– Boehringer Ingelheim obtains exclusive global rights for development and commercialization of CureVac’s investigational therapeutic cancer vaccine CV9202
– CV9202 is based on CureVac’s RNA technology (RNActive®)
– Clinical investigation of CV9202 will be initiated in at least two different lung cancer treatment settings, in combination with Boehringer Ingelheim’s afatinib, and in the chemo-radiation therapy setting
– The in-licensing of this investigational cancer compound adds an innovative new approach to Boehringer Ingelheim’s lung cancer development portfolio
INGELHEIM and TUBINGEN, Germany, and RIDGEFIELD, CT, USA I September 18, 2014 I Boehringer Ingelheim and CureVac, leader in mRNA (messenger ribonucleic acid)-based drug development, today jointly announce an exclusive global license and development collaboration. The new collaboration focuses on CureVac’s CV9202, a novel investigational therapeutic mRNA vaccine in early clinical development for the treatment of lung cancer. Boehringer Ingelheim will start clinical investigation of CV9202 in at least two different lung cancer settings, in combination with afatinib in patients with advanced or metastatic epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer (NSCLC) and in combination with chemo-radiation therapy in patients with unresectable stage III NSCLC. CureVac receives EUR 35 million (approximately $45 million). Further, CureVac can achieve milestone payments of up to EUR 430 million (approximately $556 million) and royalties on sales.
This new agreement is part of Boehringer Ingelheim’s long-term commitment to delivering tomorrow’s cancer therapies through the discovery of novel treatment options with high therapeutic value for patients. The company’s oncology portfolio includes afatinib, a once-daily kinase inhibitor that irreversibly binds and inhibits ErbB1, ErbB2 and ErbB4 receptors and is approved in a number of markets including the EU and US. In the US, afatinib is marketed as Gilotrif® for the first-line treatment of common types of EGFR-mutation positive metastatic NSCLC (Del 19 or L858R). Boehringer Ingelheim’s oncology pipeline covers a broad range of solid tumors and hematologic malignancies (blood cancer), including two investigational compounds in Phase III clinical development: nintedanib in NSCLC and colorectal cancer, and volasertib in acute myeloid leukemia. These compounds are not approved, and their safety and efficacy have not been established.
“At Boehringer Ingelheim we are proud of our commitment to help improve the treatment of cancers with a high medical need. In our collaboration with CureVac, we will investigate combining existing treatments with the approach of sustained activation of the immune system. With this we hope to be able to develop new treatments and further expand our broad pipeline in lung cancer,” said Professor Klaus Dugi, Chief Medical Officer, Boehringer Ingelheim.
CureVac’s mRNA-based technology represents a potential novel approach in cancer treatment. For the first time mRNA could be optimized to mobilize the patient’s own immune system to fight the tumor with a specific immune response elicited through the RNActive® vaccine. Cancer immunotherapy has been chosen as the “Breakthrough of the year 2013” by SCIENCE magazine. CV9202 is a combination of mRNA molecules coding for six antigens overexpressed in lung cancer, designed to induce an immune response against the tumor. CV9202 and the preceding RNActive® cancer vaccine CV9201 tested in initial clinical trials by CureVac demonstrated activity in generating immune responses against all anti-tumor antigens.
Ingmar Hoerr, co-founder and CEO of CureVac GmbH commented: “This collaboration is extremely relevant for CureVac because, as a biotech enterprise, we rely on collaboration with strong partners for the clinical development and commercialization of our compounds. Cancer immunotherapy represents one of the biggest innovations in cancer treatment of recent times and we are delighted to now be working with Boehringer Ingelheim. The out-licensing and clinical development of our promising therapeutic vaccine CV9202 represents the logical next step in developing this novel treatment for cancer patients, and the significant commitment from Boehringer Ingelheim underscores the relevance of the mRNA technology.”
