Immune Checkpoint Inhibitors in "Special" NSCLC Populations: A Viable Approach?

Over the last decade, the therapeutic scenario for advanced non-small-cell lung cancer (NSCLC) has undergone a major paradigm shift. Immune checkpoint inhibitors (ICIs) have shown a meaningful clinical and survival improvement in different settings of the disease. However, the real benefit of this therapeutic approach remains controversial in selected NSCLC subsets, such as those of the elderly with active brain metastases or oncogene-addicted mutations. This is mainly due to the exclusion or underrepresentation of these patient subpopulations in most pivotal phase III studies; this precludes the generalization of ICI efficacy in this context. Moreover, no predictive biomarkers of ICI response exist that can help with patient selection for this therapeutic approach. Here, we critically summarize the current state of ICI efficacy in the most common "special" NSCLC subpopulations.

Anetumab ravtansine versus vinorelbine in patients with relapsed, mesothelin-positive malignant pleural mesothelioma (ARCS-M): a randomised, open-label phase 2 trial.

BACKGROUND: Few treatment options exist for second-line treatment of malignant pleural mesothelioma. We aimed to assess the antibody-drug conjugate anetumab ravtansine versus vinorelbine in patients with unresectable locally advanced or metastatic disease overexpressing mesothelin who had progressed on first-line platinum-pemetrexed chemotherapy with or without bevacizumab. METHODS: In this phase 2, randomised, open-label study, done at 76 hospitals in 14 countries, we enrolled adults (aged ≥18 years) with unresectable locally advanced or metastatic malignant pleural mesothelioma, an Eastern Cooperative Oncology Group performance status of 0-1, and who had progressed on first-line platinum-pemetrexed chemotherapy with or without bevacizumab. Participants were prospectively screened for mesothelin overexpression (defined as 2+ or 3+ mesothelin membrane staining intensity on at least 30% of viable tumour cells by immunohistochemistry) and were randomly assigned (2:1), using an interactive voice and web response system provided by the sponsor, to receive intravenous anetumab ravtansine (6·5 mg/kg on day 1 of each 21-day cycle) or intravenous vinorelbine (30 mg/m2 once every week) until progression, toxicity, or death. The primary endpoint was progression-free survival according to blinded central radiology review, assessed in the intention-to-treat population, with safety assessed in all participants who received any study treatment. This study is registered with ClinicalTrials.gov, NCT02610140, and is now completed. FINDINGS: Between Dec 3, 2015, and May 31, 2017, 589 patients were enrolled and 248 mesothelin-overexpressing patients were randomly allocated to the two treatment groups (166 patients were randomly assigned to receive anetumab ravtansine and 82 patients were randomly assigned to receive vinorelbine). 105 (63%) of 166 patients treated with anetumab ravtansine (median follow-up 4·0 months [IQR 1·4-5·5]) versus 43 (52%) of 82 patients treated with vinorelbine (3·9 months [1·4-5·4]) had disease progression or died (median progression-free survival 4·3 months [95% CI 4·1-5·2] vs 4·5 months [4·1-5·8]; hazard ratio 1·22 [0·85-1·74]; log-rank p=0·86). The most common grade 3 or worse adverse events were neutropenia (one [1%] of 163 patients for anetumab ravtansine vs 28 [39%] of 72 patients for vinorelbine), pneumonia (seven [4%] vs five [7%]), neutrophil count decrease (two [1%] vs 12 [17%]), and dyspnoea (nine [6%] vs three [4%]). Serious drug-related treatment-emergent adverse events occurred in 12 (7%) patients treated with anetumab ravtansine and 11 (15%) patients treated with vinorelbine. Ten (6%) treatment-emergent deaths occurred with anetumab ravtansine: pneumonia (three [2%]), dyspnoea (two [1%]), sepsis (two [1%]), atrial fibrillation (one [1%]), physical deterioration (one [1%]), hepatic failure (one [1%]), mesothelioma (one [1%]), and renal failure (one [1%]; one patient had 3 events). One (1%) treatment-emergent death occurred in the vinorelbine group (pneumonia). INTERPRETATION: Anetumab ravtansine showed a manageable safety profile and was not superior to vinorelbine. Further studies are needed to define active treatments in relapsed mesothelin-expressing malignant pleural mesothelioma. FUNDING: Bayer Healthcare Pharmaceuticals.

