Tag: Lung Cancer: Non-Small Cell

Approximately 10% to 15% of Caucasian patients and 35-50% of Asian patients with Adenocarcinomas, harbor activating EGFR (Epidermal Growth Factor Receptor) mutations and 90% of these mutations are either Exon 19 deletions or L858R point mutations in Exon 21. EGFR-Tyrosine Kinase Inhibitors (TKIs) such as TARCEVA® (Erlotinib), IRESSA® (Gefitinib) and GILOTRIF® (Afatinib), have demonstrated a 60% to 70% response rate as monotherapy when administered as first line treatment, in patients with metastatic NSCLC, who harbor the sensitizing EGFR mutations. However, majority of these patients experience disease progression within 9 to 14 months. This resistance to frontline EGFR TKI therapy has been attributed to acquired T790M “gatekeeper” point mutation in EGFR, identified in 50% – 60% of patients.
TAGRISSO® (Osimertinib), is a third-generation Epidermal Growth Factor Receptor (EGFR) TKI and in a randomized, double blind, phase III clinical trial, demonstrated superior efficacy and tolerability compared to the Standard of Care, as first-line therapy in patients with advanced EGFR mutation positive NSCLC. This benefit was seen even in those with CNS metastases at study entry. These new finding are very likely to change the treatment paradigm for NSCLC patients whose tumors harbor EGFR mutations.

 

SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 27% of all cancer deaths. The American Cancer Society estimates that for 2017 about 222,500 new cases of lung cancer will be diagnosed and over 155,000 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of Non Small Cell Lung Cancer (NSCLC), 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large cell carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer. Approximately 10% to 15% of Caucasian patients and 35-50% of Asian patients with Adenocarcinomas, harbor activating EGFR (Epidermal Growth Factor Receptor) mutations and 90% of these mutations are either Exon 19 deletions or L858R point mutations in Exon 21. EGFR-Tyrosine Kinase Inhibitors (TKIs) such as TARCEVA® (Erlotinib), IRESSA® (Gefitinib) and GILOTRIF® (Afatinib), have demonstrated a 60% to 70% response rate as monotherapy when administered as first line treatment, in patients with metastatic NSCLC, who harbor the sensitizing EGFR mutations. However, majority of these patients experience disease progression within 9 to 14 months. This resistance to frontline EGFR TKI therapy has been attributed to acquired T790M “gatekeeper” point mutation in EGFR, identified in 50% – 60% of patients.

TAGRISSO® (Osimertinib), is a third-generation Epidermal Growth Factor Receptor (EGFR) TKI presently approved by the FDA, for the treatment of patients with metastatic EGFR T790M mutation-positive NSCLC, who had progressed on prior systemic therapy, including an EGFR-TKI. Previously published studies suggested that TAGRISSO® may also be effective as initial therapy for EGFR mutation-positive advanced NSCLC.

FLAURA is a randomized, double blind, phase III clinical trial, conducted to compare the efficacy and safety of first line TAGRISSO® to TARCEVA® or IRESSA® (which are considered Standard of Care as first line therapy), in NSCLC patients with activating mutations EGFR Exon 19 deletions or L858R substitution mutation on Exon 21. This study randomized 556 advanced NSCLC treatment naïve patients, with EGFR Exon 19 or 21 mutations in a 1:1 ratio, to TAGRISSO® 80 mg orally once daily (N=279) or Standard of Care EGFR-TKI, IRESSA® 250 mg or TARCEVA® 150 mg, orally once daily (N=277). Patients were stratified by mutation status (Exon 19 vs 21 mutations) and race (Asian vs non-Asian). Patients with CNS metastases who were neurologically stable, were allowed in this study. The Primary endpoint was Progression Free Survival (PFS).

