ORR Predicts Single-Agent Oncology Regulatory Approval

Regulatory approval of a single-agent oncology drug is significantly associated with the achievement of an objective response rate of at least 30%

medwireNews: US researchers have uncovered a direct correlation between objective response rate (ORR) in single-agent oncology clinical trials and the likelihood of regulatory approval.

Lawrence Schwartz, from Columbia University College of Physicians and Surgeons in New York, and co-workers examined 1800 palliative clinical trials of at least 20 patients with advanced non-small-cell lung cancer (NSCLC), colorectal cancer, melanoma or renal cell cancer. The final analysis contained ORR data for 578 studies, including 542 trial arms for 294 single- or multi-drug regimens.

Both maximum and mean ORR for a single agent significantly predicted receipt of regulatory approval for the treatment of advanced cancer by at least one country. A maximum ORR above 30% was 98% specific for this outcome, with a positive predictive value of 89%; both these values plateaued at 100% when the maximum ORR reached 45%.

However, the relationship between multi-drug combinations and ORR was weaker, the authors report in JAMA Oncology. There was no predictive ORR in this setting, with a maximum positive predictive value of 60%.

“A key challenge in the development of combination therapies is the ability to isolate the effect of an individual component of the combination, which can be difficult using a single-arm trial”, the authors say.

“Supporting this point, we found that combination therapies achieving high ORRs often do not receive regulatory approval”, they write, explaining that a randomised study is likely required to demonstrate how the addition of a second agent improves survival endpoints.

And ORR had poor sensitivity for predicting approval in both single- and multi-agent studies, “highlighting that high ORR is not a sensitive metric for identifying all regimens that can achieve regulatory approval”, Schwartz et al add.

Noting that traditional phase II trials are designed only to show biological activity and require confirmatory studies in the event of high ORR results, the team postulates that an alternative single-arm study designed to reveal breakthrough activity could have adequate statistical power to prove a high ORR in small groups of patients with genotype-defined disease.

“Given the historical precedent that agents with such a high ORR routinely achieve regulatory approval and demonstrate improved [progression-free survival] or [overall survival], proving a high ORR in such a hypothesis- driven trial has the potential to be an efficient alternative for drug development in rare cancer populations”, the researchers write.

However, they caution: “We did restrict this analysis to common and easily measured solid tumors; further study will be needed before these data can be applied to such cancers as breast cancer, prostate cancer, and ovarian cancer, which can have a substantial burden of disease that is more difficult to measure on computed tomography.”

In an accompanying comment, Gideon Blumenthal and Richard Pazdur, from the US Food and Drug Administration in Silver Spring, Maryland, note that while a high, durable ORR indicates drug efficacy, ORR criteria may not “fully capture” the clinical benefit of immunotherapies and they believe that other markers of tumour response and clinical benefit are required.

“This will be critical for researchers and drug developers to assist in compound prioritization, optimization of combinatorial approaches, and to better inform “go/no-go” decision making”, the commentators write.

“For regulators, more sophisticated and refined response metrics will assist in identifying future breakthrough therapies and in developing better surrogates to predict long-term clinical outcome.”


Oxnard GR, Wilcox KH, Gonen M, et al. Response rate as a regulatory end point in single-arm studies of advanced solid tumors. JAMA Oncol 2016; Advance online publication 25 February.doi:10.1001/jamaoncol.2015.6315

Blumenthal GM, Pazdur R. Response rate as an approval end point in oncology. Back to the future. JAMA Oncol 2016; Advance online publication 25 February.doi:10.1001/jamaoncol.2015.6352

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