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TON - June 2020, Vol 13, No 3 - FDA Updates

This section provides a brief overview of new cancer drugs or new indications approved by the FDA between April 17, 2020, and May 8, 2020.

Retevmo First Therapy Approved for 3 Types of Cancers with RET Mutations

On May 8, 2020, the FDA accelerated the approval of a new kinase inhibitor, selpercatinib (Retevmo; Loxo Oncology) capsules, for the treatment of 3 types of cancer—metastatic non–small-cell lung cancer (NSCLC), metastatic medullary thyroid cancer, and other types of thyroid cancer—that are associated with RET gene mutations or fusions, as determined by an FDA-approved test. Selpercatinib is the first therapy approved specifically for the treatment of patients with cancer that is linked to RET mutations or fusions. The FDA granted selpercatinib breakthrough therapy and orphan drug designations.

“The FDA is committed to reviewing treatments like Retevmo that are targeted to specific subsets of patients with cancer,” said Richard Pazdur, MD, Director of the FDA’s Oncology Center of Excellence.

Specifically, selpercatinib is indicated for the treatment of (1) metastatic NSCLC with RET fusions in adults, (2) advanced or metastatic medullary thyroid cancer with RET mutations in patients aged ≥12 years who require systemic therapy, and (3) advanced thyroid cancer with RET gene fusion in patients aged ≥12 years who require systemic therapy and cannot use, or their cancer has stopped responding to, radioactive iodine therapy.

This approval was based on results of a clinical trial of patients who had 1 of the 3 types of tumors associated with RET mutations or fusions. All patients received 160 mg of selpercatinib twice daily until disease progression or unacceptable toxicity. The major efficacy outcome measures were overall response rate (ORR) and duration of response.

The study included 105 adults with NSCLC and RET fusion who had previously received platinum chemotherapy. The ORR with selpercatinib was 64%, and the response lasted ≥6 months in 81% of the patients. The efficacy in NSCLC and RET fusion was also evaluated in 39 treatment-naïve patients, resulting in an ORR of 84%, with responses lasting ≥6 months.

In addition, the study included 143 patients aged ≥12 years with advanced or metastatic medullary thyroid cancer and RET mutations, including 55 patients who had received previous chemotherapy with cabozantinib, vandetanib, or both, as well as 88 treatment-naïve patients. The ORR for the patients who had received previous therapy was 69%, with a response lasting ≥6 months in 76% of these patients. Among the 88 treatment-naïve patients, the ORR was 73%, with a response lasting ≥6 months in 61% of these patients.

The study also evaluated the efficacy of selpercatinib in 19 patients aged ≥12 years with thyroid cancer and RET fusion whose disease was refractory to radioactive iodine and who had previously received another systemic treatment, as well as 8 treatment-naïve patients with this cancer. The ORR was 79% among the 19 patients who had received previous therapy, with 87% of responses lasting ≥6 months. Of the 8 treatment-naïve patients, the ORR was 100%, with 75% of responses lasting ≥6 months.

The most common side effects with selpercatinib were increased AST, ALT, and blood glucose levels; decreased white blood cell count, albumin, and calcium levels; dry mouth; diarrhea; increased creatinine, alkaline phosphatase, and hypertension; fatigue; swelling in the body or limbs; low platelet count; increased cholesterol; rash; constipation; and decreased sodium levels. The serious side effects with selpercatinib included hepatotoxicity, elevated blood pressure, QT prolongation, bleeding, and allergic reactions.

Tabrecta First FDA-Approved Targeted Therapy for Metastatic NSCLC and MET Exon 14 Skipping

On May 6, 2020, the FDA accelerated the approval of oral capmatinib (Tabrecta; Novartis), a kinase inhibitor, for the treatment of adults with metastatic non–small-cell lung cancer (NSCLC). Capmatinib is the first agent approved by the FDA for the treatment of metastatic NSCLC associated with mutations that lead to mesenchymal-epithelial transition (MET) exon 14 skipping, as determined by an FDA-approved test. The FDA granted capmatinib breakthrough therapy and orphan drug designations.

On the same day, the FDA also approved Foundation Medicine’s FoundationOne CDx assay (F1CDx) as a companion diagnostic to capmatinib. F1CDx is a next-generation sequencing–based in vitro diagnostic device that can detect several mutations, including mutations that lead to MET exon 14 skipping.

“Tabrecta is the first approval specifically for the treatment of patients with non–small-cell lung cancer whose tumors have mutations that lead to MET exon 14 skipping. This patient population now has an option for a targeted therapy, which they didn’t have prior to today,” said Richard Pazdur, MD, Director of the FDA’s Oncology Center of Excellence.

The approval of capmatinib was based on the results of a clinical trial of patients with NSCLC and mutations leading to MET exon 14 skipping; all patients had negative status for EGFR and ALK gene mutations. The patients received oral capmatinib 400 mg twice daily until disease progression or unacceptable toxicity. The primary efficacy end point was overall response rate (ORR); the secondary end point was duration of response.

In all, 28 patients had never received treatment for NSCLC, whereas 69 patients had received previous therapy. The ORR for the 28 treatment-naïve patients was 68%, which included 4% complete responses and 64% partial responses. The ORR for the 69 patients who had received previous therapy was 41%, all being partial responses. Of the patients who had a response to capmatinib therapy, 47% of treatment-naïve patients and 32.1% of those who had previously received therapy for NSCLC had a response lasting ≥12 months.

The most common (≥20%) adverse effects associated with the use of capmatinib treatment were peripheral edema, nausea, fatigue, vomiting, dyspnea, and decreased appetite. The serious side effects with capmatinib treatment included interstitial lung disease or pneumonitis; patients with these serious side effects should discontinue capmatinib therapy permanently.

