Anna Azvolinsky

The targeted, oral therapy crizotinib (Xalkori), has been 

 priority review by the US Food and Drug Administration (FDA) for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) who have c-ros oncogene 1 (

A final decision by the FDA is expected by April of next year. Crizotinib received an FDA Breakthrough Designation for this potential indication in April 2015. If approved, it would be the first biomarker-driven therapy for ROS1-rearranged metastatic NSCLSC.

Crizotinib is an oral inhibitor of two kinases: anaplastic lymphoma kinase (ALK) and ROS1. The drug has been approved by the FDA since 2011 for the treatment of NSCLC that harbors the EML4-ALK fusion.

-mutated lung cancer is based on a phase 1 clinical trial 

. In the 50-patient trial, treatment with crizotinib resulted in an overall response rate of 72% in those with 

-rearranged tumors. Six percent (3 patients) had a complete response and 66% (33 patients) had a partial response. An additional 18% (9 patients) had stable disease.

The median progression-free survival was 19.2 months. The 12-month overall survival rate was 85% at a follow-up of 16.4 months.

Median time to a first response was 7.9 weeks and the median duration of response on study was 17.6 months. The median time on treatment was 64.5 weeks with 23 of the 36 responders (64%) of patients responding to therapy at the time of analysis.

The median age of patients on the trial was 53. Patients were treated with 250 mg twice daily over a 28-day cycle. Fifty-four percent of patients were white and 42% were Asian. Ninety-eight percent of patients had an ECOG performance status of 0 or 1, 78% had never smoked, and 98% had adenocarcinoma histology. Forty-four percent of patients had previously had more than one prior therapy.

 gene occur in about 1% of NSCLC patients-about 15,000 of the estimated 1.5 million new cases of NSCLC worldwide. As with 

 rearrangements are more commonly found in lung cancer patients who have no history of smoking or a history of light smoking, and are more likely to have adenocarcinoma histology.

Fluorescence in situ hybridization (FISH) was used to detect the presence of 

 rearrangement in 49 of the 50 patients. According to the study authors, research is ongoing to establish an assay that will best serve as a biomarker test for screening patients for the 

The adverse event profile of crizotinib in 

-rearrangement patients was similar to that previously reported in 

-rearranged NSCLC. The most common adverse events were visual impairment (82%), diarrhea (44%), nausea (40%), peripheral edema (40%), constipation (34%), vomiting (34%), an elevated aspartate aminotransferase level (22%), and fatigue (20%). Common grade 3 adverse events were neutropenia (10%), hypophosphatemia (10%), and elevated alanine aminotransferase levels (4%).

Articles

The targeted, oral therapy crizotinib (Xalkori), has been granted priority review by the US Food and Drug Administration (FDA) for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) who have c-ros oncogene 1 (ROS1)-rearranged tumors. 

FDA Grants Crizotinib Priority Review in ROS1-Mutated Lung Cancer 

The combination of radiation therapy plus the EGFR inhibitor cetuximab had higher rates of acute toxicity among patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) compared with radiation therapy plus the chemotherapy cisplatin, according to results of a phase II trial based in Italy. Efficacy was similar with both combination therapies.

According to Stefano Maria Magrini, MD, professor of radiotherapy at the UniversitÃ  degli Studi di Brescia in Italy, and colleagues, this is the first clinical trial to directly compare radiation therapy plus cetuximab to a chemoradiation regimen for SCCHN.

Cetuximab was approved in combination with radiation therapy by the US Food and Drug Administration in 2006 for the treatment of unresectable SCCHN.

Despite a goal of recruiting 130 patients, only 70 patients were recruited between 2011 and 2014.

The 1- and 2-year overall survival rates were 75% and 68% in the cetuximab arm compared with 78% in the cisplatin arm. The 1- and 2-year local control rates were 64% and 53% in the cetuximab arm and 84% and 80% in the cisplatin arm, yet the differences between arms were not statistically significant (

 = .073), reflecting the inadequate statistical power of the relatively small trial.

Compliance in both treatment arms was relatively low. Only 28% of patients in the cetuximab arm and 20% of patients in the cisplatin arm received at least 7 cycles of therapy.

