Real-World Data on Pembrolizumab for Pretreated Non-Small-Cell Lung Cancer: Clinical Outcome and Relevance of the Lung Immune Prognostic Index.

BACKGROUND: Pembrolizumab is licensed for the treatment of pre-treated and PD-L1 positive non-small cell lung cancer (NSCLC), but response is heterogeneous. In this context, the Lung Immune Prognostic Index (LIPI) has been proposed as tool to prognosticate outcome. OBJECTIVE: To investigate the real-world efficacy and safety of pembrolizumab in pre-treated NSCLC patients and the clinical utility of LIPI for patients' selection. PATIENTS AND METHODS: Patients with pre-treated NSCLC and PD-L1 ≥ 1% treated with pembrolizumab were included in this retrospective series. The LIPI was used to classify patients in 3 prognostics subgroups according to the pre-treatment dNLR (derived neutrophil to lymphocyte ratio) and LDH in blood. The prognostic impact of the LIPI on progression free survival (PFS) and overall survival (OS) was evaluated with Cox regression. The combined effect of LIPI and other relevant prognostic factors was explored with multivariate regression. RESULTS: In total, 113 consecutive patients were included. Median (mPFS) and mOS was 4.3 (2.6-6.7) and 13.5 (10.3-17.7) months, respectively. Good-, intermediate-, and poor-LIPI was found in 54 (47.8%), 45 (39.8%), and 8 (7.1%) patients, respectively. Median PFS was 5.1 (2.8-9.1), 3.0 (2.5-6.8), and 1.4 (0.5-18.7) months, and mOS was 17.2 (12.0-26.4), 11.8 (8.4-17.1), and 3.7 (0.5-not calculable) months for good-, intermediate-, and poor-LIPI group, respectively. Patients with intermediate-LIPI and poor-LIPI had worse PFS versus good-LIPI, and statistically significant worse OS (p = 0.030 and p = 0.013, respectively). In the multivariate analysis, intermediate- versus good-LIPI (p = 0.190) was not independently associated to PFS or OS. Patients with both good-LIPI and high (≥ 50%) PD-L1 had better OS than all other subgroups defined by LIPI and PD-L1. Immune-related adverse events (irAEs) occurred in 47 (41.6%) patients (12.4% grade ≥ 3). In a time-varying analysis, irAEs were statistically associated with longer OS (HR 0.51, 0.31-0.84; p = 0.008). CONCLUSION: In our series, the outcome of pembrolizumab in pre-treated NSCLC is consistent with the registration trial. Lung Immune Prognostic Index is a readily available tool able to prognosticate outcome, also in PD-L1-high patients. The positive association between irAEs and OS might aid decision making.

Circulating Tumor DNA: An Emerging Tool in Gastrointestinal Cancers.

Circulating tumor DNA (ctDNA) is tumor-derived fragmented DNA in the bloodstream that has come from primary or metastatic cancer sites. Neoplasm-specific genetic and epigenetic abnormalities are increasingly being identified through liquid biopsy: a novel, minimally invasive technique used to isolate and analyze ctDNA in the peripheral circulation. Liquid biopsy and other emerging ctDNA technologies represent a paradigm shift in cancer diagnostics because they allow for the detection of minimal residual disease in patients with early-stage disease, improve risk stratification, capture tumor heterogeneity and genomic evolution, and enhance ctDNA-guided adjuvant and palliative cancer therapy. Moreover, ctDNA can be used to monitor the tumor response to neoadjuvant and postoperative therapy in patients with metastatic disease. Using clearance of ctDNA as an endpoint for escalation/de-escalation of adjuvant chemotherapy for patients considered to have high-risk disease has become an important area of research. The possibility of using ctDNA as a surrogate for treatment response-including for overall survival, progression-free survival, and disease-free survival-is an attractive concept; this surrogate will arguably reduce study duration and expedite the development of new therapies. In this review, we summarize the current evidence on the applications of ctDNA for the diagnosis and management of gastrointestinal tumors. Gastrointestinal cancers-including tumors of the esophagus, stomach, colon, liver, and pancreas-account for one-quarter of global cancer diagnoses and contribute to more than one-third of cancer-related deaths. Given the prevalence of gastrointestinal malignancies, ctDNA technology represents a powerful tool to reduce the global burden of disease.

