Second-line therapy in pancreatic ductal adenocarcinoma (PDAC) patients with germline BRCA1-2 pathogenic variants (gBRCA1-2pv).

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) harbouring germline BRCA1-2 pathogenic variants (gBRCA1-2pv) is a distinct nosological entity. Information on second-line therapy (2LT) outcome in this setting is lacking. METHODS: Data of gBRCA1-2pv metastatic PDAC patients treated with chemotherapy were collected. A primary analysis of 2LT RECIST response, median progression-free survival (mPFS2) and overall survival (mOS2), was performed. A secondary analysis addressed the impact of timing of platinum introduction on the outcome of patients receiving at least a first-line combination chemotherapy (1LT). RESULTS: Eighty-four gBRCA1-2pv metastatic PDAC patients were enrolled. The primary analysis, including 43 patients, highlighted a significant improvement of mPFS2 and a doubled response rate, in the platinum-based 2LT subgroup as compared to the platinum-free (8.8 versus 3.7 months, p = 0.013). Seventy-seven patients were included in the secondary analysis. Median PFS1 of 3- and 4-drug platinum-based 1LT significantly outperformed both platinum-free combinations and platinum-based doublets (11.4 versus 6.4 versus 7.9 months, p = 0.01). Albeit still immature, data on mOS paralleled those on mPFS. CONCLUSIONS: This study highlighted the beneficial role of platinum agents in gBRCA1-2pv PDAC patients also in second-line treatment setting. However, our data suggest that early use of 3- and 4-drug platinum-based chemotherapy combinations provides a survival outcome advantage.

Cyclophosphamide maintenance to extend combination chemotherapy-free interval in metastatic pancreatic ductal adenocarcinoma.

BACKGROUND: Administering chemotherapy until progression to metastatic pancreatic ductal adenocarcinoma (PDAC) patients lacks of supporting evidence and causes cumulative toxicity. We explored the role of cyclophosphamide as maintenance therapy. METHODS: PDAC germline BRCA1-2 wild-type patients who were progression-free after ≥6 months of any regimen and line of chemotherapy and received maintenance cyclophosphamide (mCTX) (50 mg/day), were included in the analysis. RESULTS: 42 patients were included in the analysis. Thirty-nine patients had progression of disease. Median PFS was 3.5 (range 1.0-31+) months. PFS rates at 6 and 12 months were 26.2% and 11.9%. At a median follow-up of 20.0 months (range 12.1-31.0 months), 20 patients died and 22 are alive. Median OS was 20.0 months (range 2.2-31.0+). OS at 6 and 12 months was 97.6% (95%CI: 93.4-100), and 73.8% (95% CI: 61.1-86.5), respectively. Only 2 patients receiving mCTX had Grade 3 toxicity. CONCLUSIONS: mCTX therapy yielded promising PFS and OS outcome in PDAC patients who were progression-free after induction chemotherapy, with unremarkable toxicity. Accordingly, this approach warrants further investigation.

Exploring external validity of chemotherapy for pancreatic ductal adenocarcinoma in real life.

INTRODUCTION: Cisplatin, nab-paclitaxel, capecitabine, and gemcitabine (PAXG) regimen activity was assessed in a single institution phase II trial (PACT-19) on pancreatic ductal adenocarcinoma (PDAC). The PACT-31 study explored the external validity of PACT-19 results. MATERIALS AND METHODS: Patients aged ≥18 and ≤75 years with KPS ≥70, and PDAC diagnosis receiving PAXG in the participating institutions were eligible and categorized as follows: A) PACT-19; B) PACT-31-HSR; C) PACT-31-non-HSR. With a sample of 175 patients, assuming a target 1-year overall survival of 60 % for metastatic and of 80 % for non-metastatic patients, the trial will be considered successful with the 1-year OS falling into the 95 % CI. RESULTS: Data from 68 PACT-19 and 168 PACT-31 patients were retrieved. After 124 events, 1yOS was 52.5 % (95 %CI: 44.6-60.4 %) for metastatic and 80.5 % (95 %CI: 71.9-89.1 %) for non-metastatic patients. Survival overlapped between PACT-19 and PACT-31-HSR (median 17.6 and 17.4 months, p = 0.21) and was significantly shorter in PACT-31-non-HSR (median 11.3 months; p = 0.03). Differences of dose-intensity, use of maintenance therapy, and treatment after progression between PACT-31-HSR and non-HSR were evidenced. DISCUSSION: PACT-19 results have external validity. The outcome difference between HSR and non-HSR centers endorses the need of creating a hub-and-spoke network aimed at sharing the expertise on rare-diseases.

