FDA Drug Approvals, Hematology and Oncology — 2021 Midyear Review

August 20, 2021

Rybrevant (amivantamab)

Amivantamab is a bispecific antibody that binds to the extracellular domains of epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition (MET). Amivantamab is indicated for locally advanced or metastatic non–small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutations in adults whose disease has progressed on or after platinum-based chemotherapy.

Approval was supported by the CHRYSALIS trial, which included 81 patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations whose disease had progressed on or after platinum-based chemotherapy. The overall response rate, as evaluated by blinded independent central review and response duration, was 40% (95% confidence interval [CI]: 29%, 51%) with a median response duration of 11.1 months (95% CI: 6.9, not evaluable). J Clin Oncol. 2020 38:15_suppl, 9512-9512

Empaveli (pegcetacoplan)

Pegcetacoplan is a complement inhibitor by binding to complement protein C3 and its activation fragment C3b, thereby regulating C3 cleavage and generation of downstream effectors of complement activation. It is indicated for paroxysmal nocturnal hemoglobinuria.

In the phase 3 PEGASUS study (n =80), pegcetacoplan demonstrated superiority to eculizumab for the change from baseline in hemoglobin level at week 16, with an adjusted mean increase of 3.84 g/dL of hemoglobin (P <.0001). N Engl J Med. 2021; 384:1028-1037

Zynlonta (loncastuximab tesirine)

Loncastuximab tesirine is an antibody-drug conjugate composed of a CD19-targeting antibody and pyrrolobenzodiazepine (PBD) dimers. Upon binding to CD19, loncastuximab tesirine is internalized, followed by release of PBD dimer via proteolytic cleavage; released PBD dimer binds to the DNA minor groove and forms highly cytotoxic DNA interstrand crosslinks, subsequently inducing cell death. Loncastuximab tesirine is indicated for relapsed or refractory large B-cell lymphoma after 2 or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, DLBCL arising from low-grade lymphoma, and high-grade B-cell lymphoma.

Approval for loncastuximab tesirine was based on the LOTIS-2 study (n = 145). The overall response rate, as assessed by an independent review committee using Lugano 2014 criteria, was 48.3% (95% confidence interval [CI]: 39.9, 56.7) with a complete response rate of 24.1% (95% CI: 17.4, 31.9). After a median follow-up of 7.3 months, median response duration was 10.3 months (95% CI: 6.9, not evaluable). Lancet Oncol. 2021 May 11;S1470-2045(21)

Jemperli (dostarlimab)

Dostarlimab is a humanized monoclonal antibody of the IgG4 isotype, which binds to programmed death 1 (PD-1) receptor and blocks its interaction with PD ligand (PDL)–1 and PD-L2, releasing PD-1 pathway–mediated inhibition of the immune response, including antitumor immune response. Dostarlimab is indicated for adults with mismatch repair–deficient recurrent or advanced endometrial cancer that has progressed on or following a prior platinum-containing regimen.

Approval for dostarlimab was based on the GARNET trial (n = 71). The overall response rate, as assessed by blinded independent central review, was 42.3% (95% confidence interval: 30.6%, 54.6%). The complete response rate was 12.7%, and partial response rate was 29.6%. Median duration of response (DOR) was not reached. Current data show 93.3% of patients have a mean DOR longer than 6 months (range, 2.6-22.4 months; ongoing at last assessment). JAMA Oncol. 2020 Nov 1;6(11):1766-1772

Fotivda

Tivozanib is a tyrosine kinase inhibitor that inhibits phosphorylation of vascular endothelial growth factor receptor (VEGFR)–1, VEGFR-2, and VEGFR-3 and inhibits other kinases, including c-kit and platelet-derived growth factor receptor (PDGFR)–beta at clinically relevant concentrations. Tivozanib is indicated for relapsed or refractory advanced renal cell carcinoma in patients previously treated with more than 2 systemic therapies.

