Alice Goodman

-Two angiogenesis inhibitors that are widely used in metastatic 

 (RCC) did not improve survival compared with placebo when used as adjuvant treatment, a new study found. The federally funded randomized trial studied the agents’ use in patients with locally advanced kidney cancer.

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	“Patients with locally advanced kidney cancer should not be treated with either adjuvant sorafenib or sunitinib,” stated lead author Naomi B. Haas, MD, associate professor of medicine at the Abramson Cancer Center, University of Pennsylvania, Philadelphia, speaking at a pre-meeting press event for the Genitourinary Cancers Symposium in Orlando, FL.

NEXT: No benefit seen for adjuvant therapy with either sunitinib or sorafenib compared to placebo

Dr. HaasNo benefit was seen for adjuvant therapy with either sunitinib (Sutent) or sorafenib (Nexavar) compared to placebo. Treatment with either drug resulted in median disease-free survival (DFS) of 5.6 years; DFS was 5.7 years with placebo. The 40% rate of recurrence was also similar among the two treatment arms and placebo group.

	These findings are of importance because both drugs have been used in the adjuvant setting off-label in about 45% of patients with locally advanced kidney cancer.

	The phase III ASSURE (Adjuvant Sorafenib or Sunitinib in Unfavorable REnal cell carcinoma) trial was designed to test whether these agents would prove as effective in the adjuvant setting as they have for patients with advanced/metastatic RCC.

	The randomized, double-blind, multicenter trial enrolled 1,943 patients with resected, intermediate, and very high-risk clear cell and non-clear cell RCC who had no prior systemic treatment. Patients were randomized to receive sorafenib, sunitinib, or placebo.

	The trial was designed to detect a 25% reduction in the hazard ratio, which would equate to an improvement in estimated median DFS of 5.8 years with placebo to 7.7 years with the experimental agents. DFS was the primary endpoint; secondary endpoints were overall survival and tolerability.

	Rates of adverse events and patient intolerance compelled lowering the original dosage of sorafenib, 400 mg twice daily to once daily, and of sunitinib, 50 mg once daily to 35 mg once daily. Discontinuation rates decreased from about 26% of patients on the original schedule to about 14% of patients who started on the lower dosages. The authors also found that discontinuation rates were reduced by dose titration.

	Both drugs were associated with an increased incidence of hypertension (16% for active agents vs. 4% placebo). Compared to placebo, the sorafenib arm had higher rates of hand-foot syndrome and rash (15% vs. <1%) and diarrhea (9% vs. 0%). Patients in the sunitinib arm had higher rates of fatigue (18% vs. 3% placebo), hand-foot syndrome (33%), and diarrhea (10%).

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	With 62% of the study information available at an interim analysis, no evidence of any trend toward efficacy benefit, and significant high-grade toxicity seen with both sorafenib and sunitinib, the Data Safety Monitoring Committee recommended release of results even though no efficacy or futility boundaries had been reached.

	The results of this study raise the question of whether anti-angiogenic agents have any role as treatment and prevention of recurrence in the adjuvant setting. If they do, how long should they be administered? Hopefully, the answers to these and other questions will emerge from further studies. Currently, ATLAS (NCT0599754) is looking at another anti-angiogenesis agent, axitinib (Inlyta), in very high-risk clear cell RCC patients; and SORCE (NCT00492258) is investigating sorafenib versus placebo for 1 or 3 years in resected patients with clear cell and non-clear cell RCC.

	Dr. Haas has stock and other ownership interests in TetraLogic Pharmaceuticals, serves as a consultant/adviser for Bristol-Myers Squibb, GlaxoSmithKline, and Merck; and has provided expert testimony for Lilly. One of Dr. Haas’ co-authors is a consultant/adviser for Bayer and Pfizer and has received travel, accommodations, and expenses remuneration from Pfizer, and others have served as consultants/advisers to and/or have received honoraria from pharmaceutical companies.

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Two angiogenesis inhibitors that are widely used in metastatic renal cell carcinoma did not improve survival compared with placebo when used as adjuvant treatment, a new study found.

Adjuvant therapy fails in locally advanced kidney Ca

-Researchers have come up with a potential blood-based biomarker that can identify men with castration-resistant 

 (CRPC) who are not likely to respond to enzalutamide (XTANDI).

	A simple blood test that can detect the presence of the androgen receptor (AR)-V7 splice variant appears to predict non-response to this new therapy.

	“Although enzalutamide is a highly effective drug for many men with advanced prostate cancer, about 21% failed to respond to this agent in the pivotal phase II AFFIRM trial. Our data show that AR-V7 seems to predict resistance to enzalutamide in virtually all cases. These findings are clinically relevant and can save both time and money, as oncologists could identify men likely to be resistant to this drug before they needlessly prescribe it. This could allow oncologists to steer men to other available therapies that are more likely to work,” noted lead author Emmanuel Antonarakis, MD, assistant professor of oncology at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore.

