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Here we report a phase 1b clinical trial testing the impact of oncolytic virotherapy with talimogene laherparepvec on cytotoxic T cell infiltration and therapeutic efficacy of the anti-PD-1 antibody pembrolizumab. Twenty-one patients with advanced melanoma were treated with talimogene laherparepvec followed by combination therapy with pembrolizumab. Therapy was generally well tolerated, with fatigue, fevers, and chills as the most common adverse events. No dose-limiting toxicities occurred. Confirmed objective response rate was 62%, with a complete response rate of 33% per immune-related response criteria. Patients who responded to combination therapy had increased CD8+ T cells, elevated PD-L1 protein expression, as well as IFN-γ gene expression on several cell subsets in tumors after talimogene laherparepvec treatment. Response to combination therapy did not appear to be associated with baseline CD8+ T cell infiltration or baseline IFN-γ signature. These findings suggest that oncolytic virotherapy may improve the efficacy of anti-PD-1 therapy by changing the tumor microenvironment. VIDEO ABSTRACT.
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Anticorpos Monoclonais Humanizados/administração & dosagem , Melanoma/terapia , Terapia Viral Oncolítica/efeitos adversos , Terapia Combinada , Herpesviridae/genética , Humanos , Imunoterapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Microambiente TumoralRESUMO
BACKGROUND: TROP2 (TACSTD2) expression is associated with decreased overall survival (OS) in some solid tumors, and the TROP2-targeting antibody-drug conjugate (ADC) sacituzumab govitecan has been approved in breast and urothelial carcinomas. We aimed to explore the multi-omic landscape associated with TACSTD2 gene expression in various solid tumors to identify patients most likely to benefit from this approach. METHODS: Breast (Nâ =â 11 246), colorectal (Nâ =â 15 425), hepatocellular (Nâ =â 433), pancreatic (Nâ =â 5488), and urothelial (Nâ =â 4125) tumors were stratified into quartiles by TACSTD2 gene expression, analyzed by next-generation DNA sequencing, whole transcriptome sequencing, and immunohistochemistry at Caris Life Sciences (Phoenix, AZ). Survival data were obtained from insurance claims, and Kaplan-Meier estimates were calculated for molecularly defined cohorts. RESULTS: Several pathogenic mutations were associated with TACSTD2-high tumors, including TP53 in breast, colorectal (CRC), pancreatic, and hepatocellular cancers; KRAS in pancreatic and CRC cancers; ARID1A and FGFR3 in urothelial cancer; and CTNNB1 in hepatocellular cancer. TACSTD2-low breast tumors were enriched for copy number amplifications in CCND1 and FGF/R family member genes. TACSTD2 high was generally associated with more immune cell infiltration and greater T-cell inflammation scores. Patients with TACSTD2-high breast, CRC, and pancreatic cancers demonstrated a significantly shorter OS than TACSTD2-low tumors. This was restricted to CRC with microsatellite stable tumors and patients with pancreatic cancer with KRAS-mutant tumors. Patients with breast cancer with TACSTD2-high tumors also experienced significantly worse OS following immune checkpoint inhibitors. CONCLUSIONS: TACSTD2 expression is associated with key driver alterations and a more active immune microenvironment, suggesting possible combinatorial strategies with TROP2-targeting ADCs plus immunotherapy in various solid tumors.
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BACKGROUND: Two ROS1 tyrosine kinase inhibitors have been approved for ROS1 fusion positive (ROS1+) non-small cell lung cancer (NSCLC) tumors. We performed a pan-tumor analysis of the incidence of ROS1 fusions to assess if more ROS1+ patients who could benefit from ROS1 TKIs could be identified. METHODS: A retrospective analysis of ROS1 positive solid malignancies identified by targeted RNA sequencing and whole transcriptome sequencing of clinical tumor samples performed at Caris Life Science (Phoenix, AZ). RESULTS: A total of 259 ROS1+ solid malignancies were identified from approximately 175,350 tumors that underwent next-generation sequencing (12% from targeted RNA sequencing [Archer]; 88% from whole transcriptome sequencing). ROS1+ NSCLC constituted 78.8% of the ROS1+ solid malignancies, follow by glioblastoma (GBM) (6.9%), and breast cancer (2.7%). The frequency of ROS1 fusion was approximately 0.47% among NSCLC, 0.29% for GBM, 0.04% of breast cancer. The mean tumor mutation burden for all ROS1+ tumors was 4.8 mutations/megabase. The distribution of PD-L1 (22C3) expression among all ROS1+ malignancies were 0% (18.6%), 1%-49% (29.4%), and ≥ 50% (60.3%) [for NSCLC: 0% (17.8%); 1-49% (27.7%); ≥ 50% (53.9%). The most common genetic co-alterations of ROS1+ NSCLC were TP53 (29.1%), SETD2 (7.3%), ARIAD1A (6.3%), and U2AF1 (5.6%). CONCLUSIONS: ROS1+ NSCLC tumors constituted the majority of ROS1+ solid malignancies with four major fusion partners. Given that > 20% of ROS1+ solid tumors may benefit from ROS1 TKIs treatment, comprehensive genomic profiling should be performed on all solid tumors.
