Article Content

Tivozanib for Relapsed or Refractory Advanced Renal Cell Carcinoma

Tivozanib has been approved for adult patients with relapsed or refractory advanced renal cell carcinoma (RCC) following two or more prior systemic therapies. Efficacy was evaluated in TIVO-3 (NCT02627963), a randomized (1:1), open-label, multicenter trial of tivozanib versus sorafenib in patients with relapsed or refractory advanced RCC who received two or three prior systemic treatments, including at least one VEGFR kinase inhibitor other than sorafenib or tivozanib.

FDA; oncology resear... - Click to enlarge in new windowFDA; oncology research. FDA; oncology research

Patients were randomized to either tivozanib 1.34 mg orally once daily for 21 consecutive days every 28 days or sorafenib 400 mg orally twice a day continuously, until disease progression or unacceptable toxicity. The main efficacy outcome measure was progression-free survival (PFS), assessed by a blinded independent radiology review committee. Other efficacy endpoints were overall survival (OS) and objective response rate (ORR).


Median PFS was 5.6 months (95% CI: 4.8, 7.3) in the tivozanib arm (n=175) compared with 3.9 months (95% CI: 3.7, 5.6) for those treated with sorafenib (HR 0.73; 95% CI: 0.56, 0.95; p=0.016). Median OS was 16.4 (95% CI: 13.4, 21.9) and 19.2 months (95% CI: 14.9, 24.2) for the tivozanib and sorafenib arms, respectively (HR 0.97; 95% CI: 0.75, 1.24). The ORR was 18 percent (95% CI: 12%, 24%) for the tivozanib arm and 8 percent (95% CI: 4%, 13%) for the sorafenib arm.


The most common (>=20%) adverse reactions were fatigue, hypertension, diarrhea, decreased appetite, nausea, dysphonia, hypothyroidism, cough, and stomatitis. The most common grade 3 or 4 laboratory abnormalities (>=5%) were decreased sodium, increased lipase, and decreased phosphate. The recommended tivozanib dose is 1.34 mg once daily (with or without food) for 21 consecutive days every 28 days until disease progression or unacceptable toxicity.


Pembrolizumab for Esophageal or GEJ Carcinoma

The FDA approved pembrolizumab in combination with platinum and fluoropyrimidine-based chemotherapy for patients with metastatic or locally advanced esophageal or gastroesophageal (GEJ) (tumors with epicenter 1-5 centimeters above the gastroesophageal junction) carcinoma who are not candidates for surgical resection or definitive chemoradiation.


Efficacy was evaluated in KEYNOTE-590 (NCT03189719), a multicenter, randomized, placebo-controlled trial that enrolled 749 patients with metastatic or locally advanced esophageal or gastroesophageal junction carcinoma who were not candidates for surgical resection or definitive chemoradiation. PD-L1 status was centrally determined in tumor specimens in all patients using the PD-L1 IHC 22C3 pharmDx kit. Patients were randomized (1:1) to pembrolizumab in combination with cisplatin and fluorouracil or placebo with cisplatin and fluorouracil, until unacceptable toxicity or disease progression.


The main efficacy outcome measures were overall survival (OS) and progression-free survival (PFS), as assessed by the investigator according to RECIST 1.1 (modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ). The trial demonstrated a statistically significant improvement in OS and PFS for patients randomized to pembrolizumab with chemotherapy.


Median OS was 12.4 months (95% CI: 10.5, 14.0) for the pembrolizumab arm versus 9.8 months (95% CI: 8.8, 10.8) for the chemotherapy arm (HR 0.73; 95% CI: 0.62, 0.86; p<0.0001). Median PFS was 6.3 (95% CI: 6.2, 6.9) and 5.8 months (95% CI: 5.0, 6.0), respectively (HR 0.65; 95% CI: 0.55, 0.76; p<0.0001).


Most common adverse reactions reported in >=20 percent of patients who received the pembrolizumab combination in KEYNOTE-590 were nausea, constipation, diarrhea, vomiting, stomatitis, fatigue/asthenia, decreased appetite, and weight loss. The recommended pembrolizumab dose for esophageal cancer is 200 mg every 3 weeks or 400 mg every 6 weeks.


Idecabtagene Vicleucel for Multiple Myeloma

Idecabtagene vicleucel was approved for the treatment of adult patients with relapsed or refractory multiple myeloma after four or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody.


Idecabtagene vicleucel is a B-cell maturation antigen (BCMA)-directed genetically modified autologous chimeric antigen receptor (CAR) T-cell therapy. Each dose is customized using a patient's own T cells, which are collected and genetically modified, then infused back into the patient.


Safety and efficacy were evaluated in a multicenter study of 127 patients with relapsed and refractory multiple myeloma who received at least three prior lines of antimyeloma therapies; 88 percent had received four or more prior lines of therapies. Efficacy was evaluated in 100 patients who received idecabtagene vicleucel in the dose range of 300 to 460 x 106 CAR-positive T cells. Efficacy was established based on overall response rate (ORR), complete response (CR) rate, and duration of response (DOR), as evaluated by an Independent Response committee using the International Myeloma Working Group Uniform Response Criteria for Multiple Myeloma.


The ORR was 72 percent (95% CI: 62%, 81%) and CR rate was 28 percent (95% CI 19%, 38%). An estimated 65 percent of patients who achieved CR remained in CR for at least 12 months.


The idecabtagene vicleucel label carries a boxed warning for cytokine release syndrome (CRS), neurologic toxicities, hemophagocytic lymphohistiocytosis/macrophage activation syndrome, and prolonged cytopenias. Common side effects of the therapy include CRS, infections, fatigue, musculoskeletal pain, and hypogammaglobulinemia.


Idecabtagene vicleucel is approved with a risk evaluation and mitigation strategy requiring that health care facilities dispensing the therapy must be specially certified to recognize and manage CRS and nervous system toxicities. To evaluate long-term safety, the FDA is requiring the manufacturer to conduct a post-marketing observational study involving patients treated with idecabtagene vicleucel.


Orphan Drug Designation for Padeliporfin ImPACT in Upper Tract Urothelial Cancer

The FDA granted Orphan Drug Designation to padeliporfin ImPACT for the treatment of adult patients with upper tract urothelial cancer (UTUC). The FDA has already given the green light to the Investigational New Drug application, allowing initiation of the pivotal Phase III clinical trial of this treatment in patients with low-grade UTUC, which is expected to begin enrollment later this month. It has also received Fast Track designation from the FDA for the treatment of adult patients with low-grade and unifocal high-grade UTUC.


Padeliporfin ImPACT (Immune Photo Activated Cancer Therapy) offers surgery-like efficacy combined with organ preservation. This oncology platform offers the intravenous delivery of an inactive drug, padeliporfin. Upon activation, the drug rapidly triggers the constriction of the blood supply in the illuminated area only, resulting in targeted tumor necrosis that activates anti-tumor immunity, which enhances cancer cell eradication.


Neihulizumab for Steroid Refractory Acute Graft-Versus-Host Disease

The FDA granted Fast Track designation to neihulizumab (AbGn-168H), for steroid refractory acute graft-versus-host disease (SR-aGVHD).


Neihulizumab is an immune checkpoint regulator targeting PSGL-1, triggering the depletion of chronically activated T cells. This mechanism has been evaluated in four autoimmune and inflammatory diseases and demonstrated clinical proof of concept and safety in more than 170 patients. It is being studied in a Phase Ib multi-dose trial in SR-aGVHD, as well as for frontline acute graft-versus-host disease.