Mutation detection using plasma- and urine-based circulating tumor DNA (ctDNA) assays is growing in frequency among the ever-expanding field of liquid biopsies, especially for identifying patients with nonsmall cell lung cancer (NSCLC) with an

&ldquo;Looking for T790M is something that&rsquo;s an area of active investigation and there are a lot of different platforms being developed,&rdquo; Heather Wakelee, MD said.

Wakelee, an associate professor of medicine in the Division of Oncology at Stanford University Medical Center, and colleagues examined T790M mutation detection among different platforms in an analysis from the TIGER-X trial that was presented at the International Association for the Study of Lung Cancer 17th World Conference on Lung Cancer.

Examining molecular diagnostic results from 174 matched tissue samples and plasma and urine ctDNA specimens, researchers found that 170 of these patients (97.7%) tested positive for the T790M mutation, which was discovered by any one of the 3 methods. Plasma ctDNA testing alone identified 142 total cases (81.6%), urine ctDNA testing identified 139 (79.9%), and combined urine and plasma ctDNA testing identified 165 cases (94.8%). Further, combination testing identified T790M in 92.7% of patients with intrathoracic disease and in 95.8% of patients with extrathoracic disease (P = .47).

(TTO), Wakelee discusses the sensitivity of plasma and urine ctDNA platforms and the benefits of each, as well as the possibility for combined plasma and urine ctDNA testing for T790M mutation detection.

TTO: How was T790M mutation detection analyzed between different platforms?

The study was an additional analysis from the TIGER-X trial. That was a study looking at the drug rociletinib, which is no longer in development now, but was at the time. It&rsquo;s an

- specific drug, designed for the T790M resistance mutation. The patients who went on the trial all had

-mutated lung cancer and had progressed on a standard first-generation drug. With that, the patients who were enrolled all theoretically had T790M.

We had tissue from over 500 patients, plasma from almost as many, and then we had urine from over 200 patientsthe urine was a secondary test so not all of the patients participated&mdash;but we looked to see if we could find the T790M mutation in different platforms. We had 2 different tests for the plasma&mdash;one was the BEAMing assay, which is a bit more standard, and the other one was the Trovera next-generation sequencing (NGS) analysis; it was that same technology that also looked for the urine T790M. For tissue testing, it was the more standard cobas or Qiagen. We then looked across these different platforms for how frequently we could find T790M.

TTO: How did the results differ between each of the platforms?

The sensitivity of all the assays is quite good. We could find about 80% sensitivity for T790M with either of the plasma assays, as well as with the urine assay. What&rsquo;s particularly interesting is when you look at how they all intersect. For most of the patients, we were able to find T790M by all 3 assays. But there were some subsets of patients where we only found it with the plasma assay or only with the urine assay or only in the tissue. When we looked back to see how that correlated with drug response, it didn&rsquo;t matter how you found T790M; whatever way you found it predicted for drug response.

TTO: What is the significance of this finding according to each of the platforms?

It tells us that it&rsquo;s not that you&rsquo;re getting false positives, it&rsquo;s more that there&rsquo;s some false negatives. For tissue, that&rsquo;s more likely [due to] tissue heterogeneity, where you might have a specific piece of tumor biopsy but that&rsquo;s not necessarily where T790M is. With both the plasma and urine assays, it has more to do with the sensitivity of the test.

From a practical standpoint, I think what it tells us is that we can definitely consider doing either the urine or a plasma assay to look for T790M in our patients with EGFR mutations who are now becoming resistant. But if we don&rsquo;t necessarily find T790M that way we shouldn&rsquo;t say "Oh, they don&rsquo;t have it,&rsquo; but we should then think about doing the tissue analysis.

TTO: What sets the urine platform apart from the plasma assays?

Looking for T790M is something that&rsquo;s an area of active investigation and there are a lot of different platforms being developed. This is really the first urine assay, which is what&rsquo;s unique about it. I&rsquo;ve had examples in my clinic where a patient will come in and they&rsquo;ve already had their blood drawn before they come see me, and then we see the scan result that shows progression, so then we talk about T790M testing and many of them say, "I really don&rsquo;t want to go back and get my blood drawn," so that&rsquo;s one particular utility of the urine.

One other thing, especially in a subset of patients where the progression is not everywhere but just in the lungsthe M1a patients&mdash; for those, the sensitivity of the plasma was a little bit lower for the M1a patients versus the M1b patients, where there were more extensive metastases. But with the urine assay it didn&rsquo;t seem to matter as much. When you combine the urine and the plasma together, the sensitivity for the M1a patients was over 90%, and for the M1b patients it was over 95%. So that&rsquo;s really good. If we could do a urine and a plasma test, you&rsquo;re going to increase your sensitivity such that we&rsquo;ll be able to do a biopsy for the majority of patients, hopefully.

TTO: What remaining challenges in the area of T790M testing in patients with NSCLC would you like to see addressed in the future?

