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Old 09-21-2010, 05:01 PM
gdpawel gdpawel is offline
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Default New Paradigms of Cancer Treatment

A New York Times story about a randomized controlled clinical trial for an experimental therapy for melanoma, put a human face on a dilemma that randomized clinical trials have faced ever since they were invented.

It recruited two young men, cousins, both in their 20s, both with metastatic disease. One was randomized to an experimental targeted therapy (PLX4032) and lived, and one was randomized to usual care with a near worthless chemotherapy drug and died.

[url]http://www.nytimes.com/2010/09/19/health/research/19trial.html?_r=2&hp

One oncology observer noted that what was left out of the story are the actual efforts to find new designs for clinical trials. One of those, called adaptive trial design, is now being pioneered (BATTLE and I-SPY trials).

Another area of discussion revolves around surrogates for overall survival that have been proposed or already adopted to speed up trials. Researchers are also talking about designing small trials that will look for gains in biomarker-defined subgroups.

Also, the article makes no mention of the wide availability of non-randomized trials. There are currently 13 non-randomized trials for BRAF-mutant, advanced melanoma listed in the National Cancer Institute's clinical trials database.

In 2002, scientists discovered that about half of melanomas are driven by the BRAF mutation. A biotechnology company, Plexxikon, developed an oral drug (PLX4032) that targets the product of that mutation.

In a study published in August 2010, in The New England Journal of Medicine, scientists reported that the drug shrank the metastases (in bone, liver, and bowel) of 80 percent of patients with metastatic melanoma; in two of 32 patients, the cancer vanished.

An 80 percent response rate in a solid tumor is unheard of. If the drug is approved by the FDA, it might do for metastatic melanoma what Gleevec did for CML.

Unfortunately, most of the patients relapse within a year. It’s not clear why. Maybe other mutations kick in, keeping the drug from binding to BRAF, or the melanoma switches to a different driver mutation.

[url]http://biopharmconsortium.blogspot.com/2010/03/plexxikons-discovery-of-plx4032.html

These are phase I and II trials, with either PLX4032 or for GlaxoSmithKline's version of the drug, and they are actively recruiting patients with advanced disease; previous treatment is okay for most of them.

http://www.cancer.gov/clinicaltrials/search/results?protocolsearchid=8219731

Other than the availability of non-randomized trials, there is also cell function analysis reporting prospectively on fresh "live" melanoma tissues. There are existing approved treatments that have shown reasonable success in cell culture assays (Melphalan, Interleukin-2, ImuVert [Serratia marcescens microscomes], Interferon, Temsirolimus + Bevacizumab).

And because it uses "real life" 3D analysis, makes functional profiling indicative of what willl happen in the body. Functional profiling analyses, which measure biological signals rather than DNA indicators, will continue to provide clinically validated information and play an important role in cancer drug selection. Primary tumors are heterogeneous and have a genomic signature unique to every patient.

It already uses real-time assessment that BATTLE and I-SPY are using. The functional profiling approach involves real-time assessment of "fresh" living cancer tissue and endothelial cell behaviors in the presence or absence of anti-cancer or anti-angiogenic drugs.

This method accounts not only for the existence of genes and proteins but also for their functionality and for their ineraction with other genes, other proteins, and other processes occurring within the cell.

Patients would certainly have a better chance of success had their cancer been “chemo-sensitive” rather than “chemo-resistant,” where it is more apparent that chemotherapy improves the survival of patients, and where identifying the most effective chemotherapy would be more likely to improve survival.

In a TheScientist.com article, “Crowdsourcing Drug Discovery,” there was a comment that for the last 50 years, randomized controlled trials have been the unquestioned gold standard, when in fact they have become a fiercely defended relic of our ignorance in 1962 when Congress empowered the FDA to begin regulating efficacy.

At that time, it was a “best we could do” solution - but now? They take too long, cost too much, are fraught with unsolveable ethical problems that patients and many physicians dislike, and cannot ask the patient-specific molecular questions we now know need to be asked and answered.

Yet, most clinical trialists and the FDA cling to these crude, simplistic tools like an irrational safety blanket. If we can’t reach agreement that clinical methodologies must adapt to new knowledge of the biology of disease, and that the way drug development is regulated must rapidly adapt in much the same way, then our ability to accelerate advances in medicine will remain stagnant.

