Patterns of progression in patients treated for immuno-oncology antibodies combination.

BACKGROUND: New patterns of progression under immune-oncology (IO) antibodies (mAb) have been described such as pseudoprogression. Except for melanoma, variations between studies reveal difficulties to establish their prevalence. METHODS: This retrospective study enrolled patients participating in IO phase I trials at Gustave Roussy cancer center for solid tumors excluding melanoma. Radiological assessment according to iRECIST was correlated with prospectively registered patient characteristics and outcomes. Pseudoprogression (PsPD) was defined as RECIST-defined progression followed by stabilization or decrease at the next imaging, and dissociated response (DisR) as concomitant decrease in some tumor lesions and increase in others at a same timepoint. RESULTS: Among 360 patients included, 74% received IO mAb combination: 45% with another IO mAb, 20% with targeted therapy and 10% with radiotherapy. The overall response rate was 19.7%. PsPD were observed in 10 (2.8%) patients and DisR in 12 (3.3%) patients. Atypical responses (AR), including PsPD and DisR, were not associated with any patient's baseline characteristics. Compare with typical responder patients, patients experiencing AR presented a shorter iPFS (HR 0.34; p < 0.001) and OS (HR 0.27; p = 0.026). Among the 203 patients who progressed in 12 weeks, 80 (39.4%) patients were treated beyond progression. PD was confirmed in 80% of cases, while 10% of patients presented a response. CONCLUSION: Pseudoprogression and dissociated response are uncommon patterns of progression. Their prevalence should be balanced with the rate of real progressing patients treated beyond progression. Prognosis or on-treatment biomarkers are needed to identify early patients who will benefit from immunotherapy.

Cytokines in clinical cancer immunotherapy.

Cytokines are soluble proteins that mediate cell-to-cell communication. Based on the discovery of the potent anti-tumour activities of several pro-inflammatory cytokines in animal models, clinical research led to the approval of recombinant interferon-alpha and interleukin-2 for the treatment of several malignancies, even if efficacy was only modest. These early milestones in immunotherapy have been followed by the recent addition to clinical practice of antibodies that inhibit immune checkpoints, as well as chimeric antigen receptor T cells. A renewed interest in the anti-tumour properties of cytokines has led to an exponential increase in the number of clinical trials that explore the safety and efficacy of cytokine-based drugs, not only as single agents, but also in combination with other immunomodulatory drugs. These second-generation drugs under clinical development include known molecules with novel mechanisms of action, new targets, and fusion proteins that increase half-life and target cytokine activity to the tumour microenvironment or to the desired effector immune cells. In addition, the detrimental activity of immunosuppressive cytokines can be blocked by antagonistic antibodies, small molecules, cytokine traps or siRNAs. In this review, we provide an overview of the novel trends in the cytokine immunotherapy field that are yielding therapeutic agents for clinical trials.

Clinical features and short-term outcomes of cancer patients with suspected and unsuspected pulmonary embolism: the EPIPHANY study.

The study aimed to identify predictors of overall 30-day mortality in cancer patients with pulmonary embolism including suspected pulmonary embolism (SPE) and unsuspected pulmonary embolism (UPE) events. Secondary outcomes included 30- and 90-day major bleeding and venous thromboembolism (VTE) recurrence.The study cohort included 1033 consecutive patients with pulmonary embolism from the multicentre observational ambispective EPIPHANY study (March 2006-October 2014). A subgroup of 497 patients prospectively assessed for the study were subclassified into three work-up scenarios (SPE, truly asymptomatic UPE and UPE with symptoms) to assess outcomes.The overall 30-day mortality rate was 14%. The following variables were associated with the overall 30-day mortality on multivariate analysis: VTE history, upper gastrointestinal cancers, metastatic disease, cancer progression, performance status, arterial hypotension <100 mmHg, heart rate >110 beats·min-1, basal oxygen saturation <90% and SPE (versus overall UPE).The overall 30-day mortality was significantly lower in patients with truly asymptomatic UPE events (3%) compared with those with UPE-S (20%) and SPE (21%) (p<0.0001). Thirty- and 90-day VTE recurrence and major bleeding rates were similar in all the groups.In conclusion, variables associated with the severity of cancer and pulmonary embolism were associated with short-term mortality. Our findings may help to develop pulmonary embolism risk-assessment models in this setting.

Prognostic significance of performing universal HER2 testing in cases of advanced gastric cancer.

