tag:theconversation.com,2011:/us/topics/keytruda-16319/articlesKeytruda – The Conversation2018-10-02T01:55:34Ztag:theconversation.com,2011:article/1042212018-10-02T01:55:34Z2018-10-02T01:55:34ZHow two 1990s discoveries have led to (some) cured cancers, and a Nobel Prize<p>This year’s award of the <a href="https://www.nobelprize.org/prizes/medicine/2018/press-release/">Nobel Prize for Physiology and Medicine</a> to James P. Allison and Tasuku Honjo, for their work in the early 1990s on immune checkpoint proteins CTLA4 and PD1, is a fitting recognition of how their work has led to a seismic shift in the way we treat cancer. </p>
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<a href="https://theconversation.com/james-allison-and-tasuku-honjo-deserving-winners-of-this-years-nobel-prize-in-physiology-or-medicine-104163">James Allison and Tasuku Honjo: deserving winners of this year's Nobel Prize in Physiology or Medicine</a>
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<p>In a remarkably short time, drugs that inhibit these immune checkpoints (or immune brakes) have transformed the practice of clinical oncology. Drugs like <a href="https://www.pbs.gov.au/medicine/item/10424P-10436G-10475H-10493G">pembrolizumab</a> (Keytruda), <a href="https://www.pbs.gov.au/medicine/item/2638W-2641B">ipilimumab</a> (Yervoy), <a href="https://www.pbs.gov.au/medicine/item/10745M-10748Q-10764M-10775D">nivolumab</a> (Opdivo), avelumab, durvalumab (Imfinzi) and <a href="https://www.pbs.gov.au/medicine/item/11277M-11284X-11297N-11309F">atezolizumab</a> – some of which are now being subsidised on Australia’s Pharmaceutical Benefits Scheme (PBS) – are being applied across a range of cancers.</p>
<p>From AFL player <a href="https://www.huffingtonpost.com.au/2016/05/31/it-eats-cancer-cells-jarryd-rougheads-melanoma-treatment-exp_a_21386344/">Jarryd Roughead</a> to businessman <a href="https://www.smh.com.au/business/i-dont-want-to-die-i-still-have-things-to-do-keytruda-wins-ron-walkers-war-on-cancer-20150130-1323s8.html">Ron Walker</a>, to former US president <a href="https://www.cancerresearch.org/join-the-cause/cancer-immunotherapy-month/30-facts/20">Jimmy Carter</a>, anecdotes abound for the activity of immune checkpoint inhibitors in advanced cancers such as melanoma, lung, kidney and bladder and others.</p>
<p>One of the first patients I was privileged to care for in clinic had completed four rounds of treatment with an experimental drug – three months of infusions of a checkpoint inhibitor (one of which is now on the PBS). She had managed these infusions well, but past treatments had failed, so she was understandably anxious.</p>
<p>Before going to see her, I checked her scan report. </p>
<p>Then I looked at the scans.</p>
<p>I checked the report again.</p>
<p>My first words when I walked into her room were ones I never dreamed I’d say to someone with advanced cancer: “I can’t see the cancer on your scans anymore”. My entrance would have been a lot more dramatic if the nurse hadn’t already told her the good news. </p>
<p>“When can I book a holiday?” she said.</p>
<h2>How checkpoint inhibitors work</h2>
<p>Originally, Allison and Honjo’s studies were focused on the underlying machinery of how the immune system controls itself. Like many mechanisms in our body, the immune system has the ability to sense prevailing conditions and rapidly amplify a response to defend the body. </p>
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<a href="https://theconversation.com/explainer-how-does-the-immune-system-work-27163">Explainer: how does the immune system work?</a>
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<p>This powerful process has evolved over millions of years. But a powerful system also needs powerful regulation, for which our bodies have evolved so-called “checkpoints”, or brakes, that guard against overactivity of the immune response.</p>
<p>There are myriad <a href="https://wiki.cancer.org.au/oncologyformedicalstudents/Principles_of_cancer_immunotherapy">immune checkpoint proteins</a> on the surface of immune cells and normal cells of the body to allow this regulation to occur. Immune checkpoints work in a committee to vote their approval or disapproval of whether an immune cell becomes activated and attacks when it meets and recognises another cell or organism.</p>
<p>Insufficient or impaired checkpoint signalling allows an overreaction, which may contribute to the causes of autoimmune diseases such as colitis and arthritis. Conversely overactivity of immune checkpoints can obscure and confuse the immune system, allowing infected or abnormal cells to persist.</p>
<p>Cancer cells use these immune checkpoints to hide and evade from immune cells, tipping the balance in favour of the cancer and turning each immune cell off. Checkpoint inhibitor drugs work by not allowing the brakes to come on, so the immune system can keep attacking the cancer.</p>
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<a href="https://theconversation.com/the-fourth-pillar-how-were-arming-the-immune-system-to-help-fight-cancer-48152">The fourth pillar: how we're arming the immune system to help fight cancer</a>
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<p>Allison and Honjo initially conceived that their discoveries may help treat chronic infections such as hepatitis B and C. The drugs created from their discoveries remain in trials for these conditions, but their most exciting application has come through the treatment of cancer.</p>
