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Phase III trials are also ongoing in other tumor types, in first, second, and third line in Non-small-cell lung cancer (NSCLC; PEARL NCT03003962, MYSTIC NCT02453282, ARCTIC NCT02352948, PACIFIC NCT02125461) and in Head and Neck Squamous Cell Carcinoma (KESTREL NCT02551159, EAGLE NCT02369874).
Very few data are available in older patients with only subgroup analysis and no geriatric data to better characterize the population. However, the incidence of cancer is increasing in that population. There is a tremendous need for evidence-based medicine data in that population, to better adapt treatment strategies. Indeed, compared with conventional cancer therapies, immunotherapy offers a better safety profile with <10% of severe toxicities and is therefore an attractive option in older patients.25,26
Due to the low toxicity prolife, the revolution of immune cancer therapy might especially be of great interest in the older population. Nevertheless, at the moment, there is few evidence of efficacy and tolerance of these drugs in the geriatric population. At the same time, a decline of both adaptive and innate immunity is observed with increasing age.27,28 This phenomenon, called immunosenescence (IS), is responsible for poor response to vaccination and increased susceptibility to infections.29,30
Additionally, increased prevalence of autoimmune disease which is linked with an increase of autoantibodies is observed in older patients.31,32 Especially, in older cancer patients, modification of both the IC phenotype (mainly T cell compartment), the immune microenvironment and intracellular communication are the main reasons for dysfunctional immune responses.33–35
IS is also associated with a state of chronic low-grade inflammation called inflammaging, responsible for altered level of cytokines. All these reasons urged us to analyze efficacy and toxicity of anti PD-L1 therapy.
Therefore, studies with durvalumab in patients with various solid tumors including UC, aged >70 years old incorporating geriatric data to assess safety and efficacy are ongoing.
Moreover, it was recently suggested that a subgroup of patients presents a deleterious acceleration of their cancer disease, defined as hyperprogression in different tumor types such as lung cancers and head and neck cancers.36–39 Several biological hypotheses may explain why PD1/PD-L1 blockade may paradoxically lead to this phenomenon, including, expansion of PD1+ Tregs, compensatory T-cell exhaustion, modulation of protumor immune subsets, activation of aberrant inflammation, or activation of an oncogenic pathway. Prospective trials are warranted to validate this new concept.40
Improving patient selection for immuno-oncology trials and real-life setting is an active area of research to better identify, in particular, fast progressors. Massard et al developed a tool (FastProgIO) predicting 12-week life expectancy using a multivariate regression method in patients with NSCLC and UC treated with durvalumab ± tremelimumab and compared it to existing published scores (Royal Marsden Hospital prognostic score [RMH], Gustave Roussy Immune Score [GRIM], lung immune prognostic index [LIPI]).41–43 The performance was assessed by time-dependent true positive rate (TPR) and false positive rate (FPR). FastProgIO includes neutrophils, AST, alkaline phosphatase, and hemoglobin as the predictive markers. At 12 weeks, the TPR for FastProgIO was 73%, (90% CI: 67%–80%) vs 69%, 65%, and 41% for RMH, GRIM, and LIPI, respectively.44 Furthermore, the FPR of FastProgIO (11%, 90% CI: 9.3%–13%) was comparable to LIPI (10%), but better controlled than RMH and GRIM (20% and 17%).44 This score needs to be further validated but can be an interesting option to better select patients eligible for immune-oncology trials.
Finally, new patterns of response to immune checkpoint blockers need to be further investigated and described to improve our understanding of immune checkpoint blockers and improve patient care.
CONCLUSION
Durvalumab is a safe and effective therapeutic option in UC and was granted FDA approval in May 2017 based on the results of the Phase I/II trial. Questions remain about the optimal therapeutic strategies in UC with the breakthrough of several anti-PD-1 and anti-PD-L1 recently and new treatments such as FGFR inhibitors. Answers may emerge with the recent molecular characterization of muscle-invasive bladder cancer.45 Robertson et al identified five expression subtypes that may be sensitive to different treatments.45 This characterization may help practitioners to find optimal strategies for patients. Moreover, results of trials testing combination therapies with immune checkpoint blockers are awaited. Treatment landscape of UC is moving forward, and new therapeutic options will be available in the upcoming future.
Disclosure
The authors report no conflicts of interest in this work.
Capucine Baldini, Stéphane Champiat, Perrine Vuagnat, Christophe Massard
Drug Development Department, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France
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Source: OncoTargets and Therapy.
Originally published April 3, 2019.
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