About CureVac
CureVac, a clinical stage biopharmaceutical company from Tubingen, Germany, is pioneering the field of mRNA-based technology platforms for medical purposes with which mRNA is specifically optimized and formulated. Since 2000 the company develops novel mRNA-based cancer immunotherapies and prophylactic vaccines against infectious diseases – both under the brand RNActive®. CureVac has successfully established the first GMP (good manufacturing practice) facility worldwide for the manufacture of RNA and mRNA and has pioneered mRNA-based drugs in clinical studies.
The company has successfully completed Phase I/IIa clinical studies with its RNActive® cancer vaccines in prostate cancer and non-small cell lung cancer (NSCLC). Results so far have shown that mRNA-based products induced immune responses including humoral and cellular, helper (both Th1 and Th2) and effector and memory responses. CureVac is currently conducting a number of clinical trials with its RNActive® vaccines. A large randomized Phase IIb clinical trial in castrate resistant prostate cancer with CV9104 has been fully enrolled in December 2013. In the field of cancer immunotherapy CureVac is already collaborating with the Ludwig Cancer Research Institute to enable clinical testing of novel cancer immunotherapy treatment options.CureVac’s RNActive® technology is also used to develop prophylactic vaccines for infectious diseases. In March 2014, CureVac received the EUR 2 million Vaccine Prize from the European Commission for its RNActive® vaccine technology. In particular, the jury acknowledged that mRNA-based (RNActive®) vaccines represent a novel technology enabling the development of safe, efficacious and cost-effective vaccines that are protected against elevated temperature as well as inadvertent freezing. In the field of prophylactic vaccines CureVac is amongst others collaborating with Sanofi Pasteur, In-Cell-Art, DARPA and Janssen Pharmaceuticals.
For more information please visit www.curevac.com
About Boehringer Ingelheim Pharmaceuticals, Inc.
Boehringer Ingelheim Pharmaceuticals, Inc., based in Ridgefield, CT, is the largest U.S. subsidiary of Boehringer Ingelheim Corporation (Ridgefield, CT) and a member of the Boehringer Ingelheim group of companies.
The Boehringer Ingelheim group is one of the world’s 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, it operates globally with 142 affiliates and more than 47,400 employees. Since it was founded in 1885, the family-owned company has been committed to researching, developing, manufacturing and marketing novel medications of high therapeutic value for human and veterinary medicine.
Social responsibility is a central element of Boehringer Ingelheim’s culture. Involvement in social projects, caring for employees and their families, and providing equal opportunities for all employees form the foundation of the global operations. Mutual cooperation and respect, as well as environmental protection and sustainability are intrinsic factors in all of Boehringer Ingelheim’s endeavors.
For more information, please visit http://www.us.boehringer-ingelheim.com
About Boehringer Ingelheim in Oncology
Boehringer Ingelheim has a long-term commitment to deliver tomorrow’s cancer therapies by discovering and developing novel treatment options that combine ground-breaking science with the intent of high therapeutic value for patients. It runs an extensive and diverse study program involving investigators and patients from around the world. This is supported by a significant financial investment, with the aim of developing treatments, which will make a difference to the lives of patients and their families.
The current focus of research includes compounds in signal transduction inhibition, angiogenesis inhibition and cell-cycle kinase inhibition. Boehringer Ingelheim’s first oncology compound, afatinib, is approved as Gilotrif®(afatinib) tablets, and continues to be studied in other oncology settings. Two investigational compounds are in Phase III clinical development: nintedanib in NSCLC and colorectal cancer, and volasertib in acute myeloid leukemia. A growing pipeline of early-stage oncology compounds in areas such as growth/survival signaling, immunotherapy and epigenetics adds to the late stage compounds and the CV9202 RNActive® vaccine will now be investigated in combination with afatinib and chemo-radiation therapy for the treatment of patients with NSCLC.
More than 400 employees around the world (including 250 highly skilled scientists in Vienna, Austria at the Boehringer Ingelheim cancer research centre) are dedicated to the discovery and development of new cancer treatments. They work with the Research Institute of Molecular Pathology (IMP) in Austria and experts in universities, hospitals and companies around the world.
