FDA Approves New Indication for Gilotrif (afatinib) in EGFR Mutation-Positive NSCLC

In continuation of my update on afatinib...

Boehringer Ingelheim  announced that the U.S. Food and Drug Administration (FDA) has approved a supplemental New Drug Application (sNDA) for Gilotrif (afatinib) for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have non-resistant epidermal growth factor receptor (EGFR) mutations as detected by an FDA-approved test. The new label includes data on three additional EGFR mutations: L861Q, G719X and S768I. The FDA granted Priority Review status to Gilotrif in evaluating this application.

Gilotrif, an oral, once-daily tablet, was previously approved in the U.S. for the first-line treatment of patients with NSCLC whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations. In addition, Gilotrif is approved in the U.S. for patients with squamous cell carcinoma of the lung whose disease has progressed after treatment with platinum-based chemotherapy.

“With this expanded indication for Gilotrif, NSCLC patients whose tumors have certain EGFR mutations now have an approved therapy that specifically targets these mutations,” said Sabine Luik, M.D., senior vice president of Medicine & Regulatory Affairs, Boehringer Ingelheim Pharmaceuticals, Inc. “This approval is a result of our company’s commitment to delivering meaningful treatment advances in areas with high unmet medical need and reflects the tireless efforts of physicians, researchers and patients who participated in our studies.”

The sNDA approval is based on a pooled analysis of three studies from the LUX-Lung clinical trial program (Phase II LUX-Lung 2 study and Phase III studies LUX-Lung 3 and LUX-Lung 6) that examined Gilotrif in NSCLC patients whose tumors have EGFR mutations, including L861Q, G719X or S768I. This analysis showed that Gilotrif was active in these EGFR mutations based on objective response rate, duration of response, disease control, progression-free survival and overall survival.

“Compared with other EGFR mutations, L861Q, G719X or S768I substitution mutations are associated with a poorer prognosis and limited treatment options,” said Edward Kim, M.D., Levine Cancer Institute, Carolinas HealthCare System. “The approval of Gilotrif as a targeted therapy for these additional non-resistant EGFR mutations significantly alters the treatment strategy for this population.”

To determine if a patient is eligible for Gilotrif, physicians must conduct a test for genetic mutations – also known as biomarker testing – to determine the type of EGFR mutation present.

“This approval is more welcome news for our lung cancer community,” said Laurie Fenton Ambrose, president and CEO of Lung Cancer Alliance. “These types of advances are helping expand access to treatment options for patients who might benefit from targeted therapies to fight their specific type of lung cancer.”

Ref : https://www.drugs.com/mtm/afatinib.html

FDA Approves New Indication for Gilotrif (afatinib) in EGFR Mutation-Positive NSCLC

Novel combination therapy shows strong response in phase 1 trial

In continuation of my update on Sorafenib, Premetrexed,  Vandetanib
"Though phase 1 studies are designed to evaluate the safety of a new therapy, we had strong preclinical evidence suggesting this novel drug combination could work against a variety of cancers, so we hoped that we would see a response in our patients in this early phase trial," said Andrew Poklepovic, M.D., lead investigator on the study. "With this trial, we established a safe dosing schedule, and we will now be testing the efficacy of the therapy in the phase 2 study."

The results of the clinical trial were recently published online by the journal Oncotarget (PMID: 27213589). The study enrolled 37 patients between October 2011 and December 2014. Of those patients, 36 received treatment and 33 were evaluated for response. One patient had a complete response, meaning all detectable traces of the tumor disappeared, while four patients had a partial response, which means that the tumor volume shrank by at least 30 percent. The therapy stabilized disease progression in an additional 15 patients, with some of these patients responding for up to a year. The therapy was found to be particularly active in breast cancer patients.

"Some dose-limiting toxicities associated with pemetrexed were observed in one cohort of patients, but those who were eligible were switched to the dosing schedule of the second cohort, which was found to safe and tolerable," says Poklepovic, medical oncologist and member of the Developmental Therapeutics research program at Massey as well as assistant professor in the Division of Hematology, Oncology and Palliative Care at the VCU School of Medicine.