I think that one of the remaining challenges is that no assay that we have for T790M is perfect, and so I think continuing to improve the sensitivity, specificity, also bringing cost down for patients, I think that that&rsquo;s where we have room for development. Remaining research questions are going to be: how often should we test, if you find T790M in a patient before they have clinical progression what does that mean, and when do we think about making those switches in our therapies.

Wakelee H, Melnikova V, Karlovich CA, et al. A highly sensitive next-generation sequencing platform for detection of NSCLC EGFR T790M mutation in urine and plasma. Presented at: IASLC 17th World Confer- ence on Lung Cancer; December 4-7, 2016; Vienna, Austria. Abstract MA08.01.

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Heather Wakelee, MD, discusses T790M mutation detection among different platforms in an analysis from the TIGER-X trial

Testing the Sensitivity of T790M Mutation Detection Across Platforms

Centers for Medicare and Medicaid Services (CMS) and Rep Nancy Pelosi (D, California) have confirmed the demise of the Medicare Part B Drug Payment Model experiment to cut margins paid to physicians on some of the most expensive drugs and introduce private-sector thinking into drug purchasing and pricing systems.

The proposed model had drawn strenuous broadsides from the medical community, including the Community Oncology Alliance (COA) and the American Society of Clinical Oncology (ASCO), which contended that the revision of the drug payment formula would have left physicians financially underwater on many drugs.

&ldquo;While the proposed Medicare Part B demonstration had admirable goals, our members raised a number of concerns, and we are pleased the Center for Medicare and Medicaid Innovation [CMMI] has decided not to move forward,&rdquo; Pelosi said in a statement.

In late November, CMS missed an important deadline for putting the Part B model into effect. As a result, President Barack Obama did not have enough time to enact the measure. Some health policy makers speculated that with the incoming Republican administration, the payment model would not have survived anyway.

&ldquo;Cancer patients and their providers across the country can breathe a sigh of relief now that the Part B experiment on cancer care is finally dead. It was encouraging to have such strong support from Congress to end this proposed model that was, at best, an overreach by CMS, created with no stakeholder input,&rdquo; COA said in a statement when the Part B model was confirmed to have failed.

The Part B model originated from the CMMI, an arm of CMS commissioned to design and test reform measures that would bring the government payer closer to its goals of cutting waste and inefficiency and improving patient outcomes. Dissatisfaction with the drug payment model proposal led some on Capitol Hill to call for the abolition of the CMMI.

The CMMI was also the originator of the Oncology Care Model (OCM), an experiment that was launched this year to test new payment methodology, physician performance measurement, and patient care coordination. The OCM has faced criticism, too, although some physician groups involved with it have acknowledged value in the program as they have overcome some of the hurdles of adoption.

A main point of contention of the Part B payment model was the proposal by CMS to lower the average sales price (ASP) plus 6% formula for drug payments to ASP plus 2.5%. The formula applies to drugs that are dispensed through a physician&rsquo;s office or a hospital outpatient department.

COA and ASCO had responded that there are already discounts applied to the 6% formula, as well as other factors that compromise payment margins, and that the true adjusted margin allowed for drug dispensing practices is far lower. The 2.5% rate plus the proposed at fee per drug, they said, would put them &ldquo;underwater&rdquo; for a lot of drugs they currently dispense.

For its part, CMS described the model as a drug payment experiment, which drew deep cynicism from the physician community. Ted Okon, the executive director of COA, who was a leader in the lobbying effort to defeat the measure, contended that the enormous scale of the experimentslated to involve all physicians whose patients received Part B drugs&mdash;and the lack of initial communication with the medical community about the design of the program seemed like a Democratic plot to cut drug payments under the guise of a balanced, scientific payment model.

&ldquo;The Part B model was air-dropped in with literally no stakeholder input. The administration tried to abuse the powers of the CMMI to push through a separate agenda. I think everybody saw through that,&rdquo; Okon said. He added that the Part B battle may have even jeopardized the future of the CMMI.

In her remarks, Pelosi appears to have anticipated the lasting tarnish that CMMI has suffered as a result of the failed payment model. &ldquo;The Innovation Center is a valuable tool in our continued pursuit of ways to strengthen the healthcare available to the American people,&rdquo; she said.

In addition, she stated that the effort to control soaring costs of care must continue. &ldquo;Prescription drug costs represent the largest factor driving rising healthcare costs in America today. Congress must come together in a bipartisan way to address the soaring costs of prescription drugs in a way that supports the search for cures while ensuring that patients can afford these treatments.&rdquo;

In its statement, COA said that although its membership is relieved about the official termination of the Part B Drug Payment Model, it is committed to the effort to improve the value equation in medicine.

&ldquo;COA is deeply committed to increasing the quality of cancer care and decreasing costs,for both drugs as well as hospital-related costs, the biggest driver of cancer treatment spending. We are working overtime to make the CMS Innovation Center's Oncology Care Model successful by networking participating providers and payers to share information and resources, as well as by hosting summits, conferences, and meetings to discuss and exchange ideas on oncology payment reform,&rdquo; according to the statement.

