Impact of body mass index in patients receiving atezolizumab plus bevacizumab for hepatocellular carcinoma

Background Atezolizumab plus bevacizumab (Atezo/Bev) is first line-treatment for unresectable hepatocellular carcinoma (HCC). Body mass index (BMI) has demonstrated predictive value for response to immunotherapy in non-HCC cancer types. Our study investigated the effect of BMI on safety and efficacy of real-life use of Atezo/Bev for unresectable HCC. Methods 191 consecutive patients from seven centres receiving Atezo/Bev were included in the retrospective study. Overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and disease control rate (DCR) defined by RECIST v1.1 were measured in overweight (BMI ≥ 25) and non-overweight (BMI < 25) patients. Treatment-related adverse events (trAEs) were evaluated. Results Patients in the overweight cohort (n = 94) had higher rates of non-alcoholic fatty liver disease (NAFLD) and lower rates of Hepatitis B compared to non-overweight cohort (n = 97). Baseline Child–Pugh class and Barcelona Clinic Liver Cancer stage were similar between cohorts, with lower rates of extrahepatic spread in the overweight group. Overweight patients had similar OS compared to non-overweight (median OS 15.1 vs. 14.9 months; p = 0.99). BMI did not influence median PFS (7.1 vs. 6.1 months; p = 0.42), ORR (27.2% vs. 22.0%; p = 0.44) and DCR (74.1% vs. 71.9%; p = 0.46). There were higher rates of atezolizumab-related fatigue (22.3% vs. 10.3%; p = 0.02) and bevacizumab-related thrombosis (8.5% vs. 2.1%; p = 0.045) in the overweight patients, but overall trAEs and treatment discontinuation were comparable between cohorts. Conclusion Atezo/Bev has comparable efficacy in overweight HCC patients, with an increase in treatment-related fatigue and thrombosis. Combination therapy is safe and efficacious to use in overweight patients, including those with underlying NAFLD. Supplementary Information The online version contains supplementary material available at 10.1007/s12072-023-10491-3.

The effect of BMI on immunotherapy has been evaluated in multiple cancer sites. Overweight/obese patients receiving immune checkpoint inhibition have favourable OS and PFS across multiple cancer sites [18,19] including melanoma [20], renal cell carcinoma [18,19] and non-small cell lung cancer [21] (NSCLC); the largest study being in 1434 patients with NSCLC demonstrating a survival benefit of atezolizumab in overweight/obese individuals [21].
The effect of BMI on bevacizumab response has similarly been evaluated in multiple cancer types, with positive [22], negative [23] and no associations [24] seen across multiple cancer sites. The association of BMI with immunotherapy in HCC is less well studied, with a single study demonstrating that BMI ≥ 25 is associated with improved OS in patients receiving PD-1 antibody-based regimens (17.5 vs. 5.0 months; p = 0.034). No difference in PFS was observed (2.7 vs. 2.9 months; p = 0.74) [25]. In this study, over 70% of patients had previous systemic treatment, and the effects of BMI on treatment-naïve patients receiving combination immunotherapy is not known.
To-date no study has evaluated the association of BMI on efficacy and safety outcomes of atezolizumab plus bevacizumab used for the first-line treatment of HCC in routine clinical practice. We conducted a retrospective analysis of patients receiving atezolizumab plus bevacizumab for unresectable HCC across seven tertiary centres, evaluating the effect of BMI on efficacy and safety.

Study participants and design
Patients previously undergoing systemic therapy, including oral multikinase inhibitors and immune checkpoint inhibitors, were excluded from the study. Consecutive patients with unresectable HCC receiving atezolizumab plus bevacizumab across eight tertiary centres in Germany (n = 30), Japan (n = 51), Austria (n = 12), United Kingdom (n = 15), Italy (n = 12), Taiwan (n = 11) and United States of America (n = 60) were recruited in the study. Inclusion criteria included the following : age at least 18 years old; histological or radiological diagnosis of HCC in accordance with the American Association for the Study of Liver Diseases (AASLD) criteria [26]; diagnosis of advanced disease as per Barcelona Clinic Liver Cancer (BCLC) criteria [27]-BCLC C or BCLC B not amenable to locoregional therapy.

Treatment protocol
Combination atezolizumab plus bevacizumab were administered according to the IMbrave150 protocol [5]: atezolizumab 1200 mg and bevacizumab 15 mg/kg intravenously every 3 weeks. Toxicity management and dose modifications were managed by local institutions as per summary of product characteristics (SmPC). Treatment was continued until disease progression or unacceptable toxicity as per local multidisciplinary assessment.

