From having had only modestly effective chemotherapy and cytokine treatments just two years ago, melanoma care has been revolutionised by the entry of the immunotherapy Yervoy and the targeted agent Zelboraf. And it is about to change further, as the Asco cancer meeting became the forum for data from a variety of novel approaches, with the impressive data from immune checkpoint modulators to a combination approach that may make higher doses of Yervoy more tolerable.
Whilst it cannot be said that any of the new agents represent a cure, specialists are now starting to feel as if they are spoiled for choice as new candidates from Bristol-Myers Squibb, Roche and Merck & Co report mid and late-stage data and as already approved agents have begun to stretch survival from nine months to now well over a year. “That’s what clinicians are faced with: Whether to start with a targeted therapy or start with an immunotherapy,” said Lynn Schuchter, a University of Pennsylvania oncologist. “These are wonderful questions that we now need to tackle.”
Just the beginning
Approval of the GlaxoSmithKline targeted kinase inhibitors Tafinlar and Mekinist two days before the beginning of Asco set the stage for a meeting that was heavy on data on new approaches to the skin disease.
Long-awaited data on drugs from Bristol-Myers Squibb, Roche and Merck modulating the immune response regulator PD-1 was the spotlight of the show, with a combination of Bristol’s nivolumab with Yervoy the highlight of the annual global meeting of oncologists (Asco preview: Bristol’s PD-1 combo seizes the early limelight, May 16, 2013). Merck’s lambrolizumab (MK-3475) also impressed, with analysts suggesting that its phase I single agent study showed efficacy signals that approached the Bristol-Myers combination.
Yervoy plus the PD-1-blocking antibody achieved an objective response in 53% of patients taking the maximum tolerated dose of the combination. Given Yervoy’s safety profile – it has a black box warning for immune-related adverse reactions – a single-agent PD-1 inhibitor that can match the Yervoy-nivolumab combination on efficacy would be a worthy competitor.
Shares in both companies were up on Monday, the first trading day after the data were disclosed, with Merck up 4% to $8.45 and Bristol-Myers up 6% to $48.82. Goldman Sachs analyst Jami Rubin raised the Bristol-Myers price target to $55 from $48, reflecting the value of having a wholly owned combination that looks to be taking a leadership position in the race to deliver new therapies.
However, novel approaches do not require the use of novel agents, as researcher Stephen Hodi, an associate professor at the Dana Farber Cancer Institute. In a phase II trial, Dr Hodi combined high-dose Yervoy – 10mg per kilogram of body weight, compared with the 3mg labelled dose – with the granulocyte-macrophage colony stimulating factor sargromostim, and produced a significantly higher overall survival rate – 68.9% after one year, compared with 52.9% in a Yervoy-only arm.
In addition, the trial showed there were fewer side effects when the GM-CSF agent was added, with big differences in lung and gastrointestinal toxicity.
Stephen Hodi, associate professor at the Dana-Farber Cancer Institute, said the survival findings were surprising, and suggested that “changes in the tumour microenvironment” may result from synergistic effects. Whilst the survival benefit could be a result of Yervoy toxicity in the placebo arm, he said, “I think there may be something more there.”
“It’s very intriguing that there are fewer side effects,” Dr Schuchter said. “That’s the one result in melanoma that we can actually think about when we go home because we have been using GM-CSF treatment with melanoma over the last decade. We’ll see if payers will cover this.”
Disappointment and questions
For AstraZeneca, there was disappointment with selumetinib. Whilst it is looking like it will be the only treatment for a rare form of ocular cancer called uveal melanoma, it was a disappointment in the larger melanoma indication. In combination with dacarbazine, selumetinib failed to help advanced patients with BRAF-mutated melanoma live longer, but it did extend progression free survival, reaching 5.6 months when compared with three months for chemotherapy alone.
With the as-yet unapproved combination of the new Glaxo agents showing signs that they may be able to achieve progression free survival of around 10 months in patients new to BRAF inhibition, selumetinib may have difficulty finding a significant role in an increasingly crowded space. That said, as the only treatment that has shown efficacy in uveal melanoma in patients with the GNAQ and GNA11 mutation, it is probably still a viable candidate; with 2,000 patients diagnosed with that disease each year in the US, it also has orphan potential.
Roche’s antibody Avastin also had a successful interim readout in an adjuant setting, with the Avast-M trial reporting significantly more patients having up to two years without disease recurrence following surgery in the five year trial – 59% in the Avastin arm compared with 57% in an observational arm. Given that the angiogenesis inhibitor failed as an adjuvant treatment in colon and triple-negative breast cancer, positive signs in melanoma should come as a pleasant surprise, even though there is still a long way to go in that trial.
As with selumetinib, positive results for Amgen’s oncolytic virus T-Vec yielded only disappointment as physicians were underwhelmed by both its efficacy and its complicated delivery (Asco – Despite promise, future of oncolytic viruses remains clouded, June 3, 2013).
A research focus on melanoma finally appears to be bearing fruit. From having almost no options until very recently, melanoma specialists are now beginning to weigh new agents and may soon be grappling with questions about the best sequence of treatments rather than how to keep patients alive for a few more weeks.
|Yervoy + nivolumab (Checkmate 064)||NCT01783938|
|Selumetinib (uveal melanoma)||NCT01143402|