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RATIONALE: Immune checkpoint inhibitor-related pneumonitis is a serious autoimmune event affecting up to 20% of patients with non-small cell lung cancer, yet the factors underpinning its development in some patients and not others are poorly understood. OBJECTIVES: To investigate the role of autoantibodies and autoreactive T cells against surfactant-related proteins in the development of pneumonitis. METHODS: The study cohort consisted of non-small cell lung cancer patients who gave blood samples before and during immune checkpoint inhibitor treatment. Serum was used for proteomics analyses and to detect autoantibodies present during pneumonitis. T cell stimulation assays and single-cell RNA sequencing were performed to investigate the specificity and functionality of peripheral autoreactive T cells. The findings were confirmed in a validation cohort comprising patients with non-small cell lung cancer and patients with melanoma. MEASUREMENTS AND MAIN RESULTS: Across both cohorts, patients who developed pneumonitis had higher pre-treatment levels of immunoglobulin G autoantibodies targeting surfactant protein-B. At the onset of pneumonitis, these patients also exhibited higher frequencies of CD4+ interferon-gamma-positive surfactant protein B-specific T cells, and expanding T cell clonotypes recognizing this protein, accompanied by a pro-inflammatory serum proteomic profile. CONCLUSIONS: Our data suggest that the co-occurrence of surfactant protein-B-specific immunoglobulin G autoantibodies and CD4+ T cells is associated with the development of pneumonitis during ICI therapy. Pre-treatment levels of these antibodies may represent a potential biomarker for elevated risk of developing pneumonitis and on-treatment levels may provide a diagnostic aid. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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Immune checkpoint inhibitors (ICIs) are emerging as the new standard of care for treating various metastatic cancers. It is known that effective anti-tumor immune responses are associated with a stronger presence of tumor-infiltrating lymphocytes (TILs) in solid tumor tissue. Cancer patients with relapsing-remitting multiple sclerosis (RRMS) are often under continuous treatment with fingolimod, an immune-modulating drug that inhibits lymphocyte egress from secondary lymphatic organs. Little is known about the effect of fingolimod on ICI cancer therapy, as fingolimod may limit the number of TILs. Here we present three patients with RRMS, who developed various cancers during fingolimod treatment. Histology of all tumors consistently showed low numbers of TILs. A second biopsy taken from one of the tumors, a melanoma, revealed a significant increase of TILs after stopping fingolimod and starting pembrolizumab, indicating a surge in the number and re-invigoration of T cells. Our study suggests that fingolimod limits the number of TILs in solid tumors and may, thus, inhibit anti-cancer immune responses.
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Cloridrato de Fingolimode/uso terapêutico , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunossupressores/uso terapêutico , Linfócitos do Interstício Tumoral/imunologia , Linfócitos/imunologia , Neoplasias/tratamento farmacológico , Feminino , Cloridrato de Fingolimode/farmacologia , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Imunossupressores/farmacologia , Pessoa de Meia-Idade , Neoplasias/imunologiaRESUMO
BACKGROUND: Anti-programmed cell death protein 1 (PD1)/programmed death-ligand 1(PD-L1) therapy frequently entails immune-related adverse events (irAEs), and biomarkers to predict irAEs are lacking. Although checkpoint inhibitors have been found to reinvigorate T cells, the relevance of autoantibodies remains elusive. OBJECTIVE: Our aim was to explore whether IgG autoantibodies directed against coexpressed antigens by tumor tissue and healthy skin correlate with skin irAEs and therapy outcome. METHODS: We measured skin-specific IgG via enzyme-linked immunosorbent assay in patients with non-small cell lung cancer (NSCLC) who received anti-PD1/PD-L1 treatment between July 2015 and September 2017 at the Kantonsspital St. Gallen. Sera were sampled at baseline and during therapy after 8 weeks. RESULTS: Analysis of publicly available tumor expression data revealed that NSCLC and skin coexpress BP180, BP230, and type VII collagen. A skin irAE developed in 16 of 40 recruited patients (40%). Only elevated anti-BP180 IgG at baseline significantly correlated with the development of skin irAEs (P = .04), therapy response (P = .01), and overall survival (P = .04). LIMITATIONS: The patients were recruited in a single tertiary care center. CONCLUSIONS: Our data suggest that the level of anti-BP180 IgG of NSCLC patients at baseline is associated with better therapy response and overall survival and with a higher probability to develop skin irAEs during anti-PD1/PD-L1 treatment.
