	The tiny “raise” touted in the latest temporary fix to Medicare’s Sustainable Growth Rate (SGR), which was wrapped inside the bipartisan budget deal President Barack Obama signed December 26, 2013,

 is anything but good news for oncologists, according to experts from 2 major medical associations.

	In fact, according to Ted Okon, executive director of the Community Oncology Alliance (COA), Congress sent signals that chemotherapy administration is going to continue its march into the

	hospital setting, leaving community oncologists and private practice physicians out in the cold.

	News reports on the latest SGR legislation, known as a “patch,” touted a purported 0.5% increase in Medicare rates for the first quarter of 2014.

 But beyond that headline, the real news is less rosy: the SGR stopgap, designed to forestall cuts above 20% to make up for years of shortfalls, includes a provision to keep in place—possibly until 2021&mdash;the 2% cuts to Medicare’s reimbursement of physicians for patient care and buy-and-bill medication services that were imposed earlier this year due to the sequester.

	The Senate approved the overall budget package December 18, 2013, with a 64-36 vote, following a lopsided House vote of 332-94 the week prior.

	The votes translate into bad news for community oncologists, according to Okon of COA, a lobbying group for oncologists in community practices. “On January 1, the Centers for Medicare & Medicaid Services will pay less for chemotherapy administration—about 7.4% less,” Okon said. “Eventually, CMS will pay 10% less to administer chemotherapy drugs with no cost-base justification.”

	The latest 3-month fix, following 12 years’ worth of stopgap measures to avoid catastrophic cuts to Medicare rates, is designed to let Congress finish designing a plan to permanently eliminate

	and replace SGR. Critics of SGR call it a flawed instrument that has never kept pace with the true cost of administering care. Congress has vowed to use SGR reform to move Medicare away from a fee-for-service reimbursement model to one that rewards quality care, but many details have yet to be worked out. Left unresolved is how the bill will be funded; that duty will fall to House and Senate appropriators.

	Although the military, programs for the needy such as Head Start and Meals on Wheels, and the Transportation Security Administration will benefit from the budget deal, noticeably missing is specific funding for individual federal agencies and programs, including the National Institutes of Health, a critical source of research funding for oncologists, hematologists, and other cancer researchers. It’s unlikely that NIH funding will return to pre-sequestration levels, according to a statement from the American Society of Hematologists (ASH).

	“The passage of the bill is good news for the nation, with no looming government shutdown, but the demands of the sequester and constraints on NIH funding remain,” said Alan Lichtin, MD, chair of government affairs at ASH. Lichtin added that the institution where he works as a hematologist, the Cleveland Clinic, “is not immune to budget constraints [and] has experienced more voluntary retirements. With reimbursement rates going down, Cleveland Clinic has not been able to expand many of its research programs.”

	The budget deal is disappointing to groups that embraced aspects of an earlier bipartisan plan for SGR reform, drafted by Congress and unveiled on October 30, but now being revised. The day before that announcement, Okon spoke at a Chicago conference, Value-Based Oncology Management, and outlined the “destructive” effects that current Medicare reimbursement policies have had on community clinics.

	Since 2005, after Congress altered Medicare cancer drug reimbursement formulas—tying them to average sales price instead of average wholesale price&mdash;Okon said 288 clinics have closed, and 469 have been acquired or have a physicians’ services agreement with a hospital. “The community share of oncology patients is declining,” Okon said.

	The problem with SGR dates to 1997, when Congress created the formula in an effort to control spending. The formula was supposed to set realistic yearly and cumulative spending targets; if the cost of care exceeded the target in any given year, rates would be cut the following year to make up the difference.

	However, inaccurate forecasts meant actual Medicare Part B spending has exceeded the target for more than a decade. American Medical Association (AMA) President Ardis Hoven, MD, told 

 after the October 30 announcement that, each year, the “sword of Damocles” would hang over physicians’ heads as they waited for Congress to pass legislation to thwart the automatic cuts.

 Yet the longer Congress failed to fix SGR, the worse the problem grew.

	How big is the problem? Estimates for getting rid of SGR include $377 billion for 2012 and $139 billion for 2013, and there are no good answers on how to address the problem. When asked how the repeal would be funded, AMA’s Hoven said, “I don’t think we really know.”

 Some accounts attribute the shrinking SGR shortfall to the fact that physicians have already sustained so many cuts.

	Problems with Medicare’s dysfunctional reimbursement model have hit oncology especially hard, and the effects of the federal sequester have only made things worse, Okon explained in Chicago. Oncology’s buy-and-bill system of administering increasingly expensive medications, the diversity of disease states, and the fact that so many cancer patients are older and reliant on

	Medicare mean an outdated reimbursement model is acutely felt in oncology. According to the American Cancer Society’s 2013 report, 77% of all new cancers are diagnosed in persons 55 years or older.

	The lack of resolution has not been good for doctors or patients, Okon told the Chicago gathering. More and more patients who need chemotherapy have been pushed into hospitals, where costs are higher. Shortages of key chemotherapy drugs, especially generics, have emerged, along with parts of the country where care is limited. 

	1. Lederman J. Obama signs bipartisan budget deal, defense bill. Associated Press. http://www.boston.com/2013/12/26/obama-signs-bipartisanbudget-deal-easingcuts/YDVAgpYUlFLBTilPKCb6gL/story.html. Published December 26, 2013. Accessed January 2, 2014.

	2. Pittman D. Senate agrees to 3-month SGR ‘patch.’ MedPage Today. http://www.medpagetoday.com/ PublicHealthPolicy/Medicare/43507. Published December 18, 2013. Accessed January 2, 2014.

	3. American Society of Hematology. Statement from the American Society of Hematology on Congressional Budget Deal [press release]. Washington, DC: ASH Newsroom; December 18, 2013. http://www.hematology.org/News/2013/11941.aspx. Accessed January 2, 2014.

	4. Caffrey MK. Oncology groups active in efforts to repeal SGR. Am J Manag Care. 2013;19(SP13): SP440-SP441.

	5. Pittman D. AMA president discusses SGR repeal efforts. MedPage Today. http://www.medpagetoday.com/MeetingCoverage/AMA/43041. Published November 20, 2013. Accessed November

	6. American Cancer Society. Cancer facts and figures, 2013. http://www.cancer.org/acs/groups/content/@epidemiologysurveilance/documents/document/acspc-036845.pdf. Accessed November22, 2013.

