Phase III Soft Tissue Sarcoma Trials: Success or Failure?
Two recently reported phase III randomised control trials (RCTs) have resulted in the registration of two new systemic therapies for advanced soft tissue sarcoma. Both of these trials' designs were informed by phase II data that guided the selection of sensitive STS diagnoses, enabling the demonstration of benefit in certain subtypes. A number of other phase III trials reported in the last 18 months have seemingly fit into a recurrent pattern of failure-promising efficacy signals in earlier phase studies being lost in the survival follow-up of large, highly heterogeneous cohorts. Greater effort is needed to identify histological and molecularly defined subgroups associated with differential treatment response in order to avoid the tremendous disappointment and loss of resources associated with a failed phase III trial. Additionally, improvements in available treatment of advanced STS have underpinned a prolongation in overall survival (OS). Consequently, surrogate efficacy endpoints are of increasing importance to STS drug trials. Whilst progression-free survival (PFS) should arguably replace overall survival as the primary endpoint of choice in first-line studies, more work is required to provide definitive validation of surrogacy, as well as developing more sophisticated techniques of assessing radiological response and expanding the inclusion of quality-of-life-related endpoints.
Sarcoma Unit, The Royal Marsden NHS Foundation Trust, London, UK.|Division of Cancer Biology, The Institute of Cancer Research, London, SW3 6JB, UK.
Alexander T J
AT
Lee
Fred Hutchinson Cancer Research Center, Seattle, WA, USA.|University of Washington, Seattle, WA, USA.
Seth M
SM
Pollack
Division of Cancer Biology, The Institute of Cancer Research, London, SW3 6JB, UK.
Paul
P
Huang
Sarcoma Unit, The Royal Marsden NHS Foundation Trust, London, UK. robin.jones4@nhs.net.|Division of Clinical Studies, The Institute of Cancer Research, London, UK. robin.jones4@nhs.net.|Sarcoma Unit, Royal Marsden Hospital, Fulham Road, London, SW3 6JJ, UK. robin.jones4@nhs.net.
Robin L
RL
Jones
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D017326:Clinical Trials, Phase III as Topic; D006801:Humans; D009367:Neoplasm Staging; D016032:Randomized Controlled Trials as Topic; D012107:Research Design; D012509:Sarcoma / Q000473:pathology / Q000628:therapy*; D059039:Standard of Care; D017211:Treatment Failure; D016896:Treatment Outcome
Clinical trial design; Soft tissue sarcoma; Systemic therapy; Trial endpoints