Patients in the radiation therapy plus cetuximab arm experienced more serious adverse events including severe cutaneous toxicity of grade 3 or higher. Four patients in the cetuximab arm developed infectious complications that led to septic shock and three of the patients died after the end of treatment. An additional patient died from respiratory failure caused by aspiration pneumonia.

Patients in the cisplatin arm had more frequent hematologic toxicities compared to patients in the cetuximab arm and one patient died from adverse events possibly related to treatment.

“The incidence of both the infusion reactions and of the other severe adverse events does not allow to consider cetuximab a safer and easy-to-use alternative to standard chemotherapy regimens,” wrote the study authors.

Based on the study results, larger prospective trials are needed to understand which SCCNH patients would best benefit from radiation therapy plus cetuximab regimen.

, Roy H. Decker, MD, PhD, associate professor of therapeutic radiology at the Yale School of Medicine in New Haven, Connecticut, and colleagues highlighted the limitations of the current trial but look forward to results from ongoing studies to clarify the role of cetuximab in the treatment of SCCHN.

“We continue to selectively consider the use of cetuximab-based radiation therapy in patients with otherwise-favorable, low-risk disease-

-positive, T1–T3 N0–N2b with a smoking history of less than 10 pack-years,” wrote the editorial authors.

The combination of radiation therapy plus cetuximab had higher rates of acute toxicity among patients with locally advanced squamous cell carcinoma of the head and neck compared with radiation therapy plus cisplatin.

Cetuximab Plus RT Linked With High Toxicity in Head and Neck Cancer

Today, ahead of the American Society of Hematology meeting, being held in Orlando, Florida from December 5th to the 8th, we are speaking with Dr. Jeffrey Tyner, an assistant professor of cell, developmental, and cancer biology at the Oregon Health & Science University in Portland. Professor Tyner who will present research from his lab on a way to screen tumor cells derived from patients for sensitivity to available anticancer drugs to guide treatment decisions. His talk, "Functional Screening to Guide Personalized Cancer Therapy" will be on Saturday, December 5th at the ASH meeting.

Whole genome sequencing is becoming more readily available and cheaper. Can you talk about the way that sequencing of tumor samples is currently being used to guide treatment for cancer patients? Is this approach still only being applied in a clinical trial and research setting?

Sure, great question. You’re absolutely right that whole genome sequencing and deep sequencing in general is becoming much cheaper and faster, and more readily available. There are at least a couple of different ways that it is being applied clinically right now. Of course there are certain genetic tests that have been around for a long time, for decades even, for specific genes that have been known about early on, that correlated with a particular treatment that was effective.

The great example of course being, is BCR-ABL, detected with a basic karyotype and led to the development of very effective therapies to combat the disease that harbors that genetic mutation, CML [chronic myeloid leukemia]. And now as we get more broad whole genome sequencing or even whole exome or more targeted sequencing approaches that cover many more genes, the amount of information you get is really incredible. And there are at least two different areas to which this is being applied, certainly in a clinical trial setting.

There are trials underway, some that have been going on for some time now where patients are enrolled onto different arms, different therapeutic arms of the trial based on different mutational subtypes of disease. So if you have a mutation in gene A that predicts a response to a particularly drug, you get that drug, and if you get a mutation in a different gene you get a different drug. So certainly clinical trials are one major area where this is being applied, but there is also a more ad hoc way of doing this where the sequencing ongoing now is performed in a CLIA approved setting, meaning it is approved in a format that is compatible with clinical decision making.

So it is now possible to send tumor DNA out for this clinically approved sequencing and then it is really up to the treating clinician as to how to use that information, and whether that information is useful in providing a therapeutic option for a patient. And there certainly are great examples of mutations that do provide an obvious therapy that is likely to positively influence the disease course of a patient. Unfortunately, there are a whole lot of mutations that we don't yet know what to do with yet from a therapeutic perspective, there really aren’t therapies that are immediately obvious that should be applied, so as a biologist we really have a lot of work ahead to be able to make connections between mutational events and the drugs that are likely to impact those mutations.

You mentioned one of the limitations of whole genome sequencing as far as applications in cancer patients. Are there other limitations as far as identifying potential target somatic mutations through whole genome sequencing?

