Acknowledgements: Bristol-Myers Squibb Pharmaceuticals Limited has had full editorial control over the content of this Insight article. Medical writing assistance was provided by Reynolds Mackenzie and supported by Bristol-Myers Squibb Pharmaceuticals Limited. Prescribing information has been included at the end of this article.
Support: This promotional article has been developed and funded by Bristol-Myers Squibb Pharmaceuticals Limited.
Ten years ago, long-term survival for advanced melanoma seemed far-fetched, but are we now getting close? Professor John Wagstaff, professor of medical oncology, from the College of Medicine, Swansea University, UK, shares his thoughts on the latest research findings and his experience of treating advanced melanoma.
Q. How has the treatment of advanced melanoma evolved over the past 5 years?
In the last 5 years, we have seen treatment of advanced melanoma transform, having moved away from a non-specific immune approach to targeted therapy. Before immunotherapy, the standard treatment for patients with advanced melanoma was chemotherapy and median overall survival (OS) of patients was about 9 months.1 Now, with the use of immunotherapy, we have seen in one trial of Opdivo®▼ (nivolumab) in combination with Yervoy® (ipilimumab) (herein referred as: NIVO+IPI, and on their own NIVO and IPI, respectively) that over half of patients were alive at 4 years, with median OS not yet reached.2
Immunotherapy is now recognised as a pillar of cancer treatment which stands alongside surgery, radiotherapy and chemotherapy as a mainstay of therapy.3 The status of immunotherapy as a treatment for advanced melanoma was confirmed when the National Institute for Health and Care Excellence recommended IPI and NIVO+IPI as an option for treating advanced previously treated advanced (unresectable or metastatic) melanoma in December 2012 and July 2016, respectively.4,5
NIVO is a monoclonal antibody that targets the programmed death-1 (PD-1) receptor, which in turn activates the immune system against cancer cells.6 IPI is a monoclonal antibody that targets cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), a protein receptor, to activate the immune system.7
One of the key studies supporting the use of this combination, and for which I was an investigator, is CheckMate 067. Last month, we presented 4-year follow-up data from CheckMate 067 at the European Society for Medical Oncology (ESMO), showing that over half of advanced melanoma patients receiving this combination were still alive 4 years later. When you consider that this is comparable to the proportion of patients who were still alive after 3 years,8 you have to wonder whether we are seeing some sort of plateau and that perhaps some of these patients will not experience a recurrence of their melanoma.
Q. What impact has this had on the lives of patients with advanced melanoma?
Advances in treatment mean that we have been able to improve survival for advanced melanoma patients. Immunotherapy appears to work well in patients with poorer prognosis (e.g. stage III and stage IV) melanoma and we are getting a significant number of patients who are achieving long term survival (35–45% achieving progression-free or overall survival with combination treatment).9
If you think of the patients we treated in the CheckMate 067 trial who are still alive now, when they were diagnosed their prognosis appeared extremely bleak. Talking to them today, a lot of them really feel lucky to be alive. At the start of the study it didn’t really seem possible that we would have so many of them survive for so long, and in generally good health.
Q. Can you tell us a bit more about the latest data from the CheckMate 067 study and what it means for the treatment of advanced melanoma?
The 4-year follow-up data presented at ESMO was the longest follow-up seen to date with immunotherapies in this patient population, and we found that first-line treatment with NIVO+IPI continues to demonstrate durable, long-term survival benefits, compared with IPI alone, in patients with advanced melanoma.2
- At a minimum follow-up of 48 months, NIVO+IPI and NIVO continued to show a higher objective response rate and improved progression-free survival and OS compared to IPI.
- Four-year OS rates were 53% for NIVO+IPI combined, versus 46% for NIVO and 30% for IPI.
- The proportion of patients experiencing a complete response has continued to increase, with complete response rates of 21% for NIVO+IPI, 18% for NIVO and 5% for IPI.