Articles

Evidence-Based Oncology

Fine Print of Budget Deal Doesn't Bode Well for SGR Overhaul

	The US Food and Drug Administration (FDA) has granted an accelerated approval to the combination of the MEK inhibitor trametinib (Mekinist) and the BRAF inhibitor dabrafenib (Tafinlar), both developed by GlaxoSmithKline (GSK), as a treatment for patients with unresectable or metastatic melanoma who harbor a 

mutation. The approval was based on results from an open-label phase I/II trial, which showed that trametinib combined with dabrafenib nearly doubled the duration of response and significantly improved overall response rates (ORR) compared with dabrafenib alone.

	Both drugs were approved as single agents in May 2013 along with a companion diagnostic. This is the first approval for a targeted therapy combination in advanced melanoma.

	“Mekinist and Tafinlar are the first drugs approved for the combination treatment of melanoma,” said Richard Pazdur, MD, director of the Office of Hematology and Oncology Products at the FDA’s Center for Drug Evaluation and Research. “Their development for combination use is based on the strong understanding of the biological pathways of the disease. This approval illustrates the value of continuing to study drugs in combination for clinical development.”

	The study was based on the rationale that a more complete inhibition of the mitogen-activated protein kinase pathway could help overcome the resistance developed by 50% of the patients within 6 to 7 months following the administration of a single-agent BRAF or MEK inhibitor. The phase I/II study was conducted in 4 segments, with phase II generating the majority of information regarding clinical activity. In this segment of the trial, 162 patients with advanced melanoma and 

mutations were randomized in a 1:1:1 ratio, with 54 patients in each arm who had not previously received BRAF or MEK inhibitors. Patient characteristics were balanced between arms, with an ECOG (Eastern Cooperative Oncology Group) performance status of 0 or 1.

	The patients received 150 mg of dabrafenib twice a day, plus 1 mg of trametinib once daily (combination 150/1), or 150 mg of dabrafenib twice a day plus 2 mg trametinib once daily (combination 150/2). Patients in the control group received single-agent dabrafenib at 150 mg twice a day. The primary endpoints included progression-free survival (PFS), ORR, and duration of response. Overall survival (OS) was assessed as a secondary end point; however, crossover was allowed following progression.

	The trial results confirmed the superiority of the 150/2 combination, which was chosen as the FDA-approved dose. Compared with the control (54%) the ORR of the 150/2 group was observed at 76% (P = 0 .03), and the median duration of response was 5.6 months compared with 10.5 months, respectively. The median PFS with the 150/2 combination was 9.4 months compared with 5.8

	months for the control (hazard ratio [HR] = 0.39; 95% confidence interval [CI], 0.25-0.62; P < .001). However, the HR for PFS by independent review was less pronounced at 0.55 (95% CI, 0.33-

	After 1 year, 41% of patients in the 150/2 group were alive and progressfree compared with only 9% in the control group (P < .001), and approximately 80% of patients crossed over from the control group to the 150/2 group following disease progression.

	The BRAF and MEK inhibitor combination significantly reduced the incidence of secondary cutaneous squamous cell carcinoma, which occurred in 19% of patients receiving dabrafenib monotherapy compared with 2% for combination 150/1 (P = .004) and 7% for combination 150/2 (P = .09). The most frequent all-grade side effects associated with the combination were pyrexia

	(71%) and chills (58%), with severe pyrexia observed in 19% of patients in the 150/1 group, 25% in the 150/2 group, and in 2% in the control group.

	Paolo Paoletti, MD, president of oncology at GSK, said in a press release, “This approval marks another key moment in what continues to be a rapid evolution of the treatment landscape for

	metastatic melanoma patients. Combining agents that target different mechanisms regulating the growth of cancer cells is one of the promising areas in cancer research. We are proud that the first approved combination of targeted therapies in metastatic melanoma is Mekinist and Tafinlar, and our hope is that it will become part of the new standard of care for appropriate patients with 

mutation-positive metastatic melanoma.”

	To support the accelerated approval, the combination of dabrafenib and trametinib is being explored in a number of phase III trials for patients with metastatic melanoma. In the phase III placebo-controlled COMBI-AD study, dabrafenib in combination with trametinib is being explored as an adjuvant treatment for patients with high-risk melanoma with a 

GSK Drug Combination Approved for Advanced Melanoma

 convened an expert panel to address the impact of increased use of immunotherapy in treating cancer in a managed care setting. According to the American Cancer Society, immunotherapy is a treatment that wards off disease either by boosting the immune system in general or by training it to attack specific cancer cells. Immunotherapy may be used alone or in combination with standard chemotherapy regimens.  	

	Panelists discussed the positive and negative aspects of using immunotherapy, traditional chemotherapy, and combination regimens. They addressed the importance of promoting both patient  	and provider understanding of immunotherapy. Finally, panelists discussed the cost associated with immunotherapy in cancer care. 	

, a professor of medicine and anesthesiology at Columbia University and an associate director of surgical intensive care at NewYork-Presbyterian Hospital, New York City. The panelists included:  	

 senior member of the H. Lee Moffitt Cancer Center and director, Donald A. Adam Comprehensive Melanoma Research Center, Tampa, Florida.  	

 national medical director, Oncology Solutions, Aetna, Inc. 	

Peter Salgo, MD, initiated the discussion by stating that immunotherapy markets were expected to exceed $14 billion this year; of the 12 FDA (US Food and Drug Administration)-approved drugs in 2012, 11 cost more than $100,000 a year. He said this points to a trend toward increasing costs for everyone. Dr Salgo then specifically asked Daniel George, MD, to comment on the previously unmet medical needs that are now being met by cancer immunotherapies.

 Cancer immunotherapy, and immunotherapy in general, has a long history of almost 100 years or more of recognizing the importance of the immune system in monitoring, preventing, and controlling cancer. We probably have not used this to our best advantage, but recently there’s been a breakthrough in a number of agents and strategies that have harnessed this access of therapy, an endogenous approach to managing this disease and taking advantage of our own immune system and the way it fights cancer.  	

The way I’ve looked at it, if I may, is in the past when you gave chemotherapy, you just killed all the cells and hoped that the rapidly dividing cells went first and then salvaged patients back. That’s not what’s going on.  	

 This is a really different paradigm. The immune system is present and we are trying to manipulate it in a way to reactivate it against cancer. There’s a concept called tolerance where, by multiple different strategies, cancer cells can evade recognition by the imanothermune system; there’s a way of reharnessing the immune system by overcoming that tolerance. Unlike chemotherapy or radiation therapy, where the treatment stops when you stop the drug, these are therapies that potentially could keep going and keep working following reactivation. We’re actually sort of vaccinating, if you permit me to use an umbrella term that may be imprecise, against cancer such that you are sensitizing an immune system against a particular tumor. You don’t have to re-vaccinate every 3 days. You give it once and the immune system keeps working.  	

