https://biomedres.us/pdfs/BJSTR.MS.ID.009118.pdf 

https://www.researchgate.net/publication/383861594_An_Independent_Review_of_Camrelizumab-Rivoceranib_Combination_Therapy_for_the_Treatment_of_Hepatocellular_Carcinoma_and_Rivoceranib_for_Gastric_Cancer/

Abstract: The CARES-310 clinical trial compared the safety and efficacy of camrelizumab, an anti-PD-1 antibody, combined with rivoceranib, a vascular endothelial growth factor receptor 2 (VEGFR2)-targeted tyrosine kinase inhibitor (TKI), versus the obsolete standard of care sorafenib as first-line (1L) treatment for unresectable hepatocellular carcinoma (uHCC). In this independent analysis of the CARES-310 trial, potential bias in the choice of comparator and the clinical significance of the results are reexamined. Although rivoceranib (also known as “apatinib”) is approved in China to treat patients with advanced gastric cancer, the clinical trial conducted in the USA for patients with gastric cancer seems to indicate missed endpoints and weak evidence to justify FDA approval. Due to a nondisclosure agreement, the principal investigators are unable to comment on these results. However, from a table of functional benefits and harms, readers might well conclude that palliative hospice care is non-inferior to rivoceranib for patients with Stage 4 gastric cancer.

https://biomedres.us/pdfs/BJSTR.MS.ID.009118.pdf

Conclusion

The CARES-310 clinical trials produced a new longest median OS of 23.8 months for patients with uHCC treated with C-R.  However, the CARES-310 clinical trial may have been overweighted with an Asian population with preexposure to antiviral therapy and better preservation of liver function at time of HCC diagnosis. Conversely, the CARES-310 trial was underweighted with Western patients who have NAFLD, diabetes, obesity, and other co-morbidities and confounding factors.  Oncologists already have 1L patient treatment experience for uHCC with Roche’s FDA-approved anti-PD-L1/VEGF combination Tecentriq and Avastin and with AstraZeneca’s CTLA-4 checkpoint inhibitor Imjudo combined with its PD-L1 antagonist Imfinzi for treatment of uHCC. It would be useful to compare the C-R proposed therapy with these drug combinations and determine if C-R maintains an 8.6-month median OS advantage over the new comparator(s).

When rivoceranib plus hospice care was compared to hospice care alone in a clinical trial of patients with advanced gastric cancer or gastroesophageal adenocarcinoma, the results data were mixed. For some measures of functional benefits and harms, the patients with hospice care alone had higher percentages for certain functional benefits and lower percentages for some harms and adverse events.  The rivoceranib-treated group failed to consistently outperform hospice care alone using these measures.  Based on those benefits and harms, hospice care alone was not inferior to rivoceranib + hospice care, which calls into question the underlying clinical value, if any, of rivoceranib to the American patient population with advanced gastric cancer.  The fact that rivoceranib, known as apatinib, is approved in China for treatment of advanced gastric raises anew questions about fundamental differences in patient populations between China and the USA or Europe for medical conditions such as uHCC and advanced gastric cancer.