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Neoplasias da Mama , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Feminino , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Proteínas Tirosina Quinases/metabolismo , Estudos Retrospectivos , Sequenciamento do Exoma , Proteínas Proto-Oncogênicas/genéticaRESUMO
BACKGROUND AND OBJECTIVES: Published data comparing peritoneal metastases from appendiceal cancers (pAC) and colorectal cancers (pCRC) remain sparse. We compared pAC and pCRC using comprehensive tumor profiling (CTP). METHODS: CTP was performed, including next-generation sequencing and analysis of copy number variation (CNV), microsatellite instability (MSI) and tumor mutational burden (TMB). RESULTS: One hundred thirty-six pAC and 348 pCRC samples underwent CTP. The cohorts' age and gender were similar. pCRC demonstrated increased pathogenic variants (PATHs) in APC (48% vs. 3%, p < 0.01), ARID1A (12% vs. 2%, p < 0.01), BRAF (12% vs. 2%, p < 0.01), FBXW7 (7% vs. 2%, p < 0.01), KRAS (52% vs. 41%, p < 0.05), PIK3CA (15% vs. 2%, p < 0.01), and TP53 (53% vs. 23%, p < 0.01), and decreased PATHs in GNAS (8% vs. 31%, p < 0.01). There was no difference in CNV, fusion rate, or MSI. Median TMB was higher in pCRC (5.8 vs. 5.0 mutations per megabase, p = 0.0007). Rates of TMB-high tumors were similar (pAC 2.1% vs. pCRC 9.0%, p = 0.1957). pCRC had significantly more TMB-high tumors at lower thresholds. CONCLUSIONS: Despite a reduced overall TMB, pAC demonstrated mutations distinct from those seen in pCRC. These may serve as discrete biomarkers for future study.
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Neoplasias do Apêndice , Neoplasias Colorretais , Neoplasias Peritoneais , Humanos , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Neoplasias Peritoneais/genética , Neoplasias Peritoneais/secundário , Variações do Número de Cópias de DNA , Neoplasias do Apêndice/genética , Neoplasias do Apêndice/patologia , Mutação , Instabilidade de Microssatélites , Biomarcadores Tumorais/genéticaRESUMO
BACKGROUND: Therapies targeting HER2 have improved clinical outcomes in HER2-positive breast and gastric cancers, and are emerging as potential treatments for HER2-positive metastatic colorectal cancer. MyPathway evaluates the activity of targeted therapies in non-indicated tumour types with potentially predictive molecular alterations. We aimed to assess the activity of pertuzumab and trastuzumab in patients with HER2-amplified metastatic colorectal cancer. METHODS: MyPathway is an ongoing, phase 2a, multiple basket study. Patients in this subset analysis were aged 18 years or older and had treatment-refractory, histologically confirmed HER2-amplified metastatic colorectal cancer with measurable or evaluable disease and an Eastern Cooperative Oncology Group performance status score of 2 or less, enrolled from 25 hospitals or clinics in 16 states of the USA. Patients received pertuzumab (840 mg loading dose, then 420 mg every 3 weeks, intravenously) and trastuzumab (8 mg/kg loading dose, then 6 mg/kg every 3 weeks, intravenously). The primary endpoint was the proportion of patients who achieved an objective response based on investigator-reported tumour responses. Analyses were done per protocol. This ongoing trial is registered with ClinicalTrials.gov, number NCT02091141. FINDINGS: Between Oct 20, 2014, and June 22, 2017, 57 patients with HER2-amplified metastatic colorectal cancer were enrolled in the MyPathway study and deemed eligible for inclusionin this cohort analysis. Among these 57 evaluable patients, as of Aug 1, 2017, one (2%) patient had a complete response and 17 (30%) had partial responses; thus overall 18 of 57 patients achieved an objective response (32%, 95% CI 20-45). The most common treatment-emergent adverse events were diarrhoea (19 [33%] of 57 patients), fatigue (18 [32%] patients), and nausea (17 [30%] patients). Grade 3-4 treatment-emergent adverse events were recorded in 21 (37%) of 57 patients, most commonly hypokalaemia and abdominal pain (each three [5%] patients). Serious treatment-emergent adverse events were reported in ten (18%) patients and two (4%) of these adverse events (ie, chills and infusion-related reaction) were considered treatment related. There were no treatment-related deaths. INTERPRETATION: Dual HER2-targeted therapy with pertuzumab plus trastuzumab is well tolerated and could represent a therapeutic opportunity for patients with heavily pretreated, HER2-amplified metastatic colorectal cancer. FUNDING: F Hoffmann-La Roche/Genentech.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Receptor ErbB-2/genética , Trastuzumab/uso terapêutico , Idoso , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Resistencia a Medicamentos Antineoplásicos , Feminino , Amplificação de Genes , Humanos , Masculino , Pessoa de Meia-Idade , Receptor ErbB-2/antagonistas & inibidores , Resultado do TratamentoRESUMO
As people with cancer survive longer, and as the US population ages, skeletal effects of cancer treatment are becoming more pronounced. This is particularly true for breast and prostate cancer survivors because of the high average age of patients with these malignancies, the propensity of older adults in general toward the development of osteoporosis, and the wide use of therapeutic agents in these cancers that negatively impact bone health. Various therapies used in the treatment and prevention of cancer may cause decreases in bone mineral density and an increased risk of debilitating fracture, even in the absence of bone metastases. Aging is both a baseline risk factor in the development of osteoporosis and bony fracture, as well as a predictor of poor outcome after fracture. A variety of mechanisms may be responsible for the development of bone loss in patients with breast or prostate cancer. Cytotoxic chemotherapy may directly exert long-term toxic effects on bone. Chemotherapy and endocrine therapy can induce hypogonadism, leading to an increased rate of bone loss. The risk of skeletal events in older adults due to cancer therapy should be appreciated by all oncologists, geriatricians, and internists. The following review may serve as a guide to the skeletal side effects of cancer therapy in older adults with breast or prostate cancer, how to screen for treatment-related bone loss, and how to best prevent and/or treat skeletal events.
