2018 was another banner year for approvals by the United States Food and Drug Administration (FDA), with more than 50 new indications being awarded to immunotherapy, targeted therapies, chemotherapies, biosimilar antibodies, and diagnostic tests. Once again, immunotherapy took center stage with new indications for PD-1 and PD-L1 inhibitors across different tumor types. The most notable impact of these agents (alone or in combination) on the treatment algorithm was seen in lung cancer, including locally advanced lung cancer, first-line therapy of nononcogene-driven advanced nonsquamous and squamous non-small cell lung cancer (NSCLC), and previously treated small cell lung cancer (SCLC). In hematologic malignancies, indication for a chimeric antigen receptor modified (CAR) T-cell immunotherapy tisagenlecleucel was expanded to relapsed large B-cell lymphoma. In addition, two novel cell-targeted cytotoxins (moxetumomab pasudotox and tagraxofusp) were approved for rare blood cancers, and numerous mutation-targeted therapies were approved across solid tumors. Last but not least, biosimilars of both rituximab and trastuzumab were approved with a goal of reducing the cost of cancer care.
The FDA ended the year by issuing six approvals for oncology and hematology indications, including:
- Targeted Cytotoxin for Rare Blood Cancer. Tagraxofusp-ersz (Elonris™, Stemline Therapeutics), a unique, CD123-targeting cytotoxin comprising recombinant IL-3 bound to a truncated diphtheria toxin, was approved for treatment of adult and pediatric patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN), a rare but highly aggressive, hematologic malignancy. This approval was based on results from 2 cohorts of a multicenter, single-arm, phase II trial in patients with untreated or relapsed/refractory BPDCN. In a cohort of 13 patients, 7 (54%) achieved complete remission (CR) or CR with a skin abnormality not indicative of active disease (CRc) following treatment with tagraxofusp. In a cohort of 15 patients, 1 patient achieved CR and 1 achieved CRc. Tagraxofusp will carry a boxed warning regarding increased risk for capillary leak syndrome.
- Calasparagase Pegol, a Longer-Lasting Pegasparagase for ALL. The FDA approved calasparagase pegol-mknl (Asparalas®, Servier Pharmacetuicals LLC) to be used as part of a multicomponent chemotherapy regimen for patients aged 1 month to 21 years with acute lymphoblastic leukemia (ALL). Unlike previous pegasparagase products, calasparagase pegol-mknl uses a chemically stable succinimidyl carbonate linker, which allows for a longer interval between doses. Approval was based on data demonstrating that a 2500 mg U/m2 dose given every 3 weeks resulted in achievement and maintenance of nadir serum asparaginase activity above 0.1 U/mL.
- Olaparib First PARP Inhibitor Approved for First-Line Maintenance in Ovarian Cancer. The poly(ADP-ribose) polymerase inhibitor, olaparib (Lynparza®, AstraZeneca), was approved for use as maintenance therapy following complete or partial response (PR) on first-line chemotherapy in previously untreated patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who carry germline or somatic BRCA This decision was based on results from the phase III SOLO-1 trial where olaparib maintenance therapy resulted in a 70% reduction in the risk of progression or death, compared to placebo in patients with BRCA mutations in CR or PR following first-line chemotherapy (HR 0.30; P < .001). Olaparib is the first PARP inhibitor approved for this indication, having previously been approved as maintenance therapy for platinum-sensitive patients who have progressed on first-line treatment. The FDA also approved BRACAnalysis CDx®, a diagnostic test for germline BRCA mutations to identify patients with advanced ovarian cancer eligible for first-line maintenance with olaparib.
- Pembrolizumab, a Second Immunotherapy for Merkel Cell Carcinoma. The PD-1 inhibitor pembrolizumab (Keytruda®, Merck & Co, Inc) received accelerated approval for treatment of patients with recurrent locally advanced or metastatic Merkel cell carcinoma. The FDA granted approval on the basis of the phase II Keynote-017 trial, in which first-line treatment with pembrolizumab was associated with a 56% overall response rate (ORR) by independent review, including a 24% CR rate. Compared to historical controls, pembrolizumab resulted in improvements in progression-free survival (PFS; 16.8 months vs 3.1-4.6 months) and overall survival (OS; not reached vs 9.5-10.2 months). This approval is contingent upon results of a confirmatory trials.
- Atezolizumab in Combination With Bevacizumab-Based Chemotherapy for Non-Squamous NSCLC. The indication of the PD-L1 inhibitor atezolizumab (Tecentriq, Genentech, Inc) was expanded to include use in combination with bevacizumab, paclitaxel, and carboplatin (ABCP) for first-line treatment of patients with metastatic, non-squamous cell, non-small cell lung cancer (NSCLC) who do not carry EGFR or ALK driver mutations. In the phase III IMpower150 trial, which compared ABCP to bevacizumab and chemotherapy (BCP), the atezolizumab containing regimen was associated with a median OS of 19.2 months, compared to 14.7 months for BCP (HR 0.78; P= .02). PFS was also significantly longer (8.3 months vs 6.8 months; HR 0.62, P< .001). Outcomes favored ABCP, regardless of PD-L1 expression status. PD-L1 expression is not required for use of this regimen in the first-line setting. In addition, PFS was also longer with ABCP among patients with EGFR and ALK alterations and those with liver metastases.
- Second Trastuzumab Biosimilar for Use in HER2-Positive Breast Cancer. Herzuma® (trastuzumab-pkrb, Celltrion, Inc) was approved for treatment of patients with HER2-positive breast cancer. This is the second biosimilar of Herceptin® approved in the United States, following the approval of Ogivri™ in December 2017.