External control arms in oncology: current use and future directions

Mishra‐Kalyani, Pallavi S.; Kordestani, L. Amiri; Rivera, Donna R.; Singh, Harpreet; Ibrahim, Amna; DeClaro, R. Angelo; Shen, Yuan Li; Tang, Shenghui; Sridhara, Rajeshwari; Kluetz, Paul G.; Concato, John; Pazdur, Richard; Beaver, Julia A.

doi:10.1016/j.annonc.2021.12.015

Cited by 75 publications

(79 citation statements)

References 23 publications

(38 reference statements)

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“…Among the “shadows”, we discussed the absence of prospective randomised trials, the design and the end-points adopted in some studies, and the heterogeneity of existing schedules, even for the same drug. Recently, Mishra-Kalyani et al considered the role of control arms in oncology [ 67 ]; they suggest that, even though randomised control trials allow for a comparison of treatment arms with minimal concern for confounding by known and unknown factors, in some situations, and for some strategies, a randomised study is not feasible. These authors suggest that, when such designs are not possible, the incorporation of external control data into the study design could get around the obstacle.…”

Section: Discussionmentioning

confidence: 99%

Metronomic Chemotherapy for Metastatic Breast Cancer Treatment: Clinical and Preclinical Data between Lights and Shadows

Cazzaniga

Capici²,

Cordani

et al. 2022

JCM

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Metronomic chemotherapy (mCHT), defined as continuous administration of low-dose chemotherapeutic agents with no or short regular treatment-free intervals, was first introduced to the clinic in international guidelines in 2017, and, since then, has become one of the available strategies for the treatment of advanced breast cancer (ABC). Despite recent successes, many unsolved practical and theoretical issues remain to be addressed. The present review aims to identify the “lights and shadows” of mCHT in preclinical and clinical settings. In the preclinical setting, several findings indicate that one of the most noticeable effects of mCHT is on the tumor microenvironment, which, over the last twenty years, has been demonstrated to be pivotal in supporting tumor cell survival and proliferation. On the other hand, the direct effects on tumor cells have been less well-defined. In addition, critical items to be addressed are the lack of definition of an optimal biological dose (OBD), the method of administration of metronomic schedules, and the recognition and validation of predictive biomarkers. In the clinical context—where mCHT has mainly been used in a metastatic setting—low toxicity is the most well-recognised light of mCHT, whereas the type of study design, the absence of randomised trials and uncertainty in terms of doses and drugs remain among the shadows. In conclusion, growing evidence indicates that mCHT is a suitable treatment option for selected metastatic breast cancer (MBC) patients. Moreover, given its multimodal mechanisms of action, its addition to immunological and targeted therapies might represent a promising new approach to the treatment of MBC. More preclinical data are needed in this regard, which can only be obtained through support for translational research as the key link between basic science and patient care.

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Section: Discussionmentioning

confidence: 99%

Metronomic Chemotherapy for Metastatic Breast Cancer Treatment: Clinical and Preclinical Data between Lights and Shadows

Cazzaniga

Capici²,

Cordani

et al. 2022

JCM

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“…Patients who enroll in clinical trials are often healthier and have better socioeconomic status compared to the overall patient population (12), raising the importance of drug and biomarker effectiveness evaluations reflecting broader real-world patient populations and treatment practices (13). For these reasons, we sought to compare the outcomes of real-world patients on ICPI monotherapy vs. chemotherapy stratified by biomarkers.…”

Section: Introductionmentioning

confidence: 99%

Real-world Validation of TMB and Microsatellite Instability as Predictive Biomarkers of Immune Checkpoint Inhibitor Effectiveness in Advanced Gastroesophageal Cancer