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Envelhecimento , Antineoplásicos/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Osteoporose/induzido quimicamente , Neoplasias da Próstata/tratamento farmacológico , Densidade Óssea/efeitos dos fármacos , Feminino , Fraturas Ósseas/induzido quimicamente , Humanos , Masculino , Fatores de RiscoRESUMO
Despite the long history of bendamustine as treatment for indolent non-Hodgkin lymphoma, long-term efficacy and toxicity data are minimal. We reviewed long-term data from three clinical trials to characterize the toxicity and efficacy of patients receiving bendamustine. Data were available for 149 subjects at 21 sites. The median age was 60 years at the start of bendamustine (range 39-84), and patients had received a median of 3 prior therapies. The histologies included grades 1-2 follicular lymphoma (FL; n = 73), grade 3 FL (n = 23), small lymphocytic lymphoma (n = 20), marginal zone lymphoma (n = 15), mantle cell lymphoma (n = 9), transformed lymphomas (n = 5), lymphoplasmacytic lymphoma (n = 2) and not reported (n = 2). The median event-free survival was 14·1 months. Nine of 12 attempted stem cell collections were successful. With a median follow-up of 8·9 years, 23 patients developed 25 cancers, including 8 patients with myelodysplastic syndrome/acute myeloid leukaemia. These data provide important information regarding the long-term toxicity of bendamustine in previously treated patients. A small but meaningful number of patients achieved durable remissions following bendamustine. These rigorously collected, patient-level, long-term follow-up data provide reassurance that bendamustine or bendamustine plus rituximab is associated with efficacy and safety for patients with relapsed or refractory indolent non-Hodgkin lymphoma.
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Antineoplásicos Alquilantes/administração & dosagem , Cloridrato de Bendamustina/administração & dosagem , Mobilização de Células-Tronco Hematopoéticas/métodos , Linfoma não Hodgkin/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Alquilantes/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cloridrato de Bendamustina/efeitos adversos , Ensaios Clínicos como Assunto , Intervalo Livre de Doença , Feminino , Humanos , Leucemia Mieloide Aguda/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Síndromes Mielodisplásicas/induzido quimicamente , Segunda Neoplasia Primária/induzido quimicamente , Rituximab/administração & dosagem , Rituximab/efeitos adversos , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: We aimed to compare panitumumab, a fully human monoclonal antibody against EGFR, plus radiotherapy with chemoradiotherapy in patients with unresected, locally advanced squamous-cell carcinoma of the head and neck. METHODS: In this international, open-label, randomised, controlled, phase 2 trial, we recruited patients with locally advanced squamous-cell carcinoma of the head and neck from 22 sites in eight countries worldwide. Patients aged 18 years and older with stage III, IVa, or IVb, previously untreated, measurable (≥ 10 mm for at least one dimension), locally advanced squamous-cell carcinoma of the head and neck (non-nasopharygeal) and an Eastern Cooperative Oncology Group performance status of 0-1 were randomly assigned (2:3) by an independent vendor to open-label chemoradiotherapy (two cycles of cisplatin 100 mg/m(2) during radiotherapy) or to radiotherapy plus panitumumab (three cycles of panitumumab 9 mg/kg every 3 weeks administered with radiotherapy) using a stratified randomisation with a block size of five. All patients received 70-72 Gy to gross tumour and 54 Gy to areas of subclinical disease with accelerated fractionation radiotherapy. The primary endpoint was local-regional control at 2 years, analysed in all randomly assigned patients who received at least one dose of their assigned protocol-specific treatment (chemotherapy, radiation, or panitumumab). The trial is closed and this is the final analysis. This study is registered with ClinicalTrials.gov, number NCT00547157. FINDINGS: Between Nov 30, 2007, and Nov 16, 2009, 152 patients were enrolled, and 151 received treatment (61 in the chemoradiotherapy group and 90 in the radiotherapy plus panitumumab group). Local-regional control at 2 years was 61% (95% CI 47-72) in the chemoradiotherapy group and 51% (40-62) in the radiotherapy plus panitumumab group. The most frequent grade 3-4 adverse events were mucosal inflammation (25 [40%] of 62 patients in the chemoradiotherapy group vs 37 [42%] of 89 patients in the radiotherapy plus panitumumab group), dysphagia (20 [32%] vs 36 [40%]), and radiation skin injury (seven [11%] vs 21 [24%]). Serious adverse events were reported in 25 (40%) of 62 patients in the chemoradiotherapy group and in 30 (34%) of 89 patients in the radiotherapy plus panitumumab group. INTERPRETATION: Panitumumab cannot replace cisplatin in the combined treatment with radiotherapy for unresected stage III-IVb squamous-cell carcinoma of the head and neck, and the role of EGFR inhibition in locally advanced squamous-cell carcinoma of the head and neck needs to be reassessed. FUNDING: Amgen.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimiorradioterapia , Neoplasias de Cabeça e Pescoço/terapia , Neoplasias de Células Escamosas/terapia , Adolescente , Adulto , Idoso , Anticorpos Monoclonais/administração & dosagem , Cisplatino/administração & dosagem , Fracionamento da Dose de Radiação , Feminino , Seguimentos , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Agências Internacionais , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias de Células Escamosas/mortalidade , Neoplasias de Células Escamosas/patologia , Panitumumabe , Prognóstico , Taxa de Sobrevida , Adulto JovemRESUMO
