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.”
Note: This article describes research that was done in a laboratory setting, and not in people. However, the drug combination (ganetespib plus hormone therapy) is being tested in patients in clinical trials.
“US researchers have found that combining conventional hormone therapy with an experimental cancer drug helped overcome drug resistance in breast cancer cells in the lab.
“The research focused on a molecular ‘Sherpa’ that helps cells adapt to stressful environments, known as heat-shock protein 90 (HSP90)…
“Trials of ganetespib in combination with hormone therapy are now underway in the US, and the researchers are hoping to see results within the next few years.”
“Clinical trials to test the new drugs in patients should begin as early as 2015.
“Existing drugs target faulty versions of a protein called BRAF which drives about half of all melanomas, but while initially very effective, the cancers almost always become resistant to treatment within a year.
“The new drugs – called panRAF inhibitors – could be effective in patients with melanoma who have developed resistance to BRAF inhibitors.
“The new study was funded by the Wellcome Trust and Cancer Research UK, and jointly led by scientists at The Institute of Cancer Research, London, and the Cancer Research UK Manchester Institute.
“It is published in the prestigious journal Cancer Cell today.
“The researchers showed that the new drugs – provisionally named CCT196969 and CCT241161 – stopped the growth of BRAF-driven melanomas, including those that had stopped responding to currently available BRAF-targeted drugs.”
The gist: Drugs called gamma secretase inhibitors (GSI) are being explored as a potential way to overcome resistance to endocrine therapy drugs (like tamoxifen or letrozole) for women with estrogen-receptor-positive (ER+) breast cancer. A GSI drug called MK-0752 was recently given to patients in a clinical trial. The researchers found 18 tumor genes that could be used to predict how well GSI might work for a given patient. A larger study will explore the gene “signature” and measure just how effective GSI drugs are for breast cancer patients.
“Loyola researchers and collaborators have reported promising results from a novel therapeutic approach for women with estrogen-receptor-positive breast cancer.
“The new approach, a new drug class called gamma secretase inhibitors (GSI), specifically inhibits Notch and shuts down critical genes and cancer cells responsible for tumor growth.
“Kathy Albain, MD, FACP, who led the study, will present findings Dec. 11 during the 2014 San Antonio Breast Cancer Symposium.
“Existing cancer drugs are effective in killing mature breast cancer cells. But a handful of immature breast cancer stem cells are resistant to such drugs. They survive and are responsible for tumor growth and progression. Resistance to standard therapy is a major cause of death in women with estrogen-receptor-positive breast cancer. Approximately 75 percent of breast cancers are estrogen-receptor positive…
“Researchers are planning a larger, phase II study to evaluate the efficacy of the GSI class of drugs added to endocrine therapy versus endocrine therapy alone. This study also will determine how well the 18 gene “signature” will predict who responds to therapy.
” ‘This is an exciting new strategy to overcome resistance to a very common class of drugs (tamoxifen, letrozole), so it is our hope that in the future a vast number of patients with estrogen-receptor-positive breast cancer could benefit,’ Dr. Albain said.”
The gist: People with non-small cell lung cancer (NSCLC) that has both the EGFR and T790M mutations might benefit from a new drug. The drug is called ASP8273. A clinical trial tested ASP8273 in volunteer patients in Japan. In the trial, it shrank people’s tumors. More research is needed, but it is hoped that the drug might be a good alternative for people whose tumors are resistant to drugs like erlotinib, gefitinib and afatinib.
“In a second presentation looking at new ways of treating non-small cell lung cancer (NSCLC) that has both the EGFR and T790M mutations, researchers will tell the 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Barcelona, Spain, that an oral drug called ASP8273 has caused tumour shrinkage in patients in a phase I clinical trial in Japan.
“Mutations of the epidermal growth factor (EGFR) occur in about 30-35% of Asian patients with NSCLC (and in 10-15% of Caucasian patients). EGFR inhibitors called tyrosine kinase inhibitors (TKI), such as erlotinib, gefitinib and afatinib, can be used to treat EGFR-mutated NSCLC. However, these patients will eventually develop resistance to EGFR TKI therapy, rendering their disease resistant to current treatments. A further mutation called T790M accounts for 60% of this acquired resistance.
“ASP8273 is a new drug that inhibits the EGFR mutation and the T790M resistance mutation. Earlier research in mice had shown that it caused NSCLC to disappear completely, and so a phase I clinical trial was started in January 2014 to assess the drug’s safety and efficacy in humans.
“Twenty-four Japanese patients have enrolled so far to receive one of six levels of doses (25, 50, 100, 200, 400 and 600mg) once a day. A further seven patients have been enrolled into a second group to evaluate doses of 100mg, 200mg and 400mg a day (a dose escalation study), and the researchers are planning to enrol a total of 124 patients. Cancer had progressed in all the patients after prior treatment with EGFR TKI therapy, and most of them had the T790M mutation.”
The gist: A drug called galeterone might help lower PSA levels in certain men with castration-resistant prostate cancer (CRPC). A clinical trial recently tested the treatment in volunteer patients.
“Results from a trial of the anti-cancer drug galeterone show that it is successful in lowering prostate-specific antigen (PSA) levels in men with a form of prostate cancer that is resistant to treatment with hormone therapy (castration-resistant prostate cancer or CRPC).
“Associate professor Mary-Ellen Taplin, of the Dana-Farber Cancer Institute, Boston, USA, will tell the 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Barcelona, Spain, today (Wednesday) that galeterone was well tolerated by patients in the ARMOR2 trial, and also lowered PSA levels in a subset of men with CRPC that was resistant to other drugs that target the cancer, such as enzalutamide and abiraterone.