Whole genome sequencing or deep sequencing in general are awfully good at picking up somatic point mutations, where there is just a single nucleotide that is changed, the most simple type of mutation that occurs and these occur commonly in cancer, and deep sequencing is good at picking these up even at low levels. And the technology is getting better and better. There are certainly types of mutations that are more complex that involve more than one nucleotide, insertion or deletion of multiple nucleotides. And certainly the algorithms that sift through the large amount of data generated by whole genome sequencing and make the calls of whether a mutation is present or not, are not as successful at picking up these more complex mutations. That said, deep sequencing is good at detecting the mutations that are present in a tumor. To my mind, the main limitation is what we were just talking about, which is right now, it is very common to see mutations occur in tumors for which we really have no notion of what to do from a therapeutic perspective.

So we really have a gap that has emerged between our ability to call these somatic mutations and identify them, and then actually translate that information into clinically meaningful therapies for patients. There really is a biological gap that has emerged and we have a lot of work to do to resolve that separation.

So towards that end, what is the approach that your lab is taking to develop tools to guide treatment decisions for hematological malignancies?

So in my lab, and there are several other labs around the country and around the world that are taking a similar approach, we call it a functional screening approach. The idea is that we can take primary tumor cells from the tumor of a patient and we can culture these cells in a petri dish in vitro for a short period of time, for a few days, and we can culture them against panels of libraries of cancer drugs and we can over that short culture in vitro, understand which of the drugs are able to effectively kill the tumor cells and which of the drugs are not so good at killing the tumor cells. And therefore, on an individualized basis, we can understand, for each individual tumor and patient, what are the drugs that are most likely to be able to wipe out the tumor cells, the cancer cells from that particular patient. And this approach, we have applied on over a thousand patient specimens. And my particular focus is hematological malignancies, so these have been leukemias and lymphomas, and certainly there are others around the country and the world who are adopting similar lines of inquiry in the solid tumor space. So my feeling is that certainly until we can understand these complex connections between genotype and drug response, this is really an important way that allows us to understand what therapies might be most effective for individual patients. 

is the time frame in which this patient-specific assay can be completed, and then how do you envision this screening tool being used in the clinical setting in the long term?

So, the assay time frame is really just 3 days, and sometimes it stretches to 4 days. So really a few days which is clinical relevant in all settings. And this assay is already being used in early phases in the clinical setting. We actually have some clinical trials that are running right now that are using this assay as a tool to select individualized therapies for patients in a similar way as we discussed at the beginning, of mutations being used, we can also use this functional assay to select therapies for patients. And we are in the early stages,but I do expect and hope that this assay will grow and will continue to be used in this clinical setting much more broadly in the near future.

Thank you so much for joining us today, Dr. Tyner.

American Society of Hematology. (2015). Functional Screening to Guide Personalized Cancer Therapy. American Society of Hematology's 57th Annual Meeting & Exposition, December 5-8, 2015.

Ahead of the 57th ASH Annual Meeting & Exposition, December 5–8, 2015, Jeffrey Tyner, PhD, discusses his latest research on screening tumor cells derived from cancer patients to help guide better treatment decisions. 

Patient Tumor Cell Assays Guiding Personalized Therapy

Advanced lung cancer patients who have tumors with mutations in the epidermal growth factor receptor (

) gene may benefit from the combination treatment of erlotinib standard therapy plus tivantinib.

The results of a preplanned subset analysis of a large phase III previously reported clinical trial were 

) at the International Conference on Molecular Targets and Cancer Therapeutics conference, held November 5-9, 2015, in Boston. This conference was organized by the American Association for Cancer Research and the National Cancer Institute.

The addition of tivantinib, an experimental, oral anticancer drug that has selective anti-c-Met activity, to the standard of care EGFR inhibitor ,erlotinib, improved progression-free survival (PFS), response rate, and also overall survival in some cases, compared to erlotinib alone in patients with previously treated, advanced, non-squamous, EGFR and MET inhibitor naive non-small cell lung cancer (NSCLC).

