Immunotherapy, Cellular Therapy, and Vaccines

Dr Wilky told Cancer Therapy Advisor that the understanding of the immune microenvironment in sarcomas has made it possible to evaluate checkpoint inhibitors in sarcomas.

Data presented at the 2017 ASCO Annual Meeting showed that combining nivolumab and ipilimumab, 2 checkpoint inhibitors targeting PD-1 and CTLA-4, respectively, was more active in STS than nivolumab alone. The confirmed response rate with the combination was 16% and median OS was 11.2 months.8

Dr Wilky indicated that cellular therapies are under way that engineer T cells such that the T cell receptor is specific for the target, such as NY-ESO-1 on synovial cells. The feasibility of this approach is being evaluated in an ongoing phase 2 study in synovial sarcoma, she added.

Vaccines are also being evaluated in STS. This approach is being tested for patients with refractory Ewing sarcoma and sarcomas expressing NY-ESO-1. The NY-ESO-1-targeting vaccine is being tested in combination with atezolizumab.

Surveying the Mutational Landscape in Sarcoma

Next-generation sequencing (NGS) is now an invaluable approach in surveying the mutational landscape of cancers, providing additional diagnostic information and offering much needed insights into matching actionable targets to therapies. NGS profiles may help in changing diagnoses and identifying patients who may be unresponsive to therapies they would normally be given.

At the 2017 ASCO Annual Meeting, a retrospective analysis of NGS profiles used a panel of 405 cancer-related genes in DNA and 265 genes rearranged in RNA.9

Of the 5635 patients who underwent NGS worldwide, 56 histologies were tested. The investigators found 1165 fusions and more than 60,000 mutations.

Germline mutations suspected in 9.6% of patients constituted novel and known genes (eg, BRCA, ARID1, FANC). Tumor mutational burden was 2.5/Mb.

Importantly, 16% of patients had treatment-linked alterations (TLA) known to respond to approved treatment, while 7% had a TLA that was matched to an investigational therapy.  

Researchers also reported that NGS changed the initial diagnosis and treatment for 5% of patients. Resistance mutations were detected in 5% of patients that would have made patients unresponsive to therapy.

NGS profiling provides a rationale for the first study that will implement exome sequencing and RNA sequencing to match patients to the appropriate therapy.10

Conclusion

Targeted and immunotherapeutic approaches are poised to change how sarcoma will be treated in the future. Early phase 1/2 trials with smaller patient numbers are being used to match tumors with appropriate therapy choices.

As presenters of the education session “The Current Landscape of Early Drug Development for Patients With Sarcoma” at the 2017 ASCO Annual Meeting noted in their article, “it is critical that patients and providers are aware of the rich opportunities for clinical trials for patients with sarcoma refractory to standard therapies.”11

References

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  2. Olaratumab (Lartruvo). US Food and Drug Administration website. https://www.fda.gov/drugs/informationondrugs/ approveddrugs/ucm526087.htm. Published October 19, 2017. Accessed May 29, 2017.
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  7. Judson IR, Morden JP, Leahy MG, et al. Activity of cediranib in alveolar soft part sarcoma (ASPS) confirmed by CASPS (cediranib in ASPS), an international, randomised phase II trial (C2130/A12118). J Clin Oncol. 2017;35(suppl; abstr 11004).
  8. D’Angelo SP, Mahoney MR, Van Tine BA, et al. A multicenter phase II study of nivolumab +/- ipilimumab for patients with metastatic sarcoma. J Clin Oncol. 2017;35(suppl; abstr 11007).
  9. Gounder MM, Ali SM, Robinson V, et al. Impact of next-generation sequencing (NGS) on diagnostic and therapeutic options in soft-tissue and bone sarcoma. J Clin Oncol. 2017;35(suppl; abstr 11001).
  10. Italiano A, Khalifa E, Laizet Y, Toulmonde M, Cousin S, Lucchesi C. Genetic landscape of soft-tissue sarcomas. Moving toward personalized medicine. J Clin Oncol. 2017;35(suppl; abstr 11002).
  11. Wilky BA, Jones RL, Keedy VL. The current landscape of early drug development for patients with sarcoma. Am Soc Clin Oncol Educ Book. 2017;37:807-10.