FDA Cancer Therapy Approvals in March 2021
In March, the US Food and Drug Administration (FDA) granted six new indications to immunotherapy and targeted therapy for solid and hematological cancers:
- Pembrolizumab in Combination With Chemotherapy for Advanced Esophageal or Gastroesophageal Carcinoma. Pembrolizumab (Keytruda®, Merck, Sharp & Dohme Corp.) was approved in combination with platinum- and fluoropyrimidine-based chemotherapy as first-line therapy for patients with metastatic or locally advanced esophageal or gastroesophageal junction (GEJ) carcinoma with an epicenter 1 – 5 cm above the GEJ, who are not eligible for surgical resection or definitive chemoradiation. Approval was based on the results from the multicenter, randomized, placebo-controlled, phase III KEYNOTE-590 trial, which showed a statistically significant improvement in overall survival (OS) and progression-free survival (PFS) for patients who received pembrolizumab with chemotherapy (n=373) versus chemotherapy alone (n=376). Median OS was 12.4 versus 9.8 months, respectively (hazard ratio [HR], 0.73; P<0.0001), and median PFS was 6.3 versus 5.8 months (HR, 0.65; P<0.0001). The benefits were demonstrated regardless of PD-L1 expression status and tumor histology.
- Tivozanib for Heavily Pretreated Advanced Renal Cell Carcinoma. Approval was granted to tivozanib (Fotivda®, AVEO Pharmaceuticals, Inc.), a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor, for patients with relapsed or refractory (R/R) advanced renal cell carcinoma (RCC) following two or more prior systemic therapies, based on results from the randomized, open-label, phase III TIVO-3 trial. Patients with R/R advanced RCC who had received two or three prior systemic treatments, which included at least one VEGFR kinase inhibitor (other than sorafenib or tivozanib) and could include immunotherapy, were randomized to receive either tivozanib or sorafenib. Median PFS was significantly longer with tivozanib compared with sorafenib (5.6 versus 3.9 months; HR, 0.73; P=0.02), and overall response rate (ORR) was 18% versus 8%, respectively. However, there was no significant OS benefit with tivozanib. Nevertheless, tivozanib was shown to significantly increase quality-adjusted time without symptoms of disease and toxicity compared with sorafenib (Q-TWiST analysis). The recommended tivozanib dose is 1.34 mg orally once daily for 21 consecutive days every 28 days until disease progression or unacceptable toxicity.
- Lorlatinib for Metastatic ALK-Positive Non-Small Cell Lung Cancer (NSCLC). Lorlatinib (Lorbrena®, Pfizer Inc.) was granted full approval and expanded indication to include the first-line treatment of patients with metastatic ALK-positive NSCLC, as detected by the simultaneously approved companion diagnostic, Ventana ALK (D5F3) CDx. The expanded approval was based on the results from the randomized, multicenter, open-label, active-controlled, phase III CROWN study (Study B7461006), conducted in 296 patients with ALK-positive metastatic NSCLC who had not received prior systemic therapy for metastatic disease. Patients treated with lorlatinib (100 mg orally once daily) showed a statistically significant improvement in PFS compared with patients treated with crizotinib (250 mg orally twice daily): PFS was not estimable versus 9.3 months, respectively (HR, 0.28; P<0.0001). Of note, central nervous system (CNS) involvement was assessed in all patients, and among patients with measurable CNS lesions at baseline, the intracranial response was 82% in the lorlatinib arm versus 23% in the crizotinib arm, with a duration of response (DoR) of ≥12 months in 79% versus 0%, respectively.
- CAR-T Axicabtagene Ciloleucel for R/R Follicular Lymphoma. Accelerated approval was granted to axicabtagene ciloleucel (Yescarta®, Kite Pharma, Inc.), a CD19-directed chimeric antigen receptor (CAR) T-cell therapy, for the treatment of adult patients with R/R follicular lymphoma (FL) after two or more lines of systemic therapy. Approval was based on the findings from the FL cohort of the ongoing multicenter, single-arm, open-label, phase II ZUMA-5 trial. Patients with R/R FL after two lines of therapy, including an anti-CD20 monoclonal antibody plus an alkylating agent, received a single intravenous infusion of axiacabtagene ciloleucel following lymphodepleting chemotherapy. According to data from the primary analysis, the ORR for patients with R/R FL (n=84) was 94%, with a complete response (CR) rate of 80%. At a median follow-up of 17.5 months, the median DoR was not reached for complete responders and the 1-year continued response rate was 78%. The prescribing information for axicabtagene ciloleucel includes a boxed warning for cytokine release syndrome (CRS) and neurologic toxicities.
- Two New Options for R/R Multiple Myeloma:
Anti-CD38 antibody Isatuximab-irfc in Combination with Carfilzomib and Dexamethasone. Isatuximab-irfc (Sarclisa®, Sanofi-Aventis US) received its second approval in R/R multiple myeloma (MM). This new approval is in combination with carfilzomib and dexamethasone for patients with R/R MM after one to three prior lines of therapy. The combination was evaluated in the multicenter, randomized, open-label, two-arm, phase III IKEMA trial, in which 302 patients received either isatuximab-irfc with carfilzomib and dexamethasone (Isa-Kd), or carfilzomib and dexamethasone alone (Kd). Median PFS was not reached in the Isa-Kd arm versus 20.3 months in the Kd arm (HR, 0.55; P=0.0032). The recommended Isa-Kd dose is 10 mg/kg as an intravenous infusion every week for 4 weeks followed by every 2 weeks until disease progression or unacceptable toxicity.
Idecabtagene Vicleucel, a Cell-Based Gene Therapy for Patients with ≥4 Prior Lines of Therapy. Idecabtagene vicleucel (Abecma®, Bristol Myers Squibb) is the first B-cell maturation antigen (BCMA)-directed genetically modified CAR T-cell therapy approved for patients with R/R MM after they have received four or more prior lines of therapy, including an immunomodulatory agent, a proteosome inhibitor, and an anti-CD38 monoclonal antibody. The approval is based on efficacy data from the multicenter, phase II KarMMa study of 127 patients with R/R MM, in which 88% of patients had received four or more prior lines of therapy. The ORR was 72% and CR rate was 28%. Of those patients who achieved CR, an estimated 65% remained in CR for at least 12 months. Idecabtagene vicleucel is provided as a single dose for infusion, containing a suspension of CAR-positive T cells in one or more infusion bags. The recommended dose range is 300 – 460 x 106 CAR-positive T cells. The prescribing information includes a boxed warning for CRS, neurologic toxicities, hemophagocytic lymphohistiocytosis/macrophage activation syndrome, and prolonged cytopenia.