To what extent is the combined use of ipilimumab and nivolumab in cancer treatment viable?'
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| Mechanism of PD-1 and Nivolumab
Evaluation of past immunotherapeutic approaches to treating cancer found limited success. Increased understanding of the checkpoint signaling pathway involving the programmed death 1 (PD-1) receptor and its ligands: PD-L1 (B7-H1) and PD-L2 (B7-DC), has clarified the role of these approaches in tumour-induced immune suppression; this has led to critical advancement in the development of immunotherapeutic drugs. (Dolan and Gupta, 2014) The interaction between PD-1 and its ligand PD-L1/2, is a key pathway that is hijacked by tumours in order to restrict immune control. Reversing the inhibition of adaptive immunity can actively stimulate the immune system, utilizing antagonistic antibodies to block checkpoint pathways, releasing tumour inhibition. These antibodies target CTLA-4, the PD-1 receptor and PD-L1 and facilitate antitumour activity. These agents are unique due to the characteristic of targeting lymphocyte receptors or their ligands. (ibid) PD-1 is an immunoinhibitory receptor, belonging to the CD28 family, and is expressed on T-cells, B-cells, monocytes, natural killer cells and many tumour-infiltrating lymphocytes (TILs). PD-L1 is expressed on many cells including resting T-cells, B-cells and macrophages, whereas PD-L2 expression is only found on macrophages and dendritic cells alone. Some tumours may have a higher expression of PD-L1. These ligands inhibit T-cell proliferation, cytokine production and cell adhesion. PD-L2 controls T-cell activation in lymphoid organs; PD-L1 seems to decrease T-cell function in peripheral tissues. The induction of PD-1 on activated T-cells takes place in response to the engagement of PD-L1/2, which limits effector T-cell activity in peripheral organs and tissues during inflammation, preventing autoimmunity; this is crucial in preventing tissue damage when the immune system is responding to infection. An antitumour immune response may be triggered if this pathway is blocked. The PD-1 pathway is similar to CTLA-4, in downregulating the response of T-cells by overlapping signaling proteins that form part of the immune checkpoint pathway; they function differently however, CTLA-4 concentrates on regulating the activation of T-cells, whereas PD-1 regulates effector t-cell activity in peripheral tissues in response to infection or the progression of a tumour. High levels of both of these molecules are expressed on regulatory T-cells, which have shown to have immune inhibitory activity, essential for self-tolerance. “The role of the PD-1 pathway in the interaction of tumour cells with the host immune response and the PD-L1 tumour cell expression may provide the basis for enhancing immune response through a blockade of this pathway. Drugs targeting the PD-1 pathway may provide antitumor immunity, especially in PD-L1 positive tumours.”(ibid). Nivolumab, a monoclonal antibody that binds to the PD-1 receptor, potentiates T-cell and antitumour responses, via blockade of PD-1 binding to its ligands. This resulted in decreased tumour growth in a study on mice. (Nivolumab BMS 10 mg/mL concentrate for solution for infusion, 2015) Potential for the Combination of these Drugs Preclinical evidence suggests that the roles of CTLA-4 and PD-1 in the regulation of adaptive immunity are complementary, providing rationale for combing drugs that will target these pathways. New data reveals that cytotoxic agents are able to antagonize immunosuppression in the microenvironment of the tumour, promoting immunity based on the concept that tumour cells die in multiple ways, and that some types of apoptosis can result in an enhanced immune response. “For example, nivolumab was combined with ipilimumab in a phase 1 trial of patients with advanced melanoma. The combination had a manageable safety profile and produced clinical activity in the majority of patients, with rapid and deep tumour regression seen in a large proportion of patients. Based on the results of this study, a phase 3 study is being under- taken to evaluate whether this combination is better than nivolumab alone in melanoma.” (Dolan and Gupta, 2014). Clinical Trials Since its development, many clinical trials have been designed