ALT-803, an IL-15 superagonist, in combination with nivolumab in patients with metastatic non-small cell lung cancer: a non-randomised, open-label, phase 1b trial.
Wrangle John M,Velcheti Vamsidhar,Patel Manish R,Garrett-Mayer Elizabeth,Hill Elizabeth G,Ravenel James G,Miller Jeffrey S,Farhad Mohammad,Anderton Kate,Lindsey Kathryn,Taffaro-Neskey Michele,Sherman Carol,Suriano Samantha,Swiderska-Syn Marzena,Sion Amy,Harris Joni,Edwards Andie R,Rytlewski Julie A,Sanders Catherine M,Yusko Erik C,Robinson Mark D,Krieg Carsten,Redmond William L,Egan Jack O,Rhode Peter R,Jeng Emily K,Rock Amy D,Wong Hing C,Rubinstein Mark P
The Lancet. Oncology
BACKGROUND:Immunotherapy with PD-1 or PD-L1 blockade fails to induce a response in about 80% of patients with unselected non-small cell lung cancer (NSCLC), and many of those who do initially respond then develop resistance to treatment. Agonists that target the shared interleukin-2 (IL-2) and IL-15Rβγ pathway have induced complete and durable responses in some cancers, but no studies have been done to assess the safety or efficacy of these agonists in combination with anti-PD-1 immunotherapy. We aimed to define the safety, tolerability, and activity of this drug combination in patients with NSCLC. METHODS:In this non-randomised, open-label, phase 1b trial, we enrolled patients (aged ≥18 years) with previously treated histologically or cytologically confirmed stage IIIB or IV NSCLC from three academic hospitals in the USA. Key eligibility criteria included measurable disease, eligibility to receive anti-PD-1 immunotherapy, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received the anti-PD-1 monoclonal antibody nivolumab intravenously at 3 mg/kg (then 240 mg when US Food and Drug Administration [FDA]-approved dosing changed) every 14 days (either as new treatment or continued treatment at the time of disease progression) and the IL-15 superagonist ALT-803 subcutaneously once per week on weeks 1-5 of four 6-week cycles for 6 months. ALT-803 was administered at one of four escalating dose concentrations: 6, 10, 15, or 20 μg/kg. The primary endpoint was to define safety and tolerability and to establish a recommended phase 2 dose of ALT-803 in combination with nivolumab. Analyses were per-protocol and included any patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT02523469; phase 2 enrolment of patients is ongoing. FINDINGS:Between Jan 18, 2016, and June 28, 2017, 23 patients were enrolled and 21 were treated at four dose levels of ALT-803 in combination with nivolumab. Two patients did not receive treatment because of the development of inter-current illness during enrolment, one patient due to leucopenia and one patient due to pulmonary dysfunction. No dose-limiting toxicities were recorded and the maximum tolerated dose was not reached. The most common adverse events were injection-site reactions (in 19 [90%] of 21 patients) and flu-like symptoms (15 [71%]). The most common grade 3 adverse events, occurring in two patients each, were lymphocytopenia and fatigue. A grade 3 myocardial infarction occurred in one patient. No grade 4 or 5 adverse events were recorded. The recommended phase 2 dose of ALT-803 is 20 μg/kg given once per week subcutaneously in combination with 240 mg intravenous nivolumab every 2 weeks. INTERPRETATION:ALT-803 in combination with nivolumab can be safely administered in an outpatient setting. The promising clinical activity observed with the addition of ALT-803 to the regimen of patients with PD-1 monoclonal antibody relapsed and refractory disease shows evidence of anti-tumour activity for a new class of agents in NSCLC. FUNDING:Altor BioScience (a NantWorks company), National Institutes of Health, and Medical University of South Carolina Hollings Cancer Center.
Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial.
Goldberg Sarah B,Gettinger Scott N,Mahajan Amit,Chiang Anne C,Herbst Roy S,Sznol Mario,Tsiouris Apostolos John,Cohen Justine,Vortmeyer Alexander,Jilaveanu Lucia,Yu James,Hegde Upendra,Speaker Stephanie,Madura Matthew,Ralabate Amanda,Rivera Angel,Rowen Elin,Gerrish Heather,Yao Xiaopan,Chiang Veronica,Kluger Harriet M
The Lancet. Oncology
BACKGROUND:Immunotherapy targeting the PD-1 axis has activity in several tumour types. We aimed to establish the activity and safety of the PD-1 inhibitor pembrolizumab in patients with untreated brain metastases from melanoma or non-small-cell lung cancer (NSCLC). METHODS:In this non-randomised, open-label, phase 2 trial, we enrolled patients aged 18 years or older with melanoma or NSCLC with untreated brain metastases from the Yale Cancer Center. Patients had at least one untreated or progressive brain metastasis between 5 and 20 mm in diameter without associated neurological symptoms or the need for corticosteroids. Patients with NSCLC had tumour tissue positive for PD-L1 expression; this was not required for patients with melanoma. Patients were given 10 mg/kg pembrolizumab every 2 weeks until progression. The primary endpoint was brain metastasis response assessed in all treated patients. The trial is ongoing and here we present an early analysis. The study is registered with ClinicalTrials.gov, number NCT02085070. FINDINGS:Between March 31, 2014, and May 31, 2015, we screened 52 patients with untreated or progressive brain metastases (18 with melanoma, 34 with NSCLC), and enrolled 36 (18 with melanoma, 18 with NSCLC). A brain metastasis response was achieved in four (22%; 95% CI 7-48) of 18 patients with melanoma and six (33%; 14-59) of 18 patients with NSCLC. Responses were durable, with all but one patient with NSCLC who responded showing an ongoing response at the time of data analysis on June 30, 2015. Treatment-related serious and grade 3-4 adverse events were grade 3 elevated aminotransferases (n=1 [6%]) in the melanoma cohort, and grade 3 colitis (n=1 [6%]), grade 3 pneumonitis (n=1 [6%]), grade 3 fatigue (n=1 [6%]), grade 4 hyperkalemia (n=1 [6%]), and grade 2 acute kidney injury (n=1 [6%]) in the NSCLC cohort. Clinically significant neurological adverse events included transient grade 3 cognitive dysfunction and grade 1-2 seizures (n=3 [17%]) in the melanoma cohort. INTERPRETATION:Pembrolizumab shows activity in brain metastases in patients with melanoma or NSCLC with an acceptable safety profile, which suggests that there might be a role for systemic immunotherapy in patients with untreated or progressive brain metastases. FUNDING:Merck and the Yale Cancer Center.
Dendritic cells combining with cytokine-induced killer cells synergize chemotherapy in patients with late-stage non-small cell lung cancer.
