“Neuroendocrine tumours (NETs) develop in the neuroendocrine system, responsible for producing the hormones that regulate the working of different organs in the body. They are rare, incurable, and treatments for them are limited, especially once they have become advanced. Now an international team of researchers has shown that the use of the mTOR inhibitor, everolimus, can delay tumour growth among both gastrointestinal and lung NETs. This is particularly important for patients with the lung tumours, the researchers say, because there is currently no approved treatment for such cases.
“Reporting on the results of the RADIANT-4 trial, a placebo-controlled, double-blind, phase III study carried out in centres in 13 European countries, Korea, Japan, Canada, and the US, Professor James Yao, MD, Chair of the Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA, will tell the 2015 European Cancer Congress today (Sunday) that the treatment had a significant effect in non-functional NETs. Non-functional NETs either do not secret a hormone, or secrete one that does not cause symptoms, and are therefore often diagnosed later when the cancer has become advanced. ‘About 80% of all NETs are thought to be non-functional, so, unfortunately, late diagnosis is common and poses a major problem for these patients,’ he will say.”
“In an international Phase III randomized study, everolimus, an inhibitor of the mammalian target of rapamycin (mTOR), has shown to dramatically improve progression-free survival for patients with advanced, nonfunctional neuroendocrine tumors (NET) of the lung and gastrointestinal tract.
“James C. Yao, M.D., professor and chair, The University of Texas MD Anderson Cancer Center’s Department of Gastrointestinal Medical Oncology, presented the findings today in Vienna, Austria during the presidential session of the European Cancer Congress, co-sponsored by the European Cancer Organisation and European Society for Medical Oncology.
“NETs develop from cells in the neuroendocrine system, which is responsible for producing specific hormones that regulate the functions of different organs in the body. NETs can be slow-growing or aggressive, and are found most commonly in the lungs or gastrointestinal system. Nonfuctional NETs are those that do not secrete a hormone. About 80 percent of all NETs are nonfunctional, and therefore, patients often have few side effects and are diagnosed later, explains Yao.”
“The dual mTOR inhibitor AZD2014, when combined with the hormonal therapy fulvestrant (Faslodex), was found to be safe in patients with advanced estrogen receptor–positive breast cancer, and some of them experienced clinical benefit from the drug combination, according to phase I clinical trial data presented at the AACR Annual Meeting 2015, April 18 to 22 in Philadelphia (Abstract CT233).
“ ‘Patients with estrogen receptor–positive breast cancer respond to hormonal therapy, but over time, some eventually develop resistance to treatment. Their tumors become dependent on a cell-signaling pathway called the mTOR pathway for survival,’ said Manish R. Patel, MD, Associate Director of Drug Development for Sarah Cannon Research Institute and Director of Drug Development at the Florida Cancer Specialists and Research Institute.
“ ‘We are testing whether combining the hormonal therapy fulvestrant with the dual mTOR inhibitor AZD2014 can help overcome this resistance. AZD2014 is a new anticancer therapy and represents a potential improvement compared with other drugs that have similar mechanisms of action,’ Dr. Patel added.
“ ‘In this trial, we tested two dosing schedules of AZD2014: continuous dosing, in which the drug is given every day, and intermittent dosing, in which the drug is given only 2 days of each week,’ Dr. Patel explained. ‘We compared the side-effect profiles of the two dosing schedules. The response of individual patients to treatment was also monitored.’ “
The gist: A clinical trial with volunteer patients tested a treatment for postmenopausal women with HR-positive, HER-2–negative advanced breast cancer. The treatment combines the drugs everolimus and exemestane. The clinical trial compared it to exemestane alone. The combination did NOT appear to give longer overall survival rates than exemestane alone.
“The addition of everolimus to exemestane extended OS in postmenopausal women with HR-positive, HER-2–negative advanced breast cancer, but the difference was not statistically significant, according to results of the BOLERO-2 study.
“BOLERO-2 is a randomized phase 3, double blind, international trial.
