Senate Community Affairs References Committee

The availability of new, innovative and specialist drugs in Australia.

2015

AUSTRALIAN MELANOMA RESEARCH FOUNDATION

www.melanomaresearch.com.au

SUMMARY COMMENTS

Brendon Coventry & Martin Ashdown

Brendon J Coventry, BMBS PhD FRACS FACS FRSM Research Director, Australian Melanoma Research Foundation & Discipline of Surgery & Immunotherapy Laboratory, University of Adelaide, Royal Adelaide Hospital.

Martin L Ashdown, BApplSci, Research Fellow, University of Melbourne

The Terms of Reference: a. the timing and affordability of access for patients; b. the operation of the Pharmaceutical Benefits Advisory Committee and the Pharmaceutical Benefits Scheme in relation to such drugs, including the impact of delays in the approvals process for Australian patients; c. the impact on the quality of care available to cancer patients; and d. any related matters.

1 EXECUTIVE SUMMARY

COSTS

• Cancer drug costs threaten to break our federal and state budgets across Australia.

• Drug costs in Australia (and internationally) are currently unsustainable, and will become unaffordable to the Australian Government, taxpayers and the public within a decade or so if measures are not taken urgently to contain costs by improving clinical outcomes.

• The highest rate of cost growth occurred in the PBS (s100) program, at 62.61%. From 2011-12 to 2012-13, expenditure on this program more than doubled, from $222.5 million to $478.9 million. [1] This arises from newer high-cost agents.

• Active lobbying by desperate individuals, patient advocacy groups, medical oncology groups and pharmaceutical groups for funding by the PBS for easier availability of expensive drugs is understandable, but is not solving the critical problems of poor clinical responses and costs.

• A 1 percent reduction in cancer mortality would be worth US$500 billion per annum [2,3].

SURVIVAL & CLINICAL RESPONSES

• Globally, about 160,000 patients per week die of advanced cancer. Some 800 patients per week die of advanced cancer in Australia.

• Many cancer drugs show only marginal effectiveness, because only unpredictable low rates of complete responses and 5-year survival are demonstrated.

• The clinical improvement in survival from advanced cancer has remained essentially static for 50 years, making the amount of money that has been spent on drugs wasteful.

• Most cancer patients still Do Not Survive despite treatment (often with multiple courses) using expensive drugs.

• A Cure for Cancer would Benefit Patients - (or even substantial improvement in clinical response rates), but would remove the need for multiple expensive, less-effective drugs, and the need for numerous expensive institutions attempting to solve cancer - representing a problem for the cancer associated industries.

2

SOLUTIONS & RECOMMENDATIONS

• Removing the Conflict of Interest problem within hospitals, which is holding back quicker resolution of the issue of the low effectiveness of cancer drugs.

• Cancer Clinical Improvement Research Fund needs to be set up by government. Drug companies would contribute to this fund when receiving PBS listing, and this would remain at "arms-length" from research centres to preserve proper independent investigation.

• Exploring Different Approaches Several tertiary research institutions should be actively encouraged and adequately funded to explore different approaches, for example, using novel dosages, combinations and timing of therapies in an effort to more rapidly improve clinical outcome results (CR rates and survival). Drug companies are often reluctant to reduce dosage, or to explore side-effects/ combinations, chiefly on commercial grounds.

• Independent Australian Clinical Institutions Setting up several institutions with complete independence from drug company sponsorship through full Government funding to permit unbiased independent investigation into ways to improve the clinical efficacy of drugs for the Australian public.

• Reform of Drug Investigation Over-reliance on drug company approaches within Australian hospitals is seriously limiting new and innovative investigator-driven and cheaper research approaches; and this needs urgent reform to find better solutions.

• Improving Complete Response (CR) Rates (where all cancer disappears) The CR phenomenon can be induced by multiple divergent agents/ approaches, but is random/ unpredictable in nature, however, when it occurs 5-year survival is usual. [4] Urgent and adequate funding is required to achieve higher CR rates to contain budgets through cost savings measures.

• Active Exploration of Ways to Improve Cancer Survival is required to significantly improve health budgets and cancer patient survival.

• Success of Clinical Outcomes/ Results must be Linked with Reimbursement to achieve better professional practice, industry responsibility and improve cost. [5] Currently, payment is not linked to successful outcomes.

• Documentation of Clinical Outcome Results should be linked with PBS Reimbursement - these results need to be documented for each drug therapy in order to properly evaluate the true efficacy of drugs/ combinations occurring in actual clinical practice. This has seldom been done by medical oncologists outside of the initial clinical trials, but is essential to evaluate drug costs & benefits adequately.

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• Exploration of Off-Patent Drugs Many current off-patent drugs demonstrate clinical efficacy against cancer, but these are not being adequately explored because of the distraction arising from newer expensive agents.

• The key objectives must Improve Clinical Outcomes (CR & Survival).

• Near-Immediate Solution Evidence shows that the problem can be solved in a near-immediate fashion with relatively small funding levels. [8-18]

• Substantially Improving Costs & Benefits Evidence shows that if many current drugs were used more accurately, there would be a significant reduction in cost while increasing clinical effectiveness. The solution is potentially close at hand, but is not being adequately explored. [8-19]

BACKGROUND DETAIL The Extent of the Problem: Every week, some 160,000 people die of advanced cancer around the world, despite our best attempts at cancer treatment globally. About $32 billion is being spent on oncology drugs and the USA National Cancer Institute/ NIH spends about $5.2 billion on cancer research, per annum. In Australia, the NHMRC funded $181M on cancer research grants in 2014, and almost 800 cancer patients per week still die of cancer, or over 40,000 Australians per annum. Sadly, cancer has remained a tremendously costly public health problem of major proportions for over 5 decades, and our progress has been puzzlingly slow towards solving this using standard methods.