” ‘Recent data have shown that a variant of the androgen receptor called AR-V7, found in tumour cells circulating in the blood of patients with metastatic CRPC, predicted resistance to treatment with enzalutamide and abiraterone,’ she will say. ‘Indeed, we believe AR-V7 and other, related variants are a mechanism of resistance in this disease and patients who have them may have a poorer prognosis.’ ”
The gist: A drug called XL888 has shown promise for people with unresectable stage III/IV BRAF V600 mutation-positive melanoma. It was tested in a clinical trial with volunteer patients. It is hoped that XL888 could help prevent resistance to the drug vemurafenib (aka Zelboraf). In the trial, a combination of XL888 and vemurafenib was safely given to patients. The patients showed good response to the treatment.
“Exelixis, Inc. (EXEL) today announced preliminary results from a phase 1 investigator-sponsored trial (IST) evaluating the safety and activity of XL888, an Exelixis-discovered small molecule oral inhibitor of Heat Shock Protein 90 (HSP90), in combination with vemurafenib in patients with unresectable stage III/IV BRAF V600 mutation-positive melanoma. Safety and efficacy results support the further investigation of 90 mg of XL888 twice weekly (BIW) and vemurafenib 960 mg twice daily (BID) in additional studies that would include a third agent.
“The trial results were presented today by Keiran Smalley, Ph.D., an investigator on the trial and an associate professor at H. Lee Moffitt Cancer Center, Tampa, Florida, in a late-breaking oral presentation session at the Society for Melanoma Research 2014 International Congress, which is taking place November 13-16, 2014, in Zurich, Switzerland. Based on these results, as well as findings from coBRIM, the phase 3 pivotal trial of cobimetinib, an Exelixis-discovered MEK inhibitor, and vemurafenib in previously untreated metastatic melanoma patients with a BRAF V600 mutation, the Moffitt Center plans to initiate a phase 1b IST of the triple combination of vemurafenib, cobimetinib, and XL888 in a similar patient population.
“ ‘The BRAF inhibitor vemurafenib is active in BRAF-mutated malignant melanoma, but development of resistance is common. Preclinical studies led by Keiran Smalley, Ph.D. suggested that most BRAF inhibitor resistance mechanisms involve proteins that are clients of HSP90, and the preclinical evaluation of XL888 showed that it is highly active in vemurafenib-resistant melanoma models,’ said Jeffrey Weber, MD, Ph.D., director of the Donald A. Adam Comprehensive Melanoma Research Center at the Moffitt Cancer Center and Research Institute in Tampa, FL. ‘The current phase 1 data show that both drugs can be given together, and compelling initial response results suggest potential cooperative activity.’ “
The gist: A recent clinical trial with volunteer patients compared two treatments for metastatic melanoma. It showed that one of the treatments might give longer survival times for people whose tumors do not have mutations in the BRAF gene. This treatment is a drug called nivolumab. It is an immunotherapy drug, meaning that it boosts a patient’s own immune system to fight cancer. In the trial, some patients took nivolumab and some took the chemotherapy drug dacarbazine. People who took nivolumab lived a few months longer than people who took dacarbazine. None of the patients had taken any previous treatments for their melanoma.
“Patients with treatment-naive, BRAF wild-type metastatic melanoma treated with nivolumab demonstrated longer OS and PFS than those treated with dacarbazine, according to phase 3 study results presented at the Society for Melanoma Research International Congress.
“Prior research showed nivolumab (Opdivo, Bristol-Myers Squibb) — a PD-1 immune checkpoint inhibitor — was associated with higher rates of objective response compared with chemotherapy in patients with ipilimumab (Yervoy, Bristol-Myers Squibb)-refractory disease.
“In the current study, Caroline Robert, MD, PhD, head of the Dermatology Unit at the Institut Gustave-Roussy in Paris, and colleagues compared the efficacy of nivolumab vs. chemotherapy in 418 previously untreated patients.
“Researchers assigned patients 3 mg/kg nivolumab every 2 weeks plus a dacarbazine-matched placebo, or 1,000 mg/m2dacarbazine every 3 weeks plus a nivolumab-matched placebo.”
The gist: Scientists are working on using individual patients’ cancer cells in the lab to figure out whether different treatments might work best for each patient. It is hoped that the approach would help patients get around the problem of treatment resistance. The research is cutting-edge, so it is not yet something that could be done for most patients.
“A new screening platform using cells grown directly from tumor biopsy samples may lead to truly individualized treatment strategies that would get around the problem of treatment resistance, which limits the effectiveness of current targeted therapy drugs. In a paper that will appear in Science and is receiving advance release on the Science Express website, researchers from the Massachusetts General Hospital (MGH) Cancer Center describe how screening samples grown from treatment-resistant tumors against a panel of current and potential targeted therapy drugs identified previously unknown resistance mechanisms, several of which could not be found by gene sequencing.
” ‘Genetics has been extremely useful to guiding treatment, but in many cases tumor genetics are ambiguous or do not reveal a mutation that informs a therapeutic strategy,’ says Jeffrey Engelman, MD, PhD, co-senior author of the report. ‘These functional pharmacologic studies can identify effective therapeutic choices even when the genetics fail to do so.’
“While the use of drugs that target genetic changes driving tumor growth induces remissions and gives many patients significant symptom relief, in almost all cases the effects are temporary because resistance appears in a year or two. Resistance develops either through secondary mutations that block the original drug’s action on the target molecule or through activation of a secondary pathway to carry molecular signals that sustain tumor growth. Previous efforts to study resistance mechanisms – either by inducing resistance in the laboratory using established cell lines or by looking for new mutations in resistant tumor cells – have significant limitations.”