T-Cell Receptor Repertoire Sequencing and Its Applications: Focus on Infectious Diseases and Cancer.

The immune system is a dynamic feature of each individual and a footprint of our unique internal and external exposures. Indeed, the type and level of exposure to physical and biological agents shape the development and behavior of this complex and diffuse system. Many pathological conditions depend on how our immune system responds or does not respond to a pathogen or a disease or on how the regulation of immunity is altered by the disease itself. T-cells are important players in adaptive immunity and, together with B-cells, define specificity and monitor the internal and external signals that our organism perceives through its specific receptors, TCRs and BCRs, respectively. Today, high-throughput sequencing (HTS) applied to the TCR repertoire has opened a window of opportunity to disclose T-cell repertoire development and behavior down to the clonal level. Although TCR repertoire sequencing is easily accessible today, it is important to deeply understand the available technologies for choosing the best fit for the specific experimental needs and questions. Here, we provide an updated overview of TCR repertoire sequencing strategies, providers and applications to infectious diseases and cancer to guide researchers' choice through the multitude of available options. The possibility of extending the TCR repertoire to HLA characterization will be of pivotal importance in the near future to understand how specific HLA genes shape T-cell responses in different pathological contexts and will add a level of comprehension that was unthinkable just a few years ago.

COVID and Lung Cancer.

PURPOSE OF REVIEW: Since the past year, the fast spread of coronavirus disease 2019 (COVID-19) has represented a global health threat, especially for cancer patients, that has required an urgent reorganization of clinical activities. Here, we will critically revise the profound impact that the pandemic has generated in lung cancer patients, as well the most significant challenges that oncologists have to face to maintain the highest possible standards in the management of lung cancer patients in the pandemic era. RECENT FINDINGS: Evidences suggested a higher susceptibility and mortality of lung cancer patients due to COVID-19. The hard management of this patient population has been also due to the potential cross interference of anti-tumor drugs on SARS-Cov-2 infection and to the differential diagnosis between COVID-19 pneumonitis and drug-related pneumonitis. COVID-19 pandemic has generated a profound reshaping of oncological activities and the development of recommendations by the oncology scientific community to prioritize anti-tumor treatments for lung cancer patients.

NK- and T-cell subsets in malignant mesothelioma patients: Baseline pattern and changes in the context of anti-CTLA-4 therapy.

Malignant mesothelioma (MM) is a highly aggressive form of cancer with limited treatment options. Although the role of NK cells has been studied in many solid tumors, the pattern of NK-cell subsets and their recognition of mesothelioma cells remain to be explored. We used RNA expression data of MM biopsies derived from the cancer genome atlas to evaluate the immune cell infiltrates. We characterized the phenotype of circulating NK and T cells of 27 MM patients before and after treatment with an anti-CTLA-4 antibody (tremelimumab). These immune cell profiles were compared to healthy controls. The RNA expression data of the MM biopsies indicated the presence of NK cells in a subgroup of patients. We demonstrated that NK cells recognize MM cell lines and that IL-15 stimulation improved NK cell-mediated lysis in vitro. Using multivariate projection models, we found that MM patients had a perturbed ratio of CD56bright and CD56dim NK subsets and increased serum concentrations of the cytokines IL-10, IL-8 and TNF-α. After tremelimumab treatment, the ratio between the CD56bright and CD56dim subsets shifted back towards physiological levels. Furthermore, the improved overall survival was correlated with low TIM-3+ CD8+ T-cell frequency, high DNAM-1+ CD56dim NK-cell frequency and high expression levels of NKp46 on the CD56dim NK cells before and after immune checkpoint blockade. Together, our observations suggest that NK cells infiltrate MM and that they can recognize and kill mesothelioma cells. The disease is associated with distinct lymphocytes patterns, some of which correlate with prognosis or are affected by treatment with tremelimumab.

Italian Cohort of Nivolumab Expanded Access Program in Squamous Non-Small Cell Lung Cancer: Results from a Real-World Population.

