Consolidative thoracic radiation therapy for extensive-stage small cell lung cancer in the era of first-line chemoimmunotherapy: preclinical data and a retrospective study in Southern Italy.

Background: Consolidative thoracic radiotherapy (TRT) has been commonly used in the management of extensive-stage small cell lung cancer (ES-SCLC). Nevertheless, phase III trials exploring first-line chemoimmunotherapy have excluded this treatment approach. However, there is a strong biological rationale to support the use of radiotherapy (RT) as a boost to sustain anti-tumor immune responses. Currently, the benefit of TRT after chemoimmunotherapy remains unclear. The present report describes the real-world experiences of 120 patients with ES-SCLC treated with different chemoimmunotherapy combinations. Preclinical data supporting the hypothesis of anti-tumor immune responses induced by RT are also presented. Methods: A total of 120 ES-SCLC patients treated with chemoimmunotherapy since 2019 in the South of Italy were retrospectively analyzed. None of the patients included in the analysis experienced disease progression after undergoing first-line chemoimmunotherapy. Of these, 59 patients underwent TRT after a multidisciplinary decision by the treatment team. Patient characteristics, chemoimmunotherapy schedule, and timing of TRT onset were assessed. Safety served as the primary endpoint, while efficacy measured in terms of overall survival (OS) and progression-free survival (PFS) was used as the secondary endpoint. Immune pathway activation induced by RT in SCLC cells was explored to investigate the biological rationale for combining RT and immunotherapy. Results: Preclinical data supported the activation of innate immune pathways, including the STimulator of INterferon pathway (STING), gamma-interferon-inducible protein (IFI-16), and mitochondrial antiviral-signaling protein (MAVS) related to DNA and RNA release. Clinical data showed that TRT was associated with a good safety profile. Of the 59 patients treated with TRT, only 10% experienced radiation toxicity, while no ≥ G3 radiation-induced adverse events occurred. The median time for TRT onset after cycles of chemoimmunotherapy was 62 days. Total radiation dose and fraction dose of TRT include from 30 Gy in 10 fractions, up to definitive dose in selected patients. Consolidative TRT was associated with a significantly longer PFS than systemic therapy alone (one-year PFS of 61% vs. 31%, p<0.001), with a trend toward improved OS (one-year OS of 80% vs. 61%, p=0.027). Conclusion: Multi-center data from establishments in the South of Italy provide a general confidence in using TRT as a consolidative strategy after chemoimmunotherapy. Considering the limits of a restrospective analysis, these preliminary results support the feasibility of the approach and encourage a prospective evaluation.

Moving Immune Checkpoint Inhibitors to Early Non-Small Cell Lung Cancer: A Narrative Review.

Lung cancer is the leading cause of cancer-related death worldwide. Since prognosis of early-stage non-small cell lung cancer (NSCLC) remains dismal for common relapses after curative surgery, considerable efforts are currently focused on bringing immunotherapy into neoadjuvant and adjuvant settings. Previously, perioperative chemotherapy showed only a modest but significative improvement in overall survival. The presence of broad tumor neoantigens load at primary tumor prior to surgery as well as the known immunosuppressive status following resection represent the main rationale for immunotherapy in early disease. Several trials have been conducted in recent years, leading to atezolizumab and nivolumab approval in the adjuvant and neoadjuvant setting, respectively, and perioperative immunotherapy in NSCLC remains a field of active clinical and preclinical investigation. Unanswered questions in perioperative therapy in NSCLC include the optimal sequence and timing of chemotherapy and immunotherapy, the potential of combination strategies, the role of predictive biomarkers for patient selection and the choice of useful endpoints in clinical investigation.

Complete response to pembrolizumab as a single agent in a patient with stage III NSCLC with high PD-L1 expression: a case report.

Non-small cell lung cancer (NSCLC) accounts for 75-80% of all lung cancer cases. Stage III NSCLC represents a highly heterogenous stage characterized by different disease presentations and a wide range of treatment options. For patients with good performance status and unresectable-stage III NSCLC with programmed death-ligands 1 (PD-L1) tumor proportion score (TPS) ≥1%, durvalumab consolidation immunotherapy after a platinum-based chemo-radiotherapy is strongly recommended. However, age, poor performance status, underlying comorbidities may represent contraindications for chemotherapy to be used in a subgroup of patients. Herein, we report a case of an 80-year-old male affected by a stage IIIB lung adenocarcinoma with overexpression of PD-L1 (TPS 90%) treated with pembrolizumab, an immune checkpoint inhibitor targeting PD-1/PD-L1 pathways, which shows a complete resolution of lung lesion after four cycles of treatment. Although randomized controlled trials are required, this case report may suggest the potential role of pembrolizumab for chemotherapy unsuitable patients with overexpressing PD-L1 unresectable-stage III NSCLC.