Progress in cancer treatment is often claimed. However, most of the real progress has been made through earlier detection and treatment of earlier stage , and these figures are masking the major problem of disappointingly very marginal (or non-existent) gains in survival for most forms of advanced metastatic cancer. Cancer death rates arise predominantly from advanced metastatic cancer which has spread to organs, and these death rates have remained essentially unchanged for most common cancers for over 50 years.[21-26]

This prompted Professor Laurence Baker, Chair of the South West Oncology Group in the USA, to state recently on the Journal of the National Cancer Institute “I am trying to get people to stop saying how successful the cancer research enterprise is. It is not true. It is just not true”. [21]

Cost Expenditure & Economics: The cost of medications and equipment is rapidly becoming unsustainable and will be unaffordable to the Australian Governments, taxpayers and public within a decade or so, if measures are not taken to contain costs. Health will quickly become a principal Federal Government issue of major importance requiring urgent central coordinated administration to solve. Rational balancing of budgets must be achieved by developing sustainable patterns of healthcare delivery through appropriate cost-benefit analysis and sensible, equitable

4 expenditure. Innovative research approaches that offer global solutions to several or many problems in healthcare must be funded and supported to create better cost- benefit returns for the Australian public and economy. Australia has an enviable track-record of such innovative discoveries and approaches.

The highest rate of cost growth occurred in the PBS Chemotherapy (s100) program, at 62.61%. [1] From 2011-12 to 2012-13, expenditure on this program more than doubled, from $222.5 million to $478.9 million.

Chemotherapy drug costs rose from $84 million in 2009-10 to $586 million last financial year. In detail these figures were: Chemotherapy 83.8M (2009-10) 94.8M (2010-11) 222.5M (2011-12) 478.9M (2012-13) 585.9M (2013-14). Average annual growth (%) was 62.61.

Taxpayers currently pay at least 3 times over for many new drug therapies, namely: (i) the initial drug cost for each drug used; (ii) the cost of side-effects and hospitalisations; (ii) the cost of premature death from cancer due to failure of the therapies. If several drugs are utilised, as is being increasingly proposed [27-28], then these costs will be repeated.

Relevant History: The field of cancer treatments has evolved historically from the days of alchemy (pre-1800), through the chemical synthetic industry (1800-present), and into the highly commercially successful pharmaceutical, scientific and medical oncology industries (1950-present). This has led to many drugs being developed, then approved, and used in our community by practitioners, patients and the public. Complex interactions have developed between industry and practitioners, together with the public and government, to support and promote the industry of cancer. It has been said that, "many more people make money out of cancer than die or suffer from it". Paradoxically, the bar for the requirement to demonstrate a substantial and significant therapeutic benefit for patients has successively been lowered. This has partly arisen through smaller incremental gains becoming achieved or accepted, together with the futility arising from the inability to 'cure' cancer after over 50 years of diligent effort.[6] The cancer drug budget has more than doubled in the last few years. This is economically unsustainable for Australian taxpayers. Mechanisms for raising the bar towards successful therapy, requires very urgent attention.

Future Directions The inability of currently available agents to cure cancer or to prolong survival for greater than 5-years after diagnosis and commencement of therapy, has heralded the proposed use of two or more therapies, either in combination or in sequence.[27,28] The cost of this type of strategy would be $200k to $500k per patient. For advanced melanoma patients, as an example, (about 1200 people) the predicted annual drug supply cost would be $240,000,000 to $600,000,000, with most patients subsequently dying within 1-3 years.

Skin Cancer forms an ideal model to commence with for investigation of cost-benefit analysis, as it includes preventative measures, detection strategies, surgical, radiotherapy and pharmaceutical approaches in the management pathways. Australia has an extensive skin cancer problem and burden of disease, which are

5 proving very costly. Melanoma forms particularly useful example due to the high disease frequency in Australia, and the development of new drug therapies.[7]

Pharmaceutical Agents have recently, been proposed and approved for use in treating advanced melanoma. The current cost for most of these agents is appreciable ($80K-$120K/ course each), but because the effectiveness of previous agents was so poor, the newer agents were immediately viewed and considered as being more effective. Further cost-benefit analysis has revealed that the efficacy of many of these agents is short-lived, marginal or absent in the majority of patients, often being associated with high toxicity rates. The cost of drug toxicity induced side- effects is substantial, including hospitalisations and deaths. Although spectacular results are seen in some patients, the vast majority of patients do not achieve a cure (> 5-year survival) from their cancer.

The Medical and Scientific Literature indicates that treatments using many of the so-termed 'targeted agents' are not very targeted, and thus cause significant side- effects, outside of the cancer [20]. Many side-effects are so serious that the drug has to be reduced in dosage or stopped. In some cases death, emergency surgery or readmission to hospital results from the treatment itself. It appears many of the initial thoughts on 'targeted therapies' have not proved quite so targeted, selective, nor effective, compared with the 'non-targeted' therapies. Indeed, much literature is emerging to show that many of the agents that have been used for melanoma therapy (and that of other cancers) work through the either directly (Ipilmumab/ CTLA-4, PD-1, PD-L-1, IL-2, vaccines) or indirectly (B-raf, chemotherapy, vascular agents) (Niraula et al, 2012; Coventry & Ashdown, 2012).