Patient outcomes
Patients' baseline demographics were collected retrospectively, and clinical outcomes were prospectively maintained at each participating site. Radiological response following atezolizumab plus bevacizumab therapy was assessed as per RECIST criteria v1.1 [28] on CT or MRI performed at 9-12 week intervals. Overall response rate was defined as all patients having complete response (CR) or partial response (PR). Disease control rate included all patients with CR, PR and stable disease (SD).Treatment-related adverse effects (trAEs) were assessed at every point of patient contact and graded as per the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v. 5.0 [29]. Atezolizumab-related and bevacizumab-related adverse events were defined by the treating physician at each treatment centre as per the SmPC for each drug.

Statistical analysis
For BMI analysis, patients were divided into two cohorts. BMI was defined as height (in metres) divided by weight squared (in kilograms). Patients were divided into those with a BMI of 25 or greater (overweight) and those with a BMI less than 25 (non-overweight). Baseline characteristics were compared within the divided BMI (overweight vs. non-overweight). χ 2 test was used to compare categorical data, and unpaired student t test for continuous data. Treatment-related adverse events and ORR/DCR were compared between BMI cohorts using χ 2 test. The distribution of BMI with patient characteristics were determined using Pearson's correlation coefficient for continuous variables and unpaired student t tests for categorical variables.
Time-to-event analysis was performed using Kaplan-Meier method. OS was defined as the time in months from the date of first administration of atezolizumab plus bevacizumab to date of death or last follow-up. PFS was defined as time in months from the date of first treatment to date of death or date of progression on radiological imaging. OS and PFS were compared between overweight and non-overweight cohorts using log-rank. A p value of less than 0.05 was defined as statistically significant. Univariate and multivariate Cox regression models for overweight/ non-overweight cohorts and established prognostic factors were conducted for OS and PFS. BCLC stage (C vs. A or B), Child-Turcotte-Pugh class (B vs. A), tumour size (7 cm vs. ≤ 7 cm), macrovascular invasion (MVI), metastatic disease and alpha-fetoprotein (AFP) (> 400 ng/dL vs. ≤ 400 ng/ dL) are all prognostic factors previously shown to correlate with HCC survival [30] and were included in Cox regression models. We conducted further analysis assessing the impact of different BMI classes on patient survival. BMI classes were defined as underweight (BMI < 18.5), normal (18.5 ≤ BMI < 25), overweight (25 ≤ BMI < 30) and obese (BMI ≥ 30). Kaplan-Meier analysis and Cox regression models were performed for the different BMI classes.

Baseline characteristics
191 patients received atezolizumab plus bevacizumab consecutively across eight tertiary referral centres. The baseline characteristics of patients are shown in Table 1
Treatment response using the RECIST criteria was available in 163 patients. ORR and DCR for the entire cohort were 24.5% and 73.0%, respectively (Supplementary Table 1 We further assessed the impact of different BMI classes on survival after therapy. Baseline characteristics were comparable between the classes (Supplementary Table 2). There  Tables 3 and 4). The difference in rates of MVI and extrahepatic spread observed in the overweight and non-overweight groups may impact survival outcomes. We conducted subgroup analysis assessing survival in overweight and non-overweight patients without MVI or extrahepatic spread. Overweight and non-overweight patients had comparable OS (median OS 23.8 vs. 14.9 months; p = 0.26) and PFS (median PFS 20.7 vs. 14.2 months; p = 0.27). Similarly, overweight BMI did not impact OS or PFS in patients with MVI and/or extrahepatic spread.

