A Faster Way to Try Many Drugs on Many Cancers

“Chemotherapy and radiation failed to thwart Erika Hurwitz’s rare cancer of white blood cells. So her doctors offered her another option, a drug for melanoma. The result was astonishing.

“Within four weeks, a red rash covering her body, so painful she had required a narcotic patch and the painkiller OxyContin, had vanished. Her cancer was undetectable.

“ ‘It has been a miracle drug,’ said Mrs. Hurwitz, 78, of Westchester County.

“She is part of a new national effort to try to treat cancer based not on what organ it started in, but on what mutations drive its growth.”


Scientist Study Skin Cancer Patients Resistant to Leading Therapy

“Powerful drugs known as BRAF-inhibitors have been crucial for melanoma patients, saving lives through their ability to turn off the BRAF protein’s power to spur cancer cell growth.

“Yet they often work for only a year or less. Scientists know some of the DNA mutations that cause the drug resistance, but scientists have not been able to determine the underlying cause of the resistance in as many as a third of these patients. As a result, identifying genomic-based follow-up therapies for these patients has been a challenge.

“Researchers at The University of Texas MD Anderson Cancer Center may have found a way to more accurately predict which patients will likely respond to genomic-based follow-up therapies, by looking at unique ‘protein patterns’ in melanoma patients.

” ‘There are patients whose DNA does not reveal how their melanomas became resistant to BRAF inhibitors,’ said Lawrence Kwong, Ph.D., instructor in Genomic Medicine at MD Anderson. ‘So we looked at patterns of changes in 150 proteins which can give clues to the causes of resistance, even when DNA sequencing data is uninformative.’ “


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 Drugs Aim to Defeat Tumor Resistance to EGFR Inhibitors


In recent years, many people with non-small cell lung cancer (NSCLC) have been successfully treated with drugs called EGFR inhibitors. But over time, most patients develop resistance, and the drugs stop working. Researchers are hard at work developing new drugs to help patients who can no longer be treated with EGFR inhibitors.

EGFR inhibitors get their name from a gene called EGFR. Many lung cancer tumors have mutations in this gene. These mutations convert EGFR from a normal gene into a cancer gene that initiates and promotes cancer growth. Approximately 10% to 15% of white and 30% to 35% of Asian patients with NSCLC have EGFR mutations. Continue reading…


Neoadjuvant HER-2–Targeted Breast Cancer Therapies Less Effective in Patients with PIK3CA Mutations

The gist: Women with HER2-positive breast cancer whose tumors also have a mutation called PIK3CA might not respond as well to HER2-targeted treatments. Scientists looked at tumor samples from patients who had taken the drugs trastuzumab (Herceptin) and/or lapatinib (Tykerb). They had also taken neoadjuvant (before surgery) chemotherapy. Patients whose tumors had PIK3CA mutations had a significantly lower rate of treatment success. These findings highlight the need for more research into PIK3CA-targeted therapy. They also echo findings from other researchers.

“Patients with HER-2–positive breast cancer who harbored activating mutations in PIK3CA were considerably less likely to achieve total pathologic complete response to neoadjuvant HER-2–targeted therapies than patients who did not have PIK3CA mutations, according to findings in the randomized, phase 3 NeoALTTO trial.

“PIK3CA activating mutations are present in all subtypes of breast cancer. However, they are enriched in HER-2–positive and ER-positive disease, according to study background.

“José Baselga, MD, PhD, physician-in-chief and chief medical officer at Memorial Sloan Kettering Cancer Center, and colleagues investigated whether an association existed between PIK3CA mutation status and patients’ response to HER-2–targeted therapy.”


Afatinib Works Best in Patients Whose Lung Cancer Has Specific Mutation in EGFR Gene

The gist: Afatinib (Gilotrif) works better than chemotherapy for people with non-small cell lung cancer (NSCLC) whose tumors have a specific mutation in the EGFR gene. This mutation is known as exon 19 deletion. In a recent clinical trial, some patients with exon 19 deletion were treated with Gilotrif and some with chemotherapy. The patients who received Gilotrif lived significantly longer than the patients who received chemotherapy. All patients had stage IIIB or IV lung adenocarcinoma.

“Patients with lung adenocarcinoma who harbored exon 19 deletion EGFR mutations experienced significantly longer OS when treated with first-line afatinib instead of chemotherapy, according to analyses of results from two phase 3 trials.

“However, researchers did not observe the survival benefit among patients with other types of EGFR mutations.

“ ‘These data provide important evidence about the use of afatinib in patients whose tumors have the del19 mutation and tell us that the standard treatments and approaches should no longer be assumed equivalent for every EGFR mutation,’ Lecia V. Sequist, MD, MPH, medical oncologist at Massachusetts General Hospital Cancer Center and associate professor of medicine at Harvard Medical School, said in a press release.”


Nivolumab Better than Chemotherapy in Untreated Melanoma

The gist: People with advanced melanoma who have not yet been treated might benefit from the drug nivolumab (Opdivo). In December, the U.S. Food and Drug Administration (FDA) approved Opdivo for people who had tried other treatments unsuccessfully. Now, a new clinical trial shows that patients without prior treatment survive longer on Opdivo than chemotherapy.

“The PD-1 inhibitor nivolumab significantly increased overall survival compared with chemotherapy in patients with previously untreated metastatic melanoma without a BRAF mutation. In addition, the drug more than doubled the progression-free survival among these patients.

“ ‘The risk of death decreased by 58% with nivolumab, as compared with dacarbazine, among previously untreated patients with advanced melanoma,’ wrote study author Caroline Robert, MD, PhD, of INSERM Unité 981, Gustave Roussy, and colleagues. ‘The survival benefit was consistent across all the prespecified subgroups, including patients with poor prognostic factors.’

“The results of the phase III double-blind study were published in the January 22 issue of the New England Journal of Medicine.”


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.”


BIND-014 Being Tested as Treatment for Advanced/Metastatic NSCLC That's Squamous or KRAS+

The gist: The first patient has been enrolled in a clinical trial testing the drug BIND-014 in patients with advanced or metastatic non-small cell lung cancer (NSCLC) that is squamous or has a mutation in the KRAS gene. An earlier clinical trial found promising results for these patients. BIND-014 is a new form of the chemotherapy drug docetaxel. It is meant to home in on cancer cells to deliver chemotherapy directly.

“BIND Therapeutics, Inc. (BIND), a clinical-stage nanomedicine platform company developing targeted and programmable therapeutics called Accurins™, today announced its 2015 strategic overview and enrollment of the first patient expressing a KRAS mutation in a global, multicenter two-tiered phase 2 trial with BIND-014 in non-small cell lung cancer (NSCLC) patients with KRAS mutant tumors (mutated Kirsten ras oncogene homolog) or squamous histology. The trial was driven by positive results from the phase 2 trial in NSCLC presented at the EORTC-NCI-AACR Annual Symposium in Barcelona on November 19, 2014, with a confirmed objective response rate of 22 percent (n=9); one KRAS mutant NSCLC PR was also seen in the phase 1 trial with BIND-014, yielding a combined total response rate of 30 percent (n=10). Results from the phase 2 trial also suggested meaningful differentiation in NSCLC patients with squamous histology when compared to historical docetaxel results. BIND-014 results presented at EORTC-NCI-AACR also demonstrated a disease control rate of 66 percent and overall survival of 11.1 months (n=9) in NSCLC patients with squamous histology. BIND intends to begin accruing NSCLC patients with squamous cell histology in the two-tier phase 2 trial in 1Q 2015.”