BACKGROUND: Nivolumab has shown a survival benefit compared with docetaxel as second-line treatment for patients with previously treated advanced squamous non-small cell lung cancer (NSCLC) in a randomized phase III trial. The experiences of patients and physicians in routine clinical practice are often different from those in a controlled clinical trial setting. We present data from the entire Italian cohort of patients with squamous NSCLC enrolled in a worldwide nivolumab NSCLC expanded access program. PATIENTS AND METHODS: Patients with pretreated advanced squamous NSCLC received nivolumab 3 mg/kg every 2 weeks for up to 24 months. Safety was monitored throughout; efficacy data collected included objective tumor response, date of progression, and survival information. RESULTS: The Italian cohort comprised 371 patients who received at least one dose of nivolumab. In the overall population, the objective response rate (ORR) was 18%, the disease control rate (DCR) was 47%, and median overall survival (OS) was 7.9 months (95% confidence interval 6.2-9.6). In subgroup analyses, ORR, DCR, and median OS were, respectively, 17%, 48%, and 9.1 months in patients previously treated with two or more lines of therapy (n = 209) and 8%, 40%, and 10.0 months in patients treated beyond disease progression (n = 65). In the overall population, the rate of any-grade and grade 3-4 adverse events was 29% and 6%, respectively. Treatment-related adverse events led to treatment discontinuation in 14 patients (5%). There were no treatment-related deaths. CONCLUSION: To date, this report represents the most extensive clinical experience with nivolumab in advanced squamous NSCLC in current practice outside the controlled clinical trial setting. These data suggest that the efficacy and safety profiles of nivolumab in a broad, real-world setting are consistent with those obtained in clinical trials. IMPLICATIONS FOR PRACTICE: Nivolumab is approved in the U.S. and Europe for the treatment of advanced non-small cell lung cancer (NSCLC) after failure of prior platinum-based chemotherapy. In this cohort of Italian patients with previously treated, advanced squamous NSCLC treated in a real-world setting as part of the nivolumab expanded access program, the efficacy and safety of nivolumab was consistent with that previously reported in nivolumab clinical trials.

Avelumab versus docetaxel in patients with platinum-treated advanced non-small-cell lung cancer (JAVELIN Lung 200): an open-label, randomised, phase 3 study.

BACKGROUND: Antibodies targeting the immune checkpoint molecules PD-1 or PD-L1 have demonstrated clinical efficacy in patients with metastatic non-small-cell lung cancer (NSCLC). In this trial we investigated the efficacy and safety of avelumab, an anti-PD-L1 antibody, in patients with NSCLC who had already received platinum-based therapy. METHODS: JAVELIN Lung 200 was a multicentre, open-label, randomised, phase 3 trial at 173 hospitals and cancer treatment centres in 31 countries. Eligible patients were aged 18 years or older and had stage IIIB or IV or recurrent NSCLC and disease progression after treatment with a platinum-containing doublet, an Eastern Cooperative Oncology Group performance status score of 0 or 1, an estimated life expectancy of more than 12 weeks, and adequate haematological, renal, and hepatic function. Participants were randomly assigned (1:1), via an interactive voice-response system with a stratified permuted block method with variable block length, to receive either avelumab 10 mg/kg every 2 weeks or docetaxel 75 mg/m2 every 3 weeks. Randomisation was stratified by PD-L1 expression (≥1% vs <1% of tumour cells), which was measured with the 73-10 assay, and histology (squamous vs non-squamous). The primary endpoint was overall survival, analysed when roughly 337 events (deaths) had occurred in the PD-L1-positive population. Efficacy was analysed in all PD-L1-positive patients (ie, PD-L1 expression in ≥1% of tumour cells) randomly assigned to study treatment (the primary analysis population) and then in all randomly assigned patients through a hierarchical testing procedure. Safety was analysed in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT02395172. Enrolment is complete, but the trial is ongoing. FINDINGS: Between March 24, 2015, and Jan 23, 2017, 792 patients were enrolled and randomly assigned to receive avelumab (n=396) or docetaxel (n=396). 264 participants in the avelumab group and 265 in the docetaxel group had PD-L1-positive tumours. In patients with PD-L1-positive tumours, median overall survival did not differ significantly between the avelumab and docetaxel groups (11·4 months [95% CI 9·4-13·9] vs 10·3 months [8·5-13·0]; hazard ratio 0·90 [96% CI 0·72-1·12]; one-sided p=0·16). Treatment-related adverse events occurred in 251 (64%) of 393 avelumab-treated patients and 313 (86%) of 365 docetaxel-treated patients, including grade 3-5 events in 39 (10%) and 180 (49%) patients, respectively. The most common grade 3-5 treatment-related adverse events were infusion-related reaction (six patients [2%]) and increased lipase (four [1%]) in the avelumab group and neutropenia (51 [14%]), febrile neutropenia (37 [10%]), and decreased neutrophil counts (36 [10%]) in the docetaxel group. Serious treatment-related adverse events occurred in 34 (9%) patients in the avelumab group and 75 (21%) in the docetaxel group. Treatment-related deaths occurred in four (1%) participants in the avelumab group, two due to interstitial lung disease, one due to acute kidney injury, and one due to a combination of autoimmune myocarditis, acute cardiac failure, and respiratory failure. Treatment-related deaths occurred in 14 (4%) patients in the docetaxel group, three due to pneumonia, and one each due to febrile neutropenia, septic shock, febrile neutropenia with septic shock, acute respiratory failure, cardiovascular insufficiency, renal impairment, leucopenia with mucosal inflammation and pyrexia, infection, neutropenic infection, dehydration, and unknown causes. INTERPRETATION: Compared with docetaxel, avelumab did not improve overall survival in patients with platinum-treated PD-L1-positive NSCLC, but had a favourable safety profile. FUNDING: Merck and Pfizer.

