Immunotherapies for advanced melanoma: as promising as they are expensive?

Introduction

Cancer immunotherapy attempts to fight cancer by acting on tumour immunity and restoring the immune-surveillance system. ¹ Although immunotherapy is now emerging as an important addition to conventional chemotherapy, it was first applied in oncology in 1891, when WB Coley injected bacteria into patients with cancer to stimulate the immune system, a strategy which occasionally led to remission. ² Despite some successes, ‘Coley’s toxin’ was not widely accepted by the scientific community at the time. During the 20th century, the attitude towards cancer immunotherapy fluctuated substantially, arousing contradictory opinions on the existence of an immune response to cancer. ³ Starting in the 1980s, immuno-oncology research has provided robust evidence that tumours are recognised by the immune system and their development can be controlled through a process known as immune surveillance. Since the 1990s, the evidence in favour of an effective tumour-specific immunity has gained importance. Many studies indicated that appropriately activated immune cells elicited a tumour-specific response; then pilot trials in patients with a wide range of cancer types demonstrated the induction of an anticancer immune response. ³ Unlike chemotherapy, which acts directly on the tumour, immunotherapy exerts its effects on the immune system and acts through a mechanism that involves building a cellular immune response, ⁴ including various approaches which range from stimulating effector mechanisms to counteracting suppressive mechanisms. ⁵

Regulatory agencies worldwide have shown significant interest in cancer immunotherapies as monotherapies or combinations. For instance, the European Medicine Agency developed programmes to support expedited clinical development of cancer immunotherapies through fast-track approval and conditional marketing authorisation for priority medicines. ⁶

Here we analyse the economic evidence on new immunotherapies for advanced melanoma, focusing on the European setting. The analysis is preceded by a clinical background on the pathology and the immunotherapies already approved.

Clinical background

Melanoma is a dangerous skin cancer with a worldwide incidence rising faster than other solid tumours.^7,8 The melanoma incidence rate in Europe is now 10–25 cases per 100,000 inhabitants, ⁹ differing substantially between areas. According to the American Joint Committee on Cancer, ¹⁰ melanoma severity can be stratified in five stages (0–IV) by thickness, number of lymph nodes involved, extent of lymph node metastases and presence of distant metastasis. Chemotherapy (such as dacarbazine or temozolomide) has been the standard of care for over 30 years in the treatment of melanoma stages III and IV, but it has recently become a second-line option for advanced melanoma in the light of the substantial anticancer activity provided by the new immunotherapies. ⁹

Ipilimumab (a CTLA-4 inhibitor), nivolumab and pembrolizumab (both PD-1 inhibitors) are the three mAbs already approved for advanced or metastatic melanoma. Ipilimumab was the first immunotherapy that showed an overall survival improvement in three controlled CTs,^11–13with a response rate of about 10% when administered alone and 15% in combination with dacarbazine. Nivolumab showed progression-free survival and overall survival benefits compared to chemotherapy, with 32% and 40% response rates in previously treated and untreated patients, respectively.^14,15 Pembrolizumab showed a progression-free survival improvement compared to chemotherapy in previously treated patients ¹⁶ and both progression-free survival and overall survival gains compared to ipilimumab, ¹⁷ with response rates from 21% to 33% depending on the regimen adopted. More recently, the combination of nivolumab + ipilimumab proved superior to both agents in monotherapy.^18,19

Finally, it is worth noting that ipilimumab and nivolumab received a high score (4) on the internationally acknowledged European Society for Medical Oncology-Magnitude of Clinical Benefits Scale,^20,21 while the combination therapy was assigned a low score (2) because of its poor toxicity profile. Although not yet officially confirmed, pembrolizumab in monotherapy is very likely to receive a high score (4) too. ²²

Economic evidence

We searched the PubMed international database to select full economic evaluations conducted in EU countries on the three immunotherapies for advanced melanoma. ¹ Unfortunately, we could not select any study. Searching further on European official databases for reports in English language, we found six NICE guidances^23–28 on immunotherapies for patients with unresectable and metastatic melanoma and screened them to assess their main characteristics and results (Table 1).

Table 1.

Main characteristics of the NICE reports on immunotherapies for advanced melanoma.

