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Breakthrough Therapy Granted to Combo Therapy for Endometrial Carcinoma

The FDA recently granted Breakthrough Therapy designation for lenvatinib, an orally available kinase inhibitor, in combination with the anti-PD-1 therapy pembrolizumab for the treatment of patients with advanced and/or metastatic non-microsatellite instability high (MSI-H)/proficient mismatch repair endometrial carcinoma who have progressed following at least one prior systemic therapy. This is the third Breakthrough Therapy designation for lenvatinib and the second for lenvatinib in combination with pembrolizumab, following the Breakthrough Therapy designation for the combination for advanced and/or metastatic renal cell carcinoma announced in January 2018.

  
FDA. FDA... - Click to enlarge in new windowFDA. FDA

The Breakthrough Therapy designation is an FDA program intended to expedite development and review of medicines for serious or life-threatening conditions. To qualify for this designation, preliminary clinical evidence must demonstrate that the drug may provide substantial improvement over currently available therapy on at least one clinically significant endpoint. The benefits of this designation include more intensive guidance on an efficient clinical development program, access to senior FDA managers and experienced FDA staff to help accelerate review time, as well as eligibility for rolling review and potentially priority review.

 

This designation was based on interim results of the endometrial carcinoma cohort in Study 111/KEYNOTE-146, which were presented in June 2018 at the ASCO Annual Meeting.

 

This trial is a multicenter, open-label, single-arm phase Ib/II basket trial evaluating the combination of lenvatinib (20 mg/day) with pembrolizumab (200 mg IV every 3 weeks) in patients with selected solid tumors (renal cell carcinoma, endometrial carcinoma, non-small cell lung cancer, urothelial cancer, squamous cell head and neck cancer, and melanoma). Patients were not preselected based on MSI or PD-L1 tumor biomarker status.

 

The primary endpoint of the phase Ib study was to determine the maximum tolerated dose of lenvatinib and pembrolizumab in combination. The primary endpoint of the phase II portion is investigator-assessed objective response rate (ORR) at week 24 based on immune-related RECIST. The secondary efficacy endpoints included ORR, progression-free survival, and duration of response for patients with complete or partial responses.

 

Fifty-three patients with previously treated, metastatic disease were evaluated in the endometrial carcinoma cohort. Currently, the phase II part is ongoing, as an endometrial carcinoma cohort expansion. A randomized, international, two-arm phase III study in recurrent endometrial carcinoma is underway (Study 309/KEYNOTE-775; NCT03517449).

 

LOXO-292 for Treatment of Lung & Thyroid Cancers

The FDA has granted Breakthrough Therapy designation to LOXO-292, a selective RET inhibitor, for:

 

* the treatment of patients with metastatic RET fusion-positive non-small cell lung cancer who require systemic therapy and have progressed following platinum-based chemotherapy and an anti-PD-1 or anti-PD-L1 therapy; and for

 

* the treatment of patients with RET-mutant medullary thyroid cancer who require systemic therapy, have progressed following prior treatment, and have no acceptable alternative treatment options.

 

 

LOXO-292 is an oral and selective investigational new drug in clinical development for the treatment of patients with cancers that harbor abnormalities in the rearranged during transfection (RET) kinase. RET fusions and mutations occur across multiple tumor types with varying frequency. LOXO-292 was designed to inhibit native RET signaling as well as anticipated acquired resistance mechanisms that could otherwise limit the activity of this therapeutic approach. The LOXO-292 Breakthrough Therapy designation was based on data from the ongoing global phase I/II LIBRETTO-001 clinical trial.

 

Pembrolizumab Monotherapy Receives Priority Review for NSCLC

The FDA has accepted and granted Priority Review to a new supplemental Biologics License Application seeking approval for pembrolizumab as monotherapy for first-line treatment of locally advanced or metastatic nonsquamous or squamous non-small cell lung cancer (NSCLC) in patients whose tumors express PD-L1 (tumor proportion score [TPS] >=1%) without EGFR or ALK genomic tumor aberrations.

 

The application is based on data from the pivotal phase III KEYNOTE-042 trial, one of five phase III clinical trials with pembrolizumab in NSCLC to demonstrate a significant improvement in overall survival. Data from the trial were presented earlier this year at the 2018 ASCO Annual Meeting. The FDA has set a Prescription Drug User Fee Act, or target action, date of Jan. 11, 2019.

 

Pembrolizumab is an anti-PD-1 therapy that works by increasing the ability of the body's immune system to help detect and fight tumor cells. It is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes that may affect both tumor cells and healthy cells.

 

In addition to KEYNOTE-042, a number of phase III studies are in development for pembrolizumab in combination with other treatments and as monotherapy across histologies and lines of treatment in both advanced and earlier stages of disease.

 

There are currently more than 800 trials studying pembrolizumab across a wide variety of cancers and treatment settings. The pembrolizumab clinical program seeks to understand the role of pembrolizumab across cancers and the factors that may predict a patient's likelihood of benefitting from treatment with pembrolizumab, including exploring several different biomarkers.

 

Encorafenib in Combination With Binimetinib & Cetuximab for Colorectal Cancer

The FDA has granted Breakthrough Therapy designation for encorafenib, in combination with binimetinib and cetuximab for the treatment of patients with BRAFV600E-mutant metastatic colorectal cancer (mCRC) as detected by an FDA-approved test, after failure of one to two prior lines of therapy for metastatic disease.

 

BRAFV600E-mutant mCRC patients have a mortality risk more than double that of mCRC patients without the mutation, and currently there are no therapies specifically approved for this high unmet need population.

