Clinical Research Breakthroughs Defining the Future of Oncology
The 2022 American Society of Clinical Oncology (ASCO) Annual Meeting is one of the largest events for those professionals working in oncology in both clinical practice and research. While there was a significant focus on providing positive outcomes from trials, there were a few major ongoing or recently concluded studies that provided significant research discoveries based on their continued or lack of success.
Preparing for the Future of Oncology Clinical Research, co-authored by PSI’s Dr. Maxim Kosov, Senior Medical Advisor, Operations, and Dr. Victor Zenzola de Toma, Medical Monitor, provides essential insights for sponsors into the trends with the greatest potential to affect clinical trial design and operationalization. Read on to learn more about the general oncology trends to be aware of in 2023.
New insights into the influence of concomitant medications on immune checkpoint inhibitors
Immune checkpoint inhibitor (ICI) therapy is currently a standard of care for many malignancies. Recent findings suggest that the outcomes of ICI therapy may be influenced by concomitant medications that also have immunomodulatory properties, such as corticosteroids and antibiotics. Two study teams presented findings that explored the effects of concomitant use of acetaminophen and the live bacterial product CBM588 on ICI efficacy in cancer patients.
Antoine Italiano (Institute Bergonié, France) assessed the impact of acetaminophen use on immunotherapy efficacy in patients with different types of cancer.i The study showed that detectable plasma acetaminophen levels at treatment onset were associated with a worse clinical outcome in ICI-treated cancer patients and reduced treatment efficacy. Important unanswered questions remain, including the nature of the influence of the previous acetaminophen exposure, whether there is a difference between sporadic and chronic acetaminophen use, and whether there is any influence of acetaminophen on ICI-related toxicity.
The negative association between ICI response and concomitant antibacterial therapy is well defined. Nazli Diman (City of Hope Comprehensive Cancer Center, California, USA) investigated whether concomitant use of the live bacterial product CBM588 (a probiotic strain of bacteria that can restore species of Bifidobacterium to the microbiome) with ICI therapy could facilitate an improved response.ii The study enrolled patients with newly diagnosed metastatic renal cell carcinoma and showed that adding CMB588 to the standard treatment scheme with nivolumab/ipilimumab increased the objective response rate from 20% to 58%. The investigators suggested that CBM588 decreases antibiotic resistance, which is significant given the common use of antibiotics in cancer patients to treat infections.
ctDNA as an Emerging Biomarker
Circulating tumor DNA (ctDNA) was first described in 1948, but the first clinical validation happened only when next-generation sequencing (NGS) technology was introduced in the 2000s.iii The symposium “ctDNA: Dawn of a New Era” at the 2022 conference discussed how this methodology is transforming the field of oncology.
During the past several years, liquid biopsy (detection of ctDNA through a simple blood draw) has gained much attention in clinical practice and clinical research. In May 2022, the U.S. Food and Drug Administration (FDA) released industry guidance on ctDNA testing when developing drugs for early-stage tumors.iv The guidance describes three potential uses for ctDNA:
- Selecting patients for treatment based on molecular alterations
- Monitoring tumor response at the molecular level via minimal residual disease to identify risk of recurrence
- Acting as an early surrogate measure of long-term outcomes
The biggest challenge with ctDNA testing is that researchers still do not know whether intervening after a positive ctDNA result will improve patients’ outcomes like survival or quality of life. Multiple clinical trials aim to address this question, particularly what should be done in the case of a positive (or negative) ctDNA result.
Another therapeutic research focus was on ctDNA testing across multiple tumor types, including head and neck cancer, non-small cell lung cancer (NSCLC), breast cancer, soft tissue sarcoma, and oropharyngeal cancer. Based on the findings from these papers, we can conclude that:
- ctDNA can be used for molecular profiling in patients with advanced solid tumors to guide therapeutic decisions
- ctDNA has the potential to identify patients who have a molecular response to therapy at an early timepoint
- Detection of ctDNA after curative therapy across many tumor types is strongly predictive of the likelihood of recurrence in many cases, and importantly, it occurs before radiographic or clinical progression.
The interpretation of ctDNA-negativity must follow the same pattern as for many diagnostic tests — ctDNA-negativity does not mean the disease is cured, but ctDNA-positivity does mean it is not cured.
Conclusion
While breakthrough technology and therapies drive much of the conversation in research, it is important to highlight the long-term effects of current treatments and therapies year-over-year. If you are interested in learning more about PSI’s in-depth experience with various oncology indications, check out our oncology therapeutic expertise page or contact us to learn how PSI can help you propel your phase 2 or 3 oncology study forward.
iItaliano, A., lsambert, N., Metges, J.-P., Toulmonde, M., Cousin, S., Pernot, S., Spalato, M., Grellety, T., Auzanneau, C., Lortal, B., Kind, M., Le Loarer, F., Sellan-Albert, S., u Bellera, C. A. (2022). Caire: A basket multicenter open-label phase 2 study evaluating the EZH2 inhibitor tazemetostat in combination with durvalumab in patients with advanced solid tumors. Journal of Clinical Oncology, 40(16_suppl), TPS2703-TPS2703 https://doi.org/10.1200/jco.2022.40.l6_suppl.tps2703
iiDizman, N., Meza, L.A., Bergerot, P. G., Dorff, T. B., Lyou, Y., Frankel, P.H., Llamas, M., Hsu, J., Zengin, Z. B., Malhotra, J., Govindarajan, A., Castro, D. V., Gillece, J. D., Reining, L. J., Trent, J.M., Takahashi, M., Oka, K., Higashi, S., Highlander, S. K., u Pal, S. K. (2022). Characterization of the microbial resistome in a prospective trial of CBM588 in metastatic renal cell carcinoma (MRCC) offers mechanism for interplay between antibiotic (abx) use and immune checkpoint inhibitor (ICI) activity. Journal of Clinical Oncology, 40(16_suppl), 4510-4510. https://doi.org/10.1200/jco.2022.40.l6_suppl.4510
iiiMandel, P. and Metais, P. (1948) Les acides nucl, eiques du plasma sanguin chez l’homme., C. R Seances Soc.Biol. Fil.142, 241-243.
ivOncology Center for Excellence. (2022, May). “Use of Circulating Tumor Deoxyribonucleic Acid for Early-Stage Solid Tumor Drug Development; Draft Guidance for Industry; Availability. U.S. Food and Drug Administration.” Retrieved July l, 2022, from https://www.fda.gov/regulatory-information/search-fda guidance-documents/use-circulating-tumor-deoxyribonucleic-acid-early stage-solid-tumor-drug-development-draft-guidance
vLipsyc-Sharf, M., De Bruin, E., Santos, K., McEwen, R, Stetson, D., Patel, A., Kirkner, G. J., Hughes, M. E., Tolaney, S. M., Krop, I.E., Knape, C., Feger, U., Marsico, G., Howarth, K., Winer, E. P., Lin, N. U., u Parsons, H. A. (2022). Circulating tumor DNA (ctdna) and late recurrence in high-risk, hormone receptor-positive, HER2-negative breast cancer (CHIRP). Journal of Clinical Oncology, 40(16_suppl). https://doi.org/10.1200/jco.2022.40.l6_suppl.103