References

1. Lexchin J, Bero LA, Djulbegovic B, Clark O. Pharmaceutical industry sponsorship and research outcome and quality: systematic review. BMJ. 2003 May 31;326(7400):1167-70. (“Systematic bias favours products which are made by the company funding the research. Explanations include the selection of an inappropriate comparator to the product being investigated and publication bias.”)
2. Sismondo S. Epistemic Corruption, the Pharmaceutical Industry, and the Body of Medical Science. Front Res Metr Anal. 2021 Mar 8;6:614013 (“Put simply, if a pharmaceutical company funds a trial, the chances of results and conclusions in that company’s favor are increased.”)
3. Bradley SH, DeVito NJ, Lloyd KE, Richards GC, Rombey T, Wayant C, Gill PJ. Reducing bias and improving transparency in medical research: a critical overview of the problems, progress and suggested next steps. J R Soc Med. 2020 Nov;113(11):433-443 (“[A]voidable methodological failings and biases lead to ‘research waste’, which is estimated to account for 85% of all medical research funding.”)
4. Sismondo S (2007) Ghost Management: How Much of the Medical Literature Is Shaped Behind the Scenes by the Pharmaceutical Industry? PLoS Med 4(9): e286. https://doi.org/10.1371/journal.pmed.0040286[1]
5. Mann H, Djulbegovic B. Comparator bias: why comparisons must address genuine uncertainties. J R Soc Med. 2013 Jan;106(1):30-3.
6. Setoguchi S, Gerhard T. Comparator Selection. In: Velentgas P, Dreyer NA, Nourjah P, et al., editors. Developing a Protocol for Observational Comparative Effectiveness Research: A User’s Guide. Rockville (MD): Agency for Healthcare Research and Quality (US); 2013 Jan. Chapter 5. Available from: https://www.ncbi.nlm.nih.gov/books/NBK126184/
7. Pinato DJ, D’Alessio A, Celsa C, Manfredi GF, Fulgenzi CAM. The price and value of therapeutic synergy in liver cancer. Lancet. 2023 Sep 30;402(10408):1108-1110.
8. Lee, W.S., Yang, H., Chon, H.J. et al. Combination of anti-angiogenic therapy and immune checkpoint blockade normalizes vascular-immune crosstalk to potentiate cancer immunity. Exp Mol Med 52, 1475–1485 (2020). https://doi.org/10.1038/s12276-020-00500-y
9. Qin S, Chan SL, Gu S, et al., CARES-310 Study Group. Camrelizumab plus rivoceranib versus sorafenib as first-line therapy for unresectable hepatocellular carcinoma (CARES-310): a randomised, open-label, international phase 3 study. Lancet. 2023 Sep 30;402(10408):1133-1146.
10. Supplement to: Qin S, Chan SL, Gu S, et al. Camrelizumab plus rivoceranib versus sorafenib as first-line therapy for unresectable hepatocellular carcinoma (CARES-310): a randomised, open-label, international phase 3 study. Lancet 2023; published online July 24. https://doi.org/10.1016/S0140-6736(23)00961-3.
11. Wang, F., Qin, S., Sun, X. et al. Reactive cutaneous capillary endothelial proliferation in advanced hepatocellular carcinoma patients treated with camrelizumab: data derived from a multicenter phase 2 trial. J Hematol Oncol 13, 47 (2020).
12. Liu Y, Chen T, Zhang C, Pan W. Emerging Treatments for Reactive Cutaneous Capillary Endothelial Proliferation. Indian J Dermatol. 2023 Jan-Feb;68(1):85-90.
13. Vogel A., Chan SL, Ren Z et al. Camrelizumab plus rivoceranib vs sorafenib as first-line therapy for unresectable hepatocellular carcinoma (uHCC): Final overall survival analysis of the phase 3 CARES-310 study. Journal of Clinical Oncology 42(16_suppl) https://doi.org/10.1200/JCO.2024.42.16_suppl.4110.
14. Li, J., Qin, S., Wen, L. et al.Safety and efficacy of apatinib in patients with advanced gastric or gastroesophageal junction adenocarcinoma after the failure of two or more lines of chemotherapy (AHEAD): a prospective, single-arm, multicenter, phase IV study. BMC Med 21, 173 (2023). https://doi.org/10.1186/s12916-023-02841-7
15. Liu, Angus, “FDA snubs another China-made PD-1 with rejection of Elevar, Hengrui’s liver cancer combo,” Fierce Pharma. 2024 May 17.https://www.fiercepharma.com/pharma/fda-pd-1-combo-elevar-hengrui-camrelizumab-liver-cancer
16. Kansteiner, Fraiser, “Elevar commits $600M-plus to take Hengrui’s liver cancer cocktail to market in US and beyond,” Fierce Pharma. 2023 Oct 17. https://www.fiercepharma.com/ pharma/elevar-ponies-600m-take-hengruis-investigational-liver-cancer-cocktail-market-us-and-beyond
17. Elevar Therapeutics, “Elevar Therapeutics Reports Plans for Near-Term Resubmission of NDA for First-Line Treatment Option for Unresectable Hepatocellular Carcinoma Following Type A FDA Meeting,” Press Release. 2024 Jul 9. https://elevartherapeutics.com/2024/07/09/ elevar-therapeutics-first-line-treatment-option/
18. Liu, Angus, “UPDATED: Elevar, Hengrui eye accelerated refile for PD-1 liver cancer combo after surprise FDA rejection” Fierce Pharma. 2024 Jul 12. https://www.fiercepharma.com/ pharma/elevar-hengrui-eye-quick-refile-pd-1-liver-cancer-combo-after-surprise-fda-rejection

Acknowledgments

Christopher Coleman, Pharm.D., provided useful comments.

Conflict of Interests

None.

In the obesity landscape, glucagoon-like peptide-1 (GLP-1) agonists dominate the weight loss market. Amylin agonists work differently from GLP-1s but may be able to induce similar weight loss with fewer adverse events. My client wanted to understand the molecular differences between various amylin assets and their hypothetical impacts on the efficacy / adverse event profile.

Project’s key research questions/topics include:
(1) Describe the medical literature as it pertains to Amylin for obesity specifically – e.g. years researching, articles on Amylin published, clinical trials, or other types of experience – please specify.

(2) Comment on the differences between cagrilintide, petrelintide, amycretin and any other amylin agonists?

(3) Describe the theoretical physiologies of the various subsets within amylin receptors (calcitonin, AMY1R, AMY2R, AMY3R).

(4) Comment on whether the pH of the assets differ, and whether these could have material impacts on the drug profile?

(5) Comment on the solubility of cagrilintide and other amylin assets, as well as the corresponding impacts on the drug profile (e.g. half-life)?

Despite the similarities between GLP-1 and Amylin agonists (e.g. both molecular classes slow gastric emptying, decrease glucagon, and inhibit food intake), there are important distinctions between the central and/or peripheral pathways that mediate their effects on hyperglycemia and energy balance.

Pictures shot by Heather Cox Richardson while kayaking.