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Immunotherapy response
Published in Anju Sahdev, Sarah J. Vinnicombe, Husband & Reznek's Imaging in Oncology, 2020
Based on the results of the aforementioned study, new criteria for the response evaluation of patients treated with immune therapy were defined by Wolchok et al. (Figure 36.3) (10). The immune-related response criteria (irRC) are based on bidimensional target lesion measurements analogous to the WHO criteria. In contrast to other criteria, new tumour lesions do not directly indicate progressive disease (PD). The bidimensional measurements of newly apparent lesions are included into the sum of product of tumour diameters (SPD) of the defined target lesions at baseline. This new sum is defined as tumour burden. Furthermore, every case of progressive disease (PD) has to be confirmed by repeated imaging with no less than a 4-week interval. Both new definitions—compared to WHO criteria—are able to reduce the frequency of pseudoprogression in tumour response assessment in ipilimumab immunotherapy for malignant melanoma.
Sequential, Multiple Assignment, Randomized Trials
Published in Susan Halabi, Stefan Michiels, Textbook of Clinical Trials in Oncology, 2019
Kelly Speth, Kelley M. Kidwell
Reliable early indicators of ultimate endpoints that are practical for clinical use are necessary to define the intermediate outcome in any SMART design. These intermediate endpoints may or may not be (statistical) surrogate outcomes, but should provide an early indication of treatment success or failure and be associated with the overall outcome. In cancer, Response Evaluation Criteria in Solid Tumors (RECIST) response (or Immune-Related Response Criteria) may be appropriate for measurable disease. If there is no measurable disease, changes in reliable tumor biomarker assays, such as serial biopsies or serial circulating protein markers or circulating tumor cells may be considered to define the tailoring variable. Toxicities may also be considered as a standalone intermediate endpoint or in addition to efficacy. The trial protocol should include a plan for patients who experience any common contingencies (e.g., toxicities or other side effects, death, excessive treatment burden, or personal choice). The plans for patients experiencing contingencies should be incorporated into the definition of the embedded treatment regimens [31]. Furthermore, when executing a SMART, standardized and real-time assessments of the chosen intermediate response measure are required.
Design Considerations for Phase II Oncology Clinical Trials
Published in Satrajit Roychoudhury, Soumi Lahiri, Statistical Approaches in Oncology Clinical Development, 2018
Jared C. Foster, Jennifer Le-Rademacher, Sumithra J. Mandrekar
Immunotherapy is a treatment strategy that uses the patient’s own immune system to fight cancer cells.27,28,29 Two types of immunotherapeutics that have gained traction in recent years are cancer vaccines and immune checkpoint blockades. Unlike chemotherapy, which directly attacks cancer cells, thus allowing its effect on the tumor (tumor shrinkage) to be observed shortly after treatment, immunotherapy must first induce a response from the host’s immune system, which then launches an attack on the cancer cells, thereby potentially resulting in a potential delayed response. Response to immunotherapy can be observed after a period of stable disease, or even after an initial period of tumor growth, or appearance of new lesions.30 Due to these differences in immunotherapy response patterns, conventional response criteria, such as the response evaluation criteria in solid tumors and the World Health Organization criteria do not effectively capture objective tumor response to immunotherapy. Furthermore, due to the delayed response, a delayed separation of survival curves has been observed when comparing immunotherapy versus placebo. To better evaluate tumor response in this setting, Hoos et al.30 suggested three novel endpoint considerations for immunotherapy trials. First, they recommended the use of assay harmonization to minimize biomarker variability among patients in multicenter trials. Second, they recommended a set of immune-related response criteria, using the percentage of change in tumor burden between assessment time points to define objective response to immune therapy. To address the issue of delayed separation in survival curves, their third recommendation is to use alternative methods, such as simulation or numerical integration, to estimate the number of events needed when designing an immunotherapy trial. Although existing infrastructure can support immunotherapy trials and the trial designs described in this chapter are appropriate in the phase II immunotherapy setting, appropriate endpoints must be considered when designing this type of trials in order to effectively assess response to treatment. Another challenge with immunotherapy is that it has shown great effectiveness in certain subsets of patients and little or no benefit in other subsets. This is an opportunity to conduct biomarker-based studies using the designs described in Section 5.3 to help identify subsets (i.e., evaluate potential predictive markers) of patients that would benefit from these treatments. Should they exist, such biomarkers could subsequently be used to better evaluate candidate immunotherapies in Phase II and III settings.
