Boehringer Ingelheim receives FDA Priority Review for afatinib to treat EGFR mutation

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Boehringer Ingelheim 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).

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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.

http://cancerfocus.org/forum/showthread.php?t=842

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.

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(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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The EGF receptor (EGFR) tyrosine kinase inhibitors (TKIs) Iressa (gefitinib) and Tarceva (erlotinib) have been included in standard treatments for advanced NSCLC. EGFR works through two different downstream signaling pathways, which are activated by the phosphorylation of the ATP-binding domain of the receptor: the MAPK cascade, which activates different genes linked to cell proliferation and survival; and the PI3K–AKT cascade, in which phosphorylated AKT inactivates proapoptotic proteins.

TKIs inhibit the phosphorylation and tyrosine kinase activity of the intracellular domain of EGFR through competitive binding to this site, thus preventing the activation of downstream signaling.

Tarceva (erlotinib), a small molecule (MW: 394 Da), has been approved for second- or third-line advanced NSCLC treatment thanks to the results reported in the BR.21 study (1), which found that, with respect to placebo, it prolonged overall survival (OS) in heavily pretreated patients.

Iressa (gefitinib), another small molecule (MW: 446 Da) that is very similar to Tarceva in terms of mechanism of action, was found to have significant anti-tumoral activity in patients with advanced NSCLC in two Phase II studies (IDEAL-1 and -2) (2,3), but its approval as a treatment for NSCLC was obtained following the IPASS trial (4), in which Iressa was compared with carboplatin–paclitaxel chemotherapy in previously untreated stage IV patients selected on the basis of clinical and histological features, such as female gender, nonsmoker history and adenocarcinoma histology.

In this trial, Iressa proved to be more effective than chemotherapy in prolonging progression-free survival (PFS) in the intention-to-treat population. In a subgroup of patients with activating EGFR mutations (exon 19 or exon 21), a 70% response rate was achieved, and the PFS and OS were longer than that following chemotherapy. Thanks to these encouraging findings, Iressa gained approval in the treatment of patients harboring EGFR mutations, also as first-line therapy.

EGFR TKIs are usually well tolerated, the main side effects being grade 1–2 diarrhea and skin rash. Only 1–2% of patients develop the potentially life-threatening adverse event of interstitial pneumonia (5,6).

1. Shepherd FA, Rodrigues Pereira J, Ciuleanu T et al.; National Cancer Institute of Canada Clinical Trials Group. Erlotinib in previously treated non-small-cell lung cancer. N. Engl. J. Med. 353(2), 123–132(2005).

2. Fukuoka M, Yano S, Giaccone G et al. Multi-institutional randomized Phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (the IDEAL 1 trial) [corrected]. J. Clin. Oncol. 21(12), 2237–2246(2003).

3. Kris MG, Natale RB, Herbst RS et al. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA 290(16), 2149–2158(2003).

4. Mok TS, Wu YL, Thongprasert S et al. Gefitinib or carboplatin–paclitaxel in pulmonary adenocarcinoma. N. Engl. J. Med. 361(10), 947–957(2009).

5. Ando M, Okamoto I, Yamamoto N et al. Predictive factors for interstitial lung disease, antitumor response, and survival in non-small-cell lung cancer patients treated with gefitinib. J. Clin. Oncol. 24(16), 2549–2556(2006).

6. Takano T, Ohe Y, Kusumoto M et al. Risk factors for interstitial lung disease and predictive factors for tumor response in patients with advanced non-small cell lung cancer treated with gefitinib. Lung Cancer 45(1), 93–104(2004).