Cutaneous malignant melanoma is the most aggressive and invasive skin cancer, resulting in the majority of skin cancer deaths. Long-term survival for metastatic disease is low; however, most

patients are initially diagnosed with localized disease, surgical excision of which is often curative.

In the last decade, the treatment of malignant melanoma has been revolutionized by immune checkpoint inhibitors targeted to PD1–PDL1, small-molecule BRAF and MEK inhibitors and combination

regimens comprising these drug classes.

plus trametinib (Tafinlar plus Mekinist; Novartis) and encorafenib plus binimetinib (Braftovi plus Mektovi; Pfizer) — and are preferentially prescribed over single-agent BRAF inhibitors.

Dabrafenib plus trametinib is also approved for the adjuvant treatment of BRAFV600-mutation-positive patients with lymph node involvement (locally advanced or stage III disease), following

complete resection; it is the only BRAF/MEK inhibitor combination approved as adjuvant treatment.

The PD1 inhibitors nivolumab (Opdivo; Bristol Myers Squibb) and pembrolizumab (Keytruda; Merck & Co.) are firmly established in the treatment paradigm in all disease settings. Their labels

are broad, covering treatment for unresectable metastatic disease (the setting they first secured approval for) and adjuvant treatment of patients with lymph node involvement who have

undergone complete resection. The FDA expanded pembrolizumab’s label further in December 2021 to include completely resected stage IIB–C patients at high risk of disease recurrence;

nivolumab is being evaluated in the same setting in an ongoing phase III trial.

Dual immune checkpoint blockade with the PD1 inhibitor nivolumab and the cytotoxic T lymphocyte antigen 4 (CTLA4) inhibitor ipilimumab (Yervoy; Bristol Myers Squibb) is also approved for

treating unresectable or metastatic disease. This combination regimen has demonstrated an unprecedented median overall survival (OS) of 6 years, when less than a decade ago survival was just

6–9 months. In March 2022, the FDA approved a new immune checkpoint inhibitor combination targeted to LAG3 and PD1. Opdualag (Bristol Myers Squibb) is a first-in-class, fixed-dose

combination of nivolumab and the LAG3 inhibitor relatlimab, for the treatment of unresectable metastatic malignant melanoma. In its phase III trial (RELATIVITY-047), the combination more

than doubled median progression-free survival (PFS) compared to nivolumab monotherapy and displayed a safety profile similar to that of nivolumab. Opdualag is also being evaluated as

adjuvant therapy after complete resection of stage III–IV disease (RELATIVITY-098).

A triplet regimen comprising the PDL1 inhibitor atezolizumab (Tecentriq; Roche/Genentech/Chugai), vemurafenib and cobimetinib offers an alternative first-line treatment for patients with

advanced BRAFV600-mutation-positive status. Although the triplet has shown longer median PFS and duration of response than doublet BRAF/MEK therapy, it lacks mature OS data and carries

higher toxicity. Another triplet comprised of PD1 (pembrolizumab) and BRAF/MEK inhibitors (encorafenib and binimetinib) is being evaluated as first-line advanced disease therapy in the phase

III STARBOARD trial.

Talimogene laherparepvec (Imlygic; Amgen) is an oncolytic viral intralesional local therapy shown to have durable anti-tumour activity. It is approved for treating patients with unresectable

cutaneous, subcutaneous and nodal lesions with recurrent disease after initial surgery. Its use is restricted to those with accessible injectable lesions.

The malignant melanoma pipeline is dominated by combinatorial approaches involving established therapies (such as PD1 inhibitors) and novel therapies (Table 1).

HDAC, histone deacetylase; IDO, indoleamine 2,3-dioxygenase; IL-2, interleukin-2; TIL, tumour-infiltrating lymphocyte; TLR9, toll-like receptor 9.

Lenvatinib (Lenvima; Eisai) is an inhibitor of multiple tyrosine kinases. It is being investigated in combination with pembrolizumab in a phase III trial (LEAP-003) as first-line treatment

for unresectable or metastatic disease. Lenvatinib plus pembrolizumab has also been evaluated in patients who have progressed on anti-PD1/PDL1 therapy, achieving a median OS of 14 months in

the LEAP-004 phase II trial.

Phase III development of an orally administered class I histone deacetylase (HDAC) inhibitor, HBI-8000 (Hiyasta; HUYABIO), in combination with nivolumab is ongoing for advanced malignant

melanoma patients who are naïve to immune checkpoint inhibition. HBI-8000 was approved in Japan for peripheral T cell lymphoma in late 2021.

Also in phase III development are two intralesional therapies. The first is the toll-like receptor 9 (TLR9) agonist, vidutolimod (Checkmate Pharmaceuticals), delivered as a biologic

virus-like particle, which activates the innate immune system. It is under investigation in combination with nivolumab as first-line treatment for advanced disease (CMP-001-011) and has

secured fast-track designation from the FDA. The second is daromun (Nidlegy, Philogen), a dual immunocytokine combination comprising L19-IL2 (darleukin) and L19-TNF (fibromun), targeted to

the EDB domain of fibronectin. Daromun is under investigation as a neoadjuvant therapy for stage IIIB–C disease.

