Interview – German Merck doubles down on dual-acting cancer agents

Pfizer and nclick="getInfo('1042'); return false;">Merck KGaA successfully got the nclick="storyWordlink('PD-L1'); return false;">PD-L1 antibody nclick="storyWordlink('Bavencio'); return false;">Bavencio over the US FDA’s finish line thanks to its orphan indication of Merkel cell carcinoma. As commercialisation proceeds, the German group is now thinking of the future of immuno-oncology by locking up bispecific assets.

During Asco, Merck announced a deal with the UK group F-star for a suite of bispecific antibodies, including a nclick="storyWordlink('Lag-3'); return false;">Lag-3/PD-L1 asset that is "close to the clinic," says Merck’s global research & development head Luciano Rossetti. Dual acting projects are quicker to develop than nclick="storyWordlink('PD-1'); return false;">PD-1 combinations, since with combos each element must first be tested separately; in addition, they could offer an alternative to two very expensive agents in an environment wher "financial toxicity" has become an nclick="storyWordlink('oft'); return false;">oft-repeated term.

"That gives you advantage in development and perhaps even makes the payer happy," Mr Rossetti said in an interview on the sidelines of Asco.

Moving swiftly

The F-star deal follows the announcement that nclick="storyWordlink('Merck'); return false;">Merck is trialling its own bispecific nclick="storyWordlink('"fusion protein"'); return false;">fusion protein, nclick="storyWordlink('M7824'); return false;">M7824, which acts on nclick="storyWordlink('PD-1'); return false;">PD-1 and nclick="storyWordlink('TGF'); return false;">TGF beta (Interview – German Merck unveils its secret weapon, January 9, 2017). Mr Rossetti says the project is moving more swiftly than nclick="storyWordlink('Bavencio'); return false;">Bavencio – first human trials began in late 2015, and today it has enrolled 600 patients in 14 expansion cohorts.

For now, nclick="storyWordlink('Merck'); return false;">Merck is moving these projects independently of the nclick="getInfo('1293'); return false;">Pfizer alliance, revenue from which will be its biggest growth driver. Key to that is nclick="storyWordlink('Bavencio'); return false;">Bavencio, the fourth of five antibodies acting on the nclick="storyWordlink('PD-1'); return false;">PD-1 pathway to receive US approval and the least loved among sellside analysts. Yet collaborators nclick="getInfo('1293'); return false;">Pfizer and nclick="getInfo('1042'); return false;">Merck KGaA see opportunities to strike in what is a crowded and competitive space.

Snagging a win in the rare disease Merkel cell carcinoma was one way to speed development, Mr Rossetti says. But now the pace of research is growing even faster as hundreds of nclick="storyWordlink('PD-1'); return false;">PD-1combination trials are underway, and Mr Rossetti says the nclick="getInfo('1293'); return false;">Pfizer-Merck alliance is responding.

"By combining [nclick="storyWordlink('Bavencio'); return false;">Bavencio] with assets that are unique to nclick="getInfo('1293'); return false;">Pfizer or nclick="storyWordlink('Merck'); return false;">Merck we can create some very good opportunities," he tells EP Vantage. "I don’t think the door is closed."

Mr Rossetti names ovarian cancer as one opportunity, and evidence to support its use here could be found in the Javelin Ovarian 100 and 200 trials. The former uses nclick="storyWordlink('Bavencio'); return false;">Bavencio as a single agent or in combination with nclick="storyWordlink('carboplatin'); return false;">carboplatin/nclick="storyWordlink('paclitaxel'); return false;">paclitaxel as a maintenance therapy following platinum-based chemotherapy in newly diagnosed patients; the latter tests nclick="storyWordlink('Bavencio'); return false;">Bavencio alone or in combination with nclick="storyWordlink('doxorubicin'); return false;">doxorubicin in patients with platinum-resistant disease.

Earlier combinations include nclick="storyWordlink('"HDAC inhibitor"'); return false;">HDAC inhibitor nclick="storyWordlink('entinostat'); return false;">entinostat and nclick="storyWordlink('FAK'); return false;">FAK inhibitor nclick="storyWordlink('defactinib'); return false;">defactinib, the latter of which nclick="getInfo('1293'); return false;">Pfizer out-licensed to nclick="getInfo('10631'); return false;">Verastem.

Something special

Renal cell carcinoma is another opportunity: combined with nclick="getInfo('1293'); return false;">Pfizer’s nclick="storyWordlink('Inlyta'); return false;">Inlyta, nclick="storyWordlink('Bavencio'); return false;">Bavencio produced a 55% response rates in a phase Ib study. As a result, the partners have launched Javelin Renal 101, a head-to-head test against nclick="getInfo('1293'); return false;">Pfizer’s nclick="storyWordlink('Sutent'); return false;">Sutent, a blockbuster nearing the end of its market exclusivity, in advanced disease.

Non-small cell lung cancer has turned into the most competitive area of all, with nclick="getInfo('1041'); return false;">Merck & Co’s nclick="storyWordlink('Keytruda'); return false;">Keytruda having firmly established itself as the agent to beat in both front-line and progressive disease. Yet even there, Mr Rossetti sees the potential to offer something special.

Data from the Javelin Solid Tumor trial suggested a better response rate in NSCLC patients with greater exposure to nclick="storyWordlink('Bavencio'); return false;">Bavencio. Because the Javelin Lung 100 trial needed to be modified owing to changes in the standard of care, nclick="storyWordlink('Merck'); return false;">Merck and nclick="getInfo('1293'); return false;">Pfizer decided to add an arm in which patients were dosed with nclick="storyWordlink('Bavencio'); return false;">Bavencio once a week for the first 12 weeks rather than once every other week, which so far has increased exposure fourfold, he says. 

"This is a test of a hypothesis that nclick="storyWordlink('Bavencio'); return false;">Bavencio might be special," he says.

nclick="storyWordlink('Keytruda'); return false;">Keytruda’s success as a monotherapy and combination in NSCLC means nclick="storyWordlink('Bavencio'); return false;">Bavencio will need to be very special. Then again, in an indication forecast to be worth nearly $27bn in 2022, it is a chance worth taking.