The trial is based on pre-clinical research conducted by a team of Massey scientists led by Paul Dent, Ph.D., who is the Universal Corporation Chair in Cancer Cell Signaling and a member of the Cancer Cell Signaling research program at Massey, and Richard Moran, Ph.D., who recently retired after 22 years at Massey and more than four decades in the field. Pemetrexed was co-developed by Moran, and is now a first-line therapy for non-small cell lung cancer (NSCLC) and mesothelioma. Sorafenib is used to treat liver, kidney and thyroid cancer. In 2011, a research team led by Dent and including Moran discovered that the two drugs synergize to induce profound killing of cancer cells through a toxic form of autophagy, a process that normally re-cycles components of cells to provide energy for maintaining cell growth and survival. The drug combination hyper-activated the autophagy process within cancer cells, causing them to literally eat themselves to death (PMID: 21622715).

 Sorafenib  Pemetrexed

  Vandetanib    Lapatinib

The phase 2 study is not the only continuation of the research. Because the initial results of the phase 1 study were so promising, Dent started a new project to discover the best "third drug" that could act to further enhance the anti-cancer properties of the pemetrexed and sorafenib combination. This work has also recently been published in Oncotarget, and it showed that the combination therapy could be enhanced by a class of drugs known as ERBB1/2/4 inhibitors (PMID: 27015562).

"We discovered in mouse models of breast cancer that the drugs lapatinib and vandetanib significantly enhanced the anti-tumor effect of the pemetrexed and sorafenib therapy without any apparent toxicity to normal tissue. We made a nearly identical observation when adding the drug afatinib in experiments involving non-small cell lung cancer," says Dent. "Based on this data, we will be submitting a grant application to the National Cancer Institute for funding that will hopefully provide data that could allow us to open a future phase 1 trial testing the addition of an ERBB1/2/4 inhibitor to pemetrexed and sorafenib in patients with advanced solid tumors."

Dent was able to determine that ERBB1/2/4 inhibitors could increase the effectiveness of the combination therapy by using a novel technology called a multiplex assay. The multiplex assay is a broad, unbiased screening approach that allows researchers to simultaneously examine the levels of multiple hormones in the blood and determine the activities of enzymes in cancer cells. Using this technology, the researchers discovered that the enzyme ERBB1 was activated in response to the pemetrexed and sorafenib therapy.

"Unlike alternative methods where a certain degree of guesswork is required, the multiplex assay allowed us to observe exactly how the cancer cells responded to therapy," says Dent. "We were surprised to see that the enzyme ERBB1 was activated because it is ordinarily thought to protect cancer cells from chemotherapy. We went on to successfully use ERBB1/2/4 inhibitors as our third drug because of this unexpected data."

The multiplex assay provided Dent's team with such invaluable additional information about how the sorafenib and pemetrexed combination worked in the mouse models that they will now be using the assay in several of their clinical trials moving forward, including the new phase 2 trial of pemetrexed and sorafenib.

"The multiplex assay will allow us to track specific levels of hormones in the blood as patients undergo treatment, which could potentially give us a molecular 'fingerprint' of the point at which tumors develop resistance to the therapy," says Dent. "Ongoing preclinical experiments show that it could be possible to pinpoint exactly how the cancer cells are developing resistance to therapies, which might eventually allow oncologists to develop in real time a personalized therapy designed to overcome drug resistance in an individual patient's tumor."

Ref : http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5b%5d=9434

FDA Approves Gilotrif (afatinib) for Patients with Squamous Cell Carcinoma of the Lung

I continuation of my update on Afitinib

Boehringer Ingelheim  announced that the U.S. Food and Drug Administration (FDA) has approved a supplemental New Drug Application (sNDA) for Gilotrif® (afatinib) tablets for the treatment of patients with advanced squamous cell carcinoma of the lung whose disease has progressed after treatment with platinum-based chemotherapy. The U.S. approval follows the recent marketing authorization of Gilotrif in this patient population by the European Commission. Gilotrif, an oral, once-daily EGFR-directed therapy, is currently approved in the U.S. for the first-line treatment of specific types of EGFR mutation-positive NSCLC.

 afatinib

“We are pleased to bring a proven therapy to patients suffering from advanced squamous cell carcinoma of the lung who have progressed despite chemotherapy,” said Sabine Luik, MD, senior vice president, Medicine & Regulatory Affairs, Boehringer Ingelheim Pharmaceuticals, Inc. “This approval is further evidence of Boehringer Ingelheim’s strong commitment to bringing new treatment options to the lung cancer community.”

