Robert C. Kane

Sorafenib for the Treatment of Advanced Renal Cell Carcinoma

Purpose: This report describes the U.S. Food and Drug Administration (FDA) review and approval of sorafenib (Nexavar, BAY43-9006), a new small-molecule, oral, multi-kinase inhibitor for the treatment of patients with advanced renal cell carcinoma (RCC). Experimental Design: After meeting with sponsors during development studies of sorafenib, the FDA reviewed the phase 3 protocol under the Special Protocol Assessment mechanism. Following new drug application submission, FDA independently analyzed the results of two studies in advanced RCC: a large, randomized, double-blinded, phase 3 international trial of single-agent sorafenib and a supportive phase 2 study. Results: In the phase 3 trial, 902 patients with advanced progressive RCC after one prior systemic therapy were randomized to 400 mg sorafenib twice daily plus best supportive care or to a matching placebo plus best supportive care. Primary study end points included overall survival and progression-free survival (PFS). A PFS analysis, pre-specified and conducted after a total of 342 events, showed statistically significant superiority for the sorafenib group (median = 167 days) compared with that for the controls (median = 84 days, log-rank P < 0.000001); the sorafenib/placebo hazard ratio was 0.44 (95% confidence interval, 0.35-0.55). Results were similar regardless of patient risk score, performance status, age, or prior therapy. The (partial) response rate to sorafenib was 2.1%. Overall survival results are preliminary. The principal toxicities in the sorafenib patients included reversible skin rashes in 40% and hand-foot skin reaction in 30%; diarrhea was reported in 43%, treatment-emergent hypertension was reported in 17%, and sensory neuropathic changes were reported in 13%. Grade 4 adverse events were uncommon. Grade 3 adverse events were hand-foot skin reaction (6%), fatigue (5%), and hypertension (3%). Laboratory findings included asymptomatic hypophosphatemia in 45% of sorafenib patients versus 11% in the placebo arm and elevation of serum lipase in 41% of sorafenib patients versus 30% in the placebo arm. Grade 4 pancreatitis was reported in two sorafenib patients, although both patients subsequently resumed sorafenib, with one at full dose. Conclusions: Sorafenib received FDA regular approval on December 20, 2005 for the treatment of advanced RCC based on the persuasive magnitude of improvement in PFS with acceptable safety. The recommended dose is 400 mg (two 200-mg tablets) twice daily taken either 1 h before or 2 h after meals. Adverse events were accommodated by temporary dose interruptions or reductions.

Approval Summary for Bortezomib for Injection in the Treatment of Multiple Myeloma

Purpose: Multiple myeloma is a malignant plasma cell disorder accounting for about 10% of hematological malignancies. Despite treatment advances, including hematopoietic stem-cell transplantation to facilitate administration of high-dose cytotoxic chemotherapy, the median survival remains

Bortezomib for the Treatment of Mantle Cell Lymphoma

Purpose: To describe the Food and Drug Administration review and marketing approval considerations for bortezomib (Velcade) for the treatment of patients with mantle cell lymphoma. Experimental Design: Food and Drug Administration reviewed a multicenter study of bortezomib in 155 patients with progressive mantle cell lymphoma after at least one prior therapy. Results: Seventy-seven percent were stage IV, and 75% had one or more extranodal sites of disease. Prior therapy included an anthracycline or mitoxantrone, cyclophosphamide, and rituximab. Median age was 65 years. All received bortezomib 1.3 mg/m2 i.v. on days 1, 4, 8, and 11 of each 3-week cycle. The primary end point was response. Response and progression were determined by independent review of serial computed tomography scans using International Lymphoma Workshop Response Criteria. The overall response rate was 31%, including complete response (CR) plus CR unconfirmed (CRu) plus partial response; median response duration was 9.3 months. The CR plus CRu response rate was 8% with a median duration of 15.4 months. Adverse events were similar to those observed previously for bortezomib. The most commonly reported treatment-emergent adverse events were asthenia (72%), peripheral neuropathies (55%), constipation (50%), diarrhea (47%), nausea (44%), and anorexia (39%). The most common adverse event leading to discontinuation was neuropathy. Conclusions: Bortezomib received regular approval for the treatment of patients with mantle cell lymphoma in relapse after prior therapy.

