Efficacy of ramucirumab combination chemotherapy as second-line treatment in patients with advanced adenocarcinoma of the stomach or gastroesophageal junction after exposure to checkpoint inhibitors and chemotherapy as first-line therapy.

FOLFOX plus nivolumab represents a standard of care for first-line therapy of advanced gastroesophageal cancer (aGEC) with positive PD-L1 expression. The efficacy of second-line VEGFR-2 inhibition with ramucirumab (RAM) plus chemotherapy after progression to immunochemotherapy remains unclear. Medical records of patients with aGEC enrolled in the randomized phase II AIO-STO-0417 trial after treatment failure to first-line FOLFOX plus nivolumab and ipilimumab were retrospectively analyzed. Patients were divided into two groups based on second-line therapy: RAM plus chemotherapy (RAM group) or treatment without RAM (control group). Eighty three patients were included. In the overall population, progression-free survival (PFS) in the RAM group was superior to the control (4.5 vs 2.9 months). Responders (CR/PR) to first-line immunochemotherapy receiving RAM containing second-line therapy had prolonged OS from start of first-line therapy (28.9 vs 16.5 months), as well as second-line OS (9.6 vs 7.5 months), PFS (5.6 vs 2.9 months) and DCR (53% vs 29%) compared to the control. PD-L1 CPS ≥1 was 42% and 44% for the RAM and the control, respectively. Patients with CPS ≥1 in the RAM group showed better tumor control (ORR 25% vs 10%) and improved survival (total OS 11.5 vs 8.0 months; second-line OS 6.5 vs 3.9 months; PFS 4.5 vs 1.6 months) compared to the control. Prior exposure to first-line FOLFOX plus dual checkpoint inhibition followed by RAM plus chemotherapy shows favorable response and survival rates especially in patients with initial response and positive PD-L1 expression and has the potential to advance the treatment paradigm in aGEC.

Neoadjuvant and adjuvant approaches in gastroesophageal cancers.

PURPOSE OF REVIEW: Despite advances in the perioperative treatment of locally advanced (T2-4 and/or N+) gastroesophageal cancer with evolving chemoradiotherapy and chemotherapy regimens, prognosis remains poor. Biomarker-based approaches with targeted therapies and immune checkpoint inhibition present a new opportunity to improve response rate and overall survival. This review aims to shed light on the current treatment strategies and therapy options that are under investigation for the curatively intended perioperative treatment of gastroesophageal cancer. RECENT FINDINGS: A major step for patients with advanced esophageal cancer and insufficient response to chemoradiotherapy was the implementation of immune checkpoint inhibition in the adjuvant treatment with positive effects on survival duration and quality of life (CheckMate577). Various studies that seek to further integrate immunotherapy or targeted therapy into (neo-) adjuvant treatment are on their way and show promising results. SUMMARY: Ongoing clinical research tries to increase the effectivity of standard of care approaches for the perioperative treatment of gastroesophageal cancer. Biomarker based immunotherapy and targeted therapy bear the opportunity to further improve the outcome.

Programmed Cell Death Protein 1 Blockade Elicits Ongoing Remission in 2 Cases of Refractory Epstein-Barr Virus-Associated Metastatic Gastric Carcinoma.

