Pfizer Presents Promising Data from Next Generation ALK/ROS1 Inhibitor in Advanced Non-Small Cell Lung Cancer

Excerpt:

“Pfizer Inc. (NYSE:PFE) today announced encouraging new data from a Phase 1/2 study of lorlatinib, the proposed generic name for PF-06463922, Pfizer’s investigational, next-generation ALK/ROS1 tyrosine kinase inhibitor. The study showed clinical response in patients with ALK-positive or ROS1-positive advanced non-small cell lung cancer (NSCLC), including patients with brain metastases. These data were presented today in an oral presentation at the 52nd Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago.

“The results presented are from the dose escalation component of an ongoing Phase 1 study of patients with ALK-positive or ROS1-positive NSCLC, with or without brain metastases, who were treatment-naïve or had disease progression after at least one prior tyrosine kinase inhibitor (TKI). Among patients with ALK-positive metastatic NSCLC, the overall response rate (ORR) with lorlatinib was 46 percent, with three patients achieving complete responses and 16 patients achieving a partial response (95% CI: 31-63). The median progression free survival (PFS) was 11.4 months (95% CI: 3.4 – 16.6). The majority of patients had received two or more prior ALK TKIs. Additionally, lorlatinib showed the ability to decrease the size of brain metastases in patients with ALK-positive or ROS1-positive metastatic NSCLC.”

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ARIAD Presents Long-Term Phase 1/2 Trial Follow up on Investigational Drug Brigatinib with Median Time on Treatment of 17 Months in ALK+ NSCLC Patients

Excerpt:

ARIAD Pharmaceuticals, Inc.(NASDAQ:ARIA) today announced updated clinical data on its investigational tyrosine kinase inhibitor (TKI), brigatinib, in patients with anaplastic lymphoma kinase-positive (ALK+) advanced non-small cell lung cancer (NSCLC) from an ongoing Phase 1/2 trial. The current results include more mature efficacy and safety data for brigatinib, including updated response rates and median duration of response in ALK+ NSCLC patients.

“The updated Phase 1/2 results are being presented today at the 2016 American Society of Clinical Oncology (ASCO) annual meeting in Chicago.”

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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).”


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).”


Clovis Completes Rociletinib NDA for EGFR T790M-positive NSCLC

“A new drug application (NDA) has been submitted for rociletinib (CO-1686) as a treatment for patients with EGFR T790M-positive metastatic non–small cell lung cancer (NSCLC) following prior administration of an EGFR TKI, according to a statement from the drug’s developer, Clovis Oncology.

“The NDA was preceded by a breakthrough therapy designation for the potent mutant-selective EGFR inhibitor in May 2014. The application was based on findings from the ongoing phase I/II TIGER-X trial, which were published in The New England Journal of Medicine and updated at the 2015 ASCO Annual Meeting. In patients with T790M-mutant NSCLC by tissue testing (n = 243), the objective response rate (ORR) across all dose levels was 53% and the disease control rate (DCR) was 85%.

“An application for premarket approval (PMA) is anticipated for Qiagen’s therascreen EGFR RGQ PCR Kit as a companion diagnostic (CDx) for rociletinib, according to the statement. The therascreen EGFR test was initially approved in 2013 as a CDx for afatinib (Gilotrif) and recently received a new indication as a CDx for gefitinib (Iressa).”


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.’ “


Multiple Types of Resistance to New Lung Cancer Drug Identified

“After identifying three different types of resistance to a promising investigational lung cancer drug in a phase 1 trial, a team of researchers led by Dana-Farber Cancer Institute scientists say new targeted inhibitors and combinations are urgently needed to stay ahead of tumors’ constant and varied molecular shape-shifting.

“The researchers, including scientists from pharmaceutical company AstraZeneca, report in an advanced online publication in Nature Medicine on May 4, that their findings indicate ‘an underappreciated genomic heterogeneity’ in mechanisms of resistance to tyrosine kinase inhibitor (TKI) drugs that target the Epidermal Growth Factor Receptor (EGFR) mutation that drive some cases of non-small cell lung cancer (NSCLC).

” ‘If resistance that is this complex is constantly evolving before us, it may mean we need multiple targeted therapies in combination to stay ahead of the resistant cancer,’ said Geoffrey Oxnard, MD, a thoracic oncologist and lung cancer researcher at Dana-Farber and senior author of the report.”


Not All EGFR Mutations Are the Same When It Comes to Therapy for Non-Small Cell Lung Cancer

The gist: Different mutations in the EGFR gene in tumor cells can help guide which drugs will work best to treat non-small cell lung cancer (NSCLC). But according to a recent study, certain rare EGFR mutations need some more attention. Targeted drugs for EGFR-mutated NSCLC are meant for the more common EGFR mutations known as “Exon 19” and “Exon 21.” But some people have rarer EGFR mutations. Recent research shows that some of these rarer mutations respond well to EGFR-targeted drugs, but some do not. The authors of the study say that it is important to identify the particular EGFR mutation for each patient, in order to better predict how to treat them.

“Certain rare epidermal growth factor receptor (EGFR) mutations are associated with tobacco smoking, worse prognosis and poor response to EGFR tyrosine kinase inhibitor (TKI) therapy compared to the more common ‘classical’ EGFR mutations. However, as not all rare mutations are the same, testing and therapy may need to be evaluated for each individual mutation.

“Lung cancer is the leading cause of cancer mortality in the world with nearly 1.4 million deaths each year. Mutations within the EGFR gene lead to an oncogenic EGFR protein which can be turned off with EGFR TKIs. These alterations with EGFR are the most frequently therapeutically-targeted genomic alterations in NSCLC. Deletions within Exon 19 or a point mutation in Exon 21 are the common predictive of response to EGFR TKI therapy and the ones most often and sometimes exclusively tested for. However, less common EGFR mutations exist and some, for example G719x and L861Q, appear sensitive to TKI therapy…

“Balazs Dome and Balazs Hegedus, co-senior authors for the study, state ‘our study clearly demonstrates that rare and classic EGFR mutations show distinct epidemiological features and have different impacts on disease outcome and TKI therapy response. Based on our findings we conclude that the determination of the sensitizing status of each particular rare EGFR mutation has clinical relevance and important implications for TKI therapy. Of note, response and progression-free survival data will be available for 21 EGFR TKI-treated patients with rare mutations in the online supplement of our study. All in all, the molecular screening methods should extend beyond the identification of classic EGFR mutations in order to prevent the exclusion of patients who may benefit from anti-EGFR therapy.’ ”


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.’ “