<p>Using the power of the immune system to fight off cancer actually goes back to the late 19th century. Surgeon <a href="https://www.cancerresearch.org/blog/april-2015/what-ever-happened-to-coleys-toxins">William Coley</a> had developed an approach to treating cancer that involved injecting patients with a mixture of heat-killed bacteria in the hopes of stimulating the body’s “resisting powers.” </p>
<p>But with rapid understanding of the physics of radiotherapy, and the chemistry of chemotherapy, the use of immune therapy for cancer languished. It waited until we had a better understanding of the biology of the immune system. </p>
<p>We now know that the current crop of immune checkpoint inhibitor drugs will help a minority of patients across many cancers, but still fail the majority. Our understanding still feels very basic. We can’t yet predict who will be helped, who will be failed, who will suffer side-effects, or who will benefit from different combinations of therapy. </p>
<p>But this platform of studies and drugs will provide us with the foundation to understand how the immune system is structured and could be reactivated in every person with cancer, to try to solve this puzzle in real-time for each individual.</p>
<p>The work of Allison and Honjo has given us hope of delivering mundane miracles to everyone with cancer, and turning cancer patients back into people.</p>
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Read more:
<a href="https://theconversation.com/cancer-immunotherapy-drugs-like-keytruda-and-opdivo-hold-hope-for-some-but-theres-still-a-way-to-go-81320">Cancer immunotherapy drugs like Keytruda and Opdivo hold hope for some, but there's still a way to go</a>
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<p class="fine-print"><em><span>Craig Gedye is the principal investigator on ANZUP cooperative group clinical trials supported by the manufacturers of nivolumab and pembrolizumab. He participates in pharmaceutical company advisory boards, but any and all fees are donated directly to the Hunter Medical Research Institute, University of Newcastle.</span></em></p>In a remarkably short period of time, drugs that harness the power of the immune system, have been used to successfully treat many cancers.Craig Gedye, Oncologist and Senior Lecturer, University of NewcastleLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/747572018-04-11T07:39:12Z2018-04-11T07:39:12ZWeekly Dose: Keytruda may be a miracle cancer drug, but can those who need it afford it?<figure><img src="https://images.theconversation.com/files/164026/original/image-20170405-11383-nlx97r.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Immunotherapy works by increasing the magnitude or quality of the patient's own immune response.</span> <span class="attribution"><span class="source">from shutterstock.com</span></span></figcaption></figure><p>Keytruda (generic name pembrolizumab) is an immunotherapy drug manufactured by the company Merck & Co. It is most <a href="https://www.keytruda.com/">commonly used</a> to treat melanoma, and was <a href="https://www.tga.gov.au/sites/default/files/auspar-pembrolizumab-rch-161014.pdf">listed for this use</a> by Australia’s Therapeutic Goods Administration in April 2015. </p>
<p>In March 2017, the TGA <a href="https://www.tga.gov.au/prescription-medicines-new-or-extended-uses-registered-medicines">extended approval</a> for Keytruda to treat a specific type of lung cancer called non small-cell lung carcinoma. In the same month it was approved by the US Food and Drug Administration (FDA) for classical <a href="https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm546893.htm">Hodgkin lymphoma</a>, and the <a href="https://www.ebs.tga.gov.au/servlet/xmlmillr6?dbid=ebs/PublicHTML/pdfStore.nsf&docid=226597&agid=(PrintDetailsPublic)&actionid=1">TGA later also approved</a> it for this condition.</p>
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Read more:
<a href="https://theconversation.com/the-fourth-pillar-how-were-arming-the-immune-system-to-help-fight-cancer-48152">The fourth pillar: how we're arming the immune system to help fight cancer</a>
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<h2>How it works</h2>
<p>Immunotherapy drugs work by increasing the patient’s own immune response. The most successful examples of immunotherapies are drugs that act as antibodies, which are natural molecules made by the immune system to fight harmful intruders.</p>
<p>The immune system launches an attack on intruders by releasing killer cells called T-lymphocytes, or T-cells. When these T-cells attack cancer cells, a certain protein, called <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5379970/">PD-1 accumulates on the T-cells</a>. The cancer cells then have their own protein that binds to PD-1, and this interaction cleverly <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4118725/">switches off the T-cells</a>, stopping them from attacking the cancer. </p>
<p>Keytruda works by binding to PD-1 and therefore blocking the cancer cells from using their own protein to slot into the same spot and switch off the immune cells. So with Keytruda, the T-cells do their job and effectively attack the cancer. Keytruda is <a href="https://www.keytruda.com/">also known</a> as an anti PD-1 immunotherapy.</p>