The median PFS was 18.9 months with TAGRISSO® compared to 10.2 months for the standard therapy (HR=0.46; P<0.0001), suggesting a 54% reduction in the risk of disease progression, compared with Standard of Care. TAGRISSO® extended the median Time To Progression by about 9 months. This PFS benefit was consistent across all subgroups of patients, including those with and without CNS metastases at study entry. The Objective Response Rate (ORR) with TAGRISSO® was 80% compared with 76% for TARCEVA® and IRESSA®. The median Duration of Response with TAGRISSO® was 17.2 versus 8.5 months in the comparator arm. The median Overall Survival was not reached. Grade 3 and 4 toxicities were lower for TAGRISSO® (34%) compared with 45% for TARCEVA® and IRESSA®. Toxicities led to treatment discontinuation for 13% and 18% of patients in the TAGRISSO® and comparator groups, respectively.

It was concluded that TAGRISSO® demonstrated superior efficacy and tolerability compared to the Standard of Care, as first-line therapy in patients with advanced EGFR mutation positive NSCLC. Studies are underway, assessing treatments, following resistance to TAGRISSO®. Osimertinib vs standard of care (SoC) EGFR-TKI as first-line therapy in patients (pts) with EGFRm advanced NSCLC: FLAURA. Ramalingam S, Reungwetwattana T, Chewaskulyong B, et al. Presented at: 2017 ESMO Congress; Madrid, Spain; September 9-12, 2017. Abstract LBA2_PR.

SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 27% of all cancer deaths. The American Cancer Society estimates that for 2017 about 222,500 new cases of lung cancer will be diagnosed and over 155,000 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. ASCO published the last clinical practice guideline update on systemic therapy for patients with Stage IV Non Small Cell Lung Cancer (NSCLC), in 2015. With the many advances in the management of these patients and availability of new practice changing evidence since the last publication, the latest ASCO guideline has been revised. The ASCO NSCLC Expert Panel updated their recommendations based on a systematic review of 14 randomized controlled trials from February 2014 to December 2016 and six nonrandomized studies on systemic therapy. This guideline is applicable to patients who had received molecular testing for EGFR/ALK/ROS1, as well as Programmed Death Ligand 1 (PD-L1), and clinicians know the test results.

Guideline Question: What systemic therapy treatment options should be offered to patients with Stage IV NSCLC, depending on the subtype of the patient’s cancer?

Target Population: Patients with Stage IV NSCLC.

Target Audience: Oncology care providers (including primary care physicians, specialists, nurses, social workers, and any other relevant member of a comprehensive multidisciplinary cancer care team), patients, and their caregivers.

Key Points:

1) There is no cure for patients with Stage IV NSCLC.

2) Decisions regarding chemotherapy should not be made based on age alone.

Recommendations: First Line Treatment for Patients

Patients with Non-Squamous Cell Carcinoma without a tumor EGFR-sensitizing mutation or ALK or ROS1 gene rearrangement and with a Performance Status (PS) of 0 or 1 (and appropriate PS of 2):

1) With high PD-L1 expression (Tumor Proportion Score [TPS] 50% or more) and no contraindications, single-agent Pembrolizumab is recommended.

2) With low PD-L1 expression (TPS less than 50%), a variety of combination cytotoxic chemotherapies (with or without Bevacizumab, if patients are receiving Carboplatin and Paclitaxel) are recommended.

3) There is insufficient evidence to recommend Bevacizumab in combination with Pemetrexed plus Carboplatin.

4) Other checkpoint inhibitors, combination checkpoint inhibitors, or immune checkpoint therapy with chemotherapy are not recommended.

5) With PS of 2, combination or single agent therapy or palliative care alone may be used.

Patients with Squamous Cell Carcinoma without a tumor EGFR-sensitizing mutation or ALK or ROS1 gene rearrangement and with a PS of 0 or 1 (and appropriate PS of 2):

1) With high PD-L1 expression (TPS 50% or more) and no contraindications, single agent Pembrolizumab is recommended.