Squamous cell carcinoma (SqCC) of the lung is associated with a poor prognosis, limited survival and symptoms like cough and dyspnea. The median overall survival (OS) after diagnosis of advanced SqCC is around one year.

LUX-Lung 8 clinical trial investigator Shirish Gadgeel, MD, leader of the Thoracic Oncology Multidisciplinary Team at the Karmanos Cancer Center, Detroit, commented: “The overall survival data and significant delay in lung cancer progression seen in the global head-to-head Phase III trial demonstrated that Gilotrif is an effective new treatment option in this patient population.”

The sNDA was based on results of the head-to-head LUX-Lung 8 trial in patients with SqCC of the lung whose tumors progressed after first-line chemotherapy. Gilotrif, compared to erlotinib, demonstrated:

• Significant delay in progression of lung cancer (PFS, progression-free survival, primary endpoint), reducing the risk of cancer progression by 18%
• Significant improvement in overall survival (OS, key secondary endpoint), reducing the risk of death by 19%
• Significantly improved disease control rate (51% vs 40%; P=0.002)

The most common adverse reactions observed with Gilotrif (reported in at least 20% of study patients) were diarrhea (75%), rash or acne (70%), stomatitis (mouth sores) (30%), decreased appetite (25%), and nausea (21%).

LUX-Lung 8 (NCT01523587) is part of the Gilotrif LUX-Lung program – the largest collection of clinical trials of any EGFR tyrosine kinase inhibitor (TKI), with over 3,760 patients across eight studies conducted around the world. The comprehensive LUX-Lung program includes two pivotal studies in the first-line setting for EGFR mutation-positive patients, LUX-Lung 3 and LUX-Lung 6, which compared Gilotrif to chemotherapy regimens. In addition, the program included two head-to-head studies (LUX-Lung 7 and LUX-Lung 8) of Gilotrif versus first-generation EGFR TKIs gefitinib and erlotinib, respectively. The LUX-Lung program has involved over 680 sites in 40 countries, reflecting the strong partnership between Boehringer Ingelheim and the lung cancer specialist community.

Afatinib a better choice for EGFR-mutated lung cancer in first-line treatment

In continuation of my update on Afatinib

Patients with EGFR-activating mutations in advanced lung cancer seem to benefit more from afatinib than gefitinib as first-line treatment, researchers report at the first ESMO Asia 2015 Congress in Singapore.

In the global, randomised, open-label Phase IIb LUX-Lung 7 (LL7) trial1, the irreversible ErbB family blocker afatinib significantly improved efficacy versus gefitinib across a range of clinically relevant endpoints, such as progression-free survival, time-to-treatment failure and objective response rate. "Based on these results I would consider afatinib as the EGFR tyrosine kinase inhibitor (TKI) of choice for the first-line treatment for patients with EGFR mutation-positive non-small-cell lung cancer (NSCLC)," lead author, Professor Keunchil Park, head of the Division of Hematology/Oncology at Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea, said.

NSCLC is the most common type of lung cancer: activating epidermal growth factor receptor (EGFR) gene mutations are more frequently observed in non-smokers and women, and occur in 50% of Asians and only 10% of non-Asians. The targeted agents afatinib and gefitinib block key pathways involved in tumour growth and spread. They have both been approved for the treatment of naive patients, based on the results of Phase III trials, confirming their superiority compared to chemotherapy. Unlike the first-generation EGFR inhibitor gefitinib, the irreversible ErbB family blocker afatinib is suggested to be active in prolonging tumour response and delaying disease progression.

Afatinib a better choice for EGFR-mutated lung cancer in first-line treatment - Medical News Today

Afatinib active against NSCLC nervous system metastases

Incontinuation of my update on Afatinib

Afatinib active against NSCLC nervous system metastases

Oral afatinib significantly improves progression-free survival in patients with head and neck cancer

The tyrosine kinase inhibitor afatinib significantly improved progression-free survival compared to methotrexate in patients with recurrent or metastatic squamous cell carcinoma of the head and neck after failure of platinum-based chemotherapy, the results of a phase III trial show.

Presented at the ESMO 2014 Congress in Madrid, the Lux-Head & Neck 1 trial showed that patients who received treatment with 40 mg/day oral afatinib had a 20% reduction in risk of progression or death compared to patients who received methotrexate, with a median progression-free survival of 2.6 months.