Trial watch: IDO inhibitors in cancer therapy
Published in OncoImmunology, 2020
Julie Le Naour, Lorenzo Galluzzi, Laurence Zitvogel, Guido Kroemer, Erika Vacchelli
All other clinical studies recently published on IDO1 inhibitors tested these agents in combination with immune checkpoint blockers. In particular, Gibney etal. reported the results for the Phase I/II clinical trial NCT01604889 enrolling patients with unresectable or metastatic melanoma and receiving epacadostat together with ipilimumab.125–127 Among the 50 participants, 20 discontinued treatment due to disease progression and 48 experienced TRAEs including hypothyroidism (10%), pruritus (28%), alanine aminotransferase elevation (28%), rash (50%), and aspartate aminotransferase elevation (24%). Dose-limiting toxicities occurred in 11 patients, and doses ≥100 mg BID were not tested due to hepatotoxicity. Among immunotherapy-naive patients (n = 39), objective response rate was 23% by response evaluation criteria in solid tumors (RECIST) and 26% by immune-related response criteria (iRECIST). No objective response was observed in the 11 patients previously treated with immunotherapy. According to the authors, these preliminary findings support continuing the evaluation of epacadostat plus ipilimumab in patients with unresectable or metastatic melanoma.128 Unfortunately the study was prematurely terminated due to the sponsor’s decision, and only the Phase I portion of the trial was completed.
Durvalumab in cancer medicine: a comprehensive review
Published in Expert Opinion on Biological Therapy, 2019
Juliana Alvarez-Argote, Constantin A. Dasanu
Using imaging to evaluate the response to immunotherapy with durvalumab seems to need a different approach compared to the evaluation of other systemic therapies. The RECIST criteria have been traditionally used to evaluate the response to systemic cytotoxic therapies. In contrast, it is currently accepted that the immune-related Response Criteria (irRC) [31] reflect more reliably the response to immunotherapy. This is perhaps driven by the mechanism of action of immunotherapeutic agents, in which the immune system is being activated against the cancer cells. Therefore, during the first few weeks, imaging may falsely suggest progression of disease with increased size of existing lesions, and even new lesions, which in reality reflects inflammation present in the vicinity of cancer lesions. Therefore, the irRC suggest evaluating the response at least four weeks after initiation of therapy. This minimizes the likelihood of initial inflammatory changes that may lead to false conclusions of progression of disease. In addition, the RECIST 1.1 incorporated the irRC and developed the iRECIST [32], in which the progression of disease is either ‘unconfirmed’ or ‘confirmed’ based on the follow-up imaging 4–6 weeks after initial imaging. Therefore, evaluation of responses with durvalumab and other immunotherapies in the studies still using classical RECIST criteria will have to be looked upon with a critical eye.
Immune checkpoint inhibitors: a new era for esophageal cancer
Published in Expert Review of Anticancer Therapy, 2019
Li-Qing Zou, Xi Yang, Yi-Da Li, Zheng-Fei Zhu
Regarding the evaluation of anti-tumor immune response, most clinical studies opt to evaluate tumor reduction based on the standard of RECIST [46]. However, due to some unique responses from immune treatment, such as pseudo-progression and mixed response [4], the immune-related response criteria (irRC) has been proposed that considers the characteristics of cancer immunotherapy. Considering that the validity of irRC has not been verified, it should be standardized when used together with RECIST in future studies. Moreover, the number and function of cancer-specific T cells can directly reflect the anti-cancer immune response. ‘Immune monitoring’ [47] refers to the digitization of this change, and future studies will be required to establish methods for better prediction and monitoring of the therapeutic effect.