2) With low PD-L1 expression (TPS less than 50%), a variety of combination cytotoxic chemotherapies are recommended.

3) Other checkpoint inhibitors, combination checkpoint inhibitors, or immune checkpoint therapy with chemotherapy are not recommended.

4) With PS of 2, combination or single agent therapy or palliative care alone may be used.

5) With Squamous NSCLC treated with Cisplatin and Gemcitabine, the Panel neither recommends for nor recommends against the addition of Necitumumab to chemotherapy.

With sensitizing EGFR mutations, Afatinib, Erlotinib, or Gefitinib is recommended.

With ALK gene rearrangements, Crizotinib is recommended. 

With ROS1 rearrangement, Crizotinib is recommended. 

Recommendations: Second Line Treatment for Patients

Without a tumor EGFR-sensitizing mutation or ALK or ROS1 gene rearrangement and with PS of 0 or 1 (and appropriate PS of 2):

1) In patients with high PD-L1 expression (TPS 1% or more), no contraindications, who received first line chemotherapy and have not received prior immune therapy, single agent Nivolumab, Pembrolizumab, or Atezolizumab is recommended.

2) In patients with negative or unknown tumor PD-L1 expression (TPS less than 1%), no contraindications and who received first line chemotherapy, single agent Nivolumab, or Atezolizumab, or a variety of combination cytotoxic chemotherapies are recommended.

3) Other checkpoint inhibitors, combination checkpoint inhibitors, and immune checkpoint therapy with chemotherapy are not recommended.

4) In patients who received an immune checkpoint inhibitor as first line therapy, a variety of combination cytotoxic chemotherapies are recommended.

5) In patients with contraindications to immune checkpoint inhibitor therapy after first line chemotherapy, Docetaxel is recommended.

6) In patients with non-Squamous Cell Carcinoma who have not previously received Pemetrexed, Pemetrexed is recommended.

With sensitizing EGFR mutations:

1) In patients with disease progression after first line therapy with an EGFR Tyrosine Kinase Inhibitor (TKI) and the presence of the T790M resistance mutation, Osimertinib is recommended. If T790M mutation is not present, a platinum doublet is recommended.

2) In patients who received an EGFR-TKI in the first-line setting, had an initial response, and subsequently experienced slow or minimal disease progression at isolated sites, EGFR-TKI with local therapy to the isolated sites is an option.

With ROS1 rearrangement:

1) In patients who have not received prior Crizotinib, Crizotinib is recommended.

2) In patients who have received prior Crizotinib, platinum-based therapy in the second line with or without Bevacizumab is recommended.

With BRAF mutations:

1) In patients without prior immune checkpoint therapy and high PD-L1 expression (TPS more than 1%), single agent Atezolizumab, Nivolumab, or Pembrolizumab is recommended.

2) In patients who have received prior immune checkpoint therapy, Dabrafenib alone or in combination with Trametinib in third line, is an option.

Recommendations: Third Line Treatment for Patients

1) In patients without a tumor EGFR-sensitizing mutation or ALK or ROS1 gene rearrangement and with non-Squamous Cell Carcinoma and PS of 0 or 1 (and appropriate PS of 2), who received chemotherapy with or without Bevacizumab and immune checkpoint therapy, single agent Pemetrexed or Docetaxel are options.

2) In patients with tumor EGFR-sensitizing mutation(s) who have received at least one first-line EGFR-TKI and prior platinum-based chemotherapy, there are insufficient data to recommend immunotherapy in preference to chemotherapy.

Recommendations: Fourth Line Treatment for Patients

Patients and clinicians should consider and discuss experimental treatment, clinical trials, and continued best supportive (palliative) care.