Lack of Diligent Investigation Much of the pharmaceutical industry's data submitted for FDA or TGA/ PBS approval cites low clinical efficacy for treatment of most advanced cancers. Yet approval has proceeded, however, in wider 'off-trial' clinical practice protocols are often not adhered to as rigidly, and clinical efficacy is often lower, in a more heterogeneous population of advanced cancer patients. Moreover, many critical aspects of drug pharmacology are frequently overlooked in the quest to reach rapid government approval, and are subsequently either never explored or are discovered later to be detrimental by academic institutions. The costs involved in this approach can be appreciable for individual patients, governments and the community.

An example is the lack of adequate exploration of the effects of soluble, circulating CTLA-4 molecules and PD-1 molecules with reference to anti-CTLA-4 and anti-PD-1 therapies. These soluble molecules are released into the blood and tissues of cancer patients and can bind the administered drug therapy, potentially reducing/ altering the clinical effectiveness in the patient. Those CTLA-4 and PD-1 molecules, although described in the literature, do not appear to have been taken into account when the inhibitory agents are administered, as these are not usually measured. The levels of these molecules might exert profound effects on clinical outcome, and thereby the consequent success or failure of the respective drug therapy. These important considerations appear to have been so far overlooked.

6 Another example is the effect of B-raf inhibitory molecules that act on cells with B-raf mutations (principally V600E). The expression of these B-raf mutant molecules is neither uniform or consistent across a tumour deposit, nor consistent between different metastatic deposits. This was perhaps inadequately explored and reported by the pharmaceutical companies prior to approval. Thus the drugs appear to act inconsistently and non-uniformly on tumour deposits, leading to unpredictable failure patterns. The drugs were also apparently under-explored in relation to the effects on the immune system, such that some critical effects that were determinants of clinical outcome appear to have been overlooked. In addition, B-raf therapies usually fail. New data indicates that if these agents are administered differently, the effectiveness might be appreciably better. Literature can be supplied on all of these aspects, if requested.

Conflict of Interest Most, if not all, Australian institutions treating cancer are currently dependent on drug company funding, and therefore potentially might be compromised with respect to their true independence when treating patients - either wittingly or unwittingly. This funding dependence occurs to a greater or lesser degree depending on the discipline/ department, and the prevailing culture and finance arrangements within each institution. Drug trials bring money into institutions and can save government funds that would otherwise be spent on standard therapies. Ethics committees' often charge considerable fees for the evaluation and approval of trials. The choice to select pharmaceutical trial options over standard, or over unfunded innovative options, may thus be considerable. The majority drug company funded clinical trials, however, do not reach PBS approval, nor do they reach clinical practice. Many patients on these trials die of their cancer. Appreciable cost-shifting between State and Federal Governments commonly occurs with these arrangements.

The presence of a 'conflict of interest' arising from a bias towards pharmaceutical trials and away from more innovative options, is a very serious consideration and can act to severely retard original innovative progress of Australian research. Any cost savings are more than offset by much higher annual costs from failure to solve the problem of ineffective cancer therapies. The magnitude of this problem cannot be overestimated. Cost savings in the short term at State level are merely being often transferred to Federal budget level.

Current Approved Melanoma Therapies - Mechanisms of Action

The Articles Attached and Cited help to explain that the mechanisms of drug action are not as clearly understood as has been proposed. Indeed, many of the agents work through unpredicted pathways involving immune activation or suppression. These important pathways are largely unexplored.

Essentially all cancer therapies/ agents show a random nature of clinical responses. In any patient cancer therapies are therefore 'experimental' as no- one can accurately predict who will and who will not respond to therapy.

7 Therefore, it is almost certain, based on mathematical probability, that the drugs are interfering with responses within the patient in a random manner.[26]

This 'chance' component has become accepted over time and has scarcely been investigated, nor solved. If this were solved, many cancer drugs would be transformed into more predictable, effective agents.

The phenomenon of complete response induction by multiple divergent agents and the random nature of responses, requires urgent and adequate funding to improve clinical efficacy and to solve the health budget problems. The evidence indicates that this can be solved with relatively small funding levels.

Examples of Pharmaceutical Profiles & Clinical Efficacy

These data are compiled from reported clinical research literature as cited.

B-raf inhibitors work through reducing the activity of the B-raf pathway in melanoma cells. They also depend on the immune system for their clinical effects, and this is emerging as an especially important mechanism. Successful B-raf responses are associated with inflammatory reactions at the site of the tumour deposits through immune system stimulation. B-raf inhibitors are prone to 'resistance' where they become less effective/ ineffective, but after a period of no treatment may again become effective at least in some patients treated again later.

MEK inhibitors block the MAP kinase signal-transduction pathway to reduce the proliferation and survival of susceptible melanoma cells. They have been used alone and in combination with B-raf inhibitors.

Adverse events/Side effects Commonest: Rash, diarrhea, peripheral edema, fatigue, and dermatitis were the commonest side-effects. <8% had grade 3 or 4 rash. Cardiac: Decreased ejection fraction or ventricular dysfunction was observed in 14 patients (7%). Serious grade 3 cardiac-related events that were considered to be drug-related, leading to permanent discontinuation of the study drug occurred in 2 patients. Eyes: Ocular events (mostly grade 1 or 2) occurredin 9% of patients, with blurred vision as the most frequent single ocularevent (4%); reversible chorio- retinopathy (grade 3) occurred in one patient (<1%). Dose Reductions/Cessation: Adverse events led to dose interruptions in 35% of patients,and dose reductions in 27% of patients (Flaherty et al, 2012).

