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U.S. FDA Grants Priority Review to Boehringer Ingelheim's Afatinib NDA for EGFR Mutation-Positive Advanced NSCLC
By Dross at 2013-01-15 23:30
U.S. FDA Grants Priority Review to Boehringer Ingelheim's Afatinib NDA for EGFR Mutation-Positive Advanced NSCLC

Boehringer Ingelheim Pharmaceuticals Inc. (BIPI) today announced that the New Drug Application (NDA) for its investigational oncology compound afatinib has been accepted for filing and granted Priority Review by the U.S. Food and Drug Administration (FDA). The application for afatinib is currently under review for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with an epidermal growth factor receptor (EGFR) mutation as detected by an FDA-approved test. Under the Prescription Drug User Fee Act (PDUFA), the FDA goal for reviewing a drug with Priority Review status is six months from the NDA filing acceptance date.1 The FDA target action date for afatinib will be in the third quarter of 2013.

Recently, afatinib was also granted orphan drug designation – a status given to a product intended for the treatment of a rare disease or condition.2 In the United States, orphan drug status provides for seven years of market exclusivity for the orphan drug indication following FDA approval.2 Currently there are no therapies specifically approved by the FDA for patients with locally advanced or metastatic NSCLC with an EGFR mutation.

"The NDA filing of afatinib represents Boehringer Ingelheim's commitment to addressing the significant need that exists for patients with EGFR mutation-positive advanced non-small cell lung cancer," said Sabine Luik, M.D., senior vice president, Medicine & Regulatory Affairs, U.S. Regional Medical Director, Boehringer Ingelheim Pharmaceuticals, Inc. "We are pleased that the FDA has accepted the afatinib application under Priority Review and look forward to working with the agency in the coming months."

The NDA submission for afatinib is supported by Boehringer Ingelheim's comprehensive LUX-Lung clinical trial program, including LUX-Lung 3, the largest Phase III trial conducted to date in first-line EGFR mutation-positive, locally advanced or metastatic NSCLC patients.

"This is an exciting milestone for Boehringer Ingelheim, as this marks our first oncology compound to be submitted for FDA review in the United States," said Kevin Lokay, vice president and business unit head, Oncology, Boehringer Ingelheim Pharmaceuticals, Inc. "Based on the acceptance of the afatinib application, along with our developing oncology pipeline, we are moving forward with our plans to establish a world-class oncology commercial organization."

To facilitate the rapid identification of EGFR mutations, Boehringer Ingelheim is partnering with QIAGEN – a leading global provider of sample and assay technologies – to develop a companion diagnostic for afatinib.

About Afatinib
Afatinib is an investigational, oral, once-daily irreversible ErbB Family Blocker that specifically inhibits epidermal growth factor receptor (EGFR or ErbB1), human epidermal receptor 2 (HER2 or ErbB2) and ErbB4.3 It is currently in Phase III clinical development in advanced NSCLC, head and neck and breast cancer. Afatinib is not approved by the FDA; its safety and efficacy have not been established.

In Europe, Boehringer Ingelheim announced submission of a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) seeking approval of afatinib as a treatment for patients with EGFR (ErbB1) mutation-positive NSCLC in September 2012.

6 comments | 2034 reads

by gdpawel on Wed, 2013-01-16 03:04
Investigators are reporting improved progression-free survival (PFS) after treatment with the investigational agent dacomitinib compared with erlotinib in patients with non–small cell lung cancer (NSCLC) experiencing progression during chemotherapy.

Erlotinib, which targets a single member of the HER family, inhibits signaling through competitive, reversible binding at the EGFR tyrosine kinase domain. The pan-HER inhibitor dacomitinib binds irreversibly to the adenosine triphosphate domain of all three kinase-active members of the HER family: EGFR, HER2, and HER4.

Suresh S. Ramalingam, MD, chief of the Thoracic Oncology Division at Emory University in Atlanta, Georgia, and coworkers randomized 188 patients to receive either 45 mg of oral dacomitinib or 150 mg of oral erlotinib once daily. In addition to having had no prior HER-directed therapy, patients enrolled in the phase II study had an ECOG performance status of 0 to 2 and had received one or two prior chemotherapy regimens. The primary endpoint of the study was PFS.

The study found that the median PFS w as 2.86 months in the dacomitinib arm versus 1.91 months in the erlotinib group (hazard ratio [HR] = 0.66; 95% CI, 0.47- 0.91; two-sided P = .012).

