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FDA Updates

FDA Updates Impacting Treatment Approaches in Oncology

doi: 10.1097/01.COT.0000549796.42936.b0
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Olaparib Given Orphan Drug Designation for Pancreatic Cancer

FDA; oncology
FDA; oncology:
FDA; oncology

The FDA has granted Orphan Drug Designation for olaparib for the treatment of pancreatic cancer. Olaparib is currently being investigated as maintenance therapy in patients with germline BRCA-mutated (gBRCAm) metastatic pancreatic cancer whose disease has not progressed following first-line platinum-based chemotherapy.

The use of olaparib in pancreatic cancer is being assessed in the ongoing phase III POLO trial, which is investigating olaparib as maintenance monotherapy versus placebo in patients with gBRCAm metastatic pancreatic cancer whose disease has not progressed following first-line platinum-based chemotherapy. Results from the POLO trial are expected in the first half of 2019.

Olaparib was the first-in-class PARP inhibitor and the first targeted treatment to potentially exploit DNA damage response pathway deficiencies, such as BRCA mutations, to preferentially kill cancer cells. Specifically, in vitro studies have shown that olaparib-induced cytotoxicity may involve inhibition of PARP-enzymatic activity and increased formation of PARP-DNA complexes, resulting in DNA damage and cancer cell death.

This is the fourth Orphan Drug Designation in the U.S. for olaparib. Orphan Drug status was granted for the treatment of ovarian cancer in October 2013. Earlier this year, an amended Orphan Drug status was granted to include both fallopian tube and primary peritoneal cancers following the expanded U.S. approval of olaparib in August 2017 for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy.

The FDA grants Orphan Drug Designation to medicines intended for the treatment, diagnosis, or prevention of rare diseases or disorders that affect fewer than 200,000 people in the U.S. Through the program, the FDA provides incentives for pharmaceutical companies to develop products for rare diseases.

Talazoparib for gBRCAm HER2- Locally Advanced or Metastatic Breast Cancer

The FDA recently approved talazoparib, a PARP inhibitor, for patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm), HER2-negative locally advanced or metastatic breast cancer. Patients must be selected for therapy based on an FDA-approved companion diagnostic for talazoparib.

Approval was based on EMBRACA (NCT01945775), an open-label trial randomizing 431 patients (2:1) with gBRCAm HER2-negative locally advanced or metastatic breast cancer to receive talazoparib (1 mg) or physician's choice of chemotherapy (capecitabine, eribulin, gemcitabine, or vinorelbine). All patients were required to have a known deleterious or suspected deleterious gBRCA mutation and must have received no more than 3 prior cytotoxic chemotherapy regimens for locally advanced or metastatic disease. Patients were required to have received treatment with an anthracycline and/or a taxane (unless contraindicated) in the neoadjuvant, adjuvant, and/or metastatic treatment setting.

The primary efficacy outcome was progression-free survival (PFS) according to RECIST 1.1, as assessed by blinded independent central review. Estimated median PFS was 8.6 and 5.6 months in the talazoparib and chemotherapy arms, respectively (HR=0.54; 95% CI: 0.41, 0.71; p<0.0001).

The prescribing information includes warnings and precautions for myelodysplastic syndrome/acute myeloid leukemia, myelosuppression, and embryo-fetal toxicity. Most common (≥20%) adverse reactions of any grade were fatigue, anemia, nausea, neutropenia, headache, thrombocytopenia, vomiting, alopecia, diarrhea, and decreased appetite.

FDA also approved the BRACAnalysis CDx test to identify patients with breast cancer with deleterious or suspected deleterious gBRCAm who are eligible for talazoparib. The effectiveness of the test was based on the EMBRACA trial population for whom deleterious or suspected deleterious gBRCAm status was confirmed with either prospective or retrospective testing with BRACAnalysis CDx.

Dacomitinib Approved for Metastatic Non-Small Cell Lung Cancer

Dacomitinib tablets have been approved for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) with EGFR exon 19 deletion or exon 21 L858R substitution mutations as detected by an FDA-approved test.

Approval was based on a randomized, multicenter, open-label, active controlled trial (ARCHER 1050; NCT01774721) comparing the safety and efficacy of dacomitinib to gefitinib in 452 patients with unresectable, metastatic NSCLC. Patients were required to have no prior therapy for metastatic or recurrent disease with a minimum of 12 months disease-free after completion of systemic non-EGFR TKI-containing therapy; an ECOG performance status of 0 or 1; and EGFR exon 19 deletion or exon 21 L858R substitution mutations. Patients were randomized (1:1) to receive either dacomitinib 45 mg orally once daily or gefitinib 250 mg orally once daily until disease progression or unacceptable toxicity.

The trial demonstrated a significant improvement in progression-free survival; no improvement in overall response rate or overall survival were demonstrated. The median progression-free survival, as determined by an independent review committee, was 14.7 and 9.2 months in the dacomitinib and gefitinib arms, respectively (HR=0.59; 95% CI: 0.47, 0.74; p<0.0001).

The prescribing information contains warnings and precautions for interstitial lung disease (ILD), diarrhea, and dermatologic adverse reactions. Of 394 patients who received dacomitinib, serious adverse reactions occurred in 27 percent. The most common adverse reactions resulting in discontinuation of dacomitinib were diarrhea and ILD. The most common (>20%) adverse reactions of dacomitinib were diarrhea, rash, paronychia, stomatitis, decreased appetite, dry skin, decreased weight, alopecia, cough, and pruritus.

The recommended dacomitinib dose is 45 mg orally once daily with or without food.

Rare Pediatric Disease Designation Granted to CLR 131 for Osteosarcoma

The FDA has granted Rare Pediatric Disease Designation to CLR 131, a phospholipid drug conjugate, for the treatment of osteosarcoma.

Since May 2018, CLR 131 has received this designation in three other pediatric cancers: neuroblastoma, rhabdomyosarcoma, and Ewing's sarcoma. The FDA grants this designation for diseases that primarily affect children from birth to 18 years old, and affect fewer than 200,000 persons in the U.S. This program is intended to encourage development of new drugs and biologics for the prevention and treatment of rare pediatric diseases.

The incidence of osteosarcoma is about 4.4 cases per 1 million per year in children younger than 24 years. While there is a 70 percent cure rate among patients with localized disease, 5-year overall survival rates are approximately 20 percent for patients who develop metastatic disease. Additionally, among patients who experience disease progression or recurrence, survival for is less than 30 percent.

CLR 131 is in a phase II clinical study in R/R multiple myeloma and a range of B-cell malignancies and a phase Ib clinical study in patients with R/R multiple myeloma exploring fractionated dosing. The objective of the multicenter, open-label, phase Ib dose-escalation study is the characterization of safety and tolerability of CLR 131 in this patient population.

Patients in Cohorts 1-4 received single doses of CLR 131 ranging from 12.5 mCi/m2 to 31.25 mCi/m2. All study doses have been deemed safe and well-tolerated by an independent Data Monitoring Committee. A phase I study is currently being initiated with CLR 131 in pediatric solid tumors and lymphoma and a second phase I study is planned in combination with external beam radiation for head and neck cancer.

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