FDA Approves Second RET Inhibitor for NSCLC

Pralsetinib (Gavreto) Approved for RET Fusion-Positive Lung Cancer

The U.S. Food and Drug Administration (FDA) has approved a second drug for the treatment of adult patients with metastatic RET fusion-positive non-small cell lung cancer (NSCLC). RET stands for “rearranged during transfection” and the RET mutation is one of seven NSCLC biomarkers that can be targeted with an FDA-approved therapy.

Pralsetinib (Gavreto) is designed to inhibit tumors that have alterations in the RET gene. About 2% of patients with NSCLC have tumors in which a piece of the RET gene is fused to part of another gene, according to the National Cancer Institute. This results in the production of abnormal RET proteins, which spur the growth of cancer cells.

Non-Small Cell Lung Cancer Treatment

“Targeted therapies have dramatically improved care for patients with non-small cell lung cancer driven by oncogenes, including EGFR and ALK…” said Dr. Vivek Subbiah, medical director for The University of Texas MD Anderson Cancer Center’s Clinical Center for Targeted Therapy, in a September 4 press release announcing the approval.

“…The approval of the selective RET inhibitor pralsetinib, or Gavreto, marks another milestone in a paradigm shift toward precision medicine.”

An estimated 228,000 Americans will be diagnosed with lung cancer in 2020, according to the American Cancer Society. A recent study by researchers at the National Cancer Institute found that NSCLC accounts for 76% of all lung cancers. While death rates have fallen sharply, according to the study, lung cancer is still the leading cause of cancer death among men and women.

Lung Cancer Clinical Trials Lead to FDA Approvals

Dr. Subbiah was an investigator in the Phase I/II ARROW trial that led to Gavreto’s approval. In 87 patients who were previously treated with platinum-based chemotherapy, there was a 57% response rate, including a 5.7% complete response rate. In 27 patients who were treatment-naive and ineligible to receive platinum chemotherapy, the overall response rate was 70%, with an 11% complete response rate and a median nine-month duration of response.

Serious side effects include lung problems, severe hypertension, liver toxicity, severe bleeding and slow wound healing. Gavreto also can cause depletion of red blood cells (anemia), white blood cells (neutropenia) and platelets (thrombocytopenia), which can lead to infection.

In recent years, the FDA has approved several new lung cancer treatment options that target genetic mutations or alterations, including epidermal growth factor receptor (EGFR), anaplastic large-cell lymphoma kinase (ALK) rearrangements and BRAF V600E, along with immunotherapies that help the immune system identify and attack cancer cells.

The agency approved the first RET inhibitor for adult patients with NSCLC in May. The accelerated approval of selpercatinib (Retevmo) was based on results from the LIBRETTO-001 trial, which included 105 adult patients with RET-fusion-positive NSCLC who had been previously treated with platinum chemotherapy.

Retevmo led to an overall response rate (complete or partial tumor shrinkage) of 64%; 81% of those patients had responses lasting six months or longer. The mediation duration of response was 17.5 months. In 39 patients who had never received systemic treatment, the overall response rate was 85%; 58% of them had responses lasting six months or longer.

Both Gavreto and Retevmo are oral drugs but Gavreto is taken once a day while Retevmo is taken twice daily. 

Treating Lung Cancer with Precision Medicine

“Literally, every time I open the news in the morning, I'm like, "Oh, there's another approval,’" said Dr. Heather Wakelee, a professor of oncology at Stanford University Medical Center, in an interview with Patient Power Co-Founder Andrew Schorr.

“So a lot of hope, and some are the targeted therapies, and we have now approved drugs for RET and MET (mesenchymal-to-epithelial transition), which we really didn't have before, so those are some of the less common, but real driver mutations, and then a lot of immune therapy options. It's really a rapidly changing field.”

The number of tumor-specific gene alterations that can be targeted with FDA-approved therapies reiterates the importance of comprehensive biomarker testing, according to Dr. Ross Camidge, director of the Thoracic Oncology Clinical and Clinical Research Programs at UCHealth Lung Cancer Clinic in Colorado.

For example, RET fusions can be identified with next-generation sequencing with tumor tissue or liquid biopsies, polymerase chain reaction, or fluorescence in situ hybridization.

Still, none of these targeted therapies are cures. If treatment stops, the cancer will start to grow, Dr. Camidge explained in a Patient Power interview last year.

“So, you clearly haven’t killed all of the cells which are even sensitive to that drug,” he said. “So, until we can address why we can’t get 100 percent cell kill — that’s a technical term — we’re never going to deal with the elephant in the room, which is, why can’t we actually cure people?”

He added: “And that’s a very different situation from, why does the cancer grow three years later? The question is, why, when you walk through the door and you have a great response on the scan, if you had a magic microscope, why is there still one in 1,000 cells left? And that to me is actually the horizon we need to look for.”

Was this article helpful? Please share across social media. Looking for more lung cancer information? Sign up for lung cancer e-newsletters and we’ll send the latest news right to your inbox.