United States Food and Drug Administration Approval Summary: Bortezomib for the Treatment of Progressive Multiple Myeloma after One Prior Therapy

Purpose: On March 25, 2005, bortezomib (Velcade for Injection; Millennium Pharmaceuticals, Inc., Cambridge, MA, and Johnson & Johnson Pharmaceutical Research & Development, L.L.C.) received regular approval from the U.S. Food and Drug Administration (U.S. FDA) for the treatment of multiple myeloma (MM) progressing after at least one prior therapy. This approval was based on bortezomibs efficacy and safety which was shown in a single, large, comparative international open-label phase 3 trial that randomized 669 patients with MM previously treated with at least one systemic regimen to receive single-agent bortezomib or high-dose dexamethasone. The FDA analysis of the trial data and bortezomibs regulatory development are summarized here. Experimental Design and Results: Following a preplanned interim analysis of time to disease progression (the primary end point), an independent data-monitoring committee advised the sponsor to halt the study and offer bortezomib to all dexamethasone-treated study patients. Time to progression was significantly prolonged in the bortezomib treatment arm (median, 6.2 months) compared with the dexamethasone arm (median, 3.5 months; log-rank test, P < 0.0001; hazard ratio, 0.55; 95% confidence interval, 0.44-0.69). Analysis of overall survival done on the interim database (with 20% of events) showed the superiority of bortezomib for patients (log-rank test, P < 0.05; hazard ratio, 0.57; 95% confidence interval, 0.40-0.81). Using criteria from the European Group for Blood and Marrow Transplantation, the response rate (complete plus partial response) with bortezomib was also superior to dexamethasone (38% versus 18%; P < 0.0001). Adverse events on the bortezomib arm were similar to those previously observed in phase 2 studies; some notable adverse events included asthenia, peripheral neuropathy, thrombocytopenia, and neutropenia. Conclusions: The U.S. FDA had earlier (May 2003) granted bortezomib accelerated approval for the treatment of patients with MM progressing after two prior therapies. The results of the phase 3 trial and the FDA analysis of the data, along with the sponsors completion of other postmarketing commitments, confirm bortezomibs benefit and support regular approval.

U.S. Food and Drug Administration Approval Summary: Brentuximab Vedotin for the Treatment of Relapsed Hodgkin Lymphoma or Relapsed Systemic Anaplastic Large-Cell Lymphoma

The U.S. Food and Drug Administration (FDA) describes the accelerated approval of brentuximab vedotin for patients with relapsed Hodgkin lymphoma and relapsed systemic anaplastic large-cell lymphoma (sALCL). FDA analyzed the results of two single-arm trials, enrolling 102 patients with Hodgkin lymphoma and 58 patients with sALCL. Both trials had primary endpoints of objective response rate (ORR) and key secondary endpoints of response duration and complete response (CR) rate. For patients with Hodgkin lymphoma, ORR was 73% (95% CI, 65–83%); median response duration was 6.7 months, and CR was 32% (95% CI, 23–42%). For patients with sALCL, ORR was 86% (95% CI, 77–95%), median response duration was 12.6 months, and CR was 57% (95% CI, 44–70%). The most common adverse reactions were neutropenia, peripheral sensory neuropathy, fatigue, nausea, anemia, upper respiratory infection, diarrhea, pyrexia, rash, thrombocytopenia, cough, and vomiting. FDA granted accelerated approval of brentuximab vedotin for the treatment of patients with Hodgkin lymphoma after failure of autologous stem cell transplantation (ASCT) or after failure of at least two prior multiagent chemotherapy regimens in patients who are not ASCT candidates, and for the treatment of patients with sALCL after failure of at least one prior multiagent chemotherapy regimen. Clin Cancer Res; 18(21); 5845–9. ©2012 AACR.