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<h2>History</h2>
<p>Tasuku Honjo and his group at Japan’s Kyoto University <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC556898/">identified the PD-1 protein</a> in the early 1990s and established that it <a href="https://www.ncbi.nlm.nih.gov/pubmed/10485649">inhibits T-cells</a>. This early research led to the development of the antibody <a href="https://en.wikipedia.org/wiki/Pembrolizumab">in 2006</a> by scientists in the Netherlands. </p>
<p>Keytruda was <a href="https://www.drugs.com/newdrugs/fda-approves-keytruda-pembrolizumab-advanced-melanoma-4079.html">approved by the FDA</a> for advanced, inoperable or drug-resistant melanoma in 2014. It has seen <a href="https://www.drugs.com/history/keytruda.html">additional indications added annually</a>, including for particular head and neck cancers, non-small cell lung cancers, and metastatic urothelial carcinoma (a type of bladder cancer). </p>
<p>The FDA approval for <a href="https://www.drugs.com/newdrugs/fda-approves-merck-s-keytruda-pembrolizumab-classical-hodgkin-lymphoma-chl-4497.html">Hodgkin’s lymphoma</a> in adults and children came after a <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5791843/">clinical trial</a> found that 22% of patients who were treated with Keytruda underwent complete remission. This is the first indication that some blood cancers can also benefit from Keytruda. </p>
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Read more:
<a href="https://theconversation.com/cancer-immunotherapy-drugs-like-keytruda-and-opdivo-hold-hope-for-some-but-theres-still-a-way-to-go-81320">Cancer immunotherapy drugs like Keytruda and Opdivo hold hope for some, but there's still a way to go</a>
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<p>While most of conditions for which it has been approved require the cancer to have resisted previous therapies, <a href="https://www.drugs.com/newdrugs/fda-approves-merck-s-keytruda-pembrolizumab-first-line-certain-patients-metastatic-non-small-cell-4449.html">Keytruda was approved as the first line therapy</a> for a subset of metastatic non-small cell lung cancers. This means patients have access to Keytruda before even receiving chemotherapy. </p>
<p>Trials in <a href="http://www.nejm.org/doi/full/10.1056/NEJMoa1606774">first-line treatment</a> for these patients show Keytruda resulted in a 50% reduction in risk of disease progression and 40% reduction in risk of death compared to chemotherapy.</p>
<p>Keytruda is currently being evaluated in close to <a href="https://www.cancer.gov/about-cancer/treatment/clinical-trials/intervention/pembrolizumab">400 clinical trials</a> covering numerous solid and blood tumour types. It is likely that more indications for Keytruda treatment will be approved in the near future. </p>
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<span class="caption">Like other treatments such as chemotherapy, Keytruda is administered intravenously.</span>
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<h2>How is it used?</h2>
<p>Keytruda is administered as an intravenous infusion <a href="https://www.keytruda.com/taking-keytruda/">every three weeks</a>. The way the cancer, and the patient, responds to treatment, will dictate its duration. But typically, treatments last up to <a href="https://www.keytruda.com/hcp/dosing/">24 months</a> in patients without disease progression.</p>
<h2>How much does it cost?</h2>
<p>Cost of treatment is a key issue around immunotherapies like Keytruda. Merck & Co do offer some <a href="https://www.keytruda.com/keytruda-patient-support-program/">subsidies and financial assistance</a>. The Pharmaceutical Benefits Scheme (PBS) also <a href="http://www.pbs.gov.au/info/industry/listing/elements/pbac-meetings/psd/2016-11/pembrolizumab-melanoma-psd-november-2016">subsidises Keytruda</a> for a subset of melanomas and non-small cell lung cancers, costing patients A$39.50 per treatment.</p>
<p>As more clinical data becomes available on the benefit of Keytruda, there is likely to be more lobbying for the government to include additional indications on the PBS.</p>
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<a href="https://theconversation.com/we-dont-need-to-change-how-we-subsidise-breakthrough-cancer-treatments-87185">We don't need to change how we subsidise 'breakthrough' cancer treatments</a>
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<p>Australian patients who don’t have any of the indications listed on the PBS, could <a href="http://www.abc.net.au/news/2015-06-28/melanoma-drug-listed-on-pbs-saving-patients-thousands/6578554">pay A$150,000 per year</a>.</p>
<h2>What are the side effects?</h2>
<p>The most <a href="https://www.keytruda.com/side-effects/">common side effects</a> of Keytruda include feeling tired, pain in muscles, bones or joints, decreased appetite, itching, diarrhoea, nausea, rash, fever, cough, shortness of breath, and constipation.</p>
<p>Because Keytruda boosts your immune system, it can also cause your immune system to attack normal organs and tissues in any area of your body and can affect the way they work. These problems can sometimes become serious or life-threatening and can lead to death. </p>
<h2>Other points of interest</h2>
