPANTS: In this study based on landmark and multivariable analyses, a total of 134 patients with advanced or recurrent NSCLC who were treated with nivolumab in the second-line setting or later between December 2015 and August 2016 were identified from a review of medical records from multiple institutions, including a university hospital and community hospitals. Data were updated as of December 31, 2016. EXPOSURES: The absence or presence of any irAE before the landmark date. MAIN OUTCOMES AND MEASURES: Kaplan-Meier curves of progression-free survival (PFS) according to the development of irAEs in 6-week landmark analysis were evaluated with the log-rank test as a preplanned primary objective. Overall survival (OS) was similarly evaluated. Multivariable analysis of both PFS and OS was performed with Cox proportional hazard regression models. RESULTS: In a cohort of 134 patients (median [range] age, 68 [33-85] years; 90 men [67%], 44 women [33%]), irAEs were observed in 69 of the 134 study patients (51%), including 12 patients (9%) with such events of grade 3 or 4, and 24 patients (18%) requiring systemic corticosteroid therapy. In 6-week landmark analysis, median PFS was 9.2 months (95% CI, 4.4 to not reached [NR]) and 4.8 months (95% CI, 3.0 to 7.5) (P = .04) whereas median OS was NR (95% CI, 12.3 to NR) and 11.1 months (95% CI, 9.6 to NR) (P = .01) for patients with or without irAEs, respectively. Multivariable analysis also revealed that irAEs were positively associated with survival outcome, with hazard ratios of 0.525 (95% CI, 0.287 to 0.937; P = .03) for PFS and 0.282 (95% CI, 0.101 to 0.667; P = .003) for OS. CONCLUSIONS AND RELEVANCE: Development of irAEs was associated with survival outcome of nivolumab treatment in patients with advanced or recurrent NSCLC. Further studies are needed to confirm our findings.
Subject(s)
Biomarkers, Pharmacological , Carcinoma, Non-Small-Cell Lung/drug therapy , Drug-Related Side Effects and Adverse Reactions , Immune System Diseases/chemically induced , Lung Neoplasms/drug therapy , Nivolumab/adverse effects , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor , Carcinoma, Non-Small-Cell Lung/diagnosis , Carcinoma, Non-Small-Cell Lung/epidemiology , Carcinoma, Non-Small-Cell Lung/pathology , Chemotherapy, Adjuvant/adverse effects , Cohort Studies , Drug-Related Side Effects and Adverse Reactions/epidemiology , Female , Humans , Immune System Diseases/epidemiology , Immunotherapy/methods , Immunotherapy/statistics & numerical data , Lung Neoplasms/diagnosis , Lung Neoplasms/epidemiology , Lung Neoplasms/pathology , Male , Middle Aged , Nivolumab/administration & dosage , Prognosis , Retrospective Studies , Treatment OutcomeABSTRACT
Clinical trials of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib have shown that some patients receiving these agents develop severe hepatotoxicity that necessitates treatment cessation. Both drugs undergo extensive hepatic metabolism mediated predominantly by cytochrome P450 family enzymes. Afatinib is a second-generation, irreversible EGFR-TKI that competes with ATP for binding to EGFR and the related proteins HER2 and HER4 and whose major circulating metabolites are covalent drug-protein adducts. We here describe a patient with EGFR mutation-positive lung adenocarcinoma who developed severe hepatotoxicity during treatment first with gefitinib and then with erlotinib, but who was subsequently able to continue treatment with afatinib for at least 44 weeks with no evidence of hepatotoxicity or disease progression. As far as we are aware, this is the first report of successful treatment with afatinib after the development of high-grade hepatotoxicity during both gefitinib and erlotinib therapy.
Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Chemical and Drug Induced Liver Injury/drug therapy , Lung Neoplasms/drug therapy , Quinazolines/therapeutic use , Afatinib , Aged , Chemical and Drug Induced Liver Injury/etiology , Erlotinib Hydrochloride/administration & dosage , Female , Gefitinib , Humans , Prognosis , Quinazolines/administration & dosage , Radiation-Sensitizing Agents/therapeutic useABSTRACT
BACKGROUND: RET fusions were recently identified in non-small cell lung cancer (NSCLC) and are considered as a potential therapeutic target of NSCLC. Sorafenib, a multi-kinase inhibitor, has potent anti-RET activity. We conducted a study to evaluate the efficacy of sorafenib in a small number of patients with RET fusion-positive NSCLC. MATERIALS AND METHODS: Eligible patients had advanced or recurrent NSCLC, were more than 20 years old, had undergone treatment with one or more previous chemotherapy regimens, had an Eastern Cooperative Oncology Group performance status 0-2, had adequate organ function, and provided informed consent. The presence of the RET fusion gene was confirmed by a split FISH assay. The patients were treated twice daily with 400mg of sorafenib taken orally. The treatment was continued until either disease progression or unacceptable toxicity. RESULTS: From March 2012 to April 2013, three patients were enrolled. The responses to sorafenib included one patient with stable disease (SD) and two patients with progressive disease (PD). One patient took sorafenib for twelve months. The most common toxicities were palmar-plantar erythrodysesthesia syndrome, hypertension, and diarrhea. CONCLUSION: Since sorafenib did not show dramatic responses, we suggest testing other RET inhibitors for the treatment of RET fusion-positive NSCLC. This study was registered at UMIN as trial number 000007515.
Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Niacinamide/analogs & derivatives , Oncogene Proteins, Fusion/genetics , Phenylurea Compounds/therapeutic use , Proto-Oncogene Proteins c-ret/genetics , Adult , Aged , Carcinoma, Non-Small-Cell Lung/diagnosis , Female , Humans , Lung Neoplasms/diagnosis , Male , Middle Aged , Neoplasm Grading , Neoplasm Staging , Niacinamide/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Sorafenib , Tomography, X-Ray Computed , Treatment OutcomeABSTRACT
Afatinib is a second generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) characterized as an irreversible pan-human EGFR (HER) family inhibitor. Afatinib remains effective for a subpopulation of patients with non-small cell lung cancer (NSCLC) with acquired resistance to first generation EGFF-TKIs such as erlotinib. Heregulin activates HER3 in an autocrine fashion and causes erlotinib resistance in NSCLC. Here we examine whether afatinib is effective against heregulin-overexpressing NSCLCs harboring EGFR activating mutations. Afatinib but not erlotinib decreased EGFR mutant NSCLC PC9HRG cell proliferation in vitro and in mouse xenografts. Afatinib inhibited phosphorylation of the cell signaling pathway proteins HER3, EGFR, HER2, and HER4, likely by prevention of trans-phosphorylation as HER3 kinase activity is inadequate for auto-phosphorylation. Afatinib, unlike erlotinib, inhibited AKT activation, resulting in elevated apoptosis in PC9HRG cells. Clinically, a subpopulation of 33 patients with EGFR mutations and NSCLC who had received first generation EGFR-TKIs exhibited elevated plasma heregulin levels compared to healthy volunteers; one of these achieved a response with afatinib therapy despite having previously developed erlotinib resistance. Afatinib can overcome heregulin-mediated resistance to erlotinib in EGFR mutant NSCLC. Further studies are necessary to determine whether heregulin can predict afatinib efficacy after development offirst generation EGFR-TKI resistance.
