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MYSTIC interim results: any future for tremelimumab?

by ecancer reporter Will Davies

According to today’s reports, the combination of durvalumab and tremelimumab in the MYSTIC trial has failed, at an interim analysis, to extend progression free survival for EGFR/ALK lung cancer. This has delivered a blow to the manufacturer, AstraZeneca. Matters are further complicated by the recent triumph of durvalumab monotherapy, in meeting its PFS endpoint early in the PACIFIC trial.

These results come a week after tremelimumab failed to significantly extend overall survival in patients with relapsed malignant mesothelioma1, despite a phase II trial describing safety and (admittedly small) activity2. This follows almost exactly the same course of events in the initial safety and activity of the MYSTIC schedule3 leading to the current situation AstraZeneca finds itself in.

Does this put all the blame on tremelimumab? As a humanised anti-CTLA-4 antibody, one might expect that it could slot neatly into combinations with PD-1 checkpoint inhibitors in place of ipilimumab. However, while tremelimumab has displayed near-identical binding properties to ipilimumab4, it has yet to reach the same headline status: Where Prof Alexander Eggermonts presentation at ESMO 2016 on adjuvant ipilimumab for melanoma reported improved overall survival in a phase III trial, and Prof Robert Andtbacka discussed successful trials of ipilimumab in combination with oncolytic viruses, tremelimumab has faltered in many skin cancer indications.

For melanoma patients with confirmed BRAF/NRAS mutation, that positivity makes no difference in median overall survival for those treated with tremelimumab compared to SOC5. In metastatic melanoma cases, front-line tremelimumab also returns no survival advantage compared to SOC6. However, response duration, in this case, was significantly longer.

And here is where the fortune for MYSTIC starts to look a little brighter: late-onset activity seems to be something of hall-mark for tremelimumab - in uveal melanoma, promising overall survival benefits came only after mundane 6 month PFS and low responses in the first interim, leading to study cessation citing futility7. Some advanced melanoma patients, meanwhile, report a long duration of objective response, beyond 12 years8.
Beyond melanoma, in case studies of bile duct cancer and squamous cell carcinoma, initial disease progression was followed by ‘remarkable’ tumour shrinkage without immune related adverse events9. In hepatocellular carcinoma, tremelimumab and tumour ablation produced positive results, increased T cell infiltration, and saw a reduction in hepatitis C viral load10.

It is worth considering the class associated toxicities of anti-ctla-4 molecules, though, and how they manifest in disease indications, which seem to include an increased risk of:
• Damage to ocular tissue11
• severe and extensive inflammatory bowel disease12
• hepatoxicity13
• high grade fatigue14
In the renal setting, combinations of tremelimumab with sunitinib have been found to cause rapid-onset renal failure, with researchers warning off further investigation15. Similarly, a lack of significant activity and toxic profile rule tremelimumab, and checkpoint inhibitors as a whole, unsuitable for multiple myeloma16.

As a whole, though, combination therapies bringing on exacerbated side effects are nothing new, and many trials of combined PD-1 / CTLA-4 targeted molecules report a manageable profile. For example, Dr Sandra D’Angelo spoke with ecancer at ASCO 2017 about such a combination for sarcoma, and some think increased toxicity may be associated with increased tumour response rate17

What this means for the ARCTIC trial18 of durvalumab in PD-L1 tumours and durvalumab with/out tremelimumab for PD-L1- tumours remains unclear. However, if that characteristic delayed duration benefit holds true for overall survival in MYSTIC, patients and AstraZeneca staff alike may breathe a sigh of relief.

 

 

