publication date: Oct. 6, 2017

Drugs & Targets

FDA approves sNDA for Alunbrig tablets, Takeda announces  

Takeda Pharmaceutical Co. Ltd. said FDA has approved the supplemental new drug application for Alunbrig (brigatinib) 180 mg tablets.

Alunbrig received an accelerated approval from the FDA in April 2017 for the treatment of patients with anaplastic lymphoma kinase-positive metastatic non-small cell lung cancer who have progressed on or are intolerant to crizotinib.

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 a confirmatory trial.

The recommended dosing regimen for ALUNBRIG is 90 mg orally once daily for the first seven days and if tolerated, the dose is then increased to 180 mg orally once daily.

The recommended dosing regimen was supported by the results of the pivotal phase II ALTA (ALK in Lung Cancer Trial of AP26113) trial. This two-arm, open-label, multicenter trial of 222 patients with locally advanced or metastatic ALK+ NSCLC who had progressed on crizotinib found that, of the patients who received the recommended dosing regimen (90→180 mg), 53 percent achieved a confirmed objective response as assessed by an independent review committee.

Additionally, 67 percent of patients with measurable brain metastases who received this dosing regimen achieved a confirmed intracranial OR by IRC assessment.

In ALTA, serious adverse reactions occurred in 38% of patients in the 90 mg group and 40% of patients in the 90→180 mg group. Overall, the most common serious adverse reactions were pneumonia and interstitial lung disease/pneumonitis.

Fatal adverse reactions occurred in 3.7% of patients and consisted of pneumonia (2 patients), sudden death, dyspnea, respiratory failure, pulmonary embolism, bacterial meningitis and urosepsis (1 patient each).

At the recommended dosing regimen, the most common adverse reactions (≥25%) with Alunbrig were nausea, diarrhea, fatigue, cough, and headache. The ALTA trial is ongoing and updated data will be presented at the 18th World Conference on Lung Cancer of the International Association for the Study of Lung Cancer, Oct. 15-18, in Yokohama, Japan.

Alunbrig was discovered by ARIAD Pharmaceuticals Inc., which was acquired by Takeda in February 2017.

APHINITY Study Results
Median follow-up for intent-to-treat (ITT) population 45.4 months (381 events)
Primary endpoint: invasive disease-free survival (iDFS)
HR=0.81; 95% CI 0.66-1.00, p=0.045
 Perjeta + Herceptin + chemotherapy
Placebo + Herceptin + chemotherapy
iDFS at 3 years
ITT population
171 events
210 events
HR=0.81; 95% CI 0.66-1.00, p=0.045

Node-positive subgroup


139 events
181 events
HR=0.77; 95% CI 0.62-0.96, p=0.019

Node-negative subgroup


32 events
29 events
HR=1.13; 95% CI 0.68-1.86, p=0.644
Hormone receptor-positive subgroup
100 events
119 events
HR=0.86; 95% CI 0.66-1.13, p=0.277
Hormone receptor-negative subgroup
71 events
91 events
HR=0.76; 95% CI 0.56-1.04, p=0.085
Estimate of iDFS at 4 years*
ITT population
Node-positive subgroup
Node-negative subgroup
Hormone receptor-positive subgroup
Hormone receptor-negative subgroup
Grade 3 or higher adverse event (AE)64.2%57.3%
Fatal AE0.8%0.8%
Primary cardiac event**0.7%0.3%
Difference 0.4%; 95% CI 0.0-0.8%
Most common (≥5%) severe (Grade 3 or higher) AEs
Decrease in a certain type of white blood cell
Febrile neutropenia
Fever associated with decrease in a certain type of white blood cell
Onset after chemotherapy, during targeted therapy
Neutrophil count decreased
Decrease in a certain type of white blood cell
Decrease in red blood cells or hemoglobin

* iDFS at four years was calculated based on data available at the time of primary analysis with median follow-up of 45.4 months

** Primary cardiac events included heart failure New York Heart Association (NYHA) class III or IV with left ventricular ejection fraction (LVEF) drop ≥10 points from baseline and to below 50 percent; and cardiac death


FDA grants priority review for Genentech’s Perjeta in adjuvant HER2+ early breast cancer

Genentech, a member of the Roche Group, said FDA has accepted the company’s supplemental Biologics License Application and granted Priority Review for Perjeta (pertuzumab), in combination with Herceptin (trastuzumab) and chemotherapy (the Perjeta-based regimen), for adjuvant treatment of HER2-positive early breast cancer.

FDA is expected to make a decision on approval by January 28, 2018. The sBLA is based on results of the phase III APHINITY study. A priority review designation is granted to medicines that the FDA has determined to have the potential to provide significant improvements in the treatment, prevention or diagnosis of a disease.

The sBLA seeks to convert the current accelerated approval to full approval. In the U.S., the combination of Perjeta, Herceptin and docetaxel chemotherapy is currently available under accelerated approval for neoadjuvant treatment of people with HER2-positive, locally advanced, inflammatory, or early stage breast cancer (either greater than two centimeters in diameter or node-positive) as part of a complete treatment regimen for early breast cancer.

