Advertisement

Reply to: “Challenges and issues in bivariate endpoints in study designs of translational medicine”

Published:August 23, 2022DOI:https://doi.org/10.1016/j.jhep.2022.08.017

      Linked Article

      • Challenges and issues in bivariate endpoints in study designs of translational medicine
        Journal of HepatologyVol. 77Issue 6
        • Preview
          We read with great interest the recent study by Chuah et al.1 aiming to find immune predictors of treatment response and mechanisms of response versus immune-related adverse events (irAE) in hepatocellular carcinoma (HCC) patients treated with anti-programmed cell death 1 (PD-1). The authors noticed the recent successful combinations of immunotherapies achieved increased response rates compared to monotherapy, but with an accompanying increase in irAEs. The authors were inspired by this and conducted an innovative study to investigate how to increase response rates and reduce irAEs simultaneously.
        • Full-Text
        • PDF
      • Uncoupling immune trajectories of response and adverse events from anti-PD-1 immunotherapy in hepatocellular carcinoma
        Journal of HepatologyVol. 77Issue 3
        • Preview
          While immune checkpoint blockade (ICB) has shown promise in patients with hepatocellular carcinoma (HCC), it is associated with modest response rates and immune-related adverse events (irAEs) are common. In this study, we aimed to decipher immune trajectories and mechanisms of response and/or irAEs in patients with HCC receiving anti-programmed cell death 1 (anti-PD-1) therapy.
        • Full-Text
        • PDF
        Open Access
      To the Editor:
      We thank Zhou
      • Zhou Q.
      Challenges and issues in bivariate endpoints in study designs of translational medicine.
      for their interest and comments on our work.
      • Chuah S.
      • Lee J.
      • Song Y.
      • Kim H.D.
      • Wasser M.
      • Kaya N.A.
      • et al.
      Uncoupling immune trajectories of response and adverse events from anti-PD-1 immunotherapy in hepatocellular carcinoma.
      Zhou commented that the two binary endpoints of efficacy and safety should be analyzed separately or reorganized into four groups. Indeed, the relationship between response and toxicity to immunotherapy is widely recognised, which we also acknowledged by citing the clinical trials of CheckMate040 and IMBRAVE150, where immune related adverse events (irAEs) increased in tandem with greater objective response rates (ORRs) in combination immunotherapy.
      • Yau T.
      • Kang Y.-K.
      • Kim T.-Y.
      • El-Khoueiry A.B.
      • Santoro A.
      • Sangro B.
      • et al.
      Nivolumab (NIVO) + ipilimumab (IPI) combination therapy in patients (pts) with advanced hepatocellular carcinoma (aHCC): results from CheckMate 040.
      ,
      • Finn R.S.
      • Qin S.
      • Ikeda M.
      • Galle P.R.
      • Ducreux M.
      • Kim T.Y.
      • et al.
      Atezolizumab plus Bevacizumab in unresectable hepatocellular carcinoma.
      There were also other analyses that correlated irAEs with clinical benefits of immune checkpoint blockade (ICB), both in HCC and other cancer types.
      • Xu S.
      • Lai R.
      • Zhao Q.
      • Zhao P.
      • Zhao R.
      • Guo Z.
      Correlation between immune-related adverse events and prognosis in hepatocellular carcinoma patients treated with immune checkpoint inhibitors.
      ,
      • Ye W.
      • Olsson-Brown A.
      • Watson R.A.
      • Cheung V.T.F.
      • Morgan R.D.
      • Nassiri I.
      • et al.
      Checkpoint-blocker-induced autoimmunity is associated with favourable outcome in metastatic melanoma and distinct T-cell expression profiles.
      With this in mind, we did explore the interaction between response and toxicity to treatment. Firstly, our multivariate analyses showed that the incidence of irAEs was a significant factor relating to progression-free survival, as would be expected (Table S8).
      • Chuah S.
      • Lee J.
      • Song Y.
      • Kim H.D.
      • Wasser M.
      • Kaya N.A.
      • et al.
      Uncoupling immune trajectories of response and adverse events from anti-PD-1 immunotherapy in hepatocellular carcinoma.
      We also split our cohorts into the four different groups to verify that our biomarkers were not confounded by the interaction between response and toxicity (Figs S2C and S3B).
      • Chuah S.
      • Lee J.
      • Song Y.
      • Kim H.D.
      • Wasser M.
      • Kaya N.A.
      • et al.
      Uncoupling immune trajectories of response and adverse events from anti-PD-1 immunotherapy in hepatocellular carcinoma.
      Due to the small sample size in some of the groupings, we have elected instead to conduct our main analysis on response and toxicity separately, while still acknowledging their potential co-dependence.
      The author further commented on combination therapy, where we have only included patients receiving monotherapy and the limited sample size of each group in our in vivo mouse studies. We would like to highlight that the objective of our study was to analyse patients undergoing anti-PD1 monotherapy in order to discover potential combination therapies that would improve response rates while not increasing the incidence of irAEs. As such, we do not yet have an adequate patient cohort to act as a control for ‘combined immunotherapies which have been proven to be positive in randomized clinical trials’. In fact, we are planning to conduct the first-in human trials using combination immunotherapy of anti-PD-1+anti-TNFR2, where we will be able to assess the patient data in the near future. Rather, in this current study, we validated the response and toxicity of the combination immunotherapy in our pre-clinical HCC mouse model, based upon our discovery in the HCC patient cohort treated with anti-PD-1 ICB. Hence, our study focused on discovery and pre-clinical validation, not clinical validation. The deeper mechanistic insights into the involvement of T cells and antigen-presentation cells in clinical response to ICB is another highlight of our study. Despite the small sample sizes, the strong data we observed provided sufficient proof-of-concept for an anti-PD1+anti-TNFR2 combination immunotherapy, which could encourage larger scale animal experiments and clinical trials in HCC.
      The differences between the Singapore and Korea cohorts were already explained in the description of our patient cohorts. The Singapore patient cohort was recruited from real-world clinical patients with advanced HCC undergoing anti-PD1 immunotherapy. As a result, their clinical characteristics were very heterogenous. To ensure that the immune targets we discovered were not affected by this heterogeneity, we collaborated and validated our targets with the group from Korea, who had a more controlled cohort of patients with HCC from their clinical trial (NCT03695952). The analyses were conducted separately in each individual cohort, with Korean patients as the validation cohort, precisely as we recognized their differences. We are encouraged by the fact that despite significant differences between the two cohorts (as analyzed by Zhou
      • Zhou Q.
      Challenges and issues in bivariate endpoints in study designs of translational medicine.
      ), the same immune targets remained robust and significant. Our multivariate analyses of these factors within each cohort also show that these clinical characteristics do not significantly confound our analyses (Table S8).
      • Chuah S.
      • Lee J.
      • Song Y.
      • Kim H.D.
      • Wasser M.
      • Kaya N.A.
      • et al.
      Uncoupling immune trajectories of response and adverse events from anti-PD-1 immunotherapy in hepatocellular carcinoma.
      We hope that this will encourage other groups to expand their work beyond Asian cohorts to examine if the same immune targets can be validated in their cohorts.
      Finally, the author commented on the rationale for using the word “trajectory” in our study. We used the word “trajectory” in a broad sense of the different paths the immune response can take in response or irAEs to immunotherapy, not in the narrower sense of a timepoint analysis. Response and irAEs in immunotherapy are generally understood to occur in tandem, as mentioned above. Our study uncouples these two events and shows that there are differences in the immune responses in each event. In addition, we have also conducted timepoint analysis with pre- and post-treatment samples with implications on the potential movements and modifications of these immune cells, supporting the distinct “trajectory” pathways that the cells took in response to ICB.
      In conclusion, we thank the author once again for the tremendous interest and time invested in interpreting and understanding our study. We would acknowledge the limited sample sizes but remain encouraged by our data that show the potential of novel combination immunotherapy, which we are currently planning to expand to a larger scale clinical validation.