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Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/uso terapêutico , Autoantígenos/imunologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Toxidermias/etiologia , Imunoglobulina G/sangue , Neoplasias Pulmonares/tratamento farmacológico , Colágenos não Fibrilares/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Idoso , Biomarcadores/sangue , Exantema/induzido quimicamente , Feminino , Humanos , Masculino , Estudos Prospectivos , Prurido/induzido quimicamente , Análise de Sobrevida , Colágeno Tipo XVIIRESUMO
BACKGROUND: Response to immune checkpoint inhibitors depends on tumor intrinsic properties and also on host factors in the tumour microenvironment including the presence of immune cells (IC). We hypothesized that nivolumab efficacy varies across different metastatic sites. METHODS: We retrospectively analyzed computed tomography scans of patients with metastatic non-small cell lung carcinoma (NSCLC) receiving nivolumab. RECIST 1.1 criteria were applied to assess the overall response rate (ORR) and organ-specific response rate (OSRR). RESULTS: We analyzed 52 patients including 44% females, 58% adenocarcinoma and 8% never smokers. Involved organs had target-lesions in the lung (42%), liver (25%), lymph nodes (56%) and soft tissue (13%) and non-target lesions in the bones (23%). ORR and disease control rate (DCR) were 20% and 45%, respectively. Median overall survival, progression-free survival and duration of response were 11.9, 2.3 and 10.3 months. OSRR and organ-specific DCR (OSDCR) were 28% and 90% in lymph nodes, 8% and 54 in the liver, and 9% and 55% in lung metastases. Nine out of 12 patients with bone metastases had progressive lesions. The cumulative incidence probability of organ-specific progression at 6 months was 14% in lymph nodes, 42% in the liver, 36% in lung metastases and 26% in the primary tumor, 29% in soft tissue and 33% in adrenal metastases. CONCLUSION: In conclusion, the efficacy of immunotherapy is dependent on the metastatic location. Treatment appears more active in lymph nodes compared to other organ sites such as liver, adrenals and bone. Future strategies may include additional local treatment in case of oligoprogression in these organs in patients with otherwise sustained treatment benefit.
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Antineoplásicos Imunológicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Imunomodulação/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Nivolumabe/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Nivolumabe/farmacologia , Especificidade de Órgãos/efeitos dos fármacos , Especificidade de Órgãos/imunologia , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologiaRESUMO
Prognosis of metastatic melanoma improved with the development of checkpoint inhibitors. The role of tumor infiltrating lymphocytes (TILs) in lymph node metastases of stage III melanoma remains unclear. We retrospectively characterized TILs in primary melanomas and matched lymph node metastases (stage III melanoma) of patients treated with the checkpoint inhibitor ipilimumab. Tumor infiltrating lymphocytes were characterized for CD3, CD4, and CD8 expressions by immunohistochemistry. 4/9 patients (44%) responded to treatment with ipilimumab (1 complete and 2 partial remissions, 1 stable disease). All responders exhibited CD4 and CD8 T-cell infiltration in their lymph node metastases, whereas all non-responders did not show an infiltration of the lymph node metastasis with TILs. The correlation between the presence and absence of TILs in responders vs. non-responders was statistically significant (p = 0.008). Median distant metastases free survival, i.e., progression from stage III to stage IV melanoma, was similar in responders and non-responders (22.1 vs. 19.3 months; p = 0.462). Median progression free and overall survival show a trend in favor of the patients having TIL rich lymph node metastases (6.8 vs. 3.3 months, p = 0.09; and all alive at last follow-up vs. 8.2 months, respectively, p = 0.08). Our data suggest a correlation between the T-cell infiltration of the lymph node metastases in stage III melanoma and the response to ipilimumab once these patients progress to stage IV disease.
