Tag: Lung Cancer: Non-Small Cell

FDA Approves KEYTRUDA® for Treatment Naïve Patients with Advanced NSCLC

RR

SUMMARY: The FDA on October 24, 2016 approved KEYTRUDA® (Pembrolizumab) for the treatment of patients with metastatic Non Small Cell Lung Cancer (NSCLC), whose tumors have high PD-L1 expression (Tumor Proportion Score greater than or equal to 50%) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and no prior systemic chemotherapy treatment for metastatic NSCLC. 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.

KEYTRUDA® is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the tumor-specific effector T cells. High level of Programmed Death-Ligand 1 (PD-L1) expression is defined as membranous PD-L1 expression on at least 50% of the tumor cells, regardless of the staining intensity. It is estimated that based on observations from previous studies, approximately 25% of the patients with advanced Non Small Cell Lung Cancer (NSCLC) have a high level of PD-L1 expression and high level of PD-L1 expression has been associated with significantly increased response rates to KEYTRUDA®.

KEYNOTE-024 is a open-label, randomized, phase III trial in which KEYTRUDA® administered at a fixed dose was compared with investigator’s choice of cytotoxic chemotherapy, as first line therapy, for patients with advanced NSCLC, with tumor PD-L1 expression of 50% or greater. Three hundred and five (N=305) treatment naïve patients with advanced NSCLC and PD-L1 expression on at least 50% of tumor cells, were randomly assigned in a 1:1 ratio to receive either KEYTRUDA® (N=154) or chemotherapy (N=151). Enrolled patients had no sensitizing EGFR mutations or ALK translocations. Treatment consisted of KEYTRUDA® administered at a fixed dose of 200 mg IV every 3 weeks for 35 cycles or the investigator’s choice of platinum-based chemotherapy for 4-6 cycles. Pemetrexed (ALIMTA®) based therapy was permitted only for patients who had non-squamous tumors and these patients could receive ALIMTA® maintenance therapy after the completion of combination chemotherapy. The primary end point was Progression Free Survival and secondary end points included Overall Survival, Objective Response Rate and safety.

The median PFS was 10.3 months in the KEYTRUDA® group versus 6.0 months in the chemotherapy group (HR=0.50; P<0.001). This benefit was observed across all patient subgroups including tumor histologic type and chemotherapy regimen administered. The estimated Overall Survival at 6 months was 80.2% in the KEYTRUDA® group versus 72.4% in the chemotherapy group (HR=0.60; P=0.005). Patients in the KEYTRUDA® group experienced higher Response Rates than in the chemotherapy group (44.8% vs. 27.8%) as well as longer median duration of response (Not Reached versus 6.3 months). These benefits were realized even after 43.7% of the patients in the chemotherapy group following progression, had crossed over to receive KEYTRUDA®. Adverse events of any grade were less frequent in the KEYTRUDA® group compared to the chemotherapy group, with diarrhea, fatigue and pyrexia being more common in the KEYTRUDA® group whereas anemia, nausea and fatigue were more often noted in the chemotherapy group. As expected, immune-mediated adverse events (including pneumonitis) occurred more frequently with KEYTRUDA® whereas cytopenias occurred more frequently with chemotherapy.

It was concluded that in treatment naïve patients with advanced NSCLC and a PD-L1 tumor proportion score of 50% or greater, KEYTRUDA® was associated with significantly longer Progression Free and Overall Survival and with fewer adverse events, compared with platinum-based chemotherapy. Pembrolizumab versus Chemotherapy for PD-L1–Positive Non–Small-Cell Lung Cancer. Reck M, Rodríguez-Abreu D, Robinson AG, et al. for the KEYNOTE-024 Investigators. October 9, 2016DOI: 10.1056/NEJMoa1606774

KEYTRUDA® (Pembrolizumab)

RR

The FDA on October 24, 2016 approved KEYTRUDA&reg; for the treatment of patients with metastatic Non Small Cell Lung Cancer (NSCLC), whose tumors express PD-L1, as determined by an FDA-approved test. This is the first FDA approval of a checkpoint inhibitor for first-line treatment of Lung cancer. This approval also expands the indication in second-line treatment of Lung cancer to include all patients with PD-L1-expressing NSCLC. KEYTRUDA&reg; is a product of Merck & Co., Inc.

TECENTRIQ® (Atezolizumab)

RR

The FDA on October 18, 2016 approved TECENTRIQ® for the treatment of patients with metastatic Non Small Cell Lung Cancer (NSCLC) whose disease progressed during or following Platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations, prior to receiving TECENTRIQ®. TECENTRIQ® is a product of Genentech, Inc.

TARCEVA® (Erlotinib)

RR

The FDA on October 18, 2016 modified the indication for TARCEVA® for treatment of Non Small Cell Lung Cancer, to limit use to patients whose tumors have specific Epidermal Growth Factor Receptor (EGFR) mutations. TARCEVA® is a product of Astellas Pharm Global Development Inc.

FDA Approves TAGRISSO® (Osimertinib) Blood-Based T790M Companion Diagnostic Test

RR

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.

