Melanoma blow confirms threats to Yervoy before other crucial readouts

Given mounting evidence of the anti-PD-1 antibodies’ impressive efficacy the results of Merck & Co’s Keynote-006 study cannot have taken many people by complete surprise. The study generated what looks to be an unequivocal win for Keytruda versus Yervoy in patients with untreated metastatic melanoma, confirming this mechanism of action as a first-line choice in this aggressive disease.

What is more surprising is that Bristol-Myers Squibb shares fell on the news, presumably partly on concerns about the impact of the study on Yervoy. However, the drug was already expected to lose out to the anti-PD-1s in melanoma this year, and this study only confirms this.

The full results from the Keynote-006 study, due to be presented at the AACR meeting next month, will now be keenly awaited to determine the extent of Keytruda’s benefit over Yervoy. All Merck said yesterday was that the two primary endpoints of progression-free survival and overall survival had been met, and the trial stopped early.

Yervoy was approved on the basis of a four-month survival advantage in previously treated patients; median survival reached 10 months. In the Checkmate-066 trial last November Opdivo generated a 58% decrease in the risk of death versus chemotherapy in first-line patients; median OS was 10.8 months for chemo patients but had not been reached in the Opdivo arm.

Largely on the basis of this study, an influential panel at the US National Comprehensive Cancer Network has been recommending since February that Keytruda and Bristol-Myers’ rival Opdivo be considered a first-line option, ahead of official regulatory endorsement. Both are only approved in secondary settings by the FDA.

As such, confirmation of Keytruda’s activity here will probably help both drugs. But while Merck shares were little changed on the news yesterday, Bristol-Myers’ stock slipped almost 3%.

Way of thinking

Given the dominant position that Bristol-Myers is expected to win in the PD-1 space with Opdivo, this share price decline must have been down to concerns about Yervoy. This is certainly viewed as an important drug – albeit dwarfed in value by Opdivo – EvaluatePharma data peg it as the company’s third-biggest sales driver, with $2.3bn in 2020 revenues.

And, interestingly, consensus has not really shifted over the past few months, despite the imminent arrival of the checkpoint inhibitors in the lucrative first-line space – analysts estimate that Yervoy generated 70% of its revenues in this setting last year.

Largely, the sellside appears happy to ignore the competitive threat, along with cautious noises from Bristol-Myers’ management about demand for Yervoy this year. It looks like numbers will start nudging downwards soon though – Bernstein recently sliced 29% from its 2020 estimate, taking it to $1.5bn.

Investors, it seems, have just caught up to this way of thinking.

In the pipeline

Those analysts still sitting on top-of-consensus numbers – JP Morgan has $2.9bn in 2020 for example – might be factoring in success in a number of trials that Bristol-Myers is running with Yervoy, in an attempt to add legs to the franchise.

In melanoma this could come with evidence that the combination of Opdivo and Yervoy can generate even better survival rates – although analysts at Bernstein point out that the data must be persuasive enough to overcome higher toxicity and the cost of the combination. The phase III Checkmate-067 will ultimately establish this next year, although results from the phase II Checkmate-069, also in this setting, are also due at AACR next month.

Another boost could come in lung cancer; Bristol-Myers has yet to detail plans for a phase III combination study, although AstraZeneca is testing MEDI4736 plus tremelimumab here, which could give insight into the potential of a PD-1/CTLA-4 combination. Data are expected at ASCO from the UK drug maker.

Bristol-Myers has also started the multi-armed Checkmate-012 study in non-small cell lung cancer, which has an Opdivo plus Yervoy arm. And it is pitting the Opdivo/Yervoy combination in other solid tumours like colon cancer, as well as investigating it as a single agent in various settings – phase III data are due before the end of the year in small-cell lung cancer and pre-chemo prostate cancer.

The coming months will help determine Yervoy's place in the fast-changing immuno-oncology space. The danger for Bristol-Myers is that it falls in love with its hand, however, and invests time, energy and money in a drug that will ultimately be superseded by more effective and tolerable mechanisms.

Keytruda trials
Keynote-006 NCT01866319
Opdivo trials
Checkmate-066 NCT01721772
Yervoy trials
Checkmate-069 NCT01927419
Checkmate-067 NCT01844505
Checkmate-012 NCT01454102
Single agent, small cell lung NCT01450761
Single agent, pre-chemo prostate NCT01057810

To contact the writer of this story email Amy Brown in London at [email protected] or follow @AmyEPVantage on Twitter

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