  1. Maio, M., Scherpereel, A., Calabrò, L., Aerts, J., Perez, S. C., Bearz, A., … Kindler, H. L. (2017). Tremelimumab as second-line or third-line treatment in relapsed malignant mesothelioma (DETERMINE): a multicentre, international, randomised, double-blind, placebo-controlled phase 2b trial. The Lancet Oncology. https://doi.org/10.1016/s1470-2045(17)30446-1
  2. Calabrò, L., Morra, A., Fonsatti, E., Cutaia, O., Amato, G., Giannarelli, D., … Maio, M. (2013). Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial. The Lancet Oncology, 14(11), 1104–1111. https://doi.org/10.1016/s1470-2045(13)70381-4
  3. Antonia S, Goldberg SB, Balmanoukian A, Chaft JE, Sanborn RE, Gupta A, Narwal R, Steele K, Gu Y, Karakunnel JJ, Rizvi NA, Safety and antitumour activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b study. Lancet Oncol. 2016 Mar; 17(3):299-308.
  4. Remarkably similar CTLA-4 binding properties of therapeutic ipilimumab and tremelimumab antibodies., He, M., Chai, Y., Qi, J., Zhang, C. W. H., Tong, Z., Shi, Y., … Gao, G. F. (2017). Remarkably similar CTLA-4 binding properties of therapeutic ipilimumab and tremelimumab antibodies. Oncotarget. https://doi.org/10.18632/oncotarget.18004
  5. Mangana J, Cheng PF, Schindler K, Weide B, Held U, Frauchiger AL, Romano E, Kähler KC, Rozati S, Rechsteiner M, Moch H, Michielin O, Garbe C, Hauschild A, Hoeller C, Dummer R, Goldinger SM. Analysis of BRAF and NRAS Mutation Status in Advanced Melanoma Patients Treated with Anti-CTLA-4 Antibodies: Association with Overall Survival? PLoS One. 2015 Oct 1;10(10):e0139438. doi: 10.1371/journal.pone.0139438. eCollection 2015.
  6. Antoni Ribas, Richard Kefford, Margaret A. Marshall, Cornelis J.A. Punt, John B. Haanen, Maribel Marmol, Claus Garbe, Helen Gogas, Jacob Schachter, Gerald Linette, Paul Lorigan, Kari L. Kendra, Michele Maio, Uwe Trefzer, Michael Smylie, Grant A. McArthur, Brigitte Dreno, Paul D. Nathan, Jacek Mackiewicz, John M. Kirkwood, Jesus Gomez-Navarro, Bo Huang, Dmitri Pavlov, and Axel Hauschild, Phase III Randomized Clinical Trial Comparing Tremelimumab With Standard-of-Care Chemotherapy in Patients With Advanced Melanoma, Journal of Clinical Oncology 2013 31:5, 616-622 
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  8. Eroglu Z, Kim DW, Wang X, Camacho LH, Chmielowski B, Seja E, Villanueva A, Ruchalski K, Glaspy JA, Kim KB, Hwu WJ, Ribas A. Long term survival with cytotoxic T lymphocyte-associated antigen 4 blockade using tremelimumab. Eur J Cancer. 2015 Nov;51(17):2689-97. doi: 10.1016/j.ejca.2015.08.012. Epub 2015 Sep 10.
  9. Shimomura A, Fujiwara Y, Kondo S, Kodaira M, Iwasa S, Kitano S, Tanabe Y, Tamura K, Yamamoto N. Tremelimumab-associated tumour regression following after initial progression: two case reports. Immunotherapy. 2016;8(1):9-15. doi: 10.2217/imt.15.89. Epub 2015 Oct 2.
  10. Duffy, A. G., Ulahannan, S. V., Makorova-Rusher, O., Rahma, O., Wedemeyer, H., Pratt, D., … Greten, T. F. (2017). Tremelimumab in combination with ablation in patients with advanced hepatocellular carcinoma. Journal of Hepatology, 66(3), 545–551. https://doi.org/10.1016/j.jhep.2016.10.029
  11. Abdel-Rahman, O., Oweira, H., Petrausch, U., Helbling, D., Schmidt, J., Mannhart, M., … Giryes, A. (2017). Immune-related ocular toxicities in solid tumor patients treated with immune checkpoint inhibitors: a systematic review. Expert Review of Anticancer Therapy, 17(4), 387–394. https://doi.org/10.1080/14737140.2017.1296765
  12. Marthey L, Mateus C, Mussini C, Nachury M, Nancey S, Grange F, Zallot C, Peyrin-Biroulet L, Rahier JF, Bourdier de Beauregard M, Mortier L, Coutzac C, Soularue E, Lanoy E, Kapel N, Planchard D, Chaput N, Robert C, Carbonnel F. Cancer Immunotherapy with Anti-CTLA-4 Monoclonal Antibodies Induces an Inflammatory Bowel Disease., J Crohns Colitis. 2016 Apr;10(4):395-401. doi: 10.1093/ecco-jcc/jjv227. Epub 2016 Jan 18.
  13. Wang, W., Lie, P., Guo, M., & He, J. (2017). Risk of hepatotoxicity in cancer patients treated with immune checkpoint inhibitors: A systematic review and meta-analysis of published data. International Journal of Cancer, 141(5), 1018–1028. https://doi.org/10.1002/ijc.30678
  14. Abdel-Rahman O, Helbling D, Schmidt J, Petrausch U, Giryes A, Mehrabi A, Schöb O, Mannhart M, Zidan A, Oweira H., Treatment-associated Fatigue in Cancer Patients Treated with Immune Checkpoint Inhibitors; a Systematic Review and Meta-analysis., Clin Oncol (R Coll Radiol). 2016 Oct;28(10):e127-38. doi: 10.1016/j.clon.2016.06.008. Epub 2016 Jun 20. Review.
  15. Rini BI, Stein M, Shannon P, Eddy S, Tyler A, Stephenson JJ Jr, et al. Phase 1 dose-escalation trial of tremelimumab plus sunitinib in patients with metastatic renal cell carcinoma. Cancer. 2011;117(4):758–67. doi:10.1002/cncr.25639.
  16. Guazzelli, A., Bakker, E., Krstic-Demonacos, M., Lisanti, M. P., Sotgia, F., & Mutti, L. (2017). Anti-CTLA-4 therapy for malignant mesothelioma. Immunotherapy, 9(3), 273–280. https://doi.org/10.2217/imt-2016-0123
  17. Tanvetyanon, T., Gray, J. E., & Antonia, S. J. (2017). PD-1 checkpoint blockade alone or combined PD-1 and CTLA-4 blockade as immunotherapy for lung cancer? Expert Opinion on Biological Therapy, 17(3), 305–312. https://doi.org/10.1080/14712598.2017.1280454
  18. Planchard D, Yokoi T, McCleod MJ, Fischer JR, Kim YC, Ballas M, Shi K, Soria JC. A Phase III Study of Durvalumab (MEDI4736) With or Without Tremelimumab for Previously Treated Patients With Advanced NSCLC: Rationale and Protocol Design of the ARCTIC Study., Clin Lung Cancer. 2016 May;17(3):232-236.e1. doi: 10.1016/j.cllc.2016.03.003. Epub 2016 Mar 17.
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