Phase II Study of Pembrolizumab in Advanced Rare Cancers Shows Promise


Favorable toxicity profiles and antitumor activity seen in this phase II study of pembrolizumab supports further evaluation of the drug in this patient population.

Favorable toxicity profiles and antitumor activity seen in a phase II study of pembrolizumab (Keytruda) in patients with advanced rare cancers supports further evaluation of the drug in this patient population.1

The study, published in the Journal for ImmunoTherapy of Cancer, evaluated pembrolizumab in patients with squamous cell carcinoma (SCC) of the skin, adrenocortical carcinoma (ACC), carcinoma of unknown primary (CUP), and paraganglioma-pheochromocytoma. 

“Studies such as this one are key since rare cancers collectively accounted for 13% of all new cancer diagnoses and 25% of all cancer-related deaths in adults in 2017,” Aung Naing, MD, associate professor of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center, said in a press release.2 “The 5-year survival rate is 15% to 20% lower than for more common cancers. The poor outcomes associated with rare cancers have been attributed to difficulty or delay in diagnosis, limited access to centers with expertise such as MD Anderson, and limited therapeutic options.”

In this cohort of individuals treated between August 15, 2016 and July 27, 2018, patients whose tumors had progressed on standard therapies, if available, within the previous 6 months were enrolled in 9 tumor-specific cohorts and a 10th cohort for other rare histologies. Overall, 127 subjects were administered 200 mg of pembrolizumab intravenously every 21 days. 

The primary endpoint was non-progression rate (NPR) at 27 weeks, and secondary endpoints included safety and tolerability, objective response rate (ORR), and clinical benefit rate (CBR). 

At the time of the data cut-off, the NPR at 27 weeks was 28% (95% CI, 19-37). A confirmed objective response (OR) was observed in 15 of 110 (14%) evaluable patients, with 1 patient achieving a complete response and the other 14 having a partial response. CBR, defined as the percentage of patients with an OR or stable disease at ≥4 months, was 38% (n = 42). 

Treatment was ongoing in 11 of 15 patients with OR at the last follow-up. In the cohort of patients with SCC of the skin, the NPR at 27 weeks was 36%, while ORR was 31% and CBR was 38%. In those with ACC, NPR, at 27 weeks, ORR, and CBR were 31%, 15%, and 54%, respectively. For patients with CUP, NPR at 27 weeks was 33%, ORR was 23%, and CBR was 54%. Moreover, in the paraganglioma-pheochromocytoma group, rates were 43%, 0%, and 75%, respectively.

Treatment-related adverse events (TRAEs) occurred in 66 of the 127 (52%) patients, and 12 (9%) had grade ≥3 TRAEs. The most common TRAEs observed were fatigue (n = 25) and rash (n = 17). In total, there were 6 deaths, all of which were unrelated to the study drug. The safety profile of pembrolizumab in these patient populations is consistent with that previously reported in other common cancers, such as melanoma and non-small cell lung cancer.

“Findings from our study support further investigation to confirm the clinical activity of pembrolizumab in advanced rare cancers, and to identify immune signatures predictive of response to treatment,” Naing said. 

Given the small sample size of the tumor-specific cohorts, the researchers were not able to make inferences applicable to all rare cancers, however. Additionally, the site from which the tissue was obtained (primary vs metastatic) for biomarker assessment could have influenced the immune marker levels. Further the differences in antitumor activity observed between the different cancer types was likely a reflection of differences in the tumor microenvironment.

“Considering the poor prognosis associated with the lack of evidence-based treatment options for many of these tumor types, we chose to report the results from the interim analysis to inform the scientific community,” the authors wrote. “Nonetheless, because these are rare tumors, the period until the final analysis may be prolonged.”


1. Naing A, Meric-Bernstam F, Stephen B, et al. Phase 2 study of pembrolizumab in patients with advanced rare cancers. Journal for ImmunoTherapy of Cancer. doi:10.1136/jitc-2019-000347.

2. Pembrolizumab shows promise for some advanced, hard-to-treat rare cancers [news release]. Houston, Texas. Published March 19, 2020. Accessed March 25, 2020. 

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