Ipilimumab (anti-CTLA-4 antibodies) work by taking the 'brake' off of the immune system, but it does so clinically unpredictably and haphazardly, causing either 'overdrive' in many cases leading to auto-immunity - see additional information.

8 Adverse events/ Side effects Commonest/ Serious: inflammation of the colon, liver, eye, skin, thyroid, adrenal, pituitary etc. • Any adverse drug-related event occurred in 80% of patients • Grade 3 or 4 in 22.9% of patients

The most common adverse events • diarrhea (27 to 31% any grade) • rash, pruritus • anorexia, and fatigue • colon perforation (1%) • liver failure (2%) • severe immune-mediated skin reactions (2.5%)

Death rate - drug related deaths from anti-CTLA-4 antibody treatment are reported in 1.2 to 2.1% of patients.

Outcomes for Melanoma (Ipilumimab)

In 137 patients (Hodi et al, 2010)

• CR 2/137 (1.5%) • PR 13 (9.5%) • SD 24 (17.5%) • ORR 15 (11%)

Anti-PD-1 antibody therapies work principally by prolonging the survival of immunological cells close to the tumour or reducing death of those cells. As at 2014 these agents are being hailed as the current most promising agents by the drug and medical oncology industries. Two PD-1 Antibody agents are in current usage in the USA and some other countries, Nivolumab (Bristol-Meters Squibb Ltd) and Lambrolizumab (MK-3475) (Merck Ltd).

Anti-PD-1 Antibody - Nivolumab

Safety/ Adverse Events/ Side effects/ Deaths Data from Topalian et al., 2012

Commonest/ Serious: In 296 cancer patients; 104 who had melanoma (35%): • 15 of 296 patients (5%) discontinued treatment owing to treatment- related adverse events • Grade 3 or 4 treatment-related adverse events were observed in 41 of 296 patients (14%). • Drug-related serious adverse events occurred in 32 of 296 patients (11%).

9 • Drug-related pneumonitis - occurred in 9 of the 296 patients (3%). • Drug-related adverse events of special interest (those with potential immune-related causes) included pneumonitis, vitiligo, colitis, hepatitis, gastrointestinal, hypophysitis, and thyroiditis.

The most common adverse events, regardless of cause were: • fatigue • diarrhea • nausea • cough • dyspnea • constipation • vomiting • Skin disorder • fever

Death rate - a drug-related death rate of 1% from anti-PD-1 antibody treatment was reported due to pneumonitis.

10 Nivolumab Anti–PD-1 Antibody (Topalian et al, 2012) [BMS-936558 (also known as MDX-1106 and ONO-4538)]

Total of 296 patients with advanced solid tumors, including melanoma (104 patients), non– small-cell lung cancer (122), renal-cell cancer (34), castration-resistant prostate cancer (17), and colorectal cancer (19).

Drug-Related Adverse Events Total (N = 296)

All Grade 3 or Events 4 Events number of patients (percent)

Any adverse event of special interest* 122 (41%) 18 (6%)

Pulmonary disorders Pneumonitis 9 (3%) 3 (1%) Allergic rhinitis 4 (1%) 0

Gastrointestinal Diarrhea 33 (11%) 3 (1%)

Skin events Rash 36 (12%) 0 Pruritus 28 (9%) 1 (<1%) Vitiligo 8 (3%) 0 Pruritic rash 6 (2%) 0 Urticaria 5 (2%) 0 Macular rash 4 (1%) 1 (<1%) Alopecia 3 (1%) 0 Hypopigmentation 3 (1%) 0

Laboratory investigations† Alanine aminotransferase increased 11 (4%) 2 (1%) Thyroid-stimulating hormone increased 9 (3%) 1 (<1%) Aspartate aminotransferase increased 8 (3%) 2 (1%)

Endocrine disorders Hypothyroidism 7 (2%) 1 (<1%) Hyperthyroidism 3 (1%) 1 (<1%)

Infusion-related reaction or hypersensitivity 9 (3%) 1 (<1%)

Deaths 3 (1%)

(Topalian etal., 2012)

NOTE: * The numbers reported within a column may not add up to the total number reported for “any adverse event of special interest” because patients who had more than one adverse event were counted for each event but were counted only once for “any adverse event of special interest” and because data for only those events that were reported in at least 1% of all treated patients are shown. Colitis, hepatitis, hypophysitis, and thyroiditis were among the adverse events of special interest that were reported in less than 1% of patients. PD-1 denotes programmed death 1. † Levels of alanine aminotransferase, thyroid-stimulating hormone, and aspartate aminotransferase were considered to be increased if they exceeded the upper limit of the normal range for the local laboratory.

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Data from Topalian etal., 2014

Commonest/ Serious: In 107 patients with melanoma: • Treatment-related adverse events of any grade occurred in 90 (84%) of 107 patients • 24 (22%) of 107 patients experienced grade 3 to 4 treatment-related adverse events • 17 of 107 (15.9%) patients discontinued treatment for other than disease progression (including treatment-related adverse events)

The most common adverse events of any grade were: • fatigue (32%), • rash (23%) • diarrhea (18%) • skin disorders (36%), • GI events (18%), and • endocrine disorders (13%)

Death rate - Deaths occurred in 3 patients (1%, or 3 of 296 patients) following treatment-related adverse events, although there were no drug-related deaths in patients specifically with melanoma (two patients with non–small-cell lung cancer and one with colorectal cancer) associated with pneumonitis.