Systemic Therapy for Stage IV Non-Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. Hanna N, Johnson D, Temin S, et al. J Clin Oncol 2017;35:3484-3515

SUMMARY: The FDA on June 22, 2017 granted regular approvals to TAFINLAR® ((Dabrafenib) and MEKINIST® (Trametinib) 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 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 TAFINLAR® and MEKINIST®. This is the first NGS oncology panel test approved by the FDA for multiple companion diagnostic indications. Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 27% of all cancer deaths. The American Cancer Society estimates that for 2017 about 222,500 new cases of lung cancer will be diagnosed and over 155,000 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States.

The approval of the combination of MEKINIST® (Trametinib) and TAFINLAR® (Dabrafenib), to treat patients with advanced NSCLC, was based on the understanding of the biological pathways of this malignancy. The Mitogen-Activated Protein Kinase pathway (MAPK pathway) is an important signaling pathway which enables the cell to respond to external stimuli. This pathway plays a dual role, regulating cytokine production and participating in cytokine dependent signaling cascade. The MAPK pathway of interest is the RAS-RAF-MEK-ERK pathway. The RAF family of kinases includes ARAF, BRAF and CRAF signaling molecules. BRAF is a very important intermediary of the RAS-RAF-MEK-ERK pathway. BRAF mutations have been demonstrated in 6%-8% of all malignancies and BRAF V600E mutation occurs in 1-2% of lung adenocarcinomas and acts as an oncogenic driver.

BRF113928 is an open-label, multicohort, multicentre, non-randomized, phase II study which sequentially enrolled patients with BRAF V600E mutation-positive metastatic NSCLC, across 3 cohorts. The first 2 cohorts included previously treated patients. The median age was 64 years, 98% had adenocarcinoma, and majority of patients (72%) were former or current smokers. In the first cohort, 84 patients received single agent TAFINLAR® following one or more prior platinum-based chemotherapy. In the second cohort, 57 patients received a combination of TAFINLAR® 150 mg orally twice daily and MEKINIST® 2 mg orally once daily. Patients in this second cohort had received at least 1 prior line of platinum-based chemotherapy regimen with disease progression and 33% had received 2 or more prior chemotherapy regimens.

It was noted that in these previously treated cohorts of patients, the Objective Response Rate (ORR) for the combination treatment based on independent review was 63%, with a median Duration of Response (DoR) of 12.6 months. The ORR for patients who received single agent TAFINLAR® was 27% and the median DoR was 9.9 months. The investigator assessed median Progression Free Survival (PFS) was 10.2 months, and median Overall Survival (OS) was 18.2 months.

The authors in this latest publication reported the the efficacy and safety of TAFINLAR® plus MEKINIST® treatment in previously untreated patients with BRAF V600E-mutant metastatic NSCLC (third cohort). This cohort enrolled 36 patients and patients received TAFINLAR® 150 mg orally twice daily plus MEKINIST® 2 mg orally once daily, until disease progression or unacceptable toxicities. The median follow up was 15.9 months. The Primary endpoint was investigator assessed ORR. Secondary endpoints included Duration of Response (DoR), PFS, OS, and safety.

The Objective Response Rate in this cohort was 64%, with 6% Complete Response and 58% Partial Response. The Disease Control Rate was 75%. The median Duration of Response was 10.4 months, median PFS was 10.9 months and median OS was 24.6 months. The most common grade 3 or 4 adverse events were pyrexia, liver function abnormalities, hypertension and vomiting.

The authors concluded that TAFINLAR® plus MEKINIST® demonstrated substantial antitumor activity and durable responses in patients with treatment-naive BRAF V600E-mutant NSCLC. This study confirmed that there is a fourth actionable biomarker, BRAF V600E, in addition to EGFR, ALK and ROS-1, for patients with Non Small Cell Lung Cancer. Dabrafenib plus trametinib in patients with previously untreated BRAF V600E-mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial. Planchard D, Smit EF, Groen HJ, et al. The Lancet Oncology 2017;18:1307-1316

SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 27% of all cancer deaths. The American Cancer Society estimates that for 2017 about 222,500 new cases of lung cancer will be diagnosed and over 155,000 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Approximately 15% of patients present with early stage (T1-2 N0) disease, and these numbers are likely to increase with the implementation of Lung Cancer screening programs. Patients with early stage disease unless medically unfit, undergo surgical resection with a curative intent. Those who are not surgical candidates, are often treated with conventional Radiation Therapy, which can result in high rates of local failure and treatment-related toxicities.

