Asco 2022 – Can Daiichi do it again?

Thanks to Enhertu's successes, the next antibody-drug conjugates emerging from Daiichi Sankyo’s pipeline are being closely watched. Four more are in the clinic and only one of them has been partnered – and the Japanese developer hopes to keep it that way.

It made sense to bring Astrazeneca on board three years ago because of the resources needed to develop Enhertu and datopotamab deruxtecan, the second ADC partnered with the UK pharma giant. “But we’ve grown since that deal so maybe we won’t need as much help [with the next projects],” Gilles Gallant, head of oncology development for Daiichi, tells Evaluate Vantage.

“We may change our mind, but it’s something we think we can manage on our own,” he says, speaking on the sidelines of the Asco meeting.

The group’s remaining unencumbered assets are still early stage so there is little real incentive for the company to sell out now. These next ADCs also target smaller populations so are perhaps more viable to keep in house anyway.

They also still need to prove their worth. Encouraging new data were seen at this year’s Asco on the most advanced, patritumab deruxtecan, which targets Her3.

“Her3 is a very different receptor to Her2,” says Mr Gallant. “It has not been very successfully hit with antibodies because it’s an incomplete receptor. Inside the cell it doesn’t have the same kinase activity as Her2. But with an ADC we only need the external parts [of the receptor] to get the active drug externalised.”

In breast cancer Her3 is thought to be involved in resistance to Her2 inhibitors. Enhertu’s strong results in broad Her2-low population arguably dent patritumab’s potential, although Mr Gallant says that opens up the possibility of dosing the drugs sequentially.

“That’s the future of these agents. If we can work out how to sequence them, we should be able to extend duration of response and hopefully overall survival,” he says.

The biggest opportunity for patritumab is non-small cell lung cancer, however; Her3 is expressed in most EGFR-mutated tumours. All eyes are on Herthena-Lung01, a potentially pivotal phase 2 trial in a very late-line, EGFR-positive population, who have been failed by TKIs, including Tagrisso, and chemo.

An earlier phase 1 trial found response rates of 39% and median PFS of 8.2 months. Daiichi might have stated a desire to go it alone with patritumab but the owner of Tagrisso, which just happens to be Astrazeneca, will be watching closely. 

“This is a population with complete unmet need, and we’re really looking forward to the results,” Mr Gallant says.

Coming after patritumab is DS-6000, which Mr Gallant describes as “one of our rising stars”. Early data in ovarian and renal cell cancer at Asco revealed encouraging responses, albeit in only 20 patients.

DS-6000 aims at CDH6, or human cadherin-6, and appears to be the only project directed at this target in the clinic. Novartis abandoned an anti-CDH6 ADC a few years ago due to toxicity.

“You have to remember that these targets we’re using, we only need the ADC to bring the drug into the cell. So when Novartis tried with CDH6, they tried to block the target. That’s not we’re trying to do. It’s a completely different mechanism of action,” Mr Gallant says.

The final ADC is the B7-H3-directed DS-7300 which along with DS-6000 Mr Gallant describes as “the most exciting drugs in our pipeline". Daiichi is not alone here, however; Macrogenics has pursued B7-H3 with various mechanisms in recent years, not always successfully, and several others are working on the target. 

The next big test of Daiichi’s ADC technology will come from datopotamab, however. The pivotal Tropion-Lung01 trial, being conducted in a broad second-line NSCLC setting, is due to read out early next year. Agents like Keytruda might have reshaped first-line NSCLC but the IO-failure space remains wide open.  

Hopes are already very high for datopotamab. Analysts at Berenberg are forecasting peak sales of $10bn, $2.9bn from the second-line lung setting.

Another hit will cement Daiichi’s reputation in the ADC space. However its success with this technology is no fluke. Enhertu and the follow-on projects are the result of decades of research into the technology, initiated by scientists at Daiichi before that company merged with Sankyo in 2007.

The payload, deruxtecan, is a derivative of exatecan, which Daiichi abandoned as a cancer agent in the late 1990s on lack of efficacy. Deruxtecan was found to be extremely potent with high cell membrane permeability, allowing it to diffuse easily into neighbouring cells.

Stable linkers were also developed to prevent the payload from being released early into the circulation. Daiichi’s linkers are broken down by lysosomal enzymes that are upregulated specifically in tumours. 

The company also managed to push the drug-to-antibody ratio higher than has been achieved elsewhere. So with Enhertu, this means that each Her2 antibody molecule delivers more payload molecules than other ADCs, with a DAR of 8 to Kadcyla’s 3.5.

This all adds up a powerful, localised payload with a strong bystander effect; a short-half life is the final ingredient, which helps limit side effects.

Toxicity remains Enhertu's major downside, however, in the shape of interstitial lung disease. Fatal cases are still being seen in clinical trials despite concerted containment efforts. Some analysts believe that the ILD risk will prevent the Daiichi ADC from moving into front-line settings.

Safety is probably also the biggest risk to the follow on projects, and is also the angle future competitors are likely to take. The Japanese company needs to make sure it stays out in front.