Neratinib Improves DFS in HER2-Positive Breast Cancer

“Treatment with the tyrosine kinase inhibitor neratinib demonstrated a 2-year disease-free survival (DFS) rate of 93.9% in patients with early-stage HER2-positive breast cancer, representing a 33% improvement compared with placebo, according to findings from the phase III ExteNET study published in The Lancet Oncology.

“In the phase III study, which was also presented at the 2015 ASCO Annual Meeting, the 2-year DFS rate with placebo was 91.6% (HR, 0.67; 95% CI, 0.50-0.91; P = .009). In patients with both HER2- and HR-positive disease, the 2-year DFS rate was 95.4% with neratinib and 91.2% with placebo, representing a 49% benefit (HR, 0.51; P = .001).”


Afatinib a Better Choice for EGFR-Mutated Lung Cancer in First-Line Treatment

“Patients with EGFR-activating mutations in advanced lung cancer seem to benefit more from afatinib than gefitinib as first-line treatment, researchers report at the first ESMO Asia 2015 Congress in Singapore.

“In the global, randomised, open-label Phase IIb LUX-Lung 7 (LL7) trial, the irreversible ErbB family blocker afatinib significantly improved efficacy versus gefitinib across a range of clinically relevant endpoints, such as progression-free survival, time-to- failure and objective response rate. ‘Based on these results I would consider afatinib as the EGFR (TKI) of choice for the first-line treatment for patients with EGFR mutation-positive non-small-cell (NSCLC),’ lead author, Professor Keunchil Park, head of the Division of Hematology/Oncology at Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea, said.”


JUNIPER Trial Branches Out in KRAS Mutation-Positive Advanced NSCLC

“In 2008 Linardou et al published results of a meta-analysis of studies in advanced non–small cell lung cancer (NSCLC) and metastatic colorectal cancer. They extracted data on 1008 patients; 165 from 17 manuscripts for the NSCLC portion of the meta-analysis had KRAS mutations. They sought to establish whether or not KRAS mutations could be candidate predictive biomarkers for antiepidermal growth factor (EGFR) treatments. The analysis yielded empirical evidence that KRAS mutations are highly specific negative predictors of response to EGFR tyrosine kinase inhibitors (TKIs) when given as single agents to patients with advanced NSCLC. Further implicating an association of KRAS mutations with poor outcomes, a retrospective analysis of data from 1036 patients with stage IV lung adenocarcinoma and KRAS mutation evaluated between 2002 and 2009, found the presence of KRAS mutations to be associated with shorter survival (HR, 1.21; P = .48).”


Meta-Analysis Shows Increased Benefit of EGFR Tyrosine Kinase Inhibitors vs Chemotherapy in Subgroups of Patients With EGFR-Mutant NSCLC

“In a meta-analysis reported in the Journal of Clinical Oncology, Lee et al found that increased progression-free survival benefit of EGFR tyrosine kinase inhibitor treatment vs chemotherapy was exhibited in patients with exon 19 deletion, never-smokers, and women.

“The meta-analysis included seven trials (N = 1,649) comparing EGFR tyrosine kinase inhibitors with chemotherapy in patients with newly diagnosed advanced EGFR-mutant disease. Overall, tyrosine kinase inhibitor therapy was associated with significantly prolonged progression-free survival (hazard ratio [HR] = 0.37, 95% confidence interval [CI] = 0.32–0.42)…

“The investigators concluded: ‘Although EGFR [tyrosine kinase inhibitors] significantly prolonged [progression-free survival] overall and in all subgroups, compared with chemotherapy, greater benefits were observed in those with exon 19 deletions, never-smokers, and women. These findings should enhance drug development and economic analyses, as well as the design and interpretation of clinical trials.’ “


New Clinical Trial is Testing MGCD265 in Advanced NSCLC with MET or Axl Mutations

The gist: A new clinical trial is testing a drug called MGCD265 in advanced non-small cell lung cancer (NSCLC) patients whose tumors have mutations in the MET or Axl genes. 

“Mirati Therapeutics, Inc. (MRTX) today announced that the first patient with Non-Small Cell Lung Cancer (NSCLC) has been dosed in a Phase 1b clinical trial of MGCD265 in selected patients exhibiting genetic alterations of MET or Axl. In this segment of the study, one of the expansion cohorts will enroll patients with NSCLC and another will enroll patients with other solid tumors. Both cohorts will enroll only those patients that have specific MET driver mutations including MET gene point mutations, gene amplification, and MET or Axl gene rearrangements.

” ‘In the dose escalation phase of this trial, we identified an optimal dose that achieved serum levels that we believe will result in greater than 90% inhibition of MET and Axl,’ said Charles M. Baum, M.D., Ph.D., president and CEO of Mirati. ‘We are focused on patients whose tumors harbor the specific MET and Axl genetic alterations that MGCD265 is designed to treat. By selecting and treating only those patients who carry the targeted mutations, there is strong rationale that we’ll see proof of concept based on a high overall response rate in early 2015 that supports accelerated drug development.’ “


Results of New Drug, ASP8273, Show Response in Patients with Treatment-Resistant NSCLC

The gist: People with non-small cell lung cancer (NSCLC) that has both the EGFR and T790M mutations might benefit from a new drug. The drug is called ASP8273. A clinical trial tested ASP8273 in volunteer patients in Japan. In the trial, it shrank people’s tumors. More research is needed, but it is hoped that the drug might be a good alternative for people whose tumors are resistant to drugs like erlotinib, gefitinib and afatinib.

“In a second presentation looking at new ways of treating non-small cell lung cancer (NSCLC) that has both the EGFR and T790M mutations, researchers will tell the 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Barcelona, Spain, that an oral drug called ASP8273 has caused tumour shrinkage in patients in a phase I clinical trial in Japan.