Immune checkpoint blockade therapy of mesothelioma: a clinical and radiological challenge.

Treatment of malignant pleural mesothelioma (MPM) represents a highly unmet medical need. Here, we discuss the results and therapeutic potential of first- and second-generation immunomodulatory antibodies targeting distinct immune checkpoints for the treatment of MPM, as well as their prospective therapeutic role in combination strategies. We also discuss the role of appropriate radiological criteria of response for MPM and the potential need of ad hoc criteria of disease evaluation in MPM patients undergoing treatment with immunotherapeutic agents.

Nivolumab in never-smokers with advanced squamous non-small cell lung cancer: Results from the Italian cohort of an expanded access program.

OBJECTIVES:: Never-smokers may be a distinct subgroup among patients with advanced non-small cell lung cancer, appearing to benefit less from immunotherapy than smokers. We report results from never-smokers enrolled in the Italian cohort of the nivolumab expanded access program in pre-treated patients with advanced squamous non-small cell lung cancer. MATERIALS AND METHODS:: Nivolumab (3 mg/kg every 2 weeks for ≤24 months) was available on physician request. Efficacy data included objective tumor response, date of progression, and survival information. Safety was monitored. RESULTS:: Overall, 371 patients received at least one dose of nivolumab, including 31 never-smokers (8%). Objective response rate, disease-control rate, and median overall survival were 23%, 45%, and 12.1 months (95% confidence interval: 3.7-20.4), respectively, in never-smokers, and 18%, 47%, and 7.9 months (95% confidence interval: 6.2-9.6), respectively, in the overall expanded access program population. Any-grade and grade 3-4 treatment-related adverse events were reported in 12 (39%) and 3 (10%) never-smokers, respectively, and in 109 (29%) and 21 (6%) patients, respectively, in the overall expanded access program population. Grade 3-4 treatment-related adverse events in non-smokers were increased transaminases (n = 2; 6%) and diarrhea (n = 1; 3%). Treatment-related adverse events led to treatment discontinuation in 4 non-smokers (17%) and in 26 patients (9%) overall. CONCLUSION:: Pre-treated never-smokers with advanced squamous non-small cell lung cancer in this Italian expanded access program demonstrated efficacy and safety that were consistent with those in the overall expanded access program population and clinical trials. These results suggest that a proportion of never-smoker patients with squamous non-small cell lung cancer may be responsive to immunotherapy. Other factors, such as the tumor mutational load and the status of programmed death-ligand 1, anaplastic lymphoma kinase, and epidermal growth factor receptor, might play a potential key role.

Tremelimumab as second-line or third-line treatment in relapsed malignant mesothelioma (DETERMINE): a multicentre, international, randomised, double-blind, placebo-controlled phase 2b trial.

