FDA News

TOP - August 2019, Vol 12, No 3 - FDA Updates
This section provides a brief overview of new cancer drugs or new indications approved by the FDA between June 10 and July 3, 2019.

 

FDA Approves Polivy in Combination with Bendamustine plus a Rituximab Product for Relapsed, Refractory DLBCL

On June 10, 2019, the FDA accelerated the approval of polatuzumab vedotin-piiq (Polivy; Genentech), a CD79b-directed antibody-drug conjugate, in combination with bendamustine plus a rituximab product (BR) for the treatment of patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after ≥2 previous therapies.

The FDA approval of polatuzumab was based on results from the phase 1b/2 GO29365 clinical trial that included 80 patients with relapsed or refractory DLBCL who had received ≥1 previous treatment regimens. Patients were randomized in a 1:1 ratio to pol­atuzumab plus BR or BR alone for six 21-day cycles. Efficacy was based on complete response rate and duration of response, defined as the time the disease remained in remission.

Results showed a complete response rate of 40% in patients treated with polatuzumab plus BR versus 18% in those treated with BR alone. Of the 25 patients who achieved a partial or complete response with polatuzumab plus BR, 16 (64%) had a duration of response of ≥6 months and 12 (48%) had a duration of response of ≥12 months.

The most common (≥20%) adverse effects associated with polatuzumab plus BR were neutropenia, thrombocytopenia, anemia, peripheral neuropathy, fatigue, diarrhea, pyrexia, decreased appetite, and pneumonia.

“Antibody-drug conjugates are an emerging class of targeted immunotherapies for cancer. This type of therapy, unlike traditional chemotherapy, is intended to target specific cells,” said Richard Pazdur, MD, Director, FDA’s Oncology Center of Excellence. “Today’s approval of Polivy provides an alternative option for patients in whom multiple treatments have not worked.”

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Keytruda Approved for 2 Indications in the First-line Treatment of Patients with HNSCC

On June 10, 2019, the FDA approved single-agent pembrolizumab (Keytruda; Merck) for the treatment of newly diagnosed patients with metastatic or unresectable recurrent head and neck squamous-cell carcinoma (HNSCC) whose tumors express PD-L1 (composite positive score [CPS] ≥1 as determined by an FDA-approved test); the agency also approved a combination of pembrolizumab plus platinum and fluorouracil (FU) for the same patient population, irrespective of PD-L1 expression.

Keytruda has received previous FDA approvals as a single agent or in combination with other agents for the treatment of many types of cancers, and was initially approved for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy in 2016 under the FDA’s accelerated approval process, based on data from the phase 1b KEYNOTE-012 clinical trial.

This latest approval was based on results from the phase 3 KEYNOTE-048 trial of 882 patients with metastatic HNSCC with recurrent disease who were deemed incurable by local therapies or who had not received previous systemic therapy for metastatic disease.

Patients were randomized in a 1:1:1 ratio to pembrolizumab alone; pembrolizumab plus chemotherapy (cisplatin or carboplatin and FU); or cetuximab (Erbitux; Lilly Oncology) plus chemotherapy (carboplatin or cisplatin and FU). PD-L1 expression (tumor proportion score and CPS) was determined using the PD-L1 IHC 22C3 pharmDx kit.

Results from a prespecified interim analysis showed that pembrolizumab monotherapy significantly improved overall survival (OS) in patients with a PD-L1 CPS of >1 and >20 compared with cetuximab plus chemotherapy. In the CPS >1 cohort, the median OS was 12.3 months for the pembrolizumab arm and 10.3 months for the cetuximab plus chemotherapy arm (hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.64-0.96; P = .0171). In the CPS ≥20 cohort, the median OS was 14.9 months for the pembrolizumab arm and 10.7 months for the cetuximab plus chemotherapy arm (HR, 0.61; 95% CI, 0.45- 0.83; P = .0015).

There was also a significant improvement in OS in the overall population of patients who received pembrolizumab plus chemotherapy compared with those who received cetuximab plus chemotherapy (median OS, 13.0 months vs 10.7 months, respectively; HR, 0.77; 95% CI, 0.63-0.93; P = .0067).

Pembrolizumab monotherapy was not superior to chemotherapy alone in the overall patient population, and there was no improvement in progression-free survival with either pembro­lizumab monotherapy or pembrolizu­mab plus chemotherapy compared with cetuximab plus chemotherapy.