Well, the Holy Grail of cancer immunology is to create a cancer vaccine. Provenge was the first and only cancer vaccine that was ever approved. But that is truly the mantra, that is, the immune system is the ultimate way to perform targeted therapy. So immunotherapy is targeted therapy, and its hallmark is memory. 	

 I was a practicing oncologist until just recently, and there’s an unmet need because what we were doing wasn’t working very well. So now we have the emergence of immunotherapy as an approach. We have the emergence of targeted therapy and even to the point of precision medicine as an approach, and we’ll see what wins. It’s very exciting because  	the science has advanced quite rapidly, but what we did earlier wasn’t very effective in most patients. 	

Dr Salgo continued the discussion by asking the panelists to clarify his understanding of the mechanism by which immune therapy works. His understanding was that we continually develop malignant cells every day that are consumed by the immune system to prevent tumor development, and the immunotherapy drugs seem to target the failure of immune recognition and immune response.

There are certainly data to suggest that this idea of immune surveillance is indeed valid. On the other hand, people on immunosuppressants don’t always present with 30 different types of solid tumors. Transplant patients often develop squamous skin cancers, especially virally related squamous skin cancers. So there are data to suggest that we always have immune surveillance to prevent cancer from developing. 	

In response, Dr Salgo queried the panelists on the different types of immunotherapy drugs that are now available and the types of cancers they treat. In their expert opinion, which of the available treatments could be considered clinical successes with a meaningful impact on patient outcomes?

You can divide immunotherapies into 4 or 5 categories: these include chemicals like cytokines; antibodies…cells, which are not really well developed; vaccines, which is always the Holy Grail to try to vaccinate someone against his or her own cancer. You’ve got 1 approved vaccine. One of the antibodies, which are the most exciting and promising, is approved. That’s ipilimumab, the anti-CTLA4 antibody. In terms of the cytokines, in 1996 and 1998 IL-2, interleukin-2, was approved for kidney cancer and for melanoma. The cell therapy is immature, and you will hear a lot more about the antibodies coming up in the next couple of years. 	

 I know we’re all very excited about the newest approvals and directions of immunotherapy, but just to take a look back, we’ve made tremendous progress with immunotherapy over the last 30 years. Bladder cancer is the tumor we use immunotherapy in the most on a regular basis, with bacillus Calmette-Guerin (BCG) in instillations for superficial bladder cancer, which has changed the natural history of superficial bladder cancer. How does IL-2, which has been around a long time, recognize that this is a mechanism that, although rare, does result in complete responses? These are durable complete responses in some tumors, some advanced metastatic solid tumors, and in renal cell and melanoma, in particular? 	

	With some of the newer approaches, however, we’re seeing even a broader range of tumors that are susceptible to these strategies and we’ll talk about some of those examples as we get into  	the drugs. But to me, this is one of the most exciting areas right now and the validation is that we’re seeing this not in the niche of one tumor or another but beginning to branch out into a whole host of different tumors in stages. 	

Immunotherapy never got respect because it was always that drug which worked in 1 or 2 cancers like melanoma or kidney cancer, which were the immunotherapeutically sensitive histologies. But now, PD-1 has definite activity against non-small cell lung cancer. So, now, for the first time, the common epithelial malignancies will have immunotherapeutic options and that’s  	great. 	

To follow up, Dr Salgo asked Dr Kolodziej and Dr George to comment on the restrictions if any that are placed on reimbursement for these agents.

 I think from a payer perspective, the science aside, there’s not a great distinction around mechanism of action or promising early results. It’s all about results. And I think managed  	care has a historical way of dealing with new therapies that are expensive, and the most typical is prior authorization or precertification. If you look at the new drugs, and you mentioned it in your  	prologue, they’re all very expensive. And then we have a lot of discussion about how we should add expensive drug A to expensive drug B. You don’t see a new drug that didn’t come out at $10,000 a month, but I don’t really know how that number is arrived at. 	

	However, there is an established way of dealing with the process, and that continues to be the way of dealing with it, and that is prior authorization or precertification. And I will say that the prior  	authorization and precertification clearly reflects the FDA label. If you’re going to get Provenge, you have to be minimally symptomatic. And, if you call us to get it approved, we will ask you that question. 	

 I think this is a good point on the FDA labels. This will gain increasing importance; you are seeing real trends for our immunotherapies now that are expensive, and people really are following these labels. These really do matter. In years past, they were just sort of an entree into the field and then people did a lot of off-label use of treatment. We see much, much less of that because of the expense, which in some ways is appropriate; we should be a data-driven field.  	

 Although, to tell you the truth, the data that we have access to are not always what is reflected in the package insert or the label. An example would be, reinduction therapy was part of the original trial that led to the registration of ipilimumab. Admittedly, a modest number of patients on those registration trials were reinduced. Over time, the reinduction rate, if you get ipilimumab, if you’re stable and respond over 24 weeks, maintain it for some modest period of time, and then relapse later, which is most patients, that you can be reinduced and have about a 40% response rate, which is very respectable by anybody’s standards. That’s not in the label, those of us who know would want to reinduce, but that doesn’t mean we’ll always get to be able to  	do it. I mean, I can argue my way pretty well with most insurers to get it done, but most community doctors won’t.  	

Dr Salgo steered the conversation to talk about the guidelines published by the NCCN and CMS. Dr Salgo sought the panelists views on the increased paperwork and requirements, whether they thought it a good thing or simply bureaucratic obstructions.

 I think you will find fairly consistently that most payers, national payers, largely respect what the NCCN has to say almost completely. Most payers realize they do not have the expertise in-house to try to adjudicate the quality of the evidence, and they look to a panel of experts to help them negotiate those waters, which is fair. The radiation therapists are not all happy with NCCN. They think that protons guidelines are not upto- date. Maybe the immunotherapists aren’t happy with the immunotherapy, although they do say you can give ipilimumab a second time in the NCCN guideline. 	

 What I’m really trying to get at here is, guidelines are fine. And what I hear you saying is guidelines are guidelines and they do make sense, and experts have approved them and signed off on them. But on top of these guidelines, there’s more paperwork, and more sign-offs, and more gatekeepers. Is this rational or is it simply a way for payers not to pay? 	