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Antineoplásicos/uso terapêutico , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Imunoterapia/métodos , Ipilimumab/uso terapêutico , Linfonodos/imunologia , Linfócitos do Interstício Tumoral/imunologia , Melanoma/imunologia , Adulto , Idoso , Animais , Antígeno CTLA-4/imunologia , Antígeno CTLA-4/metabolismo , Feminino , Humanos , Metástase Linfática , Masculino , Melanoma/tratamento farmacológico , Melanoma/mortalidade , Camundongos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Indução de Remissão , Estudos Retrospectivos , Análise de SobrevidaRESUMO
Little information is available on the very elderly patients with diffuse large B-cell lymphoma (DLBCL). We performed a retrospective analysis of 281 patients >80 years old with newly diagnosed DLBCL treated in 4 referral institutions in Switzerland and Northern Italy. Primary end points were overall survival, progression-free survival, and cause-specific survival. Systemic chemotherapy was given to 239 patients, and 119 of them received rituximab in their initial treatment. At a median follow-up of 5.5 years, 5-year progression-free survival was 26% (95% confidence interval [CI], 20-32%), 5-year overall survival was 31% (95% CI, 25-37%), and 5-year cause-specific survival was 48% (95% CI, 41-55%) for the entire cohort. Rituximab and/or anthracyclines as part of initial treatment were associated with improved outcome. Cause-specific survival in patients receiving both agents approximated 60% at 5 years. At multivariate analysis, rituximab use maintained a significant prognostic impact after controlling for age, performance status, stage, haemoglobin, and lactate dehydrogenase levels. The International Prognostic Index as well as the more recently proposed revised-International Prognostic Index and National Comprehensive Cancer Center Network-International Prognostic Index could discriminate patients with significantly different outcomes. Albeit very elderly and potentially frail, there may be a potential for cure in fit DLBCL patients ≥80 years old. Accurate selection of patients able to tolerate proper immunochemotherapy is crucial.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Imunoterapia/métodos , Idoso de 80 Anos ou mais , Feminino , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/patologia , Masculino , Prognóstico , Estudos Retrospectivos , Rituximab/farmacologia , Rituximab/uso terapêutico , Resultado do TratamentoRESUMO
Mantle cell lymphoma (MCL) is a rare non-Hodgkin's lymphoma entity with a heterogeneous clinical presentation. Various therapeutic considerations in MCL for younger and elderly patients were used over the past decade. We retrospectively analyzed all 44 patients consecutively treated in a tertiary hospital between 2000 and 2010 with newly diagnosed MCL. Patient characteristics, treatment regimens and biological markers were evaluated with regard to overall survival (OS). Treatment regimens were categorized into internationally accepted intensive standard therapies and less intensive alternative treatment regimens given with palliative intent. Biological markers were correlated with clinical outcome by univariate analysis. The median age of the entire study group was 66 years (range: 42-88), with 23 (52%) patients ≥65 years. Thirty-one (70%) patients received standard regimens, the remaining 13 (30%) patients were treated with other, less intensive regimens with palliative intent. With a median follow-up of 5.25 years, the three-year OS rate was 60% [95% confidence interval (CI) 0.47-0.77]. Patients treated with standard regimens had a three-year survival rate of 77% (range: 64-94%). Of these, patients younger than 65 years were observed to have better OS (83% at 3 years; 95% CI 68-100%) than those older than 65 years (69% at 3 years; 95% CI 48-99%). In univariate analysis, the only parameters with a statistically significant prognostic impact on OS were absolute monocyte count as a continuous variable, lactate dehydrogenase and absolute lymphocyte count (>0.5 × 10(9) /l) at diagnosis. In conclusion, our data of an unselected group of patients with newly diagnosed MCL treated at a single centre tertiary hospital are in line with results from larger randomized trials demonstrating an improved OS rate of younger as well as elderly MCL patients within the last decade.
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Linfoma de Célula do Manto/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Contagem de Células , Tratamento Farmacológico/métodos , Feminino , Humanos , Imunoterapia/métodos , L-Lactato Desidrogenase/metabolismo , Linfócitos/citologia , Masculino , Pessoa de Meia-Idade , Monócitos/citologia , Prognóstico , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Immune checkpoint inhibitors (ICIs) are among the most promising treatment options for melanoma and non-small cell lung cancer (NSCLC). While ICIs can induce effective anti-tumor responses, they may also drive serious immune-related adverse events (irAEs). Identifying biomarkers to predict which patients will suffer from irAEs would enable more accurate clinical risk-benefit analysis for ICI treatment and may also shed light on common or distinct mechanisms underpinning treatment success and irAEs. METHODS: In this prospective multi-center study, we combined a multi-omics approach including unbiased single-cell profiling of over 300 peripheral blood mononuclear cell (PBMC) samples and high-throughput proteomics analysis of over 500 serum samples to characterize the systemic immune compartment of patients with melanoma or NSCLC before and during treatment with ICIs. FINDINGS: When we combined the parameters obtained from the multi-omics profiling of patient blood and serum, we identified potential predictive biomarkers for ICI-induced irAEs. Specifically, an early increase in CXCL9/CXCL10/CXCL11 and interferon-γ (IFN-γ) 1 to 2 weeks after the start of therapy are likely indicators of heightened risk of developing irAEs. In addition, an early expansion of Ki-67+ regulatory T cells (Tregs) and Ki-67+ CD8+ T cells is also likely to be associated with increased risk of irAEs. CONCLUSIONS: We suggest that the combination of these cellular and proteomic biomarkers may help to predict which patients are likely to benefit most from ICI therapy and those requiring intensive monitoring for irAEs. FUNDING: This work was primarily funded by the European Research Council, the Swiss National Science Foundation, the Swiss Cancer League, and the Forschungsförderung of the Kantonsspital St. Gallen.
