FDA Grants Priority Review to 2 Cancer Investigational Drugs

The FDA has granted Priority Review for 2 Genentech investigational medicines—entrectinib and polatuzumab vedotin—that target hard-to-treat cancers. The FDA action date for both drugs is in August 2019.

Entrectinib has been developed for the treatment of certain adults and children with neurotrophic tropomyosin receptor kinase (NTRK) fusion-positive solid tumors and metastatic ROS1-positive non-small cell lung cancer. Entrectinib was previously granted Breakthrough Therapy Designation by the FDA in May 2017 for the treatment of NTRK fusion-positive locally advanced or metastatic solid tumors for adults and pediatrics patients who had no acceptable standard therapies.

Entrectinib was designed to block ROS1 and NTRK kinase activity and could result in the death of cancer cells with ROS1 or NTRK gene fusions.

The New Drug Application was based on what the company called the “integrated analysis” of several different phase 1 and 2 studies.

The analysis included data from the STARTRK-2, STARTRK-1 and ALKA-372-001 trials. There were 53 people with ROS1-activating gene fusions, 54 people with locally advanced metastatic NTRK fusion-positive solid tumors, plus pediatric patients from the phase 1/1b STARTRK-NG study. The patients came from 15 countries and more than 150 clinical trial sites. Several tumor types were evaluated, including breast, cholangiocarcinoma, colorectal, gynecological, neuroendocrine, non-small cell lung, salivary gland, pancreatic, sarcoma, and thyroid cancers.

The investigators observed that entrectinib shrank tumors in 57.4% of patients with NTRK fusion-positive solid tumors. Entrectinib even shrank tumors that had spread to the brain in more than half of patients, and a quarter of the patients showed complete response, they said.

Entrectinib also shrank tumors in three-quarters of patients with locally advanced or metastatic ROS1-positive non-small cell lung cancer, the investigators found. Entrectinib showed a durable response of more than 24 months, with a median response of 24.6 months.

“By going beyond a particular organ or tissue to address the genetic underpinnings of a person’s disease, tumor-agnostic therapies like entrectinib have the potential to offer people with different types of cancer, including those with rare tumor types, a more personalized option,” Josina Reddy, MD, PhD, Senior Group Medical Director at Genentech, told Rare Disease Report. “It’s a dramatic evolution that’s helping to redefine the level of personalized care we can bring to people with cancer.”

Some of the commonly reported adverse events with entrectinib included fatigue, constipation, dysgeusia, edema, dizziness, diarrhea, nausea, dysesthesia, dyspnea, pain, anemia, cognitive disorders, weight increased, vomiting, cough, blood creatinine increase, arthralgia, fever, and myalgia.

Polatuzumab vedotin, along with bendamustine plus Rituxan (BR), is for the treatment of people with relapsed or refractory diffuse large B-cell lymphoma. It is currently being investigated for the treatment of different types of non-Hodgkin’s lymphoma, and it is believed to be a promising target for new therapy development. It is designed to destroy a maximum number of B-cells through a targeted approach which can minimize the effect on normal cells.

Investigators of the GO29365 study learned that polatuzumab vedotin plus BR improved median overall survival (an exploratory endpoint) compared to BR alone (12.4 vs. 4.7 months) in people with relapsed or refractory diffuse large B-cell lymphoma. Additionally, they reported that 40% of people treated with polatuzumab vedotin plus BR achieved complete response, compared to 18% of patients treated with BR alone.

“Even with the progress that’s been made with initial treatment regimens for diffuse large B-cell lymphoma, as many as 40% of people do not respond to initial treatment or see their disease return, at which point their prognosis is poor and worsens with each subsequent relapse,” Nancy Valente, MD, Vice President, Global Hematology Development at Genentech, told Rare Disease Report. “At Genentech, we have a long history of developing innovative antibody treatments that have redefined the standard of care for many types of cancer, and we have these hopes for polatuzumab vedotin in some people with relapsed or refractory diffuse large B-cell lymphoma.”

The most common adverse events were infections and cytopenias, the study authors said. The infection and transfusion rates remained similar among patients treated with polatuzumab vedotin plus BR and BR alone.