BACKGROUND: Panitumumab is a fully human monoclonal antibody that targets EGFR. We aimed to compare chemoradiotherapy plus panitumumab with chemoradiotherapy alone in patients with unresected, locally advanced squamous-cell carcinoma of the head and neck. METHODS: In this international, open-label, randomised, controlled, phase 2 trial, we recruited patients with locally advanced squamous-cell carcinoma of the head and neck from 41 sites in nine countries worldwide. Patients aged 18 years and older with stage III, IVa, or IVb, previously untreated, measurable (≥ 10 mm for at least one dimension), locally advanced squamous-cell carcinoma of the head and neck (non-nasopharygeal) and an Eastern Cooperative Oncology Group performance status of 0-1 were randomly assigned (2:3) by an independent vendor to open-label chemoradiotherapy (three cycles of cisplatin 100 mg/m(2)) or panitumumab plus chemoradiotherapy (three cycles of intravenous panitumumab 9.0 mg/kg every 3 weeks plus cisplatin 75 mg/m(2)) using stratified randomisation with a block size of five. All patients received 70 Gy to gross tumour and 50 Gy to areas at risk for subclinical disease with standard fractionation. The primary endpoint was local-regional control at 2 years, analysed in all randomised patients who received at least one dose of their assigned protocol-specific treatment (chemotherapy, radiation, or panitumumab). The trial is closed and this is the final analysis. This trial is registered with ClinicalTrials.gov, number NCT00500760. FINDINGS: Between Oct 26, 2007, and March 26, 2009, 153 patients were enrolled and 150 received treatment (63 in the chemoradiotherapy group and 87 in the panitumumab plus chemoradiotherapy group). Local-regional control at 2 years was 68% (95% CI 54-78) in the chemoradiotherapy group and 61% (50-71) in the panitumumab plus chemoradiotherapy group. The most frequent grade 3-4 adverse events were dysphagia (17 [27%] of 63 patients in the chemoradiotherapy group vs 35 [40%] of 87 in the panitumumab plus chemoradiotherapy group), mucosal inflammation (15 [24%] vs 48 [55%]), and radiation skin injury (eight [13%] vs 27 [31%]). Serious adverse events were reported in 20 (32%) of 63 patients in the chemoradiotherapy group and in 37 (43%) of 87 patients in the panitumumab plus chemoradiotherapy group. INTERPRETATION: In patients with locally advanced squamous-cell carcinoma of the head and neck, the addition of panitumumab to standard fractionation radiotherapy and cisplatin did not confer any benefit, and the role of EGFR inhibition in these patients needs to be reassessed. FUNDING: Amgen.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimiorradioterapia , Neoplasias de Cabeça e Pescoço/terapia , Neoplasias de Células Escamosas/terapia , Adolescente , Adulto , Idoso , Anticorpos Monoclonais/administração & dosagem , Cisplatino/administração & dosagem , Fracionamento da Dose de Radiação , Feminino , Seguimentos , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Agências Internacionais , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias de Células Escamosas/mortalidade , Neoplasias de Células Escamosas/patologia , Panitumumabe , Prognóstico , Taxa de Sobrevida , Adulto JovemRESUMO
With the advent of widespread tumor genetic profiling, an increased number of mutations with unknown significance are being identified. Often, a glut of uninterpretable findings may confuse the clinician and provide little or inappropriate guidance in therapeutic decision-making. This report describes a method of protein modeling by in silico analysis (ie, using computer simulation) that is easily accessible to the practicing clinician without need for further laboratory analysis, which can potentially serve as a guide in therapeutic decisions based on poorly characterized tumor mutations. An example of this model is given wherein poorly characterized KIT, PDGFRB, and ERBB2 mutations were discovered in a patient with treatment-refractory metastatic transitional cell carcinoma of the renal pelvis. The KIT and PDGFRB mutations were predicted to be pathogenic using in silico analysis, whereas the ERBB2 mutation was predicted to be benign. Based on these findings, the patient was treated with pazopanib and achieved a partial response that lasted for 7.5 months. We propose that in silico analysis be explored as a potential means to further characterize genetic abnormalities found by tumor profiling assays, such as next-generation sequencing.
