FDA Actions & Updates
The latest approvals, designations, and new indications from the U.S. Food and Drug Administration for oncology drugs.

Monday, June 19, 2017

The FDA has approved the immunotherapy daratumumab in combination with pomalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least two prior therapies including lenalidomide (an immunomodulatory agent) and a proteasome inhibitor (PI). Clinical trial results showed an overall response rate (ORR) of 59.2 percent with daratumumab in combination with pomalidomide and dexamethasone in these patients.

Daratumumab is the first CD38-directed antibody approved anywhere in the world. It was first approved by the FDA in November 2015 as a monotherapy treatment for patients with multiple myeloma who have received at least three prior lines of therapy, including a PI and an immunomodulatory agent, or who are double refractory to a PI and an immunomodulatory agent. It received additional approvals in November 2016 in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of patients with multiple myeloma who have received at least one prior therapy. To date, approximately 16,000 patients have been treated with daratumumab.

"Despite tremendous progress, most patients with multiple myeloma continually relapse or become resistant to available therapies, such as PIs and immunomodulatory agents. Therefore, these patients continue to need new options," said Ajai Chari MD, Associate Professor of Medicine, Multiple Myeloma Program and Associate Director of Clinical Research, Mount Sinai Hospital. "With today's approval of daratumumab, we now have a promising new combination therapy that in clinical trials demonstrated pronounced clinical benefit for patients who have relapsed on two of the most widely used treatments."

This new indication is supported by data from the phase Ib EQUULEUS study, which showed that the combination of daratumumab with pomalidomide and dexamethasone resulted in an ORR of 59.2 percent (95% CI: 49.1, 68.8), with very good partial response (VGPR) achieved in 28.2 percent of patients. Complete response (CR) was achieved in 5.8 percent of patients; stringent CR (sCR) was achieved in 7.8 percent of patients; and partial response (PR) was achieved in 17.5 percent of patients. The median time to response was 1 month (range: 0.9 to 2.8 months), and the median duration of response was 13.6 months (range: 0.9+ to 14.6+ months).

Overall, the safety of the combination therapy was consistent with the known safety profiles of daratumumab monotherapy and pomalidomide plus dexamethasone, respectively. In the EQUULEUS trial, the most frequent (>20%) adverse reactions (ARs) were infusion reactions (50%), diarrhea (38%), constipation (33%), nausea (30 percent), vomiting (21%), fatigue (50%), pyrexia (25%), upper respiratory tract infection (50%), muscle spasms (26%), back pain (25%), arthralgia (22%), dizziness (21%), insomnia (23%), cough (43%), and dyspnea (33%).

The overall incidence of serious ARs was 49 percent. Serious ARs (Grade 3/4) reported in ≥5 percent of patients included pneumonia (7%). Thirteen percent of patients discontinued therapy due to an AR. The most common treatment-emergent hematology laboratory abnormalities were neutropenia (95%), lymphopenia (94%), thrombocytopenia (75%), and anemia (57%). The most common Grade 3 treatment-emergent hematology laboratory abnormalities were lymphopenia (45%), neutropenia (36%), anemia (30%), and thrombocytopenia (10%). The most common Grade 4 treatment-emergent hematology laboratory abnormalities were neutropenia (46%), lymphopenia (26%), and thrombocytopenia (10%).

The phase Ib EQUULEUS study included 103 patients with multiple myeloma who had received a prior PI and an immunomodulatory agent. Patients received 16 mg/kg of daratumumab in combination with pomalidomide and low-dose dexamethasone until disease progression. The median patient age was 64 years with 8 percent of patients aged 75 or older. Patients in the study had received a median of four prior lines of therapy, and 74 percent of patients had received prior autologous stem cell transplant (ASCT). Ninety-eight percent of patients received prior bortezomib treatment and 33 percent of patients received prior carfilzomib treatment. All patients received prior lenalidomide treatment, with 98 percent of patients previously treated with the combination of bortezomib and lenalidomide. Eighty nine percent of patients were refractory to lenalidomide, 71 percent were refractory to bortezomib and 64 percent of patients were refractory to bortezomib and lenalidomide.