About Gilotrif® (afatinib) tablets
GILOTRIF is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test.
Limitation of Use: Safety and efficacy of GILOTRIF have not been established in patients whose tumors have other EGFR mutations.
GILOTRIF is an oral, once-daily kinase inhibitor that is designed to irreversibly bind and inhibit the following receptors: EGFR (ErbB1), HER2 (ErbB2) and ErbB4.
IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS
Diarrhea
- Diarrhea has resulted in dehydration with or without renal impairment; some of these cases were fatal. In the pivotal study, diarrhea occurred in 96% of patients treated with GILOTRIF (n=229), of which 15% was Grade 3 in severity and occurred within the first 6 weeks. Renal impairment as a consequence of diarrhea occurred in 6.1% of patients treated with GILOTRIF, out of which 3 (1.3%) were Grade 3.
- For patients who develop prolonged Grade 2 diarrhea lasting more than 48 hours or greater than or equal to Grade 3 diarrhea, withhold GILOTRIF until diarrhea resolves to Grade 1 or less, and resume GILOTRIF with appropriate dose reduction. Provide patients with an anti-diarrheal agent (e.g., loperamide) for self-administration at the onset of diarrhea and instruct patients to continue anti-diarrheal therapy until loose bowel movements cease for 12 hours.
Bullous and Exfoliative Skin Disorders
- Grade 3 cutaneous reactions characterized by bullous, blistering, and exfoliating lesions occurred in 6 (0.15%) of the 3865 patients who received GILOTRIF across clinical trials. In the pivotal study, the overall incidence of cutaneous reactions consisting of rash, erythema, and acneiform rash was 90%, and the incidence of Grade 3 cutaneous reactions was 16%. In addition, the incidence of Grade 1-3 palmar-plantar erythrodysesthesia syndrome was 7%. Discontinue GILOTRIF in patients who develop life-threatening bullous, blistering, or exfoliating lesions. For patients who develop prolonged Grade 2 cutaneous adverse reactions lasting more than 7 days, intolerable Grade 2, or Grade 3 cutaneous reactions, withhold GILOTRIF until the adverse reaction resolves to Grade 1 or less, and resume GILOTRIF with appropriate dose reduction.
Interstitial Lung Disease (ILD)
- ILD or ILD-like adverse reactions (e.g., lung infiltration, pneumonitis, acute respiratory distress syndrome, or alveolitis allergic) occurred in 1.5% of the 3865 patients who received GILOTRIF across clinical trials; of these, 0.4% were fatal. The incidence of ILD appeared to be higher in patients of Asian ethnicity (2.1%) as compared to non-Asians (1.2%). In the pivotal study, the incidence of Grade greater than or equal to 3 ILD was 1.3% and resulted in death in 1% of GILOTRIF-treated patients.
- Withhold GILOTRIF during evaluation of patients with suspected ILD, and discontinue GILOTRIF in patients with confirmed ILD.
Hepatic Toxicity
- In 3865 patients who received GILOTRIF across clinical trials, 10.1% had liver test abnormalities, of which 7 (0.18%) were fatal. In the pivotal study, liver test abnormalities of any grade occurred in 17.5% of the patients treated with GILOTRIF.
- Obtain periodic liver testing in patients during treatment with GILOTRIF. Withhold GILOTRIF in patients who develop worsening of liver function. In patients who develop severe hepatic impairment while taking GILOTRIF, treatment should be discontinued.
Keratitis
- Keratitis, characterized as acute or worsening eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain, and/or red eye occurred in 0.8% of patients treated with GILOTRIF among 3865 patients across clinical trials. Keratitis was reported in 5 (2.2%) patients in the pivotal study, with Grade 3 in 1 (0.4%). Withhold GILOTRIF during evaluation of patients with suspected keratitis, and if diagnosis of ulcerative keratitis is confirmed, treatment with GILOTRIF should be interrupted or discontinued. If keratitis is diagnosed, the benefits and risks of continuing treatment should be carefully considered. GILOTRIF should be used with caution in patients with a history of keratitis, ulcerative keratitis, or severe dry eye. Contact lens use is also a risk factor for keratitis and ulceration.