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Carcinoma Pulmonar de Células não Pequenas , Doenças do Sistema Imunitário , Neoplasias Pulmonares , Melanoma , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Inibidores de Checkpoint Imunológico/efeitos adversos , Leucócitos Mononucleares/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Linfócitos T CD8-Positivos/patologia , Antígeno Ki-67 , Estudos Prospectivos , Proteômica , Melanoma/tratamento farmacológico , Doenças do Sistema Imunitário/tratamento farmacológicoRESUMO
Background: Most patients with autoimmune hepatitis respond to standard treatment with steroids and azathioprine. While the disease is usually fatal if untreated, patients who respond well to therapy have an excellent prognosis. Nevertheless, second-line treatment is necessary in approximately 20% of patients, due to either intolerance or insufficient response to first line treatment.While data for mycophenolate mofetil (MMF) in patients intolerant to azathioprine is encouraging, MMF seems of less benefit in patients with insufficient response to first line treatment, but analyzed data on this issue is limited. Aim: To evaluate the efficacy and safety of MMF as a second-line therapy in patients with AIH. Methods: Retrospective analysis of a monocentric database of AIH patients who received medical care from 2000 to 2022. Clinical, immunological and biochemical parameters were assessed at different time points including last follow-up. Results: Overall, 144 patients with AIH were identified. Fifty out of 144 (35%) AIH patients received MMF. Forty (80%) received MMF due to first line treatment intolerance, while ten (20%) due to insufficient response to first line treatment.Remission with MMF monotherapy was 81.5% in the intolerance group versus 30% in the insufficient response group. Patients switched to MMF because of an insufficient response, more often needed additional prednisolone doses higher than 5 mg/day, a switch to third-line treatment or combination regiments, to achieve disease control. Conclusions: Patients treated with MMF because of intolerance to first line treatment show a good disease control under MMF in the majority of cases. Efficacy is considerably lower in the patients switched to MMF because of an insufficient response to first line treatment.
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PURPOSE: Immune checkpoint inhibitor (ICI)-induced hepatitis belongs to the frequently occurring immune-related adverse events (irAEs), particularly with the combination therapy involving ipilimumab and nivolumab. However, predisposing factors predicting the occurrence of ICI-induced hepatitis are barely known. We investigated the association of preexisting autoantibodies in the development of ICI-induced hepatitis in a prospective cohort of cancer patients. METHODS: Data from a prospective biomarker cohort comprising melanoma and non-small cell lung cancer (NSCLC) patients were used to analyze the incidence of ICI-induced hepatitis, putatively associated factors, and outcome. RESULTS: 40 patients with melanoma and 91 patients with NSCLC received ICI between July 2016 and May 2019. 11 patients developed ICI-induced hepatitis (8.4%). Prior to treatment, 45.5% of patients in the hepatitis cohort and 43.8% of the control cohort showed elevated titers of autoantibodies commonly associated with autoimmune liver diseases (p = 0.82). We found two nominally significant associations between the occurrence of ICI-induced hepatitis and HLA alleles associated with autoimmune liver diseases among NSCLC patients. Of note, significantly more patients with ICI-induced hepatitis developed additional irAEs in other organs (p = 0.0001). Neither overall nor progression-free survival was affected in the hepatitis group. CONCLUSION: We found nominally significant associations of ICI-induced hepatitis with two HLA alleles. ICI-induced hepatitis showed no correlation with liver-specific autoantibodies, but frequently co-occurred with irAEs affecting other organs. Unlike other irAEs, ICI-induced hepatitis is not associated with a better prognosis.
