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

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.


Thursday, May 11, 2017

​​The FDA has approved the anti-PD-1 therapy, pembrolizumab, in combination with pemetrexed and carboplatin (pem/carbo), a commonly used chemotherapy regimen, for the first-line treatment of metastatic nonsquamous non-small cell lung cancer (NSCLC), irrespective of PD-L1 expression.

Under the FDA's accelerated approval regulations, this indication is approved based on tumor response rate and progression-free survival (PFS). Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

The approval was based on data from KEYNOTE-021, Cohort G1, in 123 previously untreated patients with metastatic nonsquamous NSCLC with no EGFR or ALK genomic tumor aberrations and irrespective of PD-L1 expression. In this trial, pembrolizumab + pem/carbo demonstrated an objective response rate (ORR) that was nearly double the ORR of pem/carbo alone (55% [95% CI: 42, 68] compared to 29% [95% CI: 18, 41], respectively; all responses were partial responses). Among patients who received pembrolizumab + pem/carbo, 93 percent had a duration of response of 6 months or more (range 1.4+ to 13.0+ months) compared to 81 percent who received pem/carbo alone (range 1.4+ to 15.2+ months). In addition, findings demonstrated an improvement in PFS (HR 0.53 [95% CI, 0.31-0.91; p=0.0205]), with a median PFS of 13.0 months (95% CI, 8.3-not estimable) for patients treated with KEYTRUDA + pem/carbo compared to 8.9 months (95% CI, 4.4-10.3) with pem/carbo alone.

Immune-mediated adverse reactions occurred with pembrolizumab including pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis. Based on the severity of the adverse reaction, pembrolizumab should be withheld or discontinued and corticosteroids administered when appropriate. Pembrolizumab can also cause severe or life-threatening infusion-related reactions. Monitor patients for signs and symptoms of infusion-related reactions; for grade 3 or 4 reactions, stop infusion and permanently discontinue pembrolizumab. Based on its mechanism of action, pembrolizumab can cause fetal harm when administered to a pregnant woman. Female patients of reproductive potential should be advised of the potential hazard to a fetus.

"This approval marks an important milestone in the treatment of lung cancer. Now, pembrolizumab in combination with pemetrexed and carboplatin can be prescribed in the first-line setting for patients with metastatic nonsquamous non-small cell lung cancer, irrespective of PD-L1 expression," said Corey Langer, MD, Director of Thoracic Oncology and Professor of Medicine at the Hospital of the University of Pennsylvania, Philadelphia. "Physicians should continue to use each patient's individual characteristics – including biomarker status, histology, and other clinical factors – to determine the best treatment plan for each person."

The combination therapy indication makes pembrolizumab an option for more patients. Pembrolizumab is the only anti-PD-1 approved in the first-line setting as both monotherapy and combination therapy for appropriate patients with metastatic NSCLC. Pembrolizumab is approved as monotherapy in the first-line setting for patients with metastatic NSCLC whose tumors have high PD-L1 expression (tumor proportion score [TPS] ≥50%) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations.

Pembrolizumab as monotherapy is also indicated for the second-line or greater treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving pembrolizumab.


Wednesday, May 10, 2017

The FDA has accepted a supplemental Biologics License Application that seeks to extend the use of nivolumab to patients with mismatch repair deficient (dMMR) or microsatellite instability high (MSI-H) metastatic colorectal cancer (CRC) after prior fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. The FDA granted the application priority review, and the FDA action date is Aug. 2, 2017.

The submission was based on data from the ongoing phase II CheckMate-142 trial evaluating nivolumab in patients with dMMR or MSI-H metastatic CRC. The efficacy endpoints include investigator-assessed and blinded independent central review committee-assessed objective response rate based on the Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1, duration of response, progression-free survival, and overall survival. Data from this study were presented at the 2017 Gastrointestinal Cancers Symposium in January.

Nivolumab is a PD-1 immune checkpoint inhibitor designed to uniquely harness the body's own immune system to help restore anti-tumor immune response. By harnessing the body's own immune system to fight cancer, nivolumab has become an important treatment option across multiple cancers.


Friday, May 5, 2017

Durvalumab was granted approval by the FDA for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy, or whose disease has progressed within 12 months of receiving platinum-containing neoadjuvant or adjuvant chemotherapy.

