publication date: Jan. 25, 2019

Drugs & Targets

European Commission authorizes Rubraca tablets in ovarian cancer

The European Commission approved the use of Rubraca (rucaparib) for a second indication, as monotherapy for the maintenance treatment of adults with platinum-sensitive relapsed high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete or partial) to platinum-based chemotherapy.

The drug is sponsored by Clovis Oncology Inc.

This expands Rubraca’s indication beyond its initial marketing authorization in Europe granted in May 2018 and with this label expansion, rucaparib is now available to patients regardless of their BRCA mutation status.

Rucaparib was the first PARP inhibitor licensed for an ovarian cancer treatment indication in the EU and is now the first to be available for both treatment and maintenance treatment among eligible patients.

The EC authorization is based on data from the phase III ARIEL3 clinical trial, which found that rucaparib significantly improved progression-free survival in all ovarian cancer patient populations studied.

The ARIEL3 trial was a double-blind, placebo-controlled clinical trial of rucaparib that enrolled 564 women with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer in complete or partial response to platinum-based chemotherapy. Patients were randomized (2:1) to receive rucaparib tablets 600mg twice daily (n=375) or placebo (n=189).

ARIEL3 successfully achieved its primary endpoint, of extending investigator-assessed progression-free survival versus placebo in all patients treated (intention-to-treat), population, regardless of BRCA status; the key secondary endpoint of extending PFS as assessed by independent radiological review was also achieved.

An exploratory analysis of patients in the ITT population with measurable disease at baseline showed a tumor response was reported in 18% (95% CI 12%–26%) of patients (n=26) on rucaparib compared to 8% (95% CI 3% – 17%) of patients (n=5) on placebo (p value = 0.0069), including 10 patients (7%) in the rucaparib group who achieved a complete remission.


Bristol-Myers Squibb withdraws U.S. application for Opdivo + Yervoy in first-line lung cancer

Following recent discussions with FDA, Bristol-Myers Squibb announced the voluntary withdrawal of the sBLA for the Opdivo and low-dose Yervoy (ipilimumab) combination for treatment of first-line advanced non-small cell lung cancer in patients with tumor mutational burden ≥10 mutations/megabase.

In October 2018, the company announced the submission of an exploratory overall survival analysis for the TMB <10 mut/Mb subgroup to the FDA. The FDA determined at that time, that the submission of this new information constituted a major amendment to the sBLA and extended the review period by three months, moving the Prescription Drug User Fee Act date to May 20, 2019.

After recent discussions with the FDA, the company believes further evidence on the relationship between TMB and PD-L1 is required to fully evaluate the impact of Opdivo plus Yervoy on OS in first-line NSCLC patients.

This analysis will require availability of the final data from Checkmate -227, Part 1a (Opdivo plus low-dose Yervoy or Opdivo monotherapy versus chemotherapy in patients whose tumors express PD-L1), which the company anticipates will be available in the first-half of 2019. Since these data from Checkmate -227, Part 1a, will not be available within the review cycle of the current application the company decided to withdraw.

In January, the company announced the European Commission approved the combination of Opdivo plus Yervoy for the first-line treatment of patients with intermediate- and poor-risk advanced renal cell carcinoma.


FDA finalizes policy on labeling for accelerated approval drugs

FDA issued the final guidance, Labeling for Human Prescription Drug and Biological Products Approved Under the Accelerated Approval Pathway, that aims to assist sponsors of drug and biological products in developing the Indications and Usage section of product labeling for products approved under the accelerated approval pathway.

The accelerated approval pathway is one of several approaches used by the FDA to expedite the development of drugs for serious or life-threatening diseases and conditions.

The FDA may grant accelerated approval to a product for a serious or life-threatening disease or condition upon a determination that the product has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality, that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity or prevalence of the condition and the availability or lack of alternative treatments.

This guidance focuses on how accelerated approval is represented in the Indications and Usage section of product labeling and offers recommendations to sponsors on language that best conveys different circumstances specific to accelerated approval.

During this period without a FY19 appropriation for the FDA, the agency has been focused on making sure it continues critical aspects of its work, to the extent permitted by law.

At this time, for products covered by a user fee program, our review of existing medical product applications and associated policy development regarding FDA review is funded by limited carryover user fee balances. The FDA will continue to update the public on how it’s approaching the work.


FDA grants Illumina’s TruSight Assay Breakthrough Device designation

FDA has granted Breakthrough Device Designation for Illumina’s its pan-cancer assay.

Currently in development, with plans to be marketed as TruSight Oncology Comprehensive, the assay is based on the content of Illumina’s TruSight Oncology 500, designed to detect known and emerging solid tumor biomarkers. Illumina is seeking FDA approval of the assay as a companion diagnostic.

The assay utilizes both DNA and RNA from tumor samples to identify key somatic variants underlying tumor progression. These variants include small DNA variants, fusions, and splice variants, as well as immunotherapy-associated biomarkers such as tumor mutational burden and microsatellite instability, features that are potentially key biomarkers for immunotherapies.

The Breakthrough Device Program, which supersedes the FDA’s Expedited Access Pathway, is designed for certain medical devices and device-led combination products that provide for more effective treatment in diagnosing life-threatening or irreversibly debilitating diseases or conditions.

