FDA Cancer Treatment Approvals in June and July 2021

In June and July, the United States Food and Drug Administration (FDA) granted several new and expanded drug indications for the treatment of patients with cancer.

  • Enfortumab Vedotin for Locally Advanced or Metastatic Urothelial Cancer. The accelerated approval for enfortumab vedotin (Padcev®, Astellas Pharma US, Inc.), an antibody–drug conjugate targeting nectin-4, has been changed to regular approval for the treatment of patients with locally advanced or metastatic urothelial cancer (UC) who have either previously received a programmed death receptor-1 (PD-1) or programmed death-ligand (PD-L1) inhibitor and platinum-containing chemotherapy, or who are ineligible for cisplatin-containing chemotherapy and have previously received ≥1 lines of therapy. The clinical benefit of EV was confirmed in the open-label, randomized, multicenter, phase III Trial EV-301, where overall survival (OS) was significantly prolonged with EV compared with standard chemotherapy in patients with locally advanced or metastatic UC who had previously received platinum-based treatment and a PD-1 or PD-L1 inhibitor (12.9 versus 9.0 months; hazard ratio [HR] 0.70; P=0.0014). Median progression-free survival (PFS) was 5.6 versus 3.7 months, respectively (HR 0.62; P<0.0001) and the overall response rate (ORR) more than doubled with EV (40.6% versus 17.9%; P<0.0001). For patients who have received a prior PD-1 or PD-L1 inhibitor and are ineligible for cisplatin-containing chemotherapy, efficacy was evaluated in Cohort 2 of the single-arm, multi-cohort, international EV-201 trial. Confirmed ORR by blinded independent central review (BICR) was 52%, including 20% complete response (CR), and median duration of response (DoR) was 10.9 months.

  • Regular Approval for Pembrolizumab Plus Lenvatinib Combo for Advanced Endometrial Carcinoma. Data from the open-label, randomized, phase III Study 309/KEYNOTE-775 trial (n=827) confirmed the clinical benefit of pembrolizumab (Keytruda®, Merck; 200 mg intravenously every 3 weeks) plus lenvatinib (Lenvima®, Eisai; 20 mg orally once daily) in patients with advanced mismatch repair proficient (pMMR) endometrial carcinoma, who had received ≥1 prior platinum-based chemotherapy regimens in any setting, including neoadjuvant and adjuvant. A significant improvement in median PFS was seen in patients who received the combination treatment: 6.6 versus 3.8 months (HR 0.60; P<0.0001). Median OS was 17.4 versus 12.0 months, respectively (HR, 0.68; P=0.0001) and ORR was 30% versus 15% (P<0.0001) with a median DoR of 9.2 versus 5.7 months, respectively.

  • Pembrolizumab Indication Extended to Early-Stage Triple-Negative Breast Cancer (TNBC)
    Approval was granted to pembrolizumab for high-risk, early-stage, TNBC in combination with chemotherapy as neoadjuvant treatment, and then continued as adjuvant pembrolizumab monotherapy. This approval was based on efficacy results from the randomized, multicenter, double-blind, placebo-controlled, phase III KEYNOTE-522 trial that included 1174 patients with TNBC, regardless of tumor PD-L1 expression. Patients were randomized to receive either pembrolizumab or placebo in combination with chemotherapy. Updated data showed a pathological CR (pCR) of 64.8% for patients who received pembrolizumab versus 51.2% for chemotherapy alone. Furthermore, neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab led to a significant and clinically meaningful improvement in event-free survival (HR 0.63; P=0.0003).

    In addition to early-stage TNBC, the recent accelerated approval of pembrolizumab in combination with chemotherapy for patients with locally recurrent or metastatic TNBC whose tumors express PD-L1 (combined positive score [CPS] ≥10, as determined by an FDA-approved test) was changed to regular approval.
  • Avapritinib, a New Therapy for Advanced Systemic Mastocytosis. Avapritinib (Ayvakit™, Blueprint Medicines Corp.) was approved for the treatment of patients with advanced systemic mastocytosis, including patients with aggressive systemic mastocytosis, systemic mastocytosis with an associated hematological neoplasm, and mast cell leukemia. Data from the phase I EXPLORER trial and the multicenter, single-arm, open-label, phase II PATHFINDER trial, supported the approval. The ORR in all evaluable patients in both trials combined was 57%, with 28% of patients experiencing complete remission (CR) The median duration of response was 38.3 months, and the median time to response was 2.1 months. The recommended dose is 200 mg orally once daily for patients with advanced systemic mastocytosis.

  • Liquid Biopsy-Based Comprehensive Genomic Profiling Companion Diagnostic for Selective MET Inhibitor Capmatinib. Approval was given to the next-generation sequencing liquid biopsy assay (FoundationOne® Liquid CDx,Foundation Medicine, Inc.) for use as a companion diagnostic to identify patients with advanced NSCLC harboring MET exon 14 skipping mutations. Patients eligible for capmatinib can now be identified with a tissue-based or non-invasive blood-based companion diagnostic assay.

  • Recombinant Form of Asparaginase Erwinia Chrysanthemi for Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma. Approval was granted for recombinant asparaginase erwinia chrysanthemi (RylazeTM, Jazz Pharmaceuticals, Inc.) as a component of a multi-agent chemotherapeutic regimen for the treatment of acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LBL) in adult and pediatric patients ≥1 month old, who have developed hypersensitivity to E. Coli-derived asparaginase. The approval was based on clinical data from the one part of ongoing phase II/III, open-label, multi-cohort, multicenter Study JZP 458-201 in which 102 patients with ALL or LBL with hypersensitivity to E. Coli-derived asparaginase received, as a component of a multi-agent chemotherapeutic regimen, intramuscular asparaginase erwinia chrysanthemi at various doses. The main efficacy outcome measure was achieving and maintaining a nadir serum asparaginase activity (NSAA) of >0.1 U/ml. Results of modeling and simulations showed that at a dose of 25 mg/m2 93.6% of patients maintained NSAA >0.1 U/ml at 48 hours after dosing.

  • Subcutaneous Daratumumab and Hyaluronidase with Pomalidomide/Dexamethasone for Multiple Myeloma. Approval was granted for the subcutaneous formulation of daratumumab and hyaluronidase-fihj (Darzalex Faspro®, Janssen Biotech, Inc.) in combination with pomalidomide and dexamethasone (Pd) for patients with multiple myeloma who have received ≥1 line of therapy, including lenalidomide and a proteasome inhibitor. Efficacy results from the randomized, open-label, phase III APOLLO trial supported the approval. Median PFS was nearly doubled for patients treated with the subcutaneous formulation of daratumumab and hyaluronidase in combination with Pd compared with Pd alone (12.4 versus 6.9 months; HR 0.63, P=0.0018).

  • Belumosudil, an Oral Kinase Inhibitor, for Chronic GVHD. Belumosudil (RezurockTM, Kadmon Pharmaceuticals, LLC) a selective inhibitor of Rho-associated coiled-coil protein kinase-2 (ROCK2) was approved for patients ≥12 years old with chronic GVHD after failure of ≥2 prior lines of systemic therapy. Chronic GVHD is a major cause of morbidity and late non-relapse mortality after an allogeneic hematopoietic cell transplant. The approval was based on data from 66 patients with chronic GVHD who received belumosudil (200 mg once daily) in the randomized, open-label, multicenter, dose-ranging, phase II ROCKstar study (KD025-213). The primary endpoint was best ORR, which was 74% (62% – 84%). In patients who achieved response, 62% of patients were alive with no initiation of a new systemic therapy for ≥12 months after response.