Embryofetal Toxicity
- GILOTRIF is Pregnancy Category D. Based on its mechanism of action, GILOTRIF can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
- Advise females of reproductive potential to use highly effective contraception during treatment, and for at least 2 weeks after the last dose of GILOTRIF. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking GILOTRIF.
Combination with Vinorelbine in HER2 Positive Metastatic Breast Cancer
- An early interim overall survival analysis of a randomized Phase 3 trial in HER2 positive metastatic breast cancer showed an increased mortality in patients receiving GILOTRIF in combination with vinorelbine compared to trastuzumab and vinorelbine. The combination of GILOTRIF and vinorelbine was also associated with a higher rate of adverse events (such as diarrhea, rash) and fatal events related to infections and cancer progression. GILOTRIF combined with vinorelbine should not be used in patients with HER2 positive metastatic breast cancer.
ADVERSE REACTIONS
- In GILOTRIF-treated patients (n=229) the most common adverse reactions in the pivotal study (greater than or equal to 20% all grades & vs pemetrexed/cisplatin-treated patients (n=111)) were diarrhea (96% vs 23%), rash/dermatitis acneiform (90% vs 11%), stomatitis (71% vs 15%), paronychia (58% vs 0%), dry skin (31% vs 2%), decreased appetite (29% vs 55%), pruritus (21% vs 1%).
- Serious adverse reactions were reported in 29% of patients treated with GILOTRIF. The most frequent serious adverse reactions reported in patients treated with GILOTRIF were diarrhea (6.6%); vomiting (4.8%); and dyspnea, fatigue, and hypokalemia (1.7% each). Fatal adverse reactions in GILOTRIF-treated patients included pulmonary toxicity/ILD-like adverse reactions (1.3%), sepsis (0.43%), and pneumonia (0.43%).
- More GILOTRIF-treated patients (2.2%; n=5) experienced ventricular dysfunction (defined as diastolic dysfunction, left ventricular dysfunction, or ventricular dilation; all < Grade 3) compared to chemotherapy-treated patients (0.9%; n=1).
DRUG INTERACTIONS
Effect of P-glycoprotein (P-gp) Inhibitors and Inducers
- Concomitant taking of P-gp inhibitors (including but not limited to ritonavir, cyclosporine A, ketoconazole, itraconazole, erythromycin, verapamil, quinidine, tacrolimus, nelfinavir, saquinavir, and amiodarone) with GILOTRIF can increase exposure to afatinib.
- Concomitant taking of P-gp inducers (including but not limited to rifampicin, carbamazepine, phenytoin, phenobarbital, and St. John’s wort) with GILOTRIF can decrease exposure to afatinib.
USE IN SPECIFIC POPULATIONS
Nursing Mothers
- It is not known whether afatinib is present in human milk. Because many drugs are present in human milk and because of the potential for serious adverse reactions in nursing infants from GILOTRIF, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Renal Impairment
- GILOTRIF has not been studied in patients with severely impaired renal function. Closely monitor patients with moderate (CLcr 30-59 mL/min) to severe (CLcr <30 mL/min) renal impairment and adjust GILOTRIF dose if not tolerated.
Hepatic Impairment
- GILOTRIF has not been studied in patients with severe (Child Pugh C) hepatic impairment. Closely monitor patients with severe hepatic impairment and adjust GILOTRIF dose if not tolerated.
GF PROF ISI Apr 2014
For full prescribing information, including patient information, please click here. You can also visit www.gilotrif.com or contact Boehringer Ingelheim’s Medical and Technical Information (MTI) Unit at 1-800-542-6257.