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Autoanticorpos/imunologia , Biomarcadores Tumorais/imunologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Hepatite/epidemiologia , Inibidores de Checkpoint Imunológico/efeitos adversos , Neoplasias Pulmonares/tratamento farmacológico , Melanoma/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Autoanticorpos/sangue , Biomarcadores Tumorais/sangue , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Estudos de Casos e Controles , Feminino , Seguimentos , Hepatite/sangue , Hepatite/etiologia , Hepatite/imunologia , Humanos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Masculino , Melanoma/imunologia , Melanoma/patologia , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Taxa de Sobrevida , Suíça/epidemiologiaRESUMO
Biomarkers for predicting response to anti-programmed death-1 (PD-1) immune checkpoint blockade (ICB) in non-small cell lung cancer (NSCLC) remain in demand. Since anti-tumor immune activation is a process, early dynamic changes of the acute-phase reactant C reactive protein (CRP) may serve as a predictive on-treatment biomarker. In a retrospective (N=105) and prospective (N=108) ICB-treated NSCLC cohort, early CRP kinetics were stratified after the start of immunotherapy until weeks 4, 6, and 12 as follows: an early doubling of baseline CRP followed by a drop below baseline (CRP flare-responder), a drop of at least 30% below baseline without prior flare (CRP responders), or those who remained as CRP non-responders. In our study, we observed characteristic longitudinal changes of serum CRP concentration after the initiation of ICB. In the prospective cohort, N=40 patients were defined as CRP non-responders, N=39 as CRP responders, and N=29 as CRP flare-responders with a median progression-free survival (PFS) of 2.4, 8.1, and 14.3 months, respectively, and overall survival (OS) of 6.6, 18.6, and 32.9 months (both log-rank p<0.001). Of note, CRP flare-responses, characterized by a sharp on-treatment CRP increase in the first weeks after therapy initiation, followed by a decrease of CRP serum level below baseline, predict ICB response as early as 4 weeks after therapy initiation. Of note, early CRP kinetics showed no predictive value for chemoimmunotherapy or when steroids were administered concurrently. On-treatment CRP kinetics had a predictive value for both major histological NSCLC subtypes, adenocarcinoma and squamous cell carcinoma. The results were verified in an independent retrospective cohort of 105 patients. In conclusion, CRP flare predicted anti-PD-1 monotherapy response and survival in two independent cohorts including a total of 213 patients with NSCLC, regardless of histology. Due to its wide clinical availability, early CRP kinetics could become an easily determined, cost-efficient, and non-invasive biomarker to predict response to checkpoint inhibitors in NSCLC within the first month.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Biomarcadores Tumorais , Proteína C-Reativa , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Neoplasias Pulmonares/patologia , Estudos Prospectivos , Estudos RetrospectivosRESUMO
Cancer treatment with immune checkpoint blockade (ICB) often induces immune-related adverse events (irAEs). We hypothesized that proteins coexpressed in tumors and normal cells could be antigenic targets in irAEs and herein described DITAS (discovery of tumor-associated self-antigens) for their identification. DITAS computed transcriptional similarity between lung tumors and healthy lung tissue based on single-sample gene set enrichment analysis. This identified 10 lung tissue-specific genes highly expressed in the lung tumors. Computational analysis was combined with functional T cell assays and single-cell RNA sequencing of the antigen-specific T cells to validate the lung tumor self-antigens. In patients with non-small cell lung cancer (NSCLC) treated with ICB, napsin A was a self-antigen that elicited strong CD8+ T cell responses, with ICB responders harboring higher frequencies of these CD8+ T cells compared with nonresponders. Human leukocyte antigen (HLA) class I ligands derived from napsin A were present in human lung tumors and in nontumor lung tissues, and napsin A tetramers confirmed the presence of napsin A-specific CD8+ T cells in blood and tumors of patients with NSCLC. Napsin A-specific T cell clonotypes were enriched in lung tumors and ICB-induced inflammatory lung lesions and could kill immortalized HLA-matched NSCLC cells ex vivo. Single-cell RNA sequencing revealed that these T cell clonotypes expressed proinflammatory cytokines and cytotoxic markers. Thus, DITAS successfully identified self-antigens, including napsin A, that likely mediate effective antitumor T cell responses in NSCLC and may simultaneously underpin lung irAEs.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Antígenos de Neoplasias , Autoantígenos , Linfócitos T CD8-Positivos , Carcinoma Pulmonar de Células não Pequenas/genética , Antígenos de Histocompatibilidade Classe I , Humanos , Inibidores de Checkpoint Imunológico , Pulmão , Neoplasias Pulmonares/genéticaRESUMO
Human alveolar echinococcosis (AE) is a zoonotic infection caused by the fox tapeworm Echinococcus ââââââmultilocularis. We report the case of a patient who developed an accelerated course of AE with diffuse liver involvement after high-dose steroid treatment for autoimmune encephalitis. Immunosuppressive therapies present us with new challenges regarding the management of AE. With this article, we would like to draw attention to the importance of a screening program for AE before planned immunosuppressive therapy.