to compare the use of anti-CTLA-4 monotherapy, ipilimumab, with the combination therapy of ipilimumab and nivolumab. Metastatic melanoma, metastatic renal cell carcinoma (MRCC) and small cell lung cancer (SCLC) have been tested with the use of this immunotherapeutic approach. Melanoma is a prototype of immunogenic tumour that has been known to respond to immunotherapeutic approaches with interferon alfa and interleukin 2 (ibid). This has featured in many clinical trials. A double-blind study that involved 142 metastatic melanoma patients who had not previously received treatment, was used to compare ipilimumab with ipilimumab and nivolumab. Patients were assigned in a 2:1 ratio to receive ipilimumab (3 mg per kilogram of body weight) combined with either nivolumab (1 mg per kilogram) or placebo, once every 3 weeks for four doses. This was then followed by nivolumab (3 mg per kilogram) or placebo every fortnight until the disease progressed or unacceptable toxic effects occurred. The primary end point was the rate of investigator-assessed, confirmed objective response among patients with BRAF V600 wild-type tumours. Among patients with BRAF wild-type tumours, the rate of conformed objective response was 61% (44 of 72 patients) in the combination group versus 11% (4 of 37 patients) in the ipilimumab-monotherapy group (P<0.001). 16 patients (22%) of the combination group reported complete responses versus none in the monotherapy group. The median duration of response was not reached in either group and the median progression-free survival was not reached with the combination therapy, but was 4.4 months with monotherapy (hazard ratio associated with combination therapy compared with monotherapy for disease progression or death, 0.40; 95% confidence interval [CI], 0.23 to 0.68; P<0.001). The response rate and progression-free survival results were similar for the 33 patients with BRAF mutation-positive tumours. The objective-response rate and progression-free survival among advanced melanoma patients were significantly greater with ipilimumab combined with nivolumab, rather than ipilimumab monotherapy. The combination therapy had an acceptable safety profile. (Postow et al., 2015) In a similar study, a 1:1:1 ratio was assigned to 945 previously untreated patients with unrespectable stage III or IV melanoma to nivolumab alone, nivolumab plus ipilimumab, or ipilimumab alone. Progression-free survival and overall survival were co-primary end points. The median progression-free survival was 11.5 months (95% CI, 8.9 to 16.7) with combination therapy, compared with 2.9 months (95% CI, 2.8 to 3.4) with ipilimumab monotherapy (hazard ratio for death or disease progression, 0.42; 99.5% CI, 0.31 to 0.57; P<0.001), and 6.9 months (95% CI, 4.3 to 9.5) with nivolumab monotherapy (hazard ratio for the comparison with ipilimumab, 0.57; 99.5% CI, 0.43 to 0.76; P<0.001). In patients with PD-L1 positive tumours, the median progression-free survival was 14.0 months in the combined therapy group and in the nivolumab group; in patients with PD-L1 negative tumours, progression-free survival was longer with combination therapy than with nivolumab monotherapy (11.2 months [95% CI, 8.0 to not reached] versus 5.3 months [95% CI, 2.8 to 7.1]). Among patients who had not previously been treated for metastatic melanoma, nivolumab monotherapy or combination therapy resulted in significantly longer progression-free survival than ipilimumab monotherapy. Patients with PD-L1 negative tumours responded more effectively to combination therapy of PD-1 and CTLA-4 blockade than either agent alone (Larkin et al., 2015). Dr James Larkin, a consultant at the Royal Marsden hospital and one of the UK’s lead investigators, told the BBC: “For immunotherapies, we’ve never seen tumour shrinkage rates over 50% so that’s very significant to see. This is a treatment modality that I think is going to have a big future for the treatment of cancer.” (The Guardian, 2015) Similar to melanoma, kidney cancer has also been a prototype of immunogenic tumour that responds to immunotherapy (Dolan and Gupta, 2014). A Phase I study of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma (MRCC) took place where patients were randomly split into two groups. In one group of 21 patients, they received 3mg/kg of nivolumab and 1mg/kg of ipilimumab (arm N3 +I1); in the other of 23 patients, they received 1mg/kg of nivolumab and 3mg/kg (arm N1+I3). This was administered intravenously every three weeks for four doses, and then followed by 3mg/kg of nivolumab every fortnight until progression (protocol-defined that post-progression treatment was allowed). The primary objective was to assess safety; the secondary objective was to assess efficacy. 