Metastatic melanoma: the new immunotherapies

Metastatic melanoma: the new immunotherapies

Metastatic melanoma is one of the most aggressive forms of skin cancer, with a median overall survival (OS) of between just 8 and 18 months. More than 70,000 new cases of melanoma are diagnosed each year in the USA alone, where approximately 10,000 people die from this cancer annually. Worse, the incidence of melanoma in the USA has increased threefold over the last three decades. For over 30 years, the benchmark therapy for this disease was DTIC (dacarbazine), from Bayer HealthCare, which was first approved in the 1970s. Along with interleukins like Proleukin (aldesleukin), from Novartis / Prometheus Labs, treatment achieved modest results but both therapies suffer from low response rates and toxicity issues. Yet there is some good news. After a long period where few new treatments emerged, recent successes with immunotherapy and other targeted therapies have signalled a new era in tackling the disease. Such therapies are associated with significant improvements in patient outcomes, leading to increased likelihood of long-term survival in patients but also driving research into a new generation of therapies. The result is that the metastatic melanoma drug market is set to reach an estimated $1.5–3.6 billion by 2020.

Revolution in treatment

The outlook for metastatic melanoma patients began to change in 2011 when several new treatments were approved on both sides of the Atlantic. The first was Yervoy (ipilimumab), from BMS. A human monoclonal antibody targeting a receptor called CTLA-4 that down-regulates the immune system response, ipilimumab resulted in one-year survival rates of about 50% for people with Stage III or IV melanoma – almost double the average – and 24% at two years. Though dogged by serious gastrointestinal side-effects, drug sales reached $1.38 billion in 2014. The other key metastatic melanoma approval in 2011 was Zelboraf (vemurafenib), from Genentech/Roche. This was approved in the USA in 2011 and in the EU the following year. Vemurafenib was the first therapy to target the BRAF V600E mutation which occurs in roughly half of metastatic melanoma patients. Trials show that those taking vemurafenib had a median OS of 15.9 months – double that with conventional therapies. Physicians believe that patients being given BRAF inhibitors should be tested to determine their RAS status, since the potential for secondary tumour development is of concern. Meanwhile, the Cobas 4800 BRAF V600 Mutation Test, co-developed by Roche, was approved simultaneously with vemurafenib in the USA and CE-marked in the EU. Analysts predict annual vemurafenib sales will peak at $700 million. A second therapy targeting BRAF V600E was approved in 2013 in the USA and EU. Tafinlar (dabrafenib mesylate), from Novartis, inhibits mutant BRAF about four times more strongly than vemurafenib, while maintaining a comparable selectivity for mutant BRAF over wild-type BRAF. Results of Phase III trials presented in 2014 showed 45% of patients treated with dabrafenib were still alive at two years. Final analysis of OS data is expected in 2016. Bloomberg estimates sales will reach $970 million by 2018. Novartis followed up dabrafenib with a second therapy, Mekinist (trametinib), which binds to and inhibits MEK1 and 2, targeting both BRAF V600E and V600K mutations. Trametinib was approved in the USA in 2013 and in the EU in 2014. A companion diagnostic, the THxID BRAF assay, from BioMerieux, has also been approved in the US and EU. However, analysts see trametinib as having limited clinical benefit as a single agent, and say that it may struggle to see significant uptake in this patient population.

Combination therapies

Research suggests that trametinib can play a more effective and longer-lasting role when combined with BRAF inhibitor dabrafenib. Sure enough, in Phase II trials, the dabrafenib-trametinib combination has delivered a 76% response rate, compared to 54% with dabrafenib alone. Approved in 2014 under the FDA's priority review programme, this combination has had a rougher ride in the EU, where the filing was withdrawn after the EMA warned that it required additional data to make a decision. Novartis plans to resubmit when Phase III data is available. With evidence suggesting that combination therapies are effective yet also attenuate some of the serious adverse events such the incidence of cutaneous squamous cell carcinoma, there has been growing attention on this approach. Roche responded with positive top-line data from the Phase III CoBRIM study showing that its MEK inhibitor GDC 0973 (cobimetinib), in combination with its BRAF inhibitor vemurafenib, increased progression free survival (PFS) in previously untreated BRAF V600-mutation positive metastatic melanoma patients compared with vemurafenib alone. The combined therapies reduced the risk of disease progression or death by half and showed a median PFS of 9.9 months compared to 6.2 months with vemurafenib alone. The combination was filed in both the EU and USA in 2014, and the FDA has given it priority review with a decision expected in August 2015. Analysts expect Roche and Novartis to go head to head, with success coming down to the combination that shows fewest side effects.

