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Standard of care in immunotherapy trials: Challenges and considerations.

ABSTRACT: The success of immunotherapeutics over the past decade has fundamentally altered the therapeutic landscape in melanoma and non-small cell lung (NSCLC) cancer care. Multiple clinical trials have confirmed significant improvements in survival with a variety of immunotherapeutic strategies. The careful and appropriate selection of standard of care (SOC) therapies is key to the successful design and interpretation of these trials. To date immunotherapeutic trials have used best supportive care, matched placebo, chemotherapy, targeted therapy or, more recently, established immunotherapeutics in melanoma clinical trials as SOCs. Each of these SOC choices has a fundamental impact on the selection and validity of response assessment criteria and clinical endpoints. As yet there is no established approach, thus new data must be interpreted with an understanding of the limitations of the current paradigm. Additionally, the pace of development has mandated the use of novel clinical trial designs, answering multiple therapeutic questions simultaneously and designed to expedite regulatory approval. This review addresses the most important challenges in the selection of SOC in immunotherapeutic trials and the current and future challenges in trial design.

SUBMITTER: Rivalland G

PROVIDER: S-EPMC5612282 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Standard of care in immunotherapy trials: Challenges and considerations.

Rivalland Gareth G Scott Andrew M AM John Thomas T

Human vaccines & immunotherapeutics 20170301 9

The success of immunotherapeutics over the past decade has fundamentally altered the therapeutic landscape in melanoma and non-small cell lung (NSCLC) cancer care. Multiple clinical trials have confirmed significant improvements in survival with a variety of immunotherapeutic strategies. The careful and appropriate selection of standard of care (SOC) therapies is key to the successful design and interpretation of these trials. To date immunotherapeutic trials have used best supportive care, matc ...[more]

PMID: 28267397

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Project description:Biliary tract cancers (BTCs), comprising intrahepatic, perihilar, and distal cholangiocarcinoma as well as gallbladder adenocarcinoma, continue to be challenging to manage. Conventional chemotherapy regimens for advanced disease are limited in both options and benefits, and more effective perioperative regimens are also needed. Over the last decade, immunotherapy has had a profound impact on the management of many solid tumor types, particularly in using immune checkpoint inhibition to enable a tumor-directed T cell response. Immunotherapy administered on its own has had limited utility in BTCs, in part due to a hostile immune microenvironment and the relative infrequency of biomarker-based tumor-agnostic indications for immunotherapy. However, immunotherapy in conjunction with chemotherapy, molecularly targeted therapies, and/or anti-angiogenic therapies has gained traction, supported by evidence that these agents can impart favorable immunomodulatory effects on the tumor microenvironment. The TOPAZ-1 trial led to the first BTC-specific immunotherapy approval, establishing the combination of durvalumab with gemcitabine and cisplatin as the preferred first-line treatment for advanced or metastatic disease. Recently, the KEYNOTE-966 trial showed positive results for the combination of pembrolizumab with gemcitabine and cisplatin in the same setting, adding further evidence for the addition of immune checkpoint inhibition to the standard chemotherapy backbone. Meanwhile, advances in the molecular profiling of BTCs has contributed to the recent proliferation of molecularly targeted therapeutics for the subset of BTCs harboring alterations in IDH1, FGFR2, MAP kinase signaling, HER2, and beyond, and there has been great interest in investigating combinations of these agents with immunotherapy. Emerging immunotherapy strategies beyond immune checkpoint inhibition are also being studied in BTCs, and these include immunostimulatory receptor agonists, Wnt signaling modulators, adoptive cell therapy, and cancer vaccines. A large number of trials are underway to explore promising new combinations and immune-targeted strategies, offering opportunities to expand the role of immunotherapy in BTC management in the near future.

Project description:We previously conducted a single-arm feasibility study (STRIDE1) of myeloablative bone marrow transplantation (BMT) in adolescents and young adults with sickle cell disease (SCD). The trial identified donors before entry, enrolled well, and found no unexpected regimen-related toxicity. Although many single-arm studies have been published, there are no controlled trials of either BMT or gene therapy in SCD. Therefore, we designed a comparative trial by biological assignment (available donor versus no donor). This multicenter National Institutes of Health-funded study (Blood and Marrow Transplant Clinical Trials Network 1503; STRIDE2) enrolled patients between 2016 and 2021 at 35 sites. Lagging recruitment led to study closure, and here we report the impediments to accrual. The BMT regimen and entry criteria were from STRIDE1, and 2-year survival was the primary endpoint. To minimize selection bias from prior HLA typing, STRIDE2 excluded individuals with previously identified donors. Accrual was stopped at 69% of target (138 enrolled; assigned 28 with donor, 96 with no donor). Barriers to enrollment included lower than expected frequency of HLA-matched related and unrelated donors; loss of enrollees owing to previously identified donors; conventional care arm dissuading some seeking BMT; challenging short-term endpoints in SCD, including incomplete documentation of sickle pain episodes; state Medicaid (primary insurers of SCD) denial of BMT coverage for adult SCD despite the study having secured Coverage with Evidence Development from the Center for Medicare & Medicaid Services; slowed accrual in 2019 to 2021 during the Coronavirus disease 2019 pandemic; and restriction of BMT resourcing for nonmalignant diseases by academic medical (cancer) centers. Social obstacles and access to BMT centers also limited entry, as did practitioner and participant concerns over suitability, cost, and toxicity. Planning for future controlled trials of curative therapy in SCD and other nonmalignant diseases likely will meet these enrollment challenges. Lessons from this trial may aid the development of future comparative studies.

Dataset Information

Standard of care in immunotherapy trials: Challenges and considerations.

Publications

Standard of care in immunotherapy trials: Challenges and considerations.

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