What Is a ‘Tolerable’ Dose? AACR-Industry Roundtable 2025 Examines Dose Optimization
“The right dose differentiates a poison and a remedy.”
These words of wisdom were delivered by the German physician and alchemist Paracelsus in the 16th century, and they were invoked once again during this year’s AACR-Industry Roundtable, which centered on finding the right dose for cancer therapies.
As the pinnacle event of the AACR Sustaining Membership Program, the annual AACR-Industry Roundtable convenes representatives from industry, along with speakers from academia, patient advocacy, and federal agencies to discuss timely issues facing cancer research and patient care.
The AACR-Industry Roundtable was conceptualized in 2000 by then-AACR President Daniel D. Von Hoff, MD, FAACR, and has become a recurring event to bring together diverse perspectives from industry and beyond to brainstorm opportunities to propel advances for the benefit of patients, said AACR Chief Executive Officer Margaret Foti, PhD, MD (hc), in her welcome remarks.
“AACR’s vision is to utilize cancer science and medicine, technology, and policy to fundamentally change the face of cancer for all populations,” Foti said, noting that the AACR collaborates with multiple sectors, including industry, to advance its mission to prevent and cure all cancers.
The 2025 iteration of the AACR-Industry Roundtable, held October 8-9 in Philadelphia, focused on dose optimization and was chaired by AACR President-Elect Keith T. Flaherty, MD, FAACR.
“Our agenda over the course of these two days is to deliberate on the dose-response relationship and its impacts on toxicity and efficacy for different therapeutic modalities,” said Flaherty, who is the director of clinical cancer research and the Richard Saltonstall endowed chair in oncology at Mass General Cancer Center, as well as a professor of medicine at Harvard Medical School.
As explained by Flaherty, the need for new dose optimization strategies has been raised by many clinicians, researchers, regulatory agencies, and patients in recent years. Because commonly used dose-finding methods were originally developed for chemotherapy drugs, they are not always applicable to newer therapeutic classes. For chemotherapy, efficacy typically increased with dose, so finding the highest dose that patients could tolerate (the “maximum tolerated dose”) became standard practice. For many modern treatments, however, efficacy plateaus after a certain dose, so administering more of the drug does not necessarily improve the patient’s outcome. Moreover, the traditional approach of finding the maximum tolerated dose does not account for the longer treatment courses of many modern drugs.
The undue emphasis on higher doses has consequences for both patients and drug development, said AACR Immediate Past President Patricia M. LoRusso, DO, PhD (hc), FAACR, the associate director of experimental therapeutics at Yale Cancer Center. She noted that higher doses can lead to greater toxicity and poor treatment adherence, which can ultimately lead to a drug’s withdrawal from the market or can prevent it from being approved in the first place.
In response to the concerns surrounding current methods of dose optimization, the U.S. Food and Drug Administration (FDA) launched Project Optimus in 2021 with the goal of educating, innovating, and collaborating with stakeholders to develop a dose optimization strategy that maximizes tolerability and efficacy.
“If patients can’t live on the dose, they won’t stay on the drug”
Underscoring the importance of this initiative were the perspectives offered by cancer survivor and patient advocate Manju George, PhD, who was diagnosed with early-onset rectal cancer at age 44. Her original treatment plan was to undergo surgery followed by adjuvant FOLFOX chemotherapy for six months. But after learning about a clinical trial evaluating a different chemotherapy regimen (CAPOX) that would be administered for three months instead of six, George opted to enroll in the trial.
“If there was a chance I could get less chemo, that’s what I was going to do,” she said.
George described the three months of CAPOX treatment as extremely difficult, highlighting the severe fatigue and nausea, hand-foot syndrome, and memory loss that she experienced. Now, eight years later, she remains cancer-free.
Given how gruesome the three months of chemotherapy were, George noted that she is happy that she did not have to undergo six months of treatment as was the original plan. She explained that a dose is only optimal if it is the most efficacious dose that real-world patients will adhere to.
“If patients can’t live on the dose, they won’t stay on the drug,” she said.
