The new era of immunotherapy has successfully arrived in the treatment of all metastatic/locally advanced esophageal gastric carcinomas . Recent approvals of immune checkpoint inhibitors (ICI) enrich the therapeutic landscape in almost every therapeutic line. There is a growing variety of ICIs targeting diverse molecular antigens of tumor and immune cells: Anti-PD-1, Anti-PD-L1 and Anti-CTLA-4.
Immunotherapy is now well established in the therapeutic landscape of metastatic/locally advanced esophageal gastric cancer. Already after radiochemotherapy and surgery of adeno- or squamous cell carcinoma of the esophagus, adjuvant therapy with nivolumab could be established in patients with vital residual tumor in the resectate, independent of the combined positivity score (CPS), and prolong disease-free survival, demonstrated Prof. Markus Möhler, MD, Mainz (D). Overall, pembrolizumab, nivolumab, camrelizumab, sintilimab, and toripalimab have been shown to prolong survival in phase III trials with palliative chemotherapy. In the second-line treatment of squamous cell carcinoma of the esophagus, nivolumab was approved on the basis of prolonged survival compared with chemotherapy – as was tislelizumab.
New standards of first-line therapy
Based on CHECKMATE-649, the combination of nivolumab and chemotherapy in the first-line treatment of PD-L1 (programmed cell death protein 1)-positive patients with advanced transitional gastroesophageal cancer (GEJC), esophageal cancer (EC), and gastric cancer (GC) was approved in Europe for PD-L1 CPS ≥5 patients and regardless of PD-L1 score in the United States and Taiwan. Based on approval for the KEYNOTE-590 trial, patients with advanced GEJC and EC qualify for the combination of pembrolizumab plus chemotherapy in Europe (CPS ≥10) and the US. The use of the PD-L1 inhibitor avelumab in maintenance therapy after first-line induction chemotherapy was investigated in our JAVELIN Gastric 100 trial. The superior OS benefit achieved was not met and the duration of response was not prolonged. However, an exploratory subgroup analysis using the 22C3 antibody showed a promising signal of ICI therapy as maintenance.
Patients with oligometastatic disease
Oligo-metastatic disease can be considered an intermediate state between locoregional and systemic disease, the expert said. It may reflect a distinct and favorable tumor biology in which patients could benefit from systemic treatment – as established for truly metastatic disease – and locoregional treatment, including surgery and (stereotactic) radiation. The ongoing RENAISSANCE trial, which is evaluating surgery for primarius and metastases in limited metastatic disease as an adjunct to systemic therapy with FLOT, continues to enroll patients. In preparation is a project which investigates pembrolizumab and olaparib after initial short term chemotherapy/ pembrolizumab in dependence of mutations in homologous recombination (POLESTAR).
Combination with Her2-targeted therapies
Trastuzumab has been successfully used as a standard palliative therapy with chemotherapy for over 10 years. In the new era of ICI, new combination therapies of Her2- and PD-1/PD-L1-targeted agents target synergistic effects. An initial single-arm analysis of the combination of targeted therapy of trastuzumab, chemotherapy, and pembrolizumab in the first-line setting of patients with Her2-positive metastatic EGC demonstrated a safe therapeutic combination. KEYNOTE-811 evaluates the effect of combination of trastuzumab, chemotherapy with pembrolizumab versus placebo on OS and tolerability. The first interim analysis showed a superior improved ORR of 22.7% in trastuzumab+ chemotherapy with pembrolizumab compared with placebo (ORR 74.4% vs. 51.9%). Complete response rate (CR) and disease control rate (DCR) were beneficial with the addition of pembrolizumab. The increase in ORR with the administration of pembrolizumab, trastuzumab, and chemotherapy led to the approval of this combination for patients in the United States and is expected in Europe next year.
Several novel Her2-targeted therapies are being investigated for Her2-positive patients who do not benefit from trastuzumab, including the promising antibody-drug conjugate trastuzumab-deruxtecan (T-DXd). As approved by the FDA as a Her2-targeted second-line treatment option for patients with unresectable, locally advanced or metastatic GC in 2021, T-DXd is being studied in combinations. The optimal treatment of trastuzumab-refractory patients with loss of Her2 expression remains to be clarified in future studies, as loss of Her2 expression was detected in 60.6% of patients with refractory disease after first-line trastuzumab, Möhler concluded.
Later lines of therapy in adenocarcinoma.
In second-line and third-line adenocarcinomas, the RAMIRIS phase II trial has shown that for taxane-pretreated patients, FOLFIRI + ramucirumab may be superior to paclitaxel + ramucirumab therapy. This hypothesis is now being investigated for taxane-pretreated patients in the ongoing RAMIRIS phase III trial.
In addition, in third-line therapy, superior overall survival was achieved with the administration of nivolumab. Pembrolizumab shows a positive effect on duration of response. Issues of resistance to immunotherapy or the role of sex in response to ICI need to be addressed. Also in the third line, the synergism between anti-angiogenesis and checkpoint blockade is investigated. A phase III trial of regorafinib and nivolumab has started comparing this combination vs. standard chemotherapy.
Congress: GI-Oncology
Source: “Therapy in metastatic stage in esophageal and gastric carcinomas: What is new?”, Session II. Gastroesophageal Tumors, Prof. Dr. med. Markus Möhler, University Medicine of the Johannes Gutenberg University Mainz (D).
InFo ONCOLOGY & HEMATOLOGY 2022; 10(3): 28.