Approval for tivozanib was based on the TIVO-3 trial (n = 350), which compared tivozanib versus sorafenib in patients with relapsed or refractory advanced renal cell carcinoma who received 2 or 3 prior systemic treatments. The median progression-free survival was 5.6 months (95% confidence interval [CI]: 4.8, 7.3) in the tivozanib arm (n = 175) compared with 3.9 months (95% CI: 3.7, 5.6) for those treated with sorafenib (hazard ratio, 0.73; 95% CI: 0.56, 0.95; P = .016). Lancet Oncol. 2020 Jan;21(1):95-104

Pepaxto (melphalan flufenamide)

Melphalan flufenamide is a peptide-conjugated alkylating drug acting by crosslinking of DNA, thus inhibiting proliferation, inducing apoptosis of hematopoietic and solid tumor cells, and showing synergistic cytotoxicity with dexamethasone in melphalan-resistant and nonresistant multiple myeloma cell lines. Melphalan flufenamide is indicated for using in combination with dexamethasone for relapsed or refractory multiple myeloma in adults who have received 4 or more prior lines of therapy and whose disease is refractory to at least 1 proteasome inhibitor, 1 immunomodulatory agent, and 1 CD38-directed monoclonal antibody.

Approval for melphalan flufenamide was based on the phase 2, single-arm HORIZON study (n = 157). The overall response rate (ORR) and duration of response (DOR) were assessed according to the International Myeloma Working Group Criteria. The ORR was 23.7% and median DOR was 4.2 months. J Clin Oncol. 2021 Mar 1;39(7):757-767

Cosela (trilaciclib)

Trilaciclib is a transient CDK 4/6 inhibitor and thus inhibits hematopoietic stem and progenitor cell proliferation in the bone marrow. Trilaciclib is indicated for adults with extensive-stage small cell lung cancer (SCLC) to reduce chemotherapy-induced myelosuppression when administered before platinum/etoposide-containing or topotecan-containing regimens.

Approval for trilaciclib was based on 3 randomized, double-blind, placebo-controlled studies in patients with extensive-stage SCLC (n = 245). In all 3 studies, patients who received trilaciclib had a lower chance of having severe neutropenia compared with patients who received a placebo. Among those who had severe neutropenia, patients who received trilaciclib, on average, had it for a shorter time than patients who received a placebo. Ann Oncol. 2019 Oct 1;30(10):1613-1621

Ukoniq (umbralisib)

Umbralisib is a dual inhibitor of phosphatidylinositol-3-kinase (PI3K)–delta and casein kinase (CK1) 1–epsilon expressed on malignant B cells. Umbralisib is indicated for relapsed or refractory marginal zone lymphoma (MZL) in adults who have received 1 or more prior anti-CD20 regimens and for relapsed or refractory follicular lymphoma (FL) in adults who have received 3 or more prior lines of systemic therapy.

Approval for umbralisib was based on the UNITY-NHL trial (n = 208) results. The overall response rate (ORR) for patients with MZL was 49% (95% confidence interval [CI], 37.0-61.6), with a 16% complete response (CR) rate. The median progression-free survival (PFS) was not reached for MZL patients (95% CI, 9.3 not evaluable). The ORR for FL patients was 43% (95% CI, 33.6-52.2), with 3% achieving a CR. Median PFS was 10.6 months. The median duration of response for patients with FL was 11.1 months (8.3, 16.4). J Clin Oncol. 2021;39(15):1609-1618

Tepmetko (tepotinib)

Tepotinib is a mesenchymal-epithelial transition (MET) tyrosine kinase inhibitor. It selectively binds to MET tyrosine kinase and disrupts MET and hepatocyte growth factor–dependent signal transduction pathways, which may induce apoptosis in tumor cells overexpressing this kinase. Tepotinib is indicated for metastatic non–small cell lung cancer in adults harboring MET exon 14 (ex14)–skipping alterations.

