Alectinib Promising in ALK-Positive Advanced NSCLC

“The ALK and RET inhibitor alectinib yielded good response rates and was very well tolerated in a phase II trial of patients with advanced, ALK-positive non–small-cell lung cancer (NSCLC; abstract 8008). Results were presented at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting, held May 29 to June 2, in Chicago.

“Crizotinib is currently the standard-of-care for advanced, treatment-naive ALK-positive NSCLC. ‘However, the median progression-free survival (PFS) for these patients on crizotinib is under 12 months,’ said Sai-Hong Ignatius Ou, MD, PhD, of the UC Irvine Medical Center in California. ‘This is in part due to development of ALK mutations that are resistant to crizotinib.’

“Alectinib is a next-generation inhibitor that is highly selective for ALK and RET; as an ALK inhibitor, Ou said, it is approximately five times as potent as crizotinib. It can inhibit the majority of clinically relevant acquired ALK mutations.”


New Guideline Will Expand List of Lung Cancer Molecular Tests Doctors Can Use to Help Make Treatment Decisions

The gist: A new guideline will expand the list of tumor abnormalities that doctors can test for to help their lung cancer patients make treatment decisions. Different drugs have been developed to treat patients with different tumor abnormalities, such as mutations in the ALK and EGFR genes. Molecular testing lets doctors see which abnormalities a patient might have, and suggest the best-fitting treatments. The new guidelines will include recommendations for molecular testing of abnormalities in the  ROS1, MET, ERBB2, RET, NTRK1, ALK, and EGFR genes.

“The College of American Pathologists (CAP), the International Association for the Study of Lung Cancer (IASLC), and the Association for Molecular Pathology (AMP) are teaming to revise the evidence-based guideline, “Molecular Testing Guideline for Selection of Lung Cancer Patients for EGFR and ALK Tyrosine Kinase Inhibitors.”

“The updated guideline will include new recommendations for ALK testing by IHC, ALK-EGFR resistance, and a number of emerging target molecular targets which will include, but is not limited to, ROS1, MET, ERBB2, RET, NTRK1. Multiplexed “Next Generation Sequencing” multigene panels and the reassessment of immunohistochemistry will be reviewed. The role of rebiopsy and repeat analysis in the setting of post-treatment relapse, along with testing of blood samples for mutations in circulating tumor cells, cell free tumor DNA, or exosomes will be considered.

“The revision of the guideline will again be based on evidence from unbiased review of published experimental literature. The revisions will be recommended by an expert panel made up of renowned worldwide leaders in the field. The revision will start in early 2015, taking around 18 months to complete.

” ‘Although only one year has passed since the molecular testing guideline was published, rapid accumulation of scientific knowledge and new evidence in this field indicate that the guidelines should be updated. Thus, an update has begun that includes an expanded list of genes and new methods that are clinically relevant,’ said Yasushi Yatabe, MD, PhD, chief, Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, Nagoya, Japan and IASLC member.”


Novel Oncogenic RET Mutation Found in Small Cell Lung Cancer

Editor’s note: An oncologist will sometimes test a patient’s tumor for specific mutations in order to decide what the best treatment options are. Tumors that have certain mutations can sometimes be treated with certain so-called targeted therapy drugs. This approach has worked well for many people with non-small cell lung cancer (NSCLC). However, there are no FDA-approved targeted therapies for small cell lung cancer (SCLC). A new discovery might change that. Researchers found a mutation called RET M918T in a metastatic SCLC tumor. Two targeted drugs were found to fight against tumor cells with the mutation in the lab. The drugs—ponatinib and vandetanib—are already FDA-approved to treat other types of cancer.

“For the first time, an oncogenic somatic mutation at amino acid 918 in the rearranged during transfection protein has been identified in small cell lung cancer tumors and enforced expression of this mutation within small cell lung cancer tumor cell lines produced increased intracellular signaling and cell growth.

“SCLC is a highly malignant form of lung cancer representing 15% of all lung cancers and is strongly associated with tobacco smoking. NSCLC, representing 85% of lung cancer, has been extensively examined for genomic alterations and targeted therapies are approved for patients with certain mutations, however SCLC has not been examined with the same rigor and there are no approved targeted therapies for SCLC.

“Investigators at Case Western University examined 6 SCLC tumors, 3 each from primary and metastatic tumors, for 238 somatic mutations across 19 oncogenes. RET wild type and mutant protein was then overexpressed in SCLC cell lines and these cell lines were examined for cell signaling, cell growth and responsiveness to two tyrosine kinase inhibitors of RET.”