SOURCE: Boehringer Ingelheim
Post Views: 40
– Boehringer Ingelheim obtains exclusive global rights for development and commercialization of CureVac’s investigational therapeutic cancer vaccine CV9202
– CV9202 is based on CureVac’s RNA technology (RNActive®)
– Clinical investigation of CV9202 will be initiated in at least two different lung cancer treatment settings, in combination with Boehringer Ingelheim’s afatinib, and in the chemo-radiation therapy setting
– The in-licensing of this investigational cancer compound adds an innovative new approach to Boehringer Ingelheim’s lung cancer development portfolio
INGELHEIM and TUBINGEN, Germany, and RIDGEFIELD, CT, USA I September 18, 2014 I Boehringer Ingelheim and CureVac, leader in mRNA (messenger ribonucleic acid)-based drug development, today jointly announce an exclusive global license and development collaboration. The new collaboration focuses on CureVac’s CV9202, a novel investigational therapeutic mRNA vaccine in early clinical development for the treatment of lung cancer. Boehringer Ingelheim will start clinical investigation of CV9202 in at least two different lung cancer settings, in combination with afatinib in patients with advanced or metastatic epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer (NSCLC) and in combination with chemo-radiation therapy in patients with unresectable stage III NSCLC. CureVac receives EUR 35 million (approximately $45 million). Further, CureVac can achieve milestone payments of up to EUR 430 million (approximately $556 million) and royalties on sales.
This new agreement is part of Boehringer Ingelheim’s long-term commitment to delivering tomorrow’s cancer therapies through the discovery of novel treatment options with high therapeutic value for patients. The company’s oncology portfolio includes afatinib, a once-daily kinase inhibitor that irreversibly binds and inhibits ErbB1, ErbB2 and ErbB4 receptors and is approved in a number of markets including the EU and US. In the US, afatinib is marketed as Gilotrif® for the first-line treatment of common types of EGFR-mutation positive metastatic NSCLC (Del 19 or L858R). Boehringer Ingelheim’s oncology pipeline covers a broad range of solid tumors and hematologic malignancies (blood cancer), including two investigational compounds in Phase III clinical development: nintedanib in NSCLC and colorectal cancer, and volasertib in acute myeloid leukemia. These compounds are not approved, and their safety and efficacy have not been established.
“At Boehringer Ingelheim we are proud of our commitment to help improve the treatment of cancers with a high medical need. In our collaboration with CureVac, we will investigate combining existing treatments with the approach of sustained activation of the immune system. With this we hope to be able to develop new treatments and further expand our broad pipeline in lung cancer,” said Professor Klaus Dugi, Chief Medical Officer, Boehringer Ingelheim.
CureVac’s mRNA-based technology represents a potential novel approach in cancer treatment. For the first time mRNA could be optimized to mobilize the patient’s own immune system to fight the tumor with a specific immune response elicited through the RNActive® vaccine. Cancer immunotherapy has been chosen as the “Breakthrough of the year 2013” by SCIENCE magazine. CV9202 is a combination of mRNA molecules coding for six antigens overexpressed in lung cancer, designed to induce an immune response against the tumor. CV9202 and the preceding RNActive® cancer vaccine CV9201 tested in initial clinical trials by CureVac demonstrated activity in generating immune responses against all anti-tumor antigens.
Ingmar Hoerr, co-founder and CEO of CureVac GmbH commented: “This collaboration is extremely relevant for CureVac because, as a biotech enterprise, we rely on collaboration with strong partners for the clinical development and commercialization of our compounds. Cancer immunotherapy represents one of the biggest innovations in cancer treatment of recent times and we are delighted to now be working with Boehringer Ingelheim. The out-licensing and clinical development of our promising therapeutic vaccine CV9202 represents the logical next step in developing this novel treatment for cancer patients, and the significant commitment from Boehringer Ingelheim underscores the relevance of the mRNA technology.”
