Assessment of exposure-response relationship for bevacizumab in patients with metastatic colorectal cancer

Peña-Cabia, Silvia; Vicente, Ana Royuela; Díaz, Ruth Ramos; Nicolás, F Gutiérrez; Vera, Ángela Peñalver; García, Isabel Siso; Sabag, Ricardo Hitt; Lacalle, Concepción García; Peña-Cabia, Ana; Peinado, Irene Iglesias; Díaz, Benito García; Martín, Ana López

doi:10.1016/j.biopha.2021.111827

Cited by 3 publications

(5 citation statements)

References 28 publications

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“…However, few studies have examined the bevacizumab exposure-response relationship in patients with NSCLC. Studies on metastatic colorectal cancer showed a positive relationship between survival and bevacizumab exposure [32,33]. In these studies, the frequency of AAT therapy was every three weeks.…”

Section: Discussionmentioning

confidence: 99%

Bevacizumab versus Ramucirumab in EGFR-Mutated Metastatic Non-Small-Cell Lung Cancer Patients: A Real-World Observational Study

Cheng

Shen

Chen

et al. 2023

Cancers

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The combination of bevacizumab or ramucirumab with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy, chemotherapy, or immunotherapy for non-small-cell lung cancer (NSCLC) patients with EGFR mutations could have survival benefits. However, no study, to date, has been conducted to compare the efficacy and safety of these two antiangiogenic therapies (AATs). Stage IIIB to IV EGFR-mutated NSCLC patients who received first-line EGFR-TKIs between January 2014 and May 2022 were enrolled. These patients were divided into two groups: those receiving bevacizumab and those receiving ramucirumab as a combination therapy in any line of treatment. Ninety-six patients were enrolled in this study’s final analysis. The progression-free survival (PFS) of patients who received front-line AATs combined with EGFR-TKI therapy was longer than that of patients receiving later-line AATs combined with other therapies (19.6 vs. 10.0 months, p < 0.001). No difference in overall survival (OS) was observed between front-line and later-line therapy (non-reach vs. 44.0 months, p = 0.261). Patients who received these two different AATs did not differ in PFS (24.1 vs. 15.7 months, p = 0.454) and OS (48.6 vs. 43.0 months, p = 0.924). In addition, these two AATs showed similar frequencies of the T790M mutation (43.6% vs. 38.2%; p = 0.645). Multivariate Cox regression analysis indicated several AAT cycles as an independent good prognostic factor in OS. The incidence of some adverse events such as bleeding and hepatitis was higher for bevacizumab than for ramucirumab but it was not significant. Front-line AAT and EGFR-TKI combination therapy improved the PFS of stage IV EGFR-mutated NSCLC patients. The effectiveness and safety of the two AATs were similar.

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Section: Discussionmentioning

confidence: 99%

Bevacizumab versus Ramucirumab in EGFR-Mutated Metastatic Non-Small-Cell Lung Cancer Patients: A Real-World Observational Study

Cheng

Shen

Chen

et al. 2023

Cancers

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“…32 There are a limited number of studies on the bevacizumab ER relationship, and results are conflicting on whether higher bevacizumab levels are associated with a better response. [33][34][35] Ramucirumab's own PMC study in gastroesophageal cancer showed no further improvement on PFS when dose was increased from 8 to 12 mg/kg. 36 These findings indicate that the ER relationship needs to be interpreted with caution and suggest that it may not be possible to achieve higher exposures and thus greater efficacy in all patients just by increasing dose.…”

Section: Discussionmentioning

confidence: 99%

“…The opposite was true for ipilimumab, with higher doses being associated with improved outcomes 32 . There are a limited number of studies on the bevacizumab ER relationship, and results are conflicting on whether higher bevacizumab levels are associated with a better response 33–35 . Ramucirumab's own PMC study in gastroesophageal cancer showed no further improvement on PFS when dose was increased from 8 to 12 mg/kg 36 .…”

Section: Discussionmentioning

confidence: 99%

Exposure‐response relationship of ramucirumab in RANGE, a randomized phase III trial in advanced urothelial carcinoma refractory to platinum therapy