Proton Beam Therapy May Improve Survival Compared to Conventional Radiation in Stage II and III NSCLC Patients

RR

SUMMARY: 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. Even though Photon-based external beam radiation plus concurrent chemotherapy is the current standard of care for patients with unresectable stage III NSCLC, Proton beam therapy is emerging as an alternative to conventional Photon beam therapy for many cancer types. Radiation Therapy involves the use of X-Rays, Gamma rays and charged particles for cancer treatment. External beam radiation therapy is most often delivered using a linear accelerator in the form of Photon beams (either X-rays or Gamma rays). Photons have no mass and are packets of energy of an electromagnetic wave. Electrons and Protons are charged particles and Electrons are considered light particles whereas Protons are considered heavy particles. Electron beams are used to irradiate skin and superficial tumors, as they are unable to penetrate deep into the tissues. The different types of external beam radiation treatments include 3-Dimensional Conformal Radiation Therapy (3D-CRT) meant to deliver radiation to very precisely shaped target areas, IMRT or Intensity Modulated Radiation Therapy which allows different areas of a tumor or nearby tissues to receive different doses of radiation, Image Guided Radiation Therapy (IGRT) which allows reduction in the planned volume of tissue to be treated as changes in a tumor size are noted during treatment, Stereotactic RadioSurgery (SRS) which can deliver one or more high doses of radiation to a small tumor, Stereotactic Body Radiation Therapy (SBRT) or CYBERKNIFE® which is similar to SRS but also takes the normal motion of the body into account while treating malignancies involving the lung and liver and Proton beam therapy. Proton beams unlike Photons, enter the skin and travel through the tissues and deposit much of their energy at the end of their path (known as the Bragg peak) and deposit less energy along the way. This is unlike Photons which deposit energy all along the path through the tissues and the deposited dose decreases with increasing depth. As a result, with Proton beam therapy, normal tissues are exposed to less radiation compared with Photons. Despite this advantage, tissue heterogeneity such as organ motion, tumor volume changes during treatment can have a significant negative impact on target coverage for Proton beam therapy and can result in damage to the surrounding tissues and potential complications.

It has remained unclear whether Proton beam therapy improves Overall Survival (OS) in patients with NSCLC. To address this question, the authors conducted a retrospective analysis using the National Cancer Data Base (NCDB) and analyzed outcomes and predictors associated with Proton beam therapy for NSCLC. This analysis included 140,383 patients with stage I to stage IV NSCLC, treated with thoracic radiation from 2004-2012, of whom 59% had stage II and III disease. Of these patients, 140,035 were treated with Photon beam therapy and 348 with Proton beam therapy. The median age was 68 yrs, 57% were males, 85% were Caucasian, 27% were treated at academic centers and 78% in metropolitan areas. To reduce treatment selection bias, propensity score matching method was implemented.

It was noted that patients were less likely to receive Proton beam therapy in community or comprehensive community centers compared to academic centers (P< 0.001). Further, patients who received Proton beam therapy were more likely to have a higher education and income. On multivariate analysis, it was noted that the risk for death was greater with use of Photon beam therapy compared to Proton beam therapy (HR=1.46; P<0.001). Among patients with stage II and III disease, 5 year OS was superior with Proton beam therapy compared with Photon beam therapy (22.3% versus 15%; P=0.01). Patients with stage II and III disease who received Photon beam therapy had worse OS both in multivariate (HR=1.19; P=0.06) and univariate (HR=1.23; P=0.02) analyses, compared with Proton beam therapy. Proton beam therapy was associated with better 5 year OS compared to Photon beam therapy (23% vs. 14%; P=0.02), on propensity matched analysis. The median OS was 11 months with Photon therapy compared to 19 months with Proton therapy.

The authors concluded that in this retrospective database analysis, thoracic radiation with Proton beam therapy was associated with better survival rates for patients with stage II and III NSCLC. An ongoing randomized phase III trial (NRG Oncology 1308) involving stage III NSCLC patients is evaluating if chemotherapy and Proton beam therapy is superior to chemotherapy and Photon beam therapy. National Cancer Data Base analysis of proton versus photon radiotherapy in non-small cell lung cancer (NSCLC). Behera M, OConnell KA, Liu Y, et al. J Clin Oncol 34, 2016 (suppl; abstr 8501)

Cobas EGFR Mutation Test v2

RR

The FDA on June 1, 2016 approved cobas EGFR Mutation Test v2, using plasma specimens, as a companion diagnostic test for the detection of exon 19 deletions or exon 21 (L858R) substitution mutations in the Epidermal Growth Factor Receptor (EGFR) gene, to identify patients with metastatic Non Small Cell Lung Cancer (NSCLC) eligible for treatment with TARCEVA® (Erlotinib). Cobas EGFR Mutation Test v2 is a product of Roche Molecular Systems, Inc.

XALKORI® (Crizotinib)

RR

The FDA on March 11, 2016 approved XALKORI® capsules for the treatment of patients with metastatic Non Small Cell Lung Cancer (NSCLC) whose tumors are ROS1-positive. XALKORI® is a product of Pfizer, Inc.

ALECENSA® (Alectinib)

RR

The FDA granted accelerated approval to ALECENSA® capsules for the treatment of patients with Anaplastic Lymphoma Kinase (ALK)-positive metastatic Non-Small Cell Lung Cancer (NSCLC), who have progressed on or are intolerant to Crizotinib. ALECENSA® is a product of Hoffmann-La Roche Inc.

PORTRAZZA® (Necitumumab)

RR

The FDA on November 24, 2015 granted approval to PORTRAZZA® in combination with Gemcitabine and Cisplatin for first-line treatment of patients with metastatic squamous Non-Small Cell Lung Cancer (NSCLC). PORTRAZZA® is not indicated for treatment of non-squamous NSCLC and is a product of Eli Lilly and Company.