Challenges Facing the Field
Every Patient Is Unique
The goal of dose optimization is to find a dose that is effective and tolerable. But, as noted by Mark G. Kris, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, what is tolerable for one patient may not be tolerable for another. He explained that there is no accepted definition of tolerability, and he argued that the frequently used Common Terminology Criteria for Adverse Events (CTCAE) scale is not an appropriate metric for tolerability.
As an example, he pointed to grade 2 adverse events. Despite being considered “tolerable” by many clinical researchers, this category includes symptoms such as vomiting, six extra bowel movements per day, and the need for intravenous hydration—symptoms that many patients may not consider tolerable, especially if they are experiencing them for many months or years, Kris noted.
Because of the subjective nature of tolerability, Kris emphasized that the only way to know if treatment is tolerable to a patient is to ask them.
Just as each patient may have a different threshold for tolerability, each patient also has their own wishes and risk tolerance. Some patients may want a higher dose while risking greater toxicities, and others may want a lower dose while risking lower treatment efficacy.
Moreover, patients may be hesitant to try a different dose than what has been approved and shown to be effective, which can make evaluating alternative dosing after approval difficult. Because of this, presenters emphasized the importance of optimizing the dose prior to approval.
Data Interpretation
On the research side, participants raised questions associated with interpreting the efficacy data that come from dose-reduction trials. Many noted that because these trials are often smaller and conducted at a single institution, it can be challenging to compare efficacy results with those from the larger, multicenter trial that led to the approval of the original, higher dose.
Regulatory Challenges
There are also regulatory hurdles when it comes to dosing optimization. In instances where an investigational agent is being tested in combination with an approved chemotherapeutic, the FDA may require that the approved dose for the chemotherapy is used in the clinical trial—even if a different dose is widely used in clinical practice. This can lead to a cycle in which new combination regimens propagate the use of a chemotherapy dose that has been found to be nonoptimal in the real world. (To address outdated dosing for older oncology drugs, the FDA launched Project Renewal in 2018 to review published data and update approved labels as needed. The AACR provides scientific expertise to this initiative.)
Participants also expressed concern about the prospect of “false precision”—i.e., striving for a perfection that does not exist. When will a dose be considered sufficiently optimal? How granular will the fine-tuning of a dose become?
They also questioned whether dose optimization is needed for each new indication or if dosing data could be extrapolated across cancer types, stages, or treatment lines to reduce the number of trials needed.
Financial Factors
Financial factors are another obstacle that companies face. One speaker noted that oncology is unique in the degree of competition, the need for speed, and the life-and-death impacts of subefficacious dosing. Some attendees expressed concern that added regulatory requirements would end up “hurting the little guys” due to the extra cost and resources needed to conduct dose optimization trials. Additionally, some explained how dosing modifications could complicate marketing if the modification occurs after the drug’s price has already been set.
Considerations for Specific Treatment Modalities
AACR Chief Scientific Advisor William N. Hait, MD, PhD, FAACR, who reminded attendees of Paracelsus’ famous remarks, moderated a session that explored the unique challenges associated with different therapeutic classes.
Antibody-drug Conjugates
Because of their targeted approach, antibody-drug conjugates (ADCs) are expected to lower off-target effects on healthy cells. However, Anthony Tolcher, MD, chief executive officer and cofounder of NEXT Oncology, noted that despite immense progress with this class of therapeutics, the risk of severe toxicities remains, with interstitial lung disease, hematologic toxicity, neuropathy, and rash being common during treatment with ADCs.
The safety of ADCs relies on many factors, including the target, antibody construct, linker stability, payload type, and how much ADC is administered to the patient. Scientists continue to explore ADC structure modifications to lessen toxicities, and Tolcher implored clinical researchers to focus on the part they can control—the dose.
“The dose is still the easiest factor to analyze and adjust,” he said.
He argued that the widespread use of total body weight for ADC dosing is flawed given that most of the infused ADC molecules are retained in the blood where they can cause hematologic toxicity and circulate primarily to tissues with higher vasculature, such as the lung, to cause other common toxicities.