Be-TeaM: An Italian real-world observational study on second-line therapy for EGFR-mutated NSCLC patients.

OBJECTIVES: Molecular diagnostics and care of non-small cell lung cancer (NSCLC) are continuously evolving. Few data document the current strategies to manage advanced NSCLC patients beyond progression in clinical practice. PATIENTS AND METHODS: Be-TeaM is an Italian multi-center observational study conducted on consecutive EGFR-mutated stage IV NSCLC patients, progressed during/after a first-line EGFR-TKI. It consists of a retrospective phase, from first-line EGFR-TKI therapy start until study entry (i.e. beginning of the diagnostic process), and a prospective phase, until treatment choice or for 3 months if no therapy was prescribed. Primary objective was to describe the diagnostic and therapeutic approaches adopted after progression in a real-world setting. RESULTS: Of 308 patients enrolled in 63 centers from July 2017 to June 2018, 289 were included in the analysis. In first line, 53.3 % received gefitinib, 32.5 % afatinib and 14.2 % erlotinib. The testing rate (i.e. rate of all patients undergone any biopsy -liquid and/or tissue- for the T790 M detection) was 90.7 %, with liquid biopsy being the most frequently executed. Of 262 biopsied patients, 64.5 % underwent only 1 liquid biopsy, 10.7 % only 1 tissue biopsy and 18.3 % >1 biopsy, both liquid and solid in 85.4 %. The T790M positivity rate was 45.3 %; of 166 patients undergone only a liquid biopsy and tested for the mutation, 39.8 % were T790M+ and 60.2 % T790M-/undetermined. By the observation end, 87.9 % patients had a post-progression treatment chosen, osimertinib being the most frequent among the T790M+. CONCLUSION: Be-TeaM provides the first snapshot of current practices for the management of NSCLC patients beyond progression in Italy; in clinical practice, assessing the T790M status is not always feasible.

Immune Checkpoint Blockade for Advanced NSCLC: A New Landscape for Elderly Patients.

The therapeutic scenario for elderly patients with advanced NSCLC has been limited to radiotherapy and chemotherapy. Recently, a novel therapeutic approach based on targeting the immune-checkpoints has showed noteworthy results in advanced NSCLC. PD1/PD-L1 pathway is co-opted by tumor cells through the expression of PD-L1 on the tumor cell surface and on cells within the microenvironment, leading to suppression of anti-tumor cytolytic T-cell activity by the tumor. The success of immune-checkpoints inhibitors in clinical trials led to rapid approval by the FDA and EMA. Currently, data regarding efficacy and safety of ICIs in older subjects is limited by the poor number of elderly recruited in clinical trials. Careful assessment and management of comorbidities is essential to achieve better outcomes and limit the immune related adverse events in elderly NSCLC patients.

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.

Endoscopic central airway recanalization to enable first line pembrolizumab treatment in a PD-L1 strongly positive non-small cell lung cancer: a case report.

BACKGROUND: Tracheobronchial malignant stenosis is a life-threatening condition which may cause recurrent infections due to lung atelectasis. Despite immunotherapy is less toxic than standard chemotherapy, recurrent lung infections may represent a challenge for this treatment. We report a clinical case of a patient with metastatic squamous cell carcinoma suffering from pulmonary infections due to central airway obstruction who underwent endoscopic recanalization followed by immunotherapy. CASE PRESENTATION: A 64 year-old man was referred to our attention for the management of metastatic squamous cell carcinoma obstructing the right main bronchus with recurrent pulmonary infections. Patient exhibited strong positive PD-L1 expression (> 50%). Advanced disease stage contraindicated surgical treatment. Although therapy with immune check point inhibitors was indicated as first-line treatment, recurrent pulmonary infections made it unfeasible. Therefore, we planned a combined approach including endoscopic recanalization of central airway in order to resolve lung atelectasis, and lung infection followed by immunotherapy treatment with pembrolizumab in order to avoid local and systemic disease progression. CONCLUSIONS: At 16-week follow-up, the patient was alive in stable disease with improvement of clinical condition and no signs of lung infection.

Prognostic Factors in Early-stage NSCLC: Analysis of the Placebo Group in the MAGRIT Study.