<p>The impact of the role of PD-1 in immunotherapy is profound and those responsible for its discovery are potential winners of the Nobel Prize in Physiology and Medicine in the near future. </p>
<p>The efficacy of Keytruda in metastatic melanoma has helped transform the landscape of the pharmaceutical industry and now most large pharmaceutical companies have similar, anti PD-1 products, and are investing in developing new and improved drugs to gain the competitive edge. The <a href="https://www.marketsandmarkets.com/PressReleases/cancer-immunotherapy.asp">immunotherapy market</a> is tipped to be worth more than US$100 billion by 2020.</p><img src="https://counter.theconversation.com/content/74757/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Nicholas Huntington does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Immunotherapy drugs work by increasing the patient’s own immune response. The most successful examples of immunotherapies are drugs that act as antibodies, of which Keytruda is one.Nicholas Huntington, Laboratory Head, Molecular Immunology, Walter and Eliza Hall InstituteLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/813202017-07-31T02:40:03Z2017-07-31T02:40:03ZCancer immunotherapy drugs like Keytruda and Opdivo hold hope for some, but there’s still a way to go<figure><img src="https://images.theconversation.com/files/179585/original/file-20170725-7881-3ml7zo.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Some people taking these drugs can see their cancer completely disappear – there's nothing left to see on their x-rays</span> <span class="attribution"><span class="source">from www.shutterstock.com.au</span></span></figcaption></figure><p>Imagine being able to offer hope to people with cancers that were once thought untreatable. Checkpoint immune drugs like pembrolizumab (Keytruda) and nivolumab (Opdivo) are heralding this new era in cancer treatment. Some people taking these drugs can see their cancer completely disappear; <a href="http://ascopubs.org/doi/full/10.1200/jco.2014.59.4358">there’s nothing left to see on their x-rays</a>.</p>
<p>We rightly celebrate these successes, but must face the sobering truth that only a minority of people experience these dramatic benefits. Decades of research have helped us reach this point. Now scientists and doctors from Australia and around the world are working furiously to learn more about how these immune treatments work or fail.</p>
<h2>Who it works for now</h2>
<p>Nivolumab and pembrolizumab are checkpoint immunotherapy antibodies. They work by blocking barriers (or “checkpoints”) created by cancer cells to protect against attack from the immune system. Remove the barrier and the immune system can destroy the cancer. </p>
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<p>The most success so far for these drugs is with melanoma, which has long been known to respond to immunotherapy. In Australia, single or combination checkpoint immunotherapy <a href="https://melanomanewstoday.com/2017/04/06/opdivo-yervoy-combo-improved-survival-advanced-melanoma-phase-3-trial/">substantially helps about half of people with melanoma</a>, and will soon be available for people with kidney and lung cancers. </p>
<p><a href="http://www.clintrial.org.au/">Trials continue in most types of cancer</a>. Checkpoint immunotherapy has proven beneficial in patients with <a href="https://www.cancer.gov/news-events/cancer-currents-blog/2017/approvals-fda-checkpoint-bladder">bladder cancer</a>, <a href="https://www.cancer.gov/news-events/cancer-currents-blog/2016/fda-pembrolizumab-hnscc">head and neck cancer</a> and <a href="https://www.cancer.org/cancer/hodgkin-lymphoma/treating/monoclonal-antibodies.html">Hodgkin lymphoma</a>. A smaller proportion of people, typically around 20-30%, are helped in most of these cancers. These successes and failures start to show us how checkpoint immunotherapy works, and how it might work better.</p>
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<h2>Who it might help soon</h2>
<p>Patients whose cancers are already under attack from immune cells are the people who seem most likely to be helped by checkpoint immunotherapy. But many patients’ cancers are devoid of immune cells – so removing checkpoints doesn’t help. </p>
<p>This is why the first strategy to improve checkpoint immunotherapy is to diversify and muster the immune system into tumours. Some checkpoint immunotherapy drugs (such as ipilimumab, brand name “Yervoy”) work this way. In effect they “vaccinate” the patient against their cancer, educating the immune system on how to fight the cancer, and recruiting immune cells to attack tumours.</p>
<p>A similar method uses <a href="https://www.cancer.gov/news-events/cancer-currents-blog/2015/t-vec-melanoma">modified viruses that infect and explode immune cells</a>. These can be directly injected into cancers, drawing in immune cells to attack the cancer. This is the basis of the <a href="http://discovermagazine.com/2016/april/11-germ-of-an-idea">very first immune therapy for cancer</a>, first used in 1896.</p>
<p>Finally, identifying the minority of people who naturally have immune-infiltrated cancers may identify those likely to benefit from checkpoint immunotherapy (such as <a href="http://www.ascopost.com/News/55733">aggressive breast cancer needing chemotherapy before surgery</a>).</p>