Zhong Runbo,Teng Jiajun,Han Baohui,Zhong Hua
Cancer immunology, immunotherapy : CII
BACKGROUND:Lung cancer is the leading cause for cancer-related mortality and morbidity, and the survival of late-stage non-small cell lung cancer (NSCLC) remains poor. We hereby evaluate conventional chemotherapy followed by immunotherapy using dendritic cells and cytokine-induced killer cells in the treatment for late stage of NSCLC. METHODS:Twenty-eight untreated patients suffered from IIIB to IV NSCLC were enrolled in the study between August 2004 and October 2005, and all received four courses of vinorelbine-platinum (NP) chemotherapy. Fourteen of them received conventional NP chemotherapy followed by vaccinated with CEA (605-613) peptide-pulsed autologous dendritic cells and CIK cells. Vaccination was repeated at 30-day intervals for 4 cycles. The adverse effects, time to progression (TTP), and overall survival (OS) in each group were evaluated. RESULTS:The adverse effect as a result of chemoimmunotherapy was mild and tolerable. Rash, acne, and pruritus were more frequent in the chemoimmunotherapy group than in the chemotherapy group (64.2% vs. 7.1%, P = 0.004). Non-infectious fever was more frequent in the chemoimmunotherapy group than in the chemotherapy group (71.4% vs. 21.4% P = 0.02). Less grade 3/4 fatigue was observed in patients receiving chemoimmunotherapy: 7.1% versus 57.1% in chemotherapy group, P = 0.01. Compared with patients in chemotherapy group, time to progression in chemoimmunotherapy significantly prolonged, with the median improved from 5.2 months (95% CI: 3.3-6.0) to 6.9 months (95% CI: 5.0-8.8) (P = 0.03). The 1-, 2-, and 5-year survival rates were 64.3, 49, and 21.0%, respectively in chemoimmunotherapy group. Overall survival rate showed no statistically difference between two groups (P = 0.18). CONCLUSIONS:Chemoimmunotherapy could alleviate adverse effects of conventional chemotherapy and prolong survival for patients with late-stage NSCLC.
NHS-IL2 combined with radiotherapy: preclinical rationale and phase Ib trial results in metastatic non-small cell lung cancer following first-line chemotherapy.
van den Heuvel Michel M,Verheij Marcel,Boshuizen Rogier,Belderbos José,Dingemans Anne-Marie C,De Ruysscher Dirk,Laurent Julien,Tighe Robert,Haanen John,Quaratino Sonia
Journal of translational medicine
BACKGROUND:NHS-IL2 (selectikine, EMD 521873, MSB0010445) consists of human NHS76 (antibody specific for necrotic DNA) fused to genetically modified human interleukin 2 (IL-2) and selectively activates the high-affinity IL-2 receptor. Based on an evolving investigational concept to prime the tumor microenvironment with ionizing radiation prior to initiating immunotherapy, 2 related studies were conducted and are reported here. The first, a preclinical study, tests the systemic effect of the immunocytokine NHS-IL2 and radiotherapy in a lung carcinoma animal model; the second, a phase Ib trial in patients with metastatic non-small cell lung carcinoma (NSCLC), was designed to determine the safety and tolerability of NHS-IL2 in combination with radiotherapy directly following first-line palliative chemotherapy. METHODS:Tumor-bearing C57Bl/6 mice were treated with NHS-IL2 alone (5 mg/kg; days 7-9), fractionated radiotherapy (3.6 Gy; days 0-4) plus cisplatin (4 mg/kg; day 0), or the triple combination. Metastatic NSCLC patients who achieved disease control with first-line palliative chemotherapy were enrolled in the phase Ib trial. Patients received local irradiation (5x 4 Gy) of a single pulmonary nodule. Dose-escalated NHS-IL2 was administered as 1-h intravenous infusion on 3 consecutive days every 3 weeks. RESULTS:NHS-IL2 plus radiotherapy induced immune response activation and complete tumor growth regressions in 80%-100% of mice. In patients with metastatic NSCLC treated with NHS-IL2 (3, 3, and 7 patients in the 0.15-mg/kg, 0.30-mg/kg, and 0.45-mg/kg cohorts, respectively), maximum tolerated dose was not reached. Most frequently reported adverse events were fatigue, anorexia, and rash. Transient increases in leukocyte subsets were observed. In 3 patients, thyroid gland dysfunction occurred. No objective responses were reported; long-term survival was observed in 2 patients, including 1 patient with long-term tumor control. CONCLUSIONS:Combining NHS-IL2 with radiotherapy achieved synergistic antitumor activity in preclinical studies, supporting the use in lung cancer patients. This combination was well tolerated and 2 of 13 patients achieved long-term survival. TRIAL REGISTRATION:ClinicalTrials.gov NCT00879866.
Ramucirumab and durvalumab for previously treated, advanced non-small-cell lung cancer, gastric/gastro-oesophageal junction adenocarcinoma, or hepatocellular carcinoma: An open-label, phase Ia/b study (JVDJ).
Bang Yung-Jue,Golan Talia,Dahan Laetitia,Fu Siqing,Moreno Victor,Park Keunchil,Geva Ravit,De Braud Filippo,Wainberg Zev A,Reck Martin,Goff Laura,Laing Naomi,Mi Gu,Oliveira Joana M,Wasserstrom Heather,Lin Chia-Chi
European journal of cancer (Oxford, England : 1990)
BACKGROUND:Emerging evidence supports combining immune checkpoint inhibitors (ICIs) with conventional or targeted therapies to enhance ICI antitumour activity and broaden the spectrum of patients who respond to ICIs. Here, we present the safety and preliminary efficacy of ramucirumab, an anti-VEGFR2 IgG1, plus durvalumab, an anti-PD-L1 IgG1, in previously treated patients with advanced non-small-cell lung cancer (NSCLC), gastric/gastro-oesophageal junction adenocarcinoma (gastric/GEJ), or hepatocellular carcinoma (HCC). PATIENTS AND METHODS:A 25-centre, phase Ia/b single-arm, non-randomised, multi-cohort study was undertaken in patients with advanced/metastatic disease, Eastern Cooperative Oncology Group performance status, 0-1, progression on prior therapy, no prior ramucirumab or immunotherapy and any PD-L1 status. Patients received ramucirumab (10 mg/kg) plus durvalumab (1125 mg) intravenously Q3W (NSCLC), or ramucirumab (8 mg/kg) plus durvalumab (750 mg) Q2W (gastric/GEJ, HCC). RESULTS:Phase Ia treatment was found safe for phase Ib expansion; final enrolment was NSCLC (n = 28), gastric/GEJ (n = 29), HCC (n = 28). Grade ≥3 treatment-related adverse events occurred in 32.1%, 37.9% and 42.9% of patients, respectively. The most common were fatigue (35.7%), hypertension (34.5%) and diarrhoea (28.6%), respectively. Two patients died owing to an adverse event; one was treatment-related (hepatitis acute, HCC cohort). Objective response rate was 11% for NSCLC and HCC and 21% for gastric/GEJ. Median progression-free survival and overall survival were, respectively, 2.7 and 11 months in NSCLC; 2.6 and 12.4 months in gastric/GEJ; 4.4 and 10.7 months in HCC, with more prolonged survival in patients with high PD-L1 expression. CONCLUSION:Ramucirumab/durvalumab exhibited manageable safety. The combination showed antitumour activity in all cohorts, particularly in patients with high PD-L1 expression.
Efficacy and safety of immune checkpoint inhibitor monotherapy in pretreated elderly patients with non-small cell lung cancer.