Hypofractionated radiotherapy concomitant to capecitabine after induction chemotherapy for advanced pancreatic adenocarcinoma.

Background and purpose: To assess feasibility, toxicity and outcome of moderately hypofractionated radiotherapy concomitant to capecitabine after induction chemotherapy for advanced pancreatic cancer. Materials and methods: Patients with advanced pancreatic cancer without distant progression after induction chemotherapy (CHT) were considered. Radiochemotherapy (RCT) consisted of 44.25 Gy in 15 fractions to the tumor and involved lymph-nodes concomitant to capecitabine 1250 mg/m2/day. Feasibility and toxicity were evaluated in all pts. Overall survival (OS), progression free survival (PFS), distant PFS (DPFS) and local PFS (LPFS) were assessed only in stage III patients. Results: 254 patients, 220 stage III, 34 stage IV, were treated. Median follow up was 19 months. Induction CHT consisted of Gemcitabine (35 patients), or drug combination (219 patients); median duration was 6 months.Four patients (1.6 %) did not complete RT (1 early progression, 3 toxicity), median duration of RT was 20 days, 209 patients (82 %) received ≥ 75 % of capecitabine dose.During RCT G3 gastrointestinal toxicity occurred in 3.2% of patients, G3-G4 hematologic toxicity in 5.4% of patients. Subsequently, G3, G4, G5 gastric or duodenal lesions occurred in 10 (4%), 2 (0.8%) and 1 patients (0.4%), respectively.Median PFS, LPFS, and DPFS were 11.9 months (95 % CI:11.4-13), 16 months (95 % CI:14.2-17.3) and 14.0 months (95 % CI:12.6-146.5), respectively.Median OS was 19.5 months (95 % CL:18.1-21.3). One- and two-year survival were 85.2 % and 36 %, respectively. Conclusions: The present schedule of hypofractionated RT after induction CHT is feasible with acceptable toxicity rate and provides an outcome comparable with that achievable with standard doses and fractionation.

Clinical outcomes and response to chemotherapy in a cohort of pancreatic cancer patients with germline variants of unknown significance (VUS) in BRCA1 and BRCA2 genes.

PURPOSE: The clinical outcome and the efficacy of chemotherapy in pancreatic cancer patients with BRCA1/2 Variants of Unknown Significance (VUS) is unknown. We explored the effects of chemotherapy with or without Platinum in non metastatic and metastatic pancreatic cancer patients with BRCA1/2 VUS. METHODS: A retrospective analysis of non-metastatic or metastatic pancreatic cancer patients with gBRCA1/2 VUS treated in 13 Italian centers between November 2015 and December 2020 was performed. All patients were assessed for toxicity and RECIST 1.1 response. Metastatic patients were evaluated for survival outcome. RESULTS: 30 pancreatic cancer patients with gBRCA1/2 VUS were considered: 20 were M+ and 10 were non-M+. Pl-CT was recommended to 16 patients: 10 M+ (6 FOLFIRINOX and 4 PAXG) and 6 non-M+ (3 FOLFIRINOX and 3 PAXG); 11 patients received Nabpaclitaxel-Gemcitabine (AG; 8 M+) and 3 patients (2 M+) were treated with Gemcitabine (G). The RECIST 1.1 response rate was 27% for AG and 44% for Pl-CT (22% for (m) FOLFIRINOX and 71% PAXG). 1 year Progression-Free Survival was 37.5% for patients treated with AG and 33% in the Pl-CT subgroup. Median Overall Survival (OS) was 23.5 months for patients treated with AG and 14 months for the Pl-CT subgroup. 1 Year and 2 Year OS were numerically better for AG (1 Year OS: 75% vs 60% and 2 Year OS: 50% and 20% in AG and Pl-CT subgroups, respectively) as well. CONCLUSIONS: Pl-CT does not seem to be associated with a better outcome compared to AG chemotherapy in PDAC patients with BRCA 1/2 VUS.

