Avelumab in patients with previously treated metastatic adrenocortical carcinoma: phase 1b results from the JAVELIN solid tumor trial

Tourneau, Christophe Le; Hoimes, Christopher J.; Zarwan, Corrine; Wong, Deborah Jean Lee; Bauer, Sebastian; Claus, Rainer; Wermke, Martin; Subramanian, Hariharan; Heydebreck, Anja von; Kasturi, Vijay; Chand, Vikram K.; Gulley, James L.

doi:10.1186/s40425-018-0424-9

Cited by 133 publications

(116 citation statements)

References 33 publications

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“…26 Recently, 6% ORR was reported in patients treated with avelumab, but almost half of that study's subjects had concomitant therapy with mitotane, which clouds the interpretation of the efficacy of avelumab. 27 In this context, the ORR of 15% and CBR of 54% in our study using single-agent pembrolizumab are clinically meaningful. Given that all therapies for metastatic ACC are considered palliative at best, 23 the NPR of 31% in our ACC cohort is encouraging.…”

Section: Discussionmentioning

confidence: 57%

Phase 2 study of pembrolizumab in patients with advanced rare cancers

Naing

Meric‐Bernstam

Stephen

et al. 2020

J Immunother Cancer

108

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BackgroundPatients with advanced rare cancers have poor prognosis and few treatment options. As immunotherapy is effective across multiple cancer types, we aimed to assess pembrolizumab (programmed cell death 1 (PD-1) inhibitor) in patients with advanced rare cancers.MethodsIn this open-label, phase 2 trial, patients with advanced rare cancers whose tumors had progressed on standard therapies, if available, within the previous 6 months were enrolled in nine tumor-specific cohorts and a 10th cohort for other rare histologies. Pembrolizumab 200 mg was administered intravenously every 21 days. The primary endpoint was non-progression rate (NPR) at 27 weeks; secondary endpoints were safety and tolerability, objective response rate (ORR), and clinical benefit rate (CBR).ResultsA total of 127 patients treated between August 15, 2016 and July 27, 2018 were included in this analysis. At the time of data cut-off, the NPR at 27 weeks was 28% (95% CI, 19% to 37%). A confirmed objective response (OR) was seen in 15 of 110 (14%) evaluable patients (complete response in one and partial response in 14). CBR, defined as the percentage of patients with an OR or stable disease ≥4 months, was 38% (n=42). Treatment was ongoing in 11 of 15 patients with OR at last follow-up. In the cohort with squamous cell carcinoma (SCC) of the skin, the NPR at 27 weeks was 36%, ORR 31%, and CBR 38%. In patients with adrenocortical carcinoma (ACC), NPR at 27 weeks was 31%, ORR 15%, and CBR 54%. In the patients with carcinoma of unknown primary (CUP), NPR at 27 weeks was 33%, ORR 23%, and CBR 54%. In the paraganglioma–pheochromocytoma cohort, NPR at 27 weeks was 43%, ORR 0%, and CBR 75%. Treatment-related adverse events (TRAEs) occurred in 66 of 127 (52%) patients, and 12 (9%) had grade ≥3 TRAEs. The most common TRAEs were fatigue (n=25) and rash (n=17). There were six deaths, all of which were unrelated to the study drug.ConclusionsThe favorable toxicity profile and antitumor activity seen in patients with SCC of skin, ACC, CUP, and paraganglioma–pheochromocytoma supports further evaluation of pembrolizumab in this patient population.Trial registration numberNCT02721732

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Section: Discussionmentioning

confidence: 57%

Phase 2 study of pembrolizumab in patients with advanced rare cancers

Naing

Meric‐Bernstam

Stephen

et al. 2020

J Immunother Cancer

108

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“…These data, together with the reported low expression of the immune checkpoint molecule PDL1 in ACC tumor cells [17], suggest that chances for successful immunotherapy are limited in patients with ACC. One study reported that a subset of platinum-pretreated patients with metastatic ACC had a partial response or stable disease after treatment with the anti-PDL1 antibody avelumab [18], but these results were similar to those obtained in other studies using second-line chemotherapy [19]. However, recent studies showed that the immune response may have an important role in influencing the clinical course of patients with ACC.…”