Yamaguchi Ou,Imai Hisao,Minemura Hiroyuki,Suzuki Kensuke,Wasamoto Satoshi,Umeda Yukihiro,Osaki Takashi,Kasahara Norimitsu,Uchino Junji,Sugiyama Tomohide,Ishihara Shinichi,Ishii Hisashi,Naruse Ichiro,Mori Keita,Kotake Mie,Kanazawa Kenya,Minato Koichi,Kagamu Hiroshi,Kaira Kyoichi
Cancer chemotherapy and pharmacology
PURPOSE:Immune checkpoint inhibitors (ICIs) are an effective subsequent-line treatment for patients with advanced non-small cell lung cancer (NSCLC). However, it remains unclear whether the efficacy and safety of subsequent-line ICI monotherapy in elderly patients (aged ≥ 75 years) are similar to that in non-elderly patients. Therefore, we aimed to investigate the efficacy and safety of ICI monotherapy in pretreated elderly patients with NSCLC. METHODS:Between January 2016 and February 2018, 131 elderly patients with advanced NSCLC who received subsequent-line ICI monotherapy at 13 Japanese institutions were enrolled in this study. Baseline characteristics, the efficacy of ICI treatment, and adverse events were evaluated. RESULTS:Ninety-eight men and 33 women (median age 77 [range 75-87] years) were enrolled. Among those who received subsequent-line ICI monotherapy, the overall response, disease control rates, median progression-free survival (PFS), and overall survival (OS) were 27.4%, 61.8%, 4.5 months, and 16.0 months, respectively. Adverse events such as anorexia, fatigue, pneumonitis, and hypothyroidism were observed. There were two treatment-related deaths due to pneumonitis and thrombocytopenia. Subsequent-line ICI monotherapy in patients with good performance status (PS), receiving steroids for immune-related adverse events (irAEs), and exhibiting partial response (PR) was associated with improved PFS, as well as OS in patients with good PS and PR. CONCLUSIONS:Subsequent-line ICI monotherapy in elderly patients, with previously treated NSCLC, was effective, safe and showed outcomes equivalent to those in non-elderly patients. Immunotherapy provides a survival benefit for elderly patients, who exhibit its efficacy and a favorable general condition.
A Pilot Study of Atezolizumab Plus Hypofractionated Image Guided Radiation Therapy for the Treatment of Advanced Non-Small Cell Lung Cancer.
Qin Angel,Rengan Ramesh,Lee Sylvia,Santana-Davila Rafael,Goulart Bernardo H L,Martins Renato,Baik Christina,Kalemkerian Gregory P,Hassan Khaled A,Schneider Bryan J,Hayman James A,Jolly Shruti,Hearn Jason,Lawrence Theodore S,Towlerton Andrea M H,Tewari Muneesh,Thomas Dafydd,Zhao Lili,Brown Noah,Frankel Timothy L,Warren Edus H,Ramnath Nithya
International journal of radiation oncology, biology, physics
PURPOSE:Preclinical data and subset analyses from immunotherapy clinical trials indicate that prior radiation therapy was associated with better progression-free survival and overall survival when combined with immune checkpoint inhibitors in patients with non-small cell lung cancer. We present a prospective study of hypofractionated image guided radiation therapy (HIGRT) to a single site of metastatic disease concurrently with atezolizumab in patients with metastatic non-small cell lung cancer. METHODS AND MATERIALS:Patients meeting eligibility criteria received 1200 mg of atezolizumab intravenously every 3 weeks with concurrent 3- or 5-fraction HIGRT starting no later than the second cycle. The 3-fraction regimen employed a minimum of 8 Gy per fraction compared with 6 Gy for the 5-fraction regimen. Imaging was obtained every 12 weeks to assess response. RESULTS:From October 2015 to February 2017, 12 patients were enrolled in the study (median age 64; range, 55-77 years). The best response by the Response Evaluation in Solid Tumors criteria was partial response in 3 and stable disease in 3, for a disease control rate of 50%. Five patients had a grade 3 immune-related adverse event, including choreoretinitis (n = 1), pneumonitis (n = 1), transaminitis (n = 1), fatigue (n = 1), and peripheral neuropathy (n = 1). The median progression-free survival was 2.3 months, and the median overall survival was 6.9 months (range, 0.4-not reached). There was no clear association between peripheral blood T cell repertoire characteristics at baseline, PD-L1, or tumor mutations and response or outcome. One long-term survivor exhibited oligoclonal T cell populations in a baseline tumor biopsy that were consistently detected in peripheral blood over the entire course of the study. CONCLUSIONS:HIGRT plus atezolizumab resulted in an overall response rate of 25% and disease control rate of 50% in this pilot study. The incidence of grade 3 adverse events was similar to that of atezolizumab alone. Alhough it was a pilot study with limited sample size, the results generated hypotheses worthy of further investigation.
[Unexpected adverse events of immunotherapies in non-small cell lung cancer: About 2 cases].
de Chabot G,Justeau G,Pinquié F,Nadaj-Pakleza A,Hoppé E,Hureaux J,Urban T
Revue de pneumologie clinique
Programmed death receptor 1 (PD1) checkpoint inhibitors are known for immune mediated toxicities such as colitis, endocrinopathies and pneumonitis. However, other rare adverse effects are reported in the literature. Nivolumab is an anti-PD1 immunotherapy used in the second line of non-small cell lung cancer (NSCLC). We report two cases of rare toxicities occurring under nivolumab in patients without a history of dysimmunity. A 79-year-old patient with a large-cell carcinoma showed a muscle weakness after the second course, revealing myositis with a CPK grade IV elevation as well as symptoms of myasthenia. The diagnosis of myositis was confirmed by a muscle biopsy. An 82-year-old patient followed for bronchial adenocarcinoma with EGFR mutation, presented with nivolumab shoulder and hip pain with extreme fatigue. After further investigations, the diagnosis of systemic erythematosus lupus was retained. Investigations led to the diagnosis of systemic lupus erythematosus. For both patients treatment was interrupted and systemic corticosteroid therapy was initiated permitting resolution of symptoms. The occurrence of symptoms of dysimmunity should attract the attention of the clinician, leading to discontinuation of anti-PD1 therapy and corticosteroid therapy. Retreatment after symptoms resolution must be collegially discussed if no alternative therapeutic is available.
Safety of combining thoracic radiation therapy with concurrent versus sequential immune checkpoint inhibition.
von Reibnitz Donata,Chaft Jamie E,Wu Abraham J,Samstein Robert,Hellmann Matthew D,Plodkowski Andrew J,Zhang Zhigang,Shi Weiji,Dick-Godfrey Rosalind,Panchoo Kelly H,Barker Christopher A,Rimner Andreas
Advances in radiation oncology
Purpose:The objective of this study was to evaluate adverse events (AEs) in patients who received both immune checkpoint inhibitors and thoracic radiation therapy (RT). In particular, we compared the rate of toxicities of concurrent versus sequential delivery of thoracic RT and checkpoint inhibitors. Methods and Materials:Patient and treatment characteristics were collected on all patients at our institution who were treated with programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and/or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors and underwent thoracic RT (n = 79). Receiving both treatments within 1 month was considered concurrent (n = 35; 44%), and any treatment up to 6 months apart was considered sequential (n = 44; 56%). The primary endpoint of this study was the rate of Grade ≥2 AEs from combination therapy (immunotherapy and RT), specifically those that are relevant to thoracic RT: Pneumonitis, other pulmonary events, esophagitis, dermatitis, and fatigue. Further univariate analysis was performed to compare AE rates with clinical and therapy-related variables. Results:A total of 79 patients were identified, with lung cancer (n = 45) and melanoma (n = 15) being the most common primary histology. Sixty-two (78%) patients were treated with anti-PD-1 or anti-PD-L1 antibodies, 12 (15%) with anti-CTLA-4 antibodies, and 5 (6%) received both anti-PD-1/PD-L1 and anti-CTLA-4 antibodies. The median follow-up for survivors was 5.9 months (range, 2.4-55.6 months). Grade ≥2 AEs included pneumonitis (n = 5; 6%), esophagitis (n = 6; 8%), and dermatitis (n = 8; 10%). No statistically significant correlation was found between these AEs when comparing concurrent versus sequential treatment. The only significant variable was a correlation of immunotherapy drug category with Grade ≥2 esophagitis ( = .04). Conclusions:Overall, Grade ≥2 AE rates of thoracic RT and immunotherapy appeared as expected and acceptable. The lack of significant differences in AE rates with concurrent versus sequential treatment suggests that even concurrent immunotherapy and thoracic RT may be safe.