BACKGROUND: Trastuzumab significantly improves overall survival (OS) when added to cisplatin and fluoropyrimidine as a treatment for HER2-positive advanced gastric cancers (AGC). The aim of this study was to evaluate the impact of the gradual implementation of HER2 testing on patient prognosis in a national registry of AGC. METHODS: This Spanish National Cancer Registry includes cases who were consecutively recruited at 28 centers from January 2008 to January 2016. The effect of missing HER2 status was assessed using stratified Cox proportional hazards (PH) regression. RESULTS: The rate of HER2 testing increased steadily over time, from 58.3 % in 2008 to 92.9 % in 2016. HER2 was positive in 194 tumors (21.3 %). In the stratified Cox PH regression, each 1 % increase in patients who were not tested for HER2 at the institutions was associated with an approximately 0.3 % increase in the risk of death: hazard ratio, 1.0035 (CI 95 %, 1.001-1.005), P = 0.0019. Median OS was significantly lower at institutions with the highest proportions of patients who were not tested for HER2. CONCLUSION: Patients treated at centers that took longer to implement HER2 testing exhibited worse clinical outcomes. The speed of implementation behaves as a quality-of-care indicator. Reviewed guidelines on HER2 testing should be used to achieve this goal in a timely manner.

A nomogram for predicting complications in patients with solid tumours and seemingly stable febrile neutropenia.

BACKGROUND: We sought to develop and externally validate a nomogram and web-based calculator to individually predict the development of serious complications in seemingly stable adult patients with solid tumours and episodes of febrile neutropenia (FN). PATIENTS AND METHODS: The data from the FINITE study (n=1133) and University of Salamanca Hospital (USH) FN registry (n=296) were used to develop and validate this tool. The main eligibility criterion was the presence of apparent clinical stability, defined as events without acute organ dysfunction, abnormal vital signs, or major infections. Discriminatory ability was measured as the concordance index and stratification into risk groups. RESULTS: The rate of infection-related complications in the FINITE and USH series was 13.4% and 18.6%, respectively. The nomogram used the following covariates: Eastern Cooperative Group (ECOG) Performance Status ⩾2, chronic obstructive pulmonary disease, chronic cardiovascular disease, mucositis of grade ⩾2 (National Cancer Institute Common Toxicity Criteria), monocytes <200/mm(3), and stress-induced hyperglycaemia. The nomogram predictions appeared to be well calibrated in both data sets (Hosmer-Lemeshow test, P>0.1). The concordance index was 0.855 and 0.831 in each series. Risk group stratification revealed a significant distinction in the proportion of complications. With a ⩾116-point cutoff, the nomogram yielded the following prognostic indices in the USH registry validation series: 66% sensitivity, 83% specificity, 3.88 positive likelihood ratio, 48% positive predictive value, and 91% negative predictive value. CONCLUSIONS: We have developed and externally validated a nomogram and web calculator to predict serious complications that can potentially impact decision-making in patients with seemingly stable FN.

Impact of epidermal growth factor receptor (EGFR) activating mutations and their targeted treatment in the prognosis of stage IV non-small cell lung cancer (NSCLC) patients harboring liver metastasis.

OBJECTIVES: Liver metastases appear in 20-30% of patients diagnosed with non-small cell lung cancer (NSCLC) and represent a poor prognosis feature of NSCLC and a possibly more treatment-resistant condition. Potential clinical outcome differences in NSCLC patients with liver metastases harboring molecular alterations in EGFR, KRAS and EML4-ALK genes are still to be determined. This study aims to evaluate the incidence of liver metastasis in a single population and look for potential correlations between EGFR mutations, liver infiltration and clinical outcomes. METHODS: A total of 236 consecutive stage IV NSCLC patients treated at the Clínica Universidad de Navarra were analyzed. RESULTS: At onset, liver metastases were present in 16.9% of patients conferring them a shorter overall survival (OS) compared to those with different metastatic locations excluding liver infiltration (10 vs. 21 months; p = 0.001). Patients with EGFR wild-type tumors receiving standard chemotherapy and showing no liver involvement presented a superior median OS compared to those with liver metastases (23 vs. 13 months; p = 0.001). Conversely, patients with EGFR-mutated tumors treated with EGFR tyrosin-kinase inhibitors (TKI's) presented no significant differences in OS regardless of liver involvement (median OS not reached vs. 25 months; p = 0.81). CONCLUSION: Overall, liver metastases at onset negatively impact OS of NSCLC patients. EGFR TKIs however, may reverse the effects of an initial negative prognosis of liver metastasis in first-line treatment of EGFR mutated NSCLC patients.