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Carcinoma de Células de Transição/genética , Proteínas Proto-Oncogênicas c-kit/genética , Receptor ErbB-2/genética , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Carcinoma de Células de Transição/tratamento farmacológico , Carcinoma de Células de Transição/patologia , Simulação por Computador , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Indazóis , Pelve Renal/efeitos dos fármacos , Pelve Renal/patologia , Pessoa de Meia-Idade , Modelos Moleculares , Mutação , Metástase Neoplásica , Proteínas Proto-Oncogênicas c-kit/química , Pirimidinas/uso terapêutico , Receptor ErbB-2/química , Receptor beta de Fator de Crescimento Derivado de Plaquetas/química , Sulfonamidas/uso terapêutico , Urotélio/efeitos dos fármacos , Urotélio/patologiaRESUMO
ARID genes encode subunits of SWI/SNF chromatin remodeling complexes and are frequently mutated in human cancers. We investigated the correlation between ARID mutations, molecular features, and clinical outcomes in melanoma patients. Cutaneous melanoma samples (n = 1577) were analyzed by next-generation sequencing. Samples were stratified by pathogenic/likely pathogenic mutation in ARID genes (ARID1A/2/1B/5B). PD-L1 expression was assessed using IHC (SP142; positive (+): ≥ 1%). Tumor mutation burden (TMB)-high was defined as ≥ 10 mutations/Mb. Transcriptomic signatures predictive of response to immune checkpoint inhibitors-interferon gamma and T-cell inflamed score were calculated. Real-world overall survival (OS) information was obtained from insurance claims data, with Kaplan-Meier estimates calculated from time of tissue collection until last date of contact. Mann-Whitney U, Chi-square, and Fisher exact tests were applied where appropriate, with p values adjusted for multiple comparisons. ARID2 mutations were more prevalent in cutaneous melanoma compared to ARID1A (11.0%: n = 451 vs 2.8%: n = 113), with concurrent ARID1A/ARID2 mutation in 1.1% (n = 46) of samples. ARID mutations were associated with a high prevalence of RAS pathway mutations-NF1 (ARID1A, 52.6%; ARID2, 48.5%; ARID1A/2, 63.6%; and ARID-WT, 13.3%; p < 0.0001) and KRAS (ARID1A, 3.5%; ARID2, 3.1%; ARID1A/2, 6.5%; and ARID-WT, 1.0%; p = 0.018)), although BRAF mutations were less common in ARID-mutated cohorts (ARID1A, 31.9%; ARID2, 35.6%; ARID1A/2, 26.1%; and ARID-WT, 50.4%; p < 0.0001). TMB-high was more common in ARID-mutated samples (ARID1A, 80.9%; ARID2, 89.9%; ARID1A/2, 100%; and ARID-WT, 49.4%; p < 0.0001), while PD-L1 positivity was similar across subgroups (ARID1A, 43.8%; ARID2, 51.1%; ARID1A/2, 52.5%; and ARID-WT, 44.9%; p = 0.109). Patients with ARID1A mutations had a higher prevalence of dMMR/MSI-H compared to those with ARID-WT (2.7% vs 0.2%, p = 0.030). Median IFN-γ and T-cell signatures were higher in ARID2-mutated samples compared to ARID-WT (IFN-γ: - 0.15 vs - 0.21, p = 0.0066; T-cell: 23.5 vs - 18.5, p = 0.041). ARID2-mutated patients had improved survival compared to ARID-WT; (HR: 1.22 (95% CI 1.0-1.5), p = 0.022). No additional OS benefit was observed with anti-PD-1 therapy for ARID2 mutation compared to ARID-WT. Melanoma patients with ARID mutations exhibited higher prevalence of markers associated with ICI response, including TMB-H, and immune-related signatures. Our data also suggests improved survival outcome in patients with ARID2 mutations, irrespective of anti-PD1 therapy.