INTRODUCTION: Over the last decade, immunotherapy has revolutionized oncological treatment of malignancies across all entities including gastric cancer (GC). The programmed cell death protein 1 (PD-1) inhibitor pembrolizumab has demonstrated durable responses and survival benefit in distinct patient subgroups with advanced GC (aGC). In 2017, pembrolizumab monotherapy was approved by the US Food and Drug Administration (FDA) for the treatment of refractory metastatic GC over-expressing programmed death ligand 1 (PD-L1), as well as for refractory advanced tumors with deficient DNA mismatch repair/microsatellite instability (dMMR/MSI) or high tumor mutational burden (TMB). However, several biomarker unselected studies have reported only limited single-agent immunotherapeutic efficacy. Thus, the identification of predictive biomarkers to select patient subgroups that are most eligible for immunotherapy is of particular importance. A growing number of studies consider Epstein-Barr virus (EBV)-associated GC (EBVaGC) as a molecularly distinct and immunogenic subtype which might be particularly sensitive to immune-checkpoint inhibition. CASE REPORT: Here, we present 2 cases of heavily pretreated patients with refractory, metastatic EBVaGC, who experienced a significant and sustained response to monotherapy with the PD-1 checkpoint inhibitor pembrolizumab. CONCLUSION: Comprehensive genetic testing for predictive biomarkers (e.g., PD-L1, MSI/dMMR, tTMB, EBV) to identify patient subgroups most eligible for immunotherapy is of particular importance in aGC, especially in patients that are refractory to conventional chemotherapy.

PD-1 Blockade Elicits Ongoing Remission in Two Cases of Refractory Microsatellite-Stable Cancer Harboring a POLE Mutation.

INTRODUCTION: In the last decade, immune-checkpoint therapy has led to a break-through in the treatment of cancer across all entities, while molecular markers have grown in importance for the choice of the appropriate chemotherapeutic agents. Accordingly, in 2017, the US Food and Drug Administration approved the programmed cell death protein 1 inhibitor pembrolizumab, a tissue agnostic cancer drug, for the treatment of cancer that displays microsatellite instability, regardless of histological entity and site of origin. However, a growing number of studies report that cases of microsatellite-stable (MSS) tumors harboring a DNA polymerase ε (POLE) mutation, a gene associated with proofreading deficiency, leading to an increased tumor mutational burden, likewise benefit from immune-checkpoint therapy. CASE REPORT: Here, we present 2 cases - one advanced adenocarcinoma of the ileum and one mixed neuroendocrine non-neuroendocrine neoplasm, both MSS and carrying a POLE mutation - that were refractory to initial chemotherapy but responded on immunotherapy with pembrolizumab. CONCLUSION: Colorectal cancer is a clinically and molecularly heterogenic disease which requires comprehensive genetic testing to screen for rare genetic alterations like POLE mutations to detect tumors harboring an ultramutator phenotype, especially in patients that are refractory to standard chemotherapy.

[Modern concepts of systemic treatment for adjuvant and palliative treatment of locally advanced or metastasized esophageal cancer]. / Moderne Konzepte der Systemtherapie zur adjuvanten und palliativen Behandlung des lokal fortgeschrittenen oder metastasierten Ösophaguskarzinoms.

BACKGROUND: The approval of a wide variety of PD-1/PD-L1 and CTLA­4 inhibitors has sustainably influenced the treatment landscape in many tumor entities and established immunotherapy as a new oncological treatment strategy. OBJECTIVE: This article summarizes the current clinical state of treatment for locally advanced and metastatic esophageal cancer and assesses the running and future developmental program and the implementation in the clinical routine. MATERIAL AND METHODS: Publications from Medline, ASCO and ESMO were systematically collected and evaluated. RESULTS: Many phase I-III trials focusing on immunotherapy for gastrointestinal tumors were carried out in recent years but were however without comparable success to other tumor entities and with only moderate response rates between 10% and 25% in monotherapy. Subgroups such as microsatellite instability (MSI) cancers and tumors overexpressing PD-L1 seem to particularly benefit from treatment with immune checkpoint inhibitors. Routine testing for known molecular alterations should therefore be carried out with all advanced esophageal cancers. Initial promising approaches with a combination of chemotherapy and immunotherapy were recently published and could become new treatment standards for esophageal cancer. CONCLUSION: Due to the survival advantage with a combination of chemotherapy and immunotherapy for untreated advanced stage esophageal cancer, it seems likely that this treatment strategy will become established as a new standard of care, assuming approval is granted. Immunotherapy might also become important in the adjuvant treatment of esophageal cancer.