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.

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