A key point is, the system should be patient-centric. It has to be something patients will not only tolerate, or enter under duress, but rather a system that makes sense to them personally - even when they are not yet facing a serious or terminal condition. If real patients are left out of the process of change, we will likely end up in the wrong place again.

The problem is not with using the prospective, randomized trial as a research instrument, the problem comes from applying this time and resource-consuming instrument to address hypotheses of trivial importance: do cancers prefer Coke or Pepsi?

[url]http://www.f1000scientist.com/article/display/57646/
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Last edited by gdpawel : 03-11-2012 at 01:29 PM. Reason: correct url address
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Old 09-24-2010, 07:06 PM
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Default Chemosensitivity assay-directed therapy

Eur J Med Res. 2007 Oct 30;12(10):497-502.

Does chemosensitivity-assay-directed therapy have an influence on the prognosis of patients with malignant melanoma stage IV? A retrospective study of 14 patients with malignant melanoma stage IV.

Doerler M, Hyun J, Venten I, Potthoff A, Bartke U, Serova K, Hoextermann S, Altmeyer P, Brockmeyer NH.

Department of Dermatology, Ruhr-University Bochum, Germany.

Abstract

OBJECTIVE:

To evaluate the efficacy of chemosensitivity-testing directed chemotherapy in comparison with empirically chosen therapy regimens in patients with malignant melanoma stage IV.

PATIENTS AND METHODS:

Retrospective study including 14 patients with histologically confirmed malignant melanoma and diagnosis of stage IV disease by routine diagnostic procedures. Patients in group A (n = 7) were treated according to their individual chemosensitivity testing results, whereas patients in group B (n = 7) received empirically chosen treatment regimens. Chemosensitivity testing was performed using a nonclonogenic ATP-TCA assay. For statistical analysis the Kaplan-Meier method was used to calculate survival curves. The log-rank test was performed to compare the overall survival according to treatment group, LDH level in serum and AJCC-category. To compare the distribution of sex, LDH level in serum and AJCC-category between the treatment groups, the Fisher exact test was used.

RESULTS:

The median overall survival of group A exceeded the median overall survival of group B by 8 versus 3 months, respectively with a median overall survival of 5 months for the whole study population. LDH level in serum at study entry showed a strong correlation with overall survival, with normal LDH levels leading to a statistically significant longer survival (p = 0.006 for the log-rank test, respectively). Moreover, stage AJCC M1a/b yielded to a better prognosis compared with stage AJCC M1c (log-rank test p = 0.066; not statistically significant).

CONCLUSION:

Chemosensitivity-assay directed therapy might be a useful tool in determining the optimized chemotherapeutic drug or drug combination in the individual patient and might contribute to a better prognosis in patients with metastatic melanoma stage IV.

PMID: 18024256 [PubMed - indexed for MEDLINE]
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Old 04-06-2011, 10:29 AM
gdpawel gdpawel is offline
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Default Melanoma Targeted Therapy Finder?

A patient’s treatment plan can be tailored or personalized based upon known subtypes of melanoma. This approach, known as targeted therapy, is designed to target or inhibit specific genes or pathways that contribute to melanoma cell growth. This is a major focus of research for melanoma.

A new online “app” on Cancer.Net enables people with melanoma to learn more about emerging cancer therapies and specific genetic profiles of melanoma that these drugs target. People diagnosed with melanoma can use this free tool to work with their doctor when making treatment plan decisions.

The Targeted Therapy Finder is offered through a partnership between ASCO and CollabRx, an organization that uses information technology to personalize cancer treatments and accelerate research. By providing access to published content on melanoma, it may help users with information about clinical testing of new cancer drugs.

Patients could learn more about these genes and pathways by using the Targeted Therapy Finder, a search tool that provides information on possible therapies and diagnostic tests based upon a patient’s melanoma diagnosis.

CollabRx does what is called genome sequencing (molecular profiling). Researchers have realized that cancer biology is driven by signaling pathways. Cells speak to each other and the messages they send are interpreted via intracellular pathways known as signal transduction. Many of these pathways are activated or deactivated by phosphorylations on select cellular proteins.