In the phase 2 VISION trial (n = 300), the overall response rate (ORR) for treatment-naïve patients who received tepotinib (n = 69) was 43%, with a median duration of response (DOR) of 10.8 months. Among the 83 previously treated patients, the ORR was 43% with a median DOR of 11.1 months. N Engl J Med. 2020 Sep 3;383(10):931-943

Breyanzi (lisocabtagene maraleucel)

Lisocabtagene maraleucel is a CD19-directed genetically modified autologous T-cell immunotherapy that involves reprogramming a patient's own T cells with a transgene encoding a chimeric antigen receptor (CAR) to identify and eliminate CD19-expressing malignant and normal cells. It is indicated for adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after at least 2 prior lines of systemic therapies, including DLBCL not otherwise specified (arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B.

Safety and efficacy were evaluated in the TRANSCEND trial, an open-label, multicenter, single-arm trial of patients with relapse/refractory large B-cell non-Hodgkin lymphoma after at least 2 lines of therapy. Study patients (n = 192) received a single infusion of lisocabtagene maraleucel following completion of lymphodepleting chemotherapy. Of these patients, 54% achieved complete response (CR) and 19% achieved partial response (PR). Median duration of response for all responders was 16.7 months (CR was not reached; PR, 1.4 months [95% confidence interval: 1.1-2.2 months]). Among all responders, 65% had remission for at least 6 months, and 62% had remission lasting at least 9 months. Breyanzi Prescribing Information

Abecma (idecabtagene vicleucel)

Idecabtagene vicleucel is a B-cell maturation antigen (BCMA)–directed, genetically modified autologous T-cell immunotherapy consisting of a patient's own T cells that are harvested and genetically modified ex vivo through transduction with an anti-BCMA02 chimeric antigen receptor (CAR) lentiviral vector. Antigen-specific activation of idecabtagene vicleucel results in CAR-positive T-cell proliferation, cytokine secretion, and subsequent cytolytic killing of BCMA-expressing cells. Idecabtagene vicleucel is indicated for relapsed or refractory multiple myeloma after 4 or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody.

Safety and efficacy of idecabtagene vicleucel were evaluated in a multicenter study of 127 patients with relapsed and refractory multiple myeloma who received at least 3 prior lines of antimyeloma therapies. The overall response rate and complete response (CR) rate, as evaluated by an Independent Response committee using the International Myeloma Working Group Uniform Response Criteria for Multiple Myeloma, was 72% (95% confidence interval [CI]: 62%, 81%) and 28% (95% CI 19%, 38%) separately. An estimated 65% of patients who achieved CR remained in CR for at least 12 months. N Engl J Med. 2021; 384:705-716

Truseltiq (infigratinib)

Infigratinib is indicated for adults with previously treated, unresectable, locally advanced, or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement.

Approval was based on results from a single-arm, phase 2 trial. Among 108 patients, 83 (77%) had FGFR2 fusions. The overall response rate (ORR) was 23.1%, including 1 complete response and 24 partial responses. Median duration of response (DOR) was 5 months (range, 0.9-19.1 months). Among responders, 8 (32%) patients had a DOR of 6 months or greater. Median progression-free survival was 7.3 months. Subgroup analysis included an ORR of 34% (17 of 50) in the second-line setting and 13.8% (8 of 58) in the third-/later-line setting (3-8 prior treatments). J Clin Oncol. 39, no. 3_suppl (January 20, 2021) 265-265

Lumakras (sotorasib)

Sotorasib is indicated for KRAS G12C–mutated locally advanced or metastatic non–small cell lung cancer (NSCLC) in adults who have received 1 or more prior systemic therapies. Sotorasib forms an irreversible, covalent bond with the unique cysteine of KRAS G12C, locking the protein in an inactive state that prevents downstream signaling without affecting wild-type KRAS.

Accelerated approval was supported by the CodeBreak 100 phase 2 trial. One-hundred twenty-four patients who had measurable disease at baseline were evaluated. An objective response was observed in 46 patients (37.1%), including 4 who had a complete response and 42 with partial response. Disease control occurred in 100 patients (80.6%), and median overall survival was 12.5%. N Engl J Med. 2021 Jun 24;384(25):2371-2381

Rylaze (asparaginase Erwinia chrysanthemi recombinant)

Asparaginase Erwinia chrysanthemi recombinant is indicated as part of a chemotherapeutic regimen for acute lymphoblastic leukemia or lymphoblastic lymphoma in adults and children aged 1 month or older who have developed hypersensitivity or silent inactivation to Escherichia coli–derived asparaginase.