U.S. Food and Drug Administration Approval: Carfilzomib for the Treatment of Multiple Myeloma

The U.S. Food and Drug Administration (FDA) review leading to accelerated approval of carfilzomib is described. A single-arm trial enrolled 266 patients with multiple myeloma refractory to the most recent therapy who had received prior treatment with bortezomib and an immunomodulatory agent (IMID). Patients received carfilzomib by intravenous infusion over 2 to 10 minutes at a dose of 20 mg/m2 on days 1, 2, 8, 9, 15, and 16 of the 28 days of cycle 1, and at a dose of 27 mg/m2 on the same schedule in cycle 2 and subsequent cycles. The primary efficacy endpoint was overall response rate (ORR) as determined by an independent review committee using International Myeloma Working Group Uniform Response Criteria. The safety of carfilzomib was evaluated in 526 patients with multiple myeloma treated with various dosing regimens. The ORR was 23%. The median duration of response was 7.8 months. The most common adverse reactions associated with carfilzomib infusion were fatigue, anemia, nausea, thrombocytopenia, dyspnea, diarrhea, and fever. The most common serious adverse events were pneumonia, acute renal failure, fever, and congestive heart failure. Infusion reactions to carfilzomib could be reduced by pretreatment with dexamethasone and intravenous fluids. On July 20, 2012, the FDA granted accelerated approval of carfilzomib for the treatment of patients with multiple myeloma who have received at least two prior therapies including bortezomib and an IMID and who have shown disease progression while on therapy or within 60 days of completion of the last therapy. Clin Cancer Res; 19(17); 4559–63. ©2013 AACR.

Comparative Risk of Anaphylactic Reactions Associated With Intravenous Iron Products

IMPORTANCE All intravenous (IV) iron products are associated with anaphylaxis, but the comparative safety of each product has not been well established. OBJECTIVE To compare the risk of anaphylaxis among marketed IV iron products. DESIGN, SETTING, AND PARTICIPANTS Retrospective new user cohort study of IV iron recipients (n = 688,183) enrolled in the US fee-for-service Medicare program from January 2003 to December 2013. Analyses involving ferumoxytol were limited to the period January 2010 to December 2013. EXPOSURES Administrations of IV iron dextran, gluconate, sucrose, or ferumoxytol as reported in outpatient Medicare claims data. MAIN OUTCOMES AND MEASURES Anaphylaxis was identified using a prespecified and validated algorithm defined with standard diagnosis and procedure codes and applied to both inpatient and outpatient Medicare claims. The absolute and relative risks of anaphylaxis were estimated, adjusting for imbalances among treatment groups. RESULTS A total of 274 anaphylaxis cases were identified at first exposure, with an additional 170 incident anaphylaxis cases identified during subsequent IV iron administrations. The risk for anaphylaxis at first exposure was 68 per 100,000 persons for iron dextran (95% CI, 57.8-78.7 per 100,000) and 24 per 100,000 persons for all nondextran IV iron products combined (iron sucrose, gluconate, and ferumoxytol) (95% CI, 20.0-29.5 per 100,000) , with an adjusted odds ratio (OR) of 2.6 (95% CI, 2.0-3.3; P < .001). At first exposure, when compared with iron sucrose, the adjusted OR of anaphylaxis for iron dextran was 3.6 (95% CI, 2.4-5.4); for iron gluconate, 2.0 (95% CI 1.2, 3.5); and for ferumoxytol, 2.2 (95% CI, 1.1-4.3). The estimated cumulative anaphylaxis risk following total iron repletion of 1000 mg administered within a 12-week period was highest with iron dextran (82 per 100,000 persons, 95% CI, 70.5- 93.1) and lowest with iron sucrose (21 per 100,000 persons, 95% CI, 15.3- 26.4). CONCLUSIONS AND RELEVANCE Among patients in the US Medicare nondialysis population with first exposure to IV iron, the risk of anaphylaxis was highest for iron dextran and lowest for iron sucrose.

