How valid are claims for synergy in published clinical studies?

Ocaña, Alberto; Amir, Eitan; Yeung, Celine; Šeruga, Boštjan; Tannock, Ian F.

doi:10.1093/annonc/mdr608

Cited by 34 publications

(40 citation statements)

References 5 publications

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“…An emerging literature on preclinical study quality suggests that the strength of evidence supporting phase I studies is highly variable. [33][34][35][36] Furthermore, studies generally entail numerous procedures that are demonstrably nontherapeutic (eg, blood draws for pharmacokinetics or biopsies for pharmacodynamics or marker exploration). Another reason FDA would probably not approve phase I studies, if they could be packaged and marketed as a product, is that their precise composition is highly variable.…”

Section: Conceptual Problemsmentioning

confidence: 99%

Is Participation in Cancer Phase I Trials Really Therapeutic?

Kimmelman

2017

JCO

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Phase I trials are a key step in developing anticancer treatments. But because they administer unproven drugs to populations with life-threatening disease, their design and ethics are often debated. [1][2][3][4] In 1995, ASCO issued a policy declaring the importance of phase I studies as a treatment modality for patients with cancer who have advanced disease. ASCO revisited its policy in 2014. 5 The new policy amplifies the earlier position, reasserting two closely connected claims: first, that phase I cancer studies have therapeutic intent, and second, that they potentially "provide patients [who enroll with clinical benefit." 5(p1) In this article, I reinforce the first assertion and qualify the second. The therapeutic intent of many phase I cancer studies is attested to by the fact that most studies measure disease response, and many use designs aimed at maximizing clinical benefit. However, intent alone does not underwrite an actual therapeutic claim. The assertion that phase I trials offer a vehicle for pursuing cancer treatment (the "therapeutic position") rests on weak evidence and has counterproductive implications for human protection. It also erodes the ability of oncologists to rigorously evaluate new treatments and support evidence-based practice. Instead I propose a different view-the "research position"-that stresses the investigational orientation of phase I trials while accommodating exceptional cases and the therapeutic yearnings of patients and their caregivers. I close by suggesting how groups such as ASCO might refine their recommendations. EvidenceThe kernel of the therapeutic position expressed by ASCO is that investigators can and should present phase I trial participation as providing "the prospect of a direct medical benefit." 5(p2) Because direct benefit relates to the pharmacologic action of a drug, and because benefit in medicine is always measured against how patients would be treated otherwise, the therapeutic position is equivalent to saying that the risk/benefit for receiving experimental drugs in phase I trials is consistent with and possibly superior to standard of care.Proponents of this view draw on several streams of evidence. First, meta-analyses show objective response rates (ORRs) in the neighborhood of 5% and fatal toxicities of approximately 0.5% for monotherapy studies. [6][7][8] Proponents argue that these response rates

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Section: Conceptual Problemsmentioning

confidence: 99%

Is Participation in Cancer Phase I Trials Really Therapeutic?

Kimmelman

2017

JCO

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“…Clinical trials evaluating drug combinations are often stimulated by claims of synergistic interactions in preclinical models. We have shown that inappropriate methods for evaluation of synergy and poor assessment of therapeutic index have been used in many preclinical articles, leading to inaccurate claims of synergy (11). In addition to the requirement for reproducibility from preclinical research, new research tools are needed for more efficient drug development (12).…”

Section: Preclinical Cancer Research To Support Drug Developmentmentioning

confidence: 99%

Failures in Phase III: Causes and Consequences

Šeruga

Ocaña

Amir

et al. 2015

Clinical Cancer Research

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Phase III randomized controlled trials (RCT) in oncology fail to lead to registration of new therapies more often than RCTs in other medical disciplines. Most RCTs are sponsored by the pharmaceutical industry, which reflects industry's increasing responsibility in cancer drug development. Many preclinical models are unreliable for evaluation of new anticancer agents, and stronger evidence of biologic effect should be required before a new agent enters the clinical development pathway. Whenever possible, early-phase clinical trials should include pharmacodynamic studies to demonstrate that new agents inhibit their molecular targets and demonstrate substantial antitumor activity at tolerated doses in an enriched population of patients. Here, we review recent RCTs and found that these conditions were not met for most of the targeted anticancer agents, which failed in recent RCTs. Many recent phase III RCTs were initiated without sufficient evidence of activity from earlyphase clinical trials. Because patients treated within such trials can be harmed, they should not be undertaken. The bar should also be raised when making decisions to proceed from phase II to III and from phase III to marketing approval. Many approved agents showed only better progression-free survival than standard treatment in phase III trials and were not shown to improve survival or its quality. Introduction of value-based pricing of new anticancer agents would dissuade the continued development of agents with borderline activity in early-phase clinical trials. When collaborating with industry, oncologists should be more critical and better advocates for cancer patients.

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“…Currently, there are substantial limitations to nonclinical studies, including suboptimal reproducibility (74, 75), publication bias and insufficiently characterized combination index (defined as a quantitative measure of combination drug effects) (76). In immunotherapy research, an additional barrier arises from inherent differences in immune systems across species and tumor antigen repertoire, leading to poor recapitulation of host immune effects, as highlighted by unforeseen severe immune-mediated toxicities in the first-in-human (FIH) study of a CD28 agonist (77).…”

Section: Goals and Challenges Of Immunotherapy Combinationsmentioning

confidence: 99%

From Famine to Feast: Developing Early-Phase Combination Immunotherapy Trials Wisely

Day

Monjazeb

Sharon

et al. 2017

Clinical Cancer Research

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Not until the turn of this century has immunotherapy become a fundamental component of cancer treatment. While monotherapy with immune modulators such as immune checkpoint inhibitors provides a subset of patients with durable clinical benefit and possible cure, combination therapy offers the potential for anti-tumor activity in a greater number of patients. The field of immunology has provided us with a plethora of potential molecules and pathways to target. This abundance makes it impractical to empirically test all possible combinations efficiently. We recommend that potential immunotherapy combinations be chosen based on sound rationale and available data to address the mechanisms of primary and acquired immune resistance. Novel trial designs may increase the proportion of patients receiving potentially efficacious treatments and, at the same time, better define the balance of clinical activity and safety. We believe that implementing a strategic approach in the early development of immunotherapy combinations will expedite the delivery of more effective therapies with improved safety and durable outcomes.

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How valid are claims for synergy in published clinical studies?

Cited by 34 publications

References 5 publications

Is Participation in Cancer Phase I Trials Really Therapeutic?

Is Participation in Cancer Phase I Trials Really Therapeutic?

Failures in Phase III: Causes and Consequences

From Famine to Feast: Developing Early-Phase Combination Immunotherapy Trials Wisely

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