The recommended dose of daratumumab is 16 mg/kg body weight administered as an IV infusion. The dosing schedule for daratumumab in combination with pomalidomide and dexamethasone begins with weekly administration (weeks 1-8) and reduces in frequency over time to every 2 weeks (weeks 9-24) and ultimately every 4 weeks (week 25 onwards until disease progression


Friday, May 26, 2017

The FDA has accepted for review a supplemental Biologics License Application (sBLA) for pembrolizumab, an anti-PD-1 therapy, seeking approval for treatment of patients with recurrent or advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma who have already received two or more lines of chemotherapy.

The application submitted to the FDA is seeking approval for pembrolizumab monotherapy in previously treated patients at a fixed dose of 200 mg administered intravenously every 3 weeks. The application is based on data from cohort one of the phase II KEYNOTE-059 trial investigating pembrolizumab in heavily pretreated patients with recurrent or advanced gastric or gastroesophageal junction adenocarcinoma that has progressed after two or more lines of chemotherapy. Data from cohort one of KEYNOTE-059 will be presented at the 53rd ASCO Annual Meeting in Chicago, June 2-6 (Abstract 4003). 

Pembrolizumab is being evaluated in multiple clinical trials in more than 30 tumor types, including multiple gastrointestinal cancers. Specific to gastric cancer, pembrolizumab is being investigated as a monotherapy and in combination with other cancer treatments across multiple lines of therapy. To date, this includes four gastric cancer registration-enabling studies and numerous other gastrointestinal cancer studies are underway.​


Thursday, May 25, 2017

The FDA has granted accelerated approval to a treatment for patients whose cancers have a specific biomarker. This is the first time the agency has approved a cancer treatment based on a common biomarker rather than the location in the body where the tumor originated.

Pembrolizumab is indicated for the treatment of adult and pediatric patients with unresectable or metastatic solid tumors that have been identified as having a biomarker referred to as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR). This indication covers patients with solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options and patients with colorectal cancer that has progressed following treatment with certain chemotherapy drugs.

"This is an important first for the cancer community," said Richard Pazdur, MD, Acting Director of the Office of Hematology and Oncology Products in the FDA's Center for Drug Evaluation and Research and Director of the FDA's Oncology Center of Excellence. "Until now, the FDA has approved cancer treatments based on where in the body the cancer started—for example, lung or breast cancers. We have now approved a drug based on a tumor's biomarker without regard to the tumor's original location."

MSI-H and dMMR tumors contain abnormalities that affect the proper repair of DNA inside the cell. Tumors with these biomarkers are most commonly found in colorectal, endometrial and gastrointestinal cancers, but also less commonly appear in cancers arising in the breast, prostate, bladder, thyroid gland and other places. Approximately 5 percent of patients with metastatic colorectal cancer have MSI-H or dMMR tumors.

Pembrolizumab was approved for this new indication using the Accelerated Approval pathway, under which the FDA may approve drugs for serious conditions where there is unmet medical need and a drug is shown to have certain effects that are reasonably likely to predict a clinical benefit to patients. Further study is required to verify and describe anticipated clinical benefits of pembrolizumab, and studies are currently being conducted in additional patients with MSI-H or dMMR tumors.

The safety and efficacy of pembrolizumab for this indication were studied in patients with MSI-H or dMMR solid tumors enrolled in one of five uncontrolled, single-arm clinical trials. In some trials, patients were required to have MSI-H or dMMR cancers, while in other trials, a subgroup of patients were identified as having MSI-H or dMMR cancers by testing tumor samples after treatment began.

A total of 15 cancer types were identified among 149 patients enrolled across these five clinical trials. The most common cancers were colorectal, endometrial, and other gastrointestinal cancers. The review of pembrolizumab for this indication was based on overall response rate and durability of response. Of the 149 patients who received pembrolizumab in the trials, 39.6 percent had a complete or partial response. For 78 percent of those patients, the response lasted for 6 months or more.

The FDA granted this application Priority Review designation, under which the FDA's goal is to take action on an application within six months where the agency determines that the drug, if approved, would significantly improve the safety or effectiveness of treating, diagnosing or preventing a serious condition.

Pembrolizumab was previously approved by the FDA for the treatment of certain patients with metastatic melanoma, metastatic non-small cell lung cancer, recurrent or metastatic head and neck cancer, refractory classical Hodgkin lymphoma, and urothelial carcinoma.


