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Final Guidance on Evaluating Cancer Drugs for CNS Metastases

The FDA announced the availability of a final guidance entitled "Evaluating Cancer Drugs in Patients with Central Nervous System Metastases; Guidance for Industry." This document provides recommendations regarding the design of clinical trials of drugs and biological products regulated by the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) that are intended to support product labeling describing the antitumor activity in patients with central nervous system (CNS) metastases from solid tumors originating outside the CNS.

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The guidance includes study design recommendations regarding the patient population, available therapy, prior therapies, assessment of CNS disease, study endpoints, and leptomeningeal disease. The guidance announced in this notice finalizes the draft guidance of the same title dated August 2020.


The guidance describes that CNS metastases should be evaluated in the context of the entire disease burden and discusses how treatment effects may be described in drug labeling. The recommendations pertain to clinical trials for systemic anticancer drugs where patients with CNS metastases are included in the study population. These recommendations are also applicable to trials conducted exclusively in patients with CNS metastases.


The preferred modality cited by the guidance is baseline and periodic MRI imaging with gadolinium contrast. Additionally, RECIST 1.1, Response Assessment in Neuro-Oncology Brain Metastases should be utilized for standard response criteria evaluation for patients with CNS metastases, according to the guidance.


A summary of changes to the draft guidance publishing in August 2020 includes 1) clarification on the number of stratification factors the protocol should specify in order to minimize bias, 2) confirmation of the version of RECIST that should be referred to when evaluating CNS disease, 3) clarification that both CNS and systematic duration of response should be captured and the addition of a 6-month timepoint, and 4) the addition of progression-free survival in patients with brain metastasis as another measurement to be reported when CNS is a common metastatic site.


The guidance also details appropriate endpoints for studies featuring patient populations with CNS metastases and discusses the optimal way in which leptomeningeal disease should be addressed. The FDA considers leptomeningeal disease a condition of the entire CNS compartment.


Expanded Indication for Pembrolizumab in Locally Advanced Cutaneous Squamous Cell Carcinoma

The FDA has approved an expanded label for anti-PD-1 therapy pembrolizumab as monotherapy for the treatment of patients with locally advanced cutaneous squamous cell carcinoma (cSCC) that is not curable by surgery or radiation.


This approval is based on data from the second interim analysis of the Phase II KEYNOTE-629 trial, in which pembrolizumab demonstrated an objective response rate (ORR) of 50 percent (95% CI, 36-64) (n=54), including a complete response rate of 17 percent and a partial response rate of 33 percent in the cohort of patients with locally advanced disease. Among the 27 responding patients, 81 percent had a duration of response (DOR) of 6 months or longer, and 37 percent had a DOR of 12 months or longer. In June 2020, pembrolizumab was granted its first indication in cSCC as monotherapy for the treatment of patients with recurrent or metastatic disease that is not curable by surgery or radiation.


Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue and can affect more than one body system simultaneously. Immune-mediated adverse reactions can occur at any time during or after treatment with pembrolizumab, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, dermatologic reactions, solid organ transplant rejection, and complications of allogeneic hematopoietic stem cell transplantation. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions.


Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of pembrolizumab. Based on the severity of the adverse reaction, pembrolizumab should be withheld or permanently discontinued and corticosteroids administered if appropriate. Pembrolizumab can also cause severe or life-threatening infusion-related reactions. Based on its mechanism of action, pembrolizumab can cause fetal harm when administered to a pregnant woman.


The approval was based on data from KEYNOTE-629 (NCT03284424), a multicenter, multi-cohort, non-randomized, open-label trial that enrolled patients with recurrent or metastatic cSCC or locally advanced cSCC. The trial excluded patients with autoimmune disease or a medical condition that required immunosuppression.


Patients received pembrolizumab 200 mg intravenously every 3 weeks until documented disease progression, unacceptable toxicity, or a maximum of 24 months. Patients with initial radiographic disease progression could receive additional doses of pembrolizumab during confirmation of progression unless disease progression was symptomatic, rapidly progressive, required urgent intervention, or occurred with a decline in performance status.


Assessment of tumor status was performed every 6 weeks during the first year and every 9 weeks during the second year. The major efficacy outcome measures were ORR and DOR as assessed by blinded independent central review (BICR) according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of five target lesions per organ.


Among the 54 patients with locally advanced cSCC treated, the study population characteristics were the following: median age of 76 years (range, 35-95), 80 percent age 65 or older; 72 percent male; 83 percent White, 13 percent race unknown; 41 percent Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 and 59 percent ECOG PS of 1. Twenty-two percent received one or more prior lines of therapy; 63 percent received prior radiation therapy.


The ORR was 50 percent (95% CI, 36-64), including a complete response rate of 17 percent and a partial response rate of 33 percent, for patients treated with pembrolizumab. After a median follow-up of 13.4 months, the median DOR had not yet been reached (range, 1.0+ to 17.2+ months). Among the 27 responding patients, 81 percent had a DOR of 6 months or longer, and 37 percent had a DOR of 12 months or longer.


Among the 159 patients with advanced cSCC (recurrent or metastatic or locally advanced disease) enrolled in KEYNOTE-629, the median duration of exposure to pembrolizumab was 6.9 months (range, 1 day to 28.9 months). Adverse reactions occurring in patients with recurrent or metastatic cSCC or locally advanced cSCC were similar to those occurring in 2,799 patients with melanoma or non-small cell lung cancer treated with pembrolizumab as a single agent. Laboratory abnormalities (Grades 3-4) that occurred at a higher incidence included lymphopenia (10%) and decreased sodium (10%).


Iniparib Granted Orphan Drug Designation for Treatment of Malignant Glioma

The FDA granted orphan drug designation (ODD) to iniparib for the treatment of patients with malignant gliomas. The FDA noted that the designation granted is broader than the glioblastoma indication proposed in the designation request and that treatment of glioblastoma is within the scope of this orphan drug designation.


Iniparib is a well-characterized, clinical stage drug candidate that kills cancer cells by targeting their redox metabolism, spiking oxidative stress levels, and triggering programmed cell death. Iniparib's Phase II study in newly diagnosed glioblastoma patients met its primary survival and safety end points.