FDA Drug Approvals, Hematology — 2020 Midyear Review

August 14, 2020

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 2020 Jul;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 2020 Jul;21(7):923-934 )

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. 2019 Dec 7. 394 (10214):2096-2107 )

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.

(US Food and Drug Administration. FDA approves oral combination of decitabine and cedazuridine for myelodysplastic syndromes. July 7, 2020.)

Tukysa (tucatinib)

Tucatinib is a tyrosine kinase inhibitor for human epidermal growth factor 2 (HER2). It selectively binds to and inhibits ErbB-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 2020 Feb 13;382(7):597-609 )

Cerianna (fluoroestradiol F18)

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.

(Gorovets A. Cerianna (fluoroestradiol F18) NDA approval [letter]. US Food and Drug Administration. May 20, 2020. NDA 212155.)

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 2019 Feb 21;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 2020 May;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-naive 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)

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 toward 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 2020 May;21(5):645-654 )

Other oncology approvals

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.

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:

  • 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

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