Lenvatinib plus pembrolizumab in patients with advanced gastric cancer in the first-line or second-line setting (EPOC1706): an open-label, single-arm, phase 2 trial

Kawazoe, Akihito; Fukuoka, Shota; Nakamura, Yoshiaki; Kuboki, Yasutoshi; Wakabayashi, Masashi; Nomura, Shosaku; Mikamoto, Yuichi; Shima, Hikari; Fujishiro, Noriko; Higuchi, Tsukiko; Sato, Akihiro; Kuwata, Takeshi; Shitara, Kohei

doi:10.1016/s1470-2045(20)30271-0

Cited by 198 publications

(124 citation statements)

References 27 publications

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“…However, despite these advances, hypotheses are formed on how to further improve on these outcomes. The therapeutic resistance observed, which generally converged on common pathways and mechanisms, suggests that preemptive dual targeted inhibition may lead to even further progress, such as combined RTK inhibition for concurrent RTK amplified tumors, (35,67,68) IO and antiangiogenesis, (69,70) or combination if IO and RTK inhibition, (35,37,61,62) in a similarly prioritized manner.…”

Section: Discussionmentioning

confidence: 99%

Personalized Antibodies for Gastroesophageal Adenocarcinoma (PANGEA): A Phase II Study Evaluating an Individualized Treatment Strategy for Metastatic Disease

et al. 2021

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The 1-year and median overall survivals (mOS) of advanced gastroesophageal adenocarcinomas (GEA) are ~50% and <12 months. Baseline spatial and temporal molecular heterogeneity of targetable alterations may be a cause of failure of targeted/immunooncologic therapies. This heterogeneity, coupled with infrequent incidence of some biomarkers, has resulted in stalled therapeutic progress. We hypothesized that a personalized treatment strategy, applied at first diagnosis then serially over up to three treatment lines using monoclonal antibodies combined with optimally-sequenced chemotherapy, could contend with these hurdles. This was tested using a novel clinical expansion platform type-II design with a survival primary endpoint. Of 68 patients by intention-to-treat, 1-year survival was 66% and mOS was 15.7 months, meeting the primary efficacy endpoint (one-sided p=0.0024). First-line response rate (74%), disease control rate (99%), and median progression free survival (8.2 months) were superior to historical controls. The PANGEA strategy led to improved outcomes warranting a larger randomized study. Significance This study highlights excellent outcomes achieved by individually optimizing chemotherapy, biomarker profiling, and matching of targeted therapies at baseline and over time for GEA. Testing a predefined treatment strategy resulted in improved outcomes versus historical controls. Therapeutic resistance observed in correlative analyses suggests that dual targeted inhibition may be beneficial. Research.

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Section: Discussionmentioning

confidence: 99%

Personalized Antibodies for Gastroesophageal Adenocarcinoma (PANGEA): A Phase II Study Evaluating an Individualized Treatment Strategy for Metastatic Disease

et al. 2021

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“…In fact, bevacizumab itself might not be the most effective VEGF-targeting drug [21][22][23][24] at least in breast cancer, but the investigatorinitiated nature of this trial made bevacizumab the only realistic antiangiogenic option for the study. The impressive effects of other antiangiogenics with high affinity against VEGFR2 such as lenvatinib (in gastric [34] and endometrial cancer [35]) or axitinib (in kidney cancer [36]) in combination with pembrolizumab should make at least consider these partners in for combination with immunotherapy in future trials in breast cancer exploring this concept.…”

Section: Discussionmentioning

confidence: 99%

Immuno-priming durvalumab with bevacizumab in HER2-negative advanced breast cancer: a pilot clinical trial

