FDA News - August 2018

August 2018 Vol 11, Special Issue - FDA News

A brief overview of new cancer drugs or new indications approved by the FDA between May 1 and June 13, 2018.

In This Article

Kymriah Approved for Adults with Relapsed or Refractory Large B-Cell Lymphoma

On May 1, 2018, the FDA approved a new indication for the immunotherapy tisagenlecleucel (Kym­riah; Novartis), a CD19-directed, autologous T-cell gene therapy, for the treatment of adults with relapsed or refractory large B-cell lymphoma for use after ≥2 systemic therapies, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high-grade B-cell lymphoma, or DLBCL arising from follicular lymphoma.

Tisagenlecleucel was first approved by the FDA in August 2017 for the treatment of young patients aged ≤25 years with relapsed or refractory precursor acute lymphoblastic leukemia. This was the first time the FDA approved a genetically modified CAR T-cell therapy in the United States (also known as gene therapy).

This new indication was approved based on the JULIET study, a single-arm, open-label, multicenter phase 2 clinical trial of adults with relapsed or refractory DLBCL or DLBCL that was developed from follicular lymphoma. All patients had ≥2 previous lines of systemic therapy or had a disease that relapsed after stem-cell transplant.

All patients received 1 infusion of tisagenlecleucel after chemotherapy. Among the 68 eligible patients, the overall response rate was 50%, including a 32% complete response. After a median 9.4-month follow-­up, the estimated duration of response was not reached among patients who had complete response versus 3.4 months in those with partial response.

The most common side effects (>20%) included cytokine release syndrome (CRS), infections, fever, diarrhea, nausea, fatigue, hypotension, edema, and headache. Tisa­genlecleucel is associated with serious risks for CRS and neurologic toxicities.

Tafinlar-Mekinist Combination Approved for Metastatic Thyroid Cancer with BRAF V600E Mutation

On May 4, 2018, the FDA expedited its approval of the combination of dabrafenib and trametinib (Tafinlar and Mekinist; Novartis) for the treatment of patients with locally advanced or metastatic anaplastic thyroid cancer and BRAF V600E mutation who have no appropriate locoregional therapy options.

"This is the first FDA-approved treatment for patients with this aggressive form of thyroid cancer, and the third cancer with this specific gene mutation that this drug combination has been approved to treat," said Richard Pazdur, MD, Director of the FDA's Oncology Center of Excellence. This drug combination is already approved for melanoma or non–small-cell lung cancer associated with specific BRAF V600E or V600K mutations.

This new indication was based on a multicenter, nonrandomized, open-label clinical trial involving patients with rare cancers and BRAF V600E mutation. Of 23 patients with locally advanced, unresectable, or metastatic anaplastic thyroid cancer who had no appropriate locoregional treatment options and were evaluable for response, 14 patients had response to treatment with the combination, including 57% partial responses and 4% complete responses. The overall response rate was 61%, and the responses lasted ≥6 months in 64% of patients. The side effects were similar to those seen in other tumors.

Venclexta Indicated for CLL or SLL, Alone or in Combination with Rituxan

On June 8, 2018, the FDA approved venetoclax (Venclexta; AbbVie/Genentech) for patients with chronic lymphocytic leukemia (CLL) or with small lymphocytic lymphoma (SLL), regardless of 17p deletion, who received previous therapy, as monotherapy or in combination with rituximab (Rituxan; Genentech).

The new indication for venetoclax plus rituximab was based on MURANO, a multicenter, open-­label clinical trial of 389 patients with CLL who received ≥1 previous therapies. Patients received venetoclax plus rituximab or bendamustine plus rituximab. Patients in the venetoclax arm received venetoclax 400 mg once daily for 2 years after completing a 5-week ramp-up of ven­etoclax. Rituximab was added on day 1 of each of the 6 cycles of 28-day length. Patients in the bendamustine plus ri­tuximab arm received the combination for 6 cycles of 28-day length (bendamustine on days 1-2 of each cycle, and rituximab on day 1 of each cycle).

At 23 months, the median progression-free survival was not reached in the venetoclax arm and was 18.1 months in the bendamustine arm (P <.0001). The overall response rate was 92% in the venetoclax plus rituximab arm versus 72% in the bendamustine plus rituximab arm.