Epidemiology and geographic distribution of BRCA1-2 and DNA Damage response genes pathogenic variants in pancreatic ductal adenocarcinoma patients.

Incidence of pancreatic ductal adenocarcinoma (PDAC) is increasing over the last years, while patients prognosis remains grim. Recently germline BRCA1 and 2 pathogenic variants (gBRCA1-2) have emerged as risk factors for PDAC development, as well as new predictors of response to specific therapeutic interventions. However, data on gBRCA1-2 incidence in PDAC are currently sparse and limited to selected categories of patients, as for positive cancer history cases, for patients affected only by early or late stages of disease and mainly from the North-American population, thus generating incomplete information about the gBRCA1/2 epidemiology. In Western Countries gBRCA1-2 incidence ranges between 4.5% and 8% in unselected PDAC patients, raising up to 26% in cohorts with positive family cancer history. To date a limited number of studies from Asian countries are available, reporting a 10% as highest incidence of gBRCA1-2 in familiar PDAC, claiming at least in part a role of ethnicity in the gBRCA1-2 incidence and in other genes potentially implicated in the therapeutic decisions. Drawing a better defined map for the incidence of gBRCA1-2 and other germline pathogenic variants of DNA Damage Response genes (gDDR) might help assessing the therapeutic strategies for mutated patients according to the geographic areas. These informations may enhance the chance to predict efficacy and toxicity of selected chemotherapy regimens, fostering the development and implementation of the pharmaco-ethnicity knowledge in the routine-clinical practice, and increasing the awareness of the potential incorrect generalization of trials results outside of the geographic area where they are conducted.

Treatment opportunities and future perspectives for pancreatic cancer patients with germline BRCA1-2 pathogenic variants.

Personalized treatments and predictive biomarkers of pancreatic cancer (PDAC) are still lacking. Recently germline mutations in BRCA 1 and 2 genes, leading to homologous repair deficiency, have emerged as new targets for more specific and effective therapies, exploiting the increased susceptibility to platinum salts and PARP inhibitors. In addition to BRCA, pathogenic variants in PALB2 and in other genes involved in the DNA damage response pathway (DDR) represent potential targets, as well as their respective somatic alterations. This enlarged molecularly-selected population sharing the BRCAness phenotype, is expected to show a higher sensibility to a number of DNA damaging agents and DDR inhibitors. However, the possibility of new therapeutic opportunities for DDR defective PDAC patients has to face the lack of solid evidence about the proper type and timing of targeted-treatments, the potential combination strategies and most importantly, the lack of informations on the functional impact of each specific pathogenic variant on the DDR pathway. This review summarizes the current and near-future options for the clinical management of PDAC patients harboring a DDR deficiency, analyzing the state of the art of the indications of platinum salts and other cytotoxic agents in the advanced and early stage PDAC, the development of PARP inhibitors and the rational for new combinations with immunotherapy and cycle checkpoint inhibitors, as well as the strategy to overcome the development of resistance over treatments.

Multidrug regimens for treatment of older patients with metastatic pancreatic cancer.