Testing for these pathways, those which identify DNA or RNA sequences or expression of individual genes or proteins often examine only one component of a much larger, interactive process. It doesn't matter if there is a target molecule in the cell that the targeted drug is going after. If the drug either won't "get in" in the first place or if it gets pumped out/extruded or if it gets immediately metabolized inside the cell, drug resistance is multifactorial.

It may tell you whether or not the cells are "potentially" susceptible to one pathway of attack or another. It cannot tell you if one inhibiting drug is better or worse than another which may target the mutation. You want to take the drug that actually would be "sensitive" to the targeted cancer cells, not one that would be "resistant" to the cancer cells.

Sequencing the genome of cancer cells is explicitly based upon the assumption that the pathways - network of genes - of tumor cells can be known in sufficient detail to control cancer. Each cancer cell can be different and the cancer cells that are present change and evolve with time. Genes do not operate alone within the cell but in an intricate network of interactions. The cell is a system, an integrated, interacting network of genes, proteins and other cellular constituents that produce functions.

All DNA or RNA-type tests such as CollabRx are based on "population" research. They base their predictions on the fact that a higher percentage of people with similar genetic profiles or specific mutations may tend to respond better to certain drugs. This is not really "personalized" medicine, but a refinement of statistical data.

Formalin-fixed, paraffin-embedded biopsy specimens are acceptable as are flash frozen. However, investigators can only measure those analytes (substance or chemical constituent) in paraffin wax that they know to measure. If you are not aware of and capable of measuring a biologically relevant event, you cannot seek to detect it.

Formalin-fixed, paraffin-embedded tissue can change over time. These proliferating populations of cells are biologically distince in their behavior from "fresh" live cells that comprise human tumors. Established cell-line is not reflective of the behavior of "fresh" live tumor cells in primary culture in the lab, much less in the patient. You get different results when you test passaged cell-lines compared to primary, fresh tumors.

Sources:
Cancer.Net
European Science Foundation
J Natl Cancer Inst. March 16, 2010

[url]http://mmdm.cancercommons.org/smw/index.php/A_Melanoma_Molecular_Disease_Model
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Old 04-06-2011, 10:42 AM
gdpawel gdpawel is offline
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Default Using An App to Confront Your Metastatic Melanoma?

Dazzling hardware in search of a "killer app." The use of RT-PCR and DNA microarrays in personalized oncology is analogous to the introduction of the personal computer. Dazzling hardware in search of a killer application. This was wonderful technology and the geekiest of people bought them and played with them, but they really didn't start to do anything for a mass market until the introduction of the first killer application, which was a spreadsheet program called Visicalc.

So what research scientists in universities and cancer centers have been doing for the past ten years is to try and figure out a way to use this dazzling technology to look for patterns of gene expression which correlate with and predict for the activity of anticancer drugs. Hundreds of millions of dollars have been spent on this effort. Objectively speaking, it's like the emperor's new clothes.

Academics are besides themselves over the promise of genome sequencing. It seems so cool that it simply must be good for something. How about in the area of identifying drugs which will work in individual patients? As mentioned above, all DNA or RNA-type tests are based on "population" research. They base their predictions on the fact that a higher percentage of people with similar genetic profiles or specific mutations may tend to respond better to certain drugs. This is not really "personalized" medicine, but a refinement of statistical data.

The particular sequence of DNA that an organism possess (genotype) does not determine what bodily or behaviorial form (phenotype) the organism will finally display. Among other things, environmental influences can cause the suppression of some gene functions and the activation of others. Our knowledge of genomic complexity tells us that genes and parts of genes interact with other genes, as do their protein products, and the whole system is constantly being affected by internal and external environmental factors.

The gene may not be central to the phenotype at all, or at least it shares the spotlight with other influences. Environmental tissue and cytoplasmic factors clearly dominate the phenotypic expression processes, which may in turn, be affected by a variety of unpredictable protein-interaction events. This view is not shared by all molecular biologists, who disagree about the precise roles of genes and other factors, but it signals many scientists discomfort with a strictly deterministic view of the role of genes in an organism's functioning.

Molecular profiling examines a single process within the cell or relatively small number of processes. All a gene mutation study can tell is whether or not the cells are potentially susceptible to a mechanism of attack. The aim is to tell if there is a theoretical predisposition to drug response. It doesn't tell you the effectiveness of one drug (or combination) or any other drug which may target this in the individual.

