In 2020, 10.6 million Americans over 65 were still in the workforce. By 2030, this number is projected to skyrocket to 16 million. Meanwhile, by 2050, the global elderly population is expected to increase by more than 2 billion. [1][2]
Yet while people are living longer, more active lives, they’re not necessarily living better. The reason is senescence – various time-related processes at the cellular level that lead to the deterioration of the body and its diminishing ability to heal. Cancer, for example, is often spurred on by these processes, with 7 in 10 cancer-related deaths occurring in people 65 years and older.[3]
Elderly people shoulder the burden of cancer, but only 24 percent of participants in cancer trials registered with the US Food and Drug Administration (FDA) are 70 years or older, while less than 10 percent of patients in this age group participate in National Cancer Institute (NCI)-sponsored clinical trials.[4]
A broader systemic issue
In my view, this acute problem is symptomatic of a broader systemic issue with the way therapeutics are discovered, designed, and developed. The majority of modern therapeutic innovations in oncology are discovered using a biological target-based approach, wherein drug developers identify the targets they believe are integral to the function of the disease and then design potential therapeutic agents to disrupt or modify those targets. These potential agents are then studied in vitro and in vivo models to determine which are most effective against the target. Once the agent or agents with the highest probability of success are determined, researchers move them from the lab to clinical trials in humans.
While this process is necessary and has led to many life-saving treatments, it is also fundamentally biased against marginalized populations like the elderly. Given that drug developers are incentivized to pursue agents with higher probabilities of success, and because much of that success hinges on the patients’ ability to tolerate treatment, clinical trials naturally tend to exclude populations with underlying biological characteristics that make them more difficult to treat.
As such, drugs that make it to regulatory approval have often been evaluated for safety and efficacy in younger, healthier patient populations. However, aging changes the way the elderly patients’ bodies absorb, metabolize, and distribute drugs, which may decrease the efficacy of treatment or preclude them from receiving potentially curative therapeutic options like chemotherapy due to intolerable toxicity.[5]
Improving the enrollment of elderly patients
Efforts have been made to improve the enrollment of elderly patients in clinical trials. In March 2020, The U.S. Food and Drug Administration (FDA) issued “Inclusion of Older Adults in Cancer Clinical Trials Guidance for Industry” to provide recommendations for the inclusion of patients 65 and older in the clinical trials of cancer drugs. This is a good start, but if our ultimate goal is to improve therapeutic outcomes for all patients, then focusing only on inclusion could be self-defeating. We also need to think about new scientific approaches to drug discovery and development that produce therapeutic candidates that are more broadly applicable and less toxic.[6]
I was trained as a physicist, which is why, early in my career, I initially approached cellular biology as a physics problem. Rather than taking a target-based approach, I asked questions that zeroed in on the fundamentals of cancer. For example, I asked: “Can we impact the behavior of cells using physical science? Can we design nanoparticles that can act at the subcellular label as active agents against disease? Can we lean on the universal principles of physics to develop scalable treatments that depend less on the biological characteristics of patients?”
I believe that the answer to all of these questions is yes.
Nanobiotix is developing a potential first-in-class radioenhancer called NBTXR3. Composed of hafnium oxide nanoparticles, our radioenhancer is injected into solid tumors and then activated by radiotherapy. [7] Our nanoparticles have a high electron density, which allows a tumor that contains NBTXR3 to absorb more energy than could otherwise be absorbed by the cancer cells alone. This controlled concentration of energy leads to greater localized cancer cell destruction. Moreover, recent preclinical and clinical data suggest that NBTXR3 may also prime an immune response against the target tumor as well as metastatic tumors throughout the body.
Clinical studies
In October 2021, we presented preliminary data from our phase 1 study evaluating radiotherapy-activated NBTXR3 for elderly patients with locally advanced head and neck cancer at the 2021 Annual Meeting of the American Society for Radiation Oncology (ASTRO). In terms of safety, these data showed that our treatment was well-tolerated at all dose levels. From an efficacy perspective, the data showed a best-observed target lesion objective response rate of 85.4 percent, a best-observed target lesion complete response rate of 63.4 percent, median overall survival of 18.1 months, and median progression-free survival of 10.6 months in 41 eligible patients.[8]
In January 2022, we announced the first enrollment of a patient in NANORAY-312, a global phase III study evaluating radiotherapy-activated NBTXR3 in elderly patients with locally advanced head and neck cancer who are ineligible for platinum-based chemotherapy. This pivotal study aims to enroll 500 elderly patients across sites in the United States, Europe, and Asia. To date, 139 sites have qualified across 30 countries. The primary endpoint of the study is progression-free survival. Secondary endpoints include overall survival, response rates, and quality of life. Nanobiotix expects a futility analysis at 18 months and an interim readout 30 months after the first patient is randomized.
Today, elderly people bear an outsized proportion of the cancer burden – but science can help. We believe the universal principles of physics can lead to innovative treatments that are both more broadly applicable and less toxic. By designing treatments in this way, we can hope to expand therapeutic possibilities for elderly patients.
Clinical trials
NBTXR3 With or Without Cetuximab in LA-HNSCC – NCT04892173
Reference
[1] Civilian labor force participation rate by age, sex, race, and ethnicity. Employment Projections. U.S. Bureau of Labor Statistics; Office of Occupational Statistics and Employment Projections. Online. Last accessed on February 1, 2022
[2] Shenoy P, Harugeri A. Elderly patients’ participation in clinical trials. Perspect Clin Res. 2015 Oct-Dec;6(4):184-9. doi: 10.4103/2229-3485.167099. PMID: 26623388; PMCID: PMC4640010.
[3] Cinar D, Tas D. Cancer in the elderly. North Clin Istanb. 2015 Apr 24;2(1):73-80. doi: 10.14744/nci.2015.72691. PMID: 28058345; PMCID: PMC5175057.
[4] Sedrak MS, Freedman RA, Cohen HJ, Muss HB, Jatoi A, Klepin HD, Wildes TM, Le-Rademacher JG, Kimmick GG, Tew WP, George K, Padam S, Liu J, Wong AR, Lynch A, Djulbegovic B, Mohile SG, Dale W; Cancer and Aging Research Group (CARG). Older adult participation in cancer clinical trials: A systematic review of barriers and interventions. CA Cancer J Clin. 2021 Jan;71(1):78-92. doi: 10.3322/caac.21638. Epub 2020 Oct 1. PMID: 33002206; PMCID: PMC7854940.
[5] Cancer Care Decisions for Older Adults. CancerNet.com. Online. Last Accessed on February 1, 2022.
[6] Inclusion of Older Adults in Cancer Clinical Trials Draft Guidance for Industry. U.S. Food and Drug Administration. Online. Last accessed on February 1, 2022.
[7] Hafnium Oxide: The Nanoparticle You’ve Probably Never Heard of May Help Millions of People With Cancer.Levy L. Nanobiotix. Online. Last accessed on February 1, 2022.
[8] Tourneau C, Calugaru V, Takacsi-Nagy Z, et al. Phase I study of functionalized hafnium oxide nanoparticles (NBTXR3) activated by radiotherapy in cisplatin-ineligible locally advanced HNSCC patients. J Clin Oncol. 2021;39(suppl 15):6051. doi:10.1200/JCO.2021.39.15_suppl.6051
Featured image: Nanobiotix. Photo courtesy: © 2021 – 2022. Nanobiotix. Used with permission.
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