BACKGROUND AND AIMS: Older patients with metastatic pancreatic adenocarcinoma (MPDAC) are under-represented in clinical trials. METHODS: Our single-center, retrospective study enrolled MPDAC patients ≥ 70 treated with chemotherapy RESULTS: 105 patients were divided in groups based on the received treatments: 44 gemcitabine or capecitabine monotherapy (A), 34 nabpaclitaxel-gemcitabine (B) 27 4-drugs combinations (gemcitabine, cisplatin, capecitabine plus either nab-paclitaxel or epirubicin or docetaxel) (C). Group A: median age was 78 (70-87) and Karnofsky performance status (KPS) ≥80 was found in 84% of patients; Group B: median age 77 (71-84) and KPS ≥ 80 in 88% of patients; Group C: median age 73 (70-78) and KPS ≥ 80 in 93% of patients. Median OS was 7.9, 11.7 and 14.2 months in group A, B and C respectively; 1 and 2-year OS were 27% and 8% in group A; 44% and 5% in group B; 52% and 22% in group C. When lung metastatic only patients were excluded, patients <75 and ≥ 75 had similar OS in group A (6.4 vs 5.6 months) and in group B (12.3 vs 11.1 months). In group B grade 3 thrombocytopenia, fatigue and peripheral neuropathy were more frequent in patients ≥ 75. CONCLUSIONS: In older patients, combination chemotherapy shows acceptable feasibility and promising efficacy.

Pancreatic Enzyme Replacement Therapy in Patients Undergoing First-Line Gemcitabine Plus nab-paclitaxel for Advanced Pancreatic Adenocarcinoma.

BACKGROUND: The clinical consequences of pancreatic exocrine insufficiency and its treatment in advanced pancreatic ductal adenocarcinoma (PDAC) are poorly investigated. This retrospective study aims at investigating the pancreatic enzyme replacement therapy (PERT) use and its impact on survival and maldigestion-related symptoms in advanced PDAC patients undergoing chemotherapy. METHODS: A retrospective analysis was conducted on advanced PDAC patients, treated with first-line gemcitabine plus nab-paclitaxel at two academic institutions (March 2015-October 2018). Data were correlated with overall survival (OS) using Cox regression model. Kaplan-Meier curves were compared using Log-Rank test. RESULTS: Data from 110 patients were gathered. PERT was administered in 55 patients (50%). No significant differences in baseline characteristics with those who did not receive PERT were found. Median OS for the entire group was 12 months (95% CI 9-15). At multivariate analysis, previous surgical resection of the primary tumor, (HR 2.67, p=0.11), weight gain after 3 months (HR 1.68, p=0.07) and PERT (HR 2.85, p ≤ 0.001) were independent predictors of OS. Patients who received PERT reported an improvement of maldigestion-related symptoms at 3 months more frequently than patients who did not (85.2% vs 14.8%, p ≤ 0.0001). CONCLUSION: PERT is associated with significantly prolonged survival and maldigestion-related symptoms alleviation in advanced PDAC patients.

Exploring chemotherapy holiday and drugs re-challenge in advanced pancreatic cancer patients.

PURPOSE: We aimed to explore the role of drugs re-challenge at the disease progression after a chemotherapy-free interval for pancreatic adenocarcinoma (PDAC) patients. METHODS: We retrospectively analyzed the outcome of re-treatments at the progression in two cohorts of advanced PDAC patients who had disease control (DC) and a treatment holiday ≥ 3 months after upfront chemotherapy. RESULTS: Between 2015 and 2019, 66 advanced PDAC patients (cohort A) had DC with nab-paclitaxel-based chemotherapy (i.e. AG or PAXG = cisplatin, nab-paclitaxel, gemcitabine, capecitabine). At the time of progressive disease (PD), 34 patients were re-treated with AG (A1) and 32 were treated with other regimens (A2). The median (m) duration of chemotherapy holiday was 6.1 and 5.9 months in A1 and A2, respectively. Partial response (PR) and stable disease (SD) were found in 14 (41%) and 12 (35%) of patients in A1 and in 8 (25%) and 6 (19%) patients in A2. CA19-9 response was recorded in 23/33 evaluable patients (70%) in A1 and in 5/20 (25%) in A2. mPFS2 and mOS2, defined as the time between the second line of treatment start and the disease progression or death, were 4.8 and 12.2 months in A1 and 3.9 and 8.4 months in A2, respectively. Similarly, between 2006 and 2013, 64 patients (cohort B) had DC with upfront PEFG/PEXG/PDXG regimens (epirubicin or docetaxel, cisplatin, gemcitabine, capecitabine or 5-fluorouracil) and were re-treated at PD with either 4-drug (B1; N = 30) or other regimens (B2; N = 34), yielding a mOS2 of 10.9 and 7.2 months, respectively. CONCLUSION: Our data endorse the strategy of resuming prior drugs after a chemotherapy holiday ≥ 3 months in advanced PDAC patients who achieved a  durable disease control after upfront treatments.

