TON May 2016 Vol 9 No 3 - FDA News & Updates

FDA Approves First Blood Test for Colorectal Cancer Screening

On April 13, 2016, the US Food and Drug Administration (FDA) approved Epi proColon, a blood-based, in-vitro polymerase chain reaction assay, for the screening of patients with average-risk colorectal cancer (CRC) who opt against guideline-recommended colorectal cancer screening methods (eg, colonoscopies and stool-based fecal immunochemical tests), according to an announcement by Epigenomics, Inc. The test, which requires only a simple blood sample, may become an effective and convenient screening option for millions of eligible people in the United States.

“While colorectal cancer remains the second-leading cause of cancer death in the United States, 1 out of 3 eligible Americans still does not undergo colo­rectal cancer screening,” explained Thomas Taapken, PhD, Chief Executive Officer/Chief Financial Officer of Epigenomics in a press release by the company. “Given the significant benefits for patients, healthcare professionals and payors, Epi proColon could help to meet the objective of 80% screening compliance of the eligible US population as pursued by US guideline bodies such as the American Cancer Society.”

The test, which only requires a simple blood sample to be drawn as part of a routine healthcare provider visit, imparts no dietary restrictions or alterations in medication on people receiving it.

The FDA’s approval of Epi proColon was based on the safety and efficacy results of 3 major clinical trials. The first and only blood-based CRC screening test approved by the agency, Epi proColon will be commercialized in the United States under a joint commercialization agreement with Polymedco, the company’s strategic partner, and is currently marketed in Europe, China, and select other countries.

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Imbruvica Now FDA Approved for First-Line Treatment of Patients with CLL

On March 4, 2016, the FDA approved a new indication for ibrutinib (Imbruvica; Pharmacyclics) as a first-line treatment for patients with chronic lymphocytic leukemia (CLL). This approval is based on the results from RESONATE-2, a randomized, multicenter, open-label phase 3 clinical trial, which compared ibrutinib with chlor­ambucil in 269 treatment-naïve patients (aged ≥65 years) with CLL or with small lymphocytic lymphoma.

In the RESONATE-2 study, ibrutinib significantly prolonged progression-free survival (PFS), the study primary end point, and reduced the risk for disease progression or death by 84% versus chlorambucil (hazard ratio, 0.161; 95% confidence interval [CI], 0.091-0.283; P <.001). The median PFS was not reached with ibrutinib and was 18.9 months with chlorambucil (95% CI, 14.1-22.0).

The key secondary end points included overall response rate and overall survival and safety. The overall response rates were 82.45% with ibrutinib and 35.3% with chlorambucil (P <.001). Overall, 5 (3.7%) patients in the ibrutinib arm achieved a complete response compared with 2 (1.5%) patients in the chlorambucil arm.

“The progression-free survival data seen in these previously untreated CLL patients are strong and encouraging,” said Jan Burger, MD, PhD, Associate Professor, Department of Leukemia, Division of Cancer Medicine, University of Texas M.D. Anderson Cancer Center, Houston, a lead investigator of the RESONATE-2 study. “This is especially important for first-line CLL patients, when considering the safety profile. This treatment represents another option for these patients.”

Ibrutinib is a first-in-class Bruton’s tyrosine kinase inhibitor and is the first drug approved for the treatment of patients with CLL who have not received chemotherapy first. The drug was previously approved for patients with CLL who received at least 1 chemotherapy treatment. With this new approval, ibrutinib is now approved for all patients with CLL, regardless of their treatment history.

Ibrutinib was also previously approved for the treatment of high-risk patients with CLL and the 17p deletion; for the treatment of patients with mantle-cell lymphoma who have received at least 1 previous therapy; and is the first and currently only drug approved by the FDA for the treatment of patients with Waldenström’s macroglobulinemia.

The adverse reactions associated with ibrutinib in the RESONATE-2 trial were consistent with results seen in previous studies. The most common adverse reactions of all grades occurring in ≥20% of patients with CLL who received ibrutinib were diarrhea, musculoskeletal pain, cough, and rash.

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Gazyva Approved for the Treatment of Relapsed or Refractory Follicular Lymphoma

On February 26, 2016, the FDA approved a new indication for obinutuzumab (Gazyva Injection; Genentech) for use in combination with bendamustine, followed by obinutuzumab monotherapy, for the treatment of patients with follicular lymphoma whose disease relapsed after, or is refractory to, a regimen containing rituximab. Obinutuzumab was previously approved in combination with chlorambucil for patients with treatment-naïve chronic lymphocytic leukemia.

The approval was based on the phase 3 GADOLIN clinical trial. The efficacy assessment was based on 321 patients with relapsed or refractory follicular lymphoma who were randomized to obinutuzumab plus bendamustine followed by obinutuzumab alone versus bendamustine alone.

The median progression-free survival was 13.8 months in the bendamustine arm and was not yet reached in the combination arm of bendamustine plus obinutuzumab followed by obinutuzu­mab alone (hazard ratio [HR], 0.48; 95% confidence interval [CI], 0.34-0.68; log-rank test P <.001). The median duration of response was not reached with the obinutuzumab regimen compared with 11.6 months with bendamustine alone.