There are many mechanisms/pathways to altered cellular function. I believe Functional profiling would be more beneficial. It measures what happens at the end, rather than the status of the individual mechanisms/pathways. It assesses the activity of a drug (or combinations) upon combined effect of all cellular processes, using combined metabolic and morphologic endpoints, at the cell population level, measuring the interaction of the entire genome.

What would be more beneficial is to measure the net effect of all processes within the cancer, acting with and against each other in real-time, and test living (fresh) cells actually exposed to drugs and drug combinations of interest. The key to understanding the genome is understanding how cells work. How is the cell being killed regardless of the mechanism.

Cancer cells often have many mutations in many different pathways, so even if one route is shut down by a targeted treatment, the cancer cell may be able to use other routes. Targeting one pathway may not be as effective as targeting multiple pathways in a cancer cell.

Functional profiling tests additional drug concentrations for the "targeted" agents, some of which have very steep dose response relationships. Should patients knowingly take the unknown risks of combination therapy that is known to work well in vitro against their tumor?

Again, all a mutation study can tell us is whether or not the cells are potentially susceptible to this mechanism of attack. They don't tell you if targeted drug is better or worse than some other targeted drug. There are differences. The drug has to get inside the cells in order to target anything.

Targeted drugs are poorly-predicted by measuring the ostansible target, but can be well-predicted by measuring the effect of the drug on the "function" of live cells.

Literature Citation:
PLoS Medicine, February 22, 2005
Eur J Clin Invest 37 (suppl. 1):60, 2007
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Old 04-25-2011, 02:55 PM
gdpawel gdpawel is offline
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Default Adoptive Cell Transfer Targets New Cancer Antigen for Immunotherapy

Results from a phase II trial suggest that an immunotherapy strategy called adoptive cell transfer (ACT) may be effective for patients with metastatic cancers, including melanoma and a tumor of the soft tissues of joints known as synovial cell sarcoma. The study, published January 31, 2011 in the Journal of Clinical Oncology, is part of an effort by researchers from NCI’s Center for Cancer Research to engineer a patient’s own white blood cells to recognize and attack his or her specific cancer.

For the treatment, Dr. Steven Rosenberg and his colleagues genetically modified the receptors on the patient’s own T cells to bind to an antigen called NY-ESO-1, which is expressed in 80 percent of synovial cell sarcomas and 15 to 30 percent of metastatic melanoma, breast, prostate, lung, and ovarian cancers. The antigen is not commonly present in normal tissues except in the testis.

From each patient who had tumors that heavily expressed the NY-ESO-1 antigen, T cells were removed. The extracted T cells were then genetically altered using a retrovirus that delivered the genetic code for building NY-ESO-1 receptors into the cells. The modified T cells were then grown in the laboratory and infused back into the patients. To prepare for the infusion of their altered T cells, the patients received chemotherapy to eliminate any other immune cells in their blood.

All 17 patients enrolled in the trial had progressive metastatic disease. The six patients with synovial cell sarcoma had been treated with multiple chemotherapies, and the 11 melanoma patients had been previously treated with interleukin-2. After ACT, five of the melanoma patients had measurable responses, and two of them had complete responses (disappearance of all signs of cancer) that were sustained at 20 and 22 months, respectively. Among the three remaining melanoma responders, one had a partial response (shrinkage of tumor size) that persisted 9 months after initial treatment. Four of the synovial cell sarcoma patients had objective partial responses, with one patient’s response lasting 18 months.

Patients in the trial experienced no toxic effects beyond those that are common with stem-cell transplantation and interleukin-2 treatment, which include neutropenia and thrombocytopenia, and the toxicities were less severe than in other trials in which ACT was used against different tumor antigens, the authors wrote.

The study “represents the first successful immunotherapy for patients with synovial cell sarcoma,” they concluded, noting that the small number of patients in the trial limits the interpretation of their results. However, the strategy against NY-ESO-1 should be explored further, they continued, because the antigen is expressed by common cancers and, thus, the treatment may be extended to many tumor types.
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Old 01-31-2016, 11:43 PM
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Default FDA Approval Expands Immunotherapy Options for Advanced Melanoma

Arthur N. Brodsky, Ph.D.