Approaches to Tumor Classification in Pulmonary Sarcomatoid Carcinoma.
Baldovini Chiara,Rossi Giulio,Ciarrocchi Alessia
Lung Cancer (Auckland, N.Z.)
Pulmonary sarcomatoid carcinoma (PSC) is a heterogeneous category of primary lung cancer accounting from 0.3% to 3% of all primary lung malignancies. According to the most recent 2015 World Health Organization (WHO) classification, PSC includes several different variants of malignant epithelial tumors (carcinomas) histologically mimicking sarcomas showing or entirely lacking a conventional component of non-small cell lung cancer (NSCLC). Thus, this rare subheading of lung neoplasms includes pleomorphic carcinoma, spindle cell carcinoma, giant cell carcinoma, pulmonary blastoma, and carcinosarcoma. A diagnosis of PSC may be suspected on small biopsy or cytology, but commonly requires a surgical resection to reach a conclusive definition. The majority of patients with PSC consists of elderly, smoking men with a large, peripheral mass characterized by well-defined margins. However, presentation with a central, polypoid endobronchial lesion is well-documented, particularly in pleomorphic carcinoma and carcinosarcoma showing a squamous cell carcinoma component. As expected, PSC may pose diagnostic problems and immunohistochemistry is largely used when pathologists deal these tumors in routine practice. Indeed, PSC tends to overexpress molecules associated with the epithelial-to-mesenchymal transition, such as vimentin, but the panel of immunostains also includes epithelial markers (cytokeratins, EMA), TTF-1, p40 and negative markers (e.g., melanocytic, mesothelial and sarcoma-related primary antibodies). Although rare, PSC has increased their interest among oncologist community for different reasons: a. identification of the epithelial-to-mesenchymal phenomenon as a major mechanism of secondary resistance to tyrosine kinase inhibitors; b. over-expression of PD-L1 and effective treatment with immunotherapy; c. identification of exon 14 skipping mutation representing an effective target to crizotinib and other specific inhibitors. In this review, the feasibility of the diagnosis of PSC, its differential diagnosis and novel molecular findings characterizing this group of lung tumor are discussed.
Neoadjuvant Chemoradiotherapy Treatment for a Classic Biphasic Pulmonary Blastoma with High PD-L1 Expression.
Bosch-Barrera Joaquim,Holguin Francia,Baldó Xavier,Rubio Matilde,Porta Rut,Fuentes Rafael,Teixidó Cristina,Ramirez José Luis,Ferran Nuria,Sebastián Fernando,Rosell Rafael
Pulmonary blastomas are rare malignant tumors, comprising only 0.25-0.5% of all malignant lung neoplasms. The prognosis of pulmonary blastoma is very poor, with an overall five-year survival of 16%. No standard treatment has been defined for unresectable disease. We present the case of a 25-year-old woman with unresectable locally advanced classic biphasic pulmonary blastoma (CBPB) successfully treated with neodjuvant chemoradiotherapy based on two chemotherapy induction cycles of cisplatin plus etoposide, followed by concurrent weekly cisplatin to 50.4 Gy radiotherapy treatment. The patient had a significant reduction in tumor size, allowing for complete resection by pneumonectomy. Molecular study for epidermal growth factor receptor (EGFR) mutations, anaplastic lymphoma kinase (ALK), proto-oncogene receptor tyrosine kinase (ROS1) and rearranged during transfection (RET) rearrangements, and programmed death ligand 1 (PD-L1) expression was performed in the pre-treatment tumor sample. Our patient presented a high expression (>90% of tumor cells) of PD-L1. To our knowledge, this is the first report of PD-L1 expression in CBPB. This could lead to new treatment options based on new immunotherapy agents blocking the PD-1/PD-L1 pathway for this rare disease with poor prognosis.
Efficacy and tolerability of cancer neuroimmunotherapy with subcutaneous low-dose interleukin-2 and the pineal hormone melatonin - a progress report of 200 patients with advanced solid neoplasms.
Lissoni P,Ardizzoia A,Barni S,Brivio F,Tisi E,Rovelli F,Tancini G,Maestroni G,Fumagalli L
The recent advances in psychoneuroimmunology have demonstrated the existence of a psychoneuroendocrine control of the antitumor immunity. Our previous preliminary studies indicated the possibility of amplifying the biological and therapeutic efficacy of IL-2 cancer immunotherapy by immunomodulating neurohormones, mainly the pineal indole melatonin (MLT), in most advanced solid tumors, including those which generally do not respond to IL-2 alone. This study reports on the results obtained by low-dose IL-2 plus MLT in 200 patients with advanced solid neoplasms, for whom no other effective standard therapy was available. Non-small cell lung cancer, pancreatic adenocarcinoma, hepatocarcinoma, colon cancer and gastric cancer were the neoplasms most frequently detected in our patients. In addition, all patients had a life expectancy less than 6 months. IL-2 was given subcutaneously at 3 million IU/day for 6 days/week for 4 weeks; MLT was given orally at 40 mg/day. In non-progressing patients, a second cycle was given after a 21-day rest period; then, patients underwent a maintenance period consisting of one week of therapy every month until progression. A complete response (CR) was achieved in 4 patients (hepatocarcinoma 2; pancreas 1; gastric cancer 1), a partial reasponse (PR) was achieved in 36 patients (lung 12; liver 6; stomach 4; pancreas 3; colon 3; breast 2; miscellaneous 6). Tumor response rate (CR+PR) was 40/200 (20%) patients. Longer than one year survival was achieved in 79 (39%) patients. Toxicity was mild in all patients, and therapy was administered as a home therapy. The present study confirms in a great number of patients the possibility to induce objective tumor regressions in most advanced solid tumor histotypes by low-dose IL-2 plus MLT. Thus, immunotherapy with IL-2 and MLT may be considered as a new well tolerated and effective therapy of almost all advanced solid tumors, including those which do not respond to IL-2 alone or to chemotherapy.
Cancer gene profiling in non-small cell lung cancers reveals activating mutations in JAK2 and JAK3 with therapeutic implications.