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Melanoma , Neoplasias Cutâneas , Humanos , Melanoma/genética , Antígeno B7-H1/metabolismo , Neoplasias Cutâneas/genética , Mutação , Estimativa de Kaplan-Meier , Biomarcadores Tumorais/genética , Fatores de Transcrição/genéticaRESUMO
B7-H3 (CD276) is a transmembrane glycoprotein of the B7 immune checkpoint superfamily that has emerged as a promising therapeutic target. To better understand the applicability of B7-H3-directed therapies, we analyzed 156,791 samples comprising 50 cancer types to interrogate the clinical, genomic, transcriptomic, and immunologic correlates of B7-H3 mRNA expression. DNA (592-gene/whole-exome) and RNA (whole-transcriptome) sequencing was performed from samples submitted to Caris Life Sciences. B7-H3 high versus low expression was based on top and bottom quartiles for each cancer type. Patients' overall survival was determined from insurance claims data. Pathway analysis was performed using gene set enrichment analyses. Immune cell fractions were inferred using quanTIseq. B7-H3 is expressed across several human malignancies including prostate, pancreatic, ovarian, and lung cancers. High B7-H3 expression is associated with differences in overall survival, possibly indicating a prognostic role of B7-H3 for some cancers. When examining molecular features across all cancer types, we did not identify recurrent associations between B7-H3 expression and genetic alterations in TP53, RB1, and KRAS. However, we find consistent enrichment of epithelial-to-mesenchymal transition, Wnt, TGFß, and Notch signaling pathways. In addition, tumors with high B7-H3 expression are associated with greater proportions of M1 macrophages, but lower fractions of CD8+ T cells. We have begun to define the genomic, transcriptomic, clinical, and immunologic features associated with B7-H3 expression in 50 cancer types. We report novel clinical and molecular features of B7-H3-high tumors which may inform how current B7-H3 therapeutics should be deployed and prioritized. SIGNIFICANCE: B7-H3-targeting therapeutics have shown promising results in initial clinical trials. In this pan-cancer analysis of B7-H3 mRNA expression, we found that B7-H3 exhibits robust expression in many common cancer types. These results may inform further development of B7-H3-targeting therapeutics and may guide clinical decisions for patients with limited treatment options.
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Antígenos B7 , Neoplasias , Humanos , Antígenos B7/genética , Antígenos B7/metabolismo , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/mortalidade , Neoplasias/terapia , Neoplasias/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão Gênica , Prognóstico , Masculino , FemininoRESUMO
Activating point mutations in the MET tyrosine kinase domain (TKD) are oncogenic in a subset of papillary renal cell carcinomas. Here, using comprehensive genomic profiling among >600,000 patients, we identify activating MET TKD point mutations as putative oncogenic driver across diverse cancers, with a frequency of â¼0.5%. The most common mutations in the MET TKD defined as oncogenic or likely oncogenic according to OncoKB resulted in amino acid substitutions at positions H1094, L1195, F1200, D1228, Y1230, M1250, and others. Preclinical modeling of these alterations confirmed their oncogenic potential and also demonstrated differential patterns of sensitivity to type I and type II MET inhibitors. Two patients with metastatic lung adenocarcinoma harboring MET TKD mutations (H1094Y, F1200I) and no other known oncogenic drivers achieved confirmed partial responses to a type I MET inhibitor. Activating MET TKD mutations occur in multiple malignancies and may confer clinical sensitivity to currently available MET inhibitors. Significance: The identification of targetable genomic subsets of cancer has revolutionized precision oncology and offers patients treatments with more selective and effective agents. Here, we demonstrate that activating, oncogenic MET tyrosine kinase domain mutations are found across a diversity of cancer types and are responsive to MET tyrosine kinase inhibitors.
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Neoplasias Pulmonares , Mutação Puntual , Inibidores de Proteínas Quinases , Proteínas Proto-Oncogênicas c-met , Humanos , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Animais , Camundongos , Linhagem Celular TumoralRESUMO
Background: The incidence of lung cancer in the US has been decreasing but a bigger decline has been observed in men despite similar declines in tobacco use between men and women. Multiple theories have been proposed, including exposure to exogenous estrogens. Our study seeks to understand the relationship between hormone receptors (HR), gender, and the genomic landscape of non-small lung cancer (NSCLC). Methods: 3,256 NSCLC tumor samples submitted for molecular profiling between 2013-2018 were retrospectively identified and assessed for HR expression. Hormone receptor (HR+) was defined as ≥ 1% nuclear staining of estrogen receptor-alpha (ER-a) or progesterone receptor (PR) by immunohistochemistry. DNA sequencing by NGS included cases sequenced by the Illumina MiSeq hot spot 47 gene panel (n=2753) and Illumina NextSeq 592 gene panel (n=503). An adjusted p-value (q-value) <0.05 was determined significant. Results: HR+ was identified in 18.3% of NSCLC. HR+ occurred more commonly in women compared to men (19.6% vs 11.4%, p <0.0001, q <0.0001). EGFR mutations occurred more commonly in HR+ NSCLC than HR- NSCLC (20.2% vs. 14.6%, p = 0.002, q=0.007). Overall, men with EGFR mutations were affected by HR status with a higher prevalence in HR+ NSCLC while such differences were not seen in women. However, in women ages ≤45, there was a trend towards greater prevalence HR+ NSCLC (25.25% vs. 11.32%, q= 0.0942) and 10/25 (40.0%) of HR+ cases in young women were found to be EGFR mutated. KRAS mutations and ALK+ IHC expression occurred more in HR+ NSCLC whereas TP53 mutations occurred more in HR- NSCLC. Conclusions: Women were more likely to have HR+ NSCLC than men and EGFR and KRAS mutations occurred more commonly in HR+ NSCLC. Additional studies with more strict inclusion criteria for HR+ are warranted to see if there is benefit to targeting HR in these subgroups.
