FDA Approvals, Highlights, and Summaries: Hematology/Oncology

February 24, 2021

Danyelza (naxitamab)

Naxitamab is indicated for relapsed or refractory high-risk neuroblastoma in the bone or bone marrow, in patients aged 1 year and older who have demonstrated a partial response, minor response, or stable disease with prior therapy. It is a humanized anti-GD2 3F8 monoclonal antibody that stimulates antibody-dependent cell-mediated cytotoxicity against GD2-expressing tumor cells. 

Approval was based on two trials in combination with granulocyte-macrophage colony-stimulating factor. Among 22 patients treated in the multicenter Study 201, the overall response rate (ORR) was 45% and 30% of responders had a duration of response (DOR) of at least 6 months. Among 38 patients treated in the single-center Study 12-230, the ORR was 34% with 23% of patients having a DOR of at least 6 months. Both trials observed responses in bone, bone marrow, or both. (FDA grants accelerated approval to naxitamab)

Ayvakit (avapritinib)

Avapritinib is a tyrosine kinase inhibitor that binds to and inhibits specific mutant forms of platelet-driven growth factor receptor (PDGFR)?alpha and c-Kit, including the PDGFR-alpha D842V mutant and various KIT exon 17 mutants. Avapritinib is indicated for adults with unresectable or metastatic gastrointestinal stromal tumor harboring a PDGFR-alpha exon 18 mutation, including a D842V mutation.

Approval was based, in part, on the NAVIGATOR clinical trial. Results demonstrated durable responses in patients with PDGFRA exon 18 mutations across multiple lines of treatment. In patients with PDGFRA D842V mutations (n=56), 37 (66%) patients remained on treatment at a median follow-up of 15.9 months. Also, 49 (88%) of the 56 patients had an overall response (9% complete response, 79% partial response). ( Lancet Oncol. July 2020;21(7):935-946)

Qinlock (ripretinib)

Ripretinib is platelet-driven growth factor receptor (PDGFR)?alpha inhibitor that is indicated for advanced gastrointestinal stromal tumor in adults previously treated with 3 or more kinase inhibitors, including imatinib.

In the INVICTUS trial (n=129), patients were randomized to either ripretinib (n=85) or placebo (n=44). Median progression-free survival was 6.3 months for patients receiving ripretinib compared with 1 month for those taking placebo (P <.0001). ( Lancet Oncol. July 2020;21(7):923-934)

Monjuvi (tafasitamab)

Tafasitamab is a humanized Fc-modified cytolytic CD19-directed monoclonal antibody that binds to the CD19 antigen expressed on the surface of pre-B and mature B lymphocytes and on several B-cell malignancies. It is indicated in combination with lenalidomide for relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in adults who are not eligible for autologous stem cell transplantation.

Approval was based on data from the phase 2 L-MIND study, an open label, multicenter, single-arm trial of tafasitamab in combination with lenalidomide as a treatment for adult patients with relapsed or refractory DLBCL. The study showed an overall response rate of 55%, including a complete response rate of 37% and a partial response rate of 18%. The median duration of response was 21.7 months. ( Lancet Oncol. July 2020;21(7):978-988)

Tecartus (brexucabtagene autoleucel)

Brexucabtagene autoleucel, a CD19-directed genetically modified autologous T-cell immunotherapy, is indicated for the treatment of relapsed or refractory mantle cell lymphoma (MCL) in adults. Approval was based on ZUMA-2, an open-label, multicenter, single-arm trial of patients with relapsed or refractory MCL who had previously received anthracycline- or bendamustine-containing chemotherapy, an anti-CD20 antibody, and a Bruton tyrosine kinase inhibitor.