Centers for Medicare and Medicaid Services and Rep Nancy Pelosi have confirmed the demise of the Medicare Part B Drug Payment Model experiment to cut margins.

Victory Declared in CMS Part B Payment Battle

The Society for Immunotherapy of Cancer&rsquo;s (SITC) Annual Meeting is the largest meeting dedicated solely to the field of cancer immunotherapy. In line with SITC&rsquo;s goal of improving outcomes for patients with cancer, SITC&rsquo;s 31st Annual Meeting (SITC 2016; November 9-13, 2016; National Harbor, Maryland) brought together leading cancer immunotherapy experts to discuss research and clinical practice, and national and international initiatives. This article summarizes some key highlights from SITC 2016.

New Cancer Immunotherapy Agents in Development

This dynamic program featured rapid-fire presentations on novel immunotherapeutic strategies. Combination immunotherapy approaches, especially those including immune checkpoint blockade, dominated both the clinical and preclinical sessions. The importance of understanding the mechanistic basis for the clinical efficacy of particular combination strategies was emphasized, and optimization of the drug development process and integration of biomarkers into clinical decision making were also identified as critical to ensuring that only the most promising trials are selected to move forward.

Primer on Tumor Immunology and Cancer Immunotherapy

The development of novel immune-based cancer treatment options is the result of a dramatic increase in our understanding of tumor immunology. This 1-day educational program provided a foundation in core immunology principles for students and postdoctoral fellows, and provided more senior physicians and scientists with the opportunity to solidify their understanding of immuno-oncology as it relates to basic and clinical research in cancer immunotherapy.

Workshop on Challenges, Insights, and Future Directions for Mouse and Humanized Models in Cancer Immunology and Immunotherapy Disease models are important tools to inform the future of immune drug development and aid our understanding of the mechanisms underlying antitumor immune responses. This workshop provided a comprehensive discussion on the strengths and weaknesses of a variety of models, approaches toward improving the predictive value of mouse models, and anticipated advances in cancer modeling, with a focus on how to accurately model the tumor immune microenvironment.

Presented by leaders in the field, this year&rsquo;s plenary sessions addressed topics central to progress in tumor immunology and cancer immunotherapy, including the tumor microenvironment, state-of-the-art immunotherapies, the future of combination immunotherapy, and high-priority agents under investigation in the Cancer Immunotherapy Trials Network (CITN). In addition, the 31st Annual Meeting featured a number of thought-provoking concurrent sessions, 2 of which were interdisciplinary programs organized in collaboration with the American Society for Cell Biology and the Society of Behavioral Medicine.

Building on the success of the SITC 2015 Value of Cancer Immunotherapy Session, this half-day program, which was organized in collaboration with the American Society of Clinical Oncology, united experts in cancer immunotherapy with key stakeholders in the healthcare system, and also provided a patient perspective. Presenters emphasized that the unique aspects of immune-based agents will affect the real value of these therapies and helped prioritize the direction of future discussions on the value of cancer immunotherapy. Based on the outcomes of this summit, SITC will continue its efforts to optimize the value framework for cancer therapeutics to ensure patients have access to high-quality, cost-effective care.

Abstracts featuring cutting-edge data from basic and translational research, clinical trials, and aspects of clinical management were presented throughout the meeting. Some of the most novel and practice-changing clinical trials are highlighted below.

In a highly anticipated presentation, Joaquim Bellmunt, MD, PhD, of Dana-Farber/Brigham and Women&rsquo;s Cancer Center, shared data on the effects of pembrolizumab (Keytruda) versus investigators&rsquo; choice of standard chemotherapy agents for the treatment of advanced bladder cancer. This international study reported significantly longer overall survival in patients treated with pembrolizumab (HR, 0.73; P = .0022; median 10.3 vs 7.4 months), and this was seen across all PD-L1 populations. This study was halted prematurely due to the markedly superior response in patients treated with pembrolizumab and is noteworthy in being the first in almost 20 years to demonstrate improved overall survival for patients with advanced bladder cancer.

Interim data from a multicenter phase I/II trial investigating 2 dose schedules of ipilimumab (Yervoy) and nivolumab (Opdivo; 1 mg/3 mg vs 3 mg/1 mg) in patients with advanced or metastatic urothelial cancer that progressed after chemotherapy were presented by Padmanee Sharma, MD, PhD, of The University of Texas MD Anderson Cancer Center. Patients in the nivolumab 1/ ipilimumab 3 arm had an objective response rate (ORR) of 38.5%, while ORR in the nivolumab 3/ipilimumab 1 and nivolumab monotherapy arms were 26.0% and 25.5%, respectively. Median overall survival was also higher in the nivolumab 1/ipilimumab 3 group (10.2 months [95% CI, 4.5-not reached]) than the nivolumab 3/ipilimumab 1 group (7.3 months [95% CI, 5.6-11.4]). Side effects in the combination treatment groups were similar to those observed in other studies. These results support further development of the nivolumab 1/ipilimumab 3 combination for treatment of metastatic urothelial cancer.