Discussion
This multi-centre study is the first to evaluate the effect of BMI on treatment efficacy and safety of Atezo/Bev for advanced/unresectable HCC. We show a BMI of 25 and above is associated with similar OS and PFS compared to patients with normal or underweight BMI. We observe higher rates of atezolizumab-related fatigue and bevacizumab-related thrombosis in overweight patients, without an increase in overall trAEs or treatment discontinuation. Studies evaluating the effect of BMI on HCC survival have demonstrated varied results. Elevated BMI does not influence survival in patients undergoing curative resection [16,17] and TACE [15]. In contrast, a positive association between BMI and survival for patients undergoing systemic chemotherapy has been reported [14,31]. Secondary analysis of a phase III study demonstrated a BMI 25 or above was associated with an increased OS but not PFS in 544 patients receiving sorafenib for unresectable HCC [14]. These findings were replicated in a Japanese cohort of 234 patients Inter-class variation in efficacy of immunotherapy agents has been previously reported [32], and elevated BMI may affect anti-PD-1 and anti-PD-L1 response differentially. Additionally, we observed higher rates of NAFLD in patients with the overweight cohort. Previous studies have demonstrated a lack of efficacy of immunotherapy in patients with nonviral HCC [6,33,34]. This may be due to aberrant T-cell activation within hepatic tissue impairing immune response to checkpoint inhibition [33]. Therefore, underlying NAFLD and changes in the hepatic tissue immune environment in overweight HCC patients may attenuate the survival benefit from immunotherapy observed in other cancer sites. Only a single previous study has evaluated effect of BMI on response to immunotherapy in unresectable HCC [25]. The effect of BMI and sarcopenia was investigated in 57 patients receiving anti-PD-1 antibody combination therapy in a single centre. Median OS was significantly longer in the BMI ≥ 25 group compared to BMI < 25 (17.5 vs. 5.0 months; p = 0.034), with similar PFS (2.7 vs. 2.9 months). The author's observed sarcopenia was associated with a non-significant reduced OS (5.0 vs. 14.3 months; p = 0.054), which may correlate with lower BMI. The majority of patients in this study had received previous lines of systemic therapy, and 41% had a PS of 2-3, factors which may have adversely impacted on both BMI and sarcopenia, as it is likely that patients with poor PS will have a degree of cachexia [35]. Furthermore, no information is given by the authors regarding the type of immunotherapy administered. We did not observe a correlation between BMI and either OS or PFS in our larger cohort of patients receiving first-line treatment with anti-PD-L1 antibody and anti-VEGF therapy. The differences observed between the studies may be attributed to mechanistic differences of pharmacotherapy and differences in patient demographics as described.
Underlying NAFLD is highly represented in our cohort of patients with elevated BMI. This is expected as elevated BMI is associated with NAFLD as part of the metabolic syndrome spectrum [36]. The efficacy of immunotherapy in patients with NAFLD remains debated. A subgroup analysis of IMbrave150 showed no survival benefit with Atezo/ Bev compared to sorafenib in patients with non-viral HCC [6]. This lack of efficacy of immunotherapy in non-viral related HCC was further demonstrated in two meta-analyses [33,34]. However, these studies did not distinguish between alcohol-related and NAFLD-related HCC. We observe a higher rate of NAFLD-related HCC in our overweight cohort, with no difference in survival compared to the non-overweight group. These results suggest Atezo/ Bev is efficacious in NAFLD patients, but further prospective study is needed. We found a higher rate of macrovascular invasion with overweight patients, which has been shown to be associated with NAFLD [37] as have larger sized tumors [38]. The higher rates of MVI in overweight patients may arise due to the effect of adipose tissue on the tumors microenvironment. Increased adipose tissue is associated with higher rates of hypoxia, causing release of proinflammatory cytokines including monocyte chemoattractant protein-1, interleukin-1β and tumors necrosis factor-α [34,35]. Higher levels of Interleukin-6 are seen in obesity, with increased secretion from hepatic stellate cells and Kupffer cells within the liver [41]. Cytokine release drives chronic inflammation through macrophage and lymphocyte infiltration [42], promoting angiogenesis and alterations in the extracellular matrix leading to tumors growth [43]. In liver tissue, excessive saturated fatty acids can result in alterations in glucose metabolism and production of reactive oxidative species leading to progression of hepatocellular carcinoma [44,45]. Diabetes mellitus is associated with higher rates of MVI in HCC patients [46], consistent with our observations with overweight and NAFLD patients, as part of the metabolic syndrome spectrum. Though the higher rates of MVI in the elevated BMI cohort did impact survival after immunotherapy, it may have implications for other treatments in overweight patients, including curative therapy such as hepatectomy and liver transplantation.
The impact of BMI on the safety of immunotherapy in patients has been evaluated. Cortellini et al., showed higher BMI was associated with higher rates of trAEs and subsequent treatment discontinuation in a cohort of 1070 patients receiving PD-1/PD-L1 inhibition for multiple primary cancer sites [47]. The authors observed BMI as an independent predictor for trAE in multivariate analysis. The authors speculate the higher rate of trAEs observed with higher efficacy may represent an immunogenic phenotype observed in higher BMI patients [48]. Similarly, higher BMI was associated with increase in overall trAEs in a meta-analysis of 4090 patients across multiple cancer sites receiving immunotherapy [18]. In our study, we did not report an overall increase in overall trAEs in overweight patients. We observed higher rates of atezolizumab-related fatigue and bevacizumab-related thrombosis in the overweight cohort. The mechanism for bevacizumab-related thrombosis is unclear, though may be mediated by increased vascular damage and inflammation [49]. Elevated BMI is an established risk factor for thrombosis through promotion of chronic inflammation and impaired fibrinolysis [50]. This is consistent with the higher rates of macrovascular invasion, encompassing portal vein thrombosis, observed in our overweight cohort. Sparks et al., observed BMI did not impact on rates of thrombosis in colorectal, ovarian, lung and gliblastoma multiforme cancer patients receiving bevacizumab [51]. The higher rates of thrombosis observed in our overweight cohort of HCC patients may be due to underlying liver dysfunction. Patients with cirrhosis are at increased risk of both bleeding and thrombosis [52], due to the liver's role in synthesising both anticoagulant and coagulant factors. Obesity is an independent risk factor for thrombosis in pre-transplant cirrhosis patients [53] and may be a key driver in the increased risk of bevacizumab-related thrombosis in HCC patients. Atezolizumab-related thyroiditis has been seen in up to 10% of cases [54]. We observe a lower rate of atezolizumab-related thyroid dysfunction in the overweight cohort. The relationship between elevated BMI and thyroid dysfunction is complex, and mediated by adipocytes, cytokines and iodine uptake in thyroid cells [55]. This interplay may influence the rates of immunotherapy-related thyroid dysfunction in overweight patients. The difference in trAEs observed between the overweight and non-overweight cohorts may also be due to unmeasured confounding factors between the two groups. Further large studies will be required to assess trAEs with increased use of atezolizumab plus bevacizumab specific for HCC.
Our study has limitations. Though follow-up was prospectively collected, this is a retrospective study which is subject to selection and collection bias. Baseline characteristics influencing survival such as underlying NAFLD and extrahepatic spread were higher in the overweight cohorts and may have an impact on patient survival. Additionally, there may be unmeasured confounding factors. Though patients received treatment from tertiary centres, inter-site variation in treatment protocols, follow-up and efficacy and safety assessments cannot be excluded. Lower BMI may represent poor global nutritional status and sarcopenia. Clinically and radiologically measured sarcopenia is associated with increased mortality in patients with cirrhosis [56] and HCC [57] and, therefore, may confound our findings.
Further studies assessing sarcopenia and other body composition measures such as subcutaneous adipose tissue, visceral adipose tissue and muscle volume would allow understanding of the impact of muscle mass and adipose tissue on immunotherapy response in HCC. In survival analysis we report all-cause mortality rather than liver-specific mortality. This may be influenced by unreported medical comorbidities. Despite these limitations, this study represents the largest cohort of post-registration real-time use of atezolizumab plus bevacizumab for HCC in overweight patients. As an increasing number of immunotherapy agents emerge for use in HCC [58], further studies evaluating the efficacy and safety of these agents in overweight patients will guide future clinical practice.