 I personally believe the answer is we’re going to get to a point in healthcare reform, this is not Aetna’s view, this is my view, where we go from a point where the payers are the gatekeepers to where providers become gatekeepers. And so I think that the burden of adjudication of appropriateness of evidence is going to shift. That locus of control is going to shift to providers. Now, providers may or may not like that. help, which is why pathways and other ways of treating patients are going to become paramount for oncologists, which means it will take away our autonomy. 	 		

Dr Salgo specifically wanted to know whether the increased bureaucracy and paperwork, over and above the scientific, CMS, and NCCN guidelines, would force the providers into giving up.

 No, I don’t think so. When I started (at Aetna), I reviewed every single prior authorization policy we had at Aetna. And if you can’t finish that form in 1 minute, you’ve got a problem. I get administrative burden. I was in practice for a long time, and I worked for US Oncology so I know a lot about administrative burden, and the burden is small. The truth of the matter is: give me a solution. Tell me what else we ought to do, and the answer is, we trust the providers. The idea that they’re motivated by profit, I don’t buy into that.	 		

And I would agree with Dr Kolodziej on this one. I don’t see this as a burden. Filling out the form is not the problem, but when we get the largely inappropriate peer-to-peer,	 		that’s an annoying burden that we sometimes have to carry. ... If a request for coverage gets denied, then we have to request a peerto- peer, doctor-to-doctor, or healthcareprofessional-	 		to-healthcare-professional review of the case. We take time to set that up and then review the case. It’s frequently because some of the records were either not available or there was a misinterpretation of the case. It’s usually clarified, but it just takes time. This makes us stop and think whether this really is appropriate use of therapy, and very expensive therapy at that. Going 	 		forward, we may need to pause and think about cost as well.	 		

 From a payer perspective then, which has more value? You can define value any way you like. Is it immunotherapy or genomic precision therapy? 	 		

 I’ve actually been thinking about it a long time. And I don’t mean to trivialize this, but there are different ways to get at the problem. They’re both intellectually satisfying. I’m not sure there’s a huge cost differential between them. We will find out. The data will tell us what the right approach is. 	 		

 However, they had the cost additive?	 		

Maybe yes and maybe no. So I think it’s a mistake, and I felt this way for a very long time, to focus solely on what the cost of the infusion is. I think we need to think about other 	 		things when we think about the cost of care of a cancer patient. If you look at the cost of an episode of care for a cancer patient, about 25% is the chemotherapy, but another 20% is imaging, another 30% is hospitalization. All I’m saying to you is this, if the Institute of Medicine is right, 30% of healthcare is wasteful.	 		

		As we get into a world of precision therapy, the opportunities for improving care and controlling cost is not keeping the right drug from the right patient, keeping the patient out of the 	 		hospital, keeping them out of the ED, dealing with their symptoms at home, knowing when to say when. And I can’t stress that last point enough. This is again my opinion, not Aetna’s, but the greatest return of investment (ROI), and this is from work we did with US Oncology, is really on end-of-life care and doing the right things at end of life. 	 		

Dr Salgo brought up the encapsualization of care. The cost of immunotherapy is known up front, because it keeps working with a single administration. Whereas, with traditional chemotherapy, you’re going to be paying out of pocket.

No one is saying this is curative therapy yet. Let’s just recognize that there’s an episode of immunotherapy treatment and we don’t know how long that episode is going to (require coverage). 	 		

 But let’s hold that thought for a second because as data develop with the use of ipilimumab, at least in melanoma, there has been or there is a plateau of survival in patients who are 	 		out 3, 4, or 5 years. So, if 18% of your patients are alive at year 3, 18 or 19 at 4 and 5, some of those patients are probably cured. And the best data from the longest follow-up at 7 and 8 years suggested if you have a complete response (CR) or a near complete response, made CR by surgery with ipilimumab in melanoma, you’re going to be alive continuously in remission at least 90% of the time, out at 7 or 8 years. So maybe those patients are cured. 	 		

I want to put this on the table without comment. One of the very few times I’ve heard the word “cure” in this context, whether or not we can use it reliably, the fact that we’re even discussing it is remarkable. 	 		

The fact that in current targeted trials, for example, with BRAF, BRAF/MEK drugs in melanoma, we’re seeing patients on protocol and they come in and you look at the chart. It’s 	 		week 140, week 170, week 180, which is phenomenal.

		The ultimate outcome is survival. If I were a cancer patient and I had treatments pitched to me by my oncologist, my first question would be, ‘How long am I going to live compared with not having treatment or compared with the control treatment and how am I going to feel?’ So it would essentially be the quality adjusted years of life prolonged, which is not a trivial calculation. The problem is in the medical oncology business, at least until recently, we haven’t been able to quantitatively assess what that benefit would be. Now we have more data, and I would agree with what Dr Kolodziej said, about 30% of everything we do is wasted. I’ve been saying that since I became an oncologist 25 years ago, and I was absolutely convinced that at least a third of what I did was a complete waste of time. That’s got to change. 	 		

 I think the new healthcare reforms should give us more opportunity to have a say in that. I think the challenge is that now we’re going to own that more and that’s going to come back to us in terms of a reimbursement model. And that’s something we are inexperienced in. 	 		

I think the interesting thing is that we have been stuck for a very long time in a paradigm of designing clinical trials with a view toward what registration for that drug should look like. That is going to change because now there’s going to be a burden on the innovators to look at meaningful outcomes that will allow them to position their product, immunotherapy product, or targeted agent, to position it in a global treatment for that patient. So it shifts the burden of identifying value, and as a healthcare consumer I’m all for that. 	 		

Dr Salgo then asked Dr George to comment on the newly approved mover-and-shaker drugs in literature.

I’ll simply walk through the clinical data and the mechanism of action of these drugs. Provenge is an autologous cellular immunotherapy from the patient’s own cells. It’s really the ultimate in personalized therapy. The drug is made from the person’s own cells through a process called leukapheresis; the cells are then shipped to a centralized laboratory and activated ex vivo against antigens that are relevant to prostate cancer, in this case, a fusion protein, a prostatic acid phosphatase in GMCSF (granulocyte macrophage colony-stimulating factor), an immunostimulant. That creates, within that peripheral blood mononuclear cell compartment, some activated cells against those proteins, which are then reinfused back in 3 days later, almost like a blood transfusion for the patient, an autologous blood transfusion. It’s repeated every 2 weeks for 3 doses. So it’s a 0-, 2-, and 4-week regimen.