Section: Discussionsupporting

confidence: 59%

“…In pediatric ACC, MHC class II expression by tumor-infiltrating hematopoietic cells and the number of CD8 + T-lymphocytes are important prognostic indicators [13,20]. Even if in general only a small percentage of ACC tumor cells express PDL1, as detected by IHC [17,18], higher levels of PDL1 mRNA expression are significantly correlated with an inflammatory gene expression signature and longer DFS of adult patients with ACC [21]. Furthermore, an unpublished study from the Würzburg group has shown that the number of tumor-infiltrating CD4 + and CD8 + T-lymphocytes are stage-independent prognostic indicators in patients with ACC and that glucocorticoid excess is associated with T-cell depletion and unfavorable prognosis [22].…”

Section: Discussionmentioning

confidence: 99%

Cancer-testis Antigen FATE1 Expression in Adrenocortical Tumors Is Associated with A Pervasive Autoimmune Response and Is A Marker of Malignancy in Adult, but Not Children, ACC

Doghman

Finetti

Durand

et al. 2020

Cancers

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The SF-1 transcription factor target gene FATE1 encodes a cancer-testis antigen that has an important role in regulating apoptosis and response to chemotherapy in adrenocortical carcinoma (ACC) cells. Autoantibodies directed against FATE1 were previously detected in patients with hepatocellular carcinoma. In this study, we investigated the prevalence of circulating anti-FATE1 antibodies in pediatric and adult patients with adrenocortical tumors using three different methods (immunofluorescence, ELISA and Western blot). Our results show that a pervasive anti-FATE1 immune response is present in those patients. Furthermore, FATE1 expression is a robust prognostic indicator in adult patients with ACC and is associated with increased steroidogenic and decreased immune response gene expression. These data can open perspectives for novel strategies in ACC immunotherapy.

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“…30 A phase 1b expansion cohort enrolled 50 patients with platinum-pretreated metastatic ACC. 31 To our knowledge, this is the largest prospective trial for a checkpoint inhibitor in this disease. The objective response rate (ORR) was 6%, and 21 patients (42%) had the stable disease as a best response (disease control rate: 48%).…”

Section: Introductionmentioning

confidence: 93%

PDL1 expression is associated with longer postoperative, survival in adrenocortical carcinoma

et al. 2019

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Adrenocortical carcinomas (ACCs) are heterogeneous cancers associated with a very poor prognosis. The improvement of prognostic tools and systemic therapy are urgently needed. Targeting the immune system using checkpoint inhibitors such as PD1/PDL1 inhibitors is an attractive novel therapeutic strategy for poor-prognosis tumors. Multiple clinical trials are ongoing, including in advanced ACC. However, PDL1 expression has been studied in ACC in only one heterogeneous series of 28 clinical samples. Here, we have retrospectively analyzed PDL1 mRNA expression in 146 clinical ACC samples and searched for correlations between expression and biological and clinicopathological data, including post-operative disease-free survival (DFS). PDL1 mRNA expression was heterogeneous across samples. "PDL1-high" tumors were not associated with the classical prognostic variables but were associated with longer DFS in both uni-and multivariate analyses. High PDL1 mRNA expression was associated with biological signs of the cytotoxic local immune response. Supervised analysis between "PDL1-high" and "PDL1-low" tumors identified a robust 370-gene signature whose ontology analysis suggested the existence in "PDL1-high" tumors of a cytotoxic T-cell response, however, associated with some degree of T-cell exhaustion. In conclusion, PDL1 mRNA expression refines the prognostication in ACC and high expression is associated with longer DFS. Clinical validation at the protein level and functional validation are required to fully understand the role of PDL1 in ACC. Reactivation of dormant tumor-infiltrating lymphocytes by PDL1-inhibitors could represent a promising strategy in "PDL1-high" ACCs, supporting the ongoing clinical trials.

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Avelumab in patients with previously treated metastatic adrenocortical carcinoma: phase 1b results from the JAVELIN solid tumor trial

Cited by 133 publications

References 33 publications

Phase 2 study of pembrolizumab in patients with advanced rare cancers

Phase 2 study of pembrolizumab in patients with advanced rare cancers

Cancer-testis Antigen FATE1 Expression in Adrenocortical Tumors Is Associated with A Pervasive Autoimmune Response and Is A Marker of Malignancy in Adult, but Not Children, ACC

PDL1 expression is associated with longer postoperative, survival in adrenocortical carcinoma

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