Results of New Drug, ASP8273, Show Response in Patients with Treatment-Resistant NSCLC

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 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.”


Drugs to Avoid in Patients on Tyrosine Kinase Inhibitors

Editor’s note: More and more people with cancer are being treated with drugs known as tyrosine kinase inhibitors (TKIs). As with any other drug, oncologists who prescribe TKIs must be aware of other drugs a patient is taking to ensure there will not be a dangerous drug-drug interaction. Researchers recently published a report outlining known and potential drug-drug interactions between TKIs and other drugs. Oncologists and patients may wish to take these into account when considering cancer treatment with TKIs.

“With the rapid and widespread uptake of tyrosine kinase inhibitors (TKIs) in oncology over the past several years, serious drug–drug interactions are an “increasing risk,” according a new report.

“To guarantee the safe use of TKIs, ‘a drugs review for each patient is needed,’ write Frank G.A. Jansman, PharmD, PhD, from Deventer Hospital in the Netherlands, and colleagues in a review published in the July issue of the Lancet Oncology.

“The review provides a comprehensive overview of known and suspected interactions between TKIs and conventional prescribed drugs, over-the-counter drugs, and herbal medicines.

“All 15 TKIs approved to date by the US Food and Drug Administration or the European Medicines Agency are evaluated.

“They are axitinib (Inlyta, Pfizer), crizotinib (Xalkori, Pfizer), dasatinib (Sprycel, Bristol-Myers Squibb and Otsuka America), erlotinib (Tarceva, Osi Pharmaceuticals), gefitinib (Iressa, AstraZeneca), imatinib (Gleevec, Novartis), lapatinib (Tykerb, GlaxoSmithKline), nilotinib (Tasigna, Novartis), pazopanib (Votrient, GlaxoSmithKline), regorafenib (Stivarga, Bayer), ruxolitinib (Jakafi, Incyte), sorafenib (Nexavar, Bayer), sunitinib (Sutent, Pfizer), vandetanib (Caprelsa, AstraZeneca), and vemurafenib (Zelboraf, Roche).”


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.”


Ignyta Announces Initiation of STARTRK-1 Global Phase I/II Clinical Trial of RXDX-101

The gist: Researchers are conducting a clinical trial with volunteer patients to test a new cancer treatment called RXDX-101. RXDX-101 is meant to treat cancer patients whose solid tumors have mutations in the genes TrkA, ROS1, or ALK. The clinical trial is enrolling adults with locally advanced or metastatic cancer with those mutations. 

“Ignyta, Inc. (Nasdaq: RXDX), an oncology precision medicine biotechnology company, today announced the multicenter initiation of the company’s global Phase I/II clinical trial of RXDX-101, its proprietary oral tyrosine kinase inhibitor targeting multiple solid tumor indications. This clinical trial is called STARTRK-1, which stands for Study Targeting ALK, ROS1 or TRKA/B/C, and is a Phase I/IIa, multicenter, single-arm, open-label clinical trial of continuous daily dosing of oral RXDX-101 in adult patients with locally advanced or metastatic cancer confirmed to be positive for relevant molecular alterations.

” ‘We are excited to be able to expand the clinical dosing of this product candidate to patients at leading cancer centers in the U.S., Europe and Asia,’ said Jonathan Lim, M.D., Chairman and CEO of Ignyta. ‘The initiation of the STARTRK-1 trial builds on the momentum of our presentation of interim data from the ongoing RXDX-101 Phase I clinical trial at the ASCO annual meeting, where we reported partial responses in patients with each of TrkA, ROS1 and ALK alterations, as well as in three different tumor types.’ “


Increased Overall Survival for Advanced Stage NSCLC Patients Associated with Availability of Less Toxic Chemotherapy

The gist: A long-term study investigated the effects of new lung cancer treatments over time. They found that survival has improved for people with advanced non-small cell lung cancer (NSCLC) as new, better chemotherapy and targeted therapy treatments have been developed. The researchers also noted that survival has improved for patients who receive chemotherapy and specifically additional (“second-line”) treatment after their initial treatment.

“A 10-year population-based study shows that increased availability of better systemic chemo- and targeted-therapies for patients with advanced non-small cell lung cancer (NSCLC) coincides with increased usage of these therapies. This in turn leads to a significant increase in overall survival.

“Researchers from the British Columbia Cancer Agency, Vancouver, Canada, performed a retrospective chart review of all patients referred to the agency with advanced stage (IIIB or IV) lung cancer and grouped the patients into 4 one-year time frame cohorts; one termed ‘baseline’ and three other groups that each started 6-months after a new second-line agent (docetaxel, erlotinib and pemetrexed) was made commercially available and put into practice. In British Columbia, Canada, the implementation of the second-line agents docetaxel, erlotinib and pemetrexed occurred in December 2000, October 2005 and June 2007, respectively. Cohort 1 (January to December 1998) with 555 patients was the baseline and cohort 2 (May 2001-April 2002) had 613 patients, cohort 3 (March 2006-February 2007) had 688 patients and Cohort 4 (November 2007-Ocotober 2008) had 750 patients.