Stereotactic Body Radiation Therapy (SBRT) is a non-surgical procedure that allows delivery of significantly higher doses of precisely focused radiation to the tumor, compared to conventional Radiation Therapy, with less collateral damage to the surrounding normal tissue. The technologies used for SBRT include GAMMA KNIFE® which uses highly focused gamma rays, Proton Beam therapy which uses ionized hydrogen or Protons, Linear Accelerator (LINAC) and CYBER KNIFE® which use Photons, to target the tumor tissue. Because SBRT is fractionated and delivered over 1-5 days, the short-and long-term side effects of radiation therapy are decreased and may allow higher total dosage to be given.

This guideline is based on systematic review of literature which included 172 articles, from January 1995 and August, 2016. This literature search evaluated adults with T1-2, N0, Non Small Cell Lung Cancer (NSCLC) receiving primary or salvage SBRT. Developed by the American Society for Radiation Oncology, this guideline is also endorsed by the European Society for Radiotherapy & Oncology, the Royal Australian and New Zealand College of Radiologists, and the International Association for the Study of Lung Cancer.

KEY QUESTIONS (KQ)

KQ 1: When is SBRT appropriate for patients with T1-2, N0, NSCLC who are medically operable?

Statement KQ 1A: Any patient with operable Stage I NSCLC being considered for SBRT should be evaluated by a thoracic surgeon, preferably in a multidisciplinary setting, to reduce specialty bias.

Statement KQ 1B: For patients with “standard operative risk” (ie, with anticipated operative mortality of <1.5%) and stage I NSCLC, SBRT is not recommended as an alternative to surgery outside of a clinical trial. Discussions about SBRT are appropriate, with the disclosure that long-term outcomes with SBRT >3 years are not well established. For this population, lobectomy with systematic mediastinal lymph node evaluation remains the recommended treatment, though a sublobar resection may be considered in select clinical scenarios.

Statement KQ 1C: For patients with “high operative risk” (ie, those who cannot tolerate lobectomy, but are candidates for sublobar resection) stage I NSCLC, discussions about SBRT as a potential alternative to surgery are encouraged. Patients should be informed that while SBRT may have decreased risks from treatment in the short term, the longer term outcomes >3 years are not well-established.

KQ 2: When is SBRT appropriate for medically inoperable patients with T1-2, N0, NSCLC?

For patients with centrally located tumors

Statement KQ 2A: SBRT directed toward centrally located lung tumors (tumor within 2 cm of the proximal tracheobronchial tree) carries unique and significant risks when compared to treatment directed at peripherally located tumors. The use of 3-fraction regimens should be avoided in this setting.

Statement KQ 2B: SBRT directed at central lung tumors should be delivered in 4 or 5 fractions. Adherence to volumetric and maximum dose constraints may optimize the safety profile of this treatment. For central tumors for which SBRT is deemed too high risk, hypofractionated radiation therapy utilizing 6 to 15 fractions can be considered.

For patients with tumors >5 cm in diameter

Statement KQ 2C: SBRT is an appropriate option for tumors >5 cm in diameter with an acceptable therapeutic ratio. Adherence to volumetric and maximum dose constraints may optimize the safety profile of this treatment.

For patients lacking tissue confirmation

Statement KQ 2D: Whenever possible, obtain a biopsy prior to treatment with SBRT to confirm a histologic diagnosis of a malignant lung nodule.