"The improvement in progression-free survival was associated with a significant delayed worsening of symptoms (such as pain, swallowing and global health status) versus chemotherapy. Patients treated with afatinib had less pain over time than patients treated with methotrexate. "These are important outcomes for patients with these conditions," notes study author Dr Jean-Pascal Machiels, a medical oncologist at Institut Roi Albert II, Cliniques Universitaires St. Luc, in Brussels, Belgium.

Recurrent or metastatic squamous cell carcinoma of the head and neck often has a poor outcome, Machiels explains. "This is a poor prognosis population and a disease that does not get enough attention from the scientific community, because this group of patients often has severe co-morbidities and social problems such as alcoholism and tobacco use."

"Frequently these patients have a relapse in the head and neck area. This location is responsible of many symptoms that are difficult to palliate: pain, breath disorder and swallowing difficulties."

Afatinib is a compound that irreversibly blocks the ErbB family of cell surface receptors, which includes epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), HER3 and HER4. Around 90% of squamous cell carcinomas of the head and neck overexpress EGFR.

Oral afatinib significantly improves progression-free survival in patients with head and neck cancer

Phase III trial shows afatinib offers clinical benefit to patients with EGFR mutation positive NSCLC

We know that, Afatinib (INN; trade name Gilotrif, previously Tomtovok and Tovok) is an approved drug against non-small cell lung carcinoma (NSCLC), developed by Boehringer Ingelheim As of July 2012, it is undergoing Phase III clinical trials for this indication and breast cancer, as well asPhase II trials for prostate and head and neck cancer, and a Phase I glioma trial. Afatinib is a first-line treatment

.

In October 2010 a Phase III trial in NSCLC patients called Lux-Lung 5 began with this drug. Fall 2010 interim results suggested the drug extendedprogression-free survival threefold compared to placebo, but did not extend overall survival. In May 2012, the Phase IIb/III trial Lux-Lung 1 came to the same conclusion.

Phase II results for breast cancer that over-expresses the protein human epidermal growth factor receptor 2 (Her2-positive breast cancer) were described as promising by the authors, with 19 of 41 patients achieving benefit from afatinib. Double-blind Phase III trials are under way to confirm or refute this finding. Her2-negative breast cancers showed limited or no response to the drug.

Mechanism of action :: Like lapatinib and neratinib, afatinib is a next generation tyrosine kinase inhibitor (TKI) that irreversibly inhibits human epidermal growth factor receptor 2 (Her2) and epidermal growth factor receptor (EGFR) kinases. Afatinib is not only active against EGFR mutations targeted by first generation TKIs like erlotinib or gefitinib, but also against those not sensitive to these standard therapies. Because of its additional activity against Her2, it is investigated for breast cancer as well as other EGFR and Her2 driven cancers.

Phase III trial shows afatinib offers clinical benefit to patients with EGFR mutation positive NSCLC

FDA Approves Gilotrif for Late Stage Non-Small Cell Lung Cancer

We know that, Afatinib, trade name Gilotrif, previously Tomtovok and Tovok is an approved drug against non-small cell lung carcinoma (NSCLC), developed by Boehringer Ingelheim. As of  2012, it is undergoing Phase III clinical trials for this indication and breast cancer, as well as Phase II trials for prostate and head and neck cancer, and a Phase I glioma trial. Afatinib is a first-line treatment.

Now FDA has approved...

“Today’s approvals further illustrate how a greater understanding of the underlying molecular pathways of a disease can lead to the development of targeted treatments,” said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Gilotrif is the second drug approved this year for patients with untreated metastatic NSCLC whose tumors have the EGFR exon 19 deletions or exon 21 L858R substitution mutations.”

In May, the FDA approved Tarceva (erlotinib) for first-line treatment of patients with NSCLC. Tarceva’s new indication was approved concurrently with the cobas EGFR Mutation Test, a companion diagnostic to identify patients with tumors having the EGFR gene mutations.

“The approval of companion diagnostic tests and drugs are important developments in oncology, as they help us bring safe and effective treatments to patients who need them,” said Alberto Gutierrez, Ph.D., director of the Office of In Vitro Diagnostics and Radiological Health in the FDA’s Center for Devices and Radiological Health...

More ....

Read more at http://www.drugs.com/newdrugs/fda-approves-gilotrif-late-stage-non-small-cell-lung-cancer-3851.html#y7iJKwGPFiGsiEPL.99 

FDA Approves Gilotrif for Late Stage Non-Small Cell Lung Cancer