Developing Drugs for Sarcomas in a Brave New World

Sarcomas are a rare heterogeneous group of malignant diseases. Progressive recognition of discerning histological attributes, differing molecular features, and varying clinical course in recent years has allowed for more accurate identification of specific subtypes. This stratification between sarcoma subtypes has allowed for better recognition of the disease, and to a certain extent, also for the tailoring of treatment, which we believe has improved therapeutic outcomes; however, this further subdivision also means increasing complexities and nuances in what was once a “one-size-fits-all” treatment approach. There is also a strong push to have sarcomas diagnosed and treated at dedicated high-volume centers equipped with specialized multidisciplinary teams.^[1]

Harsh lessons were learned by the sarcoma community when drugs that were seemingly efficacious in phase 2 studies failed to meet the efficacy benchmarks required in later phase 3 and registrational studies. Prior examples include the PICASSO-III trial in 2015 of palifosfamide^[2] and the SARC-21 trial of evofosfamide in 2017,^[3] which both failed to show any efficacy superiority, in combination with doxorubicin, over doxorubicin alone in patients with advanced soft tissue sarcomas who were treatment naïve. “Postmortem” analyses of these pivotal trials were performed to assess whether these failures were due to a genuine lack in efficacy versus an overzealous estimate on proposed therapeutic gains of these new agents in addition to our “gold-standard” of single-agent doxorubicin. Although the conclusion is most likely a combination of the two factors, one critical aspect common to both studies was in their clinical trial designs. There was a lack of predefined cohorts of differing sarcoma subtypes. This meant that there was no control on the number of patients with differing histological sarcoma subtypes who entered the trial, which can lead to dilution of any positive (or negative) results.

More recently, the same mistake was made. The US Food and Drug Administration (FDA) and the European Medicines Agency provided their accelerated conditional approval of olaratumab in October and November 2016, respectively, despite not having (and even to this day) a clear understanding of the mechanisms of action of olaratumab, as a large overall survival benefit of 26.5 months versus 14.7 months (hazard ratio 0.46; 95% CI, 0.30–0.71; p = .0003) was seen in the open-labeled phase 2 trial.^[4] Fast forward to 2019. At the American Society of Clinical Oncology Annual Meeting, the ANNOUNCE randomized, double-blind, placebo-controlled phase 3 study of doxorubicin and olaratumab versus doxorubicin alone in patients with advanced soft tissue sarcoma not amenable to curative therapy^[5] was presented. Not only was there no statistically significant benefit to patients' survival with addition of olaratumab to single-agent doxorubicin backbone, numerically the median overall and progression-free survival were nearly identical. A fatal flaw in the trial design of ANNOUNCE^[5] was again the fact that patients with a variety of sarcomas were recruited without being assigned to specific analysis cohorts, nor were their numbers controlled. This inherent dilution of any positive (or negative) outcomes is by far the most apparent stumbling block for drug development in sarcomas. Interestingly, the median overall survival in patients who received doxorubicin + placebo as the control arm in the ANNOUNCE trial was 19.7 months,^[5] in contrast to 12.8 months reported for patients who received doxorubicin alone in the EORTC-62012 pivotal trial in 2014.^[6] This improvement in overall survival in patients who were given seemingly identical treatment regimens, but 5 years apart, has been attributed to better supportive care as well as improved second-line treatment options, of which a large proportion of these are histology-specific treatments. There is thus a timely need for us, as a community, to recognize that sarcomas are a heterogeneous group of diseases that deserve our utmost respect for their subtype's individuality. We need to further study and understand both the overlapping similarities and distinct differences between subtypes, and how best to harness these properties to further advance our efforts in developing effective systemic therapies for our patients with sarcoma.

In this issue of Journal of Immunotherapy and Precision Oncology, we have the pleasure of providing our readers with a breadth of articles on timely topics in sarcoma molecular biology, and its influence on rational drug development. Achenbach et al.^[7] provided us with a comprehensive and timely overview on some novel therapeutic targets, as well as early-phase clinical trials data, and the rationale for possible future regulatory approvals. In original research, Arshad et al.^[8] shared their institutional experience of using circulating tumor DNA in more than 70 patients with advanced leiomyosarcomas, 40% of whom had tumors that harbored potentially targetable mutations by FDA-approved or clinical trials, thus opening potential treatment opportunities in an otherwise devastating group of diseases. Wainsztein and Chen^[9] authored a comprehensive review highlighting potential advantages, risks, nuances, and clinical trial experiences in combining the use of various molecular targeted agents with immunotherapy to enhance our therapeutic armamentarium against soft tissue sarcomas. Yang et al.^[10] described a rare case of primary osteosarcoma of the uterus under their care. Through use of whole genome sequencing, they were the first group to identify a potential therapeutic target for this rare disease. Peer education and dissemination of crucial information is of paramount importance in improving treatment outcomes for patients with rare cancers. Loong et al.^[11] shared their experience in organizing the Chinese University of Hong Kong Sarcoma Masterclass in an accompanied conference proceeding within this issue.

As we were gathering submissions for this special issue, the global medical community braced themselves into unchartered territories for a monumental challenge: COVID-19. It is most timely to have Adashek et al.^[12] provide us a brief report on whether patients with cancer are at higher risk of death from COVID-19.

We are entering a Brave New World. I would like to take this opportunity to wish all our readers good health, and to #staysafe and #stayvigilant.