FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma

Chuk, Meredith K.; Chang, Jennie; Theoret, Marc R.; Sampene, Emmanuel; He, Kun; Weis, Shawna L.; Helms, Whitney S.; Jin, Runyan; Li, Hongshan; Yu, Jingyu; Zhao, Hong; Zhao, Liang; Paciga, Mark; Schmiel, Deborah H.; Rawat, Rashmi; Keegan, Patricia; Pazdur, Richard

doi:10.1158/1078-0432.ccr-16-0663

Cited by 80 publications

(59 citation statements)

References 10 publications

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“…Pembrolizumab is an ICI administered as an intravenous infusion every 3 weeks that was initially approved for patients with advanced melanoma in 2014 . Pembrolizumab is most commonly used in late‐stage cancer patients who likely harbour known or occult metastases.…”

Section: Introductionmentioning

confidence: 99%

Liver injury is most commonly due to hepatic metastases rather than drug hepatotoxicity during pembrolizumab immunotherapy

Tsung

Dolan

Lao

et al. 2019

Aliment Pharmacol Ther

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Summary Background Pembrolizumab immunotherapy has been associated with hepatotoxicity in 1%‐10% of oncology patients treated in clinical trials. Aim To describe the incidence, phenotypes and outcomes of liver injury in a large cohort of solid organ tumour patients receiving pembrolizumab Methods Liver injury was defined by serum alanine aminotransferase, alkaline phosphatase, and/or total bilirubin levels exceeding threshold values. The likelihood of drug‐induced liver injury was adjudicated by expert opinion. Results Seventy (14.3%) of the 491 pembrolizumab‐treated patients developed liver injury at a median of 62 days (6‐478) and 71.4% had a cholestatic injury profile at onset. The median age, gender and tumour types of liver injury patients were similar to those without, but hepatic metastases (53% vs 21%, P < 0.01) and prior systemic and liver‐directed therapy (71% vs 53%, P < 0.01) were more commonly observed in liver injury patients. During follow‐up, liver injury patients were less likely to experience tumour remission (10% vs 40.4%) and had higher mortality (67.1% vs 33.7%). Only 20 (28.6%) liver injury cases were adjudicated as probable drug‐induced hepatotoxicity; these patients were significantly more likely to present with an hepatocellular/mixed injury pattern (65% vs 12%), to receive corticosteroids (55% vs 12%) and had lower mortality (45% vs 76%) during follow‐up. Conclusions Oncology patients treated with pembrolizumab who develop liver injury experience poorer outcomes during follow‐up. The low incidence of confirmed drug hepatotoxicity highlights the need for thorough medical evaluation before initiating corticosteroids to optimise patient care.

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Section: Introductionmentioning

confidence: 99%

Liver injury is most commonly due to hepatic metastases rather than drug hepatotoxicity during pembrolizumab immunotherapy

Tsung

Dolan

Lao

et al. 2019

Aliment Pharmacol Ther

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“…1 Pembrolizumab is the first anti-PD-1 antibody to be FDA approved for the treatment of patients with unresectable or metastatic melanoma who have experienced progression after treatment with ipilimumab and, if BRAF V600-mutation positive, a BRAF inhibitor. 2 Since then, pembrolizumab has also received FDA approval for the treatment of advanced non-small cell lung cancer, classical Hodgkin lymphoma, gastric cancer, head and neck squamous cell cancer, urothelial bladder cancer, and microsatellite-unstable tumors. Multiple clinical trials are currently underway to evaluate its effectiveness in other solid tumor types, including advanced triple-negative breast cancer and locally advanced or metastatic endometrial cancer.…”

Section: Introductionmentioning

confidence: 99%

The Adrenal Gland as a Sanctuary Site of Metastases After Pembrolizumab Treatment: A Case Series

Nguyen¹,

Shah²,

Liebner³

et al. 2018

J Natl Compr Canc Netw

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Therapeutic agents targeting the PD-1/PD-L1 axis have shown durable clinical responses in patients with various cancer types. Although objective responses are common, intrapatient heterogeneous responses have been described, and the mechanism for the different organ responses remains unknown. We present a series of patients in whom a lack of response was noted solely in the adrenal glands. This is the first case series describing 3 patients with heterogeneous patterns of response to pembrolizumab with progression of adrenal metastatic disease despite objective response (complete or partial response) in all other sites of metastatic disease. Two patients, one with melanoma and one with uterine carcinosarcoma, underwent robotic adrenalectomy for enlarging adrenal metastases. An additional patient with melanoma underwent laparotomy with attempted resection, but infiltration of the adrenal tumor into the inferior vena cava prohibited safe excision. This report provides additional insight into the heterogeneous patterns of disease response to anti-PD-1 therapy, highlighting the adrenal gland as a potential sanctuary site for this immunotherapy. These cases display the potential benefit of early surgical resection in this scenario and the pitfalls of delaying referral to a surgeon for assessment of operative intervention.

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“…The study evaluated different doses, schedules, biomarkers, subsets, test sets, and validation sets. It ultimately led to two accelerated approvals, one in advanced melanoma, and one in PD-L1-positive advanced NSCLC (23,28,29). As one of the largest phase I trials performed to date, the study ultimately enrolled over 1,200 patients.…”

Section: Basket Trialsmentioning

confidence: 99%

Challenges with Novel Clinical Trial Designs: Master Protocols

Cecchini

Rubin

Blumenthal

et al. 2019

Clinical Cancer Research

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The 2018 Accelerating Anticancer Agent Development (AAADV) Workshop assembled a panel of experts for an indepth discussion session to present "Challenges with Novel Clinical Trial Designs." This panel offered assessments of the challenges faced by industry, the FDA, investigators, institutional review boards, and patients. The panel focused on master protocols, which include umbrella trials, platform trials, and basket trials. Umbrella trials and platform trials share many commonalities, whereas basket trials are more distinct. Umbrella and platform trials are generally designed with multiple arms where patients of the same histology or other unifying characteristics are enrolled into different arms and multiple investigational agents are evaluated in a single protocol. In contrast, basket studies generally enroll patients with different tumor types based on the presence of a specific mutation or biomarker regardless of histology; these trials may include expansion cohorts. These novel designs offer the promise of expedited drug assessment and approval, but they also place new challenges on all the stakeholders involved in the drug development process. Only by identifying the challenges of these complex, innovative clinical trial designs and highlighting challenges from each perspective can we begin to address these challenges. The 2018 AAADV Workshop convened a panel of experts from relevant disciplines to highlight the challenges that are created by master protocols, and, where appropriate, offer strategies to address these challenges.

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FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma

Cited by 80 publications

References 10 publications

Liver injury is most commonly due to hepatic metastases rather than drug hepatotoxicity during pembrolizumab immunotherapy

Liver injury is most commonly due to hepatic metastases rather than drug hepatotoxicity during pembrolizumab immunotherapy

The Adrenal Gland as a Sanctuary Site of Metastases After Pembrolizumab Treatment: A Case Series

Challenges with Novel Clinical Trial Designs: Master Protocols

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