The FDA expanded the role of immunotherapy cancer treatments yet again, by approving the combination of two immunotherapy drugs—nivolumab (Opdivo) and ipilimumab (Yervoy)—as a frontline treatment for advanced melanoma.

Previously, the combination of these two drugs, both of which are manufactured by Bristol-Myers Squibb, had only received approval for patients whose melanoma lacked a specific mutation in the BRAF V600 gene. Saturday’s decision makes this effective combination treatment available for all previously untreated patients with advanced melanoma, and will enable improved outcomes in even more patients.

The accelerated approval for this combination was based on preliminary results from the phase III trial CheckMate-067. In this study, patients were given either: 1) nivolumab and ipilimumab in combination; 2) nivolumab alone; or 3) ipilimumab alone. According to all clinical metrics, the combination therapy led to improved responses in patients over both of the monotherapies.

Let’s look at the science behind these treatments. Both of these drugs belong to a class of immunotherapies known as checkpoint inhibitors. During cancer progression, tumor cells may develop the ability to evade the immune response through PD-1. Additionally, CTLA-4 can reign in the immune system’s response to cancer. To counter this, nivolumab blocks PD-1 activity and ipilimumab blocks CTLA-4 activity, and together enable the immune system to continue its attack. By empowering the immune response from complementary angles, the combination of nivolumab and ipilimumab made it harder for the cancer to disrupt and outsmart the immune response, leading to enhanced anti-cancer activity and improved patient responses.

Patients receiving the combination had a median progression-free survival of 11.5 months, compared to 6.9 months for nivolumab alone and 2.9 months for ipilimumab alone. Additionally, the objective response rate—complete responses plus partial responses—was 50% for patients receiving the combination therapy, compared to 40% for nivolumab alone and 14% for ipilimumab alone.

Many experts believe that these combination immunotherapies hold the key to maximizing immunotherapy’s effectiveness. They applaud the ability of both the regulatory and scientific communities to rapidly translate insights in the lab into lifesaving medicine for late-stage patients who don’t have the luxury of waiting several years for approval.

“This example actually shows that drug development doesn’t necessarily require enormous studies with many years of follow-up," said the trial’s lead investigator, Jedd D. Wolchok, M.D., Ph.D., an associate director of the Cancer Research Institute’s Scientific Advisory Council chief of Melanoma and Immunotherapeutics Service at Memorial Sloan Kettering Center. “It’s possible to move at a much faster pace when everyone is collaborating effectively,” he added.

Importantly, patients who received nivolumab alone had better responses compared to those who received ipilimumab alone. This led to the FDA additionally approving nivolumab alone for frontline treatment of all previously untreated patients with advanced melanoma. Before, nivolumab was approved only for previously untreated melanoma patients without the BRAF mutation.

While accelerated approval was based on preliminary progression-free survival, the CheckMate-067 study remains ongoing, and patients continue to be followed for overall survival in addition to other responses.

Source: Cancer Research Institute
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Old 04-29-2016, 10:41 PM
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Default More Patients Living Longer: Latest Immunotherapy Data

Medscape Medical News
April 18, 2016

NEW ORLEANS — Long-term data on immunotherapy in melanoma continues to show that with the newer agents, more people are living longer. Whereas in the preimmunotherapy era, overall survival (OS) of patients with advanced metastatic melanoma was measured in months, now it is being measured in years.

The latest data, presented here at the American Association for Cancer Research (AACR) 2016 Annual Meeting, show that about a third of patients (34%) are still alive 5 years after receiving nivolumab (Opdivo, Bristol-Myers Squibb Company) monotherapy for heavily pretreated advanced melanoma.

These are the longest-term data available to date for immunotherapy that targets cell programmed death (PD) signaling, and they look better than the data previously reported for ipilimumab (Yervoy, Bristol-Myers Squibb Company), an immunotherapy that works differently from nivolumab, by targeting CTLA-4. About 20% to 22% of patients receiving ipilimumab have long-term responses, with some patients living for up to 10 years.

For both immunotherapies, the survival curves plateau at around 3 to 4 years, and patients who are responding at that point continue to respond, often with no further treatment.