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Read more:
<a href="https://theconversation.com/explainer-how-does-keytruda-treat-melanoma-and-why-is-it-so-costly-40558">Explainer: how does Keytruda treat melanoma and why is it so costly?</a>
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<p>We may be able to identify a few people within various types of cancer most likely to benefit from checkpoint immunotherapy. For example, while checkpoint immunotherapy doesn’t help most bowel and prostate cancer patients, a small group of people whose cancers’ DNA isn’t able to repair properly <a href="http://science.sciencemag.org/content/early/2017/06/07/science.aan6733/tab-pdf">have dramatic outcomes from checkpoint immunotherapy</a>.</p>
<p>This lack of efficient DNA repair is called “mismatch repair deficiency”. Mismatch repair is one of the tools cells use to repair their DNA. Loss of mismatch repair leads to aggressive cancers that don’t respond to chemotherapy, but which throw up lots of targets for the immune system.</p>
<p>Up to a third of uterine cancers, 15% of bowel cancers, 15% of stomach cancers and perhaps 5% each of prostate, oesophageal, cervical and ovarian cancers <a href="http://oncologypro.esmo.org/Education-Library/Factsheets-on-Biomarkers/Microsatellite-Instability-Defective-DNA-Mismatch-Repair">have mismatch repair deficiency</a>, potentially making them treatable with checkpoint immunotherapy.</p>
<h2>How we might improve immune therapy further</h2>
<p>Even when fully implemented, these strategies will leave many people who won’t benefit from checkpoint immunotherapy – but a <a href="http://www.cell.com/cell/pdf/S0092-8674(17)30065-X.pdf">huge number of new treatments, combinations and ideas</a> are being tested in clinical trials.</p>
<p>Drugs that <a href="https://www.nature.com/articles/n-12336794">protect immune cells from toxic chemicals</a> released by nearby cancer cells appear very promising. A myriad of new antibodies that block other immune checkpoints are in development. And we haven’t abandoned standard cancer treatments like <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4649476/">blood-supply blocking drugs</a>, radiotherapy or chemotherapy; these may help immunotherapy by killing enough cancer cells to recruit immune cells into tumours.</p>
<p>Should everyone with cancer take checkpoint immunotherapy? <a href="https://www.cancercouncil.com.au/wp-content/uploads/2017/06/UC-Pub-Immunotherapy-CAN6479-lo-res_June-2017.pdf">These drugs are safe overall</a>, though people with autoimmune diseases (such as rheumatoid arthritis) need to be very cautious. This is because the underlying cause of checkpoint immunotherapy side effects, an overactive immune system, is very similar to the causes of autoimmune diseases.</p>
<p>And there is a social challenge: cost. We are privileged to have many publicly funded PBS-reimbursed cancer treatments in Australia, but <a href="http://dx.doi.org/10.1111/imj.12399">drug costs are rising sharply</a>. One solution will be to find more ways to <a href="http://www.cell.com/cell/abstract/S0092-8674(17)30429-4">identify the patients most likely to benefit from these drugs</a>, so we’re not using expensive drugs to treat people for whom they won’t have an effect. </p>
<p>Another, perhaps complementary, strategy would be <a href="http://catalyst.nejm.org/a-new-way-to-define-value-in-drug-pricing/">pay-for-performance</a> – treat everyone, but only reimburse the manufacturer if the patient is helped. This might particularly assist people with rare cancers, where clinical trials are extremely hard to perform.</p>
<p>Checkpoint immunotherapy is a triumph – when it works. It’s important to temper our hopes with the knowledge that these promising drugs can’t yet help every person, with every cancer. But we’re working on it.</p><img src="https://counter.theconversation.com/content/81320/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Craig Gedye is the principal investigator on ANZUP cooperative group clinical trials supported by the manufacturers of nivolumab and pembrolizumab. He participates in pharmaceutical company advisory boards, but any and all fees are donated directly to the Hunter Medical Research Institute, University of Newcastle.</span></em></p>Imagine being able to offer hope to people with cancers once thought untreatable. Checkpoint immune drugs like Opdivo and Keytruda lead this new era in treatment. But they don’t work for everyone.Craig Gedye, Oncologist and Senior Lecturer, University of NewcastleLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/440722015-07-26T20:12:12Z2015-07-26T20:12:12ZIf we don’t talk about value, cancer drugs will become terminal for health systems<figure><img src="https://images.theconversation.com/files/89712/original/image-20150726-8474-72m20i.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">A group of oncologists have called on cancer patients to challenge the high prices charged by pharmaceutical companies for new cancer drugs.