Opdivo/Yervoy combination aces melanoma trial

Combining two cancer immunotherapeutics – Bristol-Myers Squibb's Opdivo and Yervoy – has achieved unprecedented efficacy in a landmark melanoma study.

While Yervoy is firmly established as the gold standard in melanoma therapy, the CheckMate-067 trial reported at the American Society of Clinical Oncology (ASCO) meeting showed that adding Opdivo to the regimen – or using Opdivo on its own – was better at extending progression-free survival (PFS).

The combination of PD1 inhibitor Opdivo (nivolumab) and CTLA4 blocker Yervoy (ipilimumab) – both of which are checkpoint inhibitors that block mechanisms used by tumour cells to evade detection by the immune system – achieved a PFS of 11.5 months, compared to 6.9 months for Opdivo alone and 2.9 months for Yervoy.

The study is also testing overall survival rates with three regimens, although that data is not yet available, according to lead investigator Jedd Wolchok of Memorial Sloan Kettering Cancer Centre (MSKCC), who presented the data at ASCO.

Response rates were also better with the combination therapy option, and the median duration of response was not reached in any of the three groups over the follow-up period, he said.

The ASCO discussant for the Checkmate -067 trial, Michael Atkins of Georgetown University Medical Center, said the results alongside data from an earlier study comparing Merck & Co's Keytruda (pembrolizumab) and Yervoy, show that the newer checkpoint inhibitors can be considered a new standard of care for advanced melanoma.

While the efficacy of the regimen was well-received, some doubts were raised about its safety – with 55 per cent of patients experiencing grade 3 or 4 toxicities – although commentators suggested that these were manageable and there were no drug-related deaths among patients treated with the combination.

Discussion of the results also quickly moved on to the price tag for the treatment, with Leonard Saltz of MSKCC telling delegates that the regimen could cost more than $295,000 a year at average wholesale prices.

"Cancer drug prices are not related to the value of the drug, rather the prices are based on what has come before, and what the seller believes the market will bear," he said.

It is also clear that there is more to be learnt about how best to use checkpoint inhibitors, either alone or in combination, in light of another trial at ASCO that showed that PD-1 ligand (PD-L1) status is actually a pretty weak biomarker to predict patients' response to therapy.

In CheckMate-067, patients who were deemed PD-L1 positive did no better with the combination of Yervoy and Opdivo than with Opdivo alone, although this finding was reversed in the PD-L1-negative group.

That contradicts findings from earlier studies but does provide a potential rationale for targeted use of drugs, and potentially sidestepping combination therapy in some instances, with PD-L1-positive patients given Opdivo alone. It also shows, however, that better predictive tools are needed to help guide therapy with the new immuno-oncology drugs.

BRAF/MEK inhibitors

The Opdivo/Yervoy combination was just one positive trial in melanoma reported at ASCO, with other studies showing the progress made in tackling a disease that, until recently, had few effective treatment options.

Roche provided updated data from its coBRIM study of BRAF inhibitor Zelboraf (vemurafenib) with investigational MEK inhibitor cobimetinib, which showed the combination helped people with previously untreated BRAF V600 mutation-positive advanced melanoma live a median of 12.3 months without their disease progressing.

For patients treated with Zelboraf alone, progression-free survival was just over seven months, said Roche, which noted that marketing applications for cobimetinib are due for verdicts in the US in August and in Europe before the end of the year.

Moreover, Novartis reported that the combination of BRAF inhibitor Tafinlar (dabrafenib) and MEK inhibitor Mekinist (trametinib) improved overall survival compared to Tafinlar given alone in BRAF V600-positive melanoma.

Median overall survival for the combination, acquired from GlaxoSmithKline earlier this year, was 25 months, compared to 18 months for Tafinlar monotherapy. This is the first time a BRAF/MEK inhibitor combination has been shown to extend survival in phase III testing, said Novartis.