The primary efficacy analysis showed that 93% of the 60 patients in the primary efficacy analysis had an objective response and 67% had a complete response. In an intention-to-treat analysis involving all 74 patients, 85% had an objective response; 59% had a complete response. At a median follow-up of 12.3 months, 57% of the 60 patients in the primary efficacy analysis were in remission. At 12 months, the estimated progression-free survival and overall survival were 61% and 83%, respectively. ( N Engl J Med. April 2, 2020;382(14):1331-1342)

Tazverik (tazemetostat)

Tazemetostat is an enhancer of zeste homolog 2 (EZH2) inhibitor. Uncontrolled EZH2 enzyme activity results in poorly regulated genes that control cancer cell proliferation. Tazemetostat is indicated for metastatic or locally advanced epithelioid sarcoma not eligible for complete resection in adults and adolescents aged 16 years or older. It is also indicated for adults with relapsed or refractory follicular lymphoma in patients whose tumors are positive for EZH2 mutation and who have received at least 2 prior systemic therapies, or those who have no satisfactory treatment options.

Approval for epithelioid sarcoma was based on a phase 2 trial (n=62). The overall response rate was 15%, with 1.6% of patients having a complete response and 13% having a partial response. Of the 9 patients who had a response, 6 (67%) patients had a response lasting 6 months or longer. Approval for follicular lymphoma was based on a phase 2 study. In the 53 patients treated with at least 2 prior systemic therapies, the overall response rate was 34% (4% complete response, 30% partial response). The median duration of response was 13 months. (Tazverik prescribing information)

Sarclisa (isatuximab)

Isatuximab is an anti-CD38 monoclonal antibody that targets a specific epitope on the CD38 receptor on plasma cells that promote apoptosis and immunomodulatory activity. It is indicated for relapsed or refractory multiple myeloma in combination with pomalidomide and dexamethasone in adults who have received at least 2 prior therapies (including lenalidomide and a proteasome inhibitor).

Approval was based on the ICARIA-MM clinical trial (n=307). The median progression-free survival was 11.5 months in the isatuximab-pomalidomide-dexamethasone group compared with 6.5 months in the pomalidomide-dexamethasone group (P=.001). ( Lancet. December 7, 2019. 394 (10214):2096-2107)

Blenrep (belantamab mafodotin)

Belantamab mafodotin is an antibody drug conjugate consisting of an afucosylated, humanized monoclonal antibody directed against the B-cell maturation antigen (BCMA), which is conjugated to monomethyl auristatin F, a microtubule inhibitor with potential antineoplastic activity. It is indicated for relapsed or refractory multiple myeloma in adults who have received at least four prior therapies including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent. Owing to the risk of ocular toxicity, belantamab mafodotin is available only through a restricted program.

Approval was based on the open-label DREAMM-2 trial, in which the overall response rate was 31% and the duration of response was at least 6 months in 73% of responders. (Blenrep prescribing information)

Inqovi (cedazuridine/decitabine)

Cedazuridine/decitabine is indicated for adults with myelodysplastic syndromes (MDSs), including previously treated and untreated, de novo and secondary MDS with the following French-American-British subtypes (ie, refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, and chronic myelomonocytic leukemia) and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups.

Orgovyx (relugolix)

Relugolix is the first oral androgen-deprivation therapy approved by the FDA for advanced prostate cancer. It is a gonadotropin-releasing hormone receptor antagonist that decreases gonadotropin release (ie, luteinizing hormone, follicle-stimulating hormone), thereby decreasing the downstream production of testosterone by the testes in men.

Approval of relugolix was based on the HERO clinical trial (n=622). The trial observed 54% lower risk of major adverse cardiovascular events with oral relugolix compared with leuprolide injections. Sustained testosterone suppression was achieved in 96.7% of relugolix-treated patients compared with 88.8% with leuprolide at 48 weeks. ( N Engl J Med. June 4, 2020;382(23):2187-2196)

Margenza (margetuximab)

Margetuximab is a human epidermal growth factor receptor 2 (HER2)/neu receptor antagonist, chimeric Fc-engineered IgG1 kappa monoclonal antibody that targets HER2-expressing tumors. Margetuximab is indicated in combination with chemotherapy for metastatic HER2-positive breast cancer in patients who have received at least 2 anti-HER2 regimens, at least 1 of which was for metastatic disease.

