Phase 2 study of pembrolizumab in patients with advanced rare cancers

Naing, Aung; Meric‐Bernstam, Funda; Stephen, Bettzy; Karp, Daniel D.; Hajjar, Joud; Ahnert, Jordi Rodón; Piha-Paul, Sarina A.; Colen, Rivka R.; Jiménez, Camilo; Raghav, Kanwal; Ferrarotto, Renata; Tu, Shi Ming; Campbell, Matthew D.; Wang, Linghua; Sabir, Sarjeel H.; Tapia, Coya; Bernatchez, Chantale; Frumovitz, Michael; Tannir, Nizar M.; Ravi, Vinod; Khan, Sabbir; Painter, Jeane; Abonofal, Abdulrahman; Gong, Jing; Alshawa, Anas; McQuinn, Lacey; Xu, Mingxuan; Ahmed, Sara; Subbiah, Vivek; Hong, David S.; Pant, Shubham; Yap, Timothy A.; Tsimberidou, Apostolia M.; Dumbrava, Ecaterina Elena; Janků, Filip; Fu, Siqing; Simon, Richard; Hess, Kenneth R.; Varadhachary, Gauri R.; Habra, Mouhammed Amir

doi:10.1136/jitc-2019-000347

Cited by 101 publications

(79 citation statements)

References 38 publications

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“…In this open-label, phase II trial, patients with advanced rare cancers whose tumors had progressed within the previous 6 months received pembrolizumab 200 mg intravenously every 21 days. 12 Immune-Related Response Evaluation Criteria In Solid Tumors (irRECIST) 13 was applied to report responses. The adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events V.4.03.…”

Section: Methodsmentioning

confidence: 99%

Efficacy of pembrolizumab in patients with pituitary carcinoma: report of four cases from a phase II study

Majd

Waguespack

Janků

et al. 2020

J Immunother Cancer

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Pituitary carcinoma is an aggressive tumor characterized by metastatic spread beyond the sellar region. Symptoms can be debilitating due to hormonal excess and survival is poor. Pituitary carcinomas recur despite conventional multimodality treatments. Given the recent advances in the use of immune checkpoint inhibitors (CPIs) to treat various solid cancers, there has been interest in exploring the role of immunotherapy for treating aggressive, refractory pituitary tumors. We treated 4 patients with pituitary carcinoma with pembrolizumab as part of a phase II clinical trial. Two patients (patients 1 and 2) with functioning corticotroph pituitary carcinomas (refractory to surgery, radiotherapy and chemotherapy) had partial radiographic (60% and 32% per Immune-Related Response Evaluation Criteria In Solid Tumors, respectively) and hormonal responses. Patient 1’s response continues 42 months after initiation of pembrolizumab and his tumor tissue obtained after treatment with temozolomide demonstrated a hypermutator phenotype with MSH2 and MSH6 gene mutations. Patient 2’s tumor after exposure to temozolomide was not sampled, but prior somatic mutational testing was negative. One patient with a non-functioning corticotroph tumor (patient 3) had a best response of stable disease for 4 months. One patient with a prolactin-secreting carcinoma (patient 4) had progressive disease. The latter 2 patients’ tumors did not demonstrate a hypermutator phenotype after treatment with temozolomide. Programmed death-ligand 1 staining was negative in all tumors. We report 2 cases of corticotroph pituitary carcinoma responsive to pembrolizumab after prior exposure to alkylating agents. The role of CPIs in treating patients with pituitary carcinoma, the relationship between tumor subtype and response to immunotherapy and mechanisms of hypermutation in this orphan disease require further study.Trial registration number: NCT02721732.

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Section: Methodsmentioning

confidence: 99%

Efficacy of pembrolizumab in patients with pituitary carcinoma: report of four cases from a phase II study

Majd

Waguespack

Janků

et al. 2020

J Immunother Cancer

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“…An H-score of 0–300 was assigned to tumor samples. Using a recursive partitioning analysis, we identified a score of 42.5 as the optimal cut-off point for PDL-1 H-score [ 25 ]. To evaluate the presence of tumor-infiltrating lymphocytes (TILs), we performed a morphologic assessment of hematoxylin-eosin sections within the tumor nests.…”

Section: Methodsmentioning

confidence: 99%

“…We previously reported the results of an interim analysis of a phase II study of pembrolizumab in patients with rare tumors [ 25 ]. Anti-tumor activity was observed in patients with adrenal cortical carcinoma, squamous cell carcinoma, cancer of unknown origin, and MPPGs.…”

