Author: Ganessan Kichenadasse
Kichenadasse, Ganessan, 2020 Exploration of factors that determine heterogeneity in efficacy and toxicities of anticancer drugs, Flinders University, College of Medicine and Public Health
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“Variability is the law of life, and as no two faces are the same, so no two bodies are alike, and no two individuals react alike and behave alike under the abnormal conditions which we know as disease” (Osler 1905)
This thesis evaluates the previously under recognized factors that may contribute to the variations in response and toxicity from systemic cancer drugs. It was hypothesised that selected characteristics (patient anthropometric data (body mass index - BMI), use of concomitant medications such as renin-angiotensin inhibitors (RASi) and proton pump inhibitors (PPI), occurrence of immune-related adverse events (irAEs), primary site of origin of cancer and plasma concentration of the cancer drugs) can predict outcomes across a spectrum of systemic cancer drugs. All research studies in this thesis were conducted using individual patient data case report forms of 10,158 patients with five types of cancers who participated in 15 different clinical trials which were accessed using various data sharing platforms.
My research suggests that contrary to prior belief that obesity is a negative factor for drug therapy associated outcomes, patients with lung cancer (N = 1,548, from 4 trials) and high BMI had improved survival when treated with atezolizumab (pooled hazard ratios (HR) of 0.36 [95%CI, 0.21-0.62], P <0.001) for the group with obesity). While the proton pump inhibitors use was associated with worse survival (pooled HR 1.20, [95% CI 1.03-1.40], P = 0.02) in fluoropyrimidine-based chemotherapy treated colorectal cancer patients (N = 5,594 from 6 trials), the use of renin-angiotensin inhibitors were not (pooled HR 0.94, [95% CI 0.82-1.07], P = 0.38) in atezolizumab treated patients with lung, bladder, or kidney cancers (N = 2,539 from 7 trials). Both these findings on concomitant medications were surprising and unexpected as the pre-clinical data indicated the contrary with improved efficacy of fluoropyrimidine-based chemotherapy with proton pump inhibitors and renin-angiotensin inhibitors augmented immune response.
Additionally, using data from 2 clinical trials involving 830 patients with advanced melanoma, a new threshold as target steady-state trough concentration (Css,min ≥ 50 mg/L) for optimal dosing of vemurafenib, a braf inhibitor, that was associated with improved survival (HR 0.67,[95% CI 0.52–0.88] P = 0.003). For the first-time, I have described a detailed evaluation of the incidence (5% of atezolizumab treated patients), type, severity and time-profile of multi-organ irAEs using a large cohort of atezolizumab treated patients (N = 1,548 from 4 trials). Multi-organ adverse events were associated with improved survival (pooled HR = 0.47, [95%CI 0.28 - 0.78], P <0.0001). My research also demonstrated that the occurrence of any irAE was associated with improved survival in both atezolizumab treated patients as well as those treated with taxanes or vinca alkaloid-based chemotherapies, indicating that they were prognostic rather than predictive of response to immunotherapy alone.
Among the primary site of origin of urothelial cancers, prior research reported that those with upper tract origin have different molecular characteristics that predict a lower benefit from immunotherapies when compared to the more common urinary bladder cancers. However, using data from 3 clinical trials (N = 1,331 patients), my research demonstrated that both upper and lower tract urothelial cancers have no significant differences in survival (HR was 0.99, [95%CI 0.82-1.21], P = 0.98) when treated with atezolizumab.
Based on these results several conclusions were drawn: 1. baseline BMI should be considered as a stratification factor in future clinical trials if these findings are confirmed in future studies; 2. clinicians should consider minimising the concomitant use of proton pump inhibitors in patients initiating chemotherapy for advanced colorectal cancer; 3. the new threshold concentration provides further evidence to support optimized dosing to reach the trough concentration to reduce inter-individual variability in vemurafenib survival; 4. new information generated to support treating clinicians to anticipate, recognise and treat multi-organ irAEs as well as trigger further research to better understand the pathophysiology of those toxicities; 5. primary site of origin of urothelial cancers may not affect outcomes from single agent immunotherapy. Future research that address these questions and challenges raised from my thesis should be conducted to improve our understanding of inter-individual variations in drug therapies thereby supporting dose optimisation and improving outcomes of patients.
Keywords: cancer therapy; heterogeneity; response; toxicity; individual patient data; meta-analysis
Subject: Clinical Pharmacology thesis
Thesis type: Doctor of Philosophy
Completed: 2020
School: College of Medicine and Public Health
Supervisor: Michael Sorich