The gist: Genetic mutations in a patient’s tumor can help determine which drugs are more likely to work. But a tumor can sometimes develop a new genetic mutation that makes it stop responding to a particular drug. When a person becomes resistant to his or her treatment, knowing about any new tumor mutations can help determine which treatment to try next. A recent study looked at mutations in non-small cell lung cancer (NSCLC). Different kinds of mutations in a gene called ALK can make NSCLC tumors treatable with different drugs. Certain ALK mutations make NSCLC tumors resistant to certain drugs. The scientists identified two new mutations that are associated with resistance to the drugs crizotinib and alectinib. Based on the findings, they suggest that a patient should get tested for new tumor mutations each time he or she becomes resistant to a particular drug. This will allow the doctor to select the best-fitting treatment to try next.
“Two novel ALK mutations, V1180L and I1171T, were associated with resistance to crizotinib and alectinib but were sensitive to other next-generation ALK tyrosine kinase inhibitors for non–small-cell lung cancer, according to study results.
“Although crizotinib (Xalkori, Pfizer) is the standard therapy for ALK-rearranged non–small cell lung cancer (NSCLC), patients often develop resistance to this agent and the next-generation ALK tyrosine kinase inhibitor (TKI) alectinib (CH5424802/RO5424802; Chugai Pharmaceuticals, Roche), according to study background information…
“ ‘These data highlight the need for repeat tumor biopsies at the time of resistance to each individual agent to determine if ALK mutations are present in the tumor, and if so, which ones,’ Politi and Gettinger wrote. ‘This practice will allow subsequent treatment to be tailored to the most current mutational state of the tumor.’ ”
The gist: A new lung cancer treatment called AP26113 has shown promise for certain people with metastatic non-small cell lung cancer (NSCLC). Specifically, it is meant to treat people whose tumors have mutations in the ALK gene and who are resistant to the standard drug crizotinib. It has been tested in volunteer patients in clinical trials. The U.S. Food and Drug Administration (FDA) has now granted breakthrough therapy designation for AP26113, meaning that review and approval will be accelerated so that the drug can more quickly reach patients in the U.S., outside of clinical trials.
“Ariad Pharmaceuticals Inc. of Cambridge said Thursday that federal regulators have granted “breakthrough therapy designation” to a drug candidate for a form of lung cancer.
“According to the Food and Drug Administration’s website, a breakthrough therapy designation means that the FDA will expedite the development and review of such drug. The designation is given to drug candidates designed to treat a serious or life threatening disease that have shown great promise based on preliminary clinical evidence.
“Ariad’s drug candidate, currently dubbed AP26113, is for the treatment of patients with anaplastic lymphoma kinase positive metastatic non-small cell lung cancer who are resistant to crizotinib, an existing treatment on the market.
“Ariad’s press release cited data from the American Cancer Society. According to the society, non-small cell lung cancer is the most common form of lung cancer, accounting for about 85 percent of the estimated 228,190 new cases of lung cancer diagnosed each year in the United States.”
The gist: Two new, similar melanoma treatments have been tested in clinical trials—research studies with volunteer patients. Both of the trials are focused on people with advanced melanoma whose tumors have mutations in the BRAF gene. Such patients are often treated with a targeted therapy called a BRAF inhibitor, but their tumors often become resistant and keep growing. In these two trials, the researchers hope that combining BRAF inhibitors with other targeted drugs known as MEK inhibitors might help patients avoid resistance. One of the trials tested a combination of the drugs vemurafenib and cobimetinib. The other trial combined dabrafenib and trametinib. In both trials, patients treated with the combination treatment fared better than patients treated with just a BRAF inhibitor alone.
“For patients with advanced melanoma that isBRAF-mutation positive, the combination of a BRAF and MEK inhibitor works better than a BRAF inhibitor alone. The data come from 2 phase 3 trials presented here at the presidential session of the European Society for Medical Oncology (ESMO) Congress 2014.
“Experts here say that such combinations should be the new standard of care in this patient population, which accounts for about 40% of all melanoma.
“At present, the first-line treatment for these patients is a BRAF inhibitor used alone, but while these drugs can elicit dramatic responses, they do not last, and after about 5 or 6 months, patients relapse. The tumor develops resistance to the drug via the MAPK pathway, and this is blocked by a MEK inhibitor. Adding a MEK inhibitor to the BRAF inhibitor from the beginning of treatment blocks this resistance pathway and improves outcomes.