About CureVac
CureVac, a clinical stage biopharmaceutical company from Tubingen, Germany, is pioneering the field of mRNA-based technology platforms for medical purposes with which mRNA is specifically optimized and formulated. Since 2000 the company develops novel mRNA-based cancer immunotherapies and prophylactic vaccines against infectious diseases – both under the brand RNActive®. CureVac has successfully established the first GMP (good manufacturing practice) facility worldwide for the manufacture of RNA and mRNA and has pioneered mRNA-based drugs in clinical studies.
The company has successfully completed Phase I/IIa clinical studies with its RNActive® cancer vaccines in prostate cancer and non-small cell lung cancer (NSCLC). Results so far have shown that mRNA-based products induced immune responses including humoral and cellular, helper (both Th1 and Th2) and effector and memory responses. CureVac is currently conducting a number of clinical trials with its RNActive® vaccines. A large randomized Phase IIb clinical trial in castrate resistant prostate cancer with CV9104 has been fully enrolled in December 2013. In the field of cancer immunotherapy CureVac is already collaborating with the Ludwig Cancer Research Institute to enable clinical testing of novel cancer immunotherapy treatment options.CureVac’s RNActive® technology is also used to develop prophylactic vaccines for infectious diseases. In March 2014, CureVac received the EUR 2 million Vaccine Prize from the European Commission for its RNActive® vaccine technology. In particular, the jury acknowledged that mRNA-based (RNActive®) vaccines represent a novel technology enabling the development of safe, efficacious and cost-effective vaccines that are protected against elevated temperature as well as inadvertent freezing. In the field of prophylactic vaccines CureVac is amongst others collaborating with Sanofi Pasteur, In-Cell-Art, DARPA and Janssen Pharmaceuticals.
For more information please visit www.curevac.com
About Boehringer Ingelheim Pharmaceuticals, Inc.
Boehringer Ingelheim Pharmaceuticals, Inc., based in Ridgefield, CT, is the largest U.S. subsidiary of Boehringer Ingelheim Corporation (Ridgefield, CT) and a member of the Boehringer Ingelheim group of companies.
The Boehringer Ingelheim group is one of the world’s 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, it operates globally with 142 affiliates and more than 47,400 employees. Since it was founded in 1885, the family-owned company has been committed to researching, developing, manufacturing and marketing novel medications of high therapeutic value for human and veterinary medicine.
Social responsibility is a central element of Boehringer Ingelheim’s culture. Involvement in social projects, caring for employees and their families, and providing equal opportunities for all employees form the foundation of the global operations. Mutual cooperation and respect, as well as environmental protection and sustainability are intrinsic factors in all of Boehringer Ingelheim’s endeavors.
For more information, please visit http://www.us.boehringer-ingelheim.com
About Boehringer Ingelheim in Oncology
Boehringer Ingelheim has a long-term commitment to deliver tomorrow’s cancer therapies by discovering and developing novel treatment options that combine ground-breaking science with the intent of high therapeutic value for patients. It runs an extensive and diverse study program involving investigators and patients from around the world. This is supported by a significant financial investment, with the aim of developing treatments, which will make a difference to the lives of patients and their families.
The current focus of research includes compounds in signal transduction inhibition, angiogenesis inhibition and cell-cycle kinase inhibition. Boehringer Ingelheim’s first oncology compound, afatinib, is approved as Gilotrif®(afatinib) tablets, and continues to be studied in other oncology settings. Two investigational compounds are in Phase III clinical development: nintedanib in NSCLC and colorectal cancer, and volasertib in acute myeloid leukemia. A growing pipeline of early-stage oncology compounds in areas such as growth/survival signaling, immunotherapy and epigenetics adds to the late stage compounds and the CV9202 RNActive® vaccine will now be investigated in combination with afatinib and chemo-radiation therapy for the treatment of patients with NSCLC.
More than 400 employees around the world (including 250 highly skilled scientists in Vienna, Austria at the Boehringer Ingelheim cancer research centre) are dedicated to the discovery and development of new cancer treatments. They work with the Research Institute of Molecular Pathology (IMP) in Austria and experts in universities, hospitals and companies around the world.