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Melanoma brain metastases (MBM) are clinically challenging to treat and exhibit variable responses to immune checkpoint therapies. Prior research suggests that MBM exhibit poor tumor immune responses and are enriched in oxidative phosphorylation. Here, we report results from a multi-omic analysis of a large, real-world melanoma cohort. MBM exhibited lower interferon-gamma (IFNγ) scores and T cell-inflamed scores compared to primary cutaneous melanoma (PCM) or extracranial metastases (ECM), which was independent of tumor mutational burden. Among MBM, there were fewer computationally inferred immune cell infiltrates, which correlated with lower TNF and IL12B mRNA levels. Ingenuity pathway analysis (IPA) revealed suppression of inflammatory responses and dendritic cell maturation pathways. MBM also demonstrated a higher frequency of pathogenic PTEN mutations and angiogenic signaling. Oxidative phosphorylation (OXPHOS) was enriched in MBM and negatively correlated with NK cell and B cell-associated transcriptomic signatures. Modulating metabolic or angiogenic pathways in MBM may improve responses to immunotherapy in this difficult-to-treat patient subset.
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PURPOSE: The combination of talimogene laherparepvec (T-VEC) and pembrolizumab previously demonstrated an acceptable safety profile and an encouraging complete response rate (CRR) in patients with advanced melanoma in a phase Ib study. We report the efficacy and safety from a phase III, randomized, double-blind, multicenter, international study of T-VEC plus pembrolizumab (T-VEC-pembrolizumab) versus placebo plus pembrolizumab (placebo-pembrolizumab) in patients with advanced melanoma. METHODS: Patients with stage IIIB-IVM1c unresectable melanoma, naïve to antiprogrammed cell death protein-1, were randomly assigned 1:1 to T-VEC-pembrolizumab or placebo-pembrolizumab. T-VEC was administered at ≤ 4 × 106 plaque-forming unit (PFU) followed by ≤ 4 × 108 PFU 3 weeks later and once every 2 weeks until dose 5 and once every 3 weeks thereafter. Pembrolizumab was administered intravenously 200 mg once every 3 weeks. The dual primary end points were progression-free survival (PFS) per modified RECIST 1.1 by blinded independent central review and overall survival (OS). Secondary end points included objective response rate per mRECIST, CRR, and safety. Here, we report the primary analysis for PFS, the second preplanned interim analysis for OS, and the final analysis. RESULTS: Overall, 692 patients were randomly assigned (346 T-VEC-pembrolizumab and 346 placebo-pembrolizumab). T-VEC-pembrolizumab did not significantly improve PFS (hazard ratio, 0.86; 95% CI, 0.71 to 1.04; P = .13) or OS (hazard ratio, 0.96; 95% CI, 0.76 to 1.22; P = .74) compared with placebo-pembrolizumab. The objective response rate was 48.6% for T-VEC-pembrolizumab (CRR 17.9%) and 41.3% for placebo-pembrolizumab (CRR 11.6%); the durable response rate was 42.2% and 34.1% for the arms, respectively. Grade ≥ 3 treatment-related adverse events occurred in 20.7% of patients in the T-VEC-pembrolizumab arm and in 19.5% of patients in the placebo-pembrolizumab arm. CONCLUSION: T-VEC-pembrolizumab did not significantly improve PFS or OS compared with placebo-pembrolizumab. Safety results of the T-VEC-pembrolizumab combination were consistent with the safety profiles of each agent alone.
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Herpesvirus Humano 1 , Melanoma , Terapia Viral Oncolítica , Humanos , Melanoma/tratamento farmacológico , Terapia Viral Oncolítica/métodos , Método Duplo-CegoRESUMO
In this randomized phase 2 trial, blockade of cytotoxic T-lymphocyte protein 4 (CTLA-4) with continuation of programmed death protein 1 (PD-1) blockade in patients with metastatic melanoma who had received front-line anti-PD-1 or therapy against programmed cell death 1 ligand 1 and whose tumors progressed was tested in comparison with CTLA-4 blockade alone. Ninety-two eligible patients were randomly assigned in a 3:1 ratio to receive the combination of ipilimumab and nivolumab, or ipilimumab alone. The primary endpoint was progression-free survival. Secondary endpoints included the difference in CD8 T cell infiltrate among responding and nonresponding tumors, objective response rate, overall survival and toxicity. The combination of nivolumab and ipilimumab resulted in a statistically significant improvement in progression-free survival over ipilimumab (hazard ratio = 0.63, 90% confidence interval (CI) = 0.41-0.97, one-sided P = 0.04). Objective response rates were 28% (90% CI = 19-38%) and 9% (90% CI = 2-25%), respectively (one-sided P = 0.05). Grade 3 or higher treatment-related adverse events occurred in 57% and 35% of patients, respectively, which is consistent with the known toxicity profile of these regimens. The change in intratumoral CD8 T cell density observed in the present analysis did not reach statistical significance to support the formal hypothesis tested as a secondary endpoint. In conclusion, primary resistance to PD-1 blockade therapy can be reversed in some patients with the combination of CTLA-4 and PD-1 blockade. Clinicaltrials.gov identifier: NCT03033576 .
