Tag: Lung Cancer: Non-Small Cell

SUMMARY: The FDA on September 29, 2016 approved a blood-based companion diagnostic for TAGRISSO® (Osimertinib). The companion diagnostic for TAGRISSO® is the only FDA approved and clinically validated companion diagnostic test that uses either tissue or a blood sample to confirm the presence of a T790M point mutation in patients with metastatic Epidermal Growth Factor Receptor (EGFR) mutation-positive Non Small Cell Lung Cancer (NSCLC), who have had progression of disease on or after EGFR Tyrosine Kinase Inhibitor therapy. 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 2016 about 224,390 new cases of lung cancer will be diagnosed and over 158,000 patients will die of the disease. Non Small Cell Lung Cancer accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large cell carcinomas. Approximately 10% to 15% of Caucasian patients and 50% of Asian patients with Adenocarcinomas, harbor activating EGFR 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® is 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. The application of precision medicine with targeted therapy requires detection of molecular abnormalities in a tumor specimen, following progression or recurrence. Archived biopsy specimens may not be helpful as it is important to identify additional mutations in the tumor at the time of recurrence or progression, in order to plan appropriate therapy. Further, recurrent tumors may be inaccessible for a safe biopsy procedure or the clinical condition of the patient may not permit a repeat biopsy. Additionally, the biopsy itself may be subject to sampling error due to tumor heterogeneity. Genotyping circulating-free tumor DNA (cfDNA) in the plasma can potentially overcome the shortcomings of repeat biopsies and tissue genotyping, allowing the detection of many more targetable gene mutations, thus resulting in better evaluation of the tumor genome landscape.

The COBAS® Mutation Test v2, is a real-time PCR test for the qualitative detection of defined mutations of the EGFR gene in NSCLC patients. Defined EGFR mutations are detected using DNA isolated from Formalin-Fixed Paraffin-Embedded Tumor tissue (FFPET) or circulating-free tumor DNA (cfDNA) from plasma, obtained from EDTA anti-coagulated peripheral whole blood (purple top tube). This new blood-based companion diagnostic test offers an important option to identify T790M mutation in patients with metastatic EGFR mutation-positive NSCLC, who have progressed on an EGFR TKI therapy, and for whom a tissue biopsy may not be feasible.

US FDA approves Tagrisso (osimertinib) blood-based T790M companion diagnostic test. AstraZeneca website. https://www.astrazeneca-us.com/content/az-us/media/press-releases/2016/us-fda-approves-tagrisso-osimertinib-blood-based-t790m-companion-diagnostic-test-09292016.html. Updated September 29, 2016.

SUMMARY: The FDA on April 15, 2016 approved 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. Lung cancer is the second most common cancer in both men and women and the American Cancer Society estimates that for 2016, about 224,390 new cases of lung cancer will be diagnosed and over 158,000 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), 25% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large cell carcinomas. Non Small Cell Lung Cancer patients with Squamous Cell histology have been a traditionally hard- to-treat, patient group, with less than 5% of patients with advanced SCC, surviving for five years or longer. Some of the advanced NSCLC tumors are dependent on the Epidermal Growth Factor Receptor (EGFR) for cell proliferation and survival, regardless of EGFR mutation status. TARCEVA® (Erlotinib) is a reversible EGFR Tyrosine Kinase Inhibitor and is presently approved by the FDA for the treatment of locally advanced or metastatic NSCLC, after failure of at least one prior chemotherapy regimen. GILOTRIF® (Afatinib) is an oral, irreversible blocker of the ErbB family which includes EGFR (ErbB1), HER2 (ErbB2), ErbB3 and ErbB4. GILOTRIF® was approved by the FDA in July 2013, for the first line treatment of patients with metastatic NSCLC, whose tumors have Epidermal Growth Factor Receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations.