80% of patients (35 in total, 17 in N3+I1, 18 in N1+I3) had prior systemic therapy. Objective response rate was 43% (N3+I1) and 48% (N1+I3). The median duration of response was 31.1 weeks (7 ongoing) in N3+I1 and not reached (9 ongoing) in N1+13. Responses occurred by the first tumour assessment (week 6) in 44% of patient in the N3+I1 arm and in 55% of patients in the N1+I3 arm. Stable disease as the best overall response was seen in 5 (24%; N3+I1) and 8 (35%; N1+I3) patients. Nivolumab and ipilimumab showed an acceptable safety profile and encouraging antitumour activity in MRCC, with most responses ongoing. Studies are ongoing to explore this combination in a Phase III trial. (Hammers et al., 2014) There is also an ongoing trial comparing the combination of nivolumab and ipilimumab with sunitinib (another biological therapy, also known as Sutent). The aims of this trial are to see the efficiacy of nivolumab and ipilimumab in renal cell cancer and to see any possible side effects. (A trial of nivolumab combined with ipilimumab for kidney cancer (CA209214), 2015) A Phase I/II study of nivolumab with or without ipilimumab for the treatment of recurrent small cell lung cancer (SCLC) hoped to see improvement in patients who had responded well to initial platinum (PLT) based chemotherapy (CT), but the disease had rapidly progressed afterwards. Combined blockade of PD-1 and CTLA-4 immune checkpoint pathways was known to have a manageable safety profile with anti-tumour activity. Patients who were PLT sensitive or refractory and had progressive disease were enrolled regardless of tumour PD-L1 status or the number of prior CT regimens. Patients were randomised to a group that administered 3mg/kg of nivolumab intravenously every fortnight, or to other groups that involved administration of 1mg/kg of nivolumab and 1mg/kg of ipilimumab, 1mg/kg of nivolumab and 3mg/kg of ipilimumab or 3mg/kg of nivolumab, intravenously every 3 weeks. These treatments lasted for four cycles and were followed by 3 mg/kg of nivolumab every fortnight. The primary objective was the overall response rate. Other objective included safety, progression-free survival, observational study and biomarker analysis. 75 patients were enrolled (40 into the nivolumab monotherapy group, 35 into the combination therapy groups) of which 59% had less than or equal to 2 prior regimens. Of the 40 evaluable monotherapy patients, partial responses was seen in 6 (15%), the duration of ongoing responses was 80-251+ days; stable disease occurred in 9 (22.5%); and progressive disease in 25 (62.5%). In the 20 evaluable combined therapy patients, 1 had a complete response (5%), the duration of response was 322+ days; 4 had a partial response (20%), duration of response was 41-83+ days); 6 experienced stable disease (30%); and 9 had progressive disease (45%). In the combined group, 12 patients had not reached the first tumour assessment and 3 were not evaluable. 9 patients (23%) have continued treatment with nivolumab monotherapy and 19 (54%) have continued the combined therapy. In this PD-L1 unselected SCLC population with progression post-PLT, nivolumab alone or combined with ipilimumab was tolerable. Overall response rate was 15% (nivolumab) and 25% (nivolumab and ipilimumab) for evaluable patients; durable responses were noted. (Antonia et al., 2015) An ongoing trial is taking place of nivolumab and ipilimumab for people with solid tumours that have spread and have most recently recruited patients with SCLC. The aims of this trial are to compare nivolumab monotherapy with combined therapy and to test the safety of this treatment. (A trial of nivolumab and ipilimumab for people with solid tumours that have spread (CA209032), 2015) Adverse Reactions Perhaps one of the most important disadvantages of any medical treatment is the side effects. As individual drugs, both ipilimumab and nivolumab have many adverse reactions. Ipilimumab