Dr. AntonarakisHormones-including testosterone-are thought to drive prostate cancer by binding to the AR and fueling cancer growth and proliferation. AR-V7 is a shortened form of the AR protein. It lacks the ligand-binding domain that is the target of enzalutamide, but AR-V7 can still attach to cellular DNA and fuel growth and proliferation even without testosterone, Dr. Antonarakis explained.

	Many mechanisms of resistance to enzalutamide have been proposed, he continued. Splice variants of the AR gene are only one of them.

	“We have focused our research on AR-V7 [one of a number of AR splice variants] because we believe it is the most important variant,” he said.

	The study, which was presented at the American Association for Cancer Research annual meeting in San Diego, prospectively enrolled 31 men with metastatic CRPC who were slated for treatment with enzalutamide. Blood samples were obtained from each patient at three time points (at baseline, after response to treatment, and at disease progression) and analyzed for the presence of the AR-V7 mRNA. At the AACR meeting, Dr. Antonarakis presented the correlation between baseline blood tests and response to enzalutamide.

	Of the 31 men, 12 (38.7%) had detectable AR-V7 in their circulating tumor cells (CTCs) obtained at baseline. The patients who were AR-V7-positive had worse responses compared with those whose CTCs were AR-V7-negative. Further, levels of PSA did not drop in the 12 patients with AR-V7-positive CTCs, whereas 10 of the 19 patients who were AR-V7-negative had reductions in PSA level of 50% or more on enzalutamide; PSA responses (reduction in PSA of 50% or more) were observed in 0% versus 52.6% of patients, respectively (

	Disease progression occurred sooner in the 12 AR-V7-positive patients compared with those who were AR-V7-negative: Radiographic progression-free survival was 2.1 months versus 6.1 months (

<.01). In a multivariate analysis, the presence of AR-V7 and prior abiraterone (ZYTIGA) use were independently predictive of progression-free survival.

	A larger study is planned to verify these results, but before that trial can start, the test used to detect AR-V7 needs to be certified in a Clinical Laboratory Improvement Amendments setting for quality control. Dr. Antonarakis and his colleagues said they also plan to test the clinical relevance of AR-V7 in other therapeutic settings, including during treatment with abiraterone and taxane chemotherapy.

	The Prostate Cancer Foundation provided funding for the study.

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Researchers have come up with a potential blood-based biomarker that can identify men with castration-resistant prostate cancer who are not likely to respond to enzalutamide (XTANDI).

Protein may predict resistance to prostate cancer Tx

Preliminary studies suggest that inhibition of fibroblast growth factor receptors (FGFR) 1, 2, 3, and 4 may be a promising approach for the treatment of 

 and other cancers that harbor FGFR alterations.

	Phase I studies of two separate investigational FGFR inhibitors were presented at the American Association for Cancer Research annual meeting in San Diego.

	In the first study, researchers showed that that the investigational pan-FGFR inhibitor BGJ398 had activity against different types of solid tumors, including bladder cancer and lung cancer. Hypophosphatemia is the major drug-related side effect of BGJ 398 and a second pan-FGFR inhibitor that was the subject of a second abstract. In patients who are now being treated with one of the 2 FGFR inhibitors, hypophosphatemia is being managed proactively with dose interruptions.

	The first study was restricted to patients with FGFR alterations in their tumors to optimize changes of response, explained lead author Lecia V. Sequist, MD, MPH.

	“We were especially encouraged by the activity in bladder cancer, because there are few treatment options for these patients,” said Dr. Sequist, associate professor of medicine at Harvard Medical School and assistant physician at Massachusetts General Hospital, Boston.

	She went into some detail on the six bladder cancer patients included in the phase I trial, and said that the phase I data on the agent’s activity in lung cancer will be presented at the upcoming American Society of Clinical Oncology annual meeting.

	The study enrolled 107 patients with urothelial cell/bladder cancer, lung cancer, breast cancer, or cholangiocarcinoma. Of those, 43 were treated in the dose escalation phase of the trial. There were three groups treated in the expansion phase: squamous cell lung cancer treated daily and two other groups with various cancers (one group treated continuously daily and the other group for 3 weeks on and 1 week off).

	The maximum tolerated dose was identified as 125 mg/day, and the schedule chosen for phase II testing is 3 weeks on and 1 week off. This schedule demonstrated an improved safety profile, Dr. Sequist said.

	Tumor shrinkage was observed in patients treated at doses of 100 mg/day or higher in the dose escalation phase, and also among patients in all three expansion arms. Tumor shrinkage was observed in various cancer types, most notably in five of six patients with bladder cancer who had an FGFR3 mutation. Anticancer activity was also observed in squamous cell lung cancer, squamous cell head and neck cancer, breast cancer, and cholangiocarcinoma.

	In summary, Dr. Sequist said: “This study clearly demonstrates the value of a personalized approach to cancer therapy with a targeted agent by showing that patients with FGFR genetic abnormalities can respond to an FGFR inhibitor.”

	 A number of phase II studies of BGJ 398 are ongoing or planned, and these will include correlative studies of specific FGFR genetic alterations.