“Mutations of the epidermal growth factor (EGFR) occur in about 30-35% of Asian patients with NSCLC (and in 10-15% of Caucasian patients). EGFR inhibitors called tyrosine kinase inhibitors (TKI), such as erlotinib, gefitinib and afatinib, can be used to treat EGFR-mutated NSCLC. However, these patients will eventually develop resistance to EGFR TKI therapy, rendering their disease resistant to current treatments. A further mutation called T790M accounts for 60% of this acquired resistance.

“ASP8273 is a new drug that inhibits the EGFR mutation and the T790M resistance mutation. Earlier research in mice had shown that it caused NSCLC to disappear completely, and so a I clinical trial was started in January 2014 to assess the drug’s safety and efficacy in humans.

“Twenty-four Japanese patients have enrolled so far to receive one of six levels of doses (25, 50, 100, 200, 400 and 600mg) once a day. A further seven patients have been enrolled into a second group to evaluate doses of 100mg, 200mg and 400mg a day (a dose escalation study), and the researchers are planning to enrol a total of 124 patients. Cancer had progressed in all the patients after prior treatment with EGFR TKI therapy, and most of them had the T790M mutation.”


Drugs to Avoid in Patients on Tyrosine Kinase Inhibitors

Editor’s note: More and more people with cancer are being treated with drugs known as tyrosine kinase inhibitors (TKIs). As with any other drug, oncologists who prescribe TKIs must be aware of other drugs a patient is taking to ensure there will not be a dangerous drug-drug interaction. Researchers recently published a report outlining known and potential drug-drug interactions between TKIs and other drugs. Oncologists and patients may wish to take these into account when considering cancer treatment with TKIs.

“With the rapid and widespread uptake of tyrosine kinase inhibitors (TKIs) in oncology over the past several years, serious drug–drug interactions are an “increasing risk,” according a new report.

“To guarantee the safe use of TKIs, ‘a drugs review for each patient is needed,’ write Frank G.A. Jansman, PharmD, PhD, from Deventer Hospital in the Netherlands, and colleagues in a review published in the July issue of the Lancet Oncology.

“The review provides a comprehensive overview of known and suspected interactions between TKIs and conventional prescribed drugs, over-the-counter drugs, and herbal medicines.

“All 15 TKIs approved to date by the US Food and Drug Administration or the European Medicines Agency are evaluated.

“They are axitinib (Inlyta, Pfizer), crizotinib (Xalkori, Pfizer), dasatinib (Sprycel, Bristol-Myers Squibb and Otsuka America), erlotinib (Tarceva, Osi Pharmaceuticals), gefitinib (Iressa, AstraZeneca), imatinib (Gleevec, Novartis), lapatinib (Tykerb, GlaxoSmithKline), nilotinib (Tasigna, Novartis), pazopanib (Votrient, GlaxoSmithKline), regorafenib (Stivarga, Bayer), ruxolitinib (Jakafi, Incyte), sorafenib (Nexavar, Bayer), sunitinib (Sutent, Pfizer), vandetanib (Caprelsa, AstraZeneca), and vemurafenib (Zelboraf, Roche).”


18F-FGD-PET Measures Predict mRCC TKI Response

“Positron emission tomography (PET) could be used to predict the response of metastatic renal cell carcinoma (mRCC) to tyrosine kinase inhibitor (TKI) therapy within a couple of weeks of a patient beginning treatment, research suggests.

“Changes in volume-based metabolic parameters of 18F-fluorodeoxyglucose (FDG) before and after 14 days of treatment with sunitinib, sorafenib or pazopanib significantly correlated with progression-free and overall survival, say Jacob Farnebo (Karokinska University Hospital, Stockholm, Sweden) and co-authors.”

Editor’s note: Doctors and patients can make more informed treatment decisions if they can more closely monitor how well a treatment is working and predict how well it is likely to work in the long run. This story discusses how monitoring with positron emission tomography (PET) within the first couple of weeks of treatment might help predict how well certain drugs will work. PET scanning produces 3-D images of the inside of the body. Scientists conducted a study in which they gave PET scans to volunteer patients who were being treated with the drugs sunitinib, sorafenib, or pazopanib for metastatic renal cell carcinoma (mRCC). They found that, within two weeks of the patients starting treatment, they could use information from the PET scans to determine the effectiveness of the treatment. They were able to link these PET scan results to how long the patients lived and how much time passed before patients’ disease worsened.


New EGFR Inhibitor AZD9291 Shows Promising Activity in Treatment-Resistant Non–Small Cell Lung Cancer

“Findings from a phase I study of a new mutant-selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, AZD9291, point to a promising new treatment option for patients with advanced, EGFR-mutant, non–small cell lung cancer (NSCLC) that is resistant to standard EGFR inhibitors. Roughly 50% of patients experienced tumor shrinkage, and the drug worked particularly well in patients with the T790M mutation (detected in 60% of patients), which causes the most common form of EGFR therapy resistance. The study was presented at a presscast in advance of the 2014 ASCO Annual Meeting (Abstract 8009^).”

Editor’s note: This story is about a new targeted therapy drug called AZD9291 that is designed to attack tumors with a mutation in the EGFR gene, as detected by molecular testing. In particular, it is designed for patients who are resistant to other so-called EGFR inhibitors as a result of developing a particular EGFR mutation known as T790M. In a clinical trial to test the drug in patients, it was found to show promising results for patients with advanced non-small cell lung cancer (NSCLC) with EGFR mutations, and even better results in patients with the T790M mutation.