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Until recently, standard treatment for advanced melanoma comprised basically dacarbazine and interleukin-2, leading to low response rates and significant toxicity. These days, new treatments such as immunotherapy (anti-CTLA4 and anti-PD1 antibodies) and targeted therapy with BRAF/MEK-inhibitor combinations for patients harboring a BRAF mutation are available. In BRAF wild-type patients harboring an NRAS mutation, not fit for immunotherapy treatment options are still dismal. We describe an 84-year-old patient with widespread metastatic melanoma. He presented in July 2015 with a cerebral hemorrhage under anticoagulation for atrial fibrillation. Computed tomography revealed extensive metastatic disease (liver, lung, bones, lymph nodes, heart, and brain). Molecular testing was negative for BRAF but showed the presence of an NRAS mutation in exon 3 (pQ61K [c.181C>A]). The patient received as first-line treatment two cycles of cobimetinib showing a good partial remission and manageable side effects.
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Azetidinas/uso terapêutico , GTP Fosfo-Hidrolases/genética , Melanoma/tratamento farmacológico , Proteínas de Membrana/genética , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Mutação , Piperidinas/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológico , Idoso de 80 Anos ou mais , Humanos , Masculino , Melanoma/patologia , Metástase Neoplásica , Neoplasias Cutâneas/patologia , Resultado do TratamentoRESUMO
Importance: In many health systems, access to off-label drug use is controlled through reimbursement restrictions by health insurers, especially for expensive cancer drugs. Objective: To determine whether evidence from randomized clinical trials is associated with reimbursement decisions for requested off-label use of anticancer drugs in the Swiss health system. Design, Setting, and Participants: This cross-sectional study used reimbursement requests from routinely collected health records of 5809 patients with drug treatment for cancer between January 2015 and July 2018 in 3 major cancer centers, covering cancer care of approximately 5% of the Swiss population, to identify off-label drug use. For each off-label use indication with 3 or more requests, randomized clinical trial evidence on treatment benefits was systematically identified for overall survival (OS) or progression-free survival (PFS). Data were analyzed from August 2018 to December 2020. Exposures: Available randomized clinical trial evidence on benefits for OS or PFS for requested off-label use indications. Main Outcomes and Measures: The main outcome was the association between evidence for treatment benefit (expressed as improved OS or PFS) and reimbursement in multivariable regression models. Results: Among 3046 patients with cancer, 695 off-label use reimbursement requests in 303 different indications were made for 598 patients (median [interquartile range] age, 64 [53-73] years; 420 [60%] men). Off-label use was intended as first-line treatment in 311 requests (45%). Reimbursement was accepted in 446 requests (64%). For 71 indications, including 431 requests for 376 patients, there were 3 or more requests. Of these, 246 requests (57%) had no supporting evidence for OS or PFS benefit. Reimbursement was granted in 162 of 246 requests without supporting evidence (66%). Of 117 requests supported by OS benefit, 79 (67%) were reimbursed, and of 68 requests supported by PFS benefit alone, 54 (79%) were reimbursed. Evidence of OS benefit from randomized clinical trials was not associated with a higher chance of reimbursement (odds ratio, 0.76, 95% CI, 0.45-1.27). Conclusions and Relevance: These findings suggest that in a health care system enabling access to off-label use, it was frequently intended as a first-line treatment in cancer care. Availability of randomized clinical trial evidence showing survival benefit was not associated with reimbursement decisions for off-label anticancer drug treatment in Switzerland. A transparent process with criteria considering clinical evidence is needed for evidence-based reimbursement decisions to ensure fair access to cancer treatments.