In the ongoing SOPHIA phase 3 clinical trial, the second interim analysis of 536 patients showed the progression-free survival of margetuximab versus trastuzumab was 58 versus 4.9 months (P=.033). Results were more pronounced in patients with CD16A genotypes containing a 158F allele (6.9 vs 5.1 months; P=.005). (Abstract GS1-02: San Antonio Breast Cancer Symposium, December 10-14, 2019)

Tukysa (tucatinib)

Tucatinib is a tyrosine kinase inhibitor for human epidermal growth factor 2 (HER2). It selectively binds to and inhibits ErB-2 phosphorylation, which may prevent activation of ErbB-2 signal transduction pathways, resulting in growth inhibition and death of ErbB-2—expressing tumor cells. Tucatinib is indicated in combination with trastuzumab and capecitabine for advanced unresectable or metastatic HER2-positive breast cancer (including brain metastases) in patients who have received at least 1 anti-HER2—based regimen in the metastatic setting.

Approval was based on the HER2CLIMB trial (n=612). The international and multicenter study randomized patients to receive either tucatinib plus trastuzumab and capecitabine or the control arm (placebo plus trastuzumab and capecitabine). The median progression-free survival in the tucatinib-treated group was 7.8 months compared with 5.6 months in the control arm. The median overall survival in the tucatinib-treated arm was 21.9 months compared with 17.4 months in the control arm. The median progression-free survival for patients with baseline brain metastases on the tucatinib-treated arm was 7.6 months compared with 5.4 months in the control arm. ( N Engl J Med. February 13, 2020;382(7):597-609)

Trodelvy (sacituzumab govitecan)

Sacituzumab govitecan is an antibody-drug conjugate that contains SN-38, the active metabolite of irinotecan. It binds to topoisomerase I-DNA complex and prevents ligation of the cleaved DNA strand; this results in double-strand DNA breaks and, ultimately, cell death and termination of cellular replication. Sacituzumab govitecan is indicated for metastatic triple-negative breast cancer in patients who have received 2 or more prior therapies for metastatic disease.

Approval was based on the multicenter, single-arm IMMU-132-01 trial (n=108), in which patients treated with sacituzumab every 21 days had an overall response rate of 33.3% (95% confidence interval [CI], 24.6-43.1) and a median duration of response of 7.7 months (95% CI, 4.9-10.8). ( N Engl J Med. February 21, 2019;380(8):741-751)

Pemazyre (pemigatinib)

Pemigatinib is an orally bioavailable inhibitor of fibroblast growth factor receptor (FGFR) types 1, 2, and 3. Pemigatinib inhibits FGFR 1/2/3 phosphorylation and signaling, and it decreases cell viability in cancer cell lines with activating FGFR amplifications and fusions. FGFR inhibition disrupts tumor cell proliferation, survival, migration, and angiogenesis. It is indicated for unresectable locally advanced or metastatic cholangiocarcinoma in previously treated adults with an FGFR2 fusion or other rearrangement as detected by an FDA-approved test.

Approval was supported by the FIGHT-202 study (n=146). Of the 146 patients enrolled, 107 had FGFR2 fusions or rearrangements, 20 had other FGF/FGFR alterations, 18 had no alterations, and 1 had an undetermined alteration. Thirty-eight (35.5%) of the 107 patients with FGFR2 fusions or rearrangements achieved an objective response (3 complete responses, 35 partial responses). ( Lancet Oncol. May 2020;21(5):671-684)

Tabrecta (capmatinib)

Capmatinib is a mesenchymal-epithelial transition (MET) tyrosine kinase inhibitor. MET tyrosine kinase stimulates cell scattering, invasion, protection from apoptosis, and angiogenesis. A variety of cancers (eg, lung, gastric) are associated when MET becomes dysregulated, owing to MET amplifications and exon 14 skipping. Capmatinib is indicated for metastatic non—small cell lung cancer in adults whose tumors have a mutation that leads to MET exon 14 skipping.

