Everolimus Improves Progression-Free Survival for Patients with Advanced, Nonfuctional Neuroendocrine Tumors

“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.”


Two-Drug Combination Shows Promise Against One Type of Pancreatic Cancer

“One form of pancreatic cancer has a new enemy: a two-drug combination discovered by UF Health researchers that inhibits tumors and kills cancer cells in mouse models.

“For the first time, researchers have shown that a certain protein becomes overabundant in pancreatic neuroendocrine tumors, allowing them to thrive. They also found that pairing a  with an existing drug provides a more effective anticancer punch than a single drug. The findings were published recently in the Journal of the National Cancer Institute by a group that includes Rony A. François, an M.D./Ph.D. student working with Maria Zajac-Kaye, Ph.D., an associate professor in the UF College of Medicine’s department of anatomy and cell biology.

“Finding new treatments is critical because less than 5 percent of patients with pancreatic neuroendocrine tumors respond to everolimus, the most commonly used pharmaceutical, François said. Neuroendocrine tumors, which form in the hormone-making , account for 3 percent to 5 percent of pancreatic malignancies and have a five-year survival rate of about 42 percent, according to the National Cancer Institute. Pancreatic neuroendocrine tumors are increasingly common, which medical experts and researches have attributed to better diagnostic imaging, an aging population and heightened awareness of the disease stemming from the 2011 death of Apple Inc. co-founder Steve Jobs.”


Pancreatic Neuroendocrine Tumors: A Lesser Threat than Adenocarcinomas, but Still Hard to Treat


Pancreatic neuroendocrine tumors (PNETs) constitute only about 3% to 5% of all pancreatic cancers. Compared to the most common pancreatic cancer—adenocarcinoma (aka exocrine tumors), PNETs have a longer disease course and better prognosis; the 5-year survival rate is 42% for PNETs, but only about 5% to 6% for adenocarcinomas. When PNETs are localized, they can usually be removed by surgery. However, PNETs tend to metastasize, most often to the liver, and present a formidable treatment challenge at this stage. Continue reading…


Adding Everolimus to First-Line Trastuzumab-Paclitaxel Does Not Increase Progression-Free Survival in HER2-Positive Breast Cancer

“In the phase III BOLERO-1 trial, reported in The Lancet Oncology, Hurvitz et al found that the addition of the mTOR inhibitor everolimus (Afinitor) to trastuzumab (Herceptin)-paclitaxel did not significantly increase progression-free survival among patients with HER2-positive advanced breast cancer. A 7-month prolongation in progression-free survival was observed with everolimus among patients with hormone receptor–negative disease.”


Adding Everolimus Does Not Improve Trastuzumab/Paclitaxel Combo as Initial Treatment for HER2+, Advanced Breast Cancer

The gist: In a clinical trial, people with HER2-positive, advanced breast cancer did no better when given the three-drug combo trastuzumab + paclitaxel + everolimus as a first treatment than when given just trastuzumab + paclitaxel. A previous trial showed that everolimus + trastuzumab + vinorelbine could help patients overcome resistance to trastuzumab, but only if they had already been treated for their cancer. Researchers wondered whether adding everolimus would help prevent trastuzumab resistance.

“The addition of everolimus to weekly trastuzumab (Herceptin) plus paclitaxel did not improve outcomes in the phase III BOLERO-1/TRIO-019, but did provide a “signal” in the hormone receptor–negative subset. The study was reported at the 2014 San Antonio Breast Cancer Symposium by Sara A. Hurvitz, MD, of the University of California, Los Angeles (Abstract S6-01).

“ ‘Trastuzumab has dramatically improved outcomes for patients, however, it’s not a win for everyone. Resistance to treatment remains a clinically unmet challenge,’ she said at a press briefing. One means of counteracting resistance could be to add a drug that would inhibit the mTOR pathway in early metastatic disease, according to Dr. Hurvitz.

“In the previously reported BOLERO-3 trial, everolimus added to trastuzumab and vinorelbine did significantly improve progression-free survival for patients with trastuzumab-resistant previously treated cancer.

“ ‘We were interested in evaluating whether inhibiting mTOR early in metastatic disease will help delay the development of resistance to HER2-targeted therapy,’ she said.”


Everolimus–Exemestane Combination Failed to Significantly Extend OS in Advanced Breast Cancer

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.”


Everolimus Plus Exemestane Extended PFS in Invasive Lobular Carcinoma

The gist: This article discusses the results of a clinical trial—a research study with volunteer patients. The trial tested a new treatment for patients with advanced, HR-positive, HER-2-negative invasive lobular carcinoma. The new treatment combines the drugs everolimus and exemestane. The researchers found that it significantly prolonged the amount of time patients lived without their cancer worsening.

“The addition of everolimus to exemestane significantly prolonged PFS in a subset of patients with HR-positive, HER-2–negative advanced breast cancer who had invasive lobular carcinoma at baseline, according to a subanalysis of the BOLERO-2 trial presented at the Breast Cancer Symposium.

“Gabriel N. Hortobagyi, MD, FACP, professor of medicine in the department of breast medical oncology at The University of Texas MD Anderson Cancer Center, and colleagues evaluated data from 104 patients with invasive lobular carcinoma. The cohort included patients with predominantly peritoneal, gastrointestinal and ovarian metastases.

“Patients received exemestane (Aromasin, Pfizer) with everolimus (Afinitor, Novartis; n=64) or placebo (n=40).

“The median age of the patients was 63 years, and 47.1% had measurable disease. Thirty-six percent of patients had visceral metastases of the lung, liver, pleural and peritoneum; 10% had lung metastases; and 23% had liver metastases.”


Lpath Reports Interim Data From Phase 2a Study for Anti-Cancer Drug, ASONEP

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.”


Sunitinib or Everolimus First-Line for Kidney Cancer?

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.”