- A higher proportion of patients treated with NIVO+IPI were treatment free at 4 years compared to those treated with either NIVO or IPI alone.
- Interestingly we are seeing good efficacy even in patients with PD-L1 expression below 5%, with OS rates of 52% at 4 years in these patients.
- We did not observe any additional safety signals which is encouraging.
Q. This CheckMate 067 data represents the longest follow-up of a phase III study evaluating checkpoint inhibitor combination therapy in advanced melanoma. What is the significance of these data in the treatment of patients with advanced melanoma?
While the 4-year data regarding survival rates represent a huge advance in what we would have expected to see in these patients a few years ago, what is truly interesting is when you put them in the context of the 3-year data we presented last year. When you do this, you can see that the survival curve is potentially reaching a plateau, as there is very little difference between the survival rates at three and four years. As a result of this, I have felt able to say to some patients, who have been in remission for 5 years or more, that their disease may not come back at all.
Q. Can you give us any insights into how to identify an appropriate patient for immunotherapy?
It is interesting to see from the CheckMate 067 data that patients with PD-L1 expression ≤5% are doing almost as well on the combination treatment of NIVO+IPI as patients showing increased expression of PD-L1. When I first start treating a patient, I still find it very difficult to know how they are going to respond to treatment. We are still struggling for insights into those patients who are going to do well and those who might do less well. However, I feel quite confident now when talking to someone diagnosed with metastatic melanoma that their prognosis is probably going to be quite good.
Q. What is the safety profile of NIVO+IPI in advanced melanoma?
Safety and tolerability are important considerations when using these treatments as they are associated with considerable morbidity, especially those related to auto-immune reactions. These need to be managed, although I have had patients who have had serious reactions to treatment but have nonetheless survived their melanoma as a result of treatment, so you need to take a balanced view.
It is difficult to describe potential problems to a new patient – you need to strike a balance between being realistic and not scaring people. You also need to make sure patients feel able to tell you when they do experience toxicity, as sometimes they may worry that this will mean that they have to stop their treatment. For patients for whom this is a concern, it is important to note that, in my experience, survival of those patients who have had to stop treatment because of toxicity is generally better than those who continue and experience little toxicity.
I know many clinicians might not have a lot of experience of immunotherapies or may not have had many patients taking them. However, they are an important treatment option and I have seen first-hand their potential to transform outcomes in advanced melanoma in my clinic. Looking at the bigger picture, we need to be making optimal use of the therapies we have available in order to give our patients the best possible chance of making it through this disease.
For the combination of nivolumab with ipilimumab the most frequent adverse events observed in clinical trials were rash (52%), fatigue (46%), diarrhoea (43%), pruritus (36%), nausea (26%), pyrexia (19%), decreased appetite (16%), hypothyroidism (16%) and colitis (15%). The majority of adverse reactions were mild to moderate (grade 1 or 2).6
1. Larkin J, Gore M. Malignant Melanoma (metastatic). BMJ Clin Evid. 2008;08;1718.
2. Hodi FS, Chiarion-Sileni V, Gonzalez R, et al. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol. 2018;19:1480–92.
3. Bhatia S. Treatment of Metastatic Melanoma. Oncology (Williston Park). 2009;23:488–96.
4. National Institute for Health and Care Excellence. Ipilimumab for previously treated advanced (unresectable or metastatic) melanoma. Technology appraisal guidance [TA268]. London: NICE, 2012. Available at: www.nice.org.uk/guidance/ta268/chapter/1-Recommendations (accessed 15 November 2018).
5. National Institute for Health and Care Excellence. Nivolumab in combination with ipilimumab for treating advanced melanoma. Technology appraisal guidance [TA400]. London: NICE, 2012. Available at: www.nice.org.uk/guidance/ta400/chapter/1-Recommendations (accessed 15 November 2018).
6. Electronic Medicines Compendium. OPDIVO 10 mg/ml concentrate for solution for infusion, 2018. Available at: www.medicines.org.uk/emc/product/6888/smpc (accessed 15 November 2018).