Li Shuyu D,Ma Meng,Li Hui,Waluszko Aneta,Sidorenko Tatyana,Schadt Eric E,Zhang David Y,Chen Rong,Ye Fei
BACKGROUND:Next-generation sequencing (NGS) of cancer gene panels are widely applied to enable personalized cancer therapy and to identify novel oncogenic mutations. METHODS:We performed targeted NGS on 932 clinical cases of non-small-cell lung cancers (NSCLCs) using the Ion AmpliSeq™ Cancer Hotspot panel v2 assay. RESULTS:Actionable mutations were identified in 65% of the cases with available targeted therapeutic options, including 26% of the patients with mutations in National Comprehensive Cancer Network (NCCN) guideline genes. Most notably, we discovered JAK2 p.V617F somatic mutation, a hallmark of myeloproliferative neoplasms, in 1% (9/932) of the NSCLCs. Analysis of cancer cell line pharmacogenomic data showed that a high level of JAK2 expression in a panel of NSCLC cell lines is correlated with increased sensitivity to a selective JAK2 inhibitor. Further analysis of TCGA genomic data revealed JAK2 gain or loss due to genetic alterations in NSCLC clinical samples are associated with significantly elevated or reduced PD-L1 expression, suggesting that the activating JAK2 p.V617F mutation could confer sensitivity to both JAK inhibitors and anti-PD1 immunotherapy. We also detected JAK3 germline activating mutations in 6.7% (62/932) of the patients who may benefit from anti-PD1 treatment, in light of recent findings that JAK3 mutations upregulate PD-L1 expression. CONCLUSION:Taken together, this study demonstrated the clinical utility of targeted NGS with a focused hotspot cancer gene panel in NSCLCs and identified activating mutations in JAK2 and JAK3 with clinical implications inferred through integrative analysis of cancer genetic, genomic, and pharmacogenomic data. The potential of JAK2 and JAK3 mutations as response markers for the targeted therapy against JAK kinases or anti-PD1 immunotherapy warrants further investigation.
AURA3 trial: does Tagrisso (osimertinib) have the potential to become the new standard of care for second-line treatment of patients with T790M mutation-positive locally advanced or metastatic NSCLC.
Papadimitrakopoulou Vassiliki A
Lung cancer management
Dr Papadimitrakopoulou is the Jay and Lori Eisenberg Distinguished Professor of Medicine and Chief of the section of Thoracic Medical Oncology in the Department of Thoracic/Head and Neck Medical Oncology at the University of Texas/MD Anderson Cancer Center. Her areas of expertise include design and development of novel therapeutic clinical trials for lung and head and neck neoplasms, personalized genomics-driven lung cancer therapy and translational research and cancer chemoprevention. Her extensive experience in design, development and implementation of translational research in the context of multidisciplinary research teams has led to research funding from National Cancer Institute (NCI), American Society of Clinical Oncology (ASCO) and Department of Defense (DOD) both independently and as a member of a research team in the Head and Neck SPORE program. Currently, she serves as the principal investigator and leads numerous clinical and translational research projects with a focus on the development of biomarker-based targeted therapy to overcome therapeutic resistance in advanced disease and immunotherapy. Most notably, she has led the multidisciplinary clinical and translational research infrastructure dedicated to the treatment of metastatic refractory NSCLC as part of the BATTLE-2 program, designed and developed the first-in-the-world comprehensive genomics-driven umbrella approach in Squamous Lung Cancer, the Lung Master protocol, jointly sponsored by NCI-Cancer Therapy Evaluation Program (CTEP) and Foundation for the National Institutes of Health (FNIH)/industry, aiming at bringing personalized medicine to patients with this disease. She is the Co-PI of an R01 award focusing on the role of mutations and targeting in lung cancer. She is the lead author or coauthor of over 150 published articles, book chapters and reviews, and numerous abstracts involving cancer therapeutics, prevention and translational research and she has received several awards including the ASCO Young Investigator and Career Development Award. On this R01 application, she will serve as Co-PI, working closely with Roy Herbst (Yale Cancer Center) and Don Gibbons (UT/MD Anderson Cancer Center), building on the recently completed BATTLE-2 program, and capitalizing on both laboratory findings supporting MEK targeted therapy and clinical effectiveness of immunotherapy and their combinations in addressing mutated lung cancer.
Nivolumab and Ipilimumab-induced myositis and myocarditis mimicking a myasthenia gravis presentation.
Valenti-Azcarate Rafael,Esparragosa Vazquez Ines,Toledano Illan Carlos,Idoate Gastearena Miguel Angel,Gállego Pérez-Larraya Jaime
Neuromuscular disorders : NMD
The rapidly growing field of cancer immunotherapy has led to the development of new treatments such as immune checkpoint inhibitors. These agents are monoclonal antibodies that enable tumor-reactive T cells to overcome regulatory mechanisms and produce effective antitumor responses. The use of immune checkpoint inhibitors is expected to progressively increase because they have shown promising therapeutic outcomes in multiple types of cancer and clinicians should be aware of their possible side-effects. We report a case of a man diagnosed with a non-microcytic lung carcinoma who started treatment with a combination of immune checkpoint inhibitors (Nivolumab and Ipilimumab). He subsequently developed binocular diplopia, fatigue, mild dyspnea and upper back pain resembling a myasthenia gravis presentation. Finally, a diagnosis of immune checkpoint inhibitor-related myositis and myocarditis was made. The detection of GFAP antibodies in CSF has unclear clinical and pathogenic significance and they may rather represent an epiphenomenon of the immune inflammation process.
Milestone Analyses of Immune Checkpoint Inhibitors, Targeted Therapy, and Conventional Therapy in Metastatic Non-Small Cell Lung Cancer Trials: A Meta-analysis.
Blumenthal Gideon M,Zhang Lijun,Zhang Hui,Kazandjian Dickran,Khozin Sean,Tang Shenghui,Goldberg Kirsten,Sridhara Rajeshwari,Keegan Patricia,Pazdur Richard
Importance:Novel intermediate end points may be useful to detect signals of early activity and prioritize new therapies to treat patients with advanced malignant neoplasms, including metastatic non-small cell lung cancer (mNSCLC). Objective:To explore milestone rate, a proposed intermediate end point for immunotherapy trials. Data Sources:Trials submitted to the US Food and Drug Administration with more than 150 patients and in which the intention-to-treat population was assessed were identified. Study Selection:An initial meta-analysis identified 14 randomized clinical trials for treatment of mNSCLC with active controls submitted to the US Food and Drug Administration from January 1, 2003, through December 31, 2013. An additional 11 randomized clinical trials submitted from January 1, 2014, through December 31, 2016 were included. Data Extraction and Synthesis:Two investigators abstracted data and pooled data to compare trial-level milestone ratios with conventional end points. Main Outcomes and Measures:Trial-level milestone ratios for milestone rates were calculated for overall response rate (ORR) within 6 months, 9-month progression-free survival (PFS), 9-month overall survival (OS), and 12-month OS. A weighted linear regression model evaluated associations between milestone ratios and hazard ratios (HRs). Experimental and control arms of trials testing immunotherapy, targeted therapy, and other trials were pooled to compare Kaplan-Meier survival estimates in the 3 therapeutic classes. Results:A total of 20 013 unique patients (65.4% male and 34.6% female; mean age, 60 [range, 18-92] years) with advanced lung cancer were identified in 25 unique trials. A moderate association was observed between 12-month OS milestone ratio and OS HR (R2 = 0.80; 95% CI, 0.63-0.91) and 9-month OS milestone ratio and OS HR (R2 = 0.67; 95% CI, 0.49-0.82). No associations were observed between 9-month PFS milestone ratio and OS HR (R2 = 0.19; 95% CI, 0.03-0.49) or 6-month ORR and OS HR (R2 = 0.05; 95% CI, 0.0001-0.31). The aggregated Kaplan-Meier analysis of immunotherapy trials vs chemotherapy revealed an OS HR of 0.69 (95% CI, 0.63-0.75) and PFS HR of 0.82 (95% CI, 0.76-0.89). Targeted therapy trials vs chemotherapy had an OS HR of 0.98 (95% CI, 0.80-1.19) and PFS HR of 0.48 (95% CI, 0.42-0.56). Conclusions and Relevance:This analysis of milestone rates suggests a moderate association between OS milestones at 12 or 9 months and OS HR but not 9-month PFS or 6-month ORR milestones and OS HR. Although OS at 12 months had the strongest association with OS HR, it may not be the optimal time for future trials, which will increasingly have immunotherapy as the control, deploy new biomarker-enrichment strategies, and likely enroll patients with longer survival. Milestone rates may be useful as a complementary tool to summarize or interpret trial results or as a secondary end point in exploratory studies.