</span> <span class="attribution"><a class="source" href="https://www.flickr.com/photos/ep_jhu/3308079338/in/photolist-63jLJE-6sSezB-4cXa6D-9bH4ur-8VPze4-4nVDsE-8Pomnt-7V1PRy-4CZCmU-jR9gc-oH4rdU-pCYRsM-35k1qw-95qvZs-sCTxH-5ybjn2-5VQHuA-9sw3y4-9Xcshz-e8UEr-dAjLrS-kxHJW-bqRwgf-cqiNS1-6m4PWH-6ZHdXN-9d5WGV-dEWvJE-4M7pV-ncFSjE-78ePNM-2JagVw-7kihrz-jK2whx-9XtRCC-oK4qob-bq31mE-dg7YLC-e59Fxe-2zyGn9-6nrmLQ-bDvpYV-ardcyt-bkbW8T-vdvJCW-5S73oK-wnYnx-3vuBP9-vdUfav-dErKR5">ep_jhu/Flickr</a>, <a class="license" href="http://creativecommons.org/licenses/by-nc-nd/4.0/">CC BY-NC-ND</a></span></figcaption></figure><p><a href="http://www.mayoclinicproceedings.org/article/S0025-6196(15)00430-9/abstract">More than 100 prominent oncologists</a> from across the United States have called on <a href="http://www.nytimes.com/2015/07/23/business/drug-companies-pushed-from-far-and-wide-to-explain-high-prices.html?_r=1">cancer patients to challenge the high prices</a> charged by pharmaceutical companies for new cancer drugs. They claim drug companies, insurance companies, some patient advocacy groups and many hospitals and physicians are <a href="http://newsnetwork.mayoclinic.org/discussion/leading-experts-prescribe-how-to-make-cancer-drugs-more-affordable/">too financially conflicted to be driving the debate</a>. </p>
<p>Their call is motivated by the astronomical prices charged for some new cancer drugs. And Australia is in the same boat. Earlier this year, for instance, the Pharmaceutical Benefits Scheme (PBS) <a href="http://www.smh.com.au/national/health/ron-walkers-150000-cancer-drug-keytruda-approved-for-melanoma-patients-20150420-1more8.html">started subsidising pembrolizumab (Keytruda)</a> for the treatment of patients with advanced melanoma. The drug is expected to cost A$150,000 per patient for each year of treatment, which is <a href="http://www.abs.gov.au/ausstats/abs@.nsf/mf/6302.0">almost twice</a> the national average annual income.</p>
<p>Unlike in the United States, where patients’ insurance covers the costs, the Australian taxpayer subsidises <a href="http://www.pbs.gov.au/pbs/home">drugs listed on the PBS</a>. In cases where new drugs are not subsidised, they’re paid for directly by patients, or by state-funded hospitals (often after approval by drug committees). They can also be provided free or subsidised by pharmaceutical companies for “compassionate use”. </p>
<h2>Blurred by emotion</h2>
<p>Decisions to subsidise drugs and improve their accessibility should be based on an assessment of their value. In Australia, for instance, the <a href="http://www.pbs.gov.au/info/industry/listing/participants/pbac">Pharmaceutical Benefits Advisory Committee</a> examines new drugs for effectiveness, safety and value for money compared to other treatments before recommending PBS listing – or not. </p>
<p>But the imperative to “save lives” or “beat cancer” — particularly where there’s vigorous public, professional and industry advocacy — can be so profound that it overwhelms the requirement that medicines should be efficacious and cost-effective. This tension between emotional and economic considerations frequently challenges and compromises public decision-making about the value of drugs. </p>
<p>Consider the case of eribulin (Halaven), a drug for treating advanced breast cancer. The UK <a href="https://www.nice.org.uk/about">National Institute for Health and Clinical Excellence</a> (NICE is the rough equivalent of PBAC although it has a broader role) considered the drug but rejected it as too expensive. </p>
<p><a href="http://www.economist.com/news/britain/21640343-well-meaning-gesture-causing-more-and-more-trouble-benign-or-malignant">Eribulin was subsequently covered</a> by the <a href="http://www.cancerresearchuk.org/about-cancer/cancers-in-general/cancer-questions/cancer-drugs-fund">UK Cancer Drugs Fund</a>, a pool of public money allocated to pay for drugs not approved via the usual route. The price accepted by the fund was among the highest in Europe for the drug; the price rejected by NICE had been the lowest. </p>
<p>Clearly, when standards of cost-effectiveness are reduced in the name of “improved access”, prices can rise arbitrarily. In most markets, supply and demand, competition and consumer choice curtail such arbitrary fluctuations in price. </p>
<p>But the market for innovative cancer drugs doesn’t follow this pattern because prices can increase dramatically even in “growing” markets, without clear reasons. In 2013, for example, a group of <a href="http://www.bloodjournal.org/content/121/22/4439">experts in chronic myeloid leukemia described</a> how the price of imatinib (Gleevec) increased three-fold over a decade. This happened even though all research and development costs were accounted for in the original price, and the number of people using the drug was dramatically increasing. Heightened demand alone cannot explain such an increase.</p>
<h2>What makes cancer drugs different</h2>
<p>Cancer drug markets clearly behave quite differently to what we might expect. There are three key reasons for this. </p>
<p>First, governments are creating a “price deregulation eco-system” for cancer drugs by establishing special funds that challenge accepted standards of value, and by curtailing the ability of payers to negotiate prices. The UK government has the Cancer Drugs Fund discussed above, while US legislation limits the ability of <a href="https://www.medicare.gov/">Medicare</a> – the US government’s health insurance program for people who are 65 and older and certain others –
<a href="http://ww_w.nejm.org/doi/full/10.1056/NEJMhpr0807774">to negotiate drug prices</a>. Laws in the latter country effectively force the health insurer to pay for cancer drugs used for a “medically accepted indication”, and prevent it from considering related cancer drugs as interchangeable. </p>