12 Nivolumab Anti–PD-1 Antibody [BMS-936558 (also known as MDX-1106 and ONO-4538)]

Treatment-Related Adverse Events (Topalian etal., 2014) [Occurring in at Least 3% of the Total Population of Patients With Melanoma]

Patients (N = 107) All Grades Grades 3 to 4 Treatment-Related Adverse Event No. % No. %

Any adverse event*† 90 84.1% 24 22.4%

General disorders Fatigue 34 31.8% 2 1.9% Pyrexia 5 4.7% 0 0 Pain 4 3.7% 0 0

Skin and subcutaneous tissue disorders Rash 25 23.4% 0 0 Pruritus 14 13.1% 0 0 Vitiligo 10 9.3% 0 0 Dermatitis acneiform 6 5.6% 0 0 Photosensitivity reaction 4 3.7% 0 0

GI disorders Diarrhea 19 17.8% 2 1.9% Nausea 9 8.4% 1 0.9% Abdominal pain 8 7.5% 2 1.9% Dry mouth 7 6.5% 1 0.9% Vomiting 5 4.7% 1 0.9%

Musculoskeletal disorders Arthralgia 7 6.5% 0 0 Myalgia 4 3.7% 0 0

Metabolism and nutrition disorders Decreased appetite 7 6.5% 0 0 Hyperuricemia 4 3.7% 1 0.9% Hypophosphatemia 4 3.7% 1 0.9%

Blood and lymphatic system disorders Lymphopenia 7 6.5% 3 2.8% Investigations Blood thyroid-stimulating hormone increase 6 5.6% 1 0.9% Weight decreased 6 5.6% 0 0 Alanine aminotransferase increased 5 4.7% 0 0 Hemoglobin decreased 5 4.7% 1 0.9% Platelet count decreased 5 4.7% 1 0.9% Aspartate aminotransferase increased 4 3.7% 0 0 WBC count decreased 4 3.7% 0 0

Endocrine disorders Hypothyroidism 6 5.6% 1 0.9% Procedural complications

13 Infusion-related reaction 6 5.6% 0 0

Respiratory disorders Cough 4 3.7% 0 0

Vascular disorders Flushing 4 3.7% 0 0 Hypotension 4 3.7% 0 0

NOTE. Treatment-related adverse events are reported according to the nivolumab dose cohort in the Data Supplement. Treatment-related adverse events that were reported in less than 3% of the total melanoma population included pneumonitis, colitis, and renal failure (two each;2%) and hepatitis, hypophysitis, thyroiditis, uveitis, and tubulointerstitial nephritis (one each; 1%). †The numbers reported within a column may not add up to the total number reported under any adverse event, because patients who had more than one adverse event were counted for each event but were counted only once for any adverse event. Data for only those events that were reported in at least 3% of the treated patient population are presented.

Outcomes for Melanoma (Nivolumab)

All PD-1 Nivolumab doses in 94 melanoma patients (Topalian et al, 2012) • CR 1/94 (1%) • ORR 26/94 (28%) • SD 6/94 (6%) • PFS 41% (at 24 weeks)

In 107 Melanoma patients (Topalian et al., 2014):

• CR 1/107(<1%) • ORR 33/107 (31%) • SD 7/107 (7%) • PFS 27% (at 2 years) or a median of 3.7 months

14 Anti-PD-1 Antibody - Lambrolizumab (MK-3475)

Safety/ Adverse Events/ Side effects/ Deaths

Commonest/ Serious: Of the 135 melanoma patients (Hamid 2013)

• 79% reported drug-related adverse events of any grade. • 13% were grade 3 or 4 drug-related adverse events.

The most common adverse events, regardless of cause were:

• fatigue • fever and chills • myalgia • gastrointestinal disorders (Diarrhea in 20%) • Skin disorders • Respiratory disorders

Death rate - a drug-related death rate of 1% from anti-PD-1 antibody treatment was reported due to pneumonitis.

Outcomes for Melanoma (Lambrolizumab)

In 117 patients (Hamid 2013)

• CR 6/117 (5.1%) • ORR 44 (38% [25–44]) • Response Duration 1.9–10.8 months

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Lambrolizumab Anti–PD-1 Antibody

Drug-Related Adverse Events (n = 135)

All Grades Grade 3 or 4 number of patients (percent ______

Any 107 (79%) 17 (13%)

Hypothyroidism 11 (8%) 1 (1%) Gastrointestinal disorder Diarrhea 27 (20%) 1 (1%) Nausea 13 (10%) 0 Abdominal pain 7 (5%) 1 (1%)

Generalized symptom Fatigue 41 (30%) 2 (1%) Myalgia 16 (12%) 0 Headache 14 (10%) 0 Asthenia 13 (10%) 0 Pyrexia 10 (7%) 0 Chills 9 (7%) 0 Decreased appetite 6 (4%) 1 (1%)

Increase in aminotransferase level AST 13 (10%) 2 (1%) ALT 11 (8%) 0

Renal failure 3 (2%) 2 (1%)

Respiratory disorder Cough 11 (8) 0 Dyspnea 6 (4%) 0 Pneumonitis 6 (4%) 0

Skin disorder Rash 28 (21%) 3 (2%) Pruritus 28 (21%) 1 (1%) Vitiligo 12 (9%) 0

Death 1 (1%)

NOTE: * Included are drug-related adverse events that occurred in at least five patients or drug-related grade 3 or 4 adverse events that occurred in at least two patients. ALT denotes alanine aminotransferase, and AST aspartate aminotransferase.