This additional indication approved by the FDA was based on the LUX-Lung 8 study, which is a phase III trial in which 795 patients with Stage IIIB/IV Squamous Cell Carcinoma of the lung who had progressed on first line platinum based doublet therapy, were randomized 1:1 to receive GILOTRIF® 40 mg PO daily (N=398) or TARCEVA® 150 mg PO daily (N=397). Treatment was given until disease progression. The median age was 65 years. Majority of the patients were male, caucasian and ex-smokers. The Primary endpoint was Progression Free Survival (PFS) and Secondary endpoints included Overall Survival (OS), Objective Response Rate (ORR), Disease Control Rate (DCR), patient reported outcomes and safety. The Primary endpoint of Progression Free Survival (PFS) was met and reported in 2014 and favored GILOTRIF® over TARCEVA®. The authors in this analysis reported the Overall Survival data, as well as updated data on Progression Free Survival and other Secondary endpoints. The median Overall Survival was 7.9 months with GILOTRIF® and 6.8 months with TARCEVA® (HR=0.81; P=0.007). This meant a 19% reduction in the risk of death with GILOTRIF® when compared to TARCEVA® and this survival advantage was consistent across all time points. The updated median Progression Free Survival for GILOTRIF® was 2.4 months versus 1.9 months for TARCEVA® (HR=0.82; P=0.04) which meant an 18% reduction in the disease progression. The Disease Control Rate was 51% for GILOTRIF® and 40% with TARCEVA® (P=0.002). Based on patient reported outcomes, symptoms including cough and dyspnea were better with GILOTRIF® compared to TARCEVA®. Incidence of severe adverse events was similar with both therapies, with patients on GILOTRIF® experiencing more grade 3 diarrhea and stomatitis and patients receiving TARCEVA® experiencing more grade 3 rash.

The authors concluded that GILOTRIF® should be the TKI of choice for the second line treatment of patients with Squamous Cell Carcinoma of the lung, as it significantly improves Overall Survival, Progression Free Survival, Disease Control Rate and controls symptoms with manageable toxicities, when compared to TARCEVA®. Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-label randomised controlled phase 3 trial. Soria J, Felip E, Cobo M, et al. The Lancet Oncology 2015;16:897-907

SUMMARY: It has been well established that treatment with EGFR TKIs results in superior outcomes, for patients with tumors harboring exon 19 deletions and exon 21 mutations. The application of precision medicine with targeted therapy, requires detection of molecular abnormalities in a tumor specimen, following progression or recurrence. Archived biopsy specimens may not be helpful as it is important to identify additional mutations in the tumor at the time of recurrence or progression, in order to plan appropriate therapy. Further, recurrent tumors may be inaccessible for a safe biopsy procedure or the clinical condition of the patient may not permit a repeat biopsy. Additionally, the biopsy itself may be subject to sampling error due to tumor heterogeneity. Genotyping cell free DNA in the plasma can potentially overcome the shortcomings of repeat biopsies and tissue genotyping, allowing the detection of many more targetable gene mutations, thus resulting in better evaluation of the tumor genome landscape.

The purpose of this study was to prospectively validate plasma droplet digital PCR (ddPCR) for the rapid detection of common Epidermal Growth Factor Receptor (EGFR) and KRAS mutations, as well as the EGFR T790M acquired resistance mutation. The authors prospectively evaluated the feasibility and accuracy of this assay in patients with newly diagnosed advanced non-squamous Non Small Cell Lung Cancer (NSCLC) who either were newly diagnosed and initial therapy was planned (N=120) or had developed acquired resistance to an EGFR kinase inhibitor and rebiopsy was planned (N=60). The median age was 62 years and 62% were females.

Following initial blood sampling of all patients, plasma droplet digital Polymerase Chain Reaction (ddPCR) for EGFR and KRAS mutations, including EGFR exon 19 deletion, EGFR L858R, KRAS G12X and EGFR T790M acquired resistance mutation, was performed. All patients underwent biopsy for tissue genotyping, and this was used as a reference standard for comparison with the liquid biopsy results. Important study outcomes included sensitivity and specificity of plasma ddPCR assay, as well as test turnaround time, which was defined as the number of business days between blood sampling and test reporting.

Tumor genotypes identified included 80 EGFR exon 19 or L858R mutations, 35 EGFR T790M mutations, and 25 KRAS G12X mutations. The ddPCR assay median turnaround time was 3 days compared with 12 days for tissue genotyping and 27 days for patients with acquired resistance. Plasma ddPCR exhibited a positive predictive value of 100% for EGFR 19 del, 100% for EGFR L858R mutation and 100% for KRAS. The positive predictive value for EGFR T790M was lower at 79%. The sensitivity of plasma ddPCR assay was 82% for EGFR exon19 del, 74% for EGFR L858R mutation, and 77% for EGFR T790M acquired resistance mutation, but lower for KRAS at 64%. Sensitivity for EGFR or KRAS was higher in patients with multiple metastatic sites (P=0.001), specifically in those with bone and hepatic metastases.

