In a major shift, cancer patients and doctors are uniting to question the necessity of enduring harsh side effects caused by powerful drugs. As advances in cancer treatment enable millions to live longer with incurable cancers, the movement aims to radically transform the way new cancer drugs are tested. The US Food and Drug Administration (FDA) has urged drugmakers to prioritize finding the lowest effective dose, even if it means investing more time in research and development.
Traditionally, cancer drug development has focused on determining the maximum tolerated dose, a practice that often results in severe side effects for patients. To accelerate chemotherapy drug testing, researchers have historically increased the dosage for a small number of patients in early studies to determine the highest dose tolerated. However, this approach may not be suitable for newer, more targeted cancer drugs.
Unlike chemotherapy, which acts as a battering ram in its aggressive approach, newer cancer drugs function more like a front door key. They specifically target cancer cell growth drivers, such as mutations, or enhance the body's immune system to combat the disease. Consequently, lower doses of these drugs may be sufficient to achieve the desired results.
Dr. Lillian Siu, head of cancer drug development at the Princess Margaret Cancer Centre in Toronto, explains, "You might only need a low dose to turn off that cancer driver. If you can get the same bang for your buck, why go higher?"
In response to growing calls from patients and advocates for more tolerable cancer drugs, the FDA has launched a program called Project Optimus. The initiative encourages drugmakers to include a greater number of patients in early dose-finding trials to obtain more accurate data on the effectiveness of lower doses. "The motivation for the project stems from the increasing demand to develop cancer drugs that are more tolerable," states FDA spokesperson Chanapa Tantibanchachai.
Many new cancer drugs were developed using the maximum tolerated dose strategy, leading to issues when patients experience severe side effects, causing them to skip doses or discontinue treatment. Some drugs have had their recommended doses officially lowered post-approval, while individual patients often require personalized dose adjustments. According to a recent study, nearly half of the patients in late-stage trials of 28 targeted therapy drugs needed dose reductions.
Dr. Patricia LoRusso, head of drug discovery at the Yale School of Medicine, acknowledges this approach: "We were pushing the dose as high as we could go. You get side effects, and then you have to stop the drug to recover from the side effects, and the tumor can grow."
However, finding the optimal dose for all patients remains a challenge due to varying factors such as liver and kidney function. Balancing the need to avoid underdosing against the risk of severe side effects is a delicate task. "The challenge is: Where is the sweet spot?" says Dr. LoRusso.
(With inputs from AP)
Dr. Julie Gralow, Chief Medical Officer of the American Society of Clinical Oncology, is planning a 500-patient study to test whether lower doses of two drugs for metastatic breast cancer can be equally effective. The study will compare two strategies: starting with the full dose and then reducing it for side effects versus starting with a lower dose and increasing it if the patient tolerates it well.
The demand for lower doses has been driven by patients with metastatic breast cancer, including the Patient-Centered Dosing Initiative, which has conducted influential surveys among patients and cancer doctors. Lesley Kailani Glenn, a 58-year-old from Central Point, Oregon, stresses the importance of a better quality of life during treatment: "We want to try to live the best that we can, knowing that treatment is never going to stop."
Through Project Optimus, the FDA aims to encourage drug developers to conduct more head-to-head dosing comparisons. However, this may result in a longer research and development process. Dr. Alice Shaw, head of early cancer drug development at Novartis, explains, "That will require more patients, and then, as you can imagine, also will require more time to identify, enroll, and treat those patients." Shaw emphasizes the need to balance the added time against the urgent demand for new cancer drugs.
Ultimately, finding the right dose early on will result in more effective treatments. "If the patients are not taking the drug, then it's not going to work," states Dr. Timothy Yap, a drug developer at MD Anderson Cancer Centre in Houston.