Approval was based on a study in which the overall response rate in treatment-naive patients (n=28) was 68% (complete response in 4%, partial response in 64%) and the overall response rate in previously treated patients (n=69) was 41%, with all having a partial response. Median duration of response was 12.6 months in treatment-naive patients and 9.7 months in previously treated patients. ( J Clin Oncol. 2020 37(15))

Retevmo (selpercatinib)

Selpercatinib is a kinase inhibitor of wild-type rearranged during transfection (RET) and multiple mutated RET isoforms, as well as vascular endothelial growth factor receptors (VEGFR1, VEGFR3). Genomic alterations in RET kinase, which include fusions and activating point mutations, lead to overactive RET signaling and uncontrolled cell growth. Selpercatinib is indicated for metastatic RET fusion-positive non—small cell lung cancer (NSCLC) in adults. It is also indicated for advanced or metastatic RET-mutant medullary thyroid cancer (MTC) in adults and children aged 12 years or older who required systemic therapy.

In the open-label LIBRETTO-001 phase 1/2 clinical trial (n=144) for adults with NSCLC, the overall response rate was 64% in treatment-experienced patients (n=105) and 85% in treatment-naïve patients (n=39). Results for patients with MTC (n=143) showed the overall response rate was 69% in cabozantinib/vandetanib treatment-experienced patients (n=55) and 73% in treatment-naive patients (n=88). (Retevmo prescribing information)

Gavreto (pralsetinib)

Pralsetinib is another kinase inhibitor of rearranged during transfection (RET) alterations and mutations. Some RET fusion proteins can drive tumorigenic potential, which leads to uncontrolled cell proliferation. Pralsetinib has also exhibited antitumor activity. Pralsetinib is indicated for treatment of RET-fusion–positive non–small cell lung cancer (NSCLC) in adults. Pralsetinib also gained approval for advanced or metastatic RET-mutant medullary thyroid cancer (MTC) and RET-fusion–positive thyroid cancers in adults and children aged 12 years or older.

The initial approval for NSCLC was based the ARROW study, a nonrandomized, open-label phase 1/2 study (n=114). The study separated patients into separate cohorts, patients with metastatic RET-fusion–positive NSCLC who had progressed on platinum-based chemotherapy (n=87) and treatment-naïve patients with metastatic NSCLC (n=27). The overall response rate for patients who had progressed on platinum-based chemotherapy was 57%, with 5.2% of patients having a complete response and 52% having a partial response. The overall response rate for treatment-naïve patients was 70%, with 11% of patients having a complete response and 59% having a partial response. ( J Clin Oncol. May 20, 2020;38(15 suppl):9515-9515)

Zepzelca (lurbinectedin)

Lurbinectedin is an alkylating drug. It binds guanine residues in the minor groove of DNA, forming adducts and resulting in a bending of the DNA helix towards the major groove. Adduct formation triggers a cascade of events that can affect the subsequent activity of DNA-binding proteins, including some transcription factors, and DNA repair pathways. Lurbinectedin is indicated for metastatic small cell lung cancer in patients with disease progression on or after platinum-based chemotherapy.

Accelerated approval was based on a single-arm, open-label, phase 2 basket trial. Of 105 patients enrolled in the study, 37 patients had an overall response (35.2%). ( Lancet Oncol. May 2020;21(5):645-654)

Oncology diagnostic imaging agents

Cerianna (fluoroestradiol F18) is a diagnostic agent that binds to the estrogen receptor. It is indicated for use with positron-emission tomography imaging to detect estrogen receptor—positive lesions as an adjunct to biopsy in patients with recurrent or metastatic breast cancer.