BACKGROUND: New therapeutic strategies for malignant mesothelioma are urgently needed. In the DETERMINE study, we investigated the effects of the cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) monoclonal antibody tremelimumab in patients with previously treated advanced malignant mesothelioma. METHODS: DETERMINE was a double-blind, placebo-controlled, phase 2b trial done at 105 study centres across 19 countries in patients with unresectable pleural or peritoneal malignant mesothelioma who had progressed after one or two previous systemic treatments for advanced disease. Eligible patients were aged 18 years or older with Eastern Cooperative Oncology Group performance status of 0 or 1 and measurable disease as defined in the modified Response Evaluation Criteria In Solid Tumors (RECIST) version 1.0 for pleural mesothelioma or RECIST version 1.1 for peritoneal mesothelioma. Patients were randomly assigned (2:1) in blocks of three, stratified by European Organisation for Research and Treatment of Cancer status (low risk vs high risk), line of therapy (second line vs third line), and anatomic site (pleural vs peritoneal), by use of an interactive voice or web system, to receive intravenous tremelimumab (10 mg/kg) or placebo every 4 weeks for 7 doses and every 12 weeks thereafter until a treatment discontinuation criterion was met. The primary endpoint was overall survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study drug. The trial is ongoing but no longer recruiting participants, and is registered with ClinicalTrials.gov, number NCT01843374. FINDINGS: Between May 17, 2013, and Dec 4, 2014, 571 patients were randomly assigned to receive tremelimumab (n=382) or placebo (n=189), of whom 569 patients received treatment (two patients in the tremelimumab group were excluded from the safety population because they did not receive treatment). At the data cutoff date (Jan 24, 2016), 307 (80%) of 382 patients had died in the tremelimumab group and 154 (81%) of 189 patients had died in the placebo group. Median overall survival in the intention-to-treat population did not differ between the treatment groups: 7·7 months (95% CI 6·8-8·9) in the tremelimumab group and 7·3 months (5·9-8·7) in the placebo group (hazard ratio 0·92 [95% CI 0·76-1·12], p=0·41). Treatment-emergent adverse events of grade 3 or worse occurred in 246 (65%) of 380 patients in the tremelimumab group and 91 (48%) of 189 patients in the placebo group; the most common were dyspnoea (34 [9%] patients in the tremelimumab group vs 27 [14%] patients in the placebo group), diarrhoea (58 [15%] vs one [<1%]), and colitis (26 [7%] vs none). The most common serious adverse events were diarrhoea (69 [18%] patients in the tremelimumab group vs one [<1%] patient in the placebo group), dyspnoea (29 [8%] vs 24 [13%]), and colitis (24 [6%] vs none). Treatment-emergent events leading to death occurred in 36 (9%) of 380 patients in the tremelimumab group and 12 (6%) of 189 in the placebo group; those leading to the death of more than one patient were mesothelioma (three [1%] patients in the tremelimumab group vs two [1%] in the placebo group), dyspnoea (three [1%] vs two [1%]); respiratory failure (one [<1%] vs three [2%]), myocardial infarction (three [1%] vs none), lung infection (three [1%] patients vs none), cardiac failure (one [<1%] vs one [<1%]), and colitis (two [<1%] vs none). Treatment-related adverse events leading to death occurred in five (1%) patients in the tremelimumab group and none in the placebo group. The causes of death were lung infection in one patient, intestinal perforation and small intestinal obstruction in one patient; colitis in two patients, and neuritis and skin ulcer in one patient. INTERPRETATION: Tremelimumab did not significantly prolong overall survival compared with placebo in patients with previously treated malignant mesothelioma. The safety profile of tremelimumab was consistent with the known safety profile of CTLA-4 inhibitors. Investigations into whether immunotherapy combination regimens can provide greater efficacy than monotherapies in malignant mesothelioma are ongoing. FUNDING: AstraZeneca.

CTLA4 blockade in mesothelioma: finally a competing strategy over cytotoxic/target therapy?

No second-line treatment significantly prolongs the survival of malignant mesothelioma patients who have a high unmet medical need. Here, we comment on the therapeutic potential of cytotoxic T-lymphocyte-associated protein (CTLA)4-blockade by the anti-CTLA4 monoclonal antibody (mAb) tremelimumab of refractory malignant mesothelioma patients. We also focus on the critical role of an accurate tumor assessment in the course of treatment with immunomodulating mAb. Finally, treatment with potentially effective, second-generation checkpoint(s) inhibiting mAb, as well future combination strategies in this deadly disease, will be discussed.

Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial.

BACKGROUND: Monoclonal antibodies to cytotoxic T-lymphocyte antigen 4 (CTLA4) have therapeutic activity in different tumour types. We aimed to investigate the efficacy, safety, and immunological activity of the anti-CTLA4 monoclonal antibody, tremelimumab, in advanced malignant mesothelioma. METHODS: In our open-label, single-arm, phase 2 study, we enrolled patients aged 18 years or older with measurable, unresectable malignant mesothelioma and progressive disease after a first-line platinum-based regimen. Eligible patients had to have a life expectancy of 3 months or more, an Eastern Cooperative Oncology Group performance status of 2 or less, and no history of autoimmune disease. Patients received tremelimumab 15 mg/kg intravenously once every 90 days until progressive disease or severe toxicity. The primary endpoint was the proportion of patients who achieved an objective response (complete or partial response), with a target response rate of 17% according to the modified Response Evaluation Criteria in Solid Tumors (RECIST) for pleural malignant mesothelioma or standard RECIST 1.0 for peritoneal malignant mesothelioma. Analyses were done according to intention to treat. This trial is registered with EudraCT, number 2008-005171-95, and ClinicalTrials.gov, number NCT01649024. FINDINGS: Between May 27, 2009, and Jan 10, 2012, we enrolled 29 patients. All patients received at least one dose of tremelimumab (median two doses, range one to nine). No patients had a complete response and two patients (7%) had a durable partial response (one lasting 6 months and one lasting 18 months); one partial response occurred after initial progressive disease. Thus, the study did not reach its primary endpoint. However, we noted disease control in nine (31%) patients and a median progression-free survival of 6·2 months (95% CI 1·3-11·1) and a median overall survival of 10·7 months (0·0-21·9). 27 patients (93%) had at least one grade 1-2 treatment-emergent adverse event (mainly cutaneous rash, pruritus, colitis, or diarrhoea), and four patients (14%) had at least one grade 3-4 treatment-emergent adverse event (two gastrointestinal, one neurological, two hepatic, and one pancreatic). INTERPRETATION: Although the effect size was small in our phase 2 trial, tremelimumab seemed to have encouraging clinical activity and an acceptable safety and tolerability profile in previously treated patients with advanced malignant mesothelioma. FUNDING: Associazione Italiana per la Ricerca sul Cancro, Istituto Toscano Tumori, Pfizer, and Fondazione Buzzi Unicem.

Nivolumab plus ipilimumab in melanoma patients with asymptomatic brain metastases: 7-year outcomes and quality of life from the multicenter phase III NIBIT-M2 trial.

BACKGROUND: The primary analysis of the phase III NIBIT-M2 study showed a 41% 4-year overall survival (OS) of melanoma patients with asymptomatic brain metastases treated with ipilimumab plus nivolumab. METHODS: Here, we report the 7-year efficacy outcomes and the Health-Related Quality of Life (HRQoL) analyses of the NIBIT-M2 study. RESULTS: As of May 1, 2023, at a median follow-up of 67 months (mo), the median OS was 8.5 (95% CI: 6.6-10.3), 8.2 (95% CI: 2.1-14.3) and 29.2 (95% CI: 0-69.9) mo for the fotemustine (F) Arm A, ipilimumab plus fotemustine Arm B, and ipilimumab plus nivolumab Arm C, respectively. The 7-year OS rate was 10.0% (95% CI: 0-22.5) in Arm A, 10.3% (95% CI: 0-22.6) in Arm B, and 42.8% (95% CI: 23.4-62.2) in Arm C. HRQoL was preserved in all treatment arms. Most functional scales evaluated from baseline to W12 were preserved, with a lower mean score decrease for EORTC Quality of Life Questionnaire (QLQ)-C30 and an increase for EORTC QLQ-Brain neoplasm (BN20) in patients receiving ipilimumab plus nivolumab. CONCLUSIONS: With the longest follow-up available to date in melanoma patients with asymptomatic brain metastases, the NIBIT-M2 study continues to show persistent therapeutic efficacy of I ipilimumab plus nivolumab while preserving HRQoL.