Grade 3 or 4 neutropenia was 64% in the venetoclax plus rituximab arm; grade 4 neutropenia was 31%. Serious adverse events (46%) and serious infections (21%) were also reported. The most common (9%) serious infection was pneumonia. Tumor lysis syndrome is a significant risk associated with venetoclax.

Keytruda Receives 2 New Indications: Metastatic Cervical Cancer and Relapsed Mediastinal Large B-Cell Lymphoma

On June 12, 2018, the FDA granted accelerated approval to pembrolizumab (Keytruda; Merck) for patients with recurrent or metastatic cervical cancer that progressed during or after chemotherapy and whose tumors express PD-L1, as determined by an FDA-approved test. Concurrently, the FDA approved the PD-L1 IHC 22C3 pharmDx kit as a companion diagnostic test for determining the PD-L1 status in this patient population.

This approval was based on 98 patients in the KEYNOTE-158 study who had recurrent or metastatic cervical cancer expressing PD-L1, as was determined by the PD-L1 IHC 22C3 pharmDx test. At a median of 11.7-month follow-up, the overall response rate was 14.3% among 77 patients whose tumors expressed PD-L1; of these responses, 2.6% were complete responses and 11.7% were partial responses.

Based on 11 patients who responded to treatment, the median duration of response was not reached at the time of this approval; the duration of response was ≥6 months in 91% of the patients. No responses were seen in patients without PD-L1 expression.

Serious adverse reactions were reported in 39% of patients, and pembro­lizumab was discontinued in 8% of the patients because of adverse reactions.

A day later, on June 13, 2018, the FDA accelerated the approval of pembrolizumab for adult and pediatric patients with relapsed or refractory primary mediastinal large B-cell lymphoma (PMBCL). The FDA granted pembro­lizumab orphan drug designation and breakthrough therapy designation for this indication.

This approval was based on results from the KEYNOTE-170 clinical trial of 53 patients with relapsed or refractory PMBCL. Patients received intravenous pembrolizumab 200 mg every 3 weeks for up to 2 years, or until disease progression or unacceptable toxicity.

The overall response rate was 45%, with 11% complete responses and 34% partial responses. In the 9.7-month follow-up, the median duration of response was not reached. Pembrolizu­mab is not recommended for patients with PMBCL for whom cytoreductive therapy is crucial.

Adverse events led to pembroliz­umab discontinuation (8%) or in­terruption (15%), and systemic corticosteroid therapy was required in 25% of patients who had an adverse reaction. Serious adverse events were reported in 26% of patients.

Bevacizumab plus Chemotherapy Approved for Several Types of Ovarian Cancer

On June 13, 2018, the FDA approved bevacizumab (Avastin; Genentech), in combination with carboplatin and paclitaxel, for the treatment of patients with resected, stage III or IV epithelial ovarian, fallopian tube, or primary peritoneal cancer, to be followed with beva­cizumab monotherapy. Bevacizumab received orphan drug designation for this indication.

This approval was based on a multicenter, double-blind, placebo-­controlled clinical trial of 1873 ­patients with stage III or IV epithelial ovarian, fallopian tube, or primary peritoneal cancer who had initial surgical resection. Patients were randomized to carboplatin plus paclitaxel; carboplatin plus paclitaxel with bevacizumab (for up to 6 cycles); or carboplatin plus pac­litaxel with bevacizumab for 6 cycles, followed by bevacizumab monotherapy for up to 16 additional doses. Bevaciz­umab was administered intravenously every 3 weeks. A total of 1215 patients received ≥1 bevacizumab doses.

In patients receiving bevacizumab plus chemotherapy followed by beva­cizumab, the median progression-free survival (PFS) was 18.2 months compared with 12.8 months for those receiving bevacizumab plus chemotherapy but no follow-up with bevacizumab monotherapy. The ­median PFS was 12 months with chemotherapy alone. The estimated median overall survival for the bev­­acizumab plus chemotherapy followed by bevacizumab arm was 43.8 months versus 40.6 months in the chemotherapy alone arm.

The most common (≥2%) grade 3 or 4 adverse events with bevacizumab were fatigue, hypertension, thrombocytopenia, and leukopenia.

Last modified: August 31, 2018
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