Five FDA Approvals for Oncology Agents in April

  • Adjuvant Dabrafenib/Trametinib for BRAF-Positive Melanoma. The combination of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib (Tafinlar® and Mekinist®, Novartis Pharmaceuticals) was approved for use as adjuvant therapy in patients with BRAF V600E or V600K-positive stage III melanoma following complete resection. This decision was based on results from the phase III COMBI-AD study, which compared adjuvant dabrafenib/trametinib to placebo in patients with stage III melanoma. The combination resulted in a 53% reduction in the risk of relapse or death, compared to placebo, with a 3-year relapse-free survival (RFS) rate of 58% versus 39% (HR 0.47, P<.001).
  • First-Line Osimertinib Approved for EGFR-Mutant NSCLC. The US Food and Drug Administration (FDA) expanded the indication of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib (Tagrisso®, AstraZeneca) to include first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) with EGFR exon 19 deletion or exon 21 L858R. Osimertinib was previously approved for use in previously treated patients with the T790M EGFR resistance mutation. First-line approval was based on an impressive median of an 18.9-month progression-free survival (PFS) with osimertinib in the phase III FLAURA trial, compared to 10.2 months with the first-generation EGFR TKIs erlotinib or gefitinib (HR 0.46, P<.0001).
  • Combination Nivolumab and Ipilimumab for First-Line RCC. The combination of the immunotherapies nivolumab and ipilimumab (Opdivo® and Yervoy®, Bristol-Meyers Squibb) was approved for use in newly diagnosed patients with intermediate or poor- risk renal cell carcinoma (RCC). This approval was based on results from the phase III CheckMate-214 trial, which compared nivolumab plus ipilimumab to sunitinib in newly diagnosed advanced RCC. Nivolumab plus ipilimumab resulted in a statistically significant improvement in overall survival (OS), compared to sunitinib (not reached versus 25.9 months; HR 0.63, P<.0001) in patients with intermediate or poor risk disease. The objective response rate (ORR) was 41.6% with combination immunotherapy and 26.5% with sunitinib (P<.0001). This approval does not include patients with favorable risk disease who had superior outcomes on sunitinib.
  • A Third PARP Inhibitor Approved for Maintenance Therapy in Ovarian Cancer. The indication of the poly-ADP ribose polymerase (PARP) inhibitor rucaparib (Rubraca®, Clovis Oncology) was expanded to include use as maintenance therapy following complete or partial response to platinum-based chemotherapy in patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer. Importantly, rucaparib maintenance is approved for patients regardless of BRCA mutation status, while other indications of rucaparib require BRCA gene mutations as verified by an FDA approved test. In the ARIEL3 trial, which examined rucaparib maintenance in patients regardless of BRCA mutation status, rucaparib maintenance resulted in a 10.8-month PFS, compared to 5.4 months with placebo (HR 0.36, P<.0001). The PFS benefit of rucaparib was even more pronounced in the subgroup of patients with BRCA mutations (16.6 months vs 5.4 months; HR 0.23, P<.0001). With this approval, the FDA also converted the approval of rucaparib for use as a monotherapy in patients who had progressed on 2 or more chemotherapies from an accelerated to full approval.
  • New Indication for Everolimus in Seizure Control for Patients with Tuberous Sclerosis Complex. Oral suspension of everolimus tablets (Afinitor Disperz®, Novartis) was approved as an adjunctive therapy for patients 2 years and older with partial-onset seizures associated with tuberous sclerosis complex (TSC). This decision was based on the EXIST-3 trial, which examined everolimus in patients with TSC-associated partial-onset seizures who had inadequate seizure control with ≥2 anti-epileptic drugs. Everolimus resulted in statistically significant reductions in seizures, compared to placebo at both low trough (29.3% vs 14.9%; P = .003) and high trough (39.6% vs 14.9%; P<.001) concentrations. Everolimus is also approved for TSC-associated subependymal giant cell astrocytoma and TSC-associated renal angiomyolipoma.


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