As antibody-drug conjugates advance and move into earlier lines of treatment, drug developers have to build gentler therapies that don’t just extend survival but improve it.
The last thing a patient wants to do is stop treatment for cancer. But sometimes, when side effects become too burdensome, that’s a decision that Archana Ajmera has to help her patients make.
Ajmera, an adult nurse practitioner at UC San Diego Health, treats patients from the first all the way through to later lines of therapy with antibody-drug conjugates (ADCs)—the buzzy, red-hot oncology modality that has drawn myriad pharma deals in recent years. The biopharma industry is keen to improve on the model set by industry frontrunners like AstraZeneca and Daiichi Sankyo. But taking a step back, patients need more than just incremental improvements in efficacy, according to a panel of experts at the BIO International Convention in June.
“The low hanging fruit for ADCs—late-line therapies in areas of very high unmet need and large tumor types—that’s already gone,” said Sabeen Mekan, chief medical officer at Zymeworks. “If you’re going into the next round, you’ve got to build better agents.”
Ajmera offered a few hypotheticals from her experience treating patients with cancer who endure therapy with an ADC. Interstitial lung disease, a known risk of the drugs, can cause shortness of breath. A patient may experience this walking their grandkid to school, she said. Or if a patient experiences neutropenia—low levels of a type of white blood cell—they may be at risk by attending their grandchild’s birthday.
Patients are so desperate to stay on therapy that sometimes they withhold information from their doctors, Ajmera said. This can delay effective interventions.
And difficult treatments can leave patients with lifelong, challenging consequences even if they survive their cancer. Mo Trikha, CEO of Kivu Bioscience, wants future clinical trials to consider “wellness” as a factor in improving survival.
“I have to change my own vocabulary every time I think about a clinical trial,” he said during the panel. “What’s the statistical design of prolonging overall survival? I think it isn’t about increasing lifespan, I think it’s about improving wellspan.” Trikha added that he doesn’t want patients to live longer but with long COVID–like symptoms or blurred vision.
Clinical trials should be designed with overall health in mind, he continued. “It’s the wellness that we should be in the business of.”
While Jakob Dupont, executive partner at Sofinnova Investments, agreed that ADCs need to be easier on patients, he clarified that it’s not a choice between safety and efficacy.
“If you have a kinder, gentler ADC, if it’s more tolerable, those patients are going to be able to stay on drug. You’re not going to need to do those reductions,” he said. Patients will feel better while getting treatment and have better outcomes overall.
ADCs were developed as a way to make chemotherapy more targeted to boost efficacy and hopefully cut down on some of the nasty side effects. The drugs combine a monoclonal antibody to open the door with a cytotoxic drug, such as chemotherapy, to attack cancer cells, and a linker protein to connect them. Biotechs, like Kivu and Zymeworks, are working on all parts of this equation to find improvements in the model.
“They have represented a revolution, and we are living, I think, through the golden age of ADCs right now,” Dupont said.
The next generation of therapies needs to double down on the mission to improve on chemotherapy’s many flaws, particularly as ADCs move to earlier lines of treatment, Mekan added.
“I don’t think it’s an either-or efficacy or safety question. It’s a both question,” she said.
Dupont would like to see ADCs replace traditional chemotherapy altogether, if possible, by moving to front line treatment.
Imagining a better ADC
So what’s to come? The panelists pointed to advancements in linkers, finding new payloads and different chemotherapy agents. Right now, just two chemo agents—either a TOP1 inhibitor or a microtubule inhibitor—are used for existing therapies, Dupont noted.
Existing linkers were prone to deconjugation, according to Merck’s Michael Seganish, a scientist in the oncology leader’s discovery chemistry group—meaning they would fall off the antibody and cause unwanted side effects. Chemists like Seganish have been finding new ways to stabilize the linkers to ensure the payload gets where it is supposed to.
“What you’re effectively doing by making the ADC is taking a well-behaved antibody and sticking a very greasy linker payload on it,” Seganish explained. New advances have stripped away the side effects, leaving just the safety profile of that well-behaved antibody.
Trikha wants treatment with an ADC to be easier overall on patients, with less potential for hospitalization. This will open up treatment to centers outside of major cities, he said.
Capitalizing on the recent excitement around Revolution Medicines’ achievement in pancreatic cancer, Dupont said that one day, a pan-RAS inhibitor could serve as the payload in an ADC. That could even open up the door for better combination opportunities with immunotherapy, he added.
But that’s just for cancer. More and more these days, drugs are being moved from the oncology space into autoimmune diseases. Dupont sees an exciting opportunity for ADCs in this space using a steroid payload instead of chemotherapy. He has even heard suggestions that ADCs could one day be used for cardiovascular disease.
“For ADCs,” he said, “the limit is going to be our imagination.”