Because the relationship between blood volume and weight is not linear, dosing based on total body weight can be especially problematic for patients with obesity. These patients may be unnecessarily administered a very high dose and therefore face a greater risk of toxicity due to the higher concentration of ADC in their blood. Further, the mathematical equations used to calculate blood volume based on a patient’s weight and other factors do not account for the ascites or edema that often occur in patients with cancer.
Alternatives to total body weight offered by Tolcher include ideal body weight (a surrogate for lean body mass), adjusted ideal body weight (which accounts for disease- or drug-specific factors), body surface area (which avoids weight all together), and capped dosing (where the dose cannot exceed a certain level)—but he cautioned that each of these has its own issues.
While the optimal approach to dosing for ADCs is still under debate, Tolcher argued that “it is wrong to not always challenge total body weight for ADC dosing.”
Small-molecule Inhibitors
Christine M. Lovly, MD, PhD, the Ingram associate professor of cancer research at Vanderbilt-Ingram Cancer Center, explained that while small-molecule inhibitors have transformed cancer care, prolonged exposure to these therapeutics is associated with side effects, including many that would not be expected based on their mechanisms of action. These side effects can interfere with a patient’s quality of life and lead to them discontinuing the drug, Lovly said.
Acquired resistance to small-molecule inhibitors is common, so patients often receive additional therapeutics, either in combination with the inhibitor to prevent resistance or as subsequent treatment after resistance develops. Exposure to multiple therapeutics introduces a greater risk of toxicities, Lovly explained.
Another challenge is that many adverse events take years to emerge and may not be identified during the time frame of an early-phase clinical trial.
She argued that optimizing dosing for small-molecule drugs will require a deeper understanding of each drug’s target, including its involvement in signaling pathways and any potential compensatory pathways. Enhanced real-world monitoring of acute and long-term toxicities is needed, as is information from each patient about how well they are tolerating the drug.
Radionuclides
For radionuclides, Frank I. Lin, MD, head of the Targeted Radionuclide Therapy Section of the Molecular Imaging Branch of the National Cancer Institute, suggested that the issue may not be overdosing, but rather, underdosing. So far, this emerging class of therapeutics has not shown great efficacy on its own, he explained, and part of the reason may be that patients are not receiving a high enough dose.
The organ dose limits for radionuclides were set by extrapolating results from external beam radiation therapy, which Lin argued is not necessarily applicable to radionuclides. He pointed to the very low frequency of dose-limiting toxicities in patients treated with radionuclides as a reason that the dose could be raised to increase efficacy.
Since this therapeutic modality exposes patients to potentially harmful radiation, it is critical that the dose be optimized such that it maximizes radiation to the tumor while minimizing it to organs, said Lin. He suggested that incorporating radioprotectants may be beneficial, and he cautioned against conducting dose escalation in patients with long life expectancy given the potential long-term effects of radiation exposure.
Bispecific Antibodies for Multiple Myeloma
Irene Ghobrial, MD, senior vice president for experimental medicine and a professor of medicine at Dana-Farber Cancer Institute, examined considerations for dosing bispecific antibodies for the treatment of multiple myeloma.
When a bispecific antibody is given as a monotherapy, the full dose is required during the first administration for optimal efficacy, Ghobrial explained. However, given that the treatment is typically continued until disease progression, she noted that there may be opportunities to adjust subsequent doses to mitigate toxicities and potentially even lower the risk of acquired resistance.
Doses could be administered less frequently, for a fixed duration instead of indefinitely, and/or during earlier stages of disease, Ghobrial said, adding that each approach has shown promise in patients. Less frequent dosing has been shown to reduce infection incidence without compromising efficacy of the treatment, and using bispecific antibodies in earlier treatment lines or earlier stages of disease appears to improve efficacy and reduce toxicity.
She also raised several important questions—whether patients who test negative for minimal residual disease can discontinue bispecific antibody treatment, whether measuring a patient’s immune landscape prior to treatment could inform therapeutic dosing, and whether shorter duration of treatment could help prevent acquired resistance given that resistance is associated with prolonged therapy.