		Of 2 independent clinical trials, a relatively small randomized study demonstrated an overall survival advantage of about 4 months and a second pivotal trial, 512 patients randomized, demonstrated about a 4.1 month improvement in overall median survival with a hazard ratio of about 0.77. And interestingly, as alluded to by Dr Weber, the patients that live longer derive a greater benefit. So a landmark analysis at 1 year demonstrates about a 12% improvement in survival, about a 24% improvement in overall survival by 2 years, while patients that are out to 3 years, there’s a 32% improvement in overall survival for that population, showing an absolute benefit that’s much greater. Bottom line, identifying the patients who are destined to live 3 years is ideal to treating with Provenge. 	 		

 And, again, with just 3 doses, you know up front what it’s going to cost. 	 		

But the benefit is extended over the lifetime of that patient. It’s not $100,000 for 1 month. It’s an investment in a patient that we believe is going to live 3 years or more. If you annualize that out, it’s $30,000 a year. 	 		

		I don’t want to make it sound like it’s a black and white thing. This is against 1 antigen that may or may not be relevant, and some or many of these patients may not necessarily fully respond to that. I view this more like a platform. Because it has very low toxicity, there really isn’t a longterm residual toxicity from this treatment, in addition to the opportunity to building on this with subsequent therapies, whether targeted, immunologic, or otherwise. We’d now like to build and improve on this therapy. 	 		 			

 Where does ipilimumab fit in this whole group of pharmaceuticals? 		 			

 Well, ipilimumab is a very different drug. Provenge is a vaccine, again, the first cancer vaccine ever approved by the FDA. But ipilimumab is a checkpoint protein inhibitor. The immune 		 			cell has multiple brakes and accelerators. If you had a drug that bound the accelerators, you would push the immune system. It turns out that in the cancer bearing state in chronic infection, the immune system is suppressed and you have high levels of substances that are essentially the brakes like CTLA4, PD-1, TIMP-3, LAG-3. CTLA-4 plays a predominant role in the cancer bearing 		 			state; you have lots of CTLA4 on your immune cells, which means they don’t work very well. What ipilimumab does is that it blocks the braking mechanism. About 15% of the patients will have traditional anti-tumor responses and there will be a clear increment in survival over time. But the survival benefit plateaus out, meaning you have the same proportion of patients alive at 3, 4, 5, 6 years. So some of those patients may well be cured, which is unique. 		 			

Dr Salgo then asked the panelists to compare the safety profiles of Provenge and ipilimumab relative to traditional chemotherapies.

With Provenge, because we’re activating ex vivo, an infusion reaction occurs following reinfusion, likely due to the induction of cytokines within that cellular mix. It results in a very acute, short-term, generally mild inflammatory profile: fever, chills, and back pain. Less than 3% incidence of grade 3, or what we consider serious adverse events, for any one of these toxicities is observed, which is short-lived, and completely resolves within 24 to 48 hours in the vast majority of cases. So cumulative toxicity, residual toxicity, or end organ damage that are typical of chemotherapy or targeted therapy, in some circumstances, are not observed. 		 			

The beauty of a vaccine against cancer is it will not be toxic. Ipilimumab and PD-1 antibodies are a different scenario because here you’re breaking tolerance. If you break the self 		 			tolerance of the immune system, it indirectly increases the ability to recognize the cancer, but there will be some collateral damage. About 10% or less of the patients who get ipilimumab will have grade 3 and 4 clinically meaningful serious adverse events that we call IRAEs, or immune-related adverse events, including colitis, inflammation of the pituitary or hypophycitis, low thyroid, rashes, rarely pancreatitis, or hepatitis, all manageable. And I probably spent 8 or 9 years figuring out how to manage these things, and I’ve written on it extensively. But there will be a cost in side effects. 		 			

Dr Salgo then asked the panelists to discuss the associated costs. How can such expensive treatments, sometimes in the range of $90,000 to $100,000, be remunerated?

Immunotherapy in Cancer Care: Understanding the Impact of Shifting Treatment Paradigms in the Managed Care Setting

	With the rise of targeted therapies, the days of letting doctors report informally on unexpected reactions to new cancer drugs are long gone. The change signals a larger role for phase IV, the post marketing research step in the approval process.

	Accelerated approvals can take months, if not years, off the time it takes to get a life-saving drug to a cancer patient, but they may occur without sufficient efficacy data. So, today those approvals typically come with a catch: pharmaceutical companies must closely monitor patients and report reactions to toxicity. The US Food and Drug Administration (FDA) has created the Risk Evaluation

	and Mitigation Strategies (REMS) program, for drugs approved where the risk-to-benefit ratio “may not be apparent in all clinically relevant scenarios,”

 according to Mark Crowther, MD, of St. Joseph’s Hospital in Hamilton, Ontario.

	Crowther was part of the education session, “A Fresh Look at Drug Approval: Moving Away from Tradition,” offered at the 55th American Society of Hematology Annual Meeting and Exposition in

	The “post licensure” monitoring programs represent the balancing act the FDA faces in trying to hasten the time it takes to get new therapies into the market. Long approval periods not only keep beneficial drugs away from patients, they also drive up costs. Thus, the FDA awards “breakthrough” designations when it can be shown that a drug “may (provide) substantial improvement on at

	least one clinically significant end point over available therapy.”

	Such research is obviously beneficial to patients. Sometimes the size of a clinical trial, or its design, prevents researchers from detecting reactions that become apparent once a drug reaches

	the general population. Crowther cited the case of cervistatin, a cholesterollowering agent, which was taken off the market after reports of deaths from rhabdomyolysis, especially among patients also taking gembfibrozil. But data collection benefits drug developers, too. Not only does the combination of accelerated approval and post marketing research get drugs to market quickly for their original purpose, but phase IV research “may lead to new indications,” Crowther said.

	Compared with phase IV research of earlier eras, today’s studies are robust and systematic. Self-reports, which Crowther dismissed as useless, have been replaced with large data sets and obligatory, uniform reporting. The “real time” aspect of these methods allows regulators to closely monitor new therapies and act quickly if there’s a problem.

	Another game changer has been the FDA’s Sentinel project, launched in 2008. This national system, which will become more powerful as electronic record keeping takes hold, lets the FDA

	track not only toxicity reactions, but also drug and dosing changes made in response to its warnings. What’s more, unlike post market research done by pharmaceutical companies, this project

	offers the independence of a third party.

	(For a recent example, see the related story above on the FDA’s work with Ariad Pharmaceuticals on ponatinib.) 

	1. Crowther M. Phase 4 research: what happens when the rubber meets the road? Hematology Am Soc Hematol Edu Program. 2013;2013:15-18.