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Antineoplásicos/economia , Reembolso de Seguro de Saúde/normas , Neoplasias/economia , Uso Off-Label/economia , Idoso , Antineoplásicos/uso terapêutico , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Neoplasias/mortalidade , Intervalo Livre de Progressão , Ensaios Clínicos Controlados Aleatórios como Assunto , Taxa de Sobrevida , SuíçaRESUMO
BACKGROUND: Checkpoint inhibitors revolutionized the treatment of metastatic melanoma patients. Although tumor burden and lactate dehydrogenase (LDH) are associated with overall survival (OS), the impact of tumor growth kinetics remains elusive and in part contradictory. The aims of this study were to develop a novel simple and rapid method that estimates pretreatment metastatic growth rate (MGR) and to investigate its prognostic impact in melanoma patients treated with antiprogrammed death receptor-1 (PD-1) antibodies. METHODS: MGR was assessed in three independent cohorts of a total of 337 unselected consecutive metastasized stage IIIB-IV melanoma patients (discovery cohort: n=53, confirmation cohort: n=126, independent multicenter validation cohort: n=158). MGR was computed during the pretreatment period before initiation of therapy with anti-PD-1 antibodies nivolumab or pembrolizumab by measuring the increase of the longest diameter of the largest target lesion. Tumor doubling time served as quality control. Kaplan-Meier analysis and univariable as well as multivariable Cox regression were used to examine the prognostic impact of MGR. RESULTS: Pretreatment MGR >3.9 mm/month was associated with impaired OS in the discovery cohort (HR 6.19, 95% CI 2.92 to 13.10, p<0.0001), in the confirmation cohort (HR 3.62, 95% CI 2.19 to 5.98, p<0.0001) and in the independent validation cohort (HR 2.57, 95% CI 1.56 to 4.25, p=0.00023). Prior lines of systemic treatment did not influence the significance of MGR. Importantly, the prognostic impact of MGR was independent of total tumor burden, diameter of the largest metastasis, number of prior lines of systemic treatment, LDH, as well as liver and brain metastasis (discovery and confirmation cohorts: both p<0.0001). Superiority of MGR compared with these variables was confirmed in the independent multicenter validation cohort (HR 2.92, 95% CI 1.62 to 5.26, p=0.00036). CONCLUSIONS: High pretreatment MGR is an independent strong prognostic biomarker associated with unfavorable survival of melanoma patients receiving anti-PD-1 antibodies. Further investigations are warranted to assess the predictive impact of MGR in distinct systemic therapeutic regimens.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Proliferação de Células , Inibidores de Checkpoint Imunológico/uso terapêutico , Melanoma/tratamento farmacológico , Nivolumabe/uso terapêutico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias Cutâneas/tratamento farmacológico , Tomografia Computadorizada por Raios X , Anticorpos Monoclonais Humanizados/efeitos adversos , Europa (Continente) , Feminino , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Masculino , Melanoma/diagnóstico por imagem , Melanoma/imunologia , Melanoma/secundário , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Nivolumabe/efeitos adversos , Valor Preditivo dos Testes , Receptor de Morte Celular Programada 1/imunologia , Reprodutibilidade dos Testes , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Neoplasias Cutâneas/diagnóstico por imagem , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Immune-related diarrhoea/colitis (ir-D/C) is a common adverse event of immune checkpoint inhibitor (ICI) therapy. Guidelines recommend corticosteroid (CS) treatment; however, the average treatment duration for ir-D/C remains poorly defined. METHODS: All advanced melanoma patients treated with ICI therapy at the Royal Marsden Hospital between 2011 and 2016 were reviewed to identify ir-D/C cases alongside clinical variables. RESULTS: 117 any-grade ir-D/C episodes occurred in 109 (21%) patients out of a total of 519 patients treated (ipilimumab=77 episodes, anti-PD1=17 (nivolumab or pembrolizumab), ipilimumab and nivolumab=23 (ipi+nivo)) (seven patients had ir-D/C more than once on different lines of treatment) and >/=grade 3 ir-D/C occurred most frequently (63/519 patients (12%) vs 29/519 (5%) grade 1, and 25/519 (5%) grade 2). Median onset (days) of all-grade ir-D/C after starting ICI therapy was 41 for ipilimumab (IQR 24 to 59, n=77), 91 for anti-PD1 (IQR 46 to 355, n=17) and 45 for ipi+nivo (IQR 24 to 67, n=23). In 71/117 (61%) patients, ir-D/C episodes were treated with CS (17% grade 2; 79% grade 3/4): 54 being steroid-responsive; 17 being steroid-refractory and received additional anti-tumor necrosis factor (TNF) treatment. Median grade 3 ir-D/C CS duration was similar across treatments, averaging 58 days. Median overall CS duration (days) was longer in the grade 3/4 D/C steroid-refractory group (94 vs 45 days). Infection developed in 11/71 (15%) CS recipients and in 6/17 (35%) anti-TNF recipients. In 65/117 (55%) patients, ir-D/C episodes were investigated with flexible sigmoidoscopy. Of these patients, 38/65 (58%) had macroscopic colitis and 12/65 (18%) had microscopic colitis. The steroid-refractory group had more macroscopic changes, 13/17 (76%), than the steroid-responsive group, 22/41 (54%). CONCLUSION: Rates of grade 3 ir-D/C were higher than reported in clinical trials. The 58-day median duration of CS therapy for grade 3 ir-D/C places a significant number of patients at risk of complications. We demonstrate that microscopic colitis is an important subgroup, advocating biopsies in ir-D/C even with macroscopically normal bowel.