“Prior results showed the addition of 10 mg daily everolimus (Afinitor, Novartis) — an inhibitor of mammalian target of rapamycin (mTOR) — to 25 mg daily exemestane significantly extended PFS compared with exemestane alone (7.8 months vs. 3.2 months; P<.001).
“In the current study, Martine Piccart, MD, PhD, professor of oncology at the Université Libre de Bruxelles in Belgium and director of medicine at Institut Jules Bordet, and colleagues presented OS outcomes as part of a prospectively planned secondary-endpoint analysis.
“Results showed patients assigned the combination demonstrated longer median OS (31 months vs. 26.6 months; HR=0.89; 95% CI, 0.73-1.1), but the difference was not statistically significant.
“ ‘Ongoing translational research should further refine the benefit of mTOR inhibition and related pathways in this treatment setting,’ Piccart and colleagues wrote.”
The gist: Two new targeted treatment approaches are showing promise for some lung cancer patients. Researchers are testing the targeted drug dabrafenib in a clinical trial—a research study with volunteer patients. Dabrafenib is meant to treat certain people who have already been treated for advanced non-small cell lung cancer (NSCLC) but who need additional treatment. The patients who participated in the trial had a tumor mutation called BRAF V600E. The study results supported dabrafenib as an effective treatment for these patients. In another clinical trial, researchers found that a combination of the drugs temsirolimus and neratinib had beneficial effects for people with advanced non-small cell lung cancer (NSCLC) whose tumors had mutations in the HER2 gene.
“The BRAF inhibitor dabrafenib has significant anti-tumour activity in patients with advanced BRAF V600E mutant non-small cell lung cancer whose disease has progressed after chemotherapy, according to phase II data presented at the ESMO 2014 Congress in Madrid, Spain.
” ‘Reports of lung cancers bearing mutations in BRAF have generated considerable interest because these mutations may be associated with increased sensitivity to BRAF tyrosine-kinase inhibiting agents,’ says lead author Dr David Planchard, pulmonary oncologist at the Gustav-Roussy Cancer Campus, Paris, France.
“Planchard says studies suggest that activating BRAF mutations are present in around 2% of lung carcinomas — approximately 80% of which are V600E mutations. The BRAF V600E mutations are frequently associated with shorter disease-free, overall survival, and lower response rates to platinum-based chemotherapy.
“This open-label phase II study involves patients with BRAF V600E mutant non-small cell lung cancer, treated with dabrafenib alone (150 mg, twice daily). The primary endpoint is investigator-assessed overall response rate, with secondary endpoints of progression-free survival, duration of response, overall survival, safety and tolerability, and population pharmacokinetics.”
Editor’s note: Researchers are conducting a clinical trial with volunteer patients to test a new kidney cancer treatment called ASONEP. Specifically, the trial is testing the effectiveness of ASONEP for people with metastatic renal cell carcinoma (RCC) who were previously but unsuccessfully treated with at least one “VEGF inhibitor” drug (like Sutent, aka sunitinib) and no more than one “mTOR inhibitor” drug (like Afinitor, aka everolimus), with a maximum of three unsuccessful previous treatments overall. The clinical trial is ongoing, but interim results show that ASONEP is safe and hasn’t caused serious side effects. The researchers also said the drug appeared to show promise as a cancer-fighting treatment.
“Lpath, Inc. (NASDAQ: LPTN), the industry leader in bioactive lipid-targeted therapeutics, reported interim results in a Phase 2a single-arm, open-label trial where ASONEP™ is being investigated as a treatment for metastatic renal cell carcinoma (RCC) in patients that have failed at least one therapy involving a VEGF inhibitor (e.g., Sutent®/ sunitinib maleate) and no more than one mTOR inhibitor (e.g., Afinitor®/everolimus), with a maximum of three failed treatments in all. This patient population is considered “last line,” and the literature suggests cancer progression in this population within a one-to-two month time frame.
“Lpath has enrolled 26 patients in the study. ASONEP has a favorable safety profile thus far, with no serious adverse events (SAEs) deemed to be drug-related.