Study, year	Patient population	Model, time horizon Efficacy sources of immunotherapy	Results	Main conclusion
TA 268, 2012 23	Unresectable stages III and IV, previously treated	4-State Markov model, 30 years 11	IPI vs. best supportive care £42,200/QALY	IPI is recommended with the discount agreed in the PAS
TA 319, 2014 24	Unresectable stages III and IV, previously untreated	3-State Markov model, lifetime11–13	IPI vs. dacarbazine £47,900/QALY IPI vs. vemurafenib £28,600/QALY	IPI is recommended with the discount agreed in the PAS
TA 357, 2015 25	Unresectable stages III and IV, previously treated	3-State Markov model, 30 years 16	PEM vs. best supportive care £47,000/QALY	PEM is recommended with the discount agreed in the PAS
TA 366, 2015 26	Unresectable stages III and IV, previously untreated with IPI	3-State Markov model, 30 years17,a	PEM vs. IPI or dabrafenib or vemurafenib <£50,000/QALYb	PEM is recommended with the discount agreed in the PAS
TA 384, 2016 27	Unresectable stages III and IV, previously untreated	3-State Markov model, 40 years14,15,18	NIV vs. IPI or dacarbazine or vemurafenib or dabrafenib <£30,000/QALYb	NIV as monotherapy is recommended as an option for advanced melanoma in adults
TA 400, 2016 28	Unresectable stages III and IV, previously untreated	3-State Markov model, 40 years18,19	NIV+IPI vs. IPI <£30,000/QALYb	NIV in combination with IPI is recommended with the discount agreed on IPI in the PAS

IPI: ipilimumab; NIV: nivolumab; PAS: Patient Access Scheme; PEM: pembrolizumab; QALY: quality-adjusted life year.

a

Phase 1 study of pembrolizumab in patients with progressive locally advanced or metastatic carcinoma, melanoma or non-small cell lung carcinoma (P07990/MK-3475-001/KEYNOTE-001) (KEYNOTE-001). Available at: https://clinicaltrials.gov/ct2/show/NCT01295827

b

The exact incremental cost-effectiveness ratio is confidential.

Two guidances were focused on ipilimumab,^23,24 two on pembrolizumab,^25,26 one on nivolumab ²⁷ and the last on the combination of nivolumab and ipilimumab. ²⁸ Two studies compared immunotherapies with best supportive care,^23,25 the other four^24,26–28 with targeted therapies and further alternatives, including chemotherapy, ²⁴ ipilimumab itself as monotherapy^26,28 and both together. ²⁷ Depending on the alternatives analysed, all reports sourced efficacy data on immunotherapies from the nine CTs (three phase II and six phase III) conducted for market approval (Table 2).^11–19 All studies adopted long-term Markov models for economic evaluations. Except for nivolumab in monotherapy, ²⁷ all immunotherapies (alone or in combination)^23–26,28 found an acceptable incremental cost-effectiveness ratio according to the NICE indicative threshold and thus were recommended only when supplied with confidential discounts negotiated between manufacturers and NICE in the patient access schemes. ²⁹

Table 2.

Main characteristics of the phase II and III trials on immunotherapies for advanced melanoma.

