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The following information helps you to find FDA Alerts and Pharmacist’s Applications to Practice quickly and easily. In cooperation with the Food and Drug Administration (FDA), and as a service to our members, HOPA periodically distributes information about newly approved therapies for cancer patients from FDA’s Office of Oncology Drug Products Director, Dr. Richard Pazdur to inform oncologists and professionals in oncology-related fields in a timely manner. Links to product labels will take you to relevant clinical information on the indication, contraindications, dosing, and safety. In sending this information, HOPA does not endorse any product or therapy and does not take any position on the safety or efficacy of the product or therapy described.

Along with HOPA’s Publications Committee, members also review new drug updates and provide analysis and research on the application of these new drugs or indications. Pharmacist’s Applications to Practice, or PAP, are listed after drugs that include the additional analysis. If you are interested in helping the Publications Committee with creating a Pharmacist's Application to Practice, please contact Jeff Price at jprice@hoparx.org.

You can also find additional information on FDA Alerts and Updates by listening to FDA Drug Safety Podcasts.


April 30, 2018–Trametinib (MEKINIST®, Novartis Pharmaceuticals Corp.) and Dabrafenib (TAFINLAR®, Novartis Pharmaceuticals Corp.) in combination for the adjuvant treatment of patients with melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test, and involvement of lymph node(s), following complete resection.

June 22, 2017–Trametinib and Dabrafenib (Tafinlar® and Mekinist®, Novartis Pharmaceuticals Inc.) granted regular approvals administered in combination for patients with metastatic non-small cell lung cancer (NSCLC) with BRAF V600E mutation as detected by an FDA-approved test (with Pharmacist's Applications to Practice.).

November 20, 2015–Trametinib (Mekinist) and dabrafenib (Tafinlar) approved for use in combination for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA-approved test.


    April 30, 2018

https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204114s007lbl.pdf

On April 30, 2018, the Food and Drug Administration granted regular approval to trametinib (MEKINIST®, Novartis Pharmaceuticals Corp.) and dabrafenib (TAFINLAR®, Novartis Pharmaceuticals Corp.) in combination for the adjuvant treatment of patients with melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test, and involvement of lymph node(s), following complete resection.

Approval was based on COMBI-AD (NCT01682083), an international, multi-center, randomized, double-blind, placebo-controlled trial in 870 patients with Stage III melanoma with BRAF V600E or V600K mutations, and pathologic involvement of regional lymph node(s). Patients were randomly allocated (1:1) to receive dabrafenib 150 mg twice daily in combination with trametinib 2 mg once daily or two placebos for up to 1 year.

The major efficacy outcome was relapse-free survival (RFS). RFS was defined as the time from randomization to disease recurrence (local, regional, or distant metastasis), new primary melanoma, or death from any cause, whichever occurred first as assessed by the investigator. Patients who received the combination treatment had a statistically significant improvement in RFS compared with those receiving placebo. Patients in the combination arm experienced fewer recurrences/deaths at the time of data-cutoff: 38% (n=166), compared with 57% (n=248) in the placebo arm (hazard ratio 0.47; 95% confidence interval 0.39, 0.58; p<0.0001). The estimated median RFS was not reached for patients who received the combination therapy, compared with 16.6 months (95% CI: 12.7, 22.1) for those receiving placebo.

The most common adverse reactions in at least 20% of patients receiving the combination in the COMBI-AD trial were pyrexia, fatigue, nausea, headache, rash, chills, diarrhea, vomiting, arthralgia, and myalgia. Adverse reactions resulting in discontinuation, dose reduction, or dose interruption of dabrafenib occurred in 25%, 35%, and 66% of patients, respectively; the most common for each were pyrexia and chills. Adverse reactions resulting in discontinuation and dose interruption of trametinib occurred in 24% and 54% of patients respectively; the most common for each were pyrexia and chills. Adverse reactions leading to dose reduction of trametinib occurred in 23% of patients; the most common were pyrexia and decreased ejection fraction.

