Cancer drugs were at one time strictly cudgels, hitting a malignancy with the highest dose of chemotherapy a patient could endure. Now, as the industry adds new options like antibody-drug conjugates, targeted therapies and immunotherapies to a market expected to reach more than $484 billion by 2030, experts recognize that oncology treatments should be more targeted.
“In oncology, we've had the chemotherapy paradigm — if you give more chemotherapy or a higher dose, it's more effective, but you also have a higher toxicity," said Dr. David Alsadius, senior medical director and medical strategy lead for oncology at IQVIA Oncology Center of Excellence. "With the targeted therapies that's no longer the case.”
With any of these therapies, finding the right dose is paramount, otherwise the treatment can trigger serious side effects and force patients to discontinue therapy, worsening outcomes.
“The whole trial community is gradually increasing their patient centricity and patient influence.”
David Alsadius
Senior medical director, medical strategy lead for oncology, IQVIA Oncology Center of Excellence
A class of medications known as PI3K inhibitors drew the attention of the FDA after a crop of adverse events occurred following accelerated approval, he said. The FDA, through what it calls Project Optimus, is now pushing pharma companies to determine the optimal dose — the sweet spot between efficacy and tolerability — earlier in the drug development process.
In January 2023, the regulator released draft guidance to help companies get there.
“Historically, several drugs were approved, and when they came into wider use, dose adjustments or dose reductions started to come into play,” said Matt Simmons, senior director of oncology strategy at IQVIA Biotech. “The underpinning of Project Optimus was, let's do that earlier. Let's try and get the dosing right from the start, rather than potentially making many patients suffer unnecessarily with side effects that don't necessarily give them the efficacy benefits.”
Although the FDA hasn’t finalized the guidance, the agency is serious about enforcement, Simmons said.
“It’s clear that they are expecting companies to have those optimizations as part of those earlier-phase studies,” he said.
Why dosing matters
Drugmakers have historically adopted the maximum tolerated dose in oncology, ratcheting up the medication until side effects became intolerable.
“The risk balance of efficacy versus safety has been skewed toward the efficacy side in cancer patients,” Simmons said.
Side effects were seen as an acceptable trade-off for treatment of a serious, potentially life-threatening disease. But today, quality of life is a growing focus.
While targeted therapeutics are less likely to cause dose-limiting toxicities, people often need to stay on these drugs for a long time, making quality of life an important consideration. They can cause side effects from diarrhea to dangerous lung inflammation, forcing people to stop taking them, a problem that can be reduced via better dose selection, Simmons said.
But determining the optimal dose early in the development process is challenging, and the difficulty has only increased as multi-drug treatment plans become more common.
“Optimizing for a single drug, you've got an efficacy dose curve, and you've got a safety dose curve and how they overlap defines where your optimum dose is,” Simmons said. With combination therapy, researchers need to look at the toxicity and efficacy of an interplay of several drugs, which is a sizable challenge.
To be successful, biopharmas need to be diligent about data quality and use statistical modeling to understand the characteristics of the drug and how it behaves at different concentrations and dose levels. Algorithms and AI machine learning models are essential to this process. Better patient selection using advanced disease subtyping can also reduce toxicity by predicting drug response for people who may experience more side effect than treatment.
Despite the challenges related to early dose optimization, establishing the right dose sooner rather than later is better not just for patients, but for pharma companies, because they won’t need to adjust doses in the post-market setting, and they can expect fewer discontinuations and better drug adherence.
“That, in turn, will drive a positive experience in the post-market setting, and also be beneficial for the patients in the long run,” Alsadius said. “So it can be a win-win.”
A lower dose could also reduce manufacturing costs and, potentially, drug pricing. For example, researchers found that if women with breast cancer took two milligrams fewer of Herceptin per kilogram as a maintenance dose, it could save Medicare as much as $810 million a year.
Needed step changes in oncology
In the next 10 years, cancer patients can likely anticipate better outcomes. They can also expect a more patient-centric approach.
“With Project Optimus and the emphasis on diversity and patient-reported outcomes, the regulatory environment is causing sponsors to become more patient centric — not that they don't want to , because obviously that's a good thing,” he said. “The whole trial community is gradually increasing their patient centricity and patient influence.”
Cancer care will also likely become more tailored to the individual.
“I think there's going to be that continuing focus on personalized and precision medicine, looking to understand and then treat an individual's cancer based on their own particular version of that disease, rather than a higher-level organ-based therapy treatment,” Simmons said.
But there is still work to be done. For one, sponsors need to boost trial enrollment to gain broad participation. Adding more participants and increasing diversity, including older adults and other underrepresented groups is crucial to optimizing dosing and outcomes.
Understanding how treatments affect individuals from different backgrounds can help find an effective dose that minimizes the toll it takes on the people who need it.
“We want to run our clinical trials in a population that is representative of the real world and the patients who are going to be receiving that drug when it gets to market,” Simmons said.