 

Encorafenib is an oral small molecule BRAF kinase inhibitor and binimetinib is an oral small molecule MEK inhibitor that target key enzymes in the MAPK signaling pathway (RAS-RAF-MEK-ERK). Inappropriate activation of proteins in this pathway has been shown to occur in many cancers, including melanoma, colorectal cancer, non-small cell lung cancer, thyroid, and others. In the U.S., encorafenib plus binimetinib are approved for the treatment of unresectable or metastatic melanoma with a BRAFV600E or BRAFV600Kmutation, as detected by an FDA-approved test. Encorafenib is not indicated for treatment of patients with wild-type BRAF melanoma.

 

As presented at the ESMO World Congress on Gastrointestinal Cancer in June 2018, the results from the safety lead-in of the ongoing randomized phase III BEACON CRC trial showed that, at the time of analysis, the overall survival (OS) data were fully mature through 12.6 months and that the median OS had not yet been reached.

 

Thirty patients were treated in the safety lead-in and received the triplet combination (encorafenib 300 mg daily, binimetinib 45 mg twice daily, and cetuximab per label). Of the 30 patients, 29 had a BRAFV600E mutation. MSI-H, resulting from defective DNA mismatch repair, was detected in only one patient.

 

One-year OS rate for this cohort was 62 percent. Median progression-free survival for patients treated with the triplet was 8 months [95% CI 5.6-9.3] and is similar between patients receiving one prior line of therapy and patients receiving two prior lines of therapy. Confirmed overall response rate (ORR) was 48 percent and among the 17 patients who received only one prior line of therapy the ORR was 62 percent.

 

The triplet combination was generally well-tolerated with no unexpected toxicities. The most common grade 3 or 4 adverse events seen in at least 10 percent of patients were fatigue (13%), anemia (10%), increased blood creatine kinase (10%), and increased aspartate aminotransferase (10%).

 

The triplet combination of encorafenib, binimetinib, and cetuximab for the treatment of patients with BRAFV600E-mutant metastatic colorectal cancer is investigational and not approved by the FDA.

 

The randomized portion of the BEACON CRC trial is designed to assess the efficacy of encorafenib in combination with cetuximab with or without binimetinib compared to cetuximab and irinotecan-based therapy. Approximately 615 patients are expected to be randomized 1:1:1 to receive triplet combination, doublet combination (encorafenib and cetuximab), or the control arm (irinotecan-based therapy and cetuximab).

 

The primary endpoint of the trial is overall survival of the triplet combination compared to the control arm. Secondary endpoints address efficacy of the doublet combination compared to the control arm, and the triplet combination compared to the doublet therapy. Other secondary endpoints include PFS, ORR, duration of response, safety, and tolerability. Health-related quality-of-life data will also be assessed.

 

The trial is being conducted at over 200 investigational sites in North America, South America, Europe, and the Asia Pacific region. Patient enrollment is expected to be completed around the end of 2018.

 

Prescribing Information Updated for Urothelial Carcinoma Therapies

The FDA has updated the prescribing information for pembrolizumab and atezolizumab to require the use of an FDA-approved companion diagnostic test to determine PD-L1 levels in tumor tissue from patients with locally advanced or metastatic urothelial cancer who are cisplatin-ineligible. Two different companion diagnostic tests were approved, one for use with pembrolizumab and one for use with atezolizumab.

 

The Dako PD-L1 IHC 22C3 PharmDx Assay was approved as a companion diagnostic to select patients with locally advanced or metastatic urothelial carcinoma who are cisplatin-ineligible for treatment with pembrolizumab. The 22C3 assay determines PD-L1 expression by using a combined positive score (CPS) assessing PD-L1 staining in tumor and immune cells.

 

The updated indication for pembrolizumab includes the following: pembrolizumab is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 [CPS >=10] as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status.

 

The FDA approved the Ventana PD-L1 (SP142) Assay as a companion diagnostic test to select patients with locally advanced or metastatic urothelial carcinoma who are cisplatin-ineligible for treatment with atezolizumab. The SP142 assay determines PD L1 expression in immune cells.

 

The updated indication for atezolizumab includes the following: atezolizumab is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 (PD-L1 stained tumor-infiltrating immune cells covering >=5% of the tumor area), as determined by an FDA-approved test; or are not eligible for any platinum-containing therapy regardless of level of tumor PD-L1 expression.

 

The FDA updated the Prescribing Information for both drugs to require use of an FDA-approved test for selection of patients being treated in the first-line setting who are cisplatin-ineligible. The second-line indications in urothelial carcinoma for both drugs remain unchanged. The tests used in the trials to determine PD-L1 expression are listed in Section 14 of each drug label.

 

sBLA Accepted for Dasatinib in Pediatric Patients With Ph+ ALL

The FDA has accepted its supplemental Biologics License Application (sBLA) for dasatinib in combination with chemotherapy for the treatment of pediatric patients with newly diagnosed Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). The FDA action date is Dec. 29, 2018.

 

The application is based on data from CA180-372 (NCT01460160), an ongoing phase II trial evaluating the addition of dasatinib to a chemotherapy regimen modeled on a Berlin-Frankfurt-Munster high-risk backbone in pediatric patients with newly diagnosed Ph+ ALL.

 

Dasatinib first received FDA approval in 2006 for the treatment of adults with Ph+ chronic myeloid leukemia (CML) in chronic phase (CP) who are resistant or intolerant to prior therapy including imatinib. At that time, dasatinib also received FDA approval for adults with Ph+ ALL who are resistant or intolerant to prior therapy. Dasatinib is approved and marketed for these indications in more than 60 countries. Dasatinib is also an FDA-approved treatment for adults with newly diagnosed Ph+ CML-CP and is approved for this indication in more than 50 countries.

 

Both the FDA and the European Commission approved the expansion of dasatinib's indication to include pediatric patients with Ph+ CML-CP in November 2017 and July 2018.