The recommended doses for the adjuvant treatment of melanoma are 150 mg of dabrafenib orally twice daily and 2 mg of trametinib orally once daily until disease recurrence or unacceptable toxicity, for up to one year.

Full prescribing information is available at:
Trametinib PI: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204114s007lbl.pdf
Dabrafenib PI: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/202806s008lbl.pdf

FDA granted this application priority review. Dabrafenib in combination with trametinib was granted breakthrough therapy designation and orphan drug designation for this indication. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).


June 22, 2017 with PAP

https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/204114s005lbl.pdf

On June 22, 2017, the U.S. Food and Drug Administration granted regular approvals to trametinib and  dabrafenib (TAFINLAR® and MEKINIST®, Novartis Pharmaceuticals Inc.) administered in combination for patients with metastatic non-small cell lung cancer (NSCLC) with BRAF V600E mutation as detected by an FDA-approved test.

These are the first FDA approvals specifically for treatment of patients with BRAF V600E mutation-positive metastatic NSCLC..

The FDA today also approved the Oncomine™ Dx Target Test (Thermo Fisher Scientific), a next generation sequencing (NGS) test to detect multiple gene mutations for lung cancer in a single test from a single tissue specimen. This test detects the presence of BRAF, ROS1, and EGFR gene mutations or alterations in tumor tissue of patients with NSCLC. This test can be used to select patients with NSCLC with the BRAF V600E mutation for treatment with the combination of dabrafenib and trametinib. This is the first NGS oncology panel test approved by the FDA for multiple companion diagnostic indications.

The approvals are based on Study BRF113928 (NCT01336634), an international, multicenter, three-cohort, non-randomized, non-comparative, open-label, trial in patients with locally confirmed BRAF V600E mutation-positive metastatic NSCLC. Ninety-three patients were treated with the combination of dabrafenib (150 mg orally twice daily) and trametinib (2 mg orally once daily). Of these 93 patients, 36 had received no prior systemic therapy for metastatic NSCLC and 57 received at least one platinum-based chemotherapy regimen with demonstrated disease progression. Seventy-eight patients with previously treated BRAF V600E mutation-positive NSCLC received single-agent dabrafenib.

In the previously treated group, the overall response rate (ORR) for the combination based on independent radiology review committee assessment per RECIST 1.1 was 63% (95% CI: 49%, 76%) with a median duration of response (DoR) of 12.6 months (95% CI: 5.8, not estimable [NE]). In the treatment-naive group, the ORR for the combination was 61% (95% CI: 44%, 77%) and median DoR was not estimable (95% CI: 6.9, NE); however, 59% of responders had response durations greater than six months. The ORR for patients who received single-agent dabrafenib was 27% (95% CI: 18%, 38%) and the median DoR was 9.9 months.

The incidence and severity of adverse reactions occurring in patients with NSCLC were generally similar to those reported in prior approvals for patients with melanoma. The most common adverse reactions (≥20%) were pyrexia, fatigue, nausea, vomiting, diarrhea, dry skin, decreased appetite, edema, rash, chills, hemorrhage, cough, and dyspnea. The most common Grade 3-4 adverse reactions were pyrexia, fatigue, dyspnea, vomiting, rash, hemorrhage, and diarrhea. The majority of laboratory abnormalities were Grade 1-2. The most common (≥5%) Grade 3-4 laboratory abnormalities were hyponatremia, lymphopenia, anemia, hyperglycemia, neutropenia, leukopenia, hypophosphatemia, and increased alanine aminotransferase. Dabrafenib and trametinib were discontinued for adverse reactions in 18% and 19% of patients, respectively.

The recommended doses are dabrafenib 150 mg orally twice daily, approximately 12 hours apart, with trametinib 2 mg orally once daily. The presence of BRAF V600E mutation in tumor specimen should be confirmed by an FDA-approved test prior to initiation of therapy.

Full prescribing information trametinib is available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/204114s005lbl.pdf.

Full prescribing information dabrafenib is available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/202806s006lbl.pdf.