, results of the randomized phase III MARQUEE patient trial (1,048 enrolled) demonstrated that adding tivantinib to erlotinib treatment improved PFS, but did not improve overall survival compared to erlotinib alone in the overall study population. Patients in the erlotinib plus placebo arm had a median overall survival of 7.8 months compared to 8.5 months in the combination arm (

Of the 109 patients on trial who had tumors positive for an 

 mutation (56 assigned to the combination and 53 to the control arm), those treated with trivantinib had a median PFS of 13.0 months compared to 7.5 months in the control group (

Although not statistically significant, the overall response rate and median overall survival were also increased, from 43% to 61% and from 20.0 months to 25.5 months, respectively. According to Wallace Akerley, MD, director of thoracic oncology at the Huntsman Cancer Institute at the University of Utah in Salt Lake City, greater numbers of patients give a greater chance to show small differences, so this subset analysis was capable of showing only major differences in outcome. Overall survival was also improved from 20.0 months to 25.5 months in the experimental group, although the difference was not statistically significant (

The most common adverse events occurring with erlotinib plus tivantinib versus erlotinib plus placebo were rash (33.1% 

38.1%), and neutropenia (grade 3 to 4; 8.5% 

At data cutoff, six patients of the 56 patients in the combination arm were still on therapy. The duration of therapy ranges from 16 to 25 months.

Because these results are part of a preplanned analysis, the results are not sufficient to demonstrate the efficacy of the combination compared to erlotinib alone. Further studies are needed to confirm these results.

The study was sponsored by ArQule and Daiichi Sankyo.

Advanced lung cancer patients who have tumors with mutations in the epidermal growth factor receptor (EGFR) gene may benefit from the combination treatment of erlotinib standard therapy plus tivantinib. 

Subset of Lung Cancer Patients Have Improved Outcomes with Tivantinib, Erlotinib Combination

The targeted therapy, nivolumab (Opdivo, Bristol Myers Squibb), improved median overall survival by 5.4 months among patients with previously treated renal cell carcinoma (RCC) compared to standard of care everolimus (Afinitor). The results of the phase III CheckMate 025 randomized clinical trial were 

The trial was stopped early, in July 2015, when patients in the nivolumab experimental arm were shown to have superior survival compared to those in the control arm.

Patients treated with the anti-PD-1 antibody had a 27% reduced risk of death compared to those patients treated with the mTOR inhibitor everolimus (

 = .002). The study is the first, according to the manufacturer, Bristol Myers Squibb, to show a survival advantage of an immune checkpoint immunotherapy in RCC.

Patients treated with nivolumab also had a greater objective response rate, 25% compared to 5% of patients in the everolimus arm that responded to treatment (

 < .001). Complete responses occurred in four patients in the nivolumab arm and in two patients in the everolimus arm. The median progression-free survival (PFS) was 4.6 months in the nivolumab arm compared to 4.4 months in the everolimus arm (

While patients with metastatic RCC have several targeted options of therapy, including sorafenib (Nexavar) and sunitinib (Sutent), patients still develop resistance.

The open-label trial randomized 821 previously treated patients with metastatic RCC one to one to either oral, daily everolimus-the recommended second- or third-line therapy-or 3 mg/kg of nivolumab infused every 2 weeks. The primary trial endpoint was overall survival. Patients had a median age of 62 and were predominantly Caucasian men.

The most common treatment-related adverse events among patients who were treated with nivolumab were fatigue (33% of patients), nausea (14%), and pruritus (14%). Patients in the everolimus arm experienced fatigue (34%), stomatitis (29%), and anemia (24%). High-grade treatment-related adverse events occurred in 76 of the 406 patients (19%) in the nivolumab arm and in 145 of the 397 patients (37%) treated with everolimus. The most common grade 3 or grade 4 event was fatigue (2%) with

nivolumab and anemia (8%) with everolimus. There were no deaths from drug related toxicity reported in the nivolumab arm and two in the everolimus arm (one from septic shock and one from acute bowel ischemia).

“The benefit from these agents, as compared with everolimus, is unequivocal,” wrote David I. Quinn, MB, BS, PhD, of the University of Southern California Norris Comprehensive Cancer Center in Los Angeles and Primo N. Lara Jr, MD, of the University of California Davis Comprehensive Cancer Center in Sacramento, Calif., in an accompanying 

. “Given the overall survival advantage it confers and its relatively good side effect profile, nivolumab is the choice for patients who have disease progression while they are receiving VEGF-targeted therapy,” the authors added.