has some mild to moderate effects such as moderate diarrhoea or colitis, adverse reactions in the endocrine glands such as hypophysitis, and unexplained motor neuropathy or muscle weakness. More severe or life-threatening effects include gastrointestinal haemorrhage, symptoms of hepatotoxicity, severe motor neuropathy, pancreatitis and toxic epidermal necrolysis. In a clinical trial of around 10,000 patients to evaluate its use with various doses and types of tumours, therapy was discontinued for adverse reactions in 10% of patients (YERVOY 5 mg/ml concentrate for solution for infusion, 2015). Immunotherapy with ipilimumab is associated with inflammatory adverse reactions resulting from increased immune activity (known as immune-related adverse reactions), which is likely to be related to its mechanism of action. Most of these surface during the induction period of therapy, although some reactions appear months after the final dose. Life-threatening complications can be minimised with early diagnosis and appropriate management. Systemic high-dose coriticosteroid may be required for managing severe immune-related adverse reactions, although use at baseline, before starting ipilimumab, should be avoided due to the risk of potential interference with pharmacodynamic activity and efficacy; it does not appear to affect efficacy after treatment has commenced (ibid). As a response to any adverse reactions, there are four main levels of action. First, the dose of ipilimumab is withheld until the reaction resolves to Grade 1, 0 or returns to baseline; then, if resolution occurs, therapy is resumed. However, in response to no resolution, doses continue to be withheld until reaction resolves before continuing therapy. Discontinued use of ipilimumab is implemented if a resolution to Grade 1, 0 or baseline is not reached (ibid). In clinical trials of patients with unresectable or metastatic melanoma, the most common adverse reactions associated with ipilimumab 3 mg/kg in 5% or more patients were fatigue, diarrhoea, pruritus, rash and colitis. 11 of 1,024 evaluable patients tested positive for binding antibodies in an electrochemiluminescent (ECL)-based assay. However, infusion-related or peri-infusional reactions that correspond with hypersensitivity or anaphylaxis were not reported in these patients; neutralising antibodies against ipilimumab were not detected. (Fellner, 2012) Ipilimumab is not recommended for use during pregnancy, because there is no data and the potential risk of treatment to the developing foetus is currently unknown. However, animal reproductions studies have shown reproductive toxicity and it is known that human IgG1 crosses the placental barrier. It should only be considered if the clinical benefit outweighs the risk (YERVOY 5 mg/ml concentrate for solution for infusion, 2015). Ipilimumab has been shown to be present at low levels of concentration in milk from cynomolgus monkeys that were treated during pregnancy. It is not known if it is secreted in human milk, although secretion of IgGs is generally limited in breast milk. No effects are anticipated for systemically breastfed infants, although due to the potential risk, a decision must be made as to whether to continue or discontinue breastfeeding or Yervoy treatment, balancing the benefits of breastfeeding for the child and of the therapy for the woman. Studies evaluating the effect on fertility have not been carried out and so are currently unknown (ibid). Yervoy has a minor influence on the ability to operate machinery and to drive due to potential side effects such as fatigue. Therefore, patients should be advised to use caution when carrying out these activities, until they are sure that ipilimumab does not adversely impact them (ibid). Nivolumab is also associated with immune-related adverse reactions, and patients should be carefully monitored at least up to 5 months after the last dose. If any severe or life-threatening adverse reactions occur, use of Opdivo must be permanently discontinued. The most frequent adverse reactions in two studies of squamous non-small cell lung cancer (NSCLC) reported in more than 10% of patients, included fatigue, decreased appetite and nausea. The majority of these reactions were mild to moderate (Nivolumab BMS 10 mg/mL concentrate for solution for infusion, 2015). Many