Pylarify (piflufolastat F 18 injection)

Piflufolastat F 18 injection is indicated for positron-emission tomography of prostate-specific membrane antigen–positive lesions in men with prostate cancer with suspected metastasis who are candidates for initial definitive therapy or with suspected recurrence based on elevated serum prostate-specific antigen level.

Ryplazim (plasminogen)

Plasminogen is the first therapy approved for plasminogen deficiency type 1 (hypoplasminogenemia). It is a plasma-derived human plasminogen that temporarily increases plasminogen blood levels. Activated plasminogen, plasmin, is a fundamental component of the fibrinolytic system, blood clot lysis, and extravasated fibrin clearance.

Other hematology-oncology approvals

Lymphoseek - Indication for lymphatic mapping expanded to include children aged 1 year and older with solid tumors for which this procedure is a component of intraoperative management.

Ayvakit (avapritinib) - New indication for advanced systemic mastocytosis, including those associated with aggressive forms and associated hematologic neoplasm, and mast cell leukemia.

Trodelvy (sacituzumab) - New indication for locally advanced or metastatic urothelial cancer in adults previously treated with platinum-containing chemotherapy and a programmed death 1/programmed death ligand 1 (PD-1/PD-L1) inhibitor.

Sarclisa (isatuximab) - New regimen approved in combination with carfilzomib and dexamethasone for relapsed/refractory multiple myeloma in adults who have received 1-3 prior lines of therapy.

Vyxeos (cytarabine/daunorubicin liposomal) - Indication for newly diagnosed therapy-related acute myeloid leukemia (AML) or AML with myelodysplasia-related changes expanded to include children aged 1 year and older.

Lorbrena (lorlatinib) - Now approved as first-line treatment for metastatic non–small cell lung cancer with anaplastic lymphoma kinase–positive tumors.

Yescarta (axicabtagene ciloleucel) - New indication for adults with relapsed or refractory follicular lymphoma after 2 or more lines of systemic therapy.

Darzalex Faspro (daratumumab/hyaluronidase) - New indication for newly diagnosed light-chain amyloidosis in combination with bortezomib, cyclophosphamide, and dexamethasone.

Enhertu (trastuzumab deruxtecan) - Indicated for treatment of adults with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen.

Xalkori (crizotinib) - New indication for relapsed or refractory, systemic anaplastic lymphoma kinase (ALK)–positive anaplastic large cell lymphoma in children and young adults.

Libtayo (cemiplimab)

  • New indication for first-line treatment of locally advanced (ie, patient not a candidate for surgery or chemoradiation) OR metastatic non–small cell lung cancer in tumors having high programmed death ligand 1 (PD-L1) expression (Tumor Proportion Score ≥50%), with no EGFR, ALK, or ROS1 aberrations

  • New indication for locally advanced and metastatic basal cell carcinoma

Opdivo (nivolumab)

  • Completely resected esophageal or gastroesophageal junction (GEJ) cancer with residual pathologic disease who have received neoadjuvant chemoradiotherapy

  • In combination with fluoropyrimidine- and platinum-containing chemotherapy for advanced or metastatic gastric cancer, GEJ cancer, and esophageal adenocarcinoma

  • In combination with cabozantinib (Cabometyx) as first-line treatment for patients with advanced renal cell carcinoma

Keytruda (pembrolizumab)

  • First-line treatment of locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma in combination with trastuzumab, platinum, and fluoropyrimidine-based chemotherapy

  • Patients with metastatic or locally advanced esophageal or GEJ (tumors with epicenter 1-5 cm above the GEJ) carcinoma who are not candidates for surgical resection or definitive chemoradiation in combination with platinum- and fluoropyrimidine-based chemotherapy

Injectafer (ferric carboxymaltose) - New single-dose regimen for iron deficiency anemia in adults who weigh at least 50 kg.

Ferriprox (deferiprone) - Indication for transfusional iron overload expanded to include children aged 3 years and older with sickle cell anemia or other anemias.

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