Treatment Decision Drivers in Stage III Non-Small-Cell Lung Cancer: Outcomes of a Web-Based Survey of Oncologists in the United States.
Cotarla Ion,Boron Marnie L,Cullen Shawna L,Spinner Daryl S,Faulkner Eric C,Carroll Marissa C,Shah Surbhi,Yagui-Beltran Adam
JCO oncology practice
PURPOSE:We conducted a cross-sectional survey of practicing medical oncologists in the United States to obtain insight into physician and patient treatment decision making in stage III non-small-cell lung cancer (NSCLC). METHODS:A convenience sample of 150 oncologists completed a 38-question Web-based survey in January 2019. RESULTS:Surveyed oncologists (82% community based) had an average of 15 years of clinical experience and had treated an average of 20 patients newly diagnosed with stage III NSCLC in the previous 6 months. Oncologists reported presenting 55% of their patients with stage III NSCLC to tumor boards. For patients with new unresectable stage III NSCLC seen in the previous 6 months, concurrent chemoradiation therapy (cCRT) was reported as the initial treatment in an average of 48% of patients. The most frequent reason for delays in starting the initial chosen treatment was insurance preauthorization processes (reported by 65% of oncologists). A total of 55% of all patients with unresectable stage III NSCLC who received cCRT went on to receive consolidation immunotherapy; for patients who received consolidation chemotherapy after cCRT, the rate of immunotherapy was lower (42%). Biomarker test results were given as the reason for oncologists not recommending immunotherapy after cCRT in approximately a quarter of cases. The 112 oncologists with eligible patients who declined immunotherapy reported previous treatment fatigue as the reason in 34% of patients and insurance challenges in 19% of patients. CONCLUSION:Oncologists reported notable deviations from treatment guidelines for stage III NSCLC. Our findings highlight important opportunities to improve decision making and the coordination of care in stage III NSCLC.
Current knowledge of Ipilimumab and its use in treating non-small cell lung cancer.
Pinto Joseph A,Raez Luis E,Oliveres Helena,Rolfo Christian C
Expert opinion on biological therapy
: The systemic treatment of non-small cell lung cancer (NSCLC) has changed dramatically with the identification of actionable mutations and the use of targeted agents. Unfortunately, many tumors will acquire resistance and >75% of NSCLC cases lack for an actionable gene aberration. In this setting, immunotherapy rises as effective therapeutic where immune checkpoint inhibitors have entered or are entering the market in many neoplasms, including NSCLC. Ipilimumab is a monoclonal antibody targeting CTLA-4, promoting T-cell activation and its subsequent anti-tumoral immune effect. Ipilimumab might have a very important role in NSCLC as it does in melanoma because of its synergistic effect with PD-1/PDL-1 inhibitors. : We summarize current results of clinical studies of ipilimumab for efficacy and safety in NSCLC and also the current knowledge about potential biomarkers for its efficacy. : Combined use of PD-1/PDL-1 and anti-CTL4 inhibitors increases the efficacy against NSCLC and it is a very promising approach not only in NSCLC but also in small cell lung cancer (SCLC) for first or second-line therapy. It's very important to identify biomarkers that can better select the population of patients that benefit the most with these checkpoint inhibitors.
Bempegaldesleukin (NKTR-214) plus Nivolumab in Patients with Advanced Solid Tumors: Phase I Dose-Escalation Study of Safety, Efficacy, and Immune Activation (PIVOT-02).
Diab Adi,Tannir Nizar M,Bentebibel Salah-Eddine,Hwu Patrick,Papadimitrakopoulou Vassiliki,Haymaker Cara,Kluger Harriet M,Gettinger Scott N,Sznol Mario,Tykodi Scott S,Curti Brendan D,Tagliaferri Mary A,Zalevsky Jonathan,Hannah Alison L,Hoch Ute,Aung Sandra,Fanton Christie,Rizwan Ahsan,Iacucci Ernesto,Liao Yijie,Bernatchez Chantale,Hurwitz Michael E,Cho Daniel C
This single-arm, phase I dose-escalation trial (NCT02983045) evaluated bempegaldesleukin (NKTR-214/BEMPEG), a CD122-preferential IL2 pathway agonist, plus nivolumab in 38 patients with selected immunotherapy-naïve advanced solid tumors (melanoma, renal cell carcinoma, and non-small cell lung cancer). Three dose-limiting toxicities were reported in 2 of 17 patients during dose escalation [hypotension ( = 1), hyperglycemia ( = 1), metabolic acidosis ( = 1)]. The most common treatment-related adverse events (TRAE) were flu-like symptoms (86.8%), rash (78.9%), fatigue (73.7%), and pruritus (52.6%). Eight patients (21.1%) experienced grade 3/4 TRAEs; there were no treatment-related deaths. Total objective response rate across tumor types and dose cohorts was 59.5% (22/37), with 7 complete responses (18.9%). Cellular and gene expression analysis of longitudinal tumor biopsies revealed increased infiltration, activation, and cytotoxicity of CD8 T cells, without regulatory T-cell enhancement. At the recommended phase II dose, BEMPEG 0.006 mg/kg plus nivolumab 360 mg every 3 weeks, the combination was well tolerated and demonstrated encouraging clinical activity irrespective of baseline PD-L1 status. SIGNIFICANCE: These data show that BEMPEG can be successfully combined with a checkpoint inhibitor as dual immunotherapy for a range of advanced solid tumors. Efficacy was observed regardless of baseline PD-L1 status and baseline levels of tumor-infiltrating lymphocytes, suggesting therapeutic potential for patients with poor prognostic risk factors for response to PD-1/PD-L1 blockade...
MAGE3 and Survivin activated dendritic cell immunotherapy for the treatment of non-small cell lung cancer.
Li Dong,He Song
Dendritic cell (DC) immunotherapy is an optimal cancer treatment, resulting in its emergence as a therapeutic choice; however, there are limited studies investigating dual antigen-pulsed DC immunotherapy in non-small cell lung cancer (NSCLC). In order to determine the effect of a recombinant melanoma-associated antigen (rMAGE-3) and recombinant Survivin (rSurvivin) peptide-pulsed DC immunotherapy in patients with NSCLC, the present clinical study was performed. DC immunotherapy was generated from the monocytes of patients with NSCLC and primed with rMAGE-3 and rSurvivin peptides. The present open-label, non-randomised study enrolled 16 patients with histologically confirmed stage I-IIIB NSCLC between December 2013 and October 2014. A prime immunotherapy (9.1×10 cells/dose) and a single boost (8.2×10 cells/dose) were administered 1 month apart intradermally and the patients were evaluated for immunological and clinical response. DC immunotherapy was well tolerated, with no serious adverse events. There was a single incidence of grade 1 fever, chills and fatigue. Out of the 16 patients enrolled, 11 patients showed stable disease and 5 showed disease progression. There was a significant increase in IFN-γ expression on day 60 vs. day 0 (P=0.048). An increasing trend in the mean cluster of differentiation (CD)4:CD8 values of day 30 and day 90 was observed, but this was not significant. The present study established that DCs primed with rMAGE-3 and rSurvivin may be used in NSCLC treatment. However, a larger study is required to address prominent issues, including secretion of immunosuppressive cytokines and mechanisms of tumour escape from immune surveillance. Several factors associated with the manufacturing and quality of immunotherapy also require standardisation.