	The second presentation focused on an ongoing phase I study of a pan-FGFR inhibitor called JNJ-42756493. The study included 28 patients with advanced solid tumors and had a similar design, similar responses, and similar adverse events as Dr. Sequist’s study. Hyperphosphatemia was the major drug-related side effect and this will be managed proactively as the phase I study continues, reported the researchers, including first author Rodrigo Dienstmann, MD, of Fred Hutchinson Cancer Research Center, Seattle. The 9-mg/day dose was identified as the maximum tolerated dose going forward.

	Some of Dr. Sequist’s co-authors are employees of Novartis. The second study included authors who are employees of Janssen Pharmaceuticals.

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Preliminary studies suggest that inhibition of fibroblast growth factor receptors (FGFR) 1, 2, 3, and 4 may be a promising approach for the treatment of bladder cancers and other cancers that harbor FGFR alterations.

Growth factor inhibition shows promise in bladder Ca

A comprehensive molecular characterization of muscle-invasive urothelial bladder carcinoma suggests multiple opportunities for therapeutic intervention.

	Researchers presented their findings from the large-scale Cancer Genome Atlas (TCGA) project at the Genitourinary Cancers Symposium in San Francisco, and the results were published in 

Dr. RosenbergThere have been no new therapies for 

 since the 1970s, explained lead author Jonathan Rosenberg, MD, section chief of the non-prostate program in the genitourinary oncology service at Memorial Sloan-Kettering Cancer Center, New York. He and his colleagues hope that the TCGA project will lead to identification of new therapies targeted to actionable mutations and provide clinical benefits in appropriately selected subsets of patients.

	“There are two major take-home points from our work on the Cancer Genome Atlas in bladder cancer,” Dr. Rosenberg told 

	“The first is that the majority of patients with muscle-invasive urothelial bladder carcinoma have actionable mutations that can be targeted 

with either FDA-approved drugs or investigational agents,” he emphasized.

	The second is that epigenetic regulatory genes are frequently altered in this type of bladder cancer, suggesting that there may be a different paradigm for therapeutic intervention. Seventy-six percent of tumors had one inactivating epigenetic mutation and 41% had two. More clinical and laboratory research is needed with drugs that target these alterations, such as histone deacetylase inhibitors, DNA methyltransferase inhibitors, and bromodomain inhibitors.

	“These drugs may prove useful in subsets of patients, depending on the mutation profile of epigenetic regulatory genes,” Dr. Rosenberg said.

	As part of the TCGA project, the authors analyzed DNA from 131 muscle-invasive urothelial bladder cancer tumors and corresponding normal samples (predominantly blood). They determined that bladder cancer is one of the most highly mutated tumor types, with each tumor possessing an average of 302 exonic mutations, 204 segmental alterations in DNA copy number, and 22 large-scale genomic alterations. Thirty-two recurrent significantly mutated genes were identified that appear to be involved in bladder cancer pathogenesis.

	Some of these genetic abnormalities had not been previously reported in bladder cancer or in other cancers included in the TCGA, Dr. Rosenberg said.

	Mutation spectrum, rate, and focal copy number alterations or expression subtypes do not correlate with exposure to cigarettes in this cohort; 72% of patients who provided these samples were current or former smokers.

	Three clusters of abnormalities were identified based on an integrated analysis of both mutations and copy number: a genomic amplification cluster, a p16-deleted cluster, and a p53-mutated cluster.

	“These clusters suggest that there may be different oncogenic mechanisms involved in the development of muscle-invasive bladder cancer, but we don’t know yet whether any of them are clinically relevant,” Dr. Rosenberg said.

	In addition to mutations, 27 focal genomic amplifications and 30 focal deletions were observed, and many may identify potential therapeutic targets.

Potential targets in nearly 70% of tumors

	Between mutation and copy number analysis, potential targets were identified in 69% of the tumors, including 42% with targets in the phosphatidyliositol-3-OH kinase/AKT/mTOR pathway and 45% with targets in the RTK/MAPK pathway (including ERBB2).

	In addition, chromatin regulatory genes were more frequently mutated in urothelial carcinoma than in any other common cancer studied so far, indicating the future possibility of targeted therapy for chromatin abnormalities.

	These multiple signaling and cell cycle regulatory oncogenic pathways are altered in bladder cancer and offer immediate opportunity to study different targeted therapies.

	“We need carefully designed trials to leverage these data,” Dr. Rosenberg said.

	When asked whether genomics was in its infancy in bladder cancer, Dr. Rosenberg said, “It’s more accurate to say we are on the verge of adolescence. We will get there if we can get drugs that target actionable mutations into clinical trials. We need to learn from the lung cancer, breast cancer, and colon cancer experience.

	“This effort may provide parts of the answers on how best to treat bladder cancer. We are all very excited.”

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Author | Alice Goodman

Articles

Adjuvant therapy fails in locally advanced kidney Ca

Protein may predict resistance to prostate cancer Tx

Growth factor inhibition shows promise in bladder Ca

Bladder cancer study identifies therapeutic targets