<p>In other words, US Medicare cannot make the call about whether the drug is worth its asking price, or negotiate prices based on cheaper available alternatives. The fact that the US pays the most for many drugs — including many cancer drugs — should therefore be no surprise. And if other countries are paying high prices for drugs, it makes it easier to justify these high prices elsewhere.</p>
<p>Second, there’s a lack of significant competition for many new cancer drugs. In an attempt to understand why South Korea paid so much less for drugs used to treat chronic myeloid leukemia — in some instances less than 20% of the US price — the <a href="http://www.bloodjournal.org/content/121/22/4439">same group of experts mentioned previously</a> noted the country had its own locally discovered drug for treating this disease. The price of competing products appeared to be based on this local drug’s price.</p>
<p>The lack of competition in the cancer drugs market is exacerbated by the rise of new “<a href="https://www.cornerstone.com/GetAttachment/4274a2ec-56b5-403f-af6d-022aae98b97a/Emerging-Competition-Issues-in-Biologics.pdf">biological agents</a>”, which are more difficult to replicate than small-molecule drugs, and <a href="http://healthaffairs.org/blog/2013/12/04/why-are-cancer-drugs-commonly-the-target-of-schemes-to-extend-patent-exclusivity/">by industry practices</a> aimed at extending the patent lives of existing products, thwarting generic competition.</p>
<p>Finally, markets in health care, including for high-cost cancer drugs, are powerfully influenced by existential and moral considerations — specifically fear of death and disability, and desire for greater quantity and quality of life. Cancer patients, their families and the oncologists who care for them are often willing to try drugs in the hope they will work, regardless of the price or prospect of benefit, which is frequently quite limited in the case of new, expensive cancer therapies. And as long as there are people willing to pay high prices or, as is usually the case, to demand subsidised access to cancer drugs, there’s no reason for the industry to reduce its prices.</p>
<p>Hope, fear and desperation, along with the unique characteristics of the cancer drug market, create a “perfect storm” that continues to drive up prices for cancer drugs. Unless we regain sight of the need to use regulatory incentives to reward only genuine innovation and ensure that we receive sufficient value for the money we spend on new medicines, this upward trend for cancer drug prices is set to continue. </p>
<p>The call by the <a href="http://www.reuters.com/article/2015/07/23/cancer-costs-protest-idUSL1N1022Y420150723">US oncologists</a> for patients to demand reductions in the price of the new drugs may be too much of an ask as these people have more to lose in this debate. It may also be too narrowly focused as it’s not just cancer patients but all of us who should demand the drugs we need at a price that our publicly funded health systems can afford.</p>
<p><strong>CORRECTION:</strong> <em>This article has been amended to reflect the fact that the PBS lists subsidised drugs, not the Therapeutic Goods Administration it said originally.</em></p><img src="https://counter.theconversation.com/content/44072/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Narcyz Ghinea receives funding from the National Health and Medical Research Council.</span></em></p><p class="fine-print"><em><span>Ian Kerridge receives funding from NHMRC for research into high cost drugs and for the study of conflicts of interest in medicine and science.</span></em></p><p class="fine-print"><em><span>Wendy Lipworth receives funding from the National Health and Medical Research Council. She is affiliated with the DIA..</span></em></p>Hope, fear, and desperation, along with the unique characteristics of the cancer drug market, create a “perfect storm” that continues to drive up prices for cancer drugs.Narcyz Ghinea, Research Associate, Centre for Values, Ethics and the Law in Medicine, University of SydneyIan Kerridge, Associate Professor in Bioethics & Director, Centre for Values and Ethics and the Law in Medicine, University of SydneyWendy Lipworth, Senior Research Fellow, Bioethics, University of SydneyLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/405582015-04-23T05:01:34Z2015-04-23T05:01:34ZExplainer: how does Keytruda treat melanoma and why is it so costly?<figure><img src="https://images.theconversation.com/files/79009/original/image-20150422-1858-1oszuku.jpg?ixlib=rb-1.1.0&rect=0%2C82%2C1000%2C519&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Keytruda® targets a protein on the surface of immune cells that stopped them from attacking the melanoma cells.</span> <span class="attribution"><a class="source" href="http://www.shutterstock.com/pic-159846560/stock-photo-melanoma-skin-cancer-mole-high-definition-image.html?src=SAJLwoBr03ptKZAAQYM3zw-1-3">Australis Photography/Shutterstock</a></span></figcaption></figure><p>Keytruda® (pembrolizumab) is the latest drug to be <a href="http://www.melanoma.org.au/news-events/news/anti-pd1-immunotherapy-pembrolizumab-keytruda-has-been-registered-by-the-tga/">registered</a> in Australia for the treatment of widespread melanoma. This is the third class of drugs that improves survival in widespread melanoma to be registered since July 2011. Prior to this no chemotherapy drug prolonged survival once melanoma had spread. </p>