FDA granted Breakthrough Therapy Designation in 2015 for the combination of dabrafenib and trametinib for the treatment of patients with advanced and metastatic BRAF V600E mutation-positive NSCLC who received at least one prior line of platinum-containing therapy. Orphan Drug Designation was granted in 2014 to dabrafenib as a single agent for the treatment of patients with BRAF mutation positive NSLC and in 2015 combination with trametinib. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at:http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).


Pharmacist’s Applications to Practice

Dabrafenib and Trametinib in Combination for Patients with Metastatic Non-Small Cell Lung Cancer with BRAF V600E Mutation as Detected by an FDA-Approved Test

Author: Sasha Haarberg, PharmD
PGY-2 Oncology Resident
University of Colorado Skaggs School of Pharmacy and University of Colorado Cancer Center
Aurora, CO

What is the potential role for dabrafenib and trametinib in combination in the treatment of metastatic non-small cell lung cancer (NSCLC) with BRAF V600E mutation?

  • On June 22, 2017, the U.S. Food and Drug Administration (FDA) approved the first therapy for treatment of patients with BRAF V600E mutation-positive metastatic NSCLC who have received at least one prior line of platinum-containing therapy.
  • The approvals are based on Study BRF113928 (NCT01336634), an international, multicenter, three-cohort, open-label trial in patients with confirmed BRAF V600E mutation-positive metastatic NSCLC.
    • Of the 93 patients treated with combination of dabrafenib (150 mg orally twice daily) and trametinib (2 mg orally once daily), 36 had received no prior systemic therapy; 57 had received at least one platinum-based chemotherapy regimen followed by disease progression.
    • In the previously treated group, the overall response rate (ORR) for the combination was 63%, with a median duration of response (DoR) of 12.6 months in patients who had not received prior systemic therapy.
    • Sixty-one percent of the group who had previously received chemotherapy responded to treatment. Median DoR has not yet been reached; however, 59% of responders had response durations greater than 6 months.
  • Per National Comprehensive Cancer Network (NCCN) guidelines, the combination of dabrafenib and trametinib is the first-line (category 2a) recommendation for patients with BRAF V600E mutation-positive metastatic NSCLC.1
  • The combination of a BRAF and MEK inhibitor may suppress MAPK (mitogen-activated protein kinase)-driven acquired downstream resistance mechanisms.

What role can the pharmacist play in the management of patients on dabrafenib and trametinib in combination?

  • The drugs should be administered at least 1 hour before or 2 hours after a meal. The once-daily trametinib dose should be taken at the same time each day with either the morning or evening dose of dabrafenib.2,3
  • Dabrafenib and trametinib have no renal or hepatic dose reductions but may require dose reduction for toxicity. If a patient is not able to tolerate dabrafenib 50 mg twice daily or trametinib 1 mg once daily, then the medications should be permanently discontinued.2,3
  • Co-administration of dabrafenib with other substrates of CYP3A4 and CYP2C9, including dexamethasone or hormonal contraceptives, can result in decreased concentrations and loss of efficacy for the CYP3A4/CYP2C9 substrates.3
  • Both dabrafenib and trametinib carry a low to minimal emetic risk.2,3

 

Clinical Pearls

  • The FDA-approved companion diagnostic, Oncomine Dx Target Test, uses next-generation sequencing to detect multiple gene mutations (e.g., BRAF, EGFR, and ROS1) in lung cancer from a single tissue specimen. The test can be used to select NSCLC patients with the BRAF V600E mutation for treatment with the combination of dabrafenib and trametinib.4
  • Trametinib is supplied as .5-mg or 2-mg tablets.2
  • Dabrafenib is supplied as 50-mg or 75-mg capsules.3
  • Novartis Universal Co-Pay Assistance Program is available for commercially insured patients. Patients pay $20 for a 30-day supply of both Tafinlar (dabrafenib) and Mekinist (trametinib); some limitations apply. More information is available at www.copay.novartisoncology.com.5