Statement KQ 2E: SBRT can be delivered in patients who refuse a biopsy, have undergone non-diagnostic biopsy, or who are thought to be at prohibitive risk of biopsy. Prior to SBRT in patients lacking tissue confirmation of malignancy, patients are recommended to be discussed in a multidisciplinary manner with a consensus that the lesion is radiographically and clinically consistent with a malignant lung lesion based on tumor, patient, and environmental factors

For patients with synchronous primary or multifocal tumors

Statement KQ 2F: Multiple Primary Lung Cancers (MPLCs) can be difficult to differentiate from intrathoracic metastatic lung cancer and pose unique issues for parenchymal preservation; therefore, it is recommended that they are evaluated by a multidisciplinary team.

Statement KQ 2G: Positron Emission Tomography/Computed Tomography and brain Magnetic Resonance Imaging are recommended in patients suspected of having MPLC to help differentiate from intrathoracic metastatic lung cancer. Invasive mediastinal staging should be addressed on a case-by-case basis.

Statement KQ 2H: SBRT may be considered as a curative treatment option for patients with synchronous MPLC. SBRT for synchronous MPLC has equivalent rates of local control and toxicity, but decreased rates of overall survival compared with those with single tumors.

Statement KQ 2I: SBRT is recommended as a curative treatment option for patients with metachronous MPLC. SBRT for metachronous MPLC has equivalent rates of local control and toxicity and overall survival compared with those with single tumors.

For patients who underwent pneumonectomy and now have a new primary tumor in their remaining lung

Statement KQ 2J: SBRT may be considered a curative treatment option for patients with metachronous MPLC in a postpneumonectomy setting. While SBRT for metachronous MPLC appears to have equivalent rates of local control and acceptable toxicity compared to single tumors, SBRT in the post-pneumonectomy setting might have a higher rate of toxicity than in patients with higher baseline lung capacity.

KQ 3: For medically inoperable early-stage lung cancer patients, how can SBRT techniques be individually tailored to provide an adequate dose for tumor eradication with minimal risk to normal structures in “high-risk” clinical scenarios?

For tumors with intimal proximity/involvement of mediastinal structures (bronchial tree, esophagus, heart, etc.)

Statement KQ 3A: For tumors in close proximity to the proximal bronchial tree, SBRT should be delivered in 4 to 5 fractions. Physicians should endeavor to meet the constraints that have been utilized in prospective studies given the severe toxicities that have been reported.

Statement KQ 3B: For tumors in close proximity to the esophagus, physicians should endeavor to meet the constraints that have been utilized in prospective studies or otherwise reported in the literature given the severe esophageal toxicities that have been reported.

Statement KQ 3C: For tumors in close proximity to the heart and pericardium, SBRT should be delivered in 4 to 5 fractions with low incidence of serious toxicities to the heart, pericardium, and large vessels observed. Adherence to volumetric and maximum dose constraints utilized in prospective trials or reported in the literature may optimize the safety profile of this treatment.

For tumors abutting or invading the chest wall

Statement KQ 3D: SBRT is an appropriate option for treatment and should be offered for T1-2 tumors that abut the chest wall. Grade 1 and 2 chest wall toxicity is a common occurrence post SBRT that usually resolves with conservative management. Patients with peripheral tumors approximating the chest wall should be counseled on the possibility of this common toxicity.

Statement KQ 3E: SBRT may be utilized in patients with cT3 disease due to chest wall invasion without clear evidence of reduced efficacy or increased toxicity compared to tumors abutting the chest wall.

KQ 4: In medically inoperable patients, what is the role of SBRT as salvage therapy for early-stage lung cancer that recurs?

After conventionally fractionated Radiation Therapy

Statement KQ 4A: The use of salvage SBRT after primary conventionally fractionated radiation may be offered to selected patients due to reported favorable local control and survival. These patients should be informed of significant (including fatal) toxicities.

Statement KQ 4B: Patient selection for salvage SBRT after primary conventionally fractionated radiation is a highly individualized process. Radiation oncologists should assess evidence-based patient, tumor, and treatment factors prior to treatment initiation.