Several therapeutic vaccines are in clinical trials for malignant melanoma, all of which are being evaluated in combination with a PD1 inhibitor. The furthest advanced is IO102-IO103 (IO

Biotech), a peptide-based vaccine designed to target indoleamine 2,3-dioxygenase (IDO) and PDL1. In a phase III trial (IOB-013/KN-D18), IO102-IO103 plus pembrolizumab is being tested as a

first-line therapy for previously untreated unresectable or metastatic disease. Other therapeutic vaccines are mRNA-based and are in phase II trials. BNT111 (BioNTech) consists of a fixed

set of four mRNA-encoded tumour-associated antigens; it is being evaluated in combination with cemiplimab (Libtayo; Sanofi/Regeneron) for PD1 relapsed or refractory unresectable or

metastatic disease. BioNTech (in collaboration with Genentech) has another mRNA-based vaccine candidate for malignant melanoma, BNT122 (autogene cevumeran), a neoantigen- and

patient-specific therapy. Moderna and Merck & Co. are also jointly developing a neoantigen-specific mRNA-based individualized vaccine (mRNA-4157) in combination with pembrolizumab.

Adoptive cell therapies are in early-phase clinical development for unresectable or metastatic malignant melanoma. Lifileucel (Iovance Biotherapeutics) and ITIL-168 (Instil Bio) are

autologous (that is, patient-derived) tumour-infiltrating lymphocyte (TIL) cell therapies that are being investigated in multi-cohort phase II trials. Lifileucel is in two trials; one trial

in PD1-treated patients has a potential registration-enabling cohort (C-144-01) and the other in PD1-naïve patients includes evaluation in combination with pembrolizumab (IOV-COM-202).

Lifileucel has a regenerative medicines advanced therapy designation from the FDA based on data from the C-144-01 trial. ITIL-168 is being evaluated as a single agent in PD1-treated patients

(DELTA-1) and has orphan drug designation from the FDA.

Novartis is developing its own combination therapy targeted to PD1 and LAG3, spartalizumab plus LAG525. In a phase II trial known as PLATforM, the combination is being assessed for

previously treated unresectable or metastatic disease.

Tebentafusp (Kimmtrak; Immunocore) is a bispecific soluble high-affinity T cell receptor (TCR) targeted to gp100 and fused to a CD3 antibody fragment. It is being combined with AstraZeneca’s

inhibitors of PDL1 (durvalumab, Imfinzi) and/or CTLA4 (tremelimumab) in a phase Ib/II trial for malignant melanoma. Tebentafusp became the first TCR therapy to receive FDA approval in

January 2022, for uveal melanoma.

Sales of malignant melanoma therapies generated US$4.7 billion across the major markets in 2021, with the majority share (72%) held by the immune checkpoint inhibitors: nivolumab ($1.4

billion), pembrolizumab ($1.3 billion) and ipilimumab ($730 million). The malignant melanoma market is expected to increase 5% annually to $7.2 billion in 2030, driven by increased uptake of

approved therapies, including label expansions, and forecast approval of novel agents (Fig. 1).

Fig. 1 | Estimated major-market sales of key therapies for cutaneous malignant melanoma, by drug class. The 2021 sales and 2030 forecast in US$ millions for the seven major markets: the

United States, France, Germany, Italy, Spain, United Kingdom and Japan. HDAC, histone deacetylase; TIL, tumour-infiltrating lymphocyte.

Checkpoint inhibitors are expected to continue dominating during the 2021–2030 forecast period, holding 74% share of the total market in 2030. The recently approved anti-LAG3/PD1 combination

Opdualag is forecast to be the top-selling therapy ($2.3 billion), followed by pembrolizumab ($1.3 billion) and nivolumab ($1.2 billion). Although there are no long-term OS data for

Opdualag, its comparable efficacy (in terms of PFS) to that of nivolumab plus ipilimumab, coupled with its more favourable side effect profile, is anticipated to drive high prescribing and

thus sales.

During 2021–2030, the malignant melanoma market will become increasingly crowded with combination therapies, which are expected to hold an ~58% share ($4.2 billion) by 2030. BRAF/MEK

inhibitor combinations are expected to account for 15% of the total market; encorafenib plus binimetinib is forecast to be the most commercially successful BRAF/MEK regimen in 2030 ($706

million). Triplet combinations incorporating PD1/PDL1 and BRAF/MEK inhibitors are expected to struggle to gain share owing to their high toxicity, cost and competition from other combination

therapies. Other notable market entrants during 2021–2030 include first-in-class TIL therapy lifileucel, which is expected to generate $509 million in 2030. The HDAC inhibitor HBI-8000 and

peptide-based vaccine IO102-IO103 are anticipated to make a small market impact, each capturing less than $100 million, a result of competition from earlier-to-market combination therapies.