About Gilotrif® (afatinib) tablets
GILOTRIF is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test.
Limitation of Use: Safety and efficacy of GILOTRIF have not been established in patients whose tumors have other EGFR mutations.
GILOTRIF is an oral, once-daily kinase inhibitor that is designed to irreversibly bind and inhibit the following receptors: EGFR (ErbB1), HER2 (ErbB2) and ErbB4.
IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS
Diarrhea
- Diarrhea has resulted in dehydration with or without renal impairment; some of these cases were fatal. In the pivotal study, diarrhea occurred in 96% of patients treated with GILOTRIF (n=229), of which 15% was Grade 3 in severity and occurred within the first 6 weeks. Renal impairment as a consequence of diarrhea occurred in 6.1% of patients treated with GILOTRIF, out of which 3 (1.3%) were Grade 3.
- For patients who develop prolonged Grade 2 diarrhea lasting more than 48 hours or greater than or equal to Grade 3 diarrhea, withhold GILOTRIF until diarrhea resolves to Grade 1 or less, and resume GILOTRIF with appropriate dose reduction. Provide patients with an anti-diarrheal agent (e.g., loperamide) for self-administration at the onset of diarrhea and instruct patients to continue anti-diarrheal therapy until loose bowel movements cease for 12 hours.
Bullous and Exfoliative Skin Disorders
- Grade 3 cutaneous reactions characterized by bullous, blistering, and exfoliating lesions occurred in 6 (0.15%) of the 3865 patients who received GILOTRIF across clinical trials. In the pivotal study, the overall incidence of cutaneous reactions consisting of rash, erythema, and acneiform rash was 90%, and the incidence of Grade 3 cutaneous reactions was 16%. In addition, the incidence of Grade 1-3 palmar-plantar erythrodysesthesia syndrome was 7%. Discontinue GILOTRIF in patients who develop life-threatening bullous, blistering, or exfoliating lesions. For patients who develop prolonged Grade 2 cutaneous adverse reactions lasting more than 7 days, intolerable Grade 2, or Grade 3 cutaneous reactions, withhold GILOTRIF until the adverse reaction resolves to Grade 1 or less, and resume GILOTRIF with appropriate dose reduction.
Interstitial Lung Disease (ILD)
- ILD or ILD-like adverse reactions (e.g., lung infiltration, pneumonitis, acute respiratory distress syndrome, or alveolitis allergic) occurred in 1.5% of the 3865 patients who received GILOTRIF across clinical trials; of these, 0.4% were fatal. The incidence of ILD appeared to be higher in patients of Asian ethnicity (2.1%) as compared to non-Asians (1.2%). In the pivotal study, the incidence of Grade greater than or equal to 3 ILD was 1.3% and resulted in death in 1% of GILOTRIF-treated patients.
- Withhold GILOTRIF during evaluation of patients with suspected ILD, and discontinue GILOTRIF in patients with confirmed ILD.
Hepatic Toxicity
- In 3865 patients who received GILOTRIF across clinical trials, 10.1% had liver test abnormalities, of which 7 (0.18%) were fatal. In the pivotal study, liver test abnormalities of any grade occurred in 17.5% of the patients treated with GILOTRIF.
- Obtain periodic liver testing in patients during treatment with GILOTRIF. Withhold GILOTRIF in patients who develop worsening of liver function. In patients who develop severe hepatic impairment while taking GILOTRIF, treatment should be discontinued.
Keratitis
- Keratitis, characterized as acute or worsening eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain, and/or red eye occurred in 0.8% of patients treated with GILOTRIF among 3865 patients across clinical trials. Keratitis was reported in 5 (2.2%) patients in the pivotal study, with Grade 3 in 1 (0.4%). Withhold GILOTRIF during evaluation of patients with suspected keratitis, and if diagnosis of ulcerative keratitis is confirmed, treatment with GILOTRIF should be interrupted or discontinued. If keratitis is diagnosed, the benefits and risks of continuing treatment should be carefully considered. GILOTRIF should be used with caution in patients with a history of keratitis, ulcerative keratitis, or severe dry eye. Contact lens use is also a risk factor for keratitis and ulceration.