An improvement in PFS was noted in most clinical and molecular subgroups (Table). In patients with KRAS wild-type tumors, the median PFS was 3.71 months and 1.91 months for the dacomitinib and erlotinib treatment arms, respectively (HR = 0.55; 95% CI, 0.35-0.85; two-sided P = .006). Patients with KRAS wild-type/EGFR wild-type tumors receiving dacomitinib had a median PFS of 2.21 months compared with 1.84 months for patients treated with erlotinib (HR = 0.61; 95% CI, 0.37-0.99; two-sided P = .043).

Median overall survival was similar in the dacomitinib and erlotinib groups: 9.53 months in patients treated with dacomitinib and 7.44 months in patients who received erlotinib (HR = 0.80; 95% CI, 0.56-1.13; two-sided P = .205).

Treatment-related adverse events were more common with dacomitinib, primarily grade 1 and 2, and frequently involved skin and gastrointestinal events.

“The results documented here for dacomitinib suggest that irreversible pan-HER inhibition may offer a new treatment option for patients with advanced NSCLC, potentially representing an effective alternative to reversible inhibition of EGFR,” Ramalingam et al wrote.

The researchers suggested that the superior outcomes with dacomitinib might be due to its mechanism of action, “which potentially includes more complete inhibition of HER signaling by receptor homoand heterodimerization through targeting of all three kinase-active HER receptors and permanent blockade of signaling by covalent receptor modification.”

Ramalingam SS, Blackhall F, Krzakowski M, et al. Randomized phase II study of dacomitinib (PF-00299804), an irreversible pan-human epidermal growth factor receptor inhibitor, versus erlotinib in patients with advanced non-small-cell lung cancer. J Clin Oncol. 2012;30(27):3337-3344.


While Tarceva "reversibly" binds to EGFR (Her1), Afatinib "irreversibly" binds to EGFR (Her1) and EGFR type 2 (Her2), preventing their activation and hopefully inhibiting the unwanted signaling pathways. While Dacomitinib binds irreversibly to the domains of all three kinase-active members of EGFR (Her1), EGFR type 2 (Her2) and EGFR type 4 (Her4).

However, the AngioRx Assay for anti-angiogenic agents has assessed previously unanticipated direct and potentiating anti-angiogenic effects of targeted therapy drugs such as Tarceva (and Iressa) at the tyrosine kinase level.

by gdpawel on Fri, 2013-01-18 21:25
(PM Live) - The US FDA has fast-tracked two personalised non-small cell lung cancer (NSCLC) drugs from Boehringer Ingelheim and Roche/Astellas, putting the products on track for approval in the third quarter of this year.

Boehringer was granted priority review for its epidermal growth factor receptor (EGFR) inhibitor afatinib in NSCLC patients with locally advanced or metastatic disease who test positive for the EGFR mutation.

Between 10 and 25 per cent of Caucasian NSCLC patients are EGFR-positive, with the proportion rising to 30-40 per cent in some Asian populations.

The marketing application is based on the results of the phase III LUX-Lung 3 trial, which found that afatinib was able to increase progression-free survival by 11.1 months, significantly better than the 6.9-month increase achieved with Lilly's Alimta (pemetrexed) and cisplatin, which is currently considered the best-in-class therapy.

Boehringer filed for approval of afatinib for the NSCLC indication in Europe last August, and is also carrying out phase III trials of the drug in breast cancer and head and neck cancer.

Meanwhile, Roche and Astellas have been given a fast-track review for their EGFR inhibitor Tarceva (erlotinib) in first-line NSCLC, an indication for which it was approved in Europe in 2011. Once again approval is being sought to use the drug in patents with locally advanced or metastatic NSCLC who are EGFR-positive.

Tarceva's application comes on the back of the EURTAC trial, which found that Tarceva achieved a median PFS of 10.4 months while patients treated with two-drug combinations based on platinum drugs (cisplatin plus docetaxel, cisplatin plus gemcitabine, docetaxel plus carboplatin or gemcitabine plus carboplatin) achieved a PFS of 5.1 months.

The drug, which has been approved for second-line use in NSCLC for some time, has also been shown to be effective as a first-line therapy in the OPTIMAL study, which focused on Asian NSCLC patients.

The EGFR inhibitors as a class are credited with transforming the treatment of NSCLC, but do have a problem with side effects, particularly rash, and the development of resistance.

Afatinib is a slightly different member of the class in that its actions on EGFR are irreversible, which hypothetically means that it could be less prone to activity loss over time.

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