Time to CA19-9 nadir: a clue for defining optimal treatment duration in patients with resectable pancreatic ductal adenocarcinoma.

BACKGROUND: Defining optimal treatment duration in patients with resectable pancreatic ductal adenocarcinoma (PDAC) receiving primary chemotherapy is an unmet need. The role of time to CA19-9 nadir and of nadir magnitude was explored in this study. PATIENTS AND METHODS: The databases of our institution's prospective trials were queried to speculate on the time to maximum chemotherapy response. Patients with pathologically proven, metastatic (N = 356) or non-metastatic non-resected (N = 163) PDAC and elevated baseline (> 34 UI/mL) CA19-9 were analyzed. Survival curves were estimated using the Kaplan-Meier method and compared by means of the log-rank test for analyses including at least 45 patients. Multivariable Cox proportional hazards model was used to estimate clinical features for their association with OS. All probability values were from two-sided tests. RESULTS: Time to CA19-9 nadir was ≥ 4 months in 184 of 346 (53%) metastatic and 121 of 163 (74%) non-metastatic patients (p = 0.002). The likelihood of a later nadir was higher with taxane-based chemotherapy as compared to taxane-free combinations (73% versus 56%; p = 0.02). Both metastatic and non-metastatic patients had significantly longer survival when nadir occurred later. Patients with a larger CA19-9 nadir magnitude had significantly longer survival. Metastatic patients with CA19-9 reduced by < 50%, 50-89%, or > 89% and had a median survival of 7.4, 9.8, and 14.7 months, respectively (p ≤ 0.001 for all comparisons). The corresponding figures for non-metastatic patients were 10.6; 17.0; and 18.7 months, respectively (p ≤ 0.02 for < 50% versus 50-89% or > 89%; p = 0.14 for 50-89% versus > 89%). Multivariable analyses showed that time to CA19-9 nadir but not CA19-9 nadir magnitude was independently predictive of survival. CONCLUSION: The present study suggests that a 4-6 months program might be a more suitable candidate for prospective assessment in comparison to shorter pre-defined period in patients who are candidates to surgery after primary chemotherapy.

Chemotherapy in elderly patients with pancreatic cancer: Efficacy, feasibility and future perspectives.

By 2030 70% of newly diagnosed pancreatic ductal adenocarcinoma (PDAC) will occur in older adults. Elderly patients, defined by the World Health Organization (WHO) as people older than 65 years, represent a heterogeneous group with different biological and functional characteristics that need personalized anticancer treatments. Since older patients are under-represented in randomized phase III trials, their management is mostly extrapolated from studies performed in younger patients, without robust evidence-based recommendations. However, data from retrospective studies and case-control series show that elderly may benefit from chemotherapy in both the adjuvant and advanced disease settings. Although with discordant results, gemcitabine-based treatment and dose-adapted fluorouracil combination regimens seem to be effective and well tolerated in this subset of patients. A proper balance of potential treatment benefits and side effects represent the crucial point for managing elderly patients with PDAC. Therefore an appropriate patient selection is essential to maximize the therapeutic benefit in the older population: randomized studies aiming to better standardizing fitness parameters and implementing the routine use of comprehensive geriatric assessments are strongly warranted. In this light, the detection of molecular prognostic markers able to detect patients who may benefit more from oncological treatments should be a primary endpoint of age-focused clinical trials. Altogether, the field of geriatric oncology will expand in the next years, and the clinical management of elderly patients affected by PDAC will become a major public health issue.