“The 2 new trials are known as COMBI-v and coBRIM.
“Both studies used vemurafenib (Zelboraf, Roche/Plexxikon) as the single BRAF inhibitor, but each used a different combination of BRAF and MEK inhibitor.”
The gist: New research has shed light on why some patients’ melanoma tumors resist standard treatment. The scientists found that certain immune system cells produce chemical signals that may protect melanoma cells, and keep them from being destroyed. To get around this, the researchers say, drugs that affect the immune system (immunotherapy) could be combined with standard melanoma treatment. Indeed, such a combination is already being tested in a clinical trial—a research study with volunteer patients.
“Immune cells may be responsible for drug resistance in melanoma patients, according to research published in Cancer Discovery.”Cancer Research UK scientists at The University of Manchester found that chemical signals produced by a type of immune cell, called macrophages, also act as a survival signal for melanoma cells.
“When the researchers blocked the macrophages’ ability to make this signal – called TNF alpha – melanoma tumours were much smaller and easier to treat.
“When melanoma patients are given chemotherapy or radiotherapy it causes inflammation, increasing the number of macrophages in the body – and raising the levels of TNF alpha. This research suggests that targeting this chemical ‘survival signal’ could lead to new ways to treat the disease.”
The gist: This article describes the results of a clinical trial—a research study with volunteer patients. The goal of the trial was to test a new lung cancer treatment called alectinib. Specifically, the researchers wanted to find out if alectinib could be used to treat people with non-small cell lung cancer (NSCLC) who are resistant to treatment with the drug crizotinib (Xalkori). All patients who participated in the trial had tumor mutations in the ALK gene, as detected by molecular testing. (Both alectinib and crizotinib work by targeting tumor cells with mutated ALK genes.) The trial had promising results, and researchers will continue to study the drug to see how well it works.
“In the phase I portion of a phase I/II study reported in The Lancet Oncology, Gadgeel et al found that the novel ALK inhibitor alectinib showed activity against systemic disease and brain metastases in patients with non–small cell lung cancer (NSCLC) resistant to the ALK inhibitor crizotinib (Xalkori). Alectinib exhibits in vitro activity against both wild-type and mutated ALK, including mutations that confer resistance to crizotinib. An alectinib dose of 600 mg twice daily has been moved forward to phase II testing…
“In the study, 47 patients with ALK-mutant NSCLC who progressed on (n = 46) or were intolerant of (n = 1) crizotinib received oral alectinib 300 mg to 900 mg twice daily during the dose-escalation phase. Central nervous system (CNS) metastases were present at baseline in 21 patients. Seventy percent of all patients and 72% of those with CNS metastases had received at least two prior lines of chemotherapy…
“The investigators concluded: ‘Alectinib was well tolerated, with promising antitumour activity in patients with ALK-rearranged NSCLC resistant to crizotinib, including those with CNS metastases. On the basis of activity, tolerability, and pharmacokinetic data, we chose alectinib 600 mg twice a day as the recommended dose for phase 2.’ ”
The gist: Two patients with lung cancer may have distinctly different tumors that make them respond differently to the same treatment. Oncologists can use molecular tests to determine which treatments might work for which patients. These molecular tests find genetic mutations in tumors. These mutations can be targeted with specific targeted drugs. However, tumors can develop new, additional mutations that make them resistant to targeted drugs. Recent research looked at mutations that cause resistance to a drug called alectinib. (Alectinib is meant to treat tumors with mutations in the ALK gene.) The researchers identified mutations that were causing the resistance, and identified two drugs, ceritinib and AP26113, that could be used as alternatives for patients resistant to alectinib. Indeed, one patient who was resistant to alectinib was successfully treated with ceritinib.
“Two mutations that cause lung cancer resistance to the investigational ALK inhibitor alectinib were identified, and this information may help design new treatment regimens for patients with ALK-positive lung cancer, according to a study published in Clinical Cancer Research, a journal of the American Association for Cancer Research.
“In 2014, more than 159,000 men and women are expected to die of lung cancer in the United States. About 84 percent of lung cancers are non-small cell lung cancers (NSCLC), and 3 to 5 percent of NSCLCs have mutations in the gene ALK.
” ‘The goal of our study was to determine why ALK-positive lung cancers become resistant to alectinib, and we looked at this in two different ways,’ said Alice T. Shaw, MD, PhD, a thoracic oncologist at the Massachusetts General Hospital Cancer Center. ‘We studied a resistant cell line model that we generated in the lab, and we also studied a tumor sample from a patient with NSCLC who had been treated with alectinib and then became resistant.