Post Marketing Research No Longer an Afterthought With Targeted Therapies

	The US Food and Drug Administration (FDA) has approved revised US Prescribing Information (USPI) and a Risk Evaluation and Mitigation Strategy (REMS) for ponatinib, marketed as Iclusig, according to an announcement from Ariad Pharmaceuticals, Inc, the company developing the drug. The USPI and REMS allow for the immediate resumption of ponatinib’s marketing and commercial distribution. The USPI also includes a revised indication statement and a boxed warning, with alerts to the risk of vascular occlusive events and heart failure. The USPI also includes dosing recommendations, which remain at 45 mg daily.

	The approval of the revised USPI for ponatinib was based on a review of clinical trial data, including a 24-month follow-up of the pivotal PACE (Ponatinib Ph ALL and CML Evaluation) trial, which

	served as the basis for the drug’s approval in 2012.

	Approximately 640 patients had obtained ponatinib through commercial channels in the United States at the end of October 2013. Ponatinib has since been made available on a case-by-case basis to 350 patients through emergency and single-patient investigational new drug (IND) applications.

	“In less than 2 months of suspending marketing and commercial distribution of Iclusig in the US, we addressed the issues raised by the FDA and now are able to market and distribute Iclusig again in the US,” Harvey J. Berger, MD, chairman and chief executive officer of Ariad, said in a statement. “As we look ahead to relaunching Iclusig in the US and fulfilling our post-marketing requirements, we will continue to focus on understanding the benefits and risks of Iclusig treatment in patients with resistant or intolerant Philadelphia-positive leukemias.”

	Ponatinib is approved for adult patients with:

	• Chronic phase, accelerated phase, or blast phase T315I-positive chronic myeloid leukemia (CML)

	• T315I-positive Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL)

	• Chronic phase, accelerated phase, or blast phase CML or Ph+ ALL for whom no other tyrosinekinase inhibitor therapy is indicated

	The clinical development of ponatinib was placed on hold in early October 2013 while the FDA investigated the adverse events associated with the drug. This was shortly followed by the early termination of the phase III EPIC (Evaluation of Ponatinib versus Imatinib in CML) trial, which was examining ponatinib in the frontline setting for untreated patients with CML. The suspension

	in distribution followed discussions between Ariad and the FDA.

	Marty Duvall, executive vice president and chief commercial officer of Ariad, said that commercial and medical affairs teams will be deployed by mid-January. Duvall said distribution of

	ponatinib will then begin and the company expects the drug will be “cash-flow positive from the onset.” Until then, the drug will be distributed with the IND mechanism. 

Reversing Halt, FDA Reauthorizes Sale of Ponatinib

	A phase III study of the PI3K-delta inhibitor idelalisib in combination with rituximab (Rituxan) has been stopped early following a positive interim analysis, according to a statement from Gilead Sciences, Inc, the company developing the drug.

	The randomized trial, labeled Study 116, investigated the combination as a treatment for chemotherapy- ineligible patients with previously treated chronic lymphocytic leukemia (CLL). The decision to stop the trial early followed a recommendation from an independent data monitoring committee that found a highly statistically significant prolongation in the primary end point of progression-free survival (PFS). Subsequently, patients on the control arm receiving rituximab plus placebo are now eligible for treatment with idelalisib in an extension study.

	Idelalisib, a first-in-class selective PI3K-delta inhibitor, is thought to be effective in B-cell malignancies due to the role of PI3K-delta in the activation, proliferation, and survival of B cells, a

	rationale that was confirmed in earlystage trials.

	“This is the first phase III study to report positive results for a new class of targeted therapies that inhibit B-cell receptor signaling as a major component of their mechanism of action, an important area of focus in the development of chemotherapy- free regimens in CLL and other B-cell malignancies,” said Norbert W. Bischofberger, PhD, executive vice president of research and development and chief scientific officer at Gilead, in the statement.

	The study enrolled a total of 220 patients, all of whom had previously treated recurrent CLL with measurable lymphadenopathy. Patients in the trial were randomized in a 1:1 ratio to receive idelalisib at a 150 mg dose twice a day in combination with intravenous rituximab at an initial dose of 375-mg/m2 followed by 500 mg/m2 or rituximab and placebo. Patients who progressed were eligible to receive idelalisib therapy in a double-blind extension study.

	The phase III study was launched on the basis of results from a phase I trial examining the combination of idelalisib with rituximab and/or bendamustine for patients with previously treated

	CLL, presented at the 2012 meeting of the American Society of Hematology. In that study, 19 patients who had received a median of 2 prior therapies took idelalisib at 150 mg twice a day in combination with weekly rituximab at 375 mg/m2. In the intent-to-treat population, the overall response rate (ORR) was 78%, the 1-year PFS rate was 74%, and 84% of patients experienced a lymph node response (shrinkage ≥50%) resulting in marked reductions in lymphadenopathy.

	The combination of idelalisib, rituximab, and bendamustine (Treanda) presented the best response, with an ORR of 87%, a 1-year PFS rate of 87%, and lymph node response in 87% of the 15 patients. A randomized phase III study examining the combination of idelalisib, rituximab, and bendamustine is recruiting patients with previously treated CLL (NCT01569295).

	The early stop of the phase III trial indicates a promising treatment with the potential for regulatory approval, although early discontinuation of randomized clinical trials based on evidence

	of benefit is controversial, with research suggesting an overestimation of treatment effects.

	In its announcement, Gilead stated that it had informed the US Food and Drug Administration (FDA) of its decision to stop the trial. The company is engaged in conversations regarding a potential regulatory filing for idelalisib in CLL. In September 2013, Gilead submitted a New Drug Application to the FDA for approval of idelalisib for the treatment of patients with indolent

	That submission was based on data from a single-arm, open-label phase II study of 125 patients with iNHL who were refractory to rituximab and an alkylating- agent-containing chemotherapy.

	In an interim analysis of this study, single-agent idelalisib achieved an ORR of 53.6%, with a median duration of response of 11.9 months, median PFS of 11.4 months, and lymph node shrinkage experienced in 89% of patients.

	Additionally, according to results from a phase II trial presented at the 2013 annual meeting of the American Society of Clinical Oncology, idelalisib plus rituximab has demonstrated promising

	results in treatment-naïve patients with CLL. In that study, patients who were ≥65 years old with previously untreated CLL or small lymphocytic lymphoma received idelalisib at 150 mg twice a

	day combined with weekly rituximab at 375 mg/m2. At a 24-month analysis, the combination was found to be highly active in treatment-naïve elderly patients. The trial found a Kaplan-Meier estimated PFS benefit of 93%. Moreover, the combination achieved a complete response rate of 19% and an ORR of 97%.