Currently, no data have shown whether or not treatment with Perjeta prior to surgery improves survival. The safety of Perjeta in combination with doxorubicin-containing regimens has not been established. The safety of Perjeta administered for greater than six cycles for early-stage breast cancer has not been established.

Perjeta is approved for use in combination with Herceptin and docetaxel in people who have HER2-positive metastic breast cancer and who have not received anti-HER2 therapy or chemotherapy for metastatic breast cancer.

APHINITY(Adjuvant Pertuzumab and Herceptin IN Initial TherapY in Breast Cancer, NCT01358877/ BO25126/ BIG 4-11) is an international, phase III, randomized, double-blind, placebo-controlled, two-arm study evaluating the efficacy and safety of Perjeta plus Herceptin and chemotherapy compared to Herceptin and chemotherapy as adjuvant therapy in 4,805 people with operable HER2-positive EBC.

The primary efficacy endpoint of the APHINITY study is invasive disease-free survival, which in this study is defined as the time a patient lives without return of invasive breast cancer at any site or death from any cause after adjuvant treatment. Secondary endpoints include cardiac and overall safety, overall survival, disease-free survival and health-related quality of life.

The mechanisms of action of Perjeta and Herceptin are believed to complement each other, as both bind to the HER2 receptor, but to different places, the company said. Thus, the combination of Perjeta and Herceptin is thought to provide a more comprehensive, dual blockade of HER signaling pathways, thus preventing tumor cell growth and survival.

Perjeta is approved for use in combination with Herceptin and docetaxel in people who have HER2-positive metastic breast cancer and who have not received anti-HER2 therapy or chemotherapy for metastatic breast cancer.

Perjeta is approved for use prior to surgery in combination with Herceptin and docetaxel chemotherapy in people with HER2-positive, locally advanced, inflammatory, or early stage (tumor is greater than two centimeters in diameter or node-positive) breast cancer.


Mylan launches generic Gleevec tablets

Mylan N.V. announced the U.S. launch of Imatinib Mesylate Tablets, 100 mg and 400 mg, a generic version of Novartis’s Gleevec Tablets.

Mylan received final approval from FDA for its Abbreviated New Drug Application for this product, which has multiple indications, including for several blood cancers.

Imatinib Mesylate Tablets, 100 mg and 400 mg, had U.S. sales of approximately $1.7 billion for the 12 months ending July 31, 2017, according to QuintilesIMS. Mylan is one of the largest suppliers of cancer medicines by volume in the U.S., with a robust oncology portfolio of more than 40 products.

Mylan will offer a savings card for Imatinib Mesylate Tablets, which will help reduce a patient’s out-of-pocket costs.

The card provides up to $700 off the monthly out-of-pocket costs for the product and is reusable up to 12 times per calendar year. Eligible patients can participate in Mylan’s Savings Card for Imatinib Mesylate Tablets program by registering online.

Currently, Mylan has 227 ANDAs pending FDA approval, representing approximately $96.2 billion in annual brand sales, according to QuintilesIMS.

Forty-five of these pending ANDAs are potential first-to-file opportunities, representing $45.5 billion in annual brand sales, for the 12 months ending July 31, 2017, according to QuintilesIMS. Currently, one out of every 13 prescriptions filled in the U.S. – brand-name or generic – is a Mylan product.


Amgen, CytomX Therapeutics form  immuno-oncology collaboration
Amgen and CytomX Therapeutics Inc. have entered into a collaboration in immuno-oncology that will allow the companies to co-develop a CytomX Probody T-cell engaging bispecific against the epidermal growth factor receptor.

Probody T-cell engaging bispecifics are antibody constructs capable of directing cytotoxic T-cells in tumor microenvironments. In preclinical studies, CytomX’s Probody versions of EGFRxCD3 bispecific therapeutics induced tumor regressions and increased the therapeutic window for this high potential cancer target, the companies said.

Under the agreement, Amgen and CytomX will co-develop a Probody T-cell engaging bispecific against EGFRxCD3. Amgen will lead later development and commercialization with global late-stage development costs shared between the two companies.
Amgen will make an upfront payment of $40 million and purchase $20 million of CytomX common stock. CytomX will be eligible to receive up to $455 million in development, regulatory and commercial milestones for the EGFR program. Amgen will lead global commercial activities with CytomX able to opt into a profit share in the U.S. and receive tiered, double-digit royalties on net product sales outside the U.S.

Amgen will also receive exclusive worldwide rights to develop and commercialize up to three additional, undisclosed targets. Should Amgen ultimately pursue all of these targets, CytomX will be eligible to receive up to $950 million in additional upfront and milestone payments and high single-digit to mid-double digit royalty payments on any resulting products.
CytomX will receive the rights from Amgen to an undisclosed preclinical T-cell engaging bispecific program; Amgen is eligible to receive milestones and royalty payments on any resulting products from this CytomX program.  

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