Assuntos
Colite , Melanoma , Neoplasias Cutâneas , Corticosteroides/uso terapêutico , Colite/induzido quimicamente , Diarreia/induzido quimicamente , Feminino , Humanos , Inibidores de Checkpoint Imunológico , Masculino , Melanoma/tratamento farmacológico , Pessoa de Meia-Idade , Neoplasias Cutâneas/tratamento farmacológico , Inibidores do Fator de Necrose TumoralRESUMO
BACKGROUND: Checkpoint inhibitors (CIs) are highly effective but can induce severe immune-related adverse events (irAEs), which cannot be predicted. We investigated whether human leukocyte antigen (HLA) genes predispose to developing of irAEs during therapy and thus hold a predictive role. METHODS: We established a prospective observational single-centre study and collected data from patients with either metastatic non-small cell lung cancer (NSCLC) or metastatic melanoma, who were treated with anti-PD-1 (programmed cell death receptor 1), anti-CTLA4 (cytotoxic T-lymphocyte-associated protein 4) or both CIs combined. Data include irAEs and ranges from 15th July 2016 until 10th May 2018. In addition, we performed HLA typing via next generation sequencing. RESULTS: We enrolled 102 patients (median [range] age, 68 [62-74] years) with metastatic cancer in our study who received CI therapy. Of these patients, 59 (58%) developed one or more irAEs, among which pruritus (n = 32 (54%)) and rash (n = 24 (41%)) had the highest rates. We did not find evidence for a single HLA gene being associated with all irAEs (all P > .05). When assessing each irAE individually, we found a significant association between HLA-DRB1*11:01 and pruritus (OR = 4.53, X21,95 = 9.45, P < .01) as well as a nominally significant additive association between HLA-DQB1*03:01 and colitis (OR = 3.94, X21,95 = 5.67, P = .017). CONCLUSIONS: The presence of two HLA alleles that are known to predispose to autoimmune diseases were associated with the development of pruritus or colitis during therapy, suggesting a genetic aetiology of irAEs. Larger genome-wide association studies should be performed to confirm our findings.
Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Variação Genética , Cadeias beta de HLA-DQ/genética , Neoplasias Pulmonares/tratamento farmacológico , Melanoma/tratamento farmacológico , Idoso , Carcinoma Pulmonar de Células não Pequenas/patologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/patologia , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Prognóstico , Estudos ProspectivosRESUMO
Checkpoint inhibitors have improved survival of metastatic melanoma. However, reliable biomarkers to predict response are still needed. Immunoglobulin G (IgG) antibody subclasses reflect immunocompetence in individuals and are known to be involved in essential functions in our immune system. This prospective study evaluated the association between serum IgG with its subclasses IgG1, IgG2, IgG3, and IgG4 and antitumor response according to RECIST 1.1. Serum samples from 49 patients were prospectively collected before the start of treatment with a checkpoint inhibitor. We observed a statistically significant association of baseline IgG2 with response to therapy (P=0.011). After defining optimal cutpoints, we found significant associations between total IgG (>9.66 g/L, P=0.038), IgG1 (>6.22 g/L, P=0.025), IgG2 (>2.42 g/L, P=0.019), and IgG3 (>0.21 g/L, P=0.034) with progression-free survival. Prolonged overall survival was associated with elevated IgG2 (>2.42 g/L, P=0.043). Together, these findings define total IgG and subclasses as predictors of clinical successful checkpoint inhibition in metastatic melanoma patients.