Long-term survival and immunological parameters in metastatic melanoma patients who responded to ipilimumab 10 mg/kg within an expanded access programme.

BACKGROUND: Ipilimumab can result in durable clinical responses among patients with advanced melanoma. However, no predictive marker of clinical activity has yet been identified. We provide preliminary data describing the correlation between immunological parameters and response/survival among patients with advanced melanoma who received ipilimumab 10 mg/kg in an expanded access programme. METHODS: Patients received ipilimumab 10 mg/kg every 3 weeks (Q3W) for four doses (induction) and Q12W from week 24 (W24) as maintenance therapy. Tumor assessments were conducted Q12W. Expression of inducible T cell costimulator (ICOS) on CD4(+) and CD8(+) T cells was assessed at baseline, W7, W12 and W24, and the ratio between absolute neutrophils (N) and lymphocytes (L) determined at baseline, W4, W7 and W10. RESULTS: Median overall survival among 27 patients was 9.6 months (95 % CI 3.2-16.1), with 3- and 4-year survival rates of 20.4 %. Five patients survived >4 years. Patients with an increase in the number of circulating ICOS(+) T cells at W7 were more likely to experience disease control and have improved survival. An N/L ratio below the median at W7 and W10 was also associated with better survival compared with an N/L ratio above the median. CONCLUSIONS: Ipilimumab can induce long-term survival benefits in heavily pretreated patients with metastatic melanoma. Changes in the number of circulating ICOS(+) T cells or N/L ratio during ipilimumab treatment may represent early markers of response. However, given the limited sample size, further investigation is required.

Future perspectives in melanoma research. Meeting report from the "Melanoma Bridge. Napoli, December 2nd-4th 2012".

Recent insights into the genetic and somatic aberrations have initiated a new era of rapidly evolving targeted and immune-based treatments for melanoma. After decades of unsuccessful attempts to finding a more effective cure in the treatment of melanoma now we have several drugs active in melanoma. The possibility to use these drugs in combination to improve responses to overcome the resistance, to potentiate the action of immune system with the new immunomodulating antibodies, and identification of biomarkers that can predict the response to a particular therapy represent new concepts and approaches in the clinical management of melanoma. The third "Melanoma Research: "A bridge from Naples to the World" meeting, shortened as "Bridge Melanoma Meeting" took place in Naples, December 2 to 4th, 2012. The four topics of discussion at this meeting were: advances in molecular profiling and novel biomarkers, combination therapies, novel concepts toward integrating biomarkers and therapies into contemporary clinical management of patients with melanoma across the entire spectrum of disease stage, and the knowledge gained from the biology of tumor microenvironment across different tumors as a bridge to impact on prognosis and response to therapy in melanoma. This international congress gathered more than 30 international faculty members who in an interactive atmosphere which stimulated discussion and exchange of their experience regarding the most recent advances in research and clinical management of melanoma patients.

The prognostic effects of circulating myeloid-derived suppressor cells in non-small cell lung cancer: systematic review and meta-analysis.

Immunotherapy is the main standard treatment for non-small cell lung cancer (NSCLC) patients. Immune suppressive cells in tumor microenvironment can counteract its efficacy. Myeloid-derived suppressor cells (MDSCs) include two major subsets: polymorphonuclear (PMN-MDSCs) and monocytic (M-MDSCs). Many studies explored the prognostic impact of these cell populations in NSCLC patients. The aim of this systematic review is to select studies for a meta-analysis, which compares prognosis between patients with high vs low circulating MDSC levels. We collected hazard ratios (HRs) and relative 95% confidence intervals (CIs) in terms of progression-free survival (PFS) or recurrence-free survival (RFS), and overall survival (OS). Among 139 studies retrieved from literature search, 14 eligible studies (905 NSCLC patients) met inclusion criteria. Low circulating MDSC levels favor a better PFS/RFS (HR = 1.84; 95% CI = 1.28-2.65) and OS (HR = 1.78; 95% CI = 1.29-2.46). The subgroup analysis based on MDSC subtypes (total-, PMN-, and M-MDSCs) obtained a statistical significance only for M-MDSCs, both in terms of PFS/RFS (HR = 2.67; 95% CI = 2.04-3.50) and OS (HR = 2.10; 95% CI = 1.61-2.75). NSCLC patients bearing high M-MDSC levels in peripheral blood experience a worse prognosis than those with low levels, both in terms of PFS/RFS and OS. This finding suggests that detecting and targeting this MDSC subset could help to improve NSCLC treatment efficacy.

