FDA Drug Approvals — 2019 Midyear Review

Mary L Windle, PharmD


August 09, 2019

Hematologic-Oncologic Agents

Xpovio (selinexor)

Selinexor is a first-in-class selective inhibitor of nuclear export (SINE). Selinexor acts on tumor suppressor proteins (TSPs), growth regulators, and mRNAs of oncogenic proteins by blocking exportin 1 (XPO1). Inhibition of XPO1 leads to accumulation of TSPs in the nucleus, reductions in several oncoproteins (eg, c‐myc, cyclin D1), cell-cycle arrest, and apoptosis of cancer cells. It is indicated in combination with dexamethasone for adults with relapsed or refractory multiple myeloma (RRMM) who have received at least 4 prior therapies and whose disease is refractory to at least 2 proteasome inhibitors, at least 2 immunomodulatory agents, and an anti-CD38 monoclonal antibody.

The multicenter, single-arm, open-label STORM trial analyzed selinexor plus dexamethasone. STORM part 2 included 122 patients with relapsed/refractory disease who previously had 3 or more treatments, including an alkylating agent, glucocorticoids, bortezomib, carfilzomib, lenalidomide, pomalidomide, and an anti-CD38 monoclonal antibody. Trial participants also had myeloma that was refractory to glucocorticoids, a proteasome inhibitor, an immunomodulatory agent, an anti-CD38 monoclonal antibody, and the last line of therapy that they had. FDA approval was based on results from the 83 patients from the STORM trial who were refractory to bortezomib, carfilzomib, lenalidomide, pomalidomide, and daratumumab. This group had a 25.4% overall response rate, 1% stringent complete response rate, 5% very good partial response, and 19% partial response rate.[5]

Balversa (erdafitinib)

Erdafitinib is a first-in-class fibroblast growth factor receptor (FGFR) inhibitor. Erdafitinib inhibits FGFR phosphorylation and signaling, and thereby decreases cell viability in cell lines expressing FGFR genetic alterations, including point mutations, amplifications, and fusions. FGFRs regulate important biological processes, including cell proliferation and differentiation, which are part of a complex signaling pathway in tumorigenesis.

The FDA granted erdafitinib accelerated approval in April 2019 for locally advanced or metastatic urothelial carcinoma that has FGFR2 or FGFR3 genetic alterations and progressed during or following at least one line of prior platinum-containing chemotherapy, including within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy. Approval was based on a multicenter, open-label, single-arm study (N=87) of patients with urothelial carcinoma with disease that had progressed on or after at least one prior chemotherapy, with FGFR3 or FGFR2 genetic alterations. Results demonstrated a 32.2% overall response rate, with 2.3% having a complete response and almost 30% having a partial response.[6]

Piqray (alpelisib)

Alpelisib is a phosphatidylinositol-3-kinase (PI3K) inhibitor approved by the FDA in May 2019. It is indicated in combination with fulvestrant for treatment of men and postmenopausal women with hormone receptor (HR)–positive, human epidermal growth factor receptor 2 (HER2)–negative, PIK3CA-mutated, advanced or metastatic breast cancer following progression on or after an endocrine-based regimen.

Approval for alpelisib was supported by the SOLAR-1 trial (N=572). Results demonstrated that adding alpelisib to fulvestrant significantly prolonged median progression-free survival (11 months) compared with fulvestrant alone (5.7 months) in patients whose tumors had a PIK3CA mutation.[7]

Polivy (polatuzumab vedotin)

Polatuzumab vedotin is an antibody-drug conjugate that targets CD79b. The small molecule antimitotic agent monomethyl auristatin E (MMAE) portion of the conjugate binds to microtubules in B cells, which results in apoptosis. Polatuzumab vedotin is indicated for adults with relapsed or recurrent diffuse large B-cell lymphoma in combination with bendamustine and a rituximab product after at least 2 prior therapies.

Approval was based on a study that showed 40% of people treated with polatuzumab vedotin plus bendamustine and rituximab (BR) achieved a complete response (N=16/40; 95% confidence interval [CI], 25-57), compared with 18% of those receiving BR alone (N=7/40; 95% CI, 7-33). The study also showed an overall response of 45% with polatuzumab plus BR at the end of treatment (N=18/40; 95% CI, 29-62), compared with 18% given BR alone (N=7/40; 95% CI, 7-33). Of patients receiving polatuzumab plus BR who achieved a complete or partial response, 64% (N=16/25) had a duration of response (DOR) lasting at least 6 months, compared with 30% (n=3/10) of those given BR alone. Additionally, a DOR of at least 1 year was observed in 48% (N=12/25) for polatuzumab plus BR, compared with 20% (N=2/10) for those give BR alone.[8]

Cablivi (caplacizumab)

Caplacizumab is a monoclonal antibody fragment that targets the A1-domain of von Willebrand factor (vWF) and inhibits the interaction between vWF and platelets. This inhibition reduces both vWF-mediated platelet adhesion and platelet consumption. Caplacizumab is indicated for acquired thrombotic thrombocytopenic purpura (aTTP) in combination with plasma exchange and immunosuppressive therapy.

Approval was based on results from the phase 3 HERCULES trial (N=145). When caplacizumab was added to plasma exchange and immunosuppression, a significantly shorter time to platelet count response was observed compared with plasma exchange and immunosuppression alone (hazard ratio, 1.55; 95% confidence interval, 1.1-2.2; P=.01). Additionally, a significant reduction of aTTP-related death, recurrence of aTTP, or a major thromboembolic event was reduced with the addition of caplacizumab compared with plasma exchange and immunosuppression alone (12.7% vs 49.3%; P<.0001). There was also a lower recurrence of aTTP in caplacizumab-treated patients (13% vs 38%; P<.001).[9]

Other notable approvals for hematology/oncology

Jakafi (ruxolitinib) gained a new indication for acute steroid-refractory graft versus host disease in patients aged 12 years or older.

Cyramza (ramucirumab) was approved for hepatocellular carcinoma.

Revlimid (lenalidomide) in combination with a rituximab product was approved for previously treated follicular lymphoma or marginal zone lymphoma.

Keytruda (pembrolizumab) continues to gain new indications, including first-line treatment for head and neck squamous cell carcinoma and second-line treatment of metastatic small-cell lung cancer.

Venclexta (venetoclax) was approved as initial treatment for chronic lymphocytic leukemia/small lymphocytic lymphoma in combination with obinutuzumab.

Bavencio (avelumab) is now indicated for first-line treatment of advanced renal cell carcinoma in combination with axitinib.

Tecentriq (atezolizumab) gained first-line treatment for unresectable locally advanced or metastatic triple-negative breast cancer (TNBC).

Cabometyx (cabozantinib) was approved for hepatocellular carcinoma in patients previously treated with sorafenib.

Herceptin Hylecta (trastuzumab/hyaluronidase) was approved for adjuvant or metastatic breast cancer.


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