7. Electronic Medicines Compendium. YERVOY 5 mg/ml concentrate for solution for infusion, 2018. Available at: www.medicines.org.uk/emc/product/4683/smpc (accessed 15 November 2018).
8. Wolchok JD, Chiarion‐Sileni V, Gonzalez R, et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2017;377:1345–56.
9. Larkin J, Chiarion-Sileni V, Rene Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373:23–34.
Opdivo®▼ (nivolumab) Prescribing Information
Consult Summary of Product Characteristics (SmPC) prior to prescribing and for full information on the medicinal product. If prescribing OPDIVO in combination with ipilimumab, please also consult the ipilimumab SmPC.
▼This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. PRESENTATION: 10 mg/ml concentrate for solution for infusion. Available in 4 ml (contains 40 mg nivolumab), and 10 ml (contains 100 mg nivolumab) vials. INDICATION: As monotherapy or in combination with ipilimumab for treatment of advanced (unresectable or metastatic) melanoma in adults. Relative to Opdivo monotherapy, an increase in PFS and OS for combination of Opdivo with ipilimumab is established only in patients with low tumour PD-L1 expression. As monotherapy for the adjuvant treatment of adults with melanoma with involvement of lymph nodes or metastatic disease who have undergone complete resection. As monotherapy for treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) after prior chemotherapy, advanced renal cell carcinoma (RCC) after prior therapy, relapsed or refractory classical Hodgkin lymphoma (cHL) after autologous stem cell transplant (ASCT) and treatment with brentuximab vedotin, and squamous cell cancer of the head and neck (SCCHN) in adults progressing on or after platinum-based therapy. DOSAGE: Opdivo as monotherapy (excluding adjuvant therapy): Recommended dose is Opdivo 240 mg every 2 weeks over 30 minutes intravenously (iv). For advanced (unresectable or metastatic) melanoma and RCC only, Opdivo can also be administered at 480 mg every 4 weeks over 60 minutes iv (refer to section 4.2 & 5.1 of SmPC). Adjuvant treatment of melanoma: Recommended dose of Opdivo is 3 mg/kg nivolumab administered iv over 60 minutes every 2 weeks. For adjuvant therapy, the maximum treatment duration with Opdivo is 12 months. Opdivo in combination with ipilimumab: Melanoma: Recommended dose is 1 mg/kg Opdivo (iv) over 30 minutes in combination with 3 mg/kg ipilimumab (iv) over 90 minutes every 3 weeks for the first 4 doses, followed by Opdivo monotherapy (iv) at either 240 mg every 2 weeks or 480 mg every 4 weeks. For the Opdivo monotherapy phase, the first dose of Opdivo should be administered as follows: 3 weeks after the last dose of the combination phase if using 240mg every 2 weeks or, 6 weeks after the last dose of the combination phase if using 480mg every 4 weeks (refer to section 4.2 of SmPC). Administration: Opdivo is for IV use only. It is to be administered as an IV infusion over a period of 30 or 60 minutes depending on the dose (refer to section 4.2 of SmPC). Total dose of Opdivo required can be infused directly as a 10 mg/ml solution or diluted with sodium chloride 9 mg/ml (0.9%) or glucose 50 mg/ml (5%) solutions for injection. It must not be administered as an intravenous push or bolus injection. When administered in combination with ipilimumab, Opdivo should be given first followed by ipilimumab on the same day. Use separate infusion bags and filters for each infusion. Dose escalation or reduction is not recommended. Dosing delay or discontinuation may be required based on individual safety and tolerability. Special populations: Children: Safety and efficacy in children below 18 years of age not established. Elderly: No dose adjustment required. Renal impairment: No dose adjustment required in mild-to-moderate renal impairment. Hepatic impairment: No dose adjustment required in patients with mild hepatic impairment. Caution