After SBRT and sublobar resection

Statement KQ 4C: Patient selection for salvage SBRT after previous SBRT and after prior Sublobar resection is a highly individualized process. Radiation oncologists should assess evidence-based patient, tumor, and treatment factors before treatment initiation.

Stereotactic Body Radiation Therapy for early-stage Non-Small Cell Lung Cancer: Executive Summary of an ASTRO Evidence-Based Guideline. Videtic GM, Donington J, Giuliani M, et al. http://dx.doi.org/10.1016/j.prro.2017.04.014

SUMMARY: The FDA on June 22, 2017, granted regular approvals to TAFINLAR® (Dabrafenib) and MEKINIST® (Trametinib) 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 also approved the Oncomine® Dx Target Test, 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 TAFINLAR® and MEKINIST®. This is the first NGS oncology panel test approved by the FDA for multiple companion diagnostic indications.

Combining MEKINIST® (Trametinib) with TAFINLAR® (Dabrafenib) to treat patients with NSCLC, was based on the understanding of the biological pathways of this malignancy. The Mitogen-Activated Protein Kinase pathway (MAPK pathway) is an important signaling pathway which enables the cell to respond to external stimuli. This pathway plays a dual role, regulating cytokine production and participating in cytokine dependent signaling cascade. The MAPK pathway of interest is the RAS-RAF-MEK-ERK pathway. This pathway has been implicated in the development of multiple malignancies including NSCLC and Melanoma. The RAF family of kinases includes ARAF, BRAF and CRAF signaling molecules. BRAF is a very important intermediary of the RAS-RAF-MEK-ERK pathway. BRAF mutations have been demonstrated in 6-8% of all malignancies. TAFINLAR® is a selective oral BRAF inhibitor and MEKINIST® is a potent and selective inhibitor of MEK gene, which is downstream from RAF in the MAPK pathway.

The approval of TAFINLAR® and MEKINIST® combination, for patients with metastatic NSCLC was based on an international, multicenter, three-cohort, non-randomized, open-label trial, in patients with locally confirmed BRAF V600E mutation-positive, metastatic NSCLC. In this phase II trial, 93 patients were treated with the combination of TAFINLAR® 150 mg orally twice daily and MEKINIST® 2 mg orally once daily. Of these 93 patients, 36 patients had received no prior systemic therapy for metastatic NSCLC and 57 patients received at least one prior platinum-based chemotherapy regimen and had disease progression. The third cohort in this phase II trial included 78 previously treated patients with BRAF V600E mutation-positive metastatic NSCLC, who received single-agent TAFINLAR®. The primary endpoint was Overall Response Rate (ORR).

It was noted that in the previously treated group, the ORR for the combination treatment based on independent review was 63% with a median Duration of Response of 12.6 months. In the treatment-naive group, the ORR for the combination was 61% and this group had not reached the endpoint for median Duration of Response and therefore was not estimable. However, among those who responded to treatment, 59% of the responders had response durations greater than 6 months. The ORR for patients who received single agent TAFINLAR® was 27% and the median Duration of Response was 9.9 months. The most common Grade 3-4 adverse reactions were pyrexia, fatigue, dyspnea, vomiting, rash, hemorrhage, and diarrhea.

It was concluded that TAFINLAR® plus MEKINIST® combination represents a new targeted therapy for patients with BRAF V600E mutation¬-positive metastatic NSCLC, who tend to respond less favorably to standard chemotherapy. This approval marks the fourth actionable genomic biomarker in metastatic NSCLC along with EGFR, ALK and ROS-1. Dabrafenib plus trametinib in patients with previously treated BRAF(V600E)-mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial. Planchard D, Besse B, Groen HJ et al. Lancet Oncol. 2016 Jul;17(7):984-93. doi: 10.1016/S1470-2045(16)30146-2. Epub 2016 Jun 6.