Rise of the PD-1 blockbusters

Another key step in tackling metastatic melanoma came in 2014 with the arrival of programmed death 1 (PD-1) receptor inhibitors. Merck’s monoclonal antibody Keytruda (pembrolizumab) is one of a new generation of cancer drugs to block this PD-1 pathway – a powerful new way to mobilise patients' immune systems to fight their disease. In 2014 it received accelerated approval from the FDA, and was CHMP-recommended in the EU in 2015. Results have been impressive: in a head to head with ipilimumab, pembrolizumab hit its primary endpoints not only for delaying cancer progression, but also for OS. Merck stopped the study, KEYNOTE-006, after trial monitors decided the results were strong enough to prompt a halt. For melanoma patients with BRAF V600 gene mutation, pembrolizumab can be used after ipilimumab and a BRAF inhibitor like vemurafenib or dabrafenib. It is widely viewed as a potential blockbuster, with all-indication sales predicted to hit $3 billion by 2020. A second competitor in the PD-1 inhibitor race, BMS therapy Opdivo (nivolumab) has so far followed an identical regulatory pathway, with the FDA granting accelerated approval in 2014 when used after ipilimumab, and the CHMP recommending approval in 2015. The FDA has since accepted a filing for use of nivolumab with treatment-naive patients. Trial data has been similarly impressive: in PD-L1-positive patients, overall survival was improved by 70% and the objective response rate was 52.7% versus 10.8% for dacarbazine. Analysts see nivolumab, particularly in combination with ipilimumab, as a blockbuster to compete with pembrolizumab. Estimated nivolumab sales are $6.36 billion by 2020.

On the horizon

Filed in the US and EU in 2014, T Vec (talimogene laherparepvec), from Amgen has a similar mechanism of action to ipilimumab. It is a cancer-killing virus that stimulates an immune response against the disease. Though Phase III OS data has not proved as sparkling as hoped, and there were questions from FDA reviewers over investigator bias, the FDA Advisory Panel has recommended approval. It is already being investigated in Phase II as a combination melanoma therapy with pembrolizumab and ipilimumab. Meanwhile there are some 13 other drug therapies in Phase II trials, and about half that number in Phase III. For example, Abraxane (nab-paclitaxel) from Celgene is based on a generic taxol, repackaged as albumin-bound nanoparticles for targeted delivery of chemotherapy, but trials have revealed a high incidence of side effects versus dacarbazine. Novartis also has a second combination in Phase III trials: with Array Biopharma it is running the COLUMBUS trial comparing BRAF inhibitor LGX 818 (encorafenib) in combination with their MEK inhibitor MEK 162 (binimetinib) against monotherapies. Median overall PFS for BRAF inhibitor-naive patients was 11.3 months, consistent with other MEK/BRAF inhibitor treatments of BRAF mutant melanoma patients. Array projects a regulatory filing of the combination in BRAF mutant melanoma in 2016. Medimmune/AstraZeneca/Pfizer are also investigating a monoclonal antibody treatment CP-675,206 (tremelimumab) which they hope could become the next ipilimumab. Though the drug showed disappointing results in Phase II there is hope of success in Phase III thanks to a strategy that targets specific genetic mutations. Finally, as far as stem cell treatments go, Neostem has a promising candidate entering Phase III trials for metastatic melanoma: eltrapuldencel-T. In Phase II trials this showed 72% two year OS in patients with advanced disease compared to 31% for the control group.

Many challenges remain. There have been seven pivotal trial failures and treatments withdrawn, and the Phase III trial of STA 4783 (elesclomol), from Synta Pharma, was halted due to safety fears. Yet the apparent success of combination therapies brings hope of significant advances in treatment. One of the key decisions to tackle now is how all these agents should be best sequenced for optimum results. One likely option is that PD-1 inhibitors will become first-line treatments, followed up with BRAF-targeting agents, and monoclonal antibodies such as ipilimumab used as a last line of defence. Meanwhile promising results from early trials suggest combinations of MEK-inhibitors with c-KIT inhibitors such as Glivec (imatinib) have strong potential in melanomas arising from mucosal surfaces, which have so far proved difficult to treat.

References

Latest Approved Therapies for Metastatic Melanoma: What Comes Next? Menaa F. J Skin Cancer. 2013;2013:735282. doi: 10.1155/2013/735282.

Systemic therapy of metastatic melanoma: on the road to cure. Bhatia S, Tykodi SS, Lee SM, Thompson JA. Oncology (Williston Park). 2015;29:126-35.

Combined BRAF and MEK inhibition for the treatment of BRAF-mutated metastatic melanoma. Queirolo P, Picasso V, Spagnolo F. Cancer Treat Rev. 2015;41:519-526. doi: 10.1016/j.ctrv.2015.04.010.

Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. Larkin J, Ascierto PA, Dréno B, Atkinson V, Liszkay G, Maio M, et al. N Engl J Med. 2014;371(20):1867-76. doi: 10.1056/NEJMoa1408868.