ASCO – Melanoma hopes lie in combination approaches

Advances in treating metastatic melanoma, one of the deadliest forms of cancer, have rightfully earned top billing at cancer conference Asco over the last two years. Underlining where many believe the next breakthroughs are likely to come in this disease, two stars of the show, Roche and Bristol-Myers Squibb, marked the start of the meeting by announcing a collaboration to test their novel therapies in combination.

Compelling results from a phase I trial of a combination of two GlaxoSmithKline kinase inhibitors in melanoma also attracted attention at the conference - as well as prompting impressive response rates the regimen also improved the side effect profiles of the two monotherapies. A greater understanding of the genetic drivers of cancer is allowing researchers to put together novel targeted agents in a much more rational fashion; the work is still early stage but combination approaches in melanoma, and other cancers, hold the potential to be future headline acts.

Logical step

Combining the BRAF kinase inhibitor vemurifenib with immunotherapy ipilimumab – both of which have managed to promote highly impressive responses in melanoma patients – is widely viewed as the logical next step for these agents, particularly after the encouraging pivotal data presented (ASCO – Melanoma drugs take centre stage for second year, June 6, 2011).

“These results really form the foundation of combination regimens in the future,” said Dr Jedd Wolchock, an oncologist at Memorial Sloan-Kettering Cancer Center in New York and lead author of the pivotal ipilimumab study.

The two drugs’ distinct mechanisms of action means they are unlikely to compete and researchers have long believed the power of ipilimumab would lie in combination with a targeted therapy, to build on the drug’s ability to harness the immune system.

Whether vemurifenib is the correct choice remains to be seen – the companies will initially conduct a phase I/II to evaluate safety and efficacy.

Ripe for combination

Combining drugs to more effectively kill tumour cells is nothing new and studies are ongoing in a wide variety of cancer types. Melanoma is particularly ripe for this approach because many of the genetic drivers of the disease have been described, aiding the design of targeted agents. The fact that melanoma tumours are on the surface of the skin has helped in these efforts, as biopsies for study are relatively easy.

As such, it is known that a mutated BRAF gene is associated with 50% of melanomas. However, for all their success in swiftly shrinking these tumours, vemurafenib and other BRAF inhibitors do not work for long. Melanoma is an adaptable cancer and the tumour cells quickly manage to bypass the blocked receptor and reactivate the signalling pathway – median time to resistance for vemurafenib is about seven months.

One of the hopes for combining targeted agents is that resistance can be overcome, as well as boosting the proportion of patients that respond to therapy in the first place.

Signalling pathways

Roche is already testing vemurifenib in combination with another kinase inhibitor, GDC-0973, which targets the MEK gene, in a phase I melanoma study.

The RAF – BRAF - MEK signalling pathway is known to be a key driver of cell proliferation and the metastasis of tumour cells. Therefore these three driver genes have become prime targets for research. “It makes sense that a MEK inhibitor would also work in BRAF tumours because we know that BRAF signals directly through MEK,” says Dr Jeffrey Infante, an oncologist at Tennessee Oncology.

GlaxoSmithKline is also following the same hypothesis with two of its kinase inhibitors; both have generated encouraging phase I data and are already in phase III monotherapy trials, initiated at the start of the year.

GSK2118436, or dabrafenib, is a BRAF kinase inhibitor which should generate pivotal data from a monotherapy study versus dacarbazine next year, in first line BRAF mutation-positive melanoma. [NCT01227889].

Meanwhile GSK1120212, or trametinib, is an oral MEK inhibitor which is in a slightly larger three arm study, in previously treated BRAF mutation-positive melanoma – results could emerge later in 2012. [NCT01245062.]

Key toxicities

Both of these drugs were associated with high rates of specific tolerability issues in their monotherapy phase I studies, according to Dr Infante, lead investigator on the combination trial for Glaxo.

In phase I dabrafenib prompted tumour responses in 63% of patients, but it also triggered growths on the skin in about 77% of patients. “The key toxicity of these selective BRAF inhibitors has been almost paradoxical squamous cell carcincomas. So you can watch the melanomas shrink, but patients are constantly getting little squamous cells and warts taken off their skin,” he says.

Meanwhile, about 41% of patients responded to treatment with trametinib in phase I, but it caused skin rash in more than 80% of those tested. By combining the two drugs, the researchers were hoping to boost effectiveness, overcome or prevent any BRAF resistance and potentially decrease the incidence of skin lesions.

“It makes sense that the combination could really knock down signalling in that pathway,” Dr Infante says.

Significantly reduced

In the combination trial the researchers started with half the monotherapy dose of each agent and managed to safely escalate up to the full doses. The most common side effects were nausea, fever and fatigue but the most notable impact was on the key toxicity side effects seen in the monotherapy trials.

The trial started just over a year ago, and of the 109 patients dosed with the combination; so far there has only been one squamous cell carcinoma and one wart-like lesion. Rash appears to be down to the 27% or less range, according to Dr Infante.

“We can give both these drugs in full doses and significantly reduce the side effects. The tumour response has also been remarkable. The majority of patients had clinical benefit very quickly.”

Five patients have been classified as complete responders. Of the 71 patients who made it to evaluation about 98% had a partial or complete response or stable disease. “The data is early but you don’t have to be an oncologist to know that you are helping people,” says Dr Infante, who presented a picture of a patient with extensive melanoma around the ear, which substantially and visibly reduced over a four month period.

“The additional of an MEK inhibitor is the next rational step to improve upon the efficacy of single agent BRAF inhibitors. Instead of getting increased toxicity, we saw a reduction. These are early data, but over 80% of the patients are still on study and we’re anxiously awaiting longer term durability data.”

New waves

The results so far are early stage and need verifying in much larger studies. And the side effects quashed were not life threatening, so the real test of this combination will be in whether it can overcome the BRAF resistance issue.

“We see with these patients they have a dramatic response but they do develop resistance – the agents stop working and the cancer outwits us and figures out new pathways. Combining targeted therapies is going to be a wave in the future,” says Dr Lynn Schuchter, professor of haematology-oncology at the Abramson Cancer Center at the University of Pennsylvania.

A wide range of other receptors and genes have been linked with melanoma, including NRAS, c-KIT, c-MET and PI3K, all of which could yield viable agents.

Meanwhile the collaboration between BMS and Roche – combining a targeted agent with an immunotherapy – could represent a second new wave. BMS is trialling other agents in combination with ipilimumab – a phase I trial with the Raf inhibitor XL281 started earlier this year.

The cost of these combinations is another debate entirely, and the development path is unlikely to be smooth. But a growing understanding of the genetic drivers behind cancers means targets can be hit with ever more specific agents, and combination studies are likely to feature more prominently at Asco in the years to come.

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