      Financial support

      This work was supported by the National Medical Research Council (NMRC), Singapore (ref numbers: NMRC/OFLCG/003/2018, NMRC/TCR/015-NCC/2016, NMRC/CSA-SI/0013/2017, NMRC/CSA-SI/0018/2017 and NMRC/STaR/020/2013).

      Authors' contributions

      S. Chuah and V. Chew drafted the letter and D. Tai edited and approved the final version.

      Conflict of interest

      All authors declared no conflict of interest.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Supplementary data

      The following are the supplementary data to this article:

      References

        • Zhou Q.
        Challenges and issues in bivariate endpoints in study designs of translational medicine.
        J Hepatol. 2022; 77: 1726-1727
        • Chuah S.
        • Lee J.
        • Song Y.
        • Kim H.D.
        • Wasser M.
        • Kaya N.A.
        • et al.
        Uncoupling immune trajectories of response and adverse events from anti-PD-1 immunotherapy in hepatocellular carcinoma.
        J Hepatol. 2022; 77: 683-694
        • Yau T.
        • Kang Y.-K.
        • Kim T.-Y.
        • El-Khoueiry A.B.
        • Santoro A.
        • Sangro B.
        • et al.
        Nivolumab (NIVO) + ipilimumab (IPI) combination therapy in patients (pts) with advanced hepatocellular carcinoma (aHCC): results from CheckMate 040.
        J Clin Oncol. 2019; 37 (4012-4012)
        • Finn R.S.
        • Qin S.
        • Ikeda M.
        • Galle P.R.
        • Ducreux M.
        • Kim T.Y.
        • et al.
        Atezolizumab plus Bevacizumab in unresectable hepatocellular carcinoma.
        N Engl J Med. 2020; 382: 1894-1905
        • Xu S.
        • Lai R.
        • Zhao Q.
        • Zhao P.
        • Zhao R.
        • Guo Z.
        Correlation between immune-related adverse events and prognosis in hepatocellular carcinoma patients treated with immune checkpoint inhibitors.
        Front Immunol. 2021; 12794099
        • Ye W.
        • Olsson-Brown A.
        • Watson R.A.
        • Cheung V.T.F.
        • Morgan R.D.
        • Nassiri I.
        • et al.
        Checkpoint-blocker-induced autoimmunity is associated with favourable outcome in metastatic melanoma and distinct T-cell expression profiles.
        Br J Cancer. 2021; 124: 1661-1669