This durability of response is the most important take-home point, commented Louis Weiner, MD, director of the Georgetown Lombardi Comprehensive Cancer Center, in Washington, DC. He was not involved in the trials and moderated an AACR press conference at which the new data were presented.

"What distinguishes immunotherapy at this point when it is effective from every other form of cancer treatment is the durability of the benefit ― the people who have good responses really seem to be protected against the disease returning in many cases, not every case, but many cases," Dr Weiner said. "This is a marked distinction from our other therapies, such as chemotherapy and targeted therapy approaches, where you can see more rapid development of resistant disease.

"So the memory of the immune system and the adaptability of the immune response to pick off resistant disease that is trying to develop is a really important take-home point, and this is very compelling evidence to suggest that this may be the case," he said.

Data Now Out to 5 Years

The new data on nivolumab (abstract CT001) come from a long-term follow-up (minimum of 45 months) of 107 patients who participated in a phase 1 trial (CA209-003). These patients had advanced disease and had been heavily pretreated (most had undergone two prior therapies, including interleukin-2 therapy, in about 46% patients, but none had undergone prior PD or CTLA4 immunotherapy).

All patients received treatment with nivolumab monotherapy for 96 weeks. Various doses were used because this was a phase 1 dose-finding study. Eventually, a dose of 3 mg/kg IV administered every 2 weeks was chosen.

The survival curve plateaus at around 48 weeks, with about a third of patients (34%) showing durable, long-lasting response.

"The results show durable and long-term benefit from nivolumab monotherapy," concluded lead author Stephen Hodi, MD, director of the Melanoma Center at the Dana-Farber Cancer Institute and associate professor of medicine at the Ludwig Center, Harvard Medical School, in Boston, Massachusetts.

Most patients received only one course of immunotherapy. Five patients underwent a second treatment with nivolumab after they experiened disease progression after being off treatment for more than 100 days. For all 5 patients, disease control was achieved again. In one patient, a renal metastasis removed. These responses on re-treatment were also durable and showed long-term benefit from immunotherapy, Dr Hodi commented.

He noted that re-treatment with nivolumab was part of the clinical trial design. In clinical practice, such patients now have other options, such as treatment with a combination of nivolumab and ipilimumab or treatment with the other available PD inhibitor, pembrolizumab (Keytruda, Merck Sharp & Dohme Corp). However, which drug to use when is not clear yet, Dr Hodi said. At present, testing for PD-ligand expression is not a "decision point" when considering these agents, because some patients with low levels of this biomarker do respond to PD immunotherapies, he added.

The 5-year OS rate of 34% with nivolumab is more than double what can be expected in this patient population ― data from the National Cancer Institute's SEER database show a 5-year OS rate of 16.6% for patients with metastatic melanoma diagnosed from 2005 to 2011.

It is also a vast improvement on what had been seen before. In the preimmunotherapy era, patients with advanced metastatic melanoma were treated with chemotherapy and interferon, and survival was measured in months, Dr Hodi previously told Medscape Medical News.

He has also spoken previously of how the immune system, primed by the immunotherapy, adapts to hold the cancer in check. Sometimes the tumor is still visible on scans, but it does not progress, and the immune system keeps the cancer under control, often without the need for further therapy.

The new survival data are "very positive," commented Jedd Wolchok, MD, PhD, from Memorial Sloan Kettering Cancer Center, New York City, who acted as a discussant. He said that survival tails with both immunotherapies start at about 3 years, but the tail for nivolumab is higher than that for ipilimumab, with more patients living longer.

Some of these responses are being maintained for 2 to 3 years with no further treatment, he noted. And the few patients who were re-treated showed durable responses, which suggests that treatment can be stopped and then reinstated when necessary. This led him to question whether persistent dosing was necessary.

The data show evidence of immune system memory, he said, and wondered: "Could this memory last a lifetime?"

New Data With Combination Therapy

Also at the meeting, new data on OS for the combination of nivolumab and ipilimumab were presented for the first time by Michael Postow, MD, from the Memorial Sloan Kettering Cancer Center (abstract CT002).

These data come from the phase 2 checkmate 069 trial, in which 95 patients received the combination, and 47 received nivolumab alone. Previously, superior response rates and progression-free survival had been reported for the combination. Now, OS has also been shown to be superior.