John Hunter, PhD, of Compugen Inc, presented findings from an international study that used proprietary computational algorithms to identify a potential new T-cell checkpoint, PVRIG. PVRIG is a member of the TIGIT molecular family that is expressed on T cells and NK cells. The Compugen group also developed an anti- body specific for PVRIG, which enhanced CD4+ and CD8+ T cell proliferation in vitro and significantly reduced tumor growth when combined with antiPD-1 therapy growth (P = .0005; 56% tumor growth inhibition) in vivo. New immunotherapeutic targets, such as PVRIG, that can be used in combination might help expand the proportion of patients who respond to treatment with immune checkpoint inhibitors.

SITC Initiatives: Updates From the Immune Biomarkers Task Force and Immunoscore Validation Project

SITC President and Immune Biomarkers Task Force Chair Lisa Butterfield, PhD, of the University of Pittsburgh, reported recent progress from the SITC Immune Biomarkers Task Force, which was established to address novel topics in the field, including technologies and high-throughput approaches, novel and conventional agents affecting immunity, bioinformatics, complex data analysis, and advances in biological sampling. From 2015 to 2016, 4 working groups (WGs) sought to address challenges barring progress in the field. In this ongoing effort, these WGs have generated 5 white papers and led a dedicated workshop, Immunotherapy Biomarkers 2016: Overcoming the Barriers, held in collaboration with the National Institutes of Health. In addition, the WGs also authored 12 short reports highlighting novel technologies used for biomarker development in a series published in the Journal for Immunotherapy of Cancer.

As an update to the results presented at ASCO 2016, Jérôme Galon, PhD, of INSERM, presented the latest results of the SITC Immunoscore Validation Project, a SITC-led international effort to validate the Immunoscore, which is a standardized immunohisto-chemistry-based assay to measure the immune contexture in and around tumors. As presented previously, the primary objective of this study in patients with stage I-III colon cancer was reached; Immunoscore high versus low predicted time to recurrence in each of the separate groups examined. New data were also presented, in which Immunoscore was predictive of overall and disease-free survival independent of MSI status (high vs low). These findings illustrate the prognostic value of Immunoscore and justify the use of immune parameters as a new component of cancer classification.

Some key highlights from&nbsp;SITC&rsquo;s 31st Annual Meeting

Highlights from SITC's 31st Annual Meeting & Associated Programs

The growth of the oncology drug pipeline has fueled the emergence of new oral therapies. While these therapies make treatment more convenient, when compared with traditional infused chemotherapy regimens, they also present new challenges, particularly in the area of adherence. According to some studies, adherence rates for oral oncolytics dip as low as 20%.

When oncology medications are taken in a home setting and there are fewer face-to-face interactions with the prescriber, patients can find it challenging to manage side effects and adhere to complex dosing regimens. Additionally, the evolution of oncology therapies over the past decade is mirrored by a rise in treatment costs that can play a role in a patient&rsquo;s decision to begin treatment or stop using the medication. Given the access, challenges, and increased responsibilities on patients taking these therapies and the continued use of value-based reimbursement models by payers, it is critical to design patient-centric programs for oral oncolytics that improve patient adherence through stakeholder collaboration. Healthcare providers, such as oncologists, oncology nurses, and specialty pharmacists, must leverage their collective resources and expertise to enable each patient to realize the best possible outcome.

Oncology patients often face high out-of-pocket costs associated with their treatment regimens. While in-office treatments and diagnostics are often covered under the medical benefit, oral oncolytics are likely managed under the patient&rsquo;s pharmacy benefit. Normally, patients pay between 20% and 30%

out-of-pocket for the treatment, which can translate to about $24,000 to $36,000 over a year, without factoring in health insurance premiums. Patient assistance programs and private foundations exist to help patients who face affordability challenges, and specialty pharmacies, working collaboratively with physicians, play a key role in connecting patients to these resources. For example, physicians in the ION Solutions network will refer the patient to US Bioservices, Amerisource Bergen&rsquo;s national specialty pharmacy, which helps expedite the patient&rsquo;s start of therapy at the lowest out-of-pocket cost to the patient. The ION physician network includes non-dispensing practices and dispensing practices that lack access to a specific specialty product. Even after insurance authorizations are secured, financial assistance options can be difficult for a patient to navigate. Pharmacy specialists provide continued guidance related to manufacturer copay assistance program enrollment and foundation assistance temporary and long-term approvals. Ultimately, when specialty pharmacies and physicians work together to ensure patients&rsquo; access to therapy, financial barriers are overcome and speed-to-therapy is accelerated.