The targeted therapy, nivolumab (Opdivo, Bristol Myers Squibb), improved median overall survival by 5.4 months among patients with previously treated renal cell carcinoma (RCC) compared to standard of care everolimus (Afinitor). 

Nivolumab Improves Kidney Cancer Survival 

A complex, high-dose combination therapy is tolerable and effective in patients with relapsed B-cell lymphoma that has spread to the central nervous system (CNS), according to results of a phase II trial. The treatment studied consisted of cytarabine and methotrexate at high-doses, followed by rituximab plus high-dose sequential chemoimmunotherapy (R-HDS) and autologous stem-cell transplantation (ASCT).

Progression of B-cell lymphoma to the CNS is rare but can occur early in the course of aggressive disease and is difficult to treat. The study was 

Based on prior studies of treatments for CNS-disseminated B-cell lymphoma, AndrÃ©s J. M. Ferreri, MD, of the lymphoid malignancies unit at the San Raffaele Scientific Institute in Milan, Italy, and colleagues tested the novel three-part, radiation-free combination regimen.

Patients were treated with a two-course induction of high-dose methotrexate and cytarabine plus rituximab and intrathecal liposomal cytarabine. Patients with bulky, systematic disease at diagnosis could also be treated with 1 or 2 cycles of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Patients who had progression or stable disease went on to receive salvage therapy. Patients who achieved a complete or partial response after induction then received intensification of R-HDS (cyclophosphamide, cytarabine, and etoposide) at 4-week intervals. Patients with a complete or partial response after the intensification phase were referred for an ASCT. Autologous stem cells were successfully collected in 24 of 27 (89%) patients who completed the first two phases of therapy, and 20 patients received an ASCT.

After a median follow-up of 4 years, 17 of the 38 patients (45%) on study were still relapse free following treatment. The 2-year event-free survival was 50%.

Today, 16 patients from the study are still alive, for a 5-year overall survival rate of 41%. The 5-year overall survival rate for patients who went on to receive transplant was 68%.

Adverse events were generally manageable with grade 4 febrile neutropenia in 3% of patients and grade 4 non-hematologic toxicity in 2% of patients. Those 60 and older did not have many more acute adverse events compared with their younger counterparts. Four patients died on study due to toxicity.

The trial demonstrated that patients over age 65 with a poor performance status had the same survival probability as younger, more fit patients. According to the study authors, the intensive regimen is appropriate for patients between 18 and 70 years of age and should be a standard therapeutic option for B-cell lymphoma patients with secondary CNS disease.

The current study, along with a previously published phase II trial from Germany, “demonstrate that significant progress has been made toward cure in this difficult population of patients,” wrote Norbert Schmitz, MD, PhD, and Huei Shan Wu, both of the Asklepios Hospital St Georg, in Hamburg, Germany, in an 

, “a condition that was almost unanimously fatal only a few years ago.”

A complex high-dose combination therapy is tolerable and effective in patients with aggressive B-cell lymphoma that has spread to the central nervous system.

High-Dose Combination Therapy Improves Outcomes in CNS Lymphoma

Patients with EGFR-positive, non-small cell lung cancer (NSCLC) typically respond well to EGFR-targeted therapy, but eventually these tumors become resistant, leaving patients few options other than palliative care.

One of the dominant resistant mutations identified is a 

 gene. In a phase I clinical trial that enrolled 127 patients with this mutation, the response rate was 61%. Among the 61 patients without a detectable 

mutation, the response rate was 21%. The overall objective tumor response rate was 51%. The results were published April 30, 2015 in 

The median progression free survival (PFS) was 9.6 months in the EGFR T790M-positive patients compared to 2.8 months in EGFR T790M-negative patients. Eighty-eight percent of the patients responded to the drug for 6 months or longer.

In the patients that did not have a detectable 

 mutation, the mechanism of resistance to anti-EGFR targeted therapies was not clear.