Opportunities to Overcome Challenges
As Flaherty closed the 2025 AACR-Industry Roundtable, he acknowledged the many challenges facing dose optimization but encouraged attendees to think outside the box and find new ways to address the issues.
“I recognize there are some barriers,” he said. “That said, there is always a way to break things down into small, tractable starting points.”
Throughout the event, speakers and attendees expressed optimism about the field’s ability to overcome hurdles and offered insights into areas that could be addressed as first steps.
Spirited discussions during three breakout group sessions provided ideas on how to approach aspects such as immune-mediated toxicities, mild and moderate toxicities, and protracted therapies. Participants agreed on the need to “get the dose right the first time” (i.e., prior to approval) and the importance of validated biomarkers to predict efficacy and toxicity, as well as to allow for individualized dosing. Participants encouraged enhanced data sharing across institutions and companies to facilitate the identification and validation of biomarkers pertaining to toxicity.
During his presentation, Kris proposed greater reliance on patient-reported outcomes and formalizing the timing of chronic toxicity assessments. He also suggested using the patient’s symptoms as the primary readout instead of relying only on lab tests, which measure physiological changes that may not always lead to symptoms.
To improve the collection of data on long-term adverse events, attendees discussed the potential of wearable devices that could monitor and report a patient’s symptoms in real time. Offering the patient perspective, George said this would help reduce the burden on the patient to keep track of their symptoms and remember to report them to their physician. Further, discussants added that artificial intelligence (AI) tools could help analyze the incoming data and flag patients experiencing severe side effects.
AI could also be used to simulate the effects of dosing changes as one approach to supplementing real-world data, said Gideon Blumenthal, MD, the vice president of clinical development at Merck and one of the founding directors of the FDA Oncology Center for Excellence. During his presentation, Blumenthal also encouraged researchers to take advantage of adaptive clinical trial designs, which allow dosing to be modified as data on adverse events and efficacy accrues.
Another idea was to require dosing de-escalation regimens as part of approval and include these within a therapeutic’s prescribing information. The approved de-escalation should be presented as a standard part of treatment since many patients and physicians may be reluctant to lower the dose if it were presented as optional, Kris noted. Real-world data collected after approval could be analyzed to confirm the utility of the approach.
Bringing the Field Together to Drive Progress in Dose Optimization
The 2025 AACR-Industry Roundtable is just one of the many ways the AACR is helping drive meaningful progress toward optimized dosing. Last year, the AACR and the FDA cohosted the FDA-AACR Public Workshop: Optimizing Dosages for Oncology Drug Products to convene regulators, researchers, health care providers, patients, advocates, and others to discuss this important topic and ideas to move the field forward.
Presenters and panelists of that workshop—including chairs LoRusso and Stacy Shord, PharmD, of the FDA—collaborated to publish three articles in the AACR journal Clinical Cancer Research summarizing the proposed quantitative methods, clinical trial designs, and statistical analyses that researchers could implement to improve dose optimization. (A recent blog post details the strategies proposed in these three articles.)
The workshop’s chairs also noted that dose optimization for certain populations, such as pediatric patients, requires unique considerations. Because children may metabolize drugs differently than adults, LoRusso explained that understanding a drug’s pharmacology and its impacts on biological processes in patients of various ages is critical to ensuring that doses are safe and effective for the target population.
Beyond drug metabolism, age-related factors also influence drug tolerability. Older patients, for example, are more likely to have comorbidities and to be on additional medications, both of which can increase their risk for toxicities. Further, their physical condition often makes it harder to withstand the side effects of cancer treatment. Unfortunately, patients who are 70 years of age and older are underrepresented in clinical trials, which means that doses are typically determined based on results from patients younger than 70 years. Some older patients may require lower doses than what has been approved, while others may be able to tolerate more aggressive treatment.
As the field continues to make strides in treating cancer using innovative methods, careful consideration of the many factors that impact tolerability will be key to ensuring that approved treatments are not only effective, but also safe—for every patient.