Patient and caregiver education and communication is essential, not only as a patient begins therapy but also throughout treatment, when a patient may experience side effects that require dose or therapy adjustments. During infused oncology regimens for which patients travel to a care site, oncologists can educate patients about their specific therapy, manage their expectations, closely monitor the progression of their health status, and mitigate potential side effects. When a patient self-administers an oral therapy at home, an integrated approach is needed to monitor treatment, identify the barriers a patient may face and connect them to available resources and support. Specialty pharmacies can increase patient touchpoints and fill in gaps between patient-practice interactions, adding a layer of therapy-specific support and education provided by pharmacy clinicians. Through clinical assessments, specialty pharmacies gain frequent, actionable information about the patient&rsquo;s progress and work in partnership with healthcare providers to help patients overcome challenges and adhere to therapy. For example, US Bioservices specialty pharmacy partnered with oncology practices that are members of the ION Solutions group purchasing organization to establish nursing outreach programs that proactively manage patients at key milestones in their therapies. The specialty pharmacy monitors data, including information pulled from clinical trials, to determine when a patient is likely to experience side effects and then works with oncologists to develop appropriately timed communication and escalation protocols.

Additionally, resources like US Bioservices&rsquo; MyPathpoint prescriber portal improve the connectivity between a physician&rsquo;s office and the pharmacy, allowing these stakeholders to deliver more clinically integrated care to the patient. Prescribers gain real-time access to pharmacy care team notes and detailed information about patient interactions along with the status of a prescription from receipt to delivery. Prescribers can also use the portal to easily provide information back to the pharmacy, such as clinical documentation, refill approvals, and new prescriptions. With transparent information sharing, not only can the prescriber more closely monitor the patient, but also the pharmacy and the prescriber can offer more seamless and consistent patient communication, which promotes adherence.

Just as models for patient communication continue to evolve so do dispensing models. These models range from pharmacy benefit management controlled models to independent specialty pharmacies to oncology practices that offer in-office dispensing services. Regardless of the model, every member of a care team provides better patient support when they have transparency in regard to the factors that influence access, adherence and outcomes. Increased collaboration between oncologists, nurses, and pharmacists not only improves the patient experience but also helps to manage costs and resourcesand ensures appropriate clinical management.

With the changing healthcare landscape and the continued introduction of new therapies, providers will continue to face challenges associated with maximizing clinical outcomes, particularly as the growing use of oral oncolytics shifts the site of treatment from a physician&rsquo;s office to a patient&rsquo;s home. However, oncologists and specialty pharmacists, collectively, have the resources and expertise needed to help patients navigate the challenges faced throughout treatment, including adherence, so each patient can realize the full benefit of therapy.

Patient Adherence to Oral Cancer Therapies: A Nursing Resource Guide | Oncolink - Cancer Resources. Oncolinkorg. 2016.

http://www.oncolink.org/resources/article.cfm?c=424&id=7058

Glover L. Oncologists worry about rising costs of cancer treatment. US News & World Report. 2015.

http:// health.usnews.com/health-news/patient-advice/articles/2015/07/01/oncologists-worry-about-rising- costs-of-cancer-treatment

The growth of the oncology drug pipeline has fueled the emergence of new oral therapies. While these therapies make treatment more convenient, when compared with traditional infused chemotherapy regimens, they also present new challenges, particularly in the area of adherence.

Collaborative Approach to Specialty Pharmacy Improves Adherence to Oral Oncolytics

As oncologists await future treatment advances in metastatic castration-resistant prostate cancer (mCRPC), the key is to unleash the full potential of available therapies, Robert Dreicer, MD, asserted during the 2016 CFS Chemotherapy Foundation Symposium.

One agent that oncologist are focused on optimizing, Dreicer said, is radium-223 (Xofigo). Optimal use of this treatment remains mostly unknown, with current efforts focusing on exploring the agent&rsquo;s potential in combination regimens.

For instance, a phase III trial is randomizing patients with bone predominant mCRPC to radium-223 plus abiraterone acetate (Zytiga) or abiraterone alone (NCT02043678). Additionally, a randomized phase IIa study is evaluating the efficacy and safety of radium-223 in combination with abiraterone or enzalutamide (Xtandi) in patients with mCRPC to investigate bone-scan response, radiological progression-free survival, overall survival, and skeletal events (NCT02034552).

(TTO), Dreicer, associate director, Clinical Research, and deputy director, University of Virginia Cancer Center, discussed ongoing developments in mCRPC, including the latest approaches with radium-223.

Radium-223 is a very unique agent, and it&rsquo;s one of the 2 approved therapies in advanced prostate cancer that is not an AR- targeted therapy. It makes some intrinsic sense to take multiple different pathways to treat a disease, and therefore the combining of agents like abiraterone and enzalutamide with radium-223 is a very intriguing and appropriate set of studies to donot only because we&rsquo;re trying to figure out if we can do better in terms of getting better responses, more prolonged responses, changed progression-free survival, things like that, but frankly also from an economic perspective. Before we start combining very expensive agents, we need some indication that there&rsquo;s a rationale to do that. So it&rsquo;s clearly an important thing to study. Are we anywhere close to knowing the answers to that? I don&rsquo;t think so, but the studies are ongoing.