In addition, a post-hoc analysis and a period of 24.1 months of median observation showed that the obinutuzu­mab-based regimen reduced the risk for death by 38% compared with bendamustine alone (HR, 0.62; 95% CI, 0.39-0.98). The median overall survival has not yet been reached in either study arm.

The safety of obinutuzumab was evaluated in 392 patients in the GADOLIN study who had indolent non-Hodg­kin lymphoma, 81% of whom had follicular lymphoma. The most common grade 3 or 4 side effects associated with the obinutuzumab regimen were leukopenia (33%), infusion reactions (11%), and thrombocytopenia (10%).

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Ibrance Receives an Expanded Indication in Breast Cancer

On February 25, 2016, the FDA approved an expanded indication for the first-in-class cyclin-dependent kinase (CDK)4/CDK6 inhibitor palbociclib (Ibrance; Pfizer) for use in combination with fulvestrant in women with hormone receptor (HR)-positive, HER2-­negative advanced or metastatic breast cancer that has progressed after endocrine therapy. The drug was first approved by the FDA in February 2015 for the treatment of women with estrogen receptor–positive, HER2-negative metastatic breast cancer who had not received endocrine therapy. The expanded indication was based on the results of the PALOMA-3 clinical trial, which was stopped early after an interim analysis showed superior clinical benefit with the use of palbociclib in combination with fulvestrant versus fulvestrant plus placebo.

“There currently is no cure for metastatic breast cancer, so ongoing treatment is usually needed to control the spread of the disease,” said Marisa Weiss, MD, Founder and Chief Medical Officer of, in a press release. “That’s why the availability of a first-of-its-kind treatment option like Ibrance for women dealing with HR-positive, HER2-negative metastatic disease represents a very important advance.”

The median progression-free survival among the 521 women who received palbociclib plus fulvestrant was 9.5 months compared with 4.6 months with fulvestrant plus placebo (hazard ratio, 0.461; 95% confidence interval, 0.360-0.591; P <.001). The overall response rate was 24.6% with palbociclib compared with 10.9% in the placebo group. The duration of response was 9.3 months with the study drug compared with 7.6 months with fulvestrant plus placebo.

The most common adverse events of any grade with palbociclib versus placebo were neutropenia (83% vs 4%, respectively), leukopenia (53% vs 5%, respectively), infections (47% vs 31%, respectively), and fatigue (41% vs 29%, respectively).

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Kyprolis Receives New Indication for Relapsed or Refractory Multiple Myeloma

On January 21, 2016, the FDA approved a new indication for carfilzomib (Kyprolis; Onyx Pharmaceuticals, a subsidiary of Amgen) for injection, for use in combination with dexamethasone or with lenalidomide plus dexamethasone in the treatment of patients with relapsed or refractory multiple myeloma who have received 1 to 3 previous therapies. The FDA also approved carfilzomib as a single agent for the treatment of patients with relapsed or refractory multiple myeloma who have received at least 1 previous therapy. This current approval also converts the initial accelerated decision (in July 2012) for carfilzomib as a single agent to full FDA approval.

“Multiple myeloma remains an incurable disease, where relapse inevitably occurs and over time patients become resistant to treatments,” said Ruben Niesvizky, MD, Director of the Multiple Myeloma Center at Weill Cornell Medicine. “As a clinician, I’m pleased with the tremendous progress that we have seen in the past 12 months in multiple myeloma treatment. This FDA approval is important because it provides physicians with flexible options for Kyprolis use in helping to manage this challenging disease.”

The current approval is based on the results from the phase 3 ENDEAVOR clinical trial of 929 patients with multiple myeloma whose disease relapsed after 1 to 3 previous therapies. The study compared carfilzomib plus low-dose dexamethasone with bortezomib plus low-dose dexamethasone. The primary end point was progression-free survival (PFS). The results showed a PFS of 18.7 months in patients who received carfilzomib plus dexamethasone compared with a PFS of 9.4 months in the bortezomib plus dexamethasone arm, which is a significant 50% improvement with carfilzomib.

Last year (in July 2015), the FDA approved another expanded indication for carfilzomib for use in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who had received 1 to 3 previous therapies.

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Venclexta First BCL-2 Targeted Drug Approved for Patients with CLL plus 17p Deletion

On April 11, 2016, the FDA approved venetoclax (Venclexta; AbbVie/Genentech) for the treatment of patients with chronic lymphocytic leukemia (CLL) associated with chromosome 17p deletion (del17p) who have received ≥1 previous therapies.

Venetoclax is the first FDA-approved drug that targets the B-cell lymphoma (BCL)-2 protein. The overexpression of BCL-2 in CLL cells mediates tumor-cell survival and has been linked to resistance to chemotherapy. Venetoclax helps restore tumor-cell apoptosis by binding directly to the BCL-2 protein and triggering the activation of caspases.

Patients with the del17p lack a portion of the chromosome that helps to suppress cancer cell growth; this abnormality occurs in 10% of patients with untreated CLL and in 20% of patients with relapsed CLL. The most common adverse reactions associated with venetoclax therapy included neutropenia, diarrhea, nausea, anemia, upper respiratory tract infection, thrombocytopenia, and fatigue. Venetoclax is indicated for daily use in patients with CLL whose del17p status was confirmed by a companion diagnostic Vysis CLL FISH Probe Kit (manufactured by Abbott).

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Last modified: June 10, 2016