	At the time of the presentation, the principal investigator on the study, Susan M. O’Brien, MD, Ashbel Smith Professor of Medicine in the Department of Leukemia at the University of Texas

	MD Anderson Cancer Center, said, “The high overall response rate and durable disease control observed in this phase II study suggest that idelalisib in combination with rituximab could become an important therapeutic option for CLL patients new to treatment.” 

Promising Results Halt Phase III Studies of Idelalisib

	Treating newly diagnosed patients— even older ones&mdash;with a combination of lenalidomide, marketed by Celgene as Revlimid, and low-dose dexamethasone, a steroid, seems likely to become the new treatment standard for multiple myeloma, based on the presentation of a massive, multinational phase III study

presented in December at the 55th American Society of Hematology (ASH) Meeting and Exhibition in New Orleans. Lenalidomide is a vascular endothelial growth factor inhibitor.

	Thierry Facon, MD, lead author on the abstract, outlined results from the FIRST (Frontline Investigation Of Lenalidomide + Dexamethasone Versus Standard Thalidomide) Trial, which asked whether the standard of treating newly diagnosed older patients with melphalan and thalidomide first still makes sense. Facon, of the Lille Regional University in Lille, France, and his colleagues found it does not, based on results from 1623 patients from 243 cancer centers in 18 countries. In the study, sponsored by Celgene and the Intergroupe Francophone du Myelome (IFM), all patients were at least 65 years of age and the median age was 73 years; this is key because the drug combination that FIRST examined has been used in younger patients, but not among older patients who make up most of the multiple myeloma population.

	Patients were randomly assigned to 3 treatment groups: the first received treatment with the lenalidomide-dexamethasone combination—called Lex-Dex&mdash;for 18 months, the second received treatment with melphalan, prednisone, and thalidomide (MPT) for 18 months, and the third received the Lex-Dex combo continuously, or until the disease progressed. Under current standards of care, therapy ends after several months because patients begin to experience side effects.

	At 37 months, progression-free survival (PFS) among those taking the Lex- Dex combination continuously was 25.5 months. For the other 2 groups, PFS was almost the same, with the Lex-Dex group seeing 20.7 months on average and the MPT group seeing 21.2 months, which represented a 28% reduction in risk progression for the group taking Lex-Dex continuously.

	In the session, Facon said that longterm results for overall survival (OS) are not yet mature, but at the 4-year mark, OS was 59.4% for the continuous Lex- Dex group, 55.7% for the group that received Lex-Dex for 18 months, and 51.4% for the MPT group.

	What’s more, Facon said, is that cytogenetic profiles show that 762 patients were high risk; some were already suffering loss of renal function. Unlike populations typically included in clinical trials, Facon said, “This population is somewhat close to a real-life population.”

	A capacity crowd filled the giant hall at the plenary session to hear Dr Facon’s presentation, after which a questioner commented, “This is a shift in the paradigm.” Adverse effects (AEs) were

	dramatically reduced for the Lex-Dex groups compared with MPT, and remained “manageable” even for those on continuous therapy, Facon said. Grade 3 and 4 AEs for the continuous Lex-Dex

	arm versus the MPT arm included: neutropenia, 28% versus 45%; thrombocytopenia, 8% versus 11%; infection, 29% versus 17%; neuropathy, 5% versus 15%; and deep-vein thrombosis, 5% versus 3%.

	Despite the better results for continuous therapy in the trial, it is too soon to say whether it will become a standard with Lex-Dex therapy. Although less toxic than MPT, continuous therapy does

	present issues of side effects. But the bigger challenge may be cost: Revlimid prices range between $12,700 and $13,300 a month, based on online pharmacy prices from GoodRx. 

	1. Facon T, Dimopoulos, MA, Dispenzieri, A, et al. Initial phase III results of the FIRST (frontline investigation of lenalidomide + dexamethasone versus standard thalidomide) in newly diagnosed multiple myeloma patients ineligible for stem cell transplantation. Abstract 2. American Society of Hematology 55th Meeting and Exhibition, New Orleans.

When Less Is More: Results Herald 'Paradigm Shift' in Treating Newly Diagnosed Multiple Myeloma Patients

	Researchers found improved local control but not improved overall survival in a long-term study that examined the addition of chemotherapy to pre-operative radiotherapy for patients with rectal cancer. The results from the European Organisation for the Research and Treatment of Cancer (EORTC) trial 22921 were published in the February 2014 issue of 

	The study randomly assigned 1011 patients with clinical stage T3 or T4 resectable rectal cancer to receive preoperative radiotherapy, with or without concomitant chemotherapy, before surgery followed by either adjuvant chemotherapy or surveillance. Radiotherapy consisted of 45 Gy to the posterior pelvis in 25 fractions of 1·8 Gy over 5 weeks. Each course of chemotherapy consisted of fluorouracil (350 mg/m2 per day intravenous bolus) and folinic acid (leucovorin; 20 mg/m2 per day intravenous bolus). Two courses were administered (during weeks 1 and 5 of radiotherapy) for pre-operative chemotherapy, while adjuvant chemotherapy was given in 4 cycles, every 3 weeks. The primary end point was overall survival (OS).

	Following a median follow-up of 10.4 years, 10-year OS was 49.4% for the preoperative radiotherapy group, 50.7% for the pre-operative radiotherapy and chemotherapy group, 51.8% for the adjuvant chemotherapy group, and 48.4% for the surveillance group. The 10-year disease-free survival was also quite similar between the groups: 44.2%, 46.4%, 47.0%, and 43.7%, respectively. However, incidence of local relapse at 10 years was highest with radiotherapy alone (22.4%), followed by radiotherapy and adjuvant chemotherapy (14.5%), neoadjuvant radiotherapy and chemotherapy (11.8%), and adjuvant and neoadjuvant chemotherapy (11.7%). The frequency of longterm side effects did not differ between the groups.

	The authors concluded that adjuvant fluorouracil-based chemotherapy after preoperative radiotherapy (with or without chemotherapy) does not affect disease-free survival or OS and that new treatment strategies incorporating neoadjuvant chemotherapy are required.

	Research in this field continues to explore the optimal duration of chemotherapy for patients with colorectal cancer (CRC), with the standard duration declining from 18 months to the

	current standard of 12 cycles over 6 months, and a 3-month course is also being examined. According to Claus- Henning Kohne, MD, PhD, chairman of the Department of Hematology and

	Oncology, Klinikum Oldenburg, Germany, “The most exciting research currently in stage III CRC is the examination of ever-shorter duration of treatment.” 