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Melanoma , Nivolumabe , Humanos , Antígeno B7-H1 , Antígeno CTLA-4 , Ipilimumab/efeitos adversos , Ipilimumab/uso terapêutico , Melanoma/tratamento farmacológico , Nivolumabe/efeitos adversos , Nivolumabe/uso terapêuticoRESUMO
BACKGROUND: Despite their anti-tumor efficacy, immune checkpoint inhibitors (ICIs) are associated with a variety of immune-related adverse events (irAEs). Grade ≥ 2 irAEs require ICI discontinuation. The decision to resume ICI treatment often remains challenging. METHODS: We retrospectively studied 1051 adult patients with stage IV non-small cell lung cancer (NSCLC) treated with ICIs at a single institution between January 2015 and December 2020, and identified 99 (9.4%) patients with grade≥2 irAEs necessitating treatment interruption. Forty patients underwent retreatment (rechallenged group), while 59 discontinued the treatment (discontinued group). RESULTS: Baseline characteristics of patients in the 2 groups were similar. Initial irAEs were less severe in the rechallenged group. After rechallenging, 24 of 40 (60%) patients had recurrence of the same or de-novo irAEs. Twenty (50%) developed second grade≥ 2 irAEs. No grade 4 irAE or irAE-related death occurred after rechallenging. Using multivariate analysis, no statistically significant differences in overall survival (OS) (HR: 1.10, 95% CI: 0.57-2.15, P = .77) or progression-free survival (PFS) (HR: 0.87, 95% CI: 0.45-1.71, P = .69) were noted between the 2 groups, while the best objective response prior to the initial irAEs was the only variable affecting OS and PFS. CONCLUSIONS: Rechallenge was associated with a relative high risk of second grade≥ 2 irAEs. The risk was less if the initial irAEs were resolved. No differences were seen in survival outcomes of patients who had ICI rechallenge and those who did not. Permanent ICI discontinuation is an appropriate strategy after grade≥ 2 irAEs, especially severe irAEs.
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Antineoplásicos Imunológicos , Carcinoma Pulmonar de Células não Pequenas , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Neoplasias Pulmonares , Adulto , Humanos , Carcinoma Pulmonar de Células não Pequenas/patologia , Inibidores de Checkpoint Imunológico/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Neoplasias Pulmonares/patologia , Estudos Retrospectivos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologiaRESUMO
PURPOSE: Expected toxicity from chemoradiation (CRT) is an important factor in treatment decisions but is poorly understood in older adults with lower gastrointestinal (GI) malignancies. Our objective was to compare acute adverse events (AAEs) of older and younger adults with lower GI malignancies treated on NRG studies. METHODS: Data from 6 NRG trials, testing combined modality therapy in patients with anal or rectal cancer, were used to test the hypothesis that older age was associated with increased AAEs. AAEs and compliance with protocol-directed therapy were compared between patients aged ≥70 and < 70. Categorical variables were compared across age groups using the chi-square test. The association of age on AAEs was evaluated using a covariate-adjusted logistic regression model, with odds ratio (OR) reported. To adjust for multiple comparisons, a p-value <0.01 was considered statistically significant. RESULTS: There were 2525 patients, including 380 patients ≥70 years old (15%) evaluable. Older patients were more likely to have worse baseline performance status (PS 1 or 2) (23% vs. 16%, p = 0.001), but otherwise baseline characteristics were similar. Older patients were less likely to complete their chemotherapy (78% vs. 87%, p < 0.001), but had similar RT duration. On univariate analysis, older patients were more likely to experience grade ≥ 3 GI AAEs (36% vs. 23%, p < 0.001), and less likely to experience grade ≥ 3 skin AAEs (8% vs. 14%, p = 0.002). On multivariable analysis, older age was associated with grade ≥ 3 GI AAE (OR 1.93, 95% CI: 1.52, 2.47, p < 0.001) after adjusting for sex, race, PS, and disease site. CONCLUSIONS: Older patients with lower GI cancers who underwent CRT were less likely to complete chemotherapy and had higher rates of grade 3+ GI AAEs. These results can be used to counsel older adults prior to treatment and manage expected toxicities throughout pelvic CRT.