ADAURA: The Splash of Osimertinib in Adjuvant EGFR-Mutant Non-small Cell Lung Cancer.

The introduction of tyrosine kinase inhibitors (TKI) for the treatment of metastatic non-small cell lung cancer (NSCLC) harbouring sensitizing epidermal growth factor receptor (EGFR) gene mutations revolutionized the diagnostic and treatment algorithm of this subset of patients almost two decades ago. Since then, a number of trials have evaluated the role of TKI therapy in early-stage disease, with encouraging disease-free survival (DFS) results but lack of a survival advantage. ADAURA, a phase III trial evaluating 3 years of adjuvant osimertinib versus placebo in patients harbouring EGFR mutations with completely resected stage IB-IIIA NSCLC, recently reported a profound DFS benefit (hazard ratio 0.21), favourable quality of life and reduction in the risk of brain metastases. These results led to osimertinib's fast track approval by the US Food and Drug Administration, with this drug thus becoming the first EGFR-TKI approved for the treatment of early-stage disease. However, the key endpoint of overall survival remains immature and questions around indication (i.e. stage, need for adjuvant chemotherapy), optimal treatment duration, biomarkers of response and cost-effectiveness remain to be answered. In this article, we critically appraise the findings of ADAURA and discuss future challenges.

First-Line Immune Checkpoint Inhibition for Advanced Non-Small-Cell Lung Cancer: State of the Art and Future Directions.

The advent of PD-(L)1 and CTLA-4 immune check point inhibitors (CPIs) has dramatically changed the treatment landscape of advanced non-small-cell lung cancer (NSCLC). For up to a quarter of patients with advanced NSCLC, CPIs have the potential to induce durable responses with long-term survival outcomes. Since the approval of first-line pembrolizumab for patients whose tumors express a PD-L1 ≥ 50%, several pivotal first-line CPI-based phase 3 studies have been conducted investigating combination treatments combining CPIs with chemotherapy (ChT) or combining different CPIs with or without ChT. As a result, there has been an increase in front-line treatment options for advanced NSCLC, and treatment algorithms are changing very quickly. In fit patients with advanced NSCLC, combination treatments including CPI and ChT are considered the new standard of care with improved clinical outcomes. CPI combination treatments are well tolerated and quality of life also seems to be better when CPIs are implemented in the first-line setting. The aim of this review is to provide a summary of the recently published first-line phase 3 studies investigating CPIs as monotherapy or in combination with other CPIs or ChT in advanced NSCLC, and to suggest possible treatment algorithms.

Integrating immune checkpoint inhibitors and targeted therapies in the treatment of early stage non-small cell lung cancer: a narrative review.

Prognosis of early stage non-small cell lung cancer (eNSCLC) is poor even when treated radically with surgery and (neo)adjuvant chemotherapy (Cht). The discovery of tyrosine kinase inhibitors (TKIs) for oncogene addicted NSCLC and immune checkpoint inhibitors (ICIs) have revolutionised the therapeutic paradigm and improved survival of advanced NSCLC. The unprecedented impact of these drugs has shifted the focus of investigation to early stage disease aiming at improving cure. In this context, several single arm phase II studies evaluating neoadjuvant ICI alone or in combination with platinum-based Cht have shown encouraging rates of pathological response which have spurred several ongoing randomized trials with (neo)adjuvant ICI. More recently, ADAURA study evaluating adjuvant osimertinib demonstrated a profound reduction of the risk of recurrence in patients with stage I (>4 cm)-IIIA eNSCLC harbouring EGFR sensitizing mutations. ICIs and TKIs represent a true revolution in the treatment of eNSCLC call to challenge the current standard of care. However, questions regarding drug resistance, recurrence patterns, biomarker identification, optimal treatment duration and sequencing need be answered to effectively integrate new drugs in the rapidly evolving therapeutic landscape of NSCLC. In this review we critically review new developments and future perspectives of TKIs and ICI as (neo)adjuvant strategies for eNSCLC.