Nab-paclitaxel plus gemcitabine with or without capecitabine and cisplatin in metastatic pancreatic adenocarcinoma (PACT-19): a randomised phase 2 trial.

BACKGROUND: Current treatment for metastatic pancreatic ductal adenocarcinoma includes combination chemotherapy, such as FOLFIRINOX or nab-paclitaxel plus gemcitabine. We investigated the activity of a novel four-drug regimen, consisting of cisplatin, nab-paclitaxel, capecitabine, and gemcitabine, compared with nab-paclitaxel plus gemcitabine, in the PACT-19 trial. METHODS: This single-centre, randomised, open-label, phase 2 trial was done in San Raffaele Hospital in Italy. We enrolled patients aged 18-75 years with pathologically confirmed stage IV pancreatic ductal adenocarcinoma who had received no previous chemotherapy and had Karnofsky performance status of at least 70. Patients were randomly assigned (1:1) by computer-generated permutated block randomisation (block size of four) stratified by baseline concentration of carbohydrate antigen 19-9 to PAXG (cisplatin 30 mg/m2, nab-paclitaxel 150 mg/m2, and gemcitabine 800 mg/m2 on days 1 and 15 and oral capecitabine 1250 mg/m2 on days 1-28 every 4 weeks), or nab-paclitaxel and gemcitabine alone (nab-paclitaxel 125 mg/m2 and gemcitabine 1000 mg/m2 on days 1, 8, and 15 every 4 weeks). The primary endpoint was the proportion of patients who were progression-free at 6 months, analysed in the intention-to-treat population. Data cutoff was on March 31, 2018. The safety population included all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT01730222, and is now closed. FINDINGS: Between April 22, 2014, and May 30, 2016, we randomly assigned 83 patients to treatment: 42 patients to PAXG and 41 patients to nab-paclitaxel plus gemcitabine. At 6 months, 31 (74%, 95% CI 58-86) of 42 patients in the PAXG group were alive and free from disease progression compared with 19 (46%, 31-63) of 41 patients in the nab-paclitaxel plus gemcitabine group. The most frequent grade 3 adverse events were neutropenia (12 [29%] of 42 in the PAXG group vs 14 [34%] of 41 in the nab-paclitaxel plus gemcitabine group), anaemia (nine [21%] vs nine [22%]), and fatigue (seven [17%] vs seven [17%]). The most common grade 4 adverse event was neutropenia (five [12%] in the PAXG group vs two [5%] in the nab-paclitaxel plus gemcitabine group). Two (5%) treatment-related deaths occurred in the nab-paclitaxel plus gemcitabine group compared with none in the PAXG group. INTERPRETATION: Despite the small sample size, our findings suggest that the PAXG regimen warrants further investigation in a phase 3 trial in patients with metastatic pancreatic ductal adenocarcinoma. FUNDING: Celgene.

A randomised phase 2 trial of nab-paclitaxel plus gemcitabine with or without capecitabine and cisplatin in locally advanced or borderline resectable pancreatic adenocarcinoma.

BACKGROUND: The current trial assessed whether the addition of cisplatin and capecitabine to the nab-paclitaxel-gemcitabine backbone is feasible and active against borderline and locally advanced pancreatic adenocarcinoma (PDAC). METHOD: Fifty-four chemo-naive patients, aged between 18 and 75 years, with a pathological diagnosis of locally advanced or borderline resectable PDAC were randomised to receive either nab-paclitaxel, gemcitabine, cisplatin and oral capecitabine (PAXG; arm A; N = 26) or nab-paclitaxel followed by gemcitabine (AG; arm B; N = 28). The primary end-point was the tumour resection rate. If at least four such resections were performed, the treatment was considered as active. The secondary end-points were progression-free survival (PFS), overall survival (OS), Response Evaluation Criteria in Solid Tumours response rate, Hartman's pathologic response, carbohydrate antigen 19.9 response rate and toxicity. RESULTS: Eight patients (31%) in the PAXG arm and nine (32%) in the AG arm underwent resection. PFS at 1-year was 58% in arm A and 39% in arm B. OS at 18-month was 69% in arm A and 54% in arm B. CONCLUSIONS: In this phase II study, the addition of cisplatin and capecitabine to the AG backbone was feasible and yielded promising results in terms of disease control without detrimental impact on tolerability. The approach warrants further investigation in a phase III study. TRIAL REGISTRATION: NCT01730222.

