Association of Adjuvant or Metastatic Setting With Discontinuation of Cancer Drugs in Clinical Trials

IMPORTANCE: Adjuvant drugs are used to reduce the risk of tumor recurrence in patients with cancer who are successfully treated with first-line therapy. The same drugs used in the metastatic or first-line setting are often used in the adjuvant setting, and although the resulting adverse effects may be similar between the 2 settings, tolerability may be different. OBJECTIVE: To compare the discontinuation rates of drugs in the adjuvant setting and in the metastatic setting in clinical trials of cancer drugs. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study examined clinical trials of cancer drugs with results published in major medical and oncology journals between July 2018 through June 2021. Because adjuvant drugs can be used in a metastatic setting, included trials were conducted in an adjuvant setting. Data were analyzed December 2021. EXPOSURES: Drugs used in the adjuvant setting, which were also used in the metastatic setting for the same tumor indication. MAIN OUTCOMES AND MEASURES: Discontinuation rates in the adjuvant and metastatic settings, which were calculated by dividing the total number of study participants who withdrew or discontinued because of adverse events by the number of participants allocated to the drug arm. RESULTS: A total of 29 trials with a drug being used in the adjuvant and metastatic setting were found. In the adjuvant setting, the median (IQR) age for study participants was 58.0 (52.0-63.5) years, and the median (IQR) percentage of male participants was 55.5% (0.9%-64.8%). In the metastatic setting, the median (IQR) age for study participants was 61 years, and the median (IQR) percentage of male participants was 55.2% (2.0%-66.0%). Overall, a median (IQR) 21.4% (17.7%-29.4%) of participants discontinued because of adverse events or patient withdrawal in the adjuvant setting compared with a median (IQR) 15.9% (9.7%-21.3%) in the metastatic setting (P = .01). Checkpoint inhibitors (median [IQR] rate of discontinuation, 21.4% [18.6%-31.3%] vs 15.2% [9.9%-19.5%]; P = .01) and targeted drugs (median [IQR] rate of discontinuation, 27.7% vs 14.0%; P < .001) demonstrated a higher rate of discontinuation in the adjuvant setting while cytotoxic drugs (median [IQR] rate of discontinuation, 16.6% [12.2%-23.3%] vs 25.5% [19.8%-28.8%]; P = .07) showed no difference between the 2 settings. The largest differences between adjuvant and metastatic discontinuation rates were for sorafenib (renal cell carcinoma, 43.8% vs 5.5%; difference, 38.2%), imatinib (gastrointestinal stromal tumor, 37.4% vs 6.1%; difference, 31.2%), and erlotinib (non–small cell lung cancer, 37.5% vs 8.4%; difference, 29.0%). CONCLUSIONS AND RELEVANCE: In this cross-sectional study of clinical trials that involved novel cancer drugs, drugs used in the adjuvant setting were associated with significantly higher discontinuation rates than in the metastatic setting. This finding suggests that the proposed benefits of adjuvant therapy need to be taken in context of patient’s drug tolerance.