An exploratory analysis shows the OS rate at 2 years to be 69% with the combination vs 53% with nivolumab alone in patients with BRAF wild-type melanoma.

Discussing the presentation, Padmanee Sharma, MD, from the University of Texas MD Anderson Cancer Center, in Hosuton, compared this 2-year OS of 69% achieved with the combination therapy against data from previous studies, which showed a 2-year OS of 54% with ipilimumab alone and of 57% with nivolumab alone.

However, she noted that with the combination, the rate of adverse events was higher, with grade 3/4 toxicity reported in 55% of patients receiving the combination vs 22% receiving nivolumab alone.

Dr Sharma also emphasized the fact that the new survival data on the combination come from an exploratory endpoint. She said it was important to wait for the results from the phase 3 Checkmate 067 trial, for which OS is a primary endpoint. That trial has three arms ― the combination therapy vs ipilimumab alone vs nivolumab alone. That trial will give a better idea of how the agents compare with one another, she said.

There are still many questions about how best to use these therapies, she commented, noting that another PD inhibitor, pembrolizumab, is also available. There is still much work to do to determine which agents to use when in order to "maximize survival and minimize toxicities."

But the new data continue to confirm long-term benefits for patients receiving immunotherapies.

"As oncologists, we are familiar with increasing survival by a few months," commented Dr Sharma, but patients are now experiencing durable responses and are living for years.
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Old 04-29-2016, 10:44 PM
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Human Face of Durable Response

In the audience for the presentations was a melanoma survivor, T. J. Sharpe. When he was diagnosed with stage 4 melanoma nearly 4 years ago, just after his son was born, his prognosis looked bleak. The oncologist who treated him at that time suggested that he had 1 year, maybe 2 remaining. Yet he is alive and looks fit and well. Indeed, he completed a triathlon just a month ago.

In an interview with Medscape Medical News, Sharpe, who is 40 years old, said that this was his second encounter with melanoma. He was diagnosed 15 years ago with stage 1 disease, which was surgically removed. He received no further treatment. This time around, however, the disease was of stage 4. He was initially treated with tumor-infiltrating lymphocytes and ipilimumab, but the disease progressed. He enrolled in a clinical trial of pembrolizumab in April 2013. Since then, there has been almost a complete remission. Two spots have appeared on a CT scan but not on a PET scan, and he says his doctors consider him to be close to having "no evidence of disease." His oncologist said, "I feel really good about this."

Sharpe says he feels good and considers himself to be cancer free at this point. He continues to participate in the pembrolizumab clinical trial and receives a dose every 3 weeks. He undergoes blood testing and meets with his oncologist on a regular basis as part of the trial, but the rest of the time he is getting on with his life.

He says he has experienced few side effects. "After the initial few doses, there was immune system reaction, and now there is just fatigue, which I have learned to live with it, making sure that I get enough rest."

He says he looks after himself, maintains a positive attitude, and looks forward to the future. He visualizes attending his children's graduations. He is very taken with the idea that the drug is acting on the immune system and not directly on the cancer itself. As a pharmacist explained to him: "You are using immune system to best cancer," and he says he intends to do "everything in my power to make sure my immune system is working as well as possible."

The CheckMate trials are funded by Bristol-Myers Squibb. Dr Hodi serves as a nonpaid consultant for Bristol-Myers Squibb.

American Association for Cancer Research (AACR) 2016 Annual Meeting: Abstracts CT001 and CT002, both presented April 18, 2016.

Citation: More Patients Living Longer: Latest Immunotherapy Data. Medscape. Apr 18, 2016.

[url]http://www.abstractsonline.com/plan/ViewAbstract.aspx?mID=4017&sKey=371fa616-a0cf-4bf8-993d-ce424853b52c&cKey=616f965e-a236-4bd2-9f7a-6399bd6f3f6c&mKey=1d10d749-4b6a-4ab3-bcd4-f80fb1922267

[url]http://www.abstractsonline.com/plan/ViewAbstract.aspx?mID=4017&sKey=371fa616-a0cf-4bf8-993d-ce424853b52c&cKey=d4d67737-7e76-4133-9869-263896d727e8&mKey=1d10d749-4b6a-4ab3-bcd4-f80fb1922267
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Gregory D. Pawelski
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