Thymidylate synthase polymorphisms in genomic DNA as clinical outcome predictors in a European population of advanced non-small cell lung cancer patients receiving pemetrexed.

BACKGROUND: We studied whether thymidylate synthase (TS) genotype has an independent prognostic/predictive impact on a European population of advanced non-small cell lung cancer (NSCLC) patients receiving pemetrexed. METHODS: Twenty-five patients treated with pemetrexed-based regimens were included. Genomic DNA was isolated prior to treatment. The variable number of tandem repeat (VNTR) polymorphisms, the G > C single nucleotide polymorphisms (SNP) and the TS 6-bp insertion/deletion (6/6) in the 3' untranslated region (UTR) polymorphisms were analyzed and correlated with overall response rate (ORR), progression-free survival (PFS), overall-survival (OS) and toxicity. RESULTS: The genotype +6/+6 predicted a higher ORR among active/former smokers compared to +6/-6 genotype (100% vs. 50%; p = 0.085). Overall, the 3R/3R genotype predicted a higher ORR (100%) over the rest VNTR polymorphisms (p = 0.055). The presence of 3R/3R genotype significantly correlated with a superior ORR in patients without EGFR activating mutations (100%) compared to 2R/2R, 2R/3R and 3R/4R genotype (77.8%, 33.3% and 0% respectively; p = 0.017). After a median follow-up of 21 months, a trend towards a better PFS, although not significant, was found among subjects showing 3R/3R polymorphisms (p = 0.089). A significantly superior OS was found in patients showing 3R/3R genotype rather than other VNTR polymorphisms (p = 0.019). No significant correlation with the toxicity was observed. CONCLUSION: In our series, 3R/3R polymorphism correlated with a superior OS. Also, this polymorphism, when associated to wild type EGFR, was related to a higher ORR to pemetrexed. Toxicity was not significantly correlated with a specific TS genotype.

Id1 and Id3 co-expression correlates with clinical outcome in stage III-N2 non-small cell lung cancer patients treated with definitive chemoradiotherapy.

BACKGROUND: Inhibitor of DNA binding 1 (Id1) and 3 (Id3) genes have been related with the inhibition of cell differentiation, cell growth promotion and tumor metastasis. Recently, Id1 has been identified as an independent prognostic factor in patients with lung adenocarcinoma, regardless of the stage. Furthermore, Id1 may confer resistance to treatment (both, radiotherapy and chemotherapy). METHODS: We have studied, using monoclonal antibodies for immunohistochemistry, the Id1 and Id3 tumor epithelial expression in 17 patients with stage III-N2 non-small cell lung cancer (NSCLC) treated with definitive chemoradiotherapy. RESULTS: Id1 expression is observed in 82.4% of the tumors, whereas Id3 expression is present in 41.2% of the samples. Interestingly, Id1 and Id3 expression are mutually correlated (R = 0.579, p = 0.015). In a subgroup analysis of patients with the most locally advanced disease (T4N2 stage), co-expression of Id1 and Id3 showed to be related with a worse overall survival (45 vs 6 months, p = 0.002). A trend towards significance for a worse progression free survival (30 vs 1 months, p = 0.219) and a lower response rate to the treatment (RR = 50% vs 87.5%, p = 0.07) were also observed. CONCLUSIONS: A correlation between Id1 and Id3 protein expression is observed. Id1 and Id3 co-expression seems associated with a poor clinical outcome in patients with locally advanced NSCLC treated with definitive chemoradiotherapy.

Neurological and cytological response as potential early predictors of time-to-progression and overall survival in patients with leptomeningeal carcinomatosis treated with intrathecal liposomal cytarabine: a retrospective cohort study.

Interesting neurological and cytological response rates after intrathecal (i.t) liposomal cytarabine have been observed in patients with leptomeningeal carcinomatosis (LMC) from solid tumors. However, the potential use of those responses as early predictors of time-to-progression (TTP) and overall survival (OS) is unexplored. 27 consecutive patients with LMC treated with 50 mg i.t liposomal cytarabine under compassionate drug use were retrospectively studied. All patients received i.t treatment every 2 weeks during induction and every 4 weeks during maintenance periods. Neurological and cytological responses were assessed before every liposomal cytarabine cycle. Most of the patients were female (17/27) diagnosed with breast cancer (15/27). A complete neurological response was seen among 11 % of the patients; partial response in 22 % of the patients; stable disease in 30 % of the patients and progressive disease in 37 % of them. Cytological assessment was available in 11/27 patients showing a 26 % complete response rate. The median time to neurological and cytological response was 15 days and 14 days, respectively. Patients showing a combined neurological and cytological response showed a significantly longer median TTP (122 vs. 3 days; p = 0.001) and OS (141 vs. 3 days; p = 0.002) compared to those showing both neurological and cytological progression. No grade 4 toxicities were recorded. According to these preliminary results, early neurological and cytological responses may be further studied as early predictors of TTP and OS in patients receiving i.t liposomal cytarabine for LMC.