Ref.	Patients	Type of CT (duration)	Alternatives	Results
Hodi et al. 11	Unresectable stage III or IV melanoma, previously treated with dacarbazine, temozolomide, fotemustine, carboplatin or interleukin-2	Randomised, double-blind, phase III (55 months)	IPI + gp100 vaccine vs. IPI + placebo or gp100 vaccine + placebo	IPI alone or plus gp100 vaccine compared with gp100 alone improved OS (+3.6 months)
Hersh et al. 12	Unresectable stage III or IV melanoma, previously untreated with chemotherapy	Randomised, open-label, phase II (18.5 months)	IPI + dacarbazine vs. IPI	IPI plus dacarbazine compared with IPI alone improved OS (+2.9 months)
Robert et al. 13	Untreated unresectable stage III or IV melanoma	Randomised, double-blind, phase III (37 months)	IPI + dacarbazine vs. dacarbazine + placebo	IPI plus dacarbazine compared with dacarbazine alone improved OS (+2.1 months)
Robert et al. 14	Untreated unresectable stage III or IV melanoma without BRAF mutation	Randomised, double-blind, phase III (16.7 months)	Nivolumab vs. dacarbazine	NIV compared with dacarbazine improved OSa and PFS (+2.9 months)
Weber et al. 15	Unresectable stage III or IV melanoma, previously treated with ipilimumab, BRAF or MEK inhibitors or both	Randomised, open-label, phase III (8.4 months)	NIV vs. dacarbazine or carboplatin + paclitaxel	NIV compared with chemotherapy significantly improved PFS (+0.5 months)
Ribas et al. 16	Unresectable stage III or IV melanoma, previously treated with ipilimumab, BRAF or MEK inhibitors or both	Randomised, open-label, phase II (10 months)	PEM vs. paclitaxel or carboplatin or paclitaxel + carboplatin	PEM compared with chemotherapy improved PFS (+2.0 months)
Robert et al. 17	Unresectable stage III or IV melanoma, previously treated with systemic therapy	Randomised, open-label, phase III (7.9 months)	PEM vs. IPI	PEM compared with IPI improved OSa and PFS (+2.7 months)
Larkin et al. 18	Untreated unresectable stage III or IV melanoma	Randomised, double-blind, phase III (12.5 months)	NIV + placebo vs. NIV + IPI or IPI + placebo	NIV alone or plus IPI compared with IPI alone significantly improved PFS (+4.6 months; +8.6 months)
Postow et al. 19	Untreated unresectable stage III or IV melanoma	Randomised, double-blind, phase II (11 months)	NIV + IPI vs. IPI + placebo	NIV plus IPI compared with IPI alone improved PFS (+5.8 months, BRAF-mutated)

IPI: ipilimumab; NIV: nivolumab; OS: overall survival; PEM: pembrolizumab; PFS: progression-free survival.

a

Median overall survival was not reached.

Discussion

In general, the three immunotherapies analysed had greater (although uneven) efficacy on advanced melanoma than a wide range of alternative therapies. Ipilimumab caused frequent side effects and had low response rates despite an improvement of median overall survival over standard chemotherapy; ¹³ it rarely induced tumour regression and only a few patients achieved a prolonged complete duration. ³⁰ Nivolumab and pembrolizumab gave higher response rates and better overall survival and progression-free survival. Although a wide range of adverse events were reported for both, they were less frequent than for ipilimumab. Thus, the place in therapy of ipilimumab is likely to be reconsidered in advanced melanoma, downgrading it from first-line therapy to combination therapy with the two PD-1 antibodies.

Surprisingly, we did not find any published economic evaluation on the three immunotherapies conducted in EU countries, while even six guidances of the British NICE. The guidances indicated some apparent discrepancy between results and conclusions, which raise concern from our viewpoint. Although nivolumab in monotherapy was the only regimen recommended as cost-effective without any confidential discount, the punctual incremental cost-effectiveness ratio was not reported. ²⁷ Conversely, punctual incremental cost-effectiveness ratios were reported in three guidances^23–25 despite confidential discounts, while they were consistently concealed in the remaining two.^26,28

Commentary

Although immunotherapies have been seen to favour transient remission in the case of advanced melanoma, side effects are still heavy and cure rates still lower than expectations, as often happens with anticancer drugs. ³¹ However, the trend seems fairly encouraging, since the latest agents are more effective and have fewer side effects than the ‘pioneer’.

An endless worry seems to be the sky-high prices requested by industry for monoclonal antibodies (e.g. £18,750 per dose for ipilimumab), ²³ which make them hard to sustain even in wealthy European countries. The ‘novelty’ of this case study was that we did not find any European economic evaluation published in the pharmaco-economic literature, nor any study sponsored by a manufacturer to support cost-effectiveness by long-term modelling as is often the case. ³² Rather than unlikely methodological issues, the growing number of confidential discounts agreed by pharmaceutical companies with European health authorities might possibly be the ‘crux of the matter’ to explain this absence. This kind of agreement lacks transparency by definition and makes real prices a hidden variable which cannot be explicitly written down in public reports, as the NICE case shows.

To conclude, we wonder whether the EU can still tolerate these domestic confidential discounts. While the pharmaceutical industry supports their diffusion as a tool to undermine international reference pricing, these contracts are very likely to raise further inequity among Member States and are hardly likely to lead to net benefits for the EU as a whole.