16 Explanation of Terms

CR = complete response = removal of all tumour ORR = overall (objective) response rate = complete + partial response = removal of or decrease in tumour mass PR = partial response = decrease in tumour mass SD = stable disease = stability of disease growth or appearance PFS = progression free survival = survival without progression of disease

Adverse Events Grade 1: mild event Grade 2: moderate event Grade 3: severe event Grade 4: life threatening or disabling event usually requiring hospitalisation

References:

1. Harvey R and de Boer R Social Policy Section Growth in expenditure on high cost drugs in Australia. Parliamentary Library Research Paper Series 2014–15, 7 Jan 2015

2. Murphy and Topel The Value of Health and Longevity. Journal of Political Economy 114;5 2006.

3. The Value of Health and Longevity. Kevin M. Murphy and Robert H. Topel September 28, 2009 - http://www.rff.org/Publications/WPC/Pages/The-Value-of- Health-and-Longevity.aspx)

4. Coventry BJ, Ashdown ML. Complete clinical responses to cancer therapy caused by multiple divergent approaches: a repeating theme lost in translation. Cancer Manag Res. 2012;4:137-149.

5. Jack A "No Cure - No Cost" BMJ 2007 335: 122-23.

6. Tuma RS Large Trials, Small Gains: Is Change on the Way? J. Natl. Ca Inst. 2010 102(16) 1216-7, 1223. jnci.oxfordjournals.org

7. Skin Cancer in Australia: Our National Cancer. Report on the Inquiry into Skin Cancer in Australia. House of Representatives Standing Committee on Health, March 2015. http://www.aph.gov.au/Parliamentary_Business/Committees/House/Health/Skin_Can cer/Report

8. Coventry BJ, Ashdown ML, Quinn MA, Markovic SN, Yatomi-Clarke Robinson AP CRP identifies homeostatic immune oscillations in cancer patients: potential treatment targeting tool? J Transl Med 2009.;7: 102. Review.

9. Ashdown ML Coventry BJ A Matter of Time. Australasian Science 2010 May:18- 20.

17 10. Coventry BJ, Peter Hersey P, Halligan A, Michele A Immuno-Chemotherapy Using Repeated Vaccine Treatment Can Produce Successful Clinical Responses in Advanced Metastatic Melanoma. Journal of Cancer Therapy, 2010, 1, 205-213.

11. Coventry BJ, Ashdown ML. Complete clinical responses to cancer therapy caused by multiple divergent approaches: a repeating theme lost in translation. Cancer Manag Res. 2012;4:137-149.

12. Coventry BJ, Ashdown ML. The 20th anniversary of interleukin-2 therapy: bimodal role explaining longstanding random induction of complete clinical responses. Cancer Manag Res. 2012;4:215-21.

13. Coventry BJ, Lilly C, Hersey P, Michele A, Bright R Prolonged Repeated Vaccine Immuno-Chemotherapy Induces Long-Term Clinical Responses and Survival for Advanced Metastatic Melanoma. J Immunother. Cancer 2014 2: 9.

14. Coventry BJ and Ashdown ML Simpler is often better when battling the Big C. The Weekend Australian Oct 8 2011: 17. www.theaustralian.com.au

15. Ashdown ML, Coventry BJ Window of Opportunity. Cover Story Australasian Science 2014 (June) 6: 16-19.

16. Coventry BJ, Lilly C Table of Comparison of Reported Clinical Effectiveness of Treatments for Metastatic Melanoma. Australian Melanoma Research Foundation, 2014. www.melanomaresearch.com.au

18. Coventry BJ, Lilly C, Baum D Long-term survival in advanced melanoma patients using repeated therapies: successive immunomodulation improving the odds? Cancer Manag Res. 2015 (in Press)

19. Mkrtichyan M, Najjar YG, Raulfs EC, Liu L, Langerman S, Guittard G, Ozbun L, Khleif SN. B7-DC-Ig enhances vaccine effect by a novel mechanism dependent on PD-1 expression level on subsets. J Immunol. 2012 Sep 1;189(5):2338- 47.

20. Niraula S, Seruga B, Ocana A, Shao T, Goldstein R, Tannock IF, Amir E. The price we pay for progress: a meta-analysis of harms of newly approved anticancer drugs. J Clin Oncol. 2012 Aug 20;30(24):3012-9.

21. Tuma RS Large Trials, Small Gains: Is Change on the Way? J. Natl. Ca Inst. 2010 102(16) 1216-7, 1223. jnci.oxfordjournals.org

22. Murphy and Topel The Value of Health and Longevity. Journal of Political Economy 114;5 2006.

23. The Value of Health and Longevity. Kevin M. Murphy and Robert H. Topel September 28, 2009 - http://www.rff.org/Publications/WPC/Pages/The-Value-of- Health-and-Longevity.aspx)

18

24. Paul Davies ABC Oct 2013 'Adelaide Festival of Ideas' Lecture: "Rethinking Our Approach to Cancer" http://www.abc.net.au/radionational/programs/scienceshow/rethinking-our-approach- to--cancer/5246414

25. Davies P. OPINION THE BIG IDEA "What’s really going on in those cancer cells?" New Scientist 5 January 2013: 24-25.

26. Ashdown ML, Coventry BJ, Abbott D Mathematical modeling of immune kinetics in advanced cancer through meta-analyses of complete response rates: immune synchronisation emerges as the likely key determinant of clinical response. Journal for ImmunoTherapy of Cancer 2013 1(Suppl 1): P150.