Subject(s)
Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Neuregulin-1/metabolism , Protein Kinase Inhibitors/pharmacology , Quinazolines/pharmacology , Receptor, ErbB-3/metabolism , Afatinib , Animals , Carcinoma, Non-Small-Cell Lung/enzymology , Carcinoma, Non-Small-Cell Lung/metabolism , Cell Line, Tumor , Drug Resistance, Neoplasm , Female , Humans , Ligands , Lung Neoplasms/enzymology , Lung Neoplasms/metabolism , Mice , Mice, Inbred BALB C , Mice, Nude , Signal Transduction , Xenograft Model Antitumor AssaysSubject(s)
Antineoplastic Agents/adverse effects , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Platinum Compounds/adverse effects , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Humans , Platinum Compounds/administration & dosage , Platinum Compounds/therapeutic use , TabletsABSTRACT
Onartuzumab is a monovalent, humanized, monoclonal antibody that showed significant survival benefits in combination with erlotinib in MET-positive non-small-cell lung cancer (NSCLC) in pre-specified subgroup analyses of a randomized phase II study. We conducted a two-stage, open-label, multicenter, phase I study of onartuzumab in Japanese patients. Stage 1 investigated the safety, tolerability, pharmacokinetics (PK), and recommended dose of onartuzumab in patients with solid tumors, and Stage 2 determined the safety, tolerability, and PK of onartuzumab plus erlotinib in patients with MET-positive NSCLC. Nine patients received onartuzumab monotherapy (4, 15, or 30 mg/kg on Day 1 of each 21-day cycle) in Stage 1, and six patients received onartuzumab (15 mg/kg) plus erlotinib (150 mg/day) in Stage 2. There were no dose-limiting toxicities in either stage. Serious adverse events (AEs) occurred in one patient in Stage 1 (convulsion), and two patients in Stage 2 (once case each of diarrhea, vomiting, and pulmonary embolism), but there were no grade 4 AEs or AEs leading to death. Onartuzumab PKs were linear in the dose range of 4 to 30 mg/kg, and were not affected by co-administration with erlotinib. PK parameters of onartuzumab were similar to those reported in non-Japanese patients. A partial response was observed in a patient with MET immunohistochemistry 3+ NSCLC without MET gene amplification. Based on these results, the recommended dose of onartuzumab in Japanese patients with solid tumors is 15 mg/kg every 21 days. The combination of onartuzumab with erlotinib is feasible in Japanese patients with MET-positive lung cancer.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Lung Neoplasms/drug therapy , Proto-Oncogene Proteins c-met/antagonists & inhibitors , Adult , Aged , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal/blood , Antibodies, Monoclonal/pharmacokinetics , Asian People , Dose-Response Relationship, Drug , Erlotinib Hydrochloride/therapeutic use , Female , Gene Dosage , Humans , Lung Neoplasms/blood , Lung Neoplasms/pathology , Male , Middle Aged , Neoplasm Staging , Proto-Oncogene Proteins c-met/blood , Proto-Oncogene Proteins c-met/genetics , Treatment OutcomeABSTRACT
Although baseline plasma homocysteine levels are related to pemetrexed toxicities in patients treated without folate supplementation, the relationship between these parameters in patients treated with folate supplementation is not well understood. The pretreatment plasma homocysteine levels were measured in non-small-cell lung cancer patients treated with pemetrexed alone under folate supplementation. Pemetrexed (500 mg/m) was administered every 3 weeks. As folate supplementation, folic acid (0.5 mg) was orally administered daily and vitamin B12 (1 mg) was injected intramuscularly every 9 weeks starting at least 1 week before treatment. The rate of toxicities during the first cycle of pemetrexed treatment with folate supplementations was evaluated and the relationship between the plasma homocysteine levels and toxicities was examined. Between June 2009 and November 2010, 58 patients were enrolled in this study. The median pretreatment plasma homocysteine level was 7.7 µmol/ml (3.5-34.6 µmol/ml). The pretreatment plasma homocysteine levels were above 11.5 µmol/ml in nine patients (15.5%). The pretreatment plasma homocysteine level correlated significantly with the nadir of the absolute counts of leukocytes, neutrophils, and thrombocytes (r = -0.374, P = 0.004; r = -0.286, P = 0.028; r = -0.324, P = 0.012, respectively). In addition, the rates of decrease in leukocytes, neutrophils, and thrombocytes correlated significantly with the pretreatment plasma homocysteine level (r = +0.378, P = 0.003; r = +0.335, P = 0.009; r = +0.363, P = 0.005, respectively). The plasma homocysteine level is associated with hematological toxicities in patients receiving pemetrexed with folate supplementation.
Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Folic Acid/administration & dosage , Glutamates/therapeutic use , Guanine/analogs & derivatives , Homocysteine/blood , Lung Neoplasms/drug therapy , Adult , Aged , Antineoplastic Agents/adverse effects , Blood Platelets/drug effects , Blood Platelets/pathology , Carcinoma, Non-Small-Cell Lung/blood , Female , Glutamates/adverse effects , Guanine/adverse effects , Guanine/therapeutic use , Humans , Leukocytes/drug effects , Leukocytes/pathology , Lung Neoplasms/blood , Male , Middle Aged , PemetrexedABSTRACT
AIM: This phase II study was conducted to evaluate the efficacy and safety of docetaxel and bevacizumab combination therapy in patients with previously-treated non-squamous non-small cell lung cancer (Nsq NSCLC). PATIENTS AND METHODS: Patients with histologically- or cytologically-confirmed Nsq NSCLC, 20-74 years of age, who had performance status 0-2, and had undergone at least one prior chemotherapy course were eligible for the study. Patients were treated with docetaxel (60 mg/m(2)) and bevacizumab (15 mg/kg) on day 1, which was repeated every three weeks until progressive disease or unacceptable toxicity occurred. The primary end-point was the response rate (RR) and the planned sample size was 28 patients. RESULTS: Between May 2010 and July 2011, 28 patients were enrolled (16 males, 12 females; median age=65 years; performance status 0/1: 19/9; adenocarcinoma/other: 22/6; number of prior chemotherapy courses 1/2/3 or more: 16/5/7). Twenty-eight patients were included in the toxicity analysis, out of whom 27 were evaluable for response. Objective response was observed in 18 patients (partial response in 18, stable disease in 8, progressive disease in 1); the RR and disease control rates were 66.7% and 96.0%, respectively. The median follow-up was 23.9 months, median progression-free survival was 7.2 months, and median overall survival was 21.6 months. The main toxicity associated with this regimen was myelosuppression (grade 3/4 neutropenia: 82.1%; febrile neutropenia: 21%). Mild non-hematological toxicity was observed but there was no severe bleeding. CONCLUSION: The combination regimen of docetaxel-plus-bevacizumab is very active in patients with previously-treated Nsq NSCLC and warrants further research.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/pathology , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Adult , Aged , Antibodies, Monoclonal, Humanized/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Bevacizumab , Carcinoma, Non-Small-Cell Lung/mortality , Chemotherapy, Adjuvant , Docetaxel , Female , Humans , Lung Neoplasms/mortality , Male , Middle Aged , Neoplasm Staging , Taxoids/administration & dosage , Treatment OutcomeABSTRACT
BACKGROUND: Gefitinib and erlotinib are used to treat advanced non-small cell lung cancer (NSCLC). Gefitinib is a common first-line treatment, but most patients develop resistance. This phase II study evaluated the efficacy of erlotinib after acquired resistance to gefitinib. PATIENTS AND METHODS: Between January 2008 and September 2009, we enrolled 50 patients with advanced NSCLC who had received one or more chemotherapy regimens, including gefitinib monotherapy to which they had partial responses (PR) or stable disease (SD). Erlotinib (150 mg) was administered until disease progression or unacceptable toxicity. Patients were 11 males, 39 females; median age 65 years (range=36-81 years); 46 with adenocarcinoma; performance status 0/1/2: 24/19/7; and smoking status, never/former/current: 33/15/2. Prior gefitinib response, PR/SD: 36/14. Median duration of prior gefitinib therapy was 419 days (range=63-1,540 days). Median interval after gefitinib therapy was 29 days (range=13-1,198 days). RESULTS: Of 47 patients on erlotinib, four showed PR and 29 showed SD [response rate, 8.5%; disease control rate (DCR), 70.2%]. DCR for patients who continued gefitinib treatment for more than one year was significantly higher (81.5%) than for patients who could not continue (57.1%; p=0.018); but was not affected by prior gefitinib response or treatment interval. Median tiMETo treatment failure: 100 days (95% confidence interval=90-110 days); median overall survival: 342 days (95% confidence interval=242-442 days). Rash (78%) and diarrhea (68%) were the most common adverse reactions; grade 5 pneumonitis occurred in one patient (2%). CONCLUSION: Erlotinib treatment after gefitinib failure may prolong the efficacy of epidermal growth factor receptor tyrosine kinase inhibitors treatment.