	1. Bosset JF, Calais G, Mineur L, et al. Fluorouracil- based adjuvant chemotherapy after preoperative chemoradiotherapy in rectal cancer: longterm results of the EORTC 22921 randomised study. The Lancet Oncology. 2014;15(2):184-190.

	2. Managing Adjuvant Treatment in Colorectal Cancer, Part II. www.onclive.com. http://www.onclive.com/peer-exchange/colorectal-cancer/Managing-Adjuvant-Treatment-in-Colorectal-Cancer-Part-II. Accessed January 30, 2014.

Adjuvant Pre- or Post-Operative Chemotherapy Does Not Improve Survival in Rectal Cancer

	With grants from government sources looking less certain, partnerships between academic research centers and pharmaceutical companies are more important than ever to keep breakthrough hematology therapies in the pipeline, said Burt Adelman, MD, a hematologist who serves as executive vice president and chief medical officer for Dyax Inc.

	Adelman, long affiliated with Brigham and Women’s Hospital in Boston, Massachusetts, told a gathering at the 55th American Society of Hematology (ASH) Annual Meeting and Exposition in New Orleans, held December 7-10, 2013, that traditional drug development models inside pharmaceutical companies lack the one thing that academic medical centers have in abundance: access to patients in real-world settings.

	It is important, he said, for the best and brightest in academia to promote themselves to industry, and to not assume that pharmaceutical companies will find them. Try as they might to follow the literature, Adelman said, “We don’t know everyone, no matter how much exciting work you may have going on.”

	And the pharmaceutical industry has hit a plateau of sorts, he said. In 2012, worldwide drug sales fell 1.6%; while 43 new drugs were approved by the US Food and Drug Administration (FDA) in 2012, the 13-year average has been 32. What is more alarming is that between 2013 and 2019, $230 billion of US drug sales are at risk due to patent expiration. “Pharma is facing the innovation stagnation dilemma,” he said.

	This means opportunities for partnerships with academic centers, who tend to bring more of the “breakthroughs” to the FDA, compared with industry, which tends to bring more of the “me too,” drugs.

	At the same time, Adelman said, it is in academia’s interest to reach out to industry. The National Institutes of Health cut $1.55 billion from its FY 2013 budget; with the effects of the federal sequester continuing and no “grand bargain” in sight, things do not look promising for US government support for research.

	In fact, the bipartisan budget agreement reached less than 2 weeks after the meeting drew this response from ASH:

	Who creates drugs? Adelman cited data from 1998 to 2007, which broke out new drugs from the following:

	• Pharmaceutical companies, 147.2 new drugs, or 58%

	• University transfer, 60.7 drugs; 24%

	Adelman said he understands the reluctance of academic researchers to share ideas with industry; there is a fear that good work will be stolen, and the scholar will not reap the rewards. However, he said, as it stands, research institutions are not benefiting from the spending on healthcare, which in 2011 hit $2.7 trillion, including 10% on prescription drugs.

	“Very little of that annual $268 billion goes back to investigators of academic institutions. It’s a big number to not be participating in,” he said.

	And pharmaceutical companies maintain an enormous research effort: the total capital cost of the average new drug that comes to market is between $800 million and $1 billion; of course, that

	includes the cost of the many attempts that fail. “There’s a less than 10% success rate across all therapeutic areas; the average development time is 10 years,” Adelman said. As he explained, researchers inside pharmaceutical companies are more risk-averse than those in academia with those kinds of statistics. Lack of efficacy, he said, is the main reason for drug failure, and often this is not discovered until the end of phase II or even phase III.

	He cited statistics that said industry would continue to put $138 billion into research and development in 2014. Without enough new drugs coming to market, and more being spent on research, he said, “a cynic” would conclude that increased profits can only come from increased drug prices, both new and existing. Yet, there is pressure for that not to continue.

	In the meantime, in hematology especially, the race is on to find better therapies to reduce the toxicity of older chemotherapies. “You cannot practice modern hematology without a prescription pad,” Adelman said. “We are constantly in need of new solutions to difficult problems.”

	There are models in place for researchers to work either within their academic institution or directly with pharmaceutical companies to transfer technology. “The challenge is to figure out how to do this in a more reproducible way,” Adelman said. “If 24% of 252 drugs trace to academia, it is unlikely that 24% of the revenue is going to the institution.”

	“We need access to valued targets and technology. We need translational models; research tools. We need your patients, and we need your insights,” Dr Adelman said. There are also mundane needs, like access to diagnostic tools, such as MRIs, CT scans, and pathology labs.

	Academics interested in sharing should work through their institutions to understand the rules, because most have a technology transfer office that can assist. Institutions can help figure out funding to grow the idea into a company, but they are not the only source: there are venture capital sources, foundations, angel investors. “Have a patent filed. Contact your colleagues in industry. Publish and speak at meetings and work the crowd.”

	An important lesson: “An academic is rarely the best judge of IP value.” 

	1. Adelman B. Opening up drug development to everyone. Hematology Am Soc Hematol Edu Program. 2013;2013:311-315.

	2. American Society of Hematology. Statement from the American Society of Hematology on Congressional Budget Deal [press release]. Washington, DC: ASH Newsroom; December 18, 2013. http://www.hematology.org/News/2013/11941.aspx. Accessed January 2, 2014.

February 2014

Fine Print of Budget Deal Doesn't Bode Well for SGR Overhaul

GSK Drug Combination Approved for Advanced Melanoma

Immunotherapy in Cancer Care: Understanding the Impact of Shifting Treatment Paradigms in the Managed Care Setting

Post Marketing Research No Longer an Afterthought With Targeted Therapies

Reversing Halt, FDA Reauthorizes Sale of Ponatinib

Promising Results Halt Phase III Studies of Idelalisib

When Less Is More: Results Herald 'Paradigm Shift' in Treating Newly Diagnosed Multiple Myeloma Patients

Adjuvant Pre- or Post-Operative Chemotherapy Does Not Improve Survival in Rectal Cancer

Collaboration Between Academia and Pharma to Bring New Therapies to Market More Important Than Ever

As Genomics Reveals Diversity of Lymphomas, Questions Arise on Diagnosis, Treatment, and Ethical Issues

In Cancer and Beyond, Washington State Making the Transition to Value- Based Care

Sorting Out What Makes Sense in Diagnosing, Treating Prostate Cancer

Is Medicare Ready for Oncology Clinical Pathways?

Defining, Measuring, and Paying for the Work of Oncology Patient Navigators

A Test to Prevent Repeat Prostate Biopsies? Perhaps, if the Bar of 'Clinical Utility' Can Be Met