Someone asked me whether it would be possible to have an update on new therapeutics in melanoma recently and I'm pleased to say there were some interesting data in this difficult to treat cancer at the recent ASCO meeting in Orlando.
Melanona is an immune type cancer but the long held theory that various immune type therapies such as vaccines would work effectively has not yielded significant results, mainly because stimulating the body's immune response to attack the cancer cells has not led to very durable results. The bedrock of treatment has therefore remained as a stark choice between DTIC, IL-2 or interferon therapy, all of which are severely limited by side effects.
At ASCO this year, a number of new approaches were tried and tested. These included aflibercept (VEGF-Trap), an anti-angiogenic VEGF inhibitor, intetumumab (CNTO-95), an alpha integrin, ADI-PEG 20 which affects cell metabolism and arginine depletion, sagilipone (ZK-EPO), which affects microtubulin function (similar to ixabepilone), CRO11-vcMMAE, another microtubulin compound and ipilimumab, BMS's CTLA-4 antibody. This variety of new therapeutics raises a number of interesting questions, including whether the targets are clinically relevant in melanoma and were patients selected appropriately for the studies.
This blog post will focus on the data for VEGF-Trap, intetumumab and ipilumumab.
The VEGF-Trap study (Abstract #9028) looked at patients with stage III or IV melanoma with no prior chemotherapy and no brain mets. VEGF-Trap is a fusion protein combining the Fc portion of human IgG1 with the principal extracellular ligand binding domains of human VEGFR1 and 2, leading to angiogenesis inhibition. The phase II study looked at response rate and 4 month PFS. Aflibercept was given 4mg/kg iv every 2 weeks for 8 weeks. The stated goal of the trial was to improve median PFS from 2.3 months to 4 months, which corresponds to a PFS rate from 30% to 50%.
41 patients were enrolled and the therapy was shown to be well tolerated with predictable class adverse events including hypertension, GI bleeding and proteinuria. 1 response was seen and a further 20 patients had stable disease. Early results suggest that a PFS of 6 months, if so the study endpoint will be met. This is one of many trials exploring anti-angiogenesis therapy in patients with melanoma, either as a single agent or in combination with chemotherapy.
The CNTO 95 study (abstract #9029) looked at a phase II study alone or in combination with dacarbazine in patients with stage IV melanoma with two different dosage arms per treatment. 129 patients were enrolled and the main adverse events seen were cytopenias related to DTIC and uveitis related to intetumumab.
Intetumumab alone (either dose) resulted in a PFS of 1.4 months, DTIC alone was 1.8 months, while intetumumab plus DTIC was 2.5 months. Overall survival was 9.8, 7.6, 14.0 and 10.9 months respectively. This study was complicated by the sample size not based on statistical power considerations so it is difficult to draw any conclusions between the four study arms and there is little rational for the combination. Although the target may be relevant, trials to date have shown little clinical activity.
The most interesting data was on ipiliumumab (abstract #9033), which looked at the effect of the agent on 18 and 24 month survival from 3 phase II trials dosed at 10mg/kg every 3 weeks (plus maintenance therapy Q12W from week 24 in appropriate patients) in advanced melanoma, where survival outcomes are usually poor. Ipilumumab is a fully humanised monoclonal antibody that targets T-lymphocyte antigen 4 (CTLA-4). The 3 studies summarised were CA184-008, CA184-022, CA184-007.
The results clearly showed that:
– 12 month survival rates were >47%
– 18 month survival rates were >34%
– 24 month survival rates were >30%
For previously treated patients, 24 month survival rates ranged from 24% to 33%.
Long term survivors included patients with progressive disease according to WHO criteria.
These results are promising but caution must be extended because a significant number of patients were lost to follow-up, which may reduce the reliability of the results. Ongoing biomarker studies are looking at predicting which patients are most likely to benefit from ipilumumab therapy.
What did we learn from these trials? Well, there is an urgent need to define optimal endpoints for melanoma clinical trials in terms of response rate, PFS, OS and survival at 12 months. It is interesting that over the past 10 years the majority of abstracts have hyped the results in this disease as 'promising' or 'clinically active' regimens and yet very little in the way of new therapies have actually been approved by the FDA. Based on these data, I suspect it will still be a little while before we see some solid phase III data in malignant melanoma.