Bayesian interpretation of immunotherapy trials with dynamic treatment effects.

INTRODUCTION: The mechanism of action of immune checkpoints inhibitors hinders the writing of rational statistical analysis plans for phase III randomised clinical trials (RCTs) because of their unpredictable dynamic effects. The purpose is to illustrate the advantages of Bayesian reporting of treatment efficacy analysis in immunotherapy RCTs, in contrast to frequentist reporting. METHOD: Fourteen RCTs (one with two pairwise comparisons) that failed to achieve their primary objective (overall survival, OS) were selected. These RCTs were reanalysed using Bayesian Cox models with dynamic covariate coefficients and time-invariant models. RESULTS: The RCTs that met inclusion criteria were 7 lung cancer trials, various other tumours, with antiPD1, antiPDL1 or antiCTLA4 therapies. The minimum detectable effect (δS) was superior to the true benefit observed in all cases, in conditions of non-proportional hazards. Schoenfeld tests indicated the existence of PH assumption violations (p<0.05) in 6/15 cases. The Bayesian Cox models revealed a probability of benefit >79% in all the RCTs, with the therapeutic equivalence hypothesis unlikely. The OS curves diverged after a median of 9.1 months. Since the divergency, no non-proportionality was evinced in 13/15, while the Wald tests achieved p<0.05 in 12/15 datasets. In all cases, the Bayesian Cox models with dynamic coefficients detected fluctuations of the hazard ratio, and increased 2-year OS was the most likely hypothesis. CONCLUSION: We recommend progressively implementing Bayesian and dynamic analyses in all RCTs of immunotherapy to interpret and assess the credibility of frequentist results.

Novel strategies exploiting interleukin-12 in cancer immunotherapy.

Interleukin-12 is considered a potent agent to enhance antitumor immune responses. It belongs to a family of heterodimeric cytokines with key roles in the up-regulation and down-regulation of cellular immunity. Since its discovery, recombinant IL-12 was found to exert potent antitumor effects in rodent tumor models and was rapidly tested in the clinic with an unfavorable benefit/toxicity profile. Localized delivery of IL-12 dramatically improves the therapeutic index and this approach is being applied in the clinic based on in-vivo electroporation of naked plasmid DNA encoding IL-12, mRNA formulations, viral vectors and tumor-targeted fusion proteins. Other biotechnology strategies such as IL-12-engineered local adoptive cell therapy and pro-cytokines can also be used to improve results and broaden the therapeutic window. Combination strategies of such localized IL-12-based approaches with checkpoint inhibitors are yielding promising results both preclinically and in the early-phase clinical trials.

Intratumoural administration and tumour tissue targeting of cancer immunotherapies.

Immune-checkpoint inhibitors and chimeric antigen receptor (CAR) T cells are revolutionizing oncology and haematology practice. With these and other immunotherapies, however, systemic biodistribution raises safety issues, potentially requiring the use of suboptimal doses or even precluding their clinical development. Delivering or attracting immune cells or immunomodulatory factors directly to the tumour and/or draining lymph nodes might overcome these problems. Hence, intratumoural delivery and tumour tissue-targeted compounds are attractive options to increase the in situ bioavailability and, thus, the efficacy of immunotherapies. In mouse models, intratumoural administration of immunostimulatory monoclonal antibodies, pattern recognition receptor agonists, genetically engineered viruses, bacteria, cytokines or immune cells can exert powerful effects not only against the injected tumours but also often against uninjected lesions (abscopal or anenestic effects). Alternatively, or additionally, biotechnology strategies are being used to achieve higher functional concentrations of immune mediators in tumour tissues, either by targeting locally overexpressed moieties or engineering 'unmaskable' agents to be activated by elements enriched within tumour tissues. Clinical trials evaluating these strategies are ongoing, but their development faces issues relating to the administration methodology, pharmacokinetic parameters, pharmacodynamic end points, and immunobiological and clinical response assessments. Herein, we discuss these approaches in the context of their historical development and describe the current landscape of intratumoural or tumour tissue-targeted immunotherapies.

Paradigms on Immunotherapy Combinations with Chemotherapy.

