Soft tissue sarcomas (STS) and bone sarcomas are a heterogeneous group of malignant tumours of mesenchymal cell origin. The annual incidence is around 2-3/100.000, thus accounts for approx. 1 % of solid malignancies. In advanced STS patients only few cytostatic drugs like doxorubicin, ifosfamide, dacarbazine, trabectedine, gemcitabine and docetaxel have been proven to be active but toxic and in general without any curative or even a long-lasting effect when surgical resection is not possible or patient has relapsed. Although some specific alterations in different chromosomes have been identified and established as diagnostic criteria, mainly for paediatric osteosarcomas or rhabdomyosarcomas, the pathogenetic cascade remains obscure. However, new targeted therapies have also demonstrated some activity in STS and the combination with chemotherapy may be appropriate to improve outcome in these patients. Angiogenesis inhibitors may play a role particularly in angiosarcoma patients but multi tyrosine kinase inhibitors like Pazopanib (anti VEGFR/PDGFR/KIT) seem to be more active because of their potential of blocking several pathways.
Summary and discussion of the presented study
The mammalian target of rapamycin (mTOR) may be another interesting target for sarcoma patients. mTOR is as serine/threonine kinase, a central regulator in the PI3K/AKT pathway which is often deregulated in human cancer. Ridaforolimus is an analog of rapamycin and causes tumour growth inhibition in cell-line and animal models. It showed promising activity in an early phase I trial for STS patients and was well tolerated (1).
Chawla et al. tested Ridaforolimus in a multicentre, open-label, single-arm phase II study in a total of 212 patients with metastatic or unresectable STS or bone sarcoma (2). Patients received the study drug in a fixed-dose infusion of 12.5 mg once daily for 5 consecutive days every 2 weeks which based on phase I clinical experience. The most interesting part of the trial design was the innovative primary endpoint of clinical benefit response (CBR), defined as the number and percentage of patients who achieved either complete, partial response or stable disease according to RECIST criteria with duration ≥ 16 weeks. CBR reflects the need of new endpoints for targeted therapy which main potential is disease stabilisation instead of massive tumour shrinkage. 28.8 % of the patients achieved CBR. Results were stratified over different histological cohorts (bone sarcoma, leiomyosarcoma, liposarcoma, other sarcoma) with no significant discrepancy for one group. The second end points median PFS and OS were 15.3 and 40 weeks, respectively. Interestingly and confirming the above-mentioned is the matter of fact that the confirmed response according to RECIST was only seen in 1.9 % of the treated patients. Survival data are consistent with historical metrics of patients treated with conventional chemotherapy, however, these effects were achievable which much less toxicity compared to chemotherapy. The most common adverse events were stomatitis, mucosal ulcera, hyperlipidemia, fatigue, rash, nausea and haematologic cytopenia, mostly mild or moderate and all of them consistent with the expected rate. Interstitial pneumonitis, a well-known side effect mTOR inhibitors, occurred in 2 %, but only 1 patient discontinued treatment therefore.
With the results of this study Chawla et al. are able to proof Ridaforolimus as an active and well-tolerated drug in STS and bone sarcoma patients which might be able to abandon chemotherapy as the only effective therapy in the locally advanced or metastatic situation.
In a maintenance setting after prior standard cytotoxic therapy for advanced sarcoma patients Ridaforolimus met the prespecified endpoint of improved PFS (17.7 weeks vs. 14.6 weeks; HR=0.72) in the phase III randomised, placebo controlled SUCCEED trial which was presented by the same first author at ASCO annual meeting 2011 (3).
The translational part of the phase II study failed to correlate plasma VEGF levels with response rate and by analysing archival tumour probes by immunohistochemistry no upstream or downstream protein of the mTOR pathway like PTEN, p-AKT or IGF-1R could be identified as being predictable for the patients response. This is very disappointing because without any clue for a biomarker further phase II-III trials of mTOR inhibitors will not be able to prospectively validate them. This means a setback for any hope for an individualised therapy in sarcoma patients.
Taken alone all those data for mTOR inhibition in advanced STS and bone sarcomas are not very worldshaking but taken together they are able to proof the concept and give rise to further studies with Ridaforolimus and other mTOR inhibitors. In doing so the benefit of new and targeted drugs in patients with metastatic disease has to be determined by the potential of disease stabilisation and prolonging the so far bad 5-year overall survival rate of only 6 %. It has to be suggested that the common response markers like radiologic response by RECIST will become an obsolescent model in the future because our new strategy of targeting the pathways of tumour growth or angiogenesis has a greater potential of cytostasis rather than cytotoxic effects (as conventional chemotherapy has). Unless we cannot cure metastatic sarcoma in general such new drugs like Ridaforolimus have the ability to stabilise and in some case lead to chronicity with long lasting survival and less toxic effects. Understanding the mechanisms of developing Ridaforolimus resistance, identification of biomarkers which may lead to a personalised and prospective use in specific well-understood subtypes of sarcomas or the combination of different target inhibitors with or without conventional chemotherapy will help us to further improve the outcome of locally advanced and metastatic STS and bone sarcoma patients.
(1) Mita et al., J Clin Oncol 2008;26:361-367
(2) Chawla et al., J Clin Oncol 2012;30:78-84
(3) Chawla et al., J Clin Oncol 2011;29 (suppl; abstr 100005)