Graf

Fisher

Creeden

et al. 2022

Cancer Research Communications

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Patients with advanced gastroesophageal cancer (mEG) and tumor mutational burden ≥ 10 mut/mb (TMB≥10) have more favorable outcomes on immune checkpoint inhibitor (ICPI) monotherapy compared to chemotherapy in subgroup analyses of randomized controlled trials. We sought to evaluate the robustness of these associations in real-world settings where patients and practices are more diverse. 362 2L and 692 1L patients respectively received ICPI (n = 99, 33) or chemotherapy (n = 263, 659) across approximately 280 U.S. academic or community-based cancer clinics March 2014-July 2021. De-identified data was captured into a real-world clinico-genomic database (CGDB). All patients underwent Foundation Medicine testing. Time to next treatment (TTNT) and overall survival (OS) comparing ICPI vs. chemotherapy were adjusted for treatment assignment imbalances using propensity scores. 2L: TMB≥10 had more favorable TTNT (Median 24 vs. 4.1 months, HR: 0.19, 95%CI: 0.09–0.44, p=0.0001) and OS (median 43.1 vs. 6.2 months, HR: 0.24, 95%CI: 0.011–0.54, p=0.0005), TMB<10 did not (p>0.05). 1L: TMB≥10 had more favorable TTNT (not reached vs. median 4.1 months, HR: 0.13, 95%CI: 0.03–0.48, p=0.0024) and OS (not reached vs. median 17.1 months, HR: 0.30, 95%CI: 0.08–1.14, p=0.078), TMB<10 had less favorable TTNT (median 2.8 vs. 6.5 months, HR: 2.36, 95%CI: 1.25–4.45, p=0.008) and OS (median 4.5 vs. 13.1 months, HR: 1.82, 95%CI: 0.87–3.81, p=0.11). TMB ≥ 10 robustly identifies mEG patients with more favorable outcomes on 2L ICPI monotherapy vs. chemotherapy. 1L data are more limited, but effects are consistent with 2L.

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“…Some have argued that historical control arms could be developed from previous trials, evidence from routine clinical care or registries, or health claims or electronic health records to complement missing data and fill relevant knowledge gaps in SATs [ 76 , 78 ]. However, evidence generation based on such data may not always be feasible, and even when able to be gathered, these data usually present strong methodological bias (for example, selection bias) that cannot mitigate the high level of uncertainty [ 64 , 76 , 79 , 80 , 81 ].…”

Section: Challenges Arising From Clinical Trial Designsmentioning

confidence: 99%

Implications of Oncology Trial Design and Uncertainties in Efficacy-Safety Data on Health Technology Assessments

et al. 2022

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Background: Advances in cancer medicines have resulted in tangible health impacts, but the magnitude of benefits of approved cancer medicines could vary greatly. Health Technology Assessment (HTA) is a multidisciplinary process used to inform resource allocation through a systematic value assessment of health technology. This paper reviews the challenges in conducting HTA for cancer medicines arising from oncology trial designs and uncertainties of safety-efficacy data. Methods: Multiple databases (PubMed, Scopus and Google Scholar) and grey literature (public health agencies and governmental reports) were searched to inform this policy narrative review. Results: A lack of robust efficacy-safety data from clinical trials and other relevant sources of evidence has made HTA for cancer medicines challenging. The approval of cancer medicines through expedited pathways has increased in recent years, in which surrogate endpoints or biomarkers for patient selection have been widely used. Using these surrogate endpoints has created uncertainties in translating surrogate measures into patient-centric clinically (survival and quality of life) and economically (cost-effectiveness and budget impact) meaningful outcomes, with potential effects on diverting scarce health resources to low-value or detrimental interventions. Potential solutions include policy harmonization between regulatory and HTA authorities, commitment to generating robust post-marketing efficacy-safety data, managing uncertainties through risk-sharing agreements, and using value frameworks. Conclusion: A lack of robust efficacy-safety data is a central problem for conducting HTA of cancer medicines, potentially resulting in misinformed resource allocation.

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External control arms in oncology: current use and future directions

Cited by 75 publications

References 23 publications

Metronomic Chemotherapy for Metastatic Breast Cancer Treatment: Clinical and Preclinical Data between Lights and Shadows

Metronomic Chemotherapy for Metastatic Breast Cancer Treatment: Clinical and Preclinical Data between Lights and Shadows

Real-world Validation of TMB and Microsatellite Instability as Predictive Biomarkers of Immune Checkpoint Inhibitor Effectiveness in Advanced Gastroesophageal Cancer

Implications of Oncology Trial Design and Uncertainties in Efficacy-Safety Data on Health Technology Assessments

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