Checkpoint inhibitors are being added to standard-of-care chemotherapy in multiple clinical trials. Success has been reported in non-small and small cell lung carcinomas and urothelial, head and neck, gastric, and esophageal cancers, and promising results are already available in triple-negative breast and pancreatic malignancies. The potential mechanisms of synergy include immunogenic tumor cell death, antiangiogenesis, selective depletion of myeloid immunosuppressive cells, and lymphopenia, which reduces regulatory T cells and makes room for proliferation of effector T cells. However, chemotherapy regimens have not been optimized for such combinations, perhaps explaining some recent clinical trial disappointments. Approaches to make the most of chemoimmunotherapy include neoadjuvant and adjuvant schemes.Significance: Immunotherapy of cancer based on PD-1/PD-L1 blockade has prompted a revolution in cancer clinical management. Evidence in phase III clinical trials already supports combinations of immunotherapy with standard-of-care chemotherapy for a number of malignant diseases. This review focuses on such evidence and provides an overview of the potential synergistic mechanisms of action and the opportunities to optimize chemoimmunotherapy regimens.

Association of the Lung Immune Prognostic Index with Immunotherapy Outcomes in Mismatch Repair Deficient Tumors.

Background: MSI-H/dMMR is considered the first predictive marker of efficacy for immune checkpoint inhibitors (ICIs). However, around 39% of cases are refractory and additional biomarkers are needed. We explored the prognostic value of pretreatment LIPI in MSI-H/dMMR patients treated with ICIs, including identification of fast-progressors. Methods: A multicenter retrospective study of patients with metastatic MSI-H/dMMR tumors treated with ICIs between April 2014 and May 2019 was performed. LIPI was calculated based on dNLR > 3 and LDH > upper limit of normal. LIPI groups were good (zero factors), intermediate (one factor) and poor (two factors). The primary endpoint was overall survival (OS), including the fast-progressor rate (OS < 3 months). Results: A total of 151 patients were analyzed, mainly female (59%), with median age 64 years, performance status (PS) 0 (42%), and sporadic dMMR status (68%). ICIs were administered as first or second-line for 59%. The most frequent tumor types were gastrointestinal (66%) and gynecologic (22%). LIPI groups were good (47%), intermediate (43%), and poor (10%). The median follow-up was 32 months. One-year OS rates were 81.0%, 67.1%, and 21.4% for good, intermediate, and poor-risk groups (p < 0.0001). After adjustment for tumor site, metastatic sites and PS, LIPI remained independently associated with OS (HR, poor-LIPI: 3.50, 95%CI: 1.46-8.40, p = 0.02. Overall, the fast-progressor rate was 16.0%, and 35.7% with poor-LIPI vs. 7.5% in the good-LIPI group (p = 0.02). Conclusions: LIPI identifies dMMR patients who do not benefit from ICI treatment, particularly fast-progressors. LIPI should be included as a stratification factor for future trials.

Critical reappraisal of phase III trials with immune checkpoint inhibitors in non-proportional hazards settings.

BACKGROUND: The dynamic effects of immune checkpoint inhibitors (ICIs) are a challenge when designing and analysing data in non-proportional hazards (PH) scenarios. Herein, we present the risk of making type II errors, affecting pharmacotherapeutic development when methods that assume constant effects are applied. PATIENTS AND METHODS: Individual patient data from six clinical trials (KEYNOTE-062/061, IMvigor211, CA184-143 y CheckMate-057/037) were extracted. The most relevant time-varying effects were examined using the Royston-Parmar spline model (RPSM), time-driven analyses and weighted log-rank and Renyi tests. RESULTS: The RPSM yields an appropriate fit in non-PH contexts, enabling dynamic descriptions of the hazard rate, and time-varying differences of overall survival (OS)/progression-free survival. In the KEYNOTE-061, CheckMate-057 and 037 trials, 12-, 18-, and 24-month OS rates were higher with immunotherapy (differences of some 10%) (P-value <0.05). In KEYNOTE-062, CA184-043 and IMvigor-211 trials, OS rate differences were significant for past 20 months. Flemming-Harrington and Renyi tests with late weighting (e.g. with ρ-value = 0 and γ-value = 1) captured the existence of significant differences on all curves. The Cox models and log-rank tests were inefficient at detecting the effect. CONCLUSION: This analysis highlights the risk of declaring studies with ICIs negative, despite associating substantial OS benefits. Effort and consensus are needed with respect to methodology to design and evaluate trials with ICIs in non-PH settings.

Does active smoking worsen Covid-19?

Probably it does.