Analysis of Outcomes in NCI-Sponsored Phase I Trials in Solid Tumors: 2000–2019

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As reported in The Lancet by Chihara et al, analysis of outcomes in National Cancer Institute (NCI)-sponsored, investigator-initiated phase I trials in solid tumors over a 20-year period has shown a near doubling of objective response rate, with no increase in treatment-related mortality.

Study Details

The study involved patient-level data from trials reported from January 2000 to May 2019, assessing risks of treatment-related death; all on-treatment deaths; grade 3 and 4 toxicity; and proportion of overall response (complete response and partial response) and complete response rates in the study periods of 2000 to 2005, 2006 to 2012, and 2013 to 2019.

Key Findings

The analysis included 465 studies of 261 agents with a total of 13,847 enrolled patients; 144 trials (31%) used monotherapy, and 321 (69%) studied combination therapies.

The objective response rate among all trials was 12.2% (95% confidence interval [CI] = 11.5%–12.8%), with a complete response rate of 2.7% (95% CI = 2.4%–3.0%). Objective response rates increased from 9.6% (95% CI = 8.7%–10.6%) in 2000 to 2005 to 18.0% (95% CI = 15.7%–20.5%) in 2013 to 2019, with complete response rates increasing from 2.5% (95% CI = 2.0%–3.0%) to 4.3% (95% CI = 3.2%–5.7%). Objective response rates were 15.8% (95% CI = 15.0%–16.8%) in combination therapy trials, compared with 3.5% (95% CI = 2.8%–4.2%) in monotherapy trials.

Objective response rates by class of agents differed across diseases: for example, antiangiogenesis agents were associated with higher response rates in bladder, colon, kidney, and ovarian cancers, and DNA repair inhibitors were associated with higher response rates in ovarian and pancreatic cancers. Overall response rates also differed over time by disease, with greater improvements seen in bladder, breast, and kidney cancers and melanoma, and no change observed in the low response rates in pancreatic and colon cancers.

The risk of on-treatment death during the entire study period was 8.0% (95% CI = 7.6%–8.5%). The overall treatment-related death rate was 0.7% (95% CI = 0.5%–0.8%), with risk of treatment-related death not changing over time (P = .52). Treatment-related death rates were 0.7% (95% CI = 0.5%–0.8%) in combination therapy trials and 0.7% (95% CI = 0.5%–1.0%) in monotherapy trials.

The most common grade 3 or 4 adverse events were hematologic, including neutropenia in 16.9% of patients, lymphopenia in 8.9%, anemia in 6.5%, and thrombocytopenia in 7.1%.

The investigators concluded, “During the past 20 years, the response rate in phase I trials nearly doubled without an increase in the treatment-related death rate. However, there is significant heterogeneity in overall response by various factors such as cancer type, investigational agent, and trial design. Therefore, informed decision-making is crucial for patients before participating in phase I trials. This study provides updated encouraging outcomes of modern phase I trials in solid tumors.”

Naoko Takebe, MD, of the Division of Cancer Treatment and Diagnosis, National Cancer Institute, and Dai Chihara, MD, of the Department of Lymphoma & Myeloma, The University of Texas MD Anderson Cancer Center, are the corresponding authors for The Lancet article.

Disclosure: The study was funded by the National Cancer Institute. For full disclosures of the study authors, visit

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