et al. 2020

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Background Preclinical research suggests that the efficacy of immune checkpoint inhibitors in breast cancer can be enhanced by combining them with antiangiogenics, particularly in a sequential fashion. We sought to explore the efficacy and biomarkers of combining the anti-PD-L1 durvalumab plus the antiangiogenic bevacizumab after bevacizumab monotherapy for advanced HER2-negative breast cancer. Methods Patients had advanced HER2-negative disease that progressed while receiving single-agent bevacizumab maintenance as a part of a previous chemotherapy plus bevacizumab regimen. Treatment consisted of bi-weekly durvalumab plus bevacizumab (10 mg/kg each i.v.). Peripheral-blood mononuclear cells (PBMCs) were obtained before the first durvalumab dose and every 4 weeks and immunophenotyped by flow-cytometry. A fresh pre-durvalumab tumor biopsy was obtained; gene-expression studies and immunohistochemical staining to assess vascular normalization and characterize the immune infiltrate were conducted. Patients were classified as “non-progressors” if they had clinical benefit (SD/PR/CR) at 4 months. The co-primary endpoints were the changes in the percentage T cell subpopulations in PBMCs in progressors versus non-progressors, and PFS/OS time. Results Twenty-six patients were accrued. Median PFS and OS were 3.5 and 11 months; a trend for a longer OS was detected for the hormone-positive subset (19.8 versus 7.4 months in triple-negatives; P = 0.11). Clinical benefit rate at 2 and 4 months was 60% and 44%, respectively, without significant differences between hormone-positive and triple-negative (P = 0.73). Non-progressors’ tumors displayed vascular normalization features as a result of previous bevacizumab, compared with generally abnormal patterns observed in progressors. Non-progressors also showed increased T-effector and T-memory signatures and decreased TREG signatures in gene expression studies in baseline—post-bevacizumab—tumors compared with progressors. Notably, analysis of PBMC populations before durvalumab treatment was concordant with the findings in tumor samples and showed a decreased percentage of circulating TREGs in non-progressors. Conclusions This study reporting on sequential bevacizumab+durvalumab in breast cancer showed encouraging activity in a heavily pre-treated cohort. The correlative studies agree with the preclinical rationale supporting an immunopriming effect exerted by antiangiogenic treatment, probably by reducing TREGs cells both systemically and in tumor tissue. The magnitude of this benefit should be addressed in a randomized setting. Trial registration (www.clinicaltrials.gov): NCT02802098. Registered on June 16, 2020.

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“…The GEA tumor microenvironment is directly involved in tumor development and progression [ 71 ] and, for this reason, the combinations of checkpoint inhibitors and antiangiogenetic drugs is being tested. In a small phase II trial, the use of the combination of pembrolizumab and levantinib as I or II line showed, across HER2 negative Asiatic GEA, an objective response recorded in 69% of patients with an acceptable toxicity suggesting a potential role of the combination also in the MSS population that should be further explored [ 72 , 73 ]. The combination of nivolumab and regorafenib is also under evaluation [ 74 ].…”

Section: The Search For Biomarkers For Precision Immunotherapymentioning

confidence: 99%

Precision Medicine to Treat Advanced Gastroesophageal Adenocarcinoma: A Work in Progress

Gambardella

Fleitas

Tarazona

et al. 2020

JCM

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Gastroesophageal adenocarcinoma (GEA) represents a heterogeneous disease and, when diagnosed as locally advanced or metastatic, it is characterized by poor prognosis. During the last few years, several molecular classifications have been proposed to try to personalize treatment for those patients diagnosed with advanced disease. Nevertheless, despite the great effort, precision medicine is still far from being a reality. The improvement in the molecular analysis due to the application of high throughput technologies based on DNA and RNA sequencing has opened a novel scenario leading to the personalization of treatment. The possibility to target epidermal growth factor receptor (HER)2, Claudine, Fibroblast Growth Factor Receptors (FGFR), and other alterations with a molecular matched therapy could significantly improve clinical outcomes over advanced gastric cancer patients. On the other hand, the development of immunotherapy could also represent a promising strategy in a selected population. In this review, we sought to describe the novel pathways implicated in GEA progression and the results of the molecular matched therapies.

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Lenvatinib plus pembrolizumab in patients with advanced gastric cancer in the first-line or second-line setting (EPOC1706): an open-label, single-arm, phase 2 trial

Cited by 198 publications

References 27 publications

Personalized Antibodies for Gastroesophageal Adenocarcinoma (PANGEA): A Phase II Study Evaluating an Individualized Treatment Strategy for Metastatic Disease

Personalized Antibodies for Gastroesophageal Adenocarcinoma (PANGEA): A Phase II Study Evaluating an Individualized Treatment Strategy for Metastatic Disease

Immuno-priming durvalumab with bevacizumab in HER2-negative advanced breast cancer: a pilot clinical trial

Precision Medicine to Treat Advanced Gastroesophageal Adenocarcinoma: A Work in Progress

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