advised in patients with moderate or severe hepatic impairment. CONTRAINDICATIONS: Hypersensitivity to the active substance or to any of the excipients listed in SmPC. WARNINGS AND PRECAUTIONS: Immune-related adverse reactions have occurred at higher frequencies with Opdivo in combination with ipilimumab than with Opdivo monotherapy. Cardiac adverse events and pulmonary embolism have also been reported with combination therapy. Monitor patients for cardiac and pulmonary adverse reactions continuously, plus clinical signs, symptoms, and laboratory abnormalities indicative of electrolyte disturbances and dehydration before and during treatment. Discontinue Opdivo in combination with ipilimumab for lifethreatening or recurrent severe cardiac and pulmonary adverse reactions. Monitor patients continuously (at least up to 5 months after the last dose) as an adverse reaction with Opdivo or Opdivo in combination with ipilimumab may occur at any time during or after discontinuation of therapy. Most immune-related adverse reactions improved or resolved with appropriate management, including initiation of corticosteroids and treatment modifications. See SmPC for further information. Immune-related pneumonitis, colitis, hepatitis, nephritis, renal dysfunction, endocrinopathies: Monitor patients for signs and symptoms. Please refer to SmPC for further management guidance including discontinuation of treatment. Immune-related skin adverse reactions: Monitor patients for rash, including Stevens-Johnson Syndrome (SJS) or toxic epidermal necrolysis (TEN). Use caution when considering Opdivo in a patient who has previously experienced a severe or life-threatening skin adverse reaction on prior treatment with other immune-stimulatory anticancer agents. See SmPC for further information. Other immune-related adverse reactions: Opdivo as monotherapy or in combination with ipilimumab: pancreatitis, uveitis, demyelination, autoimmune neuropathy (including facial and abducens nerve paresis), Guillain-Barré syndrome, myasthenic syndrome, encephalitis, gastritis, sarcoidosis, duodenitis, myositis, myocarditis and rhabdomyolysis. Cases of Vogt-Koyanagi Harada syndrome have been reported post-marketing. If a patient develops signs and symptoms of myotoxicity, close monitoring should be implemented, and the patient referred to a specialist for assessment and treatment without delay. Based on the severity of myotoxicity, Opdivo or Opdivo in combination with ipilimumab should be withheld or discontinued and appropriate treatment instituted. Solid organ transplant rejection has been reported in the post-marketing setting in patients treated with PD-1 inhibitors. Treatment with Opdivo may increase the risk of rejection in solid organ transplant recipients. The benefit of treatment with Opdivo versus the risk of possible organ rejection should be considered in these patients. Infusion reactions: Severe infusion reactions have been reported. Disease-specific precautions: For patients with poorer prognostic features and/or aggressive disease, where nivolumab should be used with caution after careful consideration of the potential benefit/risk on an individual basis, please consult SmPC section 4.4. cHL – Complications of allogeneic haematopoietic stem cell transplant (HSCT) in cHL. Preliminary results from the follow up of patients undergoing allogeneic HSCT after previous exposure to Opdivo showed a higher than expected number of cases of acute graft-versus-host-disease (aGVHD) and transplant related mortality (TRM). Careful consideration to the potential benefits of HSCT and the possible increased risk of transplant related complications should be made case by case. Treatment with Opdivo may increase the risk of severe GVHD and death in patients who have had prior allogeneic HSCT, mainly in those with prior history of GVHD. The benefit of treatment with Opdivo versus the possible risk should