“The results published in the August Issue of the Journal of Thoracic Oncology, the official journal of the International Association for the Study of Lung Cancer, show that the usage of second-line therapy increased significantly over time. At baseline only 21% of the patients received second-line therapy but in Cohorts 2 and 3 this increased to 27% and 37% respectively, and by Cohort 4 more than half, 55%, received second-line therapy. The most common agent in Cohort 1 was docetaxel (48%) but by Cohort 4 erlotinib (EGFR TKIs) and pemetrexed were used 50% and 26% of the time. The research also found that the proportion of patients who received at least first-line systemic chemotherapy also increased over the four time points from 16% in Cohort 1 to 23%, 34% and 33% for Cohorts 2-4, respectively.”


18F-FGD-PET Measures Predict mRCC TKI Response

“Positron emission tomography (PET) could be used to predict the response of metastatic renal cell carcinoma (mRCC) to tyrosine kinase inhibitor (TKI) therapy within a couple of weeks of a patient beginning treatment, research suggests.

“Changes in volume-based metabolic parameters of 18F-fluorodeoxyglucose (FDG) before and after 14 days of treatment with sunitinib, sorafenib or pazopanib significantly correlated with progression-free and overall survival, say Jacob Farnebo (Karokinska University Hospital, Stockholm, Sweden) and co-authors.”

Editor’s note: Doctors and patients can make more informed treatment decisions if they can more closely monitor how well a treatment is working and predict how well it is likely to work in the long run. This story discusses how monitoring with positron emission tomography (PET) within the first couple of weeks of treatment might help predict how well certain drugs will work. PET scanning produces 3-D images of the inside of the body. Scientists conducted a study in which they gave PET scans to volunteer patients who were being treated with the drugs sunitinib, sorafenib, or pazopanib for metastatic renal cell carcinoma (mRCC). They found that, within two weeks of the patients starting treatment, they could use information from the PET scans to determine the effectiveness of the treatment. They were able to link these PET scan results to how long the patients lived and how much time passed before patients’ disease worsened.


Researchers Report Double Dose of Promising Lung Cancer Findings

“Researchers with UCLA’s Jonsson Comprehensive Cancer Centerreport that two new experimental drugs have shown great promise in the treatment of patients with non–small-cell lung cancer, which accounts for about 85 percent of all lung cancers. Lung cancer is the leading cause of cancer death in the United States.

“The drugs—ramucirumab and CO-1868—were shown in separate clinical trials to increase survival times with fewer toxic side effects than standard treatments. The findings were presented this week at the American Society of Clinical Oncology annual meeting in Chicago.”

Editor’s note: For more on the ramucirumab findings, see our previous news post. To learn more about targeted therapies like CO-1686 and ramucirumab, visit our lung cancer Basics.


ARIAD Presents Updated Phase 1/2 Data on AP26113 in Patients with ALK+ Non-Small Cell Lung Cancer

“ARIAD Pharmaceuticals, Inc. today announced updated clinical results on its investigational tyrosine kinase inhibitor (TKI), AP26113, in patients with advanced non-small cell lung cancer (NSCLC) from an ongoing Phase 1/2 trial. These study results show anti-tumor activity of AP26113 in patients with crizotinib-resistant anaplastic lymphoma kinase (ALK) positive NSCLC, including patients with brain metastases. Crizotinib is approved for ALK-positive NSCLC patients.”

Editor’s note: This story is about a targeted drug called AP26113, which may benefit some patients with advanced non-small cell lung cancer (NSCLC). Specifically, it has shown promise for patients whose tumors have mutations in the ALK gene, as detected by molecular testing, and who have already been treated with the drug crizotinib (Xalkori) but have grown resistant to it.


New EGFR Inhibitor AZD9291 Shows Promising Activity in Treatment-Resistant Non–Small Cell Lung Cancer

“Findings from a phase I study of a new mutant-selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, AZD9291, point to a promising new treatment option for patients with advanced, EGFR-mutant, non–small cell lung cancer (NSCLC) that is resistant to standard EGFR inhibitors. Roughly 50% of patients experienced tumor shrinkage, and the drug worked particularly well in patients with the T790M mutation (detected in 60% of patients), which causes the most common form of EGFR therapy resistance. The study was presented at a presscast in advance of the 2014 ASCO Annual Meeting (Abstract 8009^).”

Editor’s note: This story is about a new targeted therapy drug called AZD9291 that is designed to attack tumors with a mutation in the EGFR gene, as detected by molecular testing. In particular, it is designed for patients who are resistant to other so-called EGFR inhibitors as a result of developing a particular EGFR mutation known as T790M. In a clinical trial to test the drug in patients, it was found to show promising results for patients with advanced non-small cell lung cancer (NSCLC) with EGFR mutations, and even better results in patients with the T790M mutation.