What are some ongoing studies with radium-223?

A number of studies are being done, including retreatment studies, to look at more than 6 cycles of therapythe 6 being somewhat arbitrary. The retreatment paradigm is very intriguing, especially in patients who may have benefitted. Remember, one of the challenges with radium-223 is that there&rsquo;s no objective antitumor activity. It&rsquo;s a bone-targeted therapy; PSA responses are not common.

Therefore, radium-223 is still one of those therapies that we wonder how to optimally integrate into the management paradigm. And, because it&rsquo;s bone-targeted, patients with more than minimal nodal disease really are not great candidates, so that&rsquo;s another reason to think about combinatorial treatment. There are a lot of things about radium-223 that remain to be addressed, and I think its uptake in the community is still patchy. I think some of that is practice patterns, and understanding where it may be best applied, so more data will certainly help clinicians in the community to figure out when radium-223, or radium-223 combinations, may be best for their patients.

Anecdotally, how have you seen this agent specifically impact patients in terms of quality of life?

I tend to use it in a pre-docetaxel setting. These are patients who meet the label, in terms of having some minimal to moderate pain.

Pain relief is a little hard to gauge. Again, many of these patients are not that symptomatic, and of course, all of our patients have osteoar- thritis. It&rsquo;s a challenge, one that&rsquo;s not typical when we compare it to challenges associated with sipuleucel-T (Provenge). There&rsquo;s no real true way to understand objective antitumor activity.

Therefore, if you can treat someone with 6 cycles of therapy and their disease has not overtly progressed, is it because of or in spite of [the therapy]? We know from the randomized trial that there is a survival benefit. So, in a sense, when we use these therapies, because a pain endpoint was not baked into the randomized trial, it&rsquo;s a little hard to tell a patient, &ldquo;Look, we&rsquo;re doing this to try to minimize your pain. What we&rsquo;re trying to do is, we know that there&rsquo;s a decrease in symptomatic skeletal events, and that there may be a survival benefit.&rdquo; And I think that that&rsquo;s how we approach patients today. I&rsquo;d like more data to be able to be a bit more definitive.

Do you&nbsp;think that there will be a newer or second-generation version of radium-223? Is there going to be some competition there?

That&rsquo;s an interesting question. Because it&rsquo;s a unique molecule, because of its sparing of the bone marrow and relatively well-tolerated profile, it lends itself to integration earlier in the disease course, where it&rsquo;s going to be studied, and it lends itself to combinatorial therapies. I suspect we&rsquo;re going to see more and more of this. It&rsquo;s a bone-trophic disease, and therefore, there are going to be a lot of people thinking about this. Can you have a &ldquo;better&rdquo; radium-223? I don&rsquo;t know the answer to that, so I think time will tell how this goes. But I think the future is likely in combinations of therapies, as opposed to radium-223 as a monotherapy.

you think is important for community oncologists to take away from all of this?

Right now, we&rsquo;ve hit a little bit of a time delay in terms of the therapies that have been developed. Clearly, the next wave of therapies are DNA mismatch repair, and targeted therapies, but even that is only going to impact a quarter, perhaps, of patients with castration-resistant disease. It&rsquo;s really about optimizing the therapies that we have, as we begin to think about new drugs or new combinations that may be able to push us down the road a little bit.

Immunotherapyother than sipuleucel-T&mdash;has not been widely used. The checkpoints have been a little slower in prostate cancer because early data weren&rsquo;t as compelling, although recent data presented at ESMO suggested that looking at checkpoints or other combinations may be very reasonable in some subsets of patients.

Optimally using the drugs we have and guring out sequencing, which will be a clinical judgment until we get more datathat&rsquo;s what we need to walk away with to provide better care for our patients.

Robert Dreicer, MD, discusses&nbsp;ongoing developments in mCRPC, including the latest approaches with radium-223.

Optimizing Treatment With Radium-223 for Prostate Cancer

Philadelphia chromosome (Ph)like acute lymphoblastic leukemia (ALL) accounts for more than 20% of all adult patients with ALL and is associated with a poor outcome, according to findings published in the Journal of Clinical Oncology.

The cooperative, international study examined the prevalence and genomic landscape of Ph-like ALL in adult patients in order to drive future clinical trials toward common targetable rearrangements in this subgroup.

&ldquo;It&rsquo;s basic genomic research but it has enormous translational implications,&rdquo; said Charles Mullighan, MD, MBBS, a corresponding author of the report, in an interview with

. &ldquo;If one can identify these patients, they are excellent candidates for the addition of tyrosine kinase inhibitor (TKI) therapy.&rdquo;

Ph-positive ALL has been studied in depth in pediatric and adult patients, as this well-known subtype was associated with a poor outcome. However, the rate of Ph-like ALLwhich Mullighan notes has a similar gene expression profile to Ph-positive ALL but lacks BCR-ABL1&mdash;in older patients was previously unknown.