BACKGROUND/AIM: The analysis of prognostic factors is important to identify determinants of disease-free survival (DFS) and overall survival (OS) in resected non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: We examined baseline characteristics associated with DFS and OS among 757 patients with resected, histologically proven, MAGE-A3-positive Stage IB-IIIA NSCLC assigned to placebo in the MAGRIT study (NCT00480025). We explored characteristics of NSCLC that could predict DFS and OS using Cox regression models. RESULTS: The multivariate analysis showed that lower nodal stage, the presence of squamous cell carcinoma (SCC), a broader surgical resection in patients with SCC, and being female with non-SCC were significantly associated with longer DFS. Lower nodal stage and smaller tumor size were significantly associated with an improved OS. Compared to Other International, enrollment in East Asia was associated with an improved OS in patients with non-SCC. CONCLUSION: This is the first prognostic factor analysis in NSCLC performed on data from a large prospective study. These results confirm retrospective studies and add that histopathology subtype is a strong determinant of DFS in resected MAGE-A3-positive NSCLC.

Diagnosis and first-line treatment of non-small cell lung cancer in the era of novel immunotherapy: recommendations for clinical practice.

INTRODUCTION: In the era of personalized cancer therapy, the sampling of adequate tumor tissue for histologic diagnosis and genomic profiling is crucial, not only at the initial diagnosis but also in the event of resistant and recurrent disease when sequential biopsies may be required to evaluate somatic mutations and histologic changes. Areas covered: The identification of genetic driver alterations led to the selection of patients who are most likely to benefit from epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) and rat osteosarcoma (ROS-1) tyrosine kinase inhibitors; on the other hand, in the absence of oncogenic alterations, platinum-based doublet chemotherapy regimens were the cornerstone of treatment. However, the advent of immunotherapy has widely changed the first-line treatment. Expert commentary: An Italian Experts Panel Meeting was held to discuss on recommendations for diagnosis (optimization of the cyto/histologic tumor sample issue and management of tissue to molecular evaluation) and immunotherapy as first-line treatment of patients with advanced non-small-cell lung cancer.

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.

H-Prune through GSK-3ß interaction sustains canonical WNT/ß-catenin signaling enhancing cancer progression in NSCLC.

H-Prune hydrolyzes short-chain polyphosphates (PPase activity) together with an hitherto cAMP-phosphodiesterase (PDE), the latest influencing different human cancers by its overexpression. H-Prune promotes cell migration in cooperation with glycogen synthase kinase-3 (Gsk-3ß). Gsk-3ß is a negative regulator of canonical WNT/ß-catenin signaling. Here, we investigate the role of Gsk-3ß/h-Prune complex in the regulation of WNT/ß-catenin signaling, demonstrating the h-Prune capability to activate WNT signaling also in a paracrine manner, through Wnt3a secretion. In vivo study demonstrates that h-Prune silencing inhibits lung metastasis formation, increasing mouse survival. We assessed h-Prune levels in peripheral blood of lung cancer patients using ELISA assay, showing that h-Prune is an early diagnostic marker for lung cancer. Our study dissects out the mechanism of action of h-Prune in tumorigenic cells and also sheds light on the identification of a new therapeutic target in non-small-cell lung cancer.

EGFR mutations detected on cytology samples by a centralized laboratory reliably predict response to gefitinib in non-small cell lung carcinoma patients.

BACKGROUND: Epidermal growth factor receptor (EGFR) mutations are reliably detected by referral laboratories, even if most lung cancer cytology specimens sent to such laboratories contain very few cells. However, EGFR mutations may be distributed heterogeneously within tumors, thereby raising concerns that mutations detected on cytology are not representative of the entire tumor and, thus, are less reliable in predicting response to tyrosine kinase inhibitor (TKI) treatment than mutations detected on histology. To address this issue, the authors reviewed their clinical practice archives and compared the outcome of TKI treatment among patients who were selected by cytology versus patients who were selected by histology. METHODS: From July 2010 to July 2012, 364 cytology samples and 318 histology samples were received. Exon 19 deletions and the L858R point mutation in exon 21, detected by fragment assay and TaqMan assay, respectively, were confirmed by direct sequencing; discrepancies were resolved by cloning polymerase chain reaction products. The response rate (RR) and progression-free survival (PFS) at 12 months (range, 3-34 months) were evaluable in 13 EGFR-mutated patients who were selected for treatment by cytology and 13 patients who were selected by histology. RESULTS: The mutation rate was similar in histology samples (8.5%) and cytology samples (8.8%). The RR (54%) and PFS (9.2 months) were similar in histologically selected patients and cytologically selected patients (RR, 62%; PFS, 8.6 months; P = .88). The disease control rate (responsive plus stable disease) was 92% in histologically selected patients and 100% in cytologically selected patients. CONCLUSIONS: EGFR mutations detected on cytology specimens by a centralized laboratory can predict TKI treatment response equally well as mutations identified on histology samples.

