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

ABSTRACT: BACKGROUND:Adrenocortical 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. METHODS:This 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. RESULTS:Sixteen 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. CONCLUSIONS:Single-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 REGISTRATION:ClinicalTrials.gov identifier: NCT02721732 , Registered March 29, 2016.

SUBMITTER: Habra MA

PROVIDER: S-EPMC6751592 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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

Habra Mouhammed Amir MA Stephen Bettzy B Campbell Matthew M Hess Kenneth K Tapia Coya C Xu Mingxuan M Rodon Ahnert Jordi J Jimenez Camilo C Lee Jeffrey E JE Perrier Nancy D ND Boraddus Russell R RR Pant Shubham S Subbiah Vivek V Hong David S DS Zarifa Abdulrazzak A Fu Siqing S Karp Daniel D DD Meric-Bernstam Funda F Naing Aung A

Journal for immunotherapy of cancer 20190918 1

<h4>Background</h4>Adrenocortical 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.<h4>Methods</h4>This 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 month ...[more]

PMID: 31533818

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Project description:Abstract BACKGROUND: Adrenocortical carcinoma (ACC) in an aggressive malignancy with suboptimal response to frontline chemotherapy and without established second line treatment. cMET activation is associated with ACC resistance to chemotherapy. Cabozantinib is a multi-kinase inhibitor that targets the VEGFR, c-MET, AXL, and RET receptors. We report interim data about using cabozantinib in ACC through a prospective phase II clinical trial. Methods: This is an investigator-initiated, open label clinical trial to evaluate the efficacy and safety of cabozantinib in patients with unresectable/metastatic ACC (ClinicalTrials.gov Identifier: NCT03370718). The primary objective is 4-month progression-free survival rate (PFS4). Participants are ≥ 18 years old with histologically confirmed ACC. Subjects who used mitotane within 6 months of consent must have mitotane serum level of < 2 mg/L. Cabozantinib starting dose is 60 mg daily with possible dose reductions. Subjects stopped treatment at time of disease progression, death, or occurrence of severe adverse events. Objective tumor responses were assessed per RECIST v.1.1 criteria. Adverse effects were graded per CTCAE v.4.03 Results: At time of data cut off (Oct 28, 2019), we screened 16 patients for enrollment. Ten patients (3 females) received cabozantinib out of whom 5 had history of mitotane use. Nine patients were eligible for response evaluation, defined as having at least one follow up imaging. One patient was taken off study after one week due to hypertensive crisis. Median age at time of diagnosis was 45 years (range 32 - 72). Five patients had hormonally active ACC. Median number of prior lines of systemic therapy was 2 (range 0 -5). Median duration of cabozantinib therapy was 6.6 months (range 0.7 -11.3). Eight patients (80%) were without evidence of progression at 4 months (achieved study endpoint). At time of data cut off, 1 patient had partial response (53% reduction over 8.8 months and ongoing), 3 patients had stable disease, and 5 patients had progressive disease. Nine patients were alive with disease and one patient died (not drug related). Grade 3/4 clinical adverse events included thromboembolic events (3 patients), severe hypertension (1 patient), intracranial hemorrhage secondary to hypertensive crisis (1 patient), weight loss (1 patient), and abdominal pain (1 patient). Grade 3/4 laboratory adverse events included increased AST (2 patient), increased ALT (1 patient), increased GGT, increased amylase (1 patient), increased lipase (1 patient) and hyponatremia (1 patient). Conclusions: In this interim analysis of phase II study, majority of subjects reached the study primary endpoint (PFS4). These data are in favor of continuing study accrual to assess magnitude of response to therapy and safety profile in ACC. Aggressive blood pressure management and close monitoring of liver enzymes are crucial to ensure the safety of study subjects.

Project description:BackgroundRecent trials suggest that programmed cell death 1 (PD-1)-directed immunotherapy may be beneficial for some patients with anal squamous cell carcinoma and biomarkers predictive of response are greatly needed.MethodsThis multicenter phase II clinical trial (NCT02919969) enrolled patients with metastatic or locally advanced incurable anal squamous cell carcinoma (n=32). Patients received pembrolizumab 200 mg every 3 weeks. The primary endpoint of the trial was objective response rate (ORR). Exploratory objectives included analysis of potential predictive biomarkers including assessment of tumor-associated immune cell populations with multichannel immunofluorescence and analysis of circulating tumor tissue modified viral-human papillomavirus DNA (TTMV-HPV DNA) using serially collected blood samples. To characterize the clinical features of long-term responders, we combined data from our prospective trial with a retrospective cohort of patients with anal cancer treated with anti-PD-1 immunotherapy (n=18).ResultsIn the phase II study, the ORR to pembrolizumab monotherapy was 9.4% and the median progression-free survival was 2.2 months. Despite the high level of HPV positivity observed with circulating TTMV-HPV DNA testing, the majority of patients had low levels of tumor-associated CD8+PD-1+ T cells on pretreatment biopsy. Patients who benefited from pembrolizumab had decreasing TTMV-HPV DNA scores and a complete responder's TTMV-HPV DNA became undetectable. Long-term pembrolizumab responses were observed in one patient from the trial (5.3 years) and three patients (2.5, 6, and 8 years) from the retrospective cohort. Long-term responders had HPV-positive tumors, lacked liver metastases, and achieved a radiological complete response.ConclusionsPembrolizumab has durable efficacy in a rare subset of anal cancers. However, despite persistence of HPV infection, indicated by circulating HPV DNA, most advanced anal cancers have low numbers of tumor-associated CD8+PD-1+ T cells and are resistant to pembrolizumab.

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

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

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