&ldquo;It had been known for many years that the frequency of Ph-positive leukemia, BCR-ABLpositive ALL, rises with increasing age. There are some data suggesting that the frequency of Ph-like ALL may not continually increase throughout age, so we were very interested in doing a comprehensive study with a large number of patients to define the prevalence of Ph-like ALL across the age spectrum of adulthood, and also to identify the underlying genetic lesions and see how they compare to those we had described in children and young adults,&rdquo; said Mullighan, co-leader of the Hematological Malignancies Program at St. Jude Children&rsquo;s Research Hospital.

Researchers examined samples from 798 patients with B-cell ALL between the ages of 21 and 86. Gene-expression profiling was performed on the samples and patients were classified according to a coefficient (0-1) based on analysis of a 15-gene quantitative reverse transcriptase polymerase chain reaction low-density array. Patients with a coefficient of 0.5 to 1 were classified as having Ph-like ALL. In the study, 194 patients (24.3%) were found to have Ph-like ALL.

BCR-ABL1rearranged ALL was identified in 23.2% of the patients and MLL-rearranged ALL was identifed in 15.4%.

The patient population was divided into 3 groups based on age: young adult patients (aged 21-39; n = 344), adult patients (aged 40-59; n = 304), and older adult patients (aged 60-86; n = 150). The prevalence of Ph-like ALL was greatest among young adult patients at 27.9%. Adult patients had a frequency of Ph-like ALL of 20.4% and older adult patients, 24%.

Patients with nonPh-like ALL had better survival rates than patients with Ph-like ALL with a 5-year event-free survival (EFS) rate of 49.3% (95% CI, 42.8-56.2) versus 22.5% (95% CI, 14.9-29.3; P <.001). The 5-year overall survival (OS) rate for patients with non&ndash; Ph-like ALL was 52.4% (95% CI, 45.4-59.9) versus 28.8% (95% CI, 16-32.4; P <.001).

Survival disparities between patients with Ph-like ALL and non Ph-like ALL were increased in younger patients. The 5-year EFS rate for young adult patients with Ph-like ALL was 24.1% (95% CI, 12.6-34.1) versus 60.5% (95% CI, 51.2-71.4; P <.001). For adult patients with Ph-like ALL the 5-year EFS was 21.4% (95% CI, 7.6-32.5) versus 38.7% (95% CI, 27.6-50.0; P = .0021) for non&ndash; Ph-like ALL. Five-year OS for young adults with Ph-like ALL was 25.4% (95% CI, 14.8-37.5) versus 64.2% (95% CI, 53.1-73.3; P <.001). OS for adult patients with Ph-like ALL was 27% (95% CI, 13.3-42.7) versus 44.9% (95% CI, 33.5-55.7; P = .023).

The survival differences for older adult patients with Ph-like ALL were lower than older adults with nonPh-like ALL, but these differences were not statistically significant. Older adult patients with Ph-like ALL had a 3-year EFS of 8% (95% CI, 0.5-21.6) and a 3-year OS of 13.5% (95% CI, 2.3-34.3) versus 33.3% (95% CI, 15.8-52.2; P = .047) and 37.9% (95% CI, 19.2-56.6; P = .64), respectively, for older adult patients with non&ndash;Ph-like ALL. The authors noted that the smaller group of older adult patients could have affected the significance of these findings.

The prevalence of Ph-like ALL across various age groups and the association with a worse outcome stimulates the need for more clinical trials to study ways to treat this subpopulation. To that end, the researchers explored the genetic landscape of adult patients with Ph-like ALL to find mutations and pathways that could be targeted with available therapies.

Of the 194 patients with Ph-like ALL in the study, genomic alterations activating kinase signaling were identified in 171 patients (88.1%). Of these, 99 patients (51%) had high expression of CRLF2, 25 of which also had a mutation of Janus kinases (JAK1/JAK2). The frequency of CRLF2 overexpression was highest among older adult patients at 58.4% compared with 51.1% in young adults and 46.8% in adult patients.

Alterations in kinase-activating genes identified included ABL class fusions in 9.8% of patients, that have not been recognized in B-cell ALL disease before: FIP1L1- PDGFRA, SNX29-PDGFRB, SMU1-JAK2, ZNF340-JAK2, THADA- EPOR, SMARCA4-TYK2, ZNF340-TYK2, ZYMM2-FLT3, DNTT-BLNK, TMEM2-PTK2B, and KANK1-CBL1.

Alterations in cytokine receptor genes included sequence mutations of IL74, SH2B3, JAK1, or JAK3 and rearrangement of TYK2 in 7.2% of patients; Ras pathway mutations of KRAS, NF1, PTPN11, and CBL1 in 3.6%; and uncommon fusions, including FLT3, NTRK3, BLNK, and PTK2B in 4.1%.