EGFR mutations detection on liquid-based cytology: is microscopy still necessary?

Currently, there is a trend towards an increasing use of liquid-based cytology (LBC) to diagnose non-small cell lung cancer. In this study, to detect epidermal growth factor receptor mutations, different molecular techniques were applied to LBC samples with and without laser capture microdissection (LCM). In 58 LBCs, DNA was extracted twice. One sample was obtained directly from CytoLyt solution, whereas the other DNA sample was derived after slide preparation and LCM of Papanicolaou-stained cells. The rate of mutant cases obtained by direct sequencing was discordant between CytoLyt-derived (10.3%) and LCM-derived (17.2%) DNA. However, the same mutant rate (17.2%) was achieved on the matched samples by high-resolution melting analysis, fragment and TaqMan assays. Thus, LCM and direct sequencing may be replaced by more sensitive non-sequencing methods directly performed on CytoLyt-derived DNA, an easier and faster approach to improve epidermal growth factor receptor testing standardisation on LBCs.

Adjuvant chemoradiotherapy in patients with stage III or IV radically resected gastric cancer: a pilot study.

BACKGROUND: Adjuvant chemoradiotherapy does not represent the standard of care in patients with resected high-risk gastric cancer; however, results from phase 2 and randomized trials suggest improvement in overall survival. We assessed the feasibility and toxic effects of chemoradiotherapy as adjuvant treatment in locally advanced gastric cancer. DESIGN: Pilot study. SETTING: University hospital. PATIENTS: Twenty-nine patients with T4N+ or any TN23 gastric cancer previously treated with potentially curative surgery were enrolled. All of the patients received combined adjuvant chemotherapy with FOLFOX-4 (ie, a combination of folinic acid [leucovorin], fluorouracil, and oxaliplatin [Eloxatin]) for 8 cycles and concomitant radiotherapy (45 Gy in 25 daily fractions over 5 weeks). Radiotherapy was begun after the first 2 cycles of FOLFOX-4, which was reduced by 25% during the period of concomitant radiotherapy. MAIN OUTCOME MEASURES: Treatment toxic effects according to the National Cancer Institute-Common Toxicity Criteria classification, overall and disease-free survival rates, and identification of prognostic indicators. RESULTS: All of the patients completed treatment. Severe hematologic and gastrointestinal toxic effects occurred in 10% and 33%, respectively. No acute hepatic or renal toxic effects were observed; 1 patient experienced severe neurotoxicity. Disease-free and overall survival rates at 1, 2, and 3 years were 79%, 35%, and 35% and 85%, 62.6%, and 50.1%, respectively, and were shown to be substantially better than those observed in untreated patients. Long-term outcome was related to TNM stage, basal serum tumor marker level, and, particularly, lymph node ratio. CONCLUSION: A multimodal approach with FOLFOX-4 and radiotherapy is feasible and effective for the treatment of patients with resected high-risk gastric cancer.

Correlation between efficacy and skin rash occurrence following treatment with the epidermal growth factor receptor inhibitor cetuximab: a single institution retrospective analysis.

Several trials show a relationship between skin toxicity, response rate, and overall survival in cetuximab-treated patients. We analyzed our database to evaluate the importance of skin rash as a surrogate marker of favorable outcome in cancer patients referred to our institution in the last three years. We retrospectively analyzed 90 cetuximab-treated patients: 57 colon cancer patients, 10 NSCLC patients, 14 locally advanced esophageal cancer patients, and 9 miscellaneous. A significant correlation was observed between skin rash and response to therapy. Skin rash was experienced by 93% of PR and 100% of CR patients. The mean TTP was 184 days in patients showing skin rash and 94 days in patients without skin rash, respectively. On multivariate analysis, skin rash was demonstrated to be the only independent prognostic variable with regard to TTP. Patients who did not develop skin rash had a 2-fold greater likelihood to manifest tumor progression significantly earlier than patients who developed skin rash. In our series, a statistically significant correlation between rash, response rate, and TTP was demonstrated in 90 cetuximab-treated patients. Skin toxicity was confirmed as the only clinical variable able to predict the response to cetuximab.