Few RCTs of New Systemic Therapies Met ESMO Guidelines for Meaningful Outcomes

Fewer than one-third of randomized controlled trials reporting statistically significant outcomes for novel systemic therapies in solid cancers met the European Society of Medical Oncology’s (ESMO) threshold for clinically meaningful benefit, according to research published in Annals of Oncology.
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“Therapies that offer true ‘clinical benefit’ should provide meaningful improvement in the quantity and/or quality of survival,” wrote Christopher Booth, MD, FRCPC, member of the division of cancer care and epidemiology at Queen’s University Cancer Research Institute (Kingston, ON), and colleagues. “The concept of ‘value’ (outcomes compared to cost) is increasingly recognized as an important consideration in both the interpretation of clinical trials and the delivery of cancer care: small incremental gains in therapeutic endpoints, especially those that are unproven surrogates for survival or its quality, provide minimal value.”

ESMO published a magnitude of clinical benefit scale to guide the adoption and/or funding of new solid cancer therapies. Dr Booth and colleagues sought to determine whether randomized controlled trials (RCTs) examining new systemic therapies for breast cancer, non–small cell lung cancer, colorectal cancer, and pancreatic cancer met the newly designed ESMO thresholds, and what proportion of RCTs were powered to detect an effect size to meet these thresholds.

The researchers identified 277 phase 3 RCTs published between 2011 and 2015. Breast cancer and non–small cell lung cancer studies comprised 71% of eligible trials; colorectal cancer studies comprised 22% of included RCTs, with pancreatic cancer studies accounting for 6%. Industry-funded studies comprised 83% of data, and 35% of trials identified overall survival as the primary endpoint. The median sample size was 532 patients (range, 39-9779).

Fifty percent (n = 138) of included RCTs showed statistically significant outcomes favoring the experimental therapy, of which 31% (n = 43) met ESMO’s clinical benefit standards based on the lower limit of the 95% CI for the hazard ratio. The percentage of statistically significant, clinically meaningful RCTs decreased to 25% (n = 35) when the researchers applied the ESMO score to a point estimate of each study’s hazard ratio. An analysis based on treatment intent found that RCTs evaluating therapies with a curative intent (n = 31) appeared more likely than therapies with a palliative intent (n = 107) to meet a clinical benefit threshold (61% vs 22%; P < .001).

Thirty-one percent of studies for which the researchers could assign an ESMO clinical benefit design score (n = 70 of 226) were deemed sufficiently powered to detect an effect size for the clinically meaningful benefit threshold. Again, studies investigating curative-intent therapies (n = 41) appeared more likely than studies investigating palliative-intent therapies (n = 163) to be designed in order to detect or exclude treatment outcomes appropriate for the clinical benefit threshold (65% vs 18%; P < .001).

An exploratory analysis found that RCTs meeting the ESMO clinical benefit threshold had higher Likert scale author endorsements (Likert score 6-7, 86% vs 58%; P < .001); however, publication in a high impact factor journal did not appear associated with meeting the threshold for benefit.

“The oncology community is in the midst of a critical policy debate on equitable delivery of affordable cancer care,” Dr Booth and colleagues wrote. “The aging population, rapid technical innovations, and static or declining economies will lead to increasing stress and demands on the health systems, with little headroom for increased total healthcare expenditures; it is therefore crucial that the oncology community delivers new cancer therapies with high value for patients and society, and that funding priority be given to treatments which lead to substantial benefit. Results from our study demonstrate that the majority of contemporary clinical trials fail to identify therapies with meaningful clinical benefit for patients.”