The disease control rate-including partial and complete responses plus stable disease was 95 percent in patients whose tumors harbored the 

A total of 253 patients enrolled on the trial received at least one dose of AZD9291 as part of the dose escalation and trial expansion phases. The median patient age was 60 and about 37% of the patients on trial were male.

The clinical trial, led by Pasi JÃ¤nne, MD, PhD, the director of the Lowe Center for Thoracic Oncology at the Dana-Farber Cancer Institute in Boston, enrolled NSCLC patients previously treated with at least one therapy including gefitinib (Iressa), erlotinib (Tarceva), and afatinib (Gilotrif), who have experienced tumor regrowth. This was the first-in-human trial with this agent, AZD9291 (AstraZeneca). The drug has received a fast track designation for approval by the US Food and Drug Administration (FDA).

-mutated lung cancer respond to initial targeted therapy, but the vast majority experience disease progression within 1 or 2 years of starting therapy due to acquired resistance. The 

 mutation is responsible for an estimated 60% of these cases of resistance, preventing EGFR-targeting agents such as gefitinib or erlotinib from binding to the tyrosine kinase domain of the EGFR protein.

AZD9291 is a novel oral, irreversible EGFR tyrosine kinase inhibitor selective for EGFR T790M resistance and tyrosine kinase inhibitor–sensitizing mutations that shows less activity against the wild-type version of the protein compared to other EGFR inhibitors.

The most common adverse events were diarrhea, rash, nausea, and decreased appetite. The rate of serious side effects was low. A total of 22% of patients experienced a serious adverse event and 6% of these events were deemed drug-related. Six percent of patients had to discontinue the drug or have their doses lowered. Six patients had cases of potential pneumonitis-like events. These patients discontinued the drug and the events were resolved. Seven fatal adverse events occurred, including one potentially drug-related pneumonia.

According to the study authors, the most effective strategy for treating resistant 

-mutated lung cancer is the combination of afatinib and cetuximab which has shown a response rate of about 29%, but is linked to considerably high skin and gastrointestinal toxicities. “In contrast, we found that AZD9291 as monotherapy was associated with a response rate of 61%, with limited skin and gastrointestinal adverse effects, among patients with EGFR T790M,” stated the authors in their discussion

The study authors note that AZD9291 was “highly active” in those patients with the 

 mutation who had disease progression following first-line EGFR tyrosine kinase inhibitor therapy.

“Previously, if a patient became resistant to kinase inhibitors like Tarceva, they were treated with chemotherapy,” said JÃ¤nne in a statement. “Now there is this option, and the beautiful part is they don’t have the side effects of Tarceva – this drug is better tolerated.”

AstraZeneca plans to file this data with the FDA in the second half of 2015.

JÃ¤nne P, Yang JCH, Kim DW, et al. (2015). 

AZD9291 in EGFR Inhibitor–Resistant Non–Small-Cell Lung Cancer

Patients with EGFR-positive, non-small cell lung cancer (NSCLC) typically respond well to EGFR-targeted therapy, but eventually these tumors become resistant, leaving patients few options other than palliative care. 

Novel Therapy for Resistant EGFR-Mutated Lung Cancer

Inherited variants in an androgen transporter gene may determine the time to progression (TTP) for men with prostate cancer receiving androgen deprivation therapy (ADT).

In a cohort of 616 men with prostate cancer treated with ADT, one of three single nucleotide polymorphisms (SNP) within the 

gene tested-the risk allele-was associated with TTP using two types of statistical analyses (

The median overall survival from the start of ADT was 6.5 years for all 1,094 patients included in the original and validation cohort.

A different SNP was significantly associated with overall survival (OS) after initiation of ADT using two types of statistical analyses (

= .014). The difference of median OS was 18 months.

 by Philip Kantoff, MD, leader of the Dana-Farber/Harvard Cancer Center Prostate Cancer Program in Boston, at the 2015 Genitourinary Cancers Symposium held February 26-28, in Orlando, Fla.

In normal prostate tissue, the predominant SNP linked to OS resulted in lower expression of SLCO2B1 compared to tissue expressing the risk allele (

-trend = .0193). According to the study authors, this suggests that the association between the predominant allele and OS may be linked to the expression levels of the SLCO2B1 protein.