Section: Introductionmentioning

confidence: 99%

Phase II Clinical Trial of Pembrolizumab in Patients with Progressive Metastatic Pheochromocytomas and Paragangliomas

Jiménez

Subbiah

Stephen

et al. 2020

Cancers

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Metastatic pheochromocytomas and paragangliomas (MPPGs) are rare endocrine malignancies that are associated with high rates of morbidity and mortality because of their large tumor burden and location, progression, and release of catecholamines. Systemic therapies for MPPGs are limited. MPPGs are characterized by pseudohypoxia that may prevent immune system recognition. We conducted a phase II clinical trial of pembrolizumab in patients with progressive MPPGs. The primary endpoint was the non-progression rate at 27 weeks. The secondary endpoints included the objective response and clinical benefit rates, progression free and overall survival duration, and safety. We also determined whether PDL-1 expression and the presence of infiltrating mononuclear inflammatory cells in the primary tumor were associated with clinical response and hereditary background. Eleven patients were included in this trial, four (36%) with germline mutations and seven (64%) with hormonally active tumors. Four patients (40%, 95% confidence interval (CI) 12–74%) achieved the primary endpoint. The objective response rate was 9% (95% CI: 0–41%). The clinical benefit rate was 73% (95% CI: 39–94%). Four patients had grade 3 adverse events related to pembrolizumab. No patients experienced grade 4 or 5 adverse events or a catecholamine crisis. Progression free survival time was 5.7 months (95% CI: 4.37—not reached). The median survival duration was 19 months (95% CI: 9.9—not reached). PDL-1 expression and the presence of infiltrating mononuclear inflammatory cells in the primary tumor did not seem to be associated with disease response. Single-agent pembrolizumab has modest treatment efficacy in patients with progressive MPPGs. Positive responses seemed to be independent of patients’ hereditary backgrounds, tumor hormonal status, and the presence of infiltrating mononuclear inflammatory cells or PDL-1 expression in the primary tumor.

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“…Evidence supporting the use of pembrolizumab in patients with PHEO/PGL is still limited. Naing et al first reported data from a single-center, phase 2 trial ( NCT02721732, Phase II Study for the Evaluation of Efficacy of Pembrolizumab (MK-3475) in Patients With Rare Tumors) with the aim to assess the efficacy and safety profile of pembrolizumab in adults with advanced rare cancers [ 38 ]. Final results from the cohort of patients with PHEO/PGL have been recently published [ 39 ].…”

Section: Resultsmentioning

confidence: 99%

Emerging Therapies in Pheochromocytoma and Paraganglioma: Immune Checkpoint Inhibitors in the Starting Blocks

Fanciulli

Molfetta

Dotto

et al. 2020

JCM

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Pheochromocytoma and paraganglioma are neuroendocrine neoplasms, originating in the adrenal medulla and in parasympathetic and sympathetic autonomic nervous system ganglia, respectively. They usually present as localized tumours curable with surgery. However, these tumours may exhibit heterogeneous clinical course, ranging from no/minimal progression to aggressive (progressive/metastatic) behavior. For this setting of patients, current therapies are unsatisfactory. Immune checkpoint inhibitors have shown outstanding results for several types of solid cancers. We therefore aimed to summarize and discuss available data on efficacy and safety of current FDA-approved immune checkpoint inhibitors in patients with pheochromocytoma and paraganglioma. After an extensive search, we found 15 useful data sources (four full-published articles, four supplements of scientific journals, seven ongoing registered clinical trials). The data we detected, even with the limit of the small number of patients treated, make a great expectation on the therapeutic use of immune checkpoint inhibitors. Besides, the newly detected predictors of response will (hopefully) be of great helps in selecting the subset of patients that might benefit the most from this class of drugs. Finally, new trials are in the starting blocks, and they are expected to shed in the next future new light on a therapy, which is considered a milestone in oncology.

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Phase 2 study of pembrolizumab in patients with advanced rare cancers

Cited by 101 publications

References 38 publications

Efficacy of pembrolizumab in patients with pituitary carcinoma: report of four cases from a phase II study

Efficacy of pembrolizumab in patients with pituitary carcinoma: report of four cases from a phase II study

Phase II Clinical Trial of Pembrolizumab in Patients with Progressive Metastatic Pheochromocytomas and Paragangliomas

Emerging Therapies in Pheochromocytoma and Paraganglioma: Immune Checkpoint Inhibitors in the Starting Blocks

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