Immunomodifiers in combination with conventional chemotherapy in small cell lung cancer: a phase II, randomized study.
Zarogoulidis Konstantinos,Ziogas Eftimios,Boutsikou Efimia,Zarogoulidis Paul,Darwiche Kaid,Kontakiotis Theodoros,Tsakiridis Kosmas,Porpodis Konstantinos,Latsios Dimitrios,Chatzizisi Olga,Karapantzos Ilias,Li Qiang,Kyriazis Georgios
Drug design, development and therapy
PURPOSE:To evaluate the effect of immunotherapy on response, survival, and certain immune markers in patients with small cell lung cancer (SCLC) who are receiving chemotherapy. PATIENTS AND METHODS:Patients with SCLC (n = 164) were assigned to receive either chemotherapy alone (group A) or a combination of chemotherapy and immunotherapy as follows: interferon α (IFN-α; 3 million IU) 3 times per week (group B); IFN-γ (3 million IU) 3 times per week (group C); and IFN-α and IFN-γ (1.5 million IU of each) 3 times per week (group D). Chemotherapy was the same for all groups and consisted of eight cycles with carboplatin 5.5 mg/m(2) intravenously on day 1, ifosfamide 3.5 mg/m(2) intravenously on day 1, and etoposide 200 mg/m(2) total dose taken orally on days 1 through 3, every 28 days. Patients completing chemotherapy were restaged, and those who were found to have limited disease received primary site and prophylactic cranial irradiation. Immunotherapy was continued throughout these treatments and during the follow-up period. Blood was taken before each course of chemotherapy and during follow-up to measure CD3+ lymphocytes, CD3+CD4+ lymphocytes, CD3+CD8+ lymphocytes, natural killer cells, and natural killer T cells. RESULTS:Differences in response and survival were not significantly different when all patients were considered. However, among patients with limited disease, Kaplan-Meier analysis disclosed a survival benefit for group B (P , 0.05). The analysis of immunologic measurements revealed that the improvement of immune markers was always accompanied by clinical improvement, whereas deterioration of all markers was accompanied by disease progression (result not statistically significant except for group C; P , 0.05). CONCLUSION:Among cytokines used in the study, only IFN-α seems to confer a survival benefit to patients with SCLC with limited disease. However, immunotherapy remains a challenge in the treatment of lung neoplasms and should be further explored.
Spotlight on landmark oncology trials: the latest evidence and novel trial designs.
Earl Helena,Molica Stefano,Rutkowski Piotr
The era of precision oncology is marked with prominent successes in the therapy of advanced soft tissue sarcomas, breast cancer, ovarian cancer and haematological neoplasms, among others. Moreover, recent trials of immune checkpoint inhibitors in melanoma, non-small cell lung carcinoma, and head and neck cancers have significantly influenced the therapeutic landscape by providing promising evidence for immunotherapy efficacy in the adjuvant setting in high-risk locoregional disease. To speed up the introduction of targeted therapy for cancer patients, novel phase II trials are being designed, and may likely form the basis for the 'landmark trials' of the future. A special article collection in BMC Medicine, "Spotlight on landmark oncology trials", features articles from invited experts on recent clinical practice-changing trials.
Sarcomatoid lung carcinomas show high levels of programmed death ligand-1 (PD-L1).
Velcheti Vamsidhar,Rimm David L,Schalper Kurt A
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
Programmed death-1 (PD-1) is a coinhibitory inducible receptor present on T-cells and macrophages. Tumor cells with increased programmed death ligand-1 (PD-L1) are believed to escape immunity through activation of PD-1/PD-L1 pathway and suppression of effector-immune responses. Recent strategies targeting the PD-1/PD-L1 axis have shown promising results in patients with several tumors types, including lung carcinomas. Preliminary data suggest that PD-L1 protein expression might have predictive response to such therapies. Sarcomatoid carcinomas (SCs) of the lung include rare subtypes of poorly differentiated non-small-cell lung carcinomas of high grade and aggressive behavior. The biology of these neoplasms is poorly understood and they frequently show increased local inflammatory and lymphocytic infiltration. Here, we report the expression of PD-L1 in 13 SCs from two large retrospective lung cancer cohorts. Using automated quantitative immunofluoresence and a mouse monoclonal antibody directed against the extracellular domain of PD-L1, we show that 9 of 13 patients (69.2%) with SCs are positive for PD-L1 and their levels are higher than in conventional non-small-cell lung carcinoma. These results provide rationale for the potential use of targeted immunotherapy in lung SCs.
Adoptive immunotherapy combined chemoradiotherapy for non-small-cell lung cancer: a meta-analysis.
Qian Haili,Wang Haijuan,Guan Xiuwen,Yi Zongbi,Ma Fei
The aim of this study was to compare the efficacies between adoptive immunotherapy combined chemoradiotherapy and chemoradiotherapy alone in patients with non-small-cell lung cancer (NSCLC). The databases PubMed, EMBASE, and Cochrane database were searched to identify eligible clinical trials. Data analyses were carried out using a comprehensive meta-analysis program, version 2 software. A total of seven articles were finally included in the analysis. Meta-analyses showed that compared with chemoradiotherapy alone, adoptive immunotherapy combined with chemoradiotherapy could improve the 2-year overall survival [odds ratio (OR)=2.45, 95% confidence interval (CI): 1.60-3.75, P<0.001], but not 2-year progression-free survival (OR=1.81, 95% CI: 0.61-5.36, P=0.284). Specifically, early (OR=3.32, 95% CI: 1.38-7.95, P<0.01) but not advanced (OR=3.75, 95% CI: 0.96-14.68, P=0.057) NSCLC patients were likely to gain a large benefit from the adoptive immunotherapy. Most of the adoptive immunotherapy-induced adverse effects were self-limited, mainly including fever, shiver, nausea, fatigue, etc. and severe toxicities were not observed. Adoptive immunotherapy combined with chemoradiotherapy can delay the recurrence of NSCLC and improve survival in patients, where the benefits are even more significant in patients with early-stage NSCLC.
Large-scale database mining reveals hidden trends and future directions for cancer immunotherapy.
Kather Jakob Nikolas,Berghoff Anna Sophie,Ferber Dyke,Suarez-Carmona Meggy,Reyes-Aldasoro Constantino Carlos,Valous Nektarios A,Rojas-Moraleda Rodrigo,Jäger Dirk,Halama Niels
Cancer immunotherapy has fundamentally changed the landscape of oncology in recent years and significant resources are invested into immunotherapy research. It is in the interests of researchers and clinicians to identify promising and less promising trends in this field in order to rationally allocate resources. This requires a quantitative large-scale analysis of cancer immunotherapy related databases. We developed a novel tool for text mining, statistical analysis and data visualization of scientific literature data. We used this tool to analyze 72002 cancer immunotherapy publications and 1469 clinical trials from public databases. All source codes are available under an open access license. The contribution of specific topics within the cancer immunotherapy field has markedly shifted over the years. We show that the focus is moving from cell-based therapy and vaccination towards checkpoint inhibitors, with these trends reaching statistical significance. Rapidly growing subfields include the combination of chemotherapy with checkpoint blockade. Translational studies have shifted from hematological and skin neoplasms to gastrointestinal and lung cancer and from tumor antigens and angiogenesis to tumor stroma and apoptosis. This work highlights the importance of unbiased large-scale database mining to assess trends in cancer research and cancer immunotherapy in particular. Researchers, clinicians and funding agencies should be aware of quantitative trends in the immunotherapy field, allocate resources to the most promising areas and find new approaches for currently immature topics.