27. Mueller KL Realizing the Promise. Science 2015 348, 56 (April).

28. Sharma P and Allison JP The future of immune checkpoint therapy. Science 2015 348, 56 (April).

Knoechel B, Lohr J, Kahn E, Bluestone JA, Abbas AK. Sequential development of -dependent effector and regulatory T cells in response to endogenous systemic antigen. J Exp Med. 2005 Nov 21;202(10):1375-86. Epub 2005 Nov 14.

Jack A "No Cure - No Cost" BMJ 2007 335: 122-23.

Niraula S, Seruga B, Ocana A, Shao T, Goldstein R, Tannock IF, Amir E. The price we pay for progress: a meta-analysis of harms of newly approved anticancer drugs. J Clin Oncol. 2012 Aug 20;30(24):3012-9.

Lineweaver CH, Davies PCW, Vincent MD Targeting cancer’s weaknesses (not its strengths): Therapeutic strategies suggested by the atavistic model. Bioessays 2014:

Chapman PB, Hauschild A, Robert C, et al; BRIM-3 Study Group. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364(26):2507–2516.

Flaherty KT, Robert C, Hersey P, et al; METRIC Study Group. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012;367(2):107–114.

Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010;363(9):809–819.

Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012;367(18):1694–1703.

Wilmott JS1, Long GV, Howle JR, Haydu LE, Sharma RN, Thompson JF, Kefford RF, Hersey P, Scolyer RA. Selective BRAF inhibitors induce marked T-cell infiltration into human metastatic melanoma. Clin Cancer Res. 2012 Mar 1;18(5):1386-94. doi: 10.1158/1078-0432.CCR-11-2479.

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Liu C1, Peng W, Xu C, Lou Y, Zhang M, Wargo JA, Chen JQ, Li HS, Watowich SS, Yang Y, Tompers Frederick D, Cooper ZA, Mbofung RM, Whittington M, Flaherty KT, Woodman SE, Davies MA, Radvanyi LG, Overwijk WW, Lizée G, Hwu P. BRAF inhibition increases tumor infiltration by T cells and enhances the antitumor activity of adoptive immunotherapy in mice. Clin Cancer Res. 2013 Jan 15;19(2):393-403.

Yuan P1, Ito K, Perez-Lorenzo R, Del Guzzo C, Lee JH, Shen CH, Bosenberg MW, McMahon M, Cantley LC, Zheng B. Phenformin enhances the therapeutic benefit of BRAF(V600E) inhibition in melanoma. Proc Natl Acad Sci U S A. 2013 Nov 5;110(45):18226-31.

Hamid O1, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, Wolchok JD, Hersey P, Joseph RW, Weber JS, Dronca R, Gangadhar TC, Patnaik A, Zarour H, Joshua AM, Gergich K, Elassaiss-Schaap J, Algazi A, Mateus C, Boasberg P, Tumeh PC, Chmielowski B, Ebbinghaus SW, Li XN, Kang SP, Ribas A. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013 Jul 11;369(2):134-44.

Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, Horn L, Drake CG, Pardoll DM, Chen L, Sharfman WH, Anders RA, Taube JM, McMiller TL, Xu H, Korman AJ, Jure-Kunkel M, Agrawal S, McDonald D, Kollia GD, Gupta A, Wigginton JM, Sznol M. Safety, activity, and immune correlates of anti- PD-1 antibody in cancer. N Engl J Med. 2012 Jun 28;366(26):2443-54.

Taube JM, Klein AP, Brahmer JR, Xu H, Pan X, Kim JH, Chen L, Pardoll DM, Topalian SL, Anders RA. Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin Cancer Res. 2014 Apr 8. [Epub ahead of print]

Topalian SL, Sznol M, McDermott DF, Kluger HM, Carvajal RD, Sharfman WH, Brahmer JR, Lawrence DP, Atkins MB, Powderly JD, Leming PD, Lipson EJ, Puzanov I, Smith DC, Taube JM, Wigginton JM, Kollia GD, Gupta A, Pardoll DM, Sosman JA, Hodi FS. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J ClinOncol. 2014 Apr 1;32(10):1020-30.

