Phase 1 Oncology Trials: Improved Outcomes Over Time

Phase 1 trials are frequently viewed as having a low probability of benefiting an individual patient, despite the novelty of agents being investigated. Often forgotten is that these trials are primarily designed to define the optimal dose of a drug to take forward for further development. A secondary goal is to identify signals of antitumor activity. Although the fraction of novel agents that go on to FDA-approval remains modest, the collective progress made with phase 1 trials deserves re-evaluation.

Investigators analyzed patient-level data from the Cancer Therapy Evaluation Program of the National Cancer Institute–sponsored investigator-initiated phase 1 trials for solid tumors between 2000 and 2019, with particular attention to high-grade toxicity and objective tumor response. A total of 465 studies that involved almost 14,000 patients and 261 agents were included; most trials (69%) evaluated combination therapy. Data were analyzed in 5-year intervals.

The overall treatment-related death rate (grade 5 toxicity) was 0.7% across all intervals. The most common grade 3–4 toxicities were neutropenia (16.9%), lymphopenia (8.9%), thrombocytopenia (7.1%), and anemia (6.5%). The overall response rate (ORR) was 12.2%, with infrequent complete responses (2.7%). The ORR increased from 9.6% during the first interval to 18.0% during the last; the complete response rate changed only from 2.5% to 4.3%. Combination therapy was associated with higher ORR than monotherapy (15.8% vs. 3.5%).

Interestingly, ORRs differed depending on the malignancy and were highest in bladder, lung, and kidney cancer and melanoma. Specific agents had differential benefits; for example, ORRs with anti-angiogenic agents were highest in bladder, colon, kidney, and ovarian cancer.