In this third interview of a 4-part series, Dr. Achim Regenauer answers questions relevant to Life & Health underwriters on advances in cancer therapy.
Our immune system is able to destroy cancer cells. However, cancer cells have the insidious capability to adapt and mutate, thereby are effectively able to hide from the immune system. Unlike chemotherapy, targeted cancer therapies mostly use the body’s own immune system to fight cancer cells by stimulating the immune system in various ways. This is currently one of the hottest areas of cancer research. Compared to chemotherapy which also destroys healthy cells, a major upside of targeted therapies is that these treatments are usually designed to target and destroy very specific cancer cells. A major downside compared to chemotherapy is that the scope of application is currently limited to a small number of cancer subtypes.
There are many different types of targeted cancer therapies. It’s worth adding here that the term targeted cancer therapy and immunotherapy are often not clearly differentiated and are used interchangeably. To give some examples of the variety of innovative targeted cancer therapies:
Monoclonal antibodies are large molecules which bind to specific antigens on the surface of cancer cells, marking them for destruction by immune cells. Immune-checkpoint Inhibitors target so-called immune checkpoints, which are key regulators of the immune system, by cancelling the dampened immune response to cancer cells. Common checkpoints that these inhibitors affect are the PD-1/PD-L1 and CTLA-4 pathways. Small molecules, such as cytokines, interferon, tumor necrosis factor (TNF) and kinase inhibitors, primarily target the inside of cancer cells. CAR T-cell therapy, also called “adoptive cell immunotherapy”, is a one-time treatment where a patient’s T cells are removed and genetically modified in a special lab in such a way that they will attack cancer cells. Last but not least, although not yet available in the clinical setting, cancer vaccines should also be mentioned here – these are in development to stimulate an immune response to attack existing cancer cells.
The use of immune-checkpoint inhibitors has heralded a new era in cancer treatment with mortality improvements of metastatic melanoma, non-small lung cancer and renal cell carcinoma.1 Another example, published recently in Nature2, indicates long-term, sustained remission in chronic lymphocytic leukaemia CAR T-cell therapy patients since 2010, results that have in a way championed the efficacy of targeted therapy.
It is difficult to answer this question as targeted therapy is an umbrella term for a genuine heterogeneity of modern cancer drugs. However, a few years ago, JAMA Oncology reported3 that the estimated percentage of US cancer patients expected to benefit from targeted therapy (i.e., responders) in 2006 was as low as 0.7%, and that in 2018 this had increased to 4.9%. Extrapolating this swift uptake, my guess is that we are now close to 10% of all cancer patients being qualified to a targeted cancer therapy of one type or another.
Cancer care has historically been one of the leading drivers of increased health care spending. Indeed, cancer is now the most expensive condition to treat per capita and its affordability is threatened. This high cost is at least partially attributable to targeted cancer therapies which are much more expensive than traditional chemotherapy. In the US, the cost of oncology medicines increased over a five-year period by 73%4, and this was primarily driven by targeted cancer therapies.
One of the most beneficial features of targeted cancer therapies is that they target malignant cells while sparing normal, healthy tissues from the damage often caused by radiation and/or chemotherapy.
However, as mentioned above, many such therapies have demonstrated efficacy only for a select group of cancers. In addition, usually only a subset of patients with those select cancer types respond to the treatment – there is a wide and unpredictable variability in the patient response. This variability can best be explained by tumor heterogeneity, different metabolic pathways and previous therapies. Cancer signaling networks are remarkably flexible and adaptive. As a result of this unpredictability and the small patient subset that ultimately benefits, the cost of future new therapies and per capita cost for existing treatments will remain high, it is unlikely to fall over time. However, in the medium-term, this situation may be improved by additional biomarkers (liquid biopsy5) that define candidates or subgroups of cancer patients who will benefit.
Another major challenge is that targeted cancer therapies often become resistant via the development of resistant cancer cell clones, hampering the efficacy of the treatment. Clinicians try to resolve this issue by combining several classes of targeted therapies or by combining a targeted therapy with a traditional chemotherapy drug.
Currently, targeted cancer therapies are mostly applied only as a second line treatment in cancer patients. However, at this stage the patient’s immune system is already compromised due to previous chemotherapy, or an advanced progression of the cancer. There is a good chance that efficacy will increase if targeted therapies are given as a first line of treatment, i.e., administered earlier to restore a robust antitumor response while the immune system is still able to recover. I am therefore convinced that during the next decade we will see more-toxic and less-effective first-line chemotherapy treatments being replaced by more personalized cancer drugs, improving patient outcomes.
Another highly promising advance area is with cancer vaccines, i.e., a therapeutic application of immunization against an already existing cancer. It was originally assumed that the path to a therapeutic vaccination would be fairly long, but the recent progress with mRNA vaccines for SARS-CoV-2 viruses has significantly expedited this new technology. Other mRNA cancer vaccines are already being investigated in clinical phase 2 trials, e.g., for advanced melanoma.6 Market entry within the next five years is expected.
First of all, targeted cancer therapies, i.e., precision oncology, equate to smaller prognostic risk groups that risk assessment will need to reflect. The medical files of applicants with a history of cancer disease will become more voluminous and particularly complex. Manual and underwriting guidelines will have to be revised more often. And, last but not least, in the medium-term, the higher efficacy of cancer therapy, once it has a sustainable effect without recurrences, will result in lower substandard loadings.
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Achim Regenauer, Chief Medical Officer, Europe and Asia Pacific
1 The Use of Immune Checkpoint Inhibitors in Oncology and the Occurrence of AKI: Where Do We Stand? Front. Immunol., 08 October 2020 https://doi.org/10.3389/fimmu.2020.574271; Immunotherapy Improves Five-year Survival Rate of People with Advanced Lung Cancer, U Magazine, Fall 2019 https://www.uclahealth.org/u-magazine/immunotherapy-improves-five-year-survival-rate-of-people-with-advanced-lung-cancer
2 Melenhorst, J.J., Chen, G.M., Wang, M. et al. Decade-long leukaemia remissions with persistence of CD4+ CAR T cells. Nature 602, 503–509 (2022). https://doi.org/10.1038/s41586-021-04390-6
3 Marquart, John et al. “Estimation of the Percentage of US Patients With Cancer Who Benefit From Genome-Driven Oncology.” JAMA oncology vol. 4,8 (2018): 1093-1098. doi:10.1001/jamaoncol.2018.1660; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6143048/
4 Global Oncology Trend Report, A Review of 2015 and Outlook to 2020. IMS Institute for Healthcare Informatics (2016). https://www.iqvia.com/-/media/iqvia/pdfs/institute-reports/global-oncology-trend-report-2016.pdf
5 Cancer Diagnostics – Earlier Detection & Impact on Incidence & Mortality; PartnerRe (2021). https://www.partnerre.com/perspectives/cancer-diagnostics-earlier-detection-impact-on-incidence-mortality
6 BioNTech Announces First Patient Dosed in Phase 2 Clinical Trial of mRNA-based BNT111 in Patients with Advanced Melanoma, Press release June 18, 2021 https://investors.biontech.de/news-releases/news-release-details/biontech-announces-first-patient-dosed-phase-2-clinical-trial/