Conclusion
Our study demonstrates atezolizumab plus bevacizumab therapy is associated with comparable efficacy in overweight HCC patients with higher rates of NALFD. Increased body mass index is associated with higher rates of treatmentrelated fatigue and thrombosis, but no increase in overall treatment-related adverse events. Combination therapy is safe and efficacious to use in overweight patients, including those with underlying NAFLD. MP is an investigator for Bayer, BMS, Ipsen, Lilly, and Roche; he received speaker honoraria fromBayer, BMS, Eisai, Lilly, MSD, and Roche; he is a consultant for Bayer, BMS, Eisai, Ipsen, Lilly, MSD, and Roche; he received travel support from Bayer and BMS. AC received consulting fees from MSD, BMS, AstraZeneca, Roche; speakers' fee from AstraZeneca, MSD, Novartis and Astellas. LR has received consulting fees from Amgen, ArQule, AstraZeneca, Basilea, Bayer, BMS, Celgene, Eisai, Exelixis, Genenta, Hengrui, Incyte, Ipsen, IQVIA, Lilly, MSD, Nerviano Medical Sciences, Roche, Sanofi, Servier, Taiho Oncology, Zymeworks; lecture fees from AbbVie, Amgen, Bayer, Eisai, Gilead, Incyte, Ipsen, Lilly, Merck Serono, Roche, Sanofi, Servier; travel expenses from AstraZeneca; and institutional research funding from Agios, ARMO BioSciences, Astra-Zeneca, BeiGene, Eisai, Exelixis, Fibrogen, Incyte, Ipsen, Lilly, MSD, Nerviano Medical Sciences, Roche, Zymeworks. DJP received lecture fees from ViiV Healthcare, Bayer Healthcare, BMS, Roche, Eisai, Falk Foundation, travel expenses from BMS and Bayer Healthcare; consulting fees for Mina Therapeutics, EISAI, Roche, DaVolterra, Mursla, Exact Sciences and Astra Zeneca; research funding (to institution) from MSD and BMS. All remaining authors have declared no conflicts of interest. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Ethics approval
The study was approved by the Imperial College Tissue Bank (R16008) and local ethics committees at each participating site.
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