Immune checkpoint inhibitors for non-small-cell lung cancer: does that represent a 'new frontier'?

Advances in the interpretation and understanding of cancer behaviour, particularly of its ability to evade the host immunosurveillance, deregulating the balance between inhibitory and stimulatory factors, led to the development of an innovative category of immunotherapeutic agents, currently under investigation. Although the disappointing data deriving from the employment of vaccines in non-small cell lung cancer (NSCLC), more promising results have been obtained in the early phase trials with immune checkpoint inhibitors, such as cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), programmed cell death protein-1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors. This review delineates the main features of the available immunotherapeutic agents, focusing the discussion on immune checkpoint inhibitors, those that have already demonstrated a relevant clinical activity (such as Ipilimumab and Nivolumab) and those molecules still in early development phase. Moreover, we underline the possible emerging issues deriving from the progressive diffusion of Immuno-Oncology into the standard clinical practice. The careful and accurate identification and management of immune-related toxicities, the validation of more reliable immune response criteria and the increasing research of potential predictive biomarkers are key points of discussion. The perspective is that immunotherapy might represent an effective 'magic bullet', able to change the treatment paradigm of NSCLC, particularly of those subgroups featured by a heavily mutant cancer (squamous histology and smokers), where the immunologic agents contribute in cancer development and progression seems to be strong and, concurrently, the efficacy of standard therapies particularly limited.

An overview of angiogenesis inhibitors in Phase II studies for non-small-cell lung cancer.

INTRODUCTION: Angiogenesis plays a major role in the development and progression of solid tumors, including lung cancer. Although some anti-angiogenic agents have demonstrated a statistically significant advantage in terms of primary outcome in clinical trials, the reliable clinical benefit obtained with these drugs is still questionable and often quantitatively limited. To better clarify this complex scenario and definitively establish the concrete benefits of anti-angiogenic strategies in lung cancer, several clinical trials have been conducted with others currently ongoing. AREAS COVERED: In this review, the authors highlight the data ascertained from Phase II trials conducted in NSCLC patients who are treated with recently discovered innovative anti-angiogenic molecules. The authors also discuss older widely investigated anti-angiogenic drugs that have been repurposed or used in different contexts and combinations. EXPERT OPINION: Globally considered, the results of the countless clinical trials evaluating anti-angiogenic agents suggest that angiogenesis (with its molecules and pathways) represents a non-ideal druggable process for several biologically relevant reasons. Consequently, it is important that the conceptual development and clinical validation of anti-angiogenic agents is different from those employed for traditional target agents (i.e., erlotinib, gefitinib and crizotinib). Indeed, the development and validation of these agents still represents a major challenge for modern scientific research.

Risk Stratification Model for Resected Squamous-Cell Lung Cancer Patients According to Clinical and Pathological Factors.