Monday, May 22, 2017

The FDA has approved two new indications for pembrolizumab, an anti-PD-1 therapy, for certain patients with locally advanced or metastatic urothelial carcinoma.

In the first-line setting, pembrolizumab is now approved for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are ineligible for cisplatin-containing chemotherapy. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

In the second-line setting, pembrolizumab is now approved for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

Pembrolizumab is approved for use in these indications at a fixed dose of 200 mg every 3 weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

The first-line approval is based on data from a multicenter, open-label, single-arm trial, KEYNOTE-052, investigating pembrolizumab in 370 patients with locally advanced or metastatic urothelial carcinoma who were not eligible for cisplatin-containing chemotherapy.

The efficacy analysis showed an overall response rate (ORR( of 29 percent (95% CI: 24, 34), with a complete response rate of 7 percent and a partial response rate of 22 percent. The median duration of response had not been reached (range: 1.4+ to 17.8+ months). The median follow-up time was 7.8 months.

The second-line approval is based on data from a multicenter, randomized, active-controlled trial, KEYNOTE-045, investigating pembrolizumab in patients with locally advanced or metastatic urothelial carcinoma with disease progression on or after platinum-containing chemotherapy. =

Pembrolizumab demonstrated superior overall survival (OS) compared to chemotherapy. Findings demonstrated that pembrolizumab resulted in a 27 percent reduction in the risk of death compared to chemotherapy – with 155 events (57%) observed in the pembrolizumab arm, compared to 179 events (66%) in the chemotherapy arm (HR, 0.73 [95% CI: 0.59, 0.91], p=0.004); the median OS was 10.3 months (95% CI: 8.0, 11.8) in the pembrolizumab arm, compared to 7.4 months (95% CI: 6.1, 8.3) in the chemotherapy arm. In October 2016, the study was stopped early at the recommendation of an independent Data Monitoring Committee following an interim analysis that showed pembrolizumab met the superiority thresholds for OS in the overall study population.

"Pembrolizumab is now available for use as a first-line treatment option for patients with advanced urothelial bladder cancer who are not eligible for the standard-of-care, cisplatin-based chemotherapy," said Dean F. Bajorin, MD, study investigator and medical oncologist at Memorial Sloan Kettering Cancer Center. "With the second-line indication, pembrolizumab also provides a new option for patients with advanced urothelial bladder cancer – and is the only anti-PD-1 therapy to show an overall survival benefit versus chemotherapy in a phase III study."

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Wednesday, May 17, 2017

The FDA has granted Priority Review designation for the New Drug Application (NDA) for copanlisib for the treatment of relapsed or refractory follicular lymphoma (FL) patients who have received at least two prior therapies.

Priority Review is granted for the applications of medicines that, if approved, would provide significant improvements in the safety or effectiveness of the treatment, diagnosis, or prevention of serious conditions when compared to standard applications.

Copanlisib is a pan-Class I phosphatidylinositol-3-kinase (PI3K) inhibitor with predominant inhibitory activity against PI3K-α and PI3K-δ isoforms. The efficacy and safety of copanlisib has not been established. The broad clinical development program for copanlisib also includes phase III studies in indolent non-Hodgkin's lymphoma (NHL) patients who have relapsed or are refractory to prior therapies.

The regulatory submission for copanlisib is based on data from the phase II open-label, single-arm CHRONOS-1 study (NCT01660451) evaluating patients with relapsed or refractory indolent non-Hodgkin's lymphoma (iNHL). CHRONOS-1 was designed to evaluate the efficacy and safety of copanlisib in patients with relapsed or refractory indolent NHL, including FL, who received at least two prior therapies. The primary endpoint is the objective tumor response rate, with duration of response, overall survival, progression-free survival, quality-of-life, and safety serving as secondary endpoints.

The full analysis set comprised 142 patients, of which 141 patients had iNHL. The full data set was presented at the American Association for Cancer Research (AACR) Annual Meeting 2017. Data from the FL subset of the CHRONOS-1 trial will be presented at the ASCO Annual Meeting 2017 in June.

Copanlisib has also been granted Orphan Drug Designation for the treatment of splenic, nodal, and extranodal subtypes of marginal zone lymphoma.