Embryofetal Toxicity
- GILOTRIF is Pregnancy Category D. Based on its mechanism of action, GILOTRIF can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
- Advise females of reproductive potential to use highly effective contraception during treatment, and for at least 2 weeks after the last dose of GILOTRIF. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking GILOTRIF.
Combination with Vinorelbine in HER2 Positive Metastatic Breast Cancer
- An early interim overall survival analysis of a randomized Phase 3 trial in HER2 positive metastatic breast cancer showed an increased mortality in patients receiving GILOTRIF in combination with vinorelbine compared to trastuzumab and vinorelbine. The combination of GILOTRIF and vinorelbine was also associated with a higher rate of adverse events (such as diarrhea, rash) and fatal events related to infections and cancer progression. GILOTRIF combined with vinorelbine should not be used in patients with HER2 positive metastatic breast cancer.
ADVERSE REACTIONS
- In GILOTRIF-treated patients (n=229) the most common adverse reactions in the pivotal study (greater than or equal to 20% all grades & vs pemetrexed/cisplatin-treated patients (n=111)) were diarrhea (96% vs 23%), rash/dermatitis acneiform (90% vs 11%), stomatitis (71% vs 15%), paronychia (58% vs 0%), dry skin (31% vs 2%), decreased appetite (29% vs 55%), pruritus (21% vs 1%).
- Serious adverse reactions were reported in 29% of patients treated with GILOTRIF. The most frequent serious adverse reactions reported in patients treated with GILOTRIF were diarrhea (6.6%); vomiting (4.8%); and dyspnea, fatigue, and hypokalemia (1.7% each). Fatal adverse reactions in GILOTRIF-treated patients included pulmonary toxicity/ILD-like adverse reactions (1.3%), sepsis (0.43%), and pneumonia (0.43%).
- More GILOTRIF-treated patients (2.2%; n=5) experienced ventricular dysfunction (defined as diastolic dysfunction, left ventricular dysfunction, or ventricular dilation; all < Grade 3) compared to chemotherapy-treated patients (0.9%; n=1).
DRUG INTERACTIONS
Effect of P-glycoprotein (P-gp) Inhibitors and Inducers
- Concomitant taking of P-gp inhibitors (including but not limited to ritonavir, cyclosporine A, ketoconazole, itraconazole, erythromycin, verapamil, quinidine, tacrolimus, nelfinavir, saquinavir, and amiodarone) with GILOTRIF can increase exposure to afatinib.
- Concomitant taking of P-gp inducers (including but not limited to rifampicin, carbamazepine, phenytoin, phenobarbital, and St. John’s wort) with GILOTRIF can decrease exposure to afatinib.
USE IN SPECIFIC POPULATIONS
Nursing Mothers
- It is not known whether afatinib is present in human milk. Because many drugs are present in human milk and because of the potential for serious adverse reactions in nursing infants from GILOTRIF, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Renal Impairment
- GILOTRIF has not been studied in patients with severely impaired renal function. Closely monitor patients with moderate (CLcr 30-59 mL/min) to severe (CLcr <30 mL/min) renal impairment and adjust GILOTRIF dose if not tolerated.
Hepatic Impairment
- GILOTRIF has not been studied in patients with severe (Child Pugh C) hepatic impairment. Closely monitor patients with severe hepatic impairment and adjust GILOTRIF dose if not tolerated.
GF PROF ISI Apr 2014
For full prescribing information, including patient information, please click here. You can also visit www.gilotrif.com or contact Boehringer Ingelheim’s Medical and Technical Information (MTI) Unit at 1-800-542-6257.
SOURCE: Boehringer Ingelheim
Post Views: 40