Lipson EJ1, Sharfman WH, Drake CG, Wollner I, Taube JM, Anders RA, Xu H, Yao S, Pons A, Chen L, Pardoll DM, Brahmer JR, TopalianSL. Durable cancer regression off-treatment and effective reinduction therapy with an anti-PD-1 antibody. Clin Cancer Res. 2013 Jan 15;19(2):462-8. Hodi, F.S., et al., Improved Survival with Ipilimumab in Patients with Metastatic Melanoma. The New England Journal of Medicine, 2010. 363: p. 711-723

RADIO INTERVIEWS - National and International

20 2010 Australian Broadcasting Commission - Radio National Science Show interview with Robin Williams April 18th 2010 “Rhythms in the Immune System” http://www.abc.net.au/rn/scienceshow/stories/2010/2871586.htm

2014 Australian Broadcasting Commission - National - The World Today "Melanoma find increases survival rate". interview with Caroline Winter reported this story on Friday, February 14, 2014 12:46:00 http://mpegmedia.abc.net.au/news/audio/twt/201402/20140214-twt10- melanomafind.mp3

2014 Australian Broadcasting Commission - National - AM Program - Caroline Winter/ Chris Uhlmann April 17th 2014 “Melanoma vaccine increases survival rate” http://mpegmedia.abc.net.au/news/audio/am/201404/20140417-eam03- melanomavaccine.mp3

2014 Listen to Your Body Clock – Cancer and Your Health by Gracegawlermedia on November 15, 2014 http://gracegawlermedia.com/2014/11/15/listen-to-your-body-clock-cancer-health- grace-gawler/

2015 Cancer vaccines and immune cycle timing: Hear Prof Brendon Coventry and Martin Ashdown on 612 ABC radio Brisbane, Queensland with Steve Austin today 10.30am Tuesday 13 January 2015. State-wide broadcast. Listen or Download later as a podcast at: http://www.abc.net.au/brisbane/programs/612_morning/

2015 Why Innovative Oncology is an Effective Way to Tackle Cancer by Gracegawlermedia on January 17, 2015 http://gracegawlermedia.com/2015/01/17/why-innovative-oncology-is-an-effective- way-to-tackle-cancer/

Every week, some 160,000 people die of advanced cancer around the world, despite our best attempts at cancer treatment globally. Some $32 billion is being spent on oncology drugs and the USA National Cancer Institute/ NIH spends about $5.2 billion on cancer research, per annum. Sadly, cancer has remained a tremendously costly public health problem of major proportions for over 5 decades, and our progress has been puzzling slow towards solving this using standard methods. On today’s show, Navigating the Cancer Maze, my guest Professor Brendon Coventry, an Adelaide-based oncology surgeon suggests there may be another way to approach the problem and shows that the immune system my hold the answer. With a special interest in Melanoma Surgery, he is a clinical researcher whose interests include anti-tumour immune response in human malignancies, tumour Immunology and cancer vaccine treatments. His group’s research paper, published in 2014, entitled “Vaccinia Melanoma Cell Lysate Vaccine (VMCL) Trial for treatment of advanced Stage IV Melanoma with and without Chemotherapy”, captured the attention of medical and scientific community. Trial conclusions reported high complete response rates (where all cancer disappears) of 17%, with useful clinical responses occurring in nearly 80% of

21 patients overall (slowing the disease), and over 15% of patients experiencing survivals past 5-years, with essentially no toxicity. The longest survivor now remains alive for over 14 years. These response rates and survivals are unusual for advanced melanoma. The researchers reason that the repetitive and prolonged delivery of the vaccine therapy might hold part of the clue, because this was a strikingly different approach to that used in other trials. Martin Ashdown says: …..”The concept of immune monitoring and accurately synchronizing therapy (immune synchronization), brings a new level of science to oncology. The published mouse experiments and human clinical trials, together with our knowledge of physiology tells us this is the way forward, particularly with the new cancer immunotherapies. This approach potentially has the triple benefit of increasing efficacy, lowering toxicity and substantially reducing the cost of treatment”

Professor Brendon Coventry BMBS, PhD, FRACS, FACS, FRSM Associate Professor of Surgery at the University of Adelaide and Senior Consultant Surgeon (General, Breast-Endocrine, Surgical Oncology & Trauma Surgery) at the Royal Adelaide Hospital since 1993. He holds a PhD in Cancer Immunology.

Positions: • Immediate Past Chairman, Surgical Oncology Section, Royal Australasian College of Surgeons; • Research Director, Australian Melanoma Research Foundation & Board Member; • Past Chairman, Melanoma and Skin Cancer Group, Clinical Oncological Society of Australia; • Foundation Chairman, Multidisciplinary Melanoma Management Group, Royal Adelaide Hospital • Senior Examiner, Australian Medical Council • Board Member of Cancer Care Centre, Unley, SA.

Fellowships: • Royal Australasian College of Surgeons • American College of Surgeons • Royal Society of Medicine.

Research: • Over 85 journal publications; including New England Journal of Medicine, British Journal of Cancer, Journal of Clinical Oncology, Lancet Oncology; widely published topics including surgical treatment for melanoma and breast cancer, sentinel node surgery, sarcoma surgery, adjuvant radiation therapy, melanoma vaccine therapies, laparoscopic spleen surgery techniques, neuroscience, microscopic methods, high- sensitivity tissue immunochemistry, public health, medical education, internet learning. • NIH Principal Investigator: Multicenter Selective Lymphadenectomy Trial (MSLT-I) surgical sentinel node; C-Vax melanoma vaccine studies (x2). • Editor-in-Chief, 7-Volume international textbook series “Surgery: Complications, Risks and Consequences” published by Springer International; General adult, Paediatric and Cardio-Vascular surgery.

22 Current Research: • Surgical Complications, Safety and Quality Improvement • Vaccine Therapies for Advanced Melanoma, novel findings from repetitive dosing where 5-year survival and Complete Response rates have been significantly improved • Timing of Therapies is novel collaborative work with Martin Ashdown concerning serial blood biomarker monitoring for advanced cancer patients for more accurate timing to improve therapy dose delivery and clinical efficacy further, which is gaining international recognition.

NOTE: Additional data can be supplied, if requested.

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