References

  1. Non-Small Cell Lung Cancer. Version 8.2017. National Comprehensive Cancer Network. Available at: https://www.nccn.org/professionals/physician_gls/pdf/nscl_blocks.pdf. Accessed August 4, 2017.
  2. Mekinist (trametinib) [package insert]. Novartis Pharmaceuticals Corporation, East Hanover, New Jersey; June 2017.
  3. Tafinlar (dabrafenib) [package insert]. Novartis Pharmaceuticals Corporation, East Hanover, New Jersey; June 2017.
  4. Products and Medical Procedures. U.S. Food and Drug Administration. Available at: https://www.fda.gov/medicaldevices/productsandmedicalprocedures/invitrodiagnostics/ucm301431.htm. Accessed August 4, 2017
  5. Novartis Oncology Copay Assistance. Available at: www.copay.novartisoncology.com. Accessed August 4, 2017.

November 20, 2015

Trametinib: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/204114s004lbl.pdf

Dabrafenib: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/202806s004lbl.pdf

On November 20, 2015, the U. S. Food and Drug Administration (FDA) approved trametinib (Mekinist, Novartis Pharmaceuticals Corp.) and dabrafenib (Tafinlar, Novartis Pharmaceuticals Corp.) for use in combination for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA-approved test.

Trametinib and dabrafenib for use in combination received accelerated approval in 2014, based on an improvement in durable objective response rates compared to dabrafenib or trametinib as single agents. Two new clinical trials described below verify the clinical benefit of the combination.

The first trial enrolled 423 patients who were randomized (1:1) to dabrafenib plus trametinib (n=211) or dabrafenib plus placebo (n=212). All patients had tumor containing BRAF V600E or V600K mutations as determined by centralized testing, 85% with BRAF V600E mutations and 15% with BRAF V600K mutations. The trial met its primary endpoint, demonstrating a significant improvement in investigator-assessed PFS [HR 0.75 (95% CI: 0.57, 0.99); p=0.035] with median PFS of 9.3 and 8.8 months in the dabrafenib/trametinib and dabrafenib/placebo arms, respectively. In addition, there was a significant improvement in OS [HR=0.71 (95% CI: 0.55, 0.92); p=0.01] with a median OS of 25.1 and 18.7 months in the dabrafenib/trametinib and dabrafenib/placebo arms, respectively. The overall response rates were 66% and 51% with median response durations of 9.2 and 10.2 months.

The second trial enrolled 704 patients who were randomized (1:1) to trametinib and dabrafenib (n=352) or to vemurafenib as a single agent (n=352).   The trial met its primary endpoint, demonstrating a significant improvement in OS [HR 0.69 (95% CI: 0.53, 0.89); p=0.005]; the median OS had not been reached in combination arm and was 17.2 months in the vemurafenib arm. In addition, there was a significant improvement in PFS [HR 0.56 (95% CI: 0.46, 0.69); p <0.001]with a median OS of 11.4 and 7.3 months in the combination and vemurafenib arms, respectively. The overall response rates were 64% and 51%with median response durations of 13.8 and 7.5 months in the combination and vemurafenib arms, respectively.

Safety was evaluated in the 559 patients who received dabrafenib with trametinib. The most common adverse reactions (greater than or equal to 20%) were pyrexia, nausea, rash, chills, diarrhea, headache, vomiting, hypertension, arthralgia, peripheral edema, and cough. Clinically significant serious adverse drug reactions were serious febrile reactions, cardiomyopathy, interstitial lung disease, new primary cutaneous and non-cutaneous malignancies, hemorrhage, venous thromboembolism, hyperglycemia, serious skin toxicity, uveitis, retinal pigment epithelial detachment, and retinal vein occlusion.

The recommended trametinib dose is 2 mg orally once daily until disease progression or unacceptable toxicity occurs. The recommended dabrafenib dose is 150 mg orally twice daily until disease progression or unacceptable toxicity occurs.

Full prescribing information is available at:

Trametinib: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/204114s004lbl.pdf

Dabrafenib: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/202806s004lbl.pdf

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

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