Immune Checkpoint Inhibitors-Associated Myocarditis: Diagnosis, Treatment and Current Status on Rechallenge.

Immune checkpoint molecules like cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death 1 (PD-1) or its ligand, programmed cell death ligand 1 (PD-L1), play a critical role in regulating the immune response, and immune checkpoint inhibitors (ICIs) targeting these checkpoints have shown clinical efficacy in cancer treatment; however, their use is associated with immune-related adverse events (irAEs), including cardiac complications. The prevalence of cardiac irAEs, particularly myocarditis, is relatively low, but they can become a severe and potentially life-threatening condition, usually occurring shortly after initiating ICI treatment; moreover, diagnosing ICI-related myocarditis can be challenging. Diagnostic tools include serum cardiac biomarkers, electrocardiography (ECG), echocardiography, cardiac magnetic resonance (CMR) and endomyocardial biopsy (EMB). The treatment of ICI-induced myocarditis involves high-dose corticosteroids, which have been shown to reduce the risk of major adverse cardiac events (MACE). In refractory cases, second-line immunosuppressive drugs may be considered, although their effectiveness is based on limited data. The mortality rates of ICI-induced myocarditis, particularly in severe cases, are high (38-46%). Therapy rechallenge after myocarditis is associated with a risk of recurrence and severe complications. The decision to rechallenge should be made on a case-by-case basis, involving a multidisciplinary team of cardiologists and oncologists. Further research and guidance are needed to optimize the management of cancer patients who have experienced such complications, evaluating the risks and benefits of therapy rechallenge. The purpose of this review is to summarize the available evidence on cardiovascular complications from ICI therapy, with a particular focus on myocarditis and, specifically, the rechallenge of immunotherapy after a cardiac adverse event.

Immunotherapy of mesothelioma: the evolving change of a long-standing therapeutic dream.

Pleural mesothelioma (PM) is an aggressive and rare disease, characterized by a very poor prognosis. For almost two decades, the world standard treatment regimen for unresectable PM has consisted of a platinum-based drug plus pemetrexed, leading to an overall survival of approximately 12 months. The dramatic therapeutic scenario of PM has recently changed with the entry into the clinic of immune checkpoint inhibition, which has proven to be an effective approach to improve the survival of PM patients. The aim of the present review is to provide a comprehensive overview of the most promising immunotherapeutic-based strategies currently under investigation for advanced PM.

Ipilimumab in pretreated patients with metastatic uveal melanoma: safety and clinical efficacy.

Current systemic treatments for metastatic uveal melanoma (UM) have not improved overall survival (OS). The fully human anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) monoclonal antibody, ipilimumab, improved OS of patients with advanced cutaneous melanoma in a phase 3 trial; however, UM patients were excluded. The aim of this subanalysis, performed by the ipilimumab-ocular melanoma expanded access program (I-OMEAP) study group, was to assess the activity and safety of ipilimumab in patients with UM in a setting similar to daily clinical practice. Patients participating in a multicenter expanded access program (EAP) received induction treatment with ipilimumab 10 mg/kg. Maintenance doses were administered in patients who experienced clinical benefit or at physicians' discretion. Tumor assessment was evaluated per modified World Health Organization criteria at baseline, Week 12, Week 24, and Week 36. Adverse events (AEs) and immune-related AEs (irAEs) were collected according to Common Terminology Criteria for Adverse Events version 3.0. Thirteen pretreated patients with metastatic UM were treated at 6 European institutions. All patients received at least one dose of ipilimumab. Overall, no objective responses were observed; however, two patients had stable disease (SD), with a third patient achieving SD after initial progressive disease. Median OS as of July 1, 2011, was 36 weeks (range 2-172+ weeks). No grade 3/4 AEs of non-immune origin were reported. Three patients (23%) experienced grade 3 irAEs (1 thrombocytopenia, 1 diarrhea, and 1 alanine/aspartate aminotransferase elevation) that resolved with steroid therapy. The results indicate UM is a potential indication for ipilimumab treatment that should be further investigated in clinical trials.