Cancer

The inside story of Enhertu's pan-tumor approval

AP

Cancer drug history was made last Friday. Enhertu, the blockbuster antibody-drug conjugate discovered by Daiichi Sankyo and co-developed by AstraZeneca, was approved in the U.S. to treat any patient with advanced, HER2-positive cancer, regardless of where the tumor is located in the body. 

Enhertu is the first antibody-drug conjugate to receive a so-called tumor agnostic approval from the Food and Drug Administration. It’s also the first HER2-directed therapy to receive the designation. Enhertu was previously approved for certain types of HER2-positive breast, lung, and gastrointestinal cancers. The new FDA clearance will trigger broader diagnosis and treatment of ovarian, bladder, cervical, and endometrial cancers that also overexpress the HER2 protein. 

“It’s another groundbreaking achievement for Enhertu and opens up a new way of thinking about how we develop these kinds of drugs,” Susan Galbraith, the head of AstraZeneca’s cancer R&D, told me.

But the clinical work needed to pursue a tumor-agnostic indication for Enhertu, which began in early 2020, almost didn’t happen. 

“It’s fair to say that not everyone thought it was a great idea at that time,” Galbraith said, recalling meetings in 2019 at the start of the Daiichi and AstraZeneca partnership where doubts were expressed about the drug’s ability to have a broader effect on HER2-expressing tumors beyond breast cancer, where it is most predominate. 

“The opposing view was, you’re going to have to prove the biology matters in a similar way across multiple different tumor types,” said Galbraith. 

Early data that Daiichi had already collected suggested the tumor-agnostic approach might be feasible, but the development path would be risky and costly. And there was a precedent where a similar pan-tumor approach tried with a different targeted cancer therapy did not work. 

“We saw the opportunity for a pan-tumor approval, but it was not in the original plan for the Daiichi-AstraZeneca partnership at all. It evolved over time,” said Ken Keller, CEO of Daiichi’s U.S. operations and global head of its cancer business. 

After more debate, the two companies decided to run a clinical trial, called DESTINY-Pantumor02, to collect more data on the use of Enhertu in patients with a broad range of HER2-positive tumors that were unresponsive to currently available therapies. The study was also designed to allow for the possibility of a regulatory filing, if those data turned out to be positive. 

The Enhertu results were, indeed, what Daiichi and AstraZeneca had hoped to see: confirmed tumor shrinkage in 51% of study participants, with a median duration of response of 19.4 months. These data, supported by results from two additional studies, formed the basis of the tumor-agnostic application that was granted an accelerated approval by the FDA on Friday. The companies will be required to confirm patient benefit in future studies. 

Paolo Tarantino, a medical oncologist at Dana-Farber Cancer Institute, said the ability to treat a large population of patients with HER2-directed tumors is “some of the biggest news” in the cancer field for quite some time. 

“This is a major change, and a major opportunity, to treat patients with cancers, especially gynecological cancers, where there was no previous antibody-drug conjugate approved,” said Tarantino. “It’s going to take some time, but this will spur broader testing for HER2 tumors.” 

Were you forwarded this email? Subscribe to STAT+ to get it in your inbox.

Wall Street

A 'stale' biotech market in search of interest rate cuts 

Earlier this week, I chatted with Jared Holz, health care strategist at Mizuho Securities, to get his perspective from the intersection of Wall Street and biotech. Here’s an edited excerpt of our conversation. 

There was a lot of talk about the sector benefiting from the Fed signaling interest rate cuts, but it doesn't seem like we've seen that so far. Lower interest rates were also supposed to entice generalist investors to return to biotech, but has that happened either?

I don't believe there's been any influx of generalist investors into biotech this year. There was a little bit last November and December as a mean-reversion trade to get long the sector, but I don’t think we've seen any follow through subsequent to that. 

On rates, they're really not coming down, or they're certainly not coming down fast enough. The fact that we're going to have higher rates for what seems like the majority of the year — maybe we get a couple cuts next year — I just don't know if that's enough to appease investors.

It feels like the sector is moving sideways. 

Yeah, it feels a little bit stale in a way. It’s not a huge year for catalysts on a relative basis. There are a few. But it seems more of a year of shoring up balance sheets and execution versus the kind of discrete events that are going to really propel the sector much higher. 

What are the catalysts, if any, that are generating the most investor attention, based on the conversations you have with clients? 

Off the top of my head, it's going to be Alnylam, Insmed, and Structure Therapeutics. In large cap, Amgen and its obesity data later in the year. That’s really it. I mean, there are a lot more but they’re smaller market caps and maybe more esoteric. I don’t think it’s a make-or-break year from the standpoint of binary events. 

We’re moving into the first-quarter earnings season. What are you listening for? 

I'm focused on commentary around drug pricing and various strategies to offset it. Companies like Pfizer, Bristol Myers Squibb, and Novartis have talked about this in the past, but I think it's going to be a recurring theme. I want to hear what companies say about the Biden administration actually adding to the IRA [drug pricing] list later in the year — whether that's a possibility. 

And then I’m listening for how companies talk about internal versus external R&D, and how that might impact biotechs and budgets. After that, we're going to start talking about the election and whether, or how, a Trump administration may influence pharma. Investors are getting a bit more nervous about that. 

Where are all the M&A deals we were promised? 

You’re right, the quantity of deals so far this year is probably a bit below expectations, but then remember, the fourth quarter was fast and furious. It’s hard to be too critical of large-cap pharma when each of them have done a couple of deals over the past few quarters, especially with Abbvie and Bristol each doing multiple deals over a one-month period. We probably got overzealous in terms of what the pacing of deals might look like this year.

Addendum: As this newsletter was being put to bed, the government said a key measure of inflation was higher than expected in March, raising more questions about when, or even if, the Federal Reserve might cut interest rates. I pinged Jared for a follow-up comment. 

This is likely to have a negative impact across most small-cap equities including biotech, given significant financing needs and the capital constraints that this may lead to. On the flip side, a more challenging macro backdrop could also accelerate M&A timelines to the extent that selling to large-cap pharma is viewed as a preferred pathway versus building a business independently. 

Hours later, Vertex Pharmaceuticals announced the acquisition of Alpine Immune Sciences for $4.9 billion. Biotech is so back!