of the side effects experienced are similar to those seen in ipilimumab. In the event of moderate to severe immune-related adverse reactions, nivolumab should be withheld and the administration of corticosteroids should commence. A taper of at least one month must be respected upon improvement before recommencing therapy, if not reactions may worsen rapidly. If no improvement occurs, non-corticosteroid immunosuppressive therapy should be used. Opdivo should not be resumed while the patient is receiving either of these alternatives (ibid). Similar to ipilimumab, little or no data is available regarding use during pregnancy, breast-feeding and effect on fertility. Therefore risk to infants cannot be excluded and nivolumab should only be used in exceptional circumstances where the benefit outweighs the risk. Additionally, effective contraception should be used for at least 5 months after the last dose, to ensure the risk is minimised (ibid). Operating machinery and driving should also be treated in the same way as ipilimumab (ibid). Some adverse effects regarding the combined therapy of these drugs have been seen in the results of clinical trials. A comparison of combined therapy and ipilimumab monotherapy found that drug-related adverse events of grade 3 or 4 were reported in 54% of patients who received combined therapy, and only 24% in the monotherapy group. Most of these events were resolved with immune-modulating medication (Postow et al., 2015). Another trial, comparing combined therapy to ipilimumab monotherapy and nivolumab monotherapy, found that adverse reactions of grade 3 or 4 occurred in 16.3% of the patients in the nivolumab group, 55% of the combined group and 27.3% of the ipilimumab group (Larkin et al., 2015). On one trial looking at nivolumab monotherapy or combined therapy in SCLC, one patient experienced myasthenia gravis during the study, which was fatal (Antonia et al., 2015). All cancer treatments may result in side effects. For example, chemotherapy, using a drug such as doxorubicin, may also damage normal cells as well as cancerous cells. These can include flu-like symptoms and a high temperature of over 38°C (can be signs of infection), hair loss, vomiting, diarrhoea and difficulty with breathing (Royal Marsden, 2014). Use of doxorubicin can also have serious effects on cardiac muscle, which could be devastating (Doxorubicin hydrochloride 2mg/ml solution for infusion - Summary of Product Characteristics (SPC) - (eMC), 2014). Sunitinab (Sutent), another biological therapy mentioned earlier for experimental use in combination with ipilimumab and nivolumab in an ongoing trial, also can have severe adverse reactions including renal failure, anaemia, fatigue, diarrhoea and hypertension. Sudden death and multi-system organ failure also had a possible link to this treatment (SUTENT 12.5mg, 25mg, 37.5mg and 50mg Hard Capsules - Summary of Product Characteristics (SPC) - (eMC), 2015). Cost of Treatment Immunotherapy drugs, though effective, come with a hefty price tag. Ipilimumab was approved by the National Institute for Health and Care Excellence (NICE) in December 2012, despite its high cost of approximately £75,000 for a four-dose treatment course, as Bristol-Myers Squibb agreed on an acceptable discount for the Department of Health (The Guardian, 2015), after previously being denied in 2011 as the long-term benefits were unclear and the cost too high for the NHS (Fellner, 2012). Pharmaceutical companies can make enormous profits by controlling knowledge of drug manufacture, and as the market of immunotherapy treatments has been estimated to be worth up to £26bn a year in sales (The Guardian, 2015), this has become the new focus. The price of the combined treatment is likely to be much higher than this figure, due to the use of the two drugs, ipilimumab and nivolumab. This can put pressure on health systems all over the world, as well as richer economies like the UK, because there are huge differences in cost; the British Generic Manufacturers Association says "The average cost to the NHS of a generic medicine is £3.79, whilst the average cost of a branded medicine is £19.73." The huge profit is the reward, funding and incentive for the research and development of new drugs (The Guardian, 2014). But retail prices aren’t reflective of the production