Phase II clinical trial of pembrolizumab efficacy and safety in advanced adrenocortical carcinoma

Abstract

BackgroundAdrenocortical carcinoma (ACC) is a rare malignancy without good treatment options. There are limited data about the use of immunotherapy in ACC. We investigated the efficacy and safety of pembrolizumab in patients with metastatic ACC.MethodsThis is a pre-specified cohort of a single-center, investigator-initiated, phase II clinical trial using pembrolizumab monotherapy in patients with rare malignancies. Patients must have had prior treatment fail in the past 6 months before study enrollment. Patients were enrolled from August 2016 to October 2018. Follow-up data were updated as of March 26, 2019.Patients received 200 mg pembrolizumab intravenously every 3 weeks without concomitant oncologic therapy. The primary endpoint was non-progression rate (NPR) at 27 weeks. Other endpoints included adverse events, tumor responses measured independently by objective radiologic criteria, and select immunological markers.ResultsSixteen patients with ACC (including eight women [50%]) were included in this cohort. Ten patients (63%) had evidence of hormonal overproduction (seven had cortisol-producing ACC). Non-progression rate at 27 weeks was evaluable in 14 patients, one patient was lost to follow-up, and one patient left the study because of an adverse event. Five of 14 patients were alive and progression-free at 27 weeks (non-progression rate at 27 weeks was 36, 95% confidence interval 13–65%). Of the 14 patients evaluable for imaging response by immune-related Response Evaluation Criteria in Solid Tumors, two had a partial response (including one with cortisol-producing ACC), seven had stable disease (including three with cortisol-producing ACC), and five had progressive disease, representing an objective response rate of 14% (95% confidence interval 2–43%). Of those who had stable disease, six had disease stabilization that lasted ≥4 months. Severe treatment-related adverse events (≥grade 3) were seen in 2 of 16 patients (13%) and resulted in one patient discontinuing study participation. All studied tumor specimens (14/14) were negative for programmed cell death ligand-1 expression. Thirteen of 14 tumor specimens (93%) were microsatellite-stable. Eight of 14 patients (57%) had a high tumor-infiltrating lymphocyte score on immunohistochemistry staining.ConclusionsSingle-agent pembrolizumab has modest efficacy as a salvage therapy in ACC regardless of the tumor’s hormonal function, microsatellite instability status, or programmed cell death ligand-1 status. Treatment was well tolerated in most study participants, with a low rate of severe adverse events.Trial registrationClinicalTrials.gov identifier: NCT02721732, Registered March 29, 2016.

Interplay between glucocorticoids and tumor-infiltrating lymphocytes on the prognosis of adrenocortical carcinoma

“…31 However, so far, four small studies with a total of 115 patients have been published in ACC and overall the results were disappointing; only 15 patients experienced partial response and 12 long-term disease control for more than 12 months. [7][8][9][10] Our study may shed some light, why strong immune infiltration is rarely seen in ACC and why current immunological therapeutic options were of limited efficacy. The fact that we found a negative correlation of tumorassociated glucocorticoid excess and T helper cells supports an expected role of steroids in this context.…”

“…Results of the first (small) trials with immunotherapy in ACC are modest, with a median progression-free survival times of 1.8, 2.1, 2.6 and 6.75 months, respectively. [7][8][9][10] However, in one study with 39 patients, disease control rate was 52% and interestingly median overall survival reached almost 25 months clearly suggesting that at least a subset of patients benefits from this therapeutic approach.…”

Adjuvant Therapy in Adrenocortical Carcinoma: Reflections and Future Directions

“…It has been used successfully as a prognostic marker in other malignancies, including breast cancer [75]; however, studies are needed to prospectively validate its use for ACC. Finally, although we have some evidence regarding the potential benefit of immunotherapy in ACC [76,77], there are no data available regarding its use in the adjuvant setting. We are hoping that this option will be explored in select patients in the near future.…”

Combined lenvatinib and pembrolizumab as salvage therapy in advanced adrenal cortical carcinoma

“…However, emerging data have shown limited efficacy for single-agent CPIs in ACC, with durable responses limited to a small subset of patients. [5][6][7] The combination of multikinase inhibitors (MKIs) with CPIs has shown promising data in multiple cancers. [8][9][10][11] In particular, the MKI lenvatinib (LEN), which inhibits Vascular Endothelial Growth Factor Receptor 1-3 (VEGFR 1-3), Fibroblast Growth Factor Receptor 1-4 (FGFR 1-4), Platellet Derived Growth Factor Receptor-α (PDGFR-α), RET, and KIT, has been combined with the anti-PD-1 monoclonal antibody pembrolizumab (PEM) in phase I/II trials.…”