<p>The first of the new drugs, Tafinlar® (dabrafenib), targets an alteration in the <a href="http://ghr.nlm.nih.gov/gene/BRAF">BRAF gene</a>, which signals the melanoma cells to divide more quickly. This altered gene was found in half of all melanomas. </p>
<p>The second drug, Yervoy® (ipilimumab), is an immune therapy. It is an antibody against a protein (<a href="http://www.nature.com/icb/journal/v77/n1/full/icb19991a.html">CTLA-4</a>) on immune T cells that stops that protein from preventing the T cells from attacking the melanoma.</p>
<p>Keytruda® also works by targeting a protein on the surface of immune cells that stops them from attacking the melanoma cells. The drug is an antibody which blocks the protein called <a href="http://www.ncbi.nlm.nih.gov/pubmed/21061197">PD-1</a> (programmed cell death 1) on the surface of the immune system T-cells. This prevents an activated PD-1 protein from stopping the immune response against the melanoma. </p>
<p>Initially, Keytruda® was <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4315269/">found to</a> prolong survival and outperform older chemotherapy drugs for patients whose melanoma had progressed after the other drugs. </p>
<p>Most recently, Keytruda® has been <a href="http://www.nejm.org/doi/full/10.1056/NEJMoa1503093">directly compared</a> to Yervoy® in patients with advanced melanoma who had either not received previous drugs or had only previously received Tafinlar® because the altered BRAF gene was present. The 834 patients with widespread melanoma from 16 countries were randomly allocated to Keytruda®, given every two weeks or three weeks, or Yervoy®. </p>
<p>In one-third of those treated with Keytruda®, their melanomas shrank, compared with only 12% of those on Yervoy®. Up to 74% of those treated with Keytruda® survived to 12 months compared with 58% of those on Yervoy®. </p>
<p>Those treated with Keytruda® also reported fewer side effects. These commonly included fatigue, diarrhoea, rash and itch, and more serious thyroid problems and inflammation of the bowel and liver.</p>
<p>The results indicate that Keytruda® could be used as the first drug in the treatment of widespread melanoma.</p>
<p>The decision to register a drug in Australia, and thereby make it available, is based on whether the beneficial effects are sufficient to justify the side effects. </p>
<p>However, there is another hurdle for a new drug: whether it gets approved for subsidy by the Pharmaceutical Benefits Scheme (PBS). Evaluators assess cost-effectiveness and how it compares to other treatments. PBS subsidisation effectively makes a drug affordable for a wide population. </p>
<p>If Keytruda® is not subsidised, the estimated cost is A$150,000 per patient for each year of treatment. </p>
<p>Why so expensive? The pharmaceutical industry points to the costs of research and development, including the expense of the large clinical trials needed to confirm efficacy. Often effective patent protection may last for only 15 years before competitors are allowed into the marketplace. </p>
<p>However, more likely, the price is set internationally by what the market is prepared to pay and that is often the American market, which can afford to pay more than many other nations. Australia has little leverage here as it represents less than 1.5% of the world’s pharmaceutical market.</p>
<p>What needs to be done? </p>
<p>In cancer, Australia has one of the highest survival rates in the world, so until now the most important cancer drugs have been subsidised on the PBS. However, with the very high cost of each new targeted therapy, the PBS clearly cannot continue to subsidise every new drug. </p>
<p>The bar needs to be set so the most effective drugs will continue to be made available. Examples would include drugs for which no alternative treatments exist, or drugs that demonstrate a large increase in survival over those currently used. </p>
<p>As now, there should always be special funding streams for drugs for rare diseases, which would otherwise not be commercially viable. </p>
<p>Drugs for life-threatening diseases should be made available as quickly as possible after efficacy is established. Here it would be desirable to have a managed entry scheme so that a drug could be approved on earlier endpoints than overall survival. Response rates or disease-free survival are examples. </p>
<p>For such a scheme to be feasible, there would have to be agreement that the subsidy could be removed or reduced if the drug did not subsequently meet its survival targets. </p>
<p>We must wait to see if Keytruda® will meet the cost-effectiveness targets.</p><img src="https://counter.theconversation.com/content/40558/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Ian Olver does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Keytruda® is the latest drug to be registered in Australia for the treatment of widespread melanoma. But we must wait to see if it meets the cost-effectiveness targets for PBS subsidisation.Ian Olver, Director, Sansom Institute for Health Research; Chair of Translational Cancer Research, University of South AustraliaLicensed as Creative Commons – attribution, no derivatives.