Rearrangements activating kinase signaling were found in 126 patients (65%) including 32 different rearrangements across 14 kinase or cytokine receptor genes. Further, 11 rearrangements were identi ed that have not been recognized in B-cell ALL disease before: FIP1L1- PDGFRA, SNX29-PDGFRB, SMU1-JAK2, ZNF340-JAK2, THADA- EPOR, SMARCA4-TYK2, ZNF340-TYK2, ZYMM2-FLT3, DNTT-BLNK, TMEM2-PTK2B, and KANK1-CBL1.

The frequency of kinase fusions did not differ greatly between age groups, except for EPOR rearrangements, which were found more often in younger adults than in older adults (P = .019).

Patients with a rearrangement of CRLF2, JAK2/EPOR, or ABL class genes were more likely to have a higher coefficient used in the classification of Ph-like ALL and were associated with a worse outcome. For patients harboring CRLF2 rearrangements, 68% were assigned a coefficient between 0.9 and 1, on the higher end of the spectrum, and 79% of patients with a JAK2/EPOR rearrangement had a coefficient between 0.9 and 1. Ninety percent of patients with an ABL-associated rearrangement had a coefficient between 0.9 and 1. However, patients with CRLF2 or JAK2/EPOR rearrangements were associated with worse 5-year EFS and OS rates than patients with ABL class rearrangements (P = .057 and P = .072, respectively).

&ldquo;This study confirmed that this is a prevalent form of leukemia, with similar kinase-activating genetic alterations to those previously described, but importantly, as we continue to sequence more cases, we find more lesions that we haven&rsquo;t found before,&rdquo; said Mullighan. &ldquo;One of our key take-home messages from this study is that accurate management really needs accurate sequencing rather than just candidate testing approaches for the most common fusions.&rdquo;

In the study, the authors suggested that the identification of patients with Ph-like ALL be incorporated in the design of future clinical trials.

Ph-like ALL is characterized by a variety of genetic alterations in adults, most of which can be targeted by existing therapies, the study authors noted.

&ldquo;In the context of these studies, the [most] promising approach is a TKI,&rdquo; said Mullighan.

The study authors note that approximately 70% of the patients with Ph-like ALL could benefit from treatment with JAK inhibitors, such as ruxolitinib (Jakafi). Patients harboring CRLF2 rearrangements, JAK2/ EPOR rearrangements, and sequence mutations of JAK1, JAK3, IL7R, or SH2B3, could all be treated with a JAK inhibitor.

Preclinical studies have shown the efficacy of ruxolitinib in Ph-like ALL or early T-cell precursor ALL. In a study of patient-derived murine xenograft models of ALL treated with the JAK1/2 inhibitor ruxolitinib, the treatment showed activity in all 6 of the xenograft models.

Patients harboring ABL1, ABL2, CSF1R, PDGFRA, or PDGFRB rearrangements could all benefit from being treated with ABL inhibitors, such as imatinib (Gleevec) or dasatinib (Sprycel), both of which have been approved for the treatment of patients with Ph-positive ALL.

In a previous study of Ph-like ALL, the researchers noted that cell lines and human leukemic cells in vitro expressing ABL1, ABL2, CSF1R, and PDGFRB fusions were sensitive to dasatinib.

Previous reports of patients with other tumor types expressing an ETV6-NTRK3 fusion have shown responses to the ALK inhibitor crizotinib (Xalkori).

&ldquo;There are likely other forms of therapy that could treat this form of leukemia as well that are not necessarily related to the genetics,&rdquo; Mullighan said. &ldquo;But in terms of how these findings directly inform therapy, the implication is for TKIs... and inhibitors of ABL and JAK2 inhibitors are the 2 main agents moving ahead in to clinical trials. There are a number of other kinases as well that require other TKIs that are less commonly mutated or rearranged but are also very likely to respond and they&rsquo;ll need to be tested in future work.&rdquo;

Trials assessing the addition of TKI therapy to chemotherapy have commenced, including a trial studying the combination of ruxolitinib or dasatinib with chemotherapy in adult patients with Ph-like ALL (NCT02420717).

Roberts KG, Gu Z, Payne-Turner D, et al. High frequency and poor outcome of Philadelphia chromo- some-like acute lymphoblastic leukemia in adults. [Published online November 21, 2016] J Clin Oncol. doi: 10.1200/JCO.2016.69.0073.

Maude SL, Dolai S, Delgado-Martin C, et al. E cacy of JAK/STAT pathway inhibition in murine xenograft models of early T-cell precursor (ETP) acute lymphoblastic leukemia. Blood. 2015;125(11):1759-1767. doi: 10.1182/blood-2014-06-580480.

Roberts KG, Li Y, Payne-Turner D, et al. Targetable kinase-activating lesions in Ph-like acute lymphoblas- tic leukemia. N Engl J Med. 2014;371(11):1005-1015. doi:10.1056/NEJMoa1403088.

Philadelphia chromosome Ph&ndash;like acute lymphoblastic leukemia accounts for more than 20% of all adult patients with ALL and is associated with a poor outcome, according to findings published in the Journal of Clinical Oncology.

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