” ‘We discovered two novel mutations that have not been described before in patients with NSCLC, and these mutations conferred high-level resistance to alectinib,’ Shaw added. ‘Another equally important finding from this study is that we were able find a way to overcome this type of resistance, in our laboratory experiments as well as in a patient, using another next-generation ALK inhibitor, ceritinib, previously known as LDK378.’ “
“Prostate cancer patients whose tumors contain a shortened protein called AR-V7, which can be detected in the blood, are less likely to respond to two widely used drugs for metastatic prostate cancer, according to results of a study led by researchers at the Johns Hopkins Kimmel Cancer Center. If large-scale studies validate the findings, the investigators say men with detectable blood levels of AR-V7 should avoid these two drugs and instead take other medicines to treat their prostate cancer. A report on the work is described online Sept. 3 in the New England Journal of Medicine.
“The study evaluated two groups of 31 men with prostate cancer that had spread and whose blood levels of prostate-specific antigen (PSA) were still rising despite low testosterone levels. Investigators gave each man either enzalutamide (Xtandi) or abiraterone (Zytiga) and tracked whether their PSA levels continued to rise, an indication that the drugs were not working. In the enzalutamide group, none of 12 patients whose blood samples tested positive for AR-V7 responded to the drug, compared with 10 responders among 19 men who had no AR-V7 detected. In the abiraterone group, none of six AR-V7-positive patients responded, compared with 17 responders among 25 patients lacking AR-V7.
“Enzalutamide and abiraterone have been very successful in lengthening the lives of about 80 percent of patients with metastatic prostate cancer, says Emmanuel Antonarakis, M.D., assistant professor of oncology at Johns Hopkins, but the drugs do not work in the remaining 20 percent of patients.
” ‘Until now, we haven’t been able to predict which patients will not respond to these therapies. If our results are confirmed by other researchers, a blood test could use AR-V7 as a biomarker to predict enzalutamide and abiraterone resistance, and let us direct patients who test positive for AR-V7 toward other types of therapy sooner, saving time and money while avoiding futile therapy,’ says Antonarakis.”
Editor’s note: Drugs known as targeted therapies can be used to treat some forms of cancer, based on specific substances found in cancer cells. Scientists have identified a protein called STAT3, which is found in basal-like breast cancer. Drugs that target STAT3 are being tested in volunteer patients in clinical trials.
“Two Northwestern University scientists have identified a biomarker strongly associated with basal-like breast cancer, a highly aggressive carcinoma that is resistant to many types of chemotherapy. The biomarker, a protein called STAT3, provides a smart target for new therapeutics designed to treat this often deadly cancer.
“Using breast cancer patient data taken from The Cancer Genome Atlas, molecular biologists Curt M. Horvath and Robert W. Tell used powerful computational and bioinformatics techniques to detect patterns of gene expression in two cancer subtypes. They found that a small number of genes are activated by STAT3 protein signaling in basal-like breast cancers but not in luminal breast cancers.
“Basal-like cancer is a category that includes a number of different breast cancers, including the highly aggressive form called triple negative cancer.”
The gist: Some people with melanoma who do not respond to treatment with ipilimumab (Yervoy) might benefit from immunotherapy drugs, which activate a patient’s own immune system to fight cancer. Researchers are testing an “anti-PD-1” immunotherapy drug called pembrolizumab in a clinical trial with volunteer patients. The results suggest that pembrolizumab might be a good treatment for advanced melanoma patients who have few other options. Learn more about immunotherapy treatments for melanoma at our Need to Know blog.
“As reported in The Lancet by Robert et al, the anti–programmed death receptor-1 (PD-1) antibody pembrolizumab produced responses and was well tolerated at two dose levels in an expansion cohort of a phase I trial in patients with ipilimumab (Yervoy)-refractory advanced melanoma.
“In this open-label multicenter trial, 173 adult patients with advanced melanoma progressing after at least two ipilimumab doses were randomly assigned to receive intravenous pembrolizumab at 2 mg/kg (n = 89) or 10 mg/kg (n = 84) every 3 weeks until disease progression, intolerable toxicity, or withdrawal of consent. The primary endpoint was overall response rate on independent central review…
“The investigators concluded, ‘The results suggest that pembrolizumab at a dose of 2 mg/kg or 10 mg/kg every 3 weeks might be an effective treatment in patients for whom there are few effective treatment options.’ ”