SLCO2B1 functions as a transporter of steroids including testosterone and other forms of androgens. The risk allele of the 

gene was previously shown by these authors to result in more efficient import of androgen precursors--dehydroepiandrosterone (DHEA) and the sulfated form, DHEAS-which boosts androgen receptor signaling and cell growth, and in turn, results in shorter TTP. Both DHEA and DHEAS are important precursors for testosterone production in the tumor microenvironment, and DHEA alone has been shown to bind to mutated forms of the androgen receptor found in prostate tumors.

“DHEAS is a precursor of testosterone and dihydrotestosterone, which are potent androgens. SLCO2B1 is the mechanism by which DHEAS gets taken up by cells,” explained Kantoff.

In the current study, in vitro knockdown of SLCOB1 results in decreased uptake of androgens and decreased prostate tumor cell growth.

From both the patient and in vitro data, the authors conclude that germline variants in the SLCO2B1 transporter can affect expression of this protein and the uptake of androgen precursors, which can affect outcomes for prostate cancer patients treated with ADT.

“Germline variants determine the activity of SLCO2B1 and thereby, the uptake of DHEAS by cells including prostate cancer cells,” said Kantoff.

The study also showed that statins interfere with the uptake of DHEAS into cells, as statins are also substrates of SLCO2B1. This increases the time to progression on androgen deprivation therapy, according to Kantoff. “This highlights the need to understand the complex interactions of cancer therapies and the other agents that patients are taking.”

The authors are currently planning further validation studies. With further validation, it may be possible to use this gene as a prognostic tool of response to ADT in prostate cancer patients. It may also be possible to inhibit the activity of this androgen transporter to improve patients’ responses to ADT.

Gene Variants May Predict Prostate Cancer Progression on ADT

Researchers have shown that reprogramming T cells to target glioblastoma in mice resulted in control of these tumors. The approach, shown to be safe in mice, is now being tested in humans: A new glioblastoma clinical trial has just opened at the University of Pennsylvania to test this chimeric antigen receptor (CAR) immunotherapy.

Marcela Maus, MD, PhD, of the division of hematology and oncology at the University of Pennsylvania Abramson Cancer Center in Philadelphia, and colleagues designed murine T cells to express a CAR that targets the epidermal growth factor receptor protein, EGFRvIII. This protein is expressed on approximately 30% of glioblastomas.

CARs are engineered, synthetic molecules that are designed to be expressed on T cells extracted from a patient. T cells are extracted from a patient’s blood sample and modified in vitro. The CAR-modified T cells are then infused back into the patient to direct the T cells to attack the protein on the tumor. The researchers at the University of Pennsylvania had developed this immunotherapy technique and demonstrated its utility in treating patients, including children, with B-cell malignancies.

Glioblastomas are generally aggressive, rapidly growing tumors. Adults with this form of brain cancer generally have a median survival of about 15 months after diagnosis. Patients whose glioblastomas express EGFRvIII have an even more aggressive form of the disease, are less likely to respond to the standard therapies-usually chemotherapy and radiation therapy-and are more likely to recur post-treatment.

In the current study, the authors first demonstrated that the CAR-expressing T cells were able to specifically proliferate, secrete cytokines, and lyse in response to the EGFRvIII antigen. The specificity of the EGFR-targeting T cells was validated both in vitro, using EGFR-expressing keratinocytes, and in vivo, using a mouse model with grafted noncancerous human skin. The EGFRvIII-targeting T cells bound only to mutated EGFR and not wild-type EGFR found in noncancerous cells.

In mouse models, the CAR T cells could control the growth of tumors expressing human EGFRvIII, as measured by magnetic resonance imaging scans of the mouse brains. In some mice, the tumors disappeared entirely.

Based on these studies in mice, the study team has started a phase I pilot trial of EGFRvIII CAR T cells in patients with glioblastoma whose tumors are EGFRvIII-positive (Clinicaltrials.gov identifier: NCT02209376). The trial plans to enroll 12 glioblastoma patients, 6 with recurrent disease and 6 with newly diagnosed disease who have 1 cm or more of tumor tissue remaining after surgery. The clinical trial is sponsored by Novartis, which has an agreement with the University of Pennsylvania to develop and commercialize the CAR T-cell immunotherapy approach.