“The first 17 patients were initiated at a dose of 15 mg/kg. Of these “lower-dose” patients: 7 had progressive disease at or before the end of four months; 8 were progression-free at the four-month mark (with 1 of these patients deemed a partial responder per Response Evaluation Criteria in Solid Tumors (RECIST) criteria and with 3 of these patients experiencing reduced tumor volume, but not enough to be categorized as a RECIST-based partial responder); and 2 exited the study due to SAEs unrelated to the drug prior to the four-month mark (and are not considered evaluable). Notably, of the 8 patients that were stable or better as of month four, 2 are now in their fifteenth month on the study, 1 is in month thirteen, and 1 is in month ten. An additional patient was stable through month seven, but then missed six treatments during a vacation, and shortly thereafter progressed.”
Editor’s note: Researchers conducted a clinical trial with volunteer patients to compare two drugs for kidney cancer: everolimus (aka Afinitor) and sunitinib (aka Sutent). The results showed that sunitinib is more effective as a first-line treatment for people diagnosed with metastatic renal cell carcinoma (mRCC). The standard treatment already widely prescribed to mRCC patients is sunitinib or a similar drug, followed by everolimus if the disease worsens. Oncologists wondered if everolimus could be a first-line therapy for mRCC, but it appears that the current standard is the better choice.
“Everolimus (Afinitor, Novartis) is not as effective as sunitinib (Sutent, Pfizer) in the first-line setting for patients with metastatic renal cell carcinoma, and it has a different toxicity profile, according to a phase 2 randomized direct comparator trial.
“The study, known as RECORD-3, was published online July 21 in the Journal of Clinical Oncology.
” ‘The hope was that everolimus would be better tolerated and as good as sunitinib in first-line treatment,’ said lead investigator Robert Motzer, MD, attending physician in the genitourinary oncology service at the Memorial Sloan Kettering Cancer Center and professor of medicine at Weill Medical College at Cornell University in New York City.
“However, ‘in first-line therapy, the efficacy of sunitinib appeared to be better than everolimus. It is clear that sunitinib remains the standard first-line therapy,’ he explained.
” ‘The current paradigm of sunitinib followed by everolimus at progression should be maintained. The experimental sequence of everolimus first followed by sunitinib second did not appear to be as effective,’ Dr. Motzer reported.”
“Only 15% of patients with squamous cell lung cancer – the second most common lung cancer – survive five years past diagnosis. Little is understood about how the deadly disease arises, preventing development of targeted therapies that could serve as a second line of defense once standard chemotherapy regimens fail.
“Published online in Cell Reports on June 19, Huntsman Cancer Institute investigators report that misregulation of two genes, sox2 and lkb1, drives squamous cell lung cancer in mice. The discovery uncovers new treatment strategies, and provides a clinically relevant mouse model in which to test them.”
Editor’s note: Some tumors have specific genetic mutations that can allow them to be treated with drugs known as targeted therapies. Studying mice with squamous cell lung cancer tumors, scientists have now discovered two new tumor mutations that open up the possibility for new drugs to be developed for humans. The mutations also indicate that some drugs that already exist for other cancers may be used to treat people with squamous cell lung cancer. More investigation is required before the results of these findings might translate to treatments for patients.
Kirkpatricka DS, Bustosa DJ, Doganb T, Chanb J, et al. PNAS. Nov 11, 2013.
“Growing evidence suggests that successful intervention in many human cancers will require combinations of therapeutic agents. Critical to this effort will be a detailed understanding of the crosstalk between signaling networks that modulate proliferation, cell death, drug sensitivity, and acquired resistance. Here we investigated DNA-damage signaling elicited by small-molecule inhibitors against MAP/ERK kinase (MEK) and PI3K in melanoma cells. This work, performed using cutting-edge mass spectrometry proteomics, uncovered a burst of signaling among proteins in the DNA-damage pathway upon initiation of the cell-death program by agents targeting the RAS–RAF–MEK and PI3K–AKT–mTOR pathways. These signals may prove important to the short- and long-term sensitivity of tumor cells to MEK- and PI3K-targeted therapies.”