Durvalumab is approved under the FDA's accelerated approval pathway, based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. It is also under investigation in the phase III DANUBE trial as first-line treatment in urothelial carcinoma as monotherapy and in combination with tremelimumab.

Additionally, VENTANA PD-L1 (SP263) Assay was approved by the FDA as a complementary diagnostic to provide PD-L1 status for patients with mUC who are being considered for treatment with durvalumab. The test evaluates patient PD-L1 status using both tumor and immune cell staining and scoring within the tumor microenvironment, providing clinicians with information that may guide treatment decisions. Understanding the expression of PD-L1 in tumors can help identify patients most likely to benefit from immunotherapy.

"The usual course of treatment for patients with advanced bladder cancer begins with a standard platinum-containing chemotherapy. Patients who have disease progression during or following chemotherapy are left with few other treatment options, said Nicholas J. Vogelzang, MD, FACP, FASCO, Clinical Professor at the University of Nevada School of Medicine; SWOG GU Vice Chair; US Oncology Research GU Chair; Comprehensive Cancer Centers of Nevada, said. "The approval of durvalumab to treat this population of select patients signifies hope for those who are currently suffering, or may find themselves with limited options in the future."

The recommended dose of durvalumab is 10 mg/kg body weight administered as an IV infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity.

The accelerated FDA approval of durvalumab, a human monoclonal antibody that blocks PD-L1, is based on data from Study 1108. This phase I/II trial evaluated the safety and efficacy in patients with locally advanced or metastatic urothelial carcinoma of the bladder. Patients had progressed while on or after a platinum-containing chemotherapy, including those who progressed within 12 months of receiving therapy in a neoadjuvant or adjuvant setting.

In the trial, durvalumab demonstrated rapid and durable responses, with an objective response rate (ORR) of 17.0 percent (95% confidence interval [CI]: 11.9; 23.3) in all evaluable patients, regardless of PD-L1 status, and 26.3 percent (95% CI: 17.8; 36.4) in patients with PD-L1 high-expressing tumors (as determined by the VENTANA PD-L1 (SP263) Assay).

PD-L1 high was defined as ≥25 percent of tumor cells (TC) or tumor-infiltrating immune cells (IC) expressing membrane PD-L1 if ICs involved >1 percent of the tumor area, or TC≥25 percent or IC=100 percent if ICs involved ≤1 percent of the tumor area. Additionally, approximately 14.3 percent of all evaluable patients achieved partial response and 2.7 percent achieved complete response. Of patients who had received only neoadjuvant or adjuvant therapy prior to trial entry, 24 percent (n=9) responded. Based on a secondary endpoint in this single-arm trial, median time to response was 6 weeks. Among the total 31 responding patients, 14 patients (45%) had ongoing responses of 6 months or longer and five patients (16%) had ongoing responses of 12 months or longer.

Patients should be monitored for immune-mediated adverse reactions including pneumonitis, hepatitis, colitis, endocrinopathies (including adrenal insufficiency, hypophysitis, or Type 1 diabetes mellitus), nephritis, rash, thrombocytopenic purpura, infection, infusion-related reactions, or embryo-fetal toxicity.

Serious adverse reactions occurred in 46 percent of patients. The most frequent serious adverse reactions (>2%) were acute kidney injury (4.9%), urinary tract infection (4.4%), musculoskeletal pain (4.4%), liver injury (3.3%), general physical health deterioration (3.3%), sepsis, abdominal pain, and pyrexia/tumor associated fever (2.7% each). Eight patients (4.4%) who were treated with durvalumab experienced grade 5 adverse events of cardiorespiratory arrest, general physical health deterioration, sepsis, ileus, pneumonitis, or immune-mediated hepatitis. Three additional patients were experiencing infection and disease progression at the time of death. Durvalumab was discontinued for adverse reactions in 3.3 percent of patients.

Clinical trials have demonstrated that patients with PD-L1 high-expressing tumors have a higher likelihood of response through blockade of the PD-1/PD-L1 pathway. PD-L1 expression testing may be a useful tool to help guide physicians in their treatment decisions, but it is not required for use of durvalumab.​