Inflammatory Monocytes are Potent Antitumor Effectors Controlled by Regulatory CD4+ T cells

“The present study evaluates the impact of immune cell populations on metastatic development in a model of spontaneous melanoma [mice expressing the human RET oncogene under the control of the metallothionein promoter (MT/ret mice)]. In this model, cancer cells disseminate early but remain dormant for several weeks. Then, MT/ret mice develop cutaneous metastases and, finally, distant metastases. A total of 35% of MT/ret mice develop a vitiligo, a skin depigmentation attributable to the lysis of normal melanocytes, associated with a delay in tumor progression. Here, we find that regulatory CD4+ T cells accumulate in the skin, the spleen, and tumor-draining lymph nodes of MT/ret mice not developing vitiligo. Regulatory T-cell depletion and IL-10 neutralization led to increased occurrence of vitiligo that correlated with a decreased incidence of melanoma metastases. In contrast, inflammatory monocytes/dendritic cells accumulate in the skin of MT/ret mice with active vitiligo. Moreover, they inhibit tumor cell proliferation in vitro through a reactive oxygen species-dependent mechanism, and both their depletion and reactive oxygen species neutralization in vivo increased tumor cell dissemination. Altogether, our data suggest that regulatory CD4+ T cells favor tumor progression, in part, by inhibiting recruitment and/or differentiation of inflammatory monocytes in the skin.”


Response to Cabozantinib in Patients with RET Fusion-Positive Lung Adenocarcinomas

We report preliminary data for the first three patients treated with the RET inhibitor cabozantinib on a prospective phase II trial for patients with RET fusion-positive NSCLCs (NCT01639508). Confirmed partial responses were observed in 2 patients, including one harboring a novel TRIM33RET fusion. A third patient with a KIF5BRET fusion has had prolonged stable disease approaching 8 months (31 weeks). All three patients remain progression-free on treatment.

This report of the activity of cabozantinib in RET fusion-positive disease provides early clinical validation of RET fusions as drivers in lung cancers and suggests that RET inhibition may represent a new treatment paradigm in this molecular cohort.


RET Mutations May Emerge as New Target for Lung Cancer Treatments

A certain type of mutation in a protein, called RET, occurs in a significant subset of lung cancer patients, a recent study shows. Known as ‘rearrangements,’ these mutations fuse the RET gene with other nearby genes, resulting in a RET protein that contains parts of other proteins and is hyperactive. Patients with similar rearrangement mutations in another gene, ALK, can experience drastic improvements from treatment with ALK inhibitors such as crizotinib (Xalkori). This raises the hope that patients with RET rearrangement mutations may be similarly helped by drugs that block RET–either novel RET inhibitors or existing tyrosine kinase inhibitors (TKIs), such as vandetanib (Caprelsa), sunitinib (Sutent), sorafenib (Nexavar), or ponatinib (Iclusig). Identifying patients who may benefit from such treatments would be made easier by the new test for RET mutations developed by the study’s authors. When examining a group of patients with lung adenocarcinoma, a type of non-small cell lung cancer (NSCLC), who did not have mutations in other cancer-relevant genes, the researchers found that 15% had RET rearrangement mutations.


Iclusig Inhibits Mutant Proteins Found in Lung Cancer

The leukemia drug ponatinib (Iclusig) also appears to target mutant versions of two proteins involved in non-small cell lung cancer (NSCLC). This is supported by two recent studies in which Iclusig slowed the growth of cells with mutant RET and FGFR proteins. The drug also shrank tumors with RET mutations that had been grown in mice. Based on these findings, Iclusig manufacturer ARIAD Pharmaceuticals is planning a phase II clinical trial to investigate the drug’s effectiveness against NSCLC with RET mutations. A phase II trial assessing Iclusig’s effects in squamous cell carcinoma (SCC) of the lung with FGFR mutations is already underway at the Dana-Farber Cancer Institute, Boston, Massachusetts, and is currently enrolling participants.


New Drug May Be Effective for Lung Cancer Patients with RET Mutations

Some patients with non-small cell lung cancer (NSCLC) have tumor mutations called “RET fusions.” RET fusions are especially common in patients who have adenocarcinoma, never smoked, and/or have no mutations in other genes commonly associated with NSCLC. In an ongoing phase II clinical trial, three patients with adenocarcinoma and RET fusions appeared to respond well to the drug cabozantinib (Cometriq). The tumors of two of the patients shrank during Cometriq treatment, while the third experienced stable disease. Further studies are needed, but these results suggest that Cometriq may be an effective treatment for NSCLC patients with RET fusions.

Research paper: http://cancerdiscovery.aacrjournals.org/content/early/2013/03/23/2159-8290.CD-13-0035.abstract


Response to Cabozantinib in Patients with RET Fusion-Positive Lung Adenocarcinomas

The discovery of RET fusions in lung cancers has uncovered a new therapeutic target for patients whose tumors harbor these changes. In an unselected population of non-small cell lung cancers (NSCLCs), RET fusions are present in 1-2% of cases. This incidence rises substantially, however, in never-smokers with lung adenocarcinomas that lack other known driver oncogenes. While pre-clinical data provide experimental support for the use of RET inhibitors in the treatment of RET fusion-positive tumors, clinical data on response are lacking. We report preliminary data for the first three patients treated with the RET inhibitor cabozantinib on a prospective phase 2 trial for patients with RET fusion-positive NSCLCs (NCT01639508)…”