PD-1 Blockade in Advanced Adrenocortical Carcinoma

Abstract

Purpose: Adrenocortical carcinomas (ACC) are rare and aggressive malignancies with limited treatment options. This study was undertaken to evaluate the immunogenicity of ACC.

Patients and methods: Patients with advanced ACC were enrolled in a phase II study to evaluate the clinical activity of pembrolizumab 200 mg every 3 weeks, without restriction on prior therapy. The primary end point was objective response rate. Efficacy was correlated with tumor programmed death-ligand 1 expression, microsatellite-high and/or mismatch repair deficient (MSI-H/MMR-D) status, and somatic and germline genomic correlates.

Results: We enrolled 39 patients with advanced ACC and herein report after a median follow-up of 17.8 months (range, 5.4 months to 34.7 months). The objective response rate to pembrolizumab was 23% (nine patients; 95% CI, 11% to 39%), and the disease control rate was 52% (16 patients; 95% CI, 33% to 69%). The median duration of response was not reached (lower 95% CI, 4.1 months). Two of six patients with MSI-H/MMR-D tumors responded. The other seven patients with objective responses had microsatellite stable tumors. The median progression-free survival was 2.1 months (95% CI, 2.0 months to 10.7 months), and the median overall survival was 24.9 months (95% CI, 4.2 months to not reached). Thirteen percent of patients (n = 5) had treatment-related grade 3 or 4 adverse events. Tumor programmed death-ligand 1 expression and MSI-H/MMR-D status were not associated with objective response.

Conclusion: MSI-H/MMR-D tumors, for which pembrolizumab is a standard therapy, are more common in ACC than has been recognized. In advanced ACC that is microsatellite stable, pembrolizumab provided clinically meaningful and durable antitumor activity with a manageable safety profile.

Trial registration: ClinicalTrials.gov NCT02673333.

Figures

FIG 1.

Tumor responses and clinical outcomes. (A) Maximum decrease from baseline in the size of tumors in patients treated with pembrolizumab who underwent blinded radiologic evaluation (n = 31) after initiation of treatment. (B) Response characteristics of patients with an objective response. Each horizontal bar represents one patient. Three patients have completed 24 months of treatment with pembrolizumab and are now on observation (top three bars). One patient experienced pseudoprogression (bar 2). One patient experienced RECIST v1.1–defined progression after objective response (bar 5). Two patients with objective responses discontinued therapy per investigator discretion; both patients are alive with continued response while on observation (bars 8 and 9). (C) Kaplan-Meier curve showing progression-free survival among 39 patients with advanced adrenocortical carcinoma who received pembrolizumab. Progression-free survival was measured from the start of treatment with pembrolizumab until progression of disease or death as a result of any cause, whichever occurred first. For nonevaluable patients by RECIST v1.1 who came off study because of clinical progression (n = 8), the date of progression of disease was noted as the day off study. Median progression-free survival was 2.1 months (95% CI, 2.0 months to 10.7 months). (D) Kaplan-Meier curve showing overall survival among 39 patients with advanced adrenocortical carcinoma who received pembrolizumab. Overall survival was measured as the time from the start of treatment with pembrolizumab until death. For patients alive at the end of study or lost to follow-up, overall survival was censored on the last date when patients were known to be alive. Median overall survival was 24.9 months (95% CI, 4.2 months to not reached). (*) Patient with MSI-H/MMMR-D tumor, maximum decrease from baseline 0%. MSI-H/MMR-D, microsatellite-high/mismatch repair-deficient; PR, partial response by RECIST v1.1.

FIG 2.

Exceptional responses to pembrolizumab in advanced adrenocortical carcinoma. (A) Baseline imaging in a patient before initiation of treatment with pembrolizumab, with tumor inferior vena cava invasion with cephalad extension of the tumor into the right atrium. The patient subsequently received a single dose of pembrolizumab, with treatment complicated by immune-mediated elevation of the liver function tests and hospitalization, and additional treatment with pembrolizumab stopped per investigator discretion. Imaging performed at week 70 after the single dose of pembrolizumab demonstrates continued objective response (−45% by RECIST v1.1). In germline genetic testing, this patient was found to have Lynch syndrome (germline MSH6 c.3261delC exon 5 alteration), which was undiagnosed before entry in the study. (B) Baseline imaging in a patient before initiation of treatment with pembrolizumab, with retroperitoneal metastases noted. This patient developed grade 2 immune-mediated elevated liver function tests and stopped additional treatment per investigator discretion after two cycles. At week 17, this patient presented with clinical hyperpigmentation of the lips, tongue, and inner oral mucosal membrane, with imaging at that time demonstrating continued objective response (−58% by RECIST v1.1).

FIG 3.

Pathologic and genomic correlates of response. (A) Oncoprint showing the genomic landscape of advanced adrenocortical carcinomas treated with pembrolizumab in this study, as identified by Memorial Sloan Kettering–Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT). (B, C, and D) Tumor mutation burden, tumor microsatellite-high/mismatch repair-deficient (MSI-H/MMR-D) status, and tumor programmed death-ligand 1 (PD-L1) status in relation to objective response to pembrolizumab. In correlative analyses, there was no association between genetic alterations, tumor mutation burden, tumor MSI-H/MMR-D status, or tumor PD-L1 status with objective response. Mut/Mb, mutations/megabase; PD, progression of disease by RECIST v1.1; PR, partial response by RECIST v1.1; SD, stable disease by RECIST v1.1; TIL, tumor-infiltrating lymphocyte.

FIG A1.

Study design. (*) All patients who discontinued study treatment proceeded to the follow-up phase. ACC, adrenocortical carcinoma.

FIG A2.

Pseudoprogression in advanced adrenocortical carcinoma during treatment with pembrolizumab. Two patients with objective responses to pembrolizumab experienced growth initially in target and nontarget lesions before response. (A) A left-sided lung metastasis observed on baseline imaging in an enrolled patient prior to initiation of pembrolizumab. (B) RECIST-defined progression (+20%) in this lung metastasis at week 27 on treatment. Objective partial response by RECIST was first noted at week 45 (−42%). (C) The lung metastasis at week 99 on treatment (−73%). A second patient enrolled in the study was also noted to have growth in the disease at week 9 (+19%); at that time, the patient was clinically feeling well, gaining weight, with excellent energy and appetite, and treatment with pembrolizumab continued. In this second patient, imaging at week 18 subsequently demonstrated a partial response by RECIST (−39%).