The Breakthrough Devices Program contains features of the EAP, as well as the Innovation Pathway, both of which were intended to facilitate the development and expedite the review of breakthrough technologies.

With Breakthrough Device Designation, Illumina’s assay will receive priority review, meaning that the review of the submission is prioritized in the queue and will receive additional review resources, as needed.


Amgen’s Blincyto approved in Europe for leukemia

Amgen said the European Commission has approved an expanded indication for Blincyto (blinatumomab) monotherapy to include adult patients with Philadelphia chromosome negative CD19 positive B-cell precursor acute lymphoblastic leukemia in first or second complete remission with minimal residual disease greater than or equal to 0.1 percent.

The approval was based on data from the phase II BLAST study in frontline and relapsed/refractory ALL, the largest prospective trial for MRD-positive ALL ever conducted. Blincyto, a bispecific CD19-directed CD3 T cell engager, is the first BiTE immunotherapy to receive regulatory approval globally.

In that study, Blincyto induced a complete MRD response, or no detectable MRD, in 78 percent of patients within one treatment cycle. Safety results among MRD-positive patients were consistent with the known safety profile of Blincyto in relapsed or refractory B-cell precursor ALL.

Approval via the centralized procedure allows for obtaining a marketing authorization from the EC, which is valid in all EU and European Economic Area-European Free Trade Association states, including Norway, Iceland and Liechtenstein.

In March 2018, FDA approved Blincyto for the treatment of adults and children with B-cell precursor ALL in first or second complete remission with MRD greater than or equal to 0.1 percent.

Blincyto is the first immunotherapy from Amgen’s BiTE platform. BiTE antibody construct technology, pioneered by Amgen, is an innovative treatment approach that helps the body’s immune system attack cancer cells without the removal of immune cells from the patient. Amgen is studying a number of “off-the-shelf” investigational BiTE immunotherapies, with distinct targets, across a range of hematologic and solid tumors.

The BLAST study is the largest ever prospective trial in patients with MRD-positive ALL. It is an open-label, multicenter, single-arm, phase II study evaluating the efficacy, safety and tolerability of Blincyto in adult patients with MRD-positive B-cell precursor ALL in complete hematologic remission after three or more cycles of intensive chemotherapy.

Patients received continuous IV infusion of Blincyto 15 µg/m2/d for four weeks, followed by two weeks off. Patients received up to four cycles of treatment and could undergo hematopoietic stem cell transplantation at any time after the first cycle, if eligible.

Efficacy was based on achievement of undetectable MRD within one cycle of Blincyto treatment and hematological relapse-free survival. Additional secondary endpoints included incidence and severity of adverse events, overall survival, time to hematological remission and duration of complete MRD response.

Blincyto is a bispecific CD19-directed CD3 T cell engager immunotherapy that binds to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of effector T cells. Blincyto was granted breakthrough therapy and priority review designations by the FDA in 2014, and carries full approval in the U.S. for the treatment of relapsed or refractory B-cell precursor ALL in adults and children.

In the U.S., Blincyto is also approved for the treatment of adults and children with B-cell precursor ALL in first or second complete remission with MRD greater than or equal to 0.1 percent. This indication is approved under accelerated approval based on MRD response rate and hematological relapse-free survival.

Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. In the EU, Blincyto is indicated for the treatment of adults with Ph- relapsed or refractory B-precursor ALL and for the treatment of Ph- CD19 positive B-cell precursor ALL in first or second complete remission with MRD greater than or equal to 0.1 percent.


Genmab initiates of FDA submission for expansion of daratumumab in multiple myeloma

Genmab said its licensing partner, Janssen Biotech, Inc. has submitted the first part of a regulatory submission to FDA for a label expansion to include the use of daratumumab in combination with lenalidomide and dexamethasone for the treatment of patients with newly diagnosed multiple myeloma who are not candidates for high dose chemotherapy and autologous stem cell transplant.

FDA plans to review this application under their Real-Time Oncology Review pilot program. Inclusion in the RTOR pilot program does not guarantee or increase the probability of approval of this supplemental Biologics License Application. In August 2012, Genmab granted Janssen an exclusive worldwide license to develop, manufacture and commercialize daratumumab.

The submission package is based on data from the phase III MAIA (MMY3008) study of daratumumab in combination with lenalidomide and dexamethasone as treatment for patients with newly diagnosed multiple myeloma, who are not candidates for high dose chemotherapy and ASCT.

The phase III study (NCT02252172) is a randomized, open-label, multicenter study that includes 737 newly diagnosed patients with multiple myeloma who are not candidates for high dose chemotherapy and ASCT.

Patients were randomized to receive either daratumumab in combination with lenalidomide and dexamethasone or lenalidomide and dexamethasone alone. In the daratumumab treatment arm, patients received 16 milligrams per kilogram (mg/kg) weekly for first 8 weeks (Cycles 1 and 2), every other week for 16 weeks (Cycles 3 to 6) and then every 4 weeks (Cycle 7 and beyond) until progression of disease or unacceptable toxicity. Lenalidomide was administered at 25 mg orally on days 1 through 21 of each 28-day cycle, and dexamethasone was administered at 40 mg once a week for both treatment arms.

Participants in both treatment arms will continue treatment with lenalidomide and dexamethasone until disease progression or unacceptable toxicity. The primary endpoint of the study is progression free survival.

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