INTRODUCTION: The aim of this analysis (AIRC-MFAG project no. 14282) was to define a risk classification for resected squamous-cell lung cancer based on the combination of clinicopathological predictors to provide a practical tool to evaluate patients' prognosis. METHODS: Clinicopathological data were retrospectively correlated to disease-free/cancer-specific/overall survival (DFS/CSS/OS) using a Cox model. Individual patient probability was estimated by logistic equation. A continuous score to identify risk classes was derived according to model ratios and dichotomized according to prognosis with receiver operating characteristic analysis. RESULTS: Data from 573 patients from five institutions were gathered. Four hundred ninety-four patients were evaluable for clinical analysis (median age: 68 years; male/female: 403/91; T-descriptor according to TNM 7th edition 1-2/3-4: 330/164; nodes 0/>0: 339/155; stages I and II/III and IV: 357/137). At multivariate analysis, age, T-descriptor according to TNM 7th edition, nodes, and grading were independent predictors for DFS and OS; the same factors, except age and grading, predicted CSS. Multivariate model predict individual patient probability with high prognostic accuracy (0.67 for DFS). On the basis of receiver operating characteristic-derived cutoff, a two-class model significantly differentiated low-risk and high-risk patients for 3-year DFS (64.6% and 32.4%, p < 0.0001), CSS (84.4% and 44.5%, p < 0.0001), and OS (77.3% and 38.8%, p < 0.0001). A three-class model separated low-risk, intermediate-risk, and high-risk patients for 3-year DFS (64.6%, 39.8%, and 21.8%, p < 0.0001), CSS (84.4%, 55.4%, and 30.9%, p< 0.0001), and OS (77.3%, 47.9%, and 27.2%, p < 0.0001). CONCLUSIONS: A risk stratification model including often adopted clinicopathological parameters accurately separates resected squamous-cell lung cancer patients into different risk classes. The project is currently ongoing to integrate the clinicopathological model with investigational molecular predictors.

Molecular heterogeneity assessment by next-generation sequencing and response to gefitinib of EGFR mutant advanced lung adenocarcinoma.

Cancer molecular heterogeneity might explain the variable response of EGFR mutant lung adenocarcinomas to tyrosine kinase inhibitors (TKIs). We assessed the mutational status of 22 cancer genes by next-generation sequencing (NGS) in poor, intermediate or good responders to first-line gefitinib. Clinical outcome was correlated with Additional Coexisting Mutations (ACMs) and the EGFR Proportion of Mutated Alleles (PMA). Thirteen ACMs were found in 10/17 patients: TP53 (n=6), KRAS (n=2), CTNNB1 (n=2), PIK3CA, SMAD4 and MET (n=1 each). TP53 mutations were exclusive of poor/intermediate responders (66.7% versus 0, p=0.009). Presence of ACMs significantly affected both PFS (median 3.0 versus 12.3 months, p=0.03) and survival (3.6 months versus not reached, p=0.03). TP53 mutation was the strongest negative modifier (median PFS 4.0 versus 14.0 months). Higher EGFR PMA was present in good versus poor/intermediate responders. Median PFS and survival were longer in patients with EGFR PMA ≥0.36 (12.0 versus 4.0 months, p=0.31; not reached versus 18.0 months, p=0.59). Patients with an EGFR PMA ≥0.36 and no ACMs fared significantly better (p=0.03), with a trend towards increased survival (p=0.06). Our exploratory data suggest that a quantitative (PMA) and qualitative (ACMs) molecular heterogeneity assessment using NGS might be useful for a better selection of patients.

Predictors of outcome for patients with lung adenocarcinoma carrying the epidermal growth factor receptor mutation receiving 1st-line tyrosine kinase inhibitors: Sensitivity and meta-regression analysis of randomized trials.

PURPOSE: We performed a sensitivity and meta-regression analysis, cumulating all randomized trials exploring the benefit of afatinib, erlotinib and gefitinib versus chemotherapy in advanced EGFR mutant NSCLC, to investigate the potential role of additional clinico-pathological predictors of TKIs efficacy. RESULTS: With regard to progression-free survival (PFS), a significant interaction according to ethnicity (Asian versus Caucasian versus mixed) and to trial design (retrospective versus prospective EGFR analysis), was found; a trend toward significance with regard to type of drug (gefitinib versus erlotinib versus afatinib) was determined. No statistically significant differences in survival were observed. With regard to response, a significant interaction according to ethnicity, trial design and type of drug, was found. CONCLUSION: These data, together with a deeper characterization of the molecular background sustaining the oncogenic process, may contribute to create a clinico-pathologic predictive model, aimed to improve the magnitude of benefit expected from the use of targeted agents.