costs, which are a tiny fraction of the overall price tag; they are “set according to the maximum amount that a market will bear in the absence of price-lowering competition” (ibid). However, all cancer treatment comes at a cost. As said by Dr Annabel Bentley, medical director of Bupa Health and Wellbeing, "A single course of chemotherapy for cancer can cost between £25,000 and £30,000, and someone may need several courses” (The Telegraph, 2011). An average six-week cycle of Sutent costs around £3,139 and Pfizer, the manufacturer, provides the first cycle of treatment to NHS patients for free (The Telegraph, 2009). A herceptin-style drug called Kadcyla (trastuzumab emtansine), manufactured by Roche, that had the ability to offer some advanced breast cancer patients nearly 6 months of extra life was turned down for use in the NHS in 2014, for its high price of £90,000 per patient. However it is being funded through the special Cancer Drugs Fund, “We are very aware of the importance that people place on life-extending cancer drugs and a decision not to recommend a cancer treatment for routine NHS funding is never taken lightly.” (The Guardian, 2014) Conclusion Immunotherapy has unsurprisingly become the forefront of cancer research in recent years (American Cancer Society, 2014). It has shown real promise of improving the lives of many cancer patients, including complete responses. The mechanism of this therapy, effectively ‘rewiring’ the immune system to create an anti-tumour response, is innovative and the use of antibodies which are able to bind to specific target proteins with high specificity, means their application in oncology is obvious (Antibodies as Tools, 2015). The new combined therapy of ipilimumab and nivolumab has shown encouraging results in clinical trials, including tumour shrinkage rates of over 50% that have never been seen before (The Guardian, 2015). This is an incredible feat, worked on by oncologists and researchers for thousands of years, since before the ancient Edwin Smith Papyrus, when there was almost no treatment for cancer (American Cancer Society, 2014). In one trial, the median progression-free survival was increased by 8.6 months by combined therapy instead of ipilimumab monotherapy (Larkin et al., 2015). These results are extremely exciting for the medical industry and there are increasing numbers of ongoing clinical trials, researching the effects this therapy will have on different types of cancers, including metastatic melanoma, renal cell carcinoma and small cell lung cancer. There is potential of this therapy being able to treat a diverse range of cancers, and therefore improve the lives of millions of patients. Although there are cases of increased adverse reactions in the combined therapy, including a 30% increase in a trial comparing monotherapy and combined therapy (Postow et al., 2015), I believe that the benefit far outweighs the risk. For many patients, if they received monotherapy or no treatment at all, their most realistic median-progression free survival was just 2.9 months (Larkin et al., 2015), and many mortalities would have occurred much sooner. In some cases, patients were able to make a full recovery, seen in a clinical trial comparing ipilimumab monotherapy with combined therapy where 22% of the combination group reported complete responses versus none in the monotherapy group (Postow et al., 2015). In addition to this, all cancer treatments have adverse reactions, such as flu-like symptoms in chemotherapy (Royal Marsden, 2014), and renal failure using Sunitinab ( Directory: 2011 2011 -> Enterprise Network Management iPost: Implementing Continuous Risk Monitoring at the Department of State 2011 -> Voices of the Old Sea Norman Lewis 2011 -> Malevil Robert Merle 2011 -> The Elephant Keeper’s Children Peter Hoeg 2011 -> January 1: Ecstasy zZz January 2: King of Anything Sara Bareillis 2011 -> Tracks, Mixes, Masters, and More!: Analyzing Preservation Priorities for Multitrack Recordings 2011 -> Department of Electrical Engineering 2011 Annual Report 2011 -> Jv packet •Mars Colonization Affirmative •Mars Colonization Negative 2011 -> Asian Pacific Mathematical Olympiad(apmo) 2011 -> Registration Form (Rev. 8-86) omb no. 1024-0018 Download 144.98 Kb. Share with your friends:
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