This mouse study underscores the ability of this immunotherapy approach to potentially work for solid tumors. Using the CAR T-cell therapy approach has been met with hurdles in solid tumors, as many of the potential antigens expressed on solid tumors are also expressed on normal tissue. “A series of Penn trials that began in 2010 have found that engineered T cells have an effect in treating some blood cancers, but expanding this approach into solid tumors has posed challenges,” said Maus in a statement. “A challenging aspect of applying engineered T-cell technology is finding the best targets that are found on tumors but not normal tissues. This is the key to making this kind of T-cell therapy both effective and safe.”

Researchers have shown that reprogramming T cells to target glioblastoma in mice resulted in control of these tumors.

Personalized T-Cell Therapy for Brain Cancer

Neither sunitinib nor sorafenib reduced disease recurrence in patients with locally advanced renal cell carcinoma (RCC) when these agents were given to patients as adjuvant therapy, according to the results of a new study. These results were 

 at a press conference in advance at the 2015 ASCO Genitourinary Cancers Symposium.

 (Eastern Oncology Cooperative Group E2805) study showed that both sunitinib and sorafenib adjuvant therapy resulted in an average disease recurrence time of 5.6 years compared to 5.7 years in the placebo arm.

“[This is] a very important study, the first adjuvant study using tyrosine kinase inhibitors in kidney cancer,” said Charles Ryan, MD, leader of the genitourinary medical oncology program at the University of California San Francisco, and press conference moderator. “The fact that it is a negative study does not diminish its importance. [Tyrosine kinase inhibitors] are not chemotherapy and act in a different manner; therefore, they may not be as effective against micro-metastatic disease as chemotherapy in other tumors.”

“It was not intuitive that adjuvant use would be beneficial, and that underscores the importance of this study,” added Ryan.

According to presenter and study author Naomi B. Haas, MD, Associate Professor of Medicine at the Abramson Cancer Center of the University of Pennsylvania in Philadelphia, the authors are currently analyzing patient samples to understand whether a subset of patients may benefit from either of these oral tyrosine kinase inhibitors against vascular endothelial growth factor receptors (VEGFR) and platelet-derived growth factor receptors (PDGFR).

This is the first study to test whether VEGF inhibitors can decrease the risk of recurrence for these locally advanced RCC patients. Approximately one-third of these patients develop metastatic disease. VEGF-targeted tyrosine kinases have resulted in some benefit in the metastatic RCC setting. Currently, there is no standard of care adjuvant therapy. Most patients are closely observed for disease progression.

A total of 1,943 patients were randomized to receive daily sunitinib, twice daily sorafenib, or placebo for 12 months. All patients were high-risk for recurrence based on tumor size and grade, and lymph node status.

There were no differences in the 5-year disease-free survival rates between the experimental arm and the placebo arm, 53.8%, 52.8%, and 55.8%, for the sunitinib, sorafenib, and placebo arms, respectively.

Likewise, there were no differences between either experimental arm or the placebo arm. The 5-year overall survival rate was 76.9%, 80.7%, and 78.7% in the sunitinib, sorafenib, and placebo arms, respectively.

There were higher incidences of hypertension in the two treatment arms compared to the placebo group. Grade 3 or higher hypertension was experienced by 16% in each of the experimental arms and in 4% of the placebo arm. Grade 3 or higher hand-foot reaction was experienced by 15%, 33%, and 1% of patients in the sunitinib, sorafenib, and placebo arms, respectively.

The side effects included hand-foot syndrome, diarrhea, and hypertension, said Haas. Hematologic effects included thrombocytopenia in 1% of patients in the sunitnib arm, less than 1% in the sorafenib arm and in no patients in the placebo arm.

Adjuvant treatment of locally advanced kidney cancer is an area of continuing research. Several trials using other VEGF inhibitors have finished accruing patients and are awaiting analysis. Trials using immunotherapy and other targeted therapy approaches are being planned as well.

Neither sunitinib nor sorafenib reduced disease recurrence in patients with locally advanced renal cell carcinoma (RCC) when these agents were given to patients as adjuvant therapy, according to the results of a new study. 