Gallium 68 PSMA-11 is a beta-positive–emitting radionuclide that binds to cells that express prostate-specific membrane antigen (PSMA), including malignant prostate cancer cells, which usually overexpress PSMA. It is indicated for positron-emission tomography of PSMA-positive lesions in males with prostate cancer who are either candidates for initial definitive therapy with suspected metastasis or those with suspected recurrence based on elevated serum prostate-specific antigen levels.

Detectnet (copper Cu 64 dotatate) is a positron beta-emitting radionuclide that binds to somatostatin receptors with highest affinity for somatostatin subtype 2 receptors (SSTR2). It is indicated for use with positron-emission tomography for localization of somatostatin receptor–positive neuroendocrine tumors.

ProHance (gadoteridol) is now approved for MRI use in newborns and toddlers to visualize lesions with disrupted blood-brain barrier and/or abnormal vascularity of intracranial lesions, spine, and associated tissues.

Other notable oncology approvals

Tecentriq (atezolizumab) - Unresectable or metastatic melanoma in patients with BRAF V60 in combination with cobimetinib and vemurafenib

Yervoy (ipilimumab) - Indicated in combination with nivolumab for patients with unresectable malignant pleural mesothelioma, as first-line treatment

Nucala (mepolizumab) - Indicated for adults and pediatric patients aged 12 years and older with hypereosinophilic syndrome with a duration of 6 months without an identifiable nonhematologic secondary cause

Phesgo (pertuzumab/trastuzumab/hyaluronidase) - Subcutaneous combination for neoadjuvant treatment of HER2-positive early-stage breast cancer

Xpovio (selinexor) - For diffuse large B-cell lymphoma (DLBCL), not otherwise specified, including DLBCL arising from follicular lymphoma, after at least 2 lines of systemic therapy

Reblozyl (luspatercept) - Indicated for anemia failing erythropoiesis-stimulating agents in adults with myelodysplastic syndromes

Braftovi (encorafenib) - Metastatic colorectal cancer with a BRAF-V600E mutation

Imfinzi (durvalumab) - First-line treatment of extensive-stage small-cell lung cancer

Cyramza (ramucirumab) - First-line treatment for metastatic EGFR-mutated non—small cell lung cancer

Pomalyst (pomalidomide) - Indicated for Kaposi sarcoma in adults with or without AIDS

Tecentriq (atezolizumab) and Avastin (bevacizumab) - First-line treatment for hepatocellular carcinoma

Lynparza (olaparib) - For HRR gene—mutated metastatic castration-resistant prostate cancer

Rubraca (rucaparib) - For deleterious BRCA mutation (germline and/or somatic)—associated metastatic castration-resistant prostate cancer

Opdivo (nivolumab) - Esophageal squamous cell carcinoma after prior fluoropyrimidine- and platinum-based chemotherapy; also, as a single agent or in combination with ipilimumab for adults with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan

Jelmyto (mitomycin pyelocalyceal) - Administered as bladder instillation for upper tract urothelial cancer

Crysvita (burosumab) - Indicated for FGF23-related hypophosphatemia in tumor-induced osteomalacia associated with phosphaturic mesenchymal tumors

Gardasil 9 (human papillomavirus vaccine nonavalent) - Indication now includes prevention of head and neck cancers

Keytruda (pembrolizumab) - Select new indications include the following:

  • New 400-mg q6wk regimen for all indications approved in adults

  • BCG-unresponsive, high-risk, non—muscle invasive bladder cancer with carcinoma in situ

  • Metastatic tumor mutational burden-high (TMB H) [≥10 mutations/megabase (mut/Mb)] solid tumors

  • Cutaneous squamous cell carcinoma

  • First-line treatment for microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer

  • Indicated in combination with chemotherapy for locally recurrent unresectable or metastatic triple-negative breast cancer whose tumors express programmed death-ligand 1 (PD-L1)


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