The authors concluded that in this first prospective study, plasma ddPCR assay can rapidly detect EGFR and KRAS mutations with high specificity, allowing treatment selection, without repeat biopsies. Additionally, this assay may also detect EGFR T790M mutation, missed by tissue genotyping, due to tumor heterogeneity in resistant disease. Prospective Validation of Rapid Plasma Genotyping for the Detection of EGFR and KRAS Mutations in Advanced Lung Cancer. Sacher AG, Paweletz C, Dahlberg SE, et al. JAMA Oncol. Published online April 07, 2016. doi:10.1001/jamaoncol.2016.0173

SUMMARY: The FDA on March 11, 2016, approved XALKORI® (Crizotinib) for the treatment of patients with metastatic Non Small Cell Lung Cancer (NSCLC), whose tumors are ROS1-positive. XALKORI® was first approved in 2011 for the treatment of patients with NSCLC, whose tumors are Anaplastic Lymphoma Kinase (ALK) positive. Lung cancer is the second most common cancer in both men and women and the American Cancer Society estimates that for 2016, about 224,390 new cases of lung cancer will be diagnosed and over 158,000 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), 25% are Squamous cell carcinomas, 40% are Adenocarcinomas and 10% are Large cell carcinomas. There is now growing body of evidence suggesting superior outcomes when advanced NSCLC patients with specific genomic alterations receive targeted therapies. Approximately 1-2% of lung adenocarcinomas harbor ROS1 gene rearrangements. ROS1 gene is located on chromosome 6q22 (long arm of chromosome 6) and plays an important role in cell growth and development. ROS1 gene fusion with another gene results in a mutated DNA sequence which then produces an abnormal protein responsible for unregulated cell growth and cancer. ROS1 gene rearrangement has been identified as a driver mutation in Non Small Cell Lung Cancer with adenocarcinoma histology. This is more common in nonsmokers or in light smokers (<10 pack years), who are relatively young (average age of 50 years) and thus share similar characteristics with ALK-positive patients. The ROS protein and the ALK protein have similar structure and function and are sensitive to Tyrosine Kinase Inhibitors such as XALKORI® (Crizotinib) and ZYKADIA® (Ceritinib). ROS1 mutations have been also been associated with Cholangiocarcinoma (Bile duct cancer) and Glioblastoma multiforme. ROS1 rearrangements are mutually exclusive with other oncogenic mutations found in NSCLC such as EGFR mutations, KRAS mutations and ALK rearrangement. The presence of a ROS1 rearrangement can be detected by Fluorescence In Situ Hybridization (FISH), ImmunoHistoChemistry (IHC), Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR) and Next Generation-Sequencing. XALKORI® is a small molecule Tyrosine Kinase Inhibitor that targets ALK, MET and ROS1 tyrosine kinases.

The latest FDA approval was based on the results of a multicenter, single-arm, expansion cohort of the phase I study of XALKORI®, in which 50 patients with advanced NSCLC, who tested positive for ROS1 rearrangement, were enrolled. The median age was 53 years, 98% had adenocarcinoma histology and majority of patients (86%) had received previous treatment for advanced disease, with 44% having received more than 1 prior therapy. XALKORI® was administered orally at 250 mg twice daily in continuous 28-day cycles. Treatment was continued until disease progression or unacceptable toxicities. The primary end point was Objective Response Rate, and Duration of Response (DoR) was an additional outcome measure.

The Objective Response Rate by investigator assessment was 72%, with 3 Complete Responses and 33 Partial Responses. The median Duration of Response was 17.6 months. The median Progression Free Survival was 19.2 months and Overall Survival rate at 12 months was 85%. The most common adverse reactions associated with XALKORI® were vision disorders, nausea, diarrhea, vomiting, edema, elevated transaminases, fatigue, upper respiratory infection and neuropathy.

The authors concluded that XALKORI® has significant antitumor activity in patients with advanced ROS1-rearranged NSCLC. The significantly superior median Duration of Response (17.6 vs 11.4 months) and median Progression Free Survival (19.2 vs 9.7 months) in the ROS1-rearranged NSCLC compared to ALK- rearranged NSCLC, may be due to more potent inhibition of ROS1 than ALK, by XALKORI®, resulting in more effective target inhibition and more durable responses. Crizotinib in ROS1-Rearranged Non–Small-Cell Lung Cancer. Shaw AT, Ou S-HI, Bang Y-J, et al. N Engl J Med 2014; 371:1963-1971