Tobacco smoking and cessation and PD-L1 inhibitors in non-small cell lung cancer (NSCLC): a review of the literature.
Norum Jan,Nieder Carsten
Background:Programmed death ligand 1 (PD-L1) targeting immunotherapies, as pembrolizumab and nivolumab, have significantly improved outcome in patients with non-small cell lung cancer (NSCLC). Tobacco smoking is the number one risk factor for lung cancer and is linked to 80%-90% of these cancers. Smoking during cancer therapy may influence on radiotherapy and chemotherapy outcome. We aimed to review the knowledge in immunotherapy. Patients and methods:A systematic review was done. We searched for documents and articles published in English language and registered in Cochrane Library, National Health Service (NHS) Centre for Reviews and Dissemination (CRD), Embase or Medline. The search terms were (A) (Lung cancer or NSCLC) with (pembrolizumab or nivolumab) with PD-L1 with (tobacco or smoking) and (B) Lung Neoplasms and Immunotherapy and (smoking cessation or patient compliance). 68 papers were detected and two more were added during review process (references) and six based on information from the manufacturers. Results:Nine papers were selected. High PD-L1 expression (≥50%) was correlated with current/ever smoking history in three studies. Six studies revealed a higher overall response rate (ORR) among current/former smokers. The ORR was generally (six studies) better among the current/former smoker group. So also when tumours had a molecular 'smoking signature' (one study). This was probably due to a higher mutational burden. In two studies, minor or no difference was revealed.One study (KEYNOTE-024) compared former and current smokers, and documented pembrolizumab being more effective among former smokers than current smokers. Conclusions:Tobacco smoking patients with NSCLC generally have a higher PD-L1 tumour proportion score and experience a better ORR of immunotherapy than no smokers. There is little evidence on the effect of smoking during immunotherapy, but one study (KEYNOTE-024) may indicate survival gains of smoking cessation.
Lambert-Eaton Myasthenic Syndrome Secondary to Nivolumab and Ipilimumab in a Patient with Small-Cell Lung Cancer.
Agrawal Kavita,Agrawal Nirav
Case reports in neurological medicine
We present a case of a 59-year-old male with a confirmed diagnosis of small-cell lung cancer (SCLC). He had progressive disease even after four cycles of cisplatin and etoposide chemotherapy and 21 cycles of radiation. He was therefore started on immunotherapy with nivolumab every 2 weeks and ipilimumab every 6 weeks. After 4 months of starting immunotherapy, he reported extreme fatigue, muscular weakness, and poor appetite. He was diagnosed with hypothyroidism, primary adrenal insufficiency, and Lambert-Eaton Myasthenic Syndrome (LEMS). LEMS can be both a paraneoplastic syndrome of SCLC and an adverse effect of immunotherapy. Currently, there is no diagnostic test available to determine if a case of LEMS is a paraneoplastic syndrome or immunotherapy-related adverse effect. In our patient, we felt that LEMS was an immunotherapy-related adverse effect rather being a paraneoplastic syndrome. Our determination was based on the time of onset of muscular weakness, presence of other immunotherapy-mediated adverse events, and the appearance of symptoms in spite of SCLC that had been stabilized on immunotherapy. Accordingly, immunotherapy was stopped and a brief tapering course of steroids was initiated. Our patient's muscular weakness from LEMS responded well. His clinical improvement persisted even with radiologic progression of disease after cessation of immunotherapy.
[Immunotherapy in non-small cell lung cancer patients: back to the future.]
Roberto Michela,Botticelli Andrea,Cecere Fabiana,Cognetti Francesco,Giusti Raffaele,Gelibter Alain,Lugini Antonio,Nelli Fabrizio,Nuti Marianna,Santini Daniele,Marchetti Paolo
Recenti progressi in medicina
With the advent of immunotherapy, the life expectancy of patients with advanced non-small cell lung cancer (NSCLC) is dramatically improved. As described in the most recent clinical trials, the addition of immunotherapy to the available therapeutic strategies, restoring an efficient immune response against neoplasms and establishing an immunological memory, is able to improve both patient's survival and quality of life. This paved the way for new therapeutic algorithms, new combination strategies, as well as the possible use of adoptive immunotherapy. Although the use of immunotherapy is now widely employed in the different phases of lung cancer, we have not yet fully understood what are both the actual mechanisms of action and resistance to checkpoint inhibitors, predictive factors of response, immuno-related response criteria, and interferences between immunotherapy and tumor microenvironment, as well as angiogenesis and its interactions with conventional therapies, such as chemotherapy. The objective of this critical review is to frame the relevant results obtained with immunotherapy in NSCLC, providing insights to help overcome decision-making for a better therapeutic choice. In addition, returning to the study of pulmonary physiology and preclinical data, we will address the new issues on the heterogeneity of response to anti-PD1/anti-PD-L1, including their combinations, in NSCLC. Moreover, to date, we are facing with patterns of response different from those previously seen with cytotoxic or target therapies. Indeed, different radiological evaluation criteria have been proposed to evaluate response to immunotherapy and further efforts are needed to identify a unique system of evaluation and other than PDL1 biomarkers, to integrate radiology in the assessment of response.
Opportunistic autoimmunity secondary to cancer immunotherapy (OASI): An emerging challenge.
Kostine M,Chiche L,Lazaro E,Halfon P,Charpin C,Arniaud D,Retornaz F,Blanco P,Jourde-Chiche N,Richez C,Stavris C
La Revue de medecine interne
With "checkpoint inhibitors" targeting PD1/PD-1-ligands or CTLA-4/CD28 pathways, immunotherapy has profoundly modified therapeutic strategies in oncology. First approved in refractory metastatic neoplasms (melanoma and lung adenocarcinoma), it is now being tested broadly in other cancers and/or as adjuvant treatment. For a significant proportion of patients, immunotherapy is responsible for "immunological" events, identified as Immune-Related Adverse Events (irAEs). Owing to the increasing number of prescriptions, identification and management of specific immunological side effects is crucial and requires close collaboration between oncologists and internists and/or other organ specialists. Within irAEs, we propose to individualize the induced autoimmunity by the term "Opportunistic Autoimmunity Secondary to Cancer Immunotherapy" (OASI). The aims of this article are (1) to present the different available checkpoint inhibitors and the OASIs reported with these treatments and (2) to propose practical recommendations for diagnosis, pre-therapeutic assessment and management of OASIs. The need for predictive biomarkers of OASIs occurrence will also be discussed.
DNA damage, tumor mutational load and their impact on immune responses against cancer.
Liontos Michalis,Anastasiou Ioannis,Bamias Aristotelis,Dimopoulos Meletios-Athanasios
Annals of translational medicine
Advances in immunotherapy have changed the therapeutic landscape in many malignancies. Immune checkpoint inhibitors have already received regulatory approval in melanomas, lung, renal and bladder carcinomas. A common feature of these neoplasms is the increased mutational load, related to a possible increase number of tumor neoantigens that are recognized by the immune system. The mechanisms that DNA damage could confer to the mutational load and the formation of neoantigens and how this could be exploited to advance our immunotherapeutic strategies is discussed in this review.