UB chemist who shed light on J&J’s newly approved chemo-free lung cancer drug calls it ‘impressive one-two punch’

BUFFALO, N.Y. — Nearly two years ago, University at Buffalo medicinal chemist David Heppner’s team published the first three-dimensional model of Johnson & Johnson’s chemotherapy-free lung cancer drug, lazertinib. 

Last week, the U.S. Federal Drug Administration (FDA) approved a therapy involving lazertinib to treat non-small cell lung cancer patients who have a key gene mutation.

The therapy combines lazertinib with another J&J drug, Rybrevant, and reduces the risk of disease progression or death by 30% compared to the current leading chemotherapy-free treatment, AstraZeneca's osimertinib.

“The co-dose of lazertinib and Rybrevant is really an impressive one-two punch,” says Heppner, PhD, Jere Solo Assistant Professor of medicinal chemistry in the UB College of Arts and Sciences. “Lung cancer has the highest mortality across all cancers, so to potentially extend someone’s life by what amounts to an additional seven months is pretty remarkable. This is one of the most optimistic therapy regimens that we've seen in advanced lung cancers.”

Heppner was the lead author on the study published in November 2022 by ACS Medicinal Chemistry Letters that detailed lazertinib, which will be sold under the brand name Lazcluze.

Heppner explains how lazertinib works, why J&J has combined it with Rybrevant, and what's next for the fight against lung cancer.

First, how were you able to study lazertinib before it was FDA approved?

Lazertinib has been approved and available in South Korea under the brand name Leclaza since 2021. Whereas companies don’t typically want to reveal the pros and cons of a drug, academic labs like ours at UB are unencumbered by those kinds of corporate guidelines. 

Determining the three-dimensional structures of drugs is highly informative within the drug development community, and putting that information out there serves our community better.

What did you learn about lazertinib?

Our study essentially unlocked the puzzle of why lazertinib alone performs better than osimertinib, which is sold under the brand Tagrisso and has been approved since 2015.

Both these drugs target the epidermal growth factor receptor (EGFR), a protein that helps cells grow and where a mutation can make cells grow too much, creating a tumor. Crucially, these drugs are designed to specifically affect cancer cells with mutated EGFR genes and do not impact healthy tissues. Chemotherapy lacks such a specificity and will affect the tumor cells as well as the healthy tissues.

They even bind to the mutated EGFR genes fairly similarly, but lazertinib binds with greater affinity, increasing potency. The difference is lazertinib’s structure, rigidified into the active binding mode by unique interactions within the drug molecule.  

So, if you were designing a new drug in this area, this rigid quality is very important.  

Why did J&J combine lazertinib with Rybrevant?

The clinical trial results published earlier this year in the New England Journal of Medicine found that although lazertinib provided better survival rates than osimertinib, the difference wasn’t massive. 

That was partly due to a related cancer-causing gene, known as cMET, that allows lung tumors to become resistant to drugs like lazertinib and osimertinib. 

Rybrevant, a major asset in J&J’s repertoire, is an antibody that targets both EGFR and cMET, so by combining it with lazertinib, this resistance pathway can be blocked.

The Rybrevant-Lazcluze therapy’s best quality is that it’s very prescient and gets out ahead of potential mutations and resistance. I like to say that the war on cancer is not solely about coming up with therapies where there presently are none — it’s about trying to thwart how the tumors are going to respond and lead to drug resistance.

How does this FDA approval change lung cancer treatment?

In cancer, especially lung cancer, extending survival is really the name of the game.

Osimertinib already has an average progression-free survival of 16.6 months, but for the Rybrevant-Lazcluze therapy to extend that to nearly two full years, 23.7 months, is significant for patients.

It should be noted that EGFR-mutated lung cancer represents 10 to 15% of lung cancer in the United States, so this new therapy is best for certain lung cancer patients.  

When will it be available?

Physicians can prescribe it right now. It was approved for first-line treatment and appears to be the top option to treat lung cancer patients with these mutations.  

What’s next in the fight against lung cancer?

Well, we know there’s the potential for other forms of resistance to form against the Rybevant-Lazcluze therapy. One of them is a known cysteine-to-serine mutation within EGFR. There’s a lot of drugs being developed across pharma that attempt to cover this specific mutation. Several have entered clinical trials but haven’t reached the end points we’re looking for yet. 

Developing drugs that can overcome a wide range of resistances is going to require a lot of more time in the lab testing out different molecules.

That’s partly why my lab is developing ways to streamline the cancer drug discovery process. We’ve received a $2.5 million grant from the National Institutes of Health, and we’re even using the EGFR and non-small cell lung cancer as a platform to do it.