FDA Approval: Blinatumomab

On December 3, 2014, the FDA granted accelerated approval of blinatumomab (Blincyto; Amgen, Inc.) for treatment of Philadelphia chromosome–negative relapsed or refractory precursor B-cell acute lymphoblastic leukemia (R/R ALL). Blinatumomab is a recombinant murine protein that acts as a bispecific CD19-directed CD3 T-cell engager. The basis for the approval was a single-arm trial with 185 evaluable adults with R/R ALL. The complete remission (CR) rate was 32% [95% confidence interval (CI), 26%–40%], and the median duration of response was 6.7 months. A minimal residual disease response was achieved by 31% (95% CI, 25%–39%) of all patients. Cytokine release syndrome and neurologic events were serious toxicities that occurred. Other common (>20%) adverse reactions were pyrexia, headache, edema, febrile neutropenia, nausea, tremor, and rash. Neutropenia, thrombocytopenia, and elevated transaminases were the most common (>10%) laboratory abnormalities related to blinatumomab. A randomized trial is required in order to confirm clinical benefit. Clin Cancer Res; 21(18); 4035–9. ©2015 AACR.

FDA Approval: Idelalisib Monotherapy for the Treatment of Patients with Follicular Lymphoma and Small Lymphocytic Lymphoma

On July 23, 2014, the FDA granted accelerated approval to idelalisib (Zydelig tablets; Gilead Sciences, Inc.) for the treatment of patients with relapsed follicular B-cell non–Hodgkin lymphoma or relapsed small lymphocytic lymphoma (SLL) who have received at least two prior systemic therapies. In a multicenter, single-arm trial, 123 patients with relapsed indolent non–Hodgkin lymphomas received idelalisib, 150 mg orally twice daily. In patients with follicular lymphoma, the overall response rate (ORR) was 54%, and the median duration of response (DOR) was not evaluable; median follow-up was 8.1 months. In patients with SLL, the ORR was 58% and the median DOR was 11.9 months. One-half of patients experienced a serious adverse reaction of pneumonia, pyrexia, sepsis, febrile neutropenia, diarrhea, or pneumonitis. Other common adverse reactions were abdominal pain, nausea, fatigue, cough, dyspnea, and rash. Common treatment-emergent laboratory abnormalities were elevations in alanine aminotransferase, aspartate aminotransferase, gamma-glutamyltransferase, absolute lymphocytes, and triglycerides. Continued approval may be contingent upon verification of clinical benefit in confirmatory trials. Clin Cancer Res; 21(7); 1525–9. ©2015 AACR. See related article by Gandhi et al., p. 1537

FDA Approval: Ibrutinib for Patients with Previously Treated Mantle Cell Lymphoma and Previously Treated Chronic Lymphocytic Leukemia

On November 13, 2013, the FDA granted accelerated approval to ibrutinib (IMBRUVICA capsules; Pharmacyclics, Inc.) for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. On February 12, 2014, the FDA granted accelerated approval for the treatment of patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy. Ibrutinib is a first-in-class Brutons tyrosine kinase (BTK) inhibitor that received all four expedited programs of the FDA: Fast-Track designation, Breakthrough Therapy designation, Priority Review, and Accelerated Approval. Both approvals were based on overall response rate (ORR) and duration of response (DOR) in single-arm clinical trials in patients with prior treatment. In MCL (N = 111), the complete and partial response rates were 17.1% and 48.6%, respectively, for an ORR of 65.8% [95% confidence interval (CI), 56.2%–74.5%]. The median DOR was 17.5 months (95% CI, 15.8–not reached). In CLL (N = 48), the ORR was 58.3% (95% CI, 43.2%–72.4%), and the DOR ranged from 5.6 to 24.2 months. The most common adverse reactions (≥30% in either trial) were thrombocytopenia, diarrhea, neutropenia, bruising, upper respiratory tract infection, anemia, fatigue, musculoskeletal pain, peripheral edema, and nausea. Clin Cancer Res; 21(16); 3586–90. ©2015 AACR.