To the Editor: Patients with BRAF-mutated metastatic melanoma benefit greatly from the novel BRAF inhibitor dabrafenib and the checkpoint inhibitor ipilimumab, recently listed under the Australian Pharmaceutical Benefits Scheme (PBS). Dabrafenib results in rapid responses; but the cancer later adapts, and patients relapse rapidly. Conversely, ipilimumab slowly reactivates anticancer immunity, meaningfully improving long-term survival (up to around 20% at 5 years).
The costs of these drugs are substantial. Dabrafenib costs A$8759 per month, and median duration of therapy is 9.4 months.1 The Australian price of ipilimumab is confidential, but potentially up to A$190 000 per patient, depending on weight. The 2014 year-to-September PBS cost of ipilimumab was $68 456 890 (data from https://www.medicareaustralia.gov.au/statistics/pbs_item.shtml).
Current PBS approval mandates that dabrafenib may only be used as first-line therapy. Commencing treatment with dabrafenib then switching to ipilimumab when the disease progresses may inadvertently deliver worse outcomes than using the slower but longer acting immunotherapy followed by the potent but impermanent BRAF inhibitor.2,3 After a BRAF inhibitor fails, there is often insufficient time to deliver the full course of ipilimumab, let alone for the immune system to reactivate. While some patients' symptoms necessitate a BRAF inhibitor upfront, most are well enough to take ipilimumab first, with dabrafenib in reserve.4
Formal randomised trials of these sequences are underway (NCT01940809, NCT01673854, NCT02224781) but our clinical experience and two international case series reinforce that administering ipilimumab then a BRAF inhibitor is very likely to be superior. (Patients treated with BRAF inhibitor then ipilimumab: objective response rate, 0; stable disease, 6%; progressive disease, 94%.3 BRAF inhibitor then ipilimumab v ipilimumab then BRAF inhibitor: overall survival, 9.9 months v 14.5 months; P = 0.04.2)
In the absence of a formal economic analysis, we assume most of the approximately 1500 Australian patients who will die with metastatic melanoma every year accept treatment.5 Forty-six per cent of these patients have BRAF-mutated melanoma;6 and of these, 85% are well enough to defer treatment with a BRAF inhibitor.4 Thus, about 585 patients receive a potentially inferior treatment sequence, and around $36 million per annum of otherwise effective treatment is administered inefficiently.
Other countries with publicly funded health care (eg, the United Kingdom) do not restrict treatment sequences in metastatic melanoma. We argue that, until randomised trials identify inferior or superior sequences, Australian melanoma patients and taxpayers would benefit from flexibility in prescribing these breakthrough treatments.
- 1. 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: 1694-1703.
- 2. Ascierto PA, Simeone E, Sileni VC, et al. Sequential treatment with ipilimumab and BRAF inhibitors in patients with metastatic melanoma: data from the Italian cohort of the ipilimumab expanded access program. Cancer Invest 2014; 32: 144-149.
- 3. Ackerman A, Klein O, McDermott DF, et al. Outcomes of patients with metastatic melanoma treated with immunotherapy prior to or after BRAF inhibitors. Cancer 2014; 120: 1695-1701.
- 4. Long GV, Menzies AM, Nagrial AM, et al. Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma. J Clin Oncol 2011; 29: 1239-1246.
- 5. Australian Institute of Health and Welfare, Australasian Association of Cancer Registries. Cancer in Australia: an overview, 2012. Canberra: AIHW, 2012: 116. (AIHW Cat. No. CAN 70; Cancer Series No. 74.)
- 6. Menzies AM, Haydu LE, Visintin L, et al. Distinguishing clinicopathologic features of patients with V600E and V600K BRAF-mutant metastatic melanoma. Clin Cancer Res 2012; 18: 3242-3249.
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