Zejula First PARP Inhibitor Approved as First-Line Maintenance Treatment for Ovarian Cancer

On April 29, 2020, the FDA accelerated the approval of the oral poly ADP-ribose polymerase (PARP) inhibitor niraparib (Zejula; GlaxoSmithKline) as the first drug approved for first-line maintenance therapy of all patients with advanced ovarian cancer—including epithelial ovarian, fallopian tube, or primary peritoneal cancer—whose cancer has had a complete or partial response to first-line platinum-based chemotherapy. The FDA used its priority review process to accelerate its approval for this new indication.

Niraparib was previously approved for several types of ovarian cancer, including for patients with homologous recombination deficiency (HRD)-positive status, defined by the presence of a BRCA mutation or genomic instability, as determined by an FDA-approved test.

The FDA approved this new indication for niraparib as first-line maintenance therapy for all women with ovarian cancer based on the PRIMA study, a double-blind, placebo-controlled randomized clinical trial. PRIMA included 733 patients with ovarian cancer who had a complete or partial response to first-line treatment with platinum-based chemotherapy; patients were randomized to receive niraparib or matched placebo.

The main efficacy outcome measure of the PRIMA study was progression-free survival (PFS), which was first tested in patients with HRD-positive disease and then in the overall population and was determined by an independent central review per RECIST 1.1. The tumor samples were tested for HRD status, which was defined by either presence of BRCA mutation or by genomic instability score ≥42.

Specifically, the results showed significant improvement in PFS among patients who received niraparib compared with those who received placebo in patients with and without HRD-­positive status. The median PFS in HRD-related patients was 21.9 months (95% confidence interval [CI], 19.3-not estimable) with niraparib compared with 10.4 months (95% CI, 8.1-12.1) with placebo (hazard ratio [HR], 0.43; 95% CI, 0.31-0.59; P <.0001). The median PFS in the overall population was 13.8 months (95% CI, 11.5-14.9) with niraparib versus 8.2 months (95% CI, 7.3-8.5) with placebo (HR, 0.62; 95% CI, 0.50-0.76; P <.0001).

The most common (≥10%) adverse reactions with niraparib in the PRIMA study were thrombocytopenia, anemia, nausea, fatigue, neutropenia, constipation, musculoskeletal pain, leukopenia, headache, insomnia, vomiting, dyspnea, decreased appetite, dizziness, cough, hypertension, AST/ALT elevation, and acute kidney injury.

Pemazyre First FDA-Approved Therapy for Cholangiocarcinoma plus FGFR2 Fusion

On April 17, 2020, the FDA approved pemigatinib (Pemazyre; Incyte), an oral kinase inhibitor, as the first treatment for adults (aged ≥18 years) with previously treated, locally advanced or metastatic cholangiocarcinoma that is associated with a fibroblast growth factor receptor 2 (FGFR2) gene fusion or other rearrangements, as detected by an FDA-approved test.

This is the first targeted therapy approved for patients with advanced cholangiocarcinoma. Until now, the standard of therapy for this patient population has been chemotherapy-based combinations.

The FDA approved pemigatinib using its priority review process and granted the drug breakthrough therapy and orphan drug designations. Approximately 9% to 14% of patients with cholangiocarcinoma have FGFR2 gene fusions.

“With Pemazyre, we considered the observed efficacy results to be clinically meaningful and the overall risk to benefit assessment for patients with tumors harboring FGFR2 gene fusions and other rearrangements to be favorable, particularly when we considered that these patients have no other good options following first line treatment with chemotherapy,” said Richard Pazdur, MD, Director of the FDA’s Oncology Center of Excellence.

On the same day, the FDA also approved Foundation Medicine’s FoundationOne CDx as the companion diagnostic for pemigatinib. FoundationOne CDx is a next-generation sequencing test and the first and only FDA-approved companion diagnostic test for this indication. This test is currently approved as a companion diagnostic for 20 therapies for various cancer types.

Pemigatinib is a potent, selective, oral inhibitor of FGFR isoforms 1, 2, and 3; in preclinical studies, the drug has demonstrated selective pharmacologic activity against cancer cells with FGFR alterations.

The FDA’s approval of pemigatinib was based on the results of the FIGHT-202 clinical trial, a multicenter, open-label, single-arm study that enrolled 107 patients with locally advanced or metastatic cholangiocarcinoma and FGFR2 fusions or rearrangements who had received previous treatment. All enrolled patients received pemigatinib 13.5 mg once daily for 14 days followed by 7 days off in 21-day cycles, until disease progression or unacceptable adverse events. The primary end point was overall response rate; the secondary end point was duration of response.

In patients with cholangiocarcinoma and FGFR1 fusions or rearrangements, the overall response rate was 36% (N = 38), including 2.8% of patients with a complete response and 33% of patients with a partial response. Among the 38 patients who had a response to treatment with pemigatinib therapy, 24 patients had a response lasting ≥6 months and 7 patients had a response lasting ≥12 months; the median duration of response was 9.1 months. No data are yet available to show whether pemigatinib improves survival duration or symptoms of the disease.

The most common (≥20%) adverse reactions associated with the use of pemigatinib were hyperphosphatemia and hypophosphatemia, alopecia, diarrhea, nail toxicity, fatigue, dysgeusia, nausea, constipation, stomatitis, dry eye and/or mouth, decreased appetite, vomiting, joint pain, abdominal pain, back pain, and dry skin.

The FDA approved pemigatinib under the accelerated approval protocol based on tumor response. Continued approval of the drug may be contingent on additional data from confirmatory clinical trials that further demonstrate the drug’s clinical benefit.

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Last modified: July 29, 2020