Wit

Powles

Castellano

et al. 2022

Brit J Clinical Pharma

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Aims Patients with advanced urothelial carcinoma (UC) who progress after platinum‐based chemotherapy have a poor prognosis, and there is a medical need to improve current treatment options. Ramucirumab plus docetaxel significantly improved progression‐free survival but not overall survival (OS) in platinum‐refractory advanced UC (RANGE trial; NCT02426125). Here, we report the exposure‐response (ER) of ramucirumab plus docetaxel using data from the RANGE trial. Methods Pharmacokinetic (PK) samples were collected (cycle 1‐3, 5, 9 [day 1] and 30 days from treatment discontinuation), and PK data were analysed using population PK (popPK) analysis. The minimum ramucirumab concentration after first dose administration (Cmin,1, or trough concentration immediately prior to the second dose) was derived by popPK analysis and used as the exposure parameter for ER analysis. Cox proportional hazards regression models and matched case‐control analyses were used to evaluate the relationship between Cmin,1 and OS. The Cmin,1 relationship with safety was assessed descriptively. Results Several poor prognostic factors (ECOG 1, haemoglobin concentration <100 g/L, presence of liver metastases) appeared more frequently in the lower exposure quartiles, suggesting a possible disease‐PK interaction. A significant association was identified between Cmin,1 and OS (P = .0108). Higher exposure quartiles were associated with longer survival and smaller hazard ratios compared to placebo. No new exposure‐safety trends were observed within the exposure range (ramucirumab 10 mg/kg once every 3 weeks). Conclusions This prespecified ER analyses suggests a positive relationship between efficacy and ramucirumab exposure, with an imbalance associated with disease prognostic factors. Further investigation may elucidate a possible disease‐PK relationship.

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“…Therefore, a positive exposure-response relationship suggests that longer overall (OS) and/or progression-free (PFS) survivals are associated with higher exposure, as identified for the bevacizumab in several studies. [3][4][5][6] However, recent studies have shown that the actual relationship is more complex, [7][8][9] which might challenge the usual strategies of description and interpretation of exposure-response analysis for mAbs in oncology. 2 The mAb exposure-response relationship may be confounded by various factors, 1,10,11 notably baseline disease status 3 and time-varying phenomena such as target engagement 12 and disease improvement 13 (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, a positive exposure‐response relationship suggests that longer overall (OS) and/or progression‐free (PFS) survivals are associated with higher exposure, as identified for the bevacizumab in several studies 3–6 . However, recent studies have shown that the actual relationship is more complex, 7–9 which might challenge the usual strategies of description and interpretation of exposure‐response analysis for mAbs in oncology 2 …”

Section: Introductionmentioning

confidence: 99%

Confounding mitigation for the exposure‐response relationship of bevacizumab in colorectal cancer patients

Lobet,

Caulet,

Paintaud

et al. 2023

Brit J Clinical Pharma

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AimsThe exposure‐response relationship of bevacizumab may be confounded by various factors, including baseline characteristics, time‐dependent target engagement and recursive relationships between exposure and response, requiring effective mitigation. This study aimed to investigate the exposure‐response relationships of bevacizumab in metastatic colorectal cancer (mCRC) patients while mitigating potential biases.MethodsBevacizumab pharmacokinetics was described using target‐mediated drug disposition modelling. Relationships between target kinetics, progression‐free (PFS) and overall (OS) survivals were assessed using joint pharmacokinetic and parametric hazard function models. Both prognostic‐driven and response‐driven potential biases were mitigated. These models evaluated the impact of increased antigen target levels, clearance and intensified dosing regimen on survival.ResultsEstimated target‐mediated pharmacokinetic parameters in 130 assessed patients were baseline target levels (R0 = 8.4 nM), steady‐state dissociation constant (KSS = 10 nM) and antibody‐target complexes elimination constant (kint = 0.52 day−1). The distribution of R0 was significantly associated with increased baseline concentrations of carcinoembryonic antigen, circulating vascular endothelial growth factor and the presence of extrahepatic metastases. Unbound target levels (R) significantly influenced both progression and death hazard functions. Increasing baseline target levels and/or clearance values led to decreased bevacizumab unbound concentrations, increased R levels and shortened PFS and OS, while increasing bevacizumab dose led to decreased R and longer survival.ConclusionThis study is the first to demonstrate the relationship between bevacizumab concentrations, target involvement and clinical efficacy by effectively mitigating potential sources of bias. Most of the target amount may be tumoural in mCRC. Future studies should provide a more in‐depth description of this relationship.

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Assessment of exposure-response relationship for bevacizumab in patients with metastatic colorectal cancer

Cited by 3 publications

References 28 publications

Bevacizumab versus Ramucirumab in EGFR-Mutated Metastatic Non-Small-Cell Lung Cancer Patients: A Real-World Observational Study

Bevacizumab versus Ramucirumab in EGFR-Mutated Metastatic Non-Small-Cell Lung Cancer Patients: A Real-World Observational Study

Exposure‐response relationship of ramucirumab in RANGE, a randomized phase III trial in advanced urothelial carcinoma refractory to platinum therapy

Confounding mitigation for the exposure‐response relationship of bevacizumab in colorectal cancer patients

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