be considered in these patients. Tumour lysis syndrome (TLS) has been observed at an unknown frequency. Patients on controlled sodium diet: Please refer to SmPC. DRUG INTERACTIONS: Opdivo is not metabolised by drug metabolising enzymes, therefore metabolic drug-drug interactions are not expected. Systemic corticosteroids and other immunosuppressants should be avoided before starting Opdivo; however, systemic corticosteroids and other immunosuppressants can be used after starting Opdivo to treat immune-related adverse reactions. PREGNANCY AND LACTATION: Opdivo is not recommended during pregnancy and in women of child-bearing potential not using effective contraception unless clinical benefit outweighs potential risk. Effective contraception should be used for at least 5 months following the last dose of Opdivo. It is unknown whether Opdivo is secreted in human milk. UNDESIRABLE EFFECTS: Opdivo monotherapy: Very Common: neutropaenia, diarrhoea, nausea, rash, pruritus, fatigue, increased AST/ALT/ALP/lipase/amylase/creatinine, hypocalcaemia, lymphopaenia, leucopoenia, thrombocytopaenia, anaemia, hypercalcaemia, hyperkalaemia, hypokalaemia, hypomagnesaemia, hyponatraemia, hyperglycaemia. Common: upper respiratory tract infection, infusion-related reaction, hypersensitivity, hypothyroidism, hyperthyroidism, hypoglycaemia, decreased appetite, peripheral neuropathy, headache, dizziness, hypertension, pneumonitis, dyspnoea, cough, stomatitis, colitis, vomiting, abdominal pain, constipation, dry mouth, vitiligo, dry skin, erythema, alopecia, musculoskeletal pain, arthralgia, pyrexia, oedema, increased total bilirubin, hypermagnesaemia, hypernatraemia, weight decreased. Opdivo in combination with ipilimumab: Very Common: dyspnoea, hypothyroidism, decreased appetite, headache, colitis, diarrhoea, vomiting, nausea, abdominal pain, rash, pruritus, arthralgia, fatigue, pyrexia, increased AST/ALT/total bilirubin/ALP/lipase/amylase/creatinine, lymphopaenia, leucopoenia, neutropenia, thrombocytopaenia, anaemia, hypocalcaemia, hyperkalaemia, hypokalaemia, hypomagnesaemia, hyponatraemia, hyperglycaemia, hypoglycaemia. Common: pneumonia, upper respiratory tract infection, eosinophilia, infusion-related reaction, hypersensitivity, adrenal insufficiency, hypopituitarism, hypophysitis, hyperthyroidism, thyroiditis, dehydration, hepatitis, peripheral neuropathy, dizziness, uveitis, blurred vision, tachycardia, hypertension, pneumonitis, pulmonary embolism, cough, stomatitis, pancreatitis, constipation, dry mouth, vitiligo, dry skin, erythema, alopecia, urticaria, musculoskeletal pain, renal failure, oedema, pain, hypercalcaemia, hypermagnesaemia, hypernatraemia, weight decreased. Please refer to SmPC for full list of adverse reactions. LEGAL CATEGORY: POM. MARKETING AUTHORISATION NUMBER AND BASIC NHS PRICE: 40 mg/4ml 1 vial (EU/1/15/1014/001) £439.00; 100 mg/10ml 1 vial (EU/1/15/1014/002) £1,097.00 MARKETING AUTHORISATION HOLDER: Bristol-Myers Squibb Pharma EEIG. LOCAL REPRESENTATIVE IN UK: Bristol-Myers Squibb Pharmaceuticals Ltd, Uxbridge Business Park, Sanderson Road, Uxbridge, Middlesex UB8 1DH. Tel: +44 0800-731-1736. LOCAL REPRESENTATIVE IN IRELAND: Bristol-Myers Squibb Pharmaceuticals, Plaza 254, Blanchardstown Corporate Park 2, Ballycoolin, Dublin 15, Tel: +353 1 483 3625. DATE OF LAST REVISION: July 2018.
ADDITIONAL INFORMATION AVAILABLE ON REQUEST. Job number: 1506UK1800909-01.
Adverse events should be reported. Reporting forms and information can be found at: UK – www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store; Ireland – Freepost HPRA Pharmacovigilance, Earlsfort Terrace, IRL – Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: firstname.lastname@example.org. Adverse events should also be reported to Bristol-Myers Squibb via email@example.com or 0800 731 1736 (UK); 1 800 749 749 (Ireland).
Job number: 1506UK1801319-01
Date of preparation: November 2018