The most common (≥20%) adverse events associated with pembrolizumab monotherapy were fatigue, constipation, and rash, whereas the most common adverse events (≥20%) associated with pembrolizumab in combination with chemotherapy were nausea, fatigue, constipation, vomiting, mucosal inflammation, diarrhea, decreased appetite, stomatitis, and cough.

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Darzalex Combined with Revlimid and Dexamethasone Approved as First-line Treatment of Patients with MM Ineligible for Transplant

On June 27, 2019, the FDA approved daratumumab (Darzalex; Janssen) in combination with lenalidomide (Revlimid; Celgene) and dexamethasone for the first-line treatment of patients with multiple myeloma (MM) who are ineligible for autologous stem-cell transplantation. This is the sixth indication for daratumumab in MM and the second for newly diagnosed patients.

This latest approval was based on results from the phase 3 MAIA clinical trial of 737 patients with newly diagnosed MM who were not candidates for high-dose chemotherapy and autologous stem-cell transplantation. Patients were randomized in a 1:1 ratio to daratumumab plus lenalidomide and dexamethasone or lenalidomide and dexamethasone alone.

Results showed an improvement in progression-free survival (PFS) with the addition of daratumumab. Median PFS had not been reached in the daratumumab arm and was 31.9 months in the lenalidomide plus dexamethasone arm (hazard ratio, 0.56; 95% confidence interval, 0.43-0.73; P <.0001). In addition, researchers reported higher rates of complete response or better (48% vs 25%, respectively) and overall response (93% vs 81%, respectively) in the daratumumab arm, as well as a higher rate of minimal residual disease negativity (24% vs 7%, respectively).

The most common (≥20%) adverse events associated with daratumu­mab-based therapy were infusion reactions, diarrhea, constipation, nausea, peripheral edema, fatigue, back pain, asthenia, pyrexia, upper respiratory tract infection, bronchitis, pneumonia, decreased appetite, muscle spasms, peripheral sensory neuropathy, dysp­nea, and cough.

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Xpovio plus Dexamethasone Combination Receives Accelerated Approval for the Treatment of Patients with Relapsed or Refractory MM

On July 3, 2019, the FDA granted accelerated approval to selinexor (Xpovio; Karyopharm Therapeutics), a selective inhibitor of nuclear export XPO1 antagonist, in combination with dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma (MM) who have received ≥4 previous therapies and whose disease is resistant to several other forms of treatment, including ≥2 proteasome inhibitors, ≥2 immunomodulatory agents, and an anti-CD38 monoclonal antibody.

This approval was based on results from the international, multicenter, single-arm, phase 2b STROM clinical trial of 122 patients with relapsed or refractory MM who had previously received ≥3 treatment regimens, including an alkylating agent, glucocorticoids, bortezomib (Velcade; Takeda), carfilzomib (Kyprolis; Amgen), lenalidomide (Revlimid; Celgene), pomalidomide (Pomalyst; Celgene), and an anti-CD38 monoclonal antibody; and whose MM was documented to be refractory to glucocorticoids, a proteasome inhibitor, an immunomodulatory agent, an anti-CD38 monoclonal antibody, and to the last line of therapy. Patients were treated with selinexor plus dexamethasone on days 1 and 3 of every week. Treatment continued until disease progression, death, or unacceptable toxicity.

In a prespecified subgroup analysis of 83 patients in the trial, treatment with the selinexor plus dexamethasone regimen resulted in an overall response rate of 25.3%, which included no complete responses, 1 stringent complete response, 4 very good partial responses, and 16 partial responses. The median time to first response was 4 weeks and the median duration of response was 3.8 months.

The most common adverse events (≥20%) were thrombocytopenia, fatigue, nausea, anemia, decreased ap­petite, decreased weight, diarrhea, vomiting, hyponatremia, neutropenia, leukopenia, constipation, dyspnea, and upper respiratory tract infections.

“While there is no cure for multiple myeloma, there are FDA-approved treatments to target the cancer and slow down the spread of the disease. Sadly, often over time, patients can exhaust all available treatments and still see their disease progress,” said Richard Pazdur, MD, Director, FDA’s Oncology Center of Excellence. “Today we approved a treatment under our accelerated approval program that provides a treatment option for patients with multiple myeloma with no available therapy.”

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FDA News
TOP - November 2019, Vol 12, No 4 published on November 7, 2019 in FDA Updates
Last modified: September 9, 2019