Study: Breast Cancer Immunotherapy Trials Make Modest Clinical Impact

Despite the numerous breast cancer immunotherapy trials conducted, they have only had a modest clinical impact, according to a review published in JAMA Network Open.¹

Historically, breast cancer was not considered an immunogenic cancer.² However, past biomarker research established the prognostic and predictive values of chemotherapy response and immune infiltration in patients with breast cancer.¹ Also, preclinical studies found that immune cell activation mediates chemotherapy effects and provides antitumor immune surveillance.³

Because of these findings, many breast cancer immunotherapy trials were launched, with researchers leveraging clinical experience with immune checkpoint inhibitors in other cancer types.¹ Despite this, as of December 2023, only 1 immunotherapy drug has been FDA-approved to treat breast cancer: pembrolizumab. In addition to pembrolizumab, atezolizumab was approved in Europe to treat patients with breast cancer.

The researchers noted that the approval of only 2 immunotherapies indicated a “surprisingly low” societal and pharmaceutical industry return on the many breast cancer immunotherapy trials in the past 15 years. Therefore, they conducted a study to assess what fraction of trials—that met their prespecified completion time points—had reported outcomes; they also analyzed what trial features were associated with failure to report results, along with what fraction of completed and reported randomized trials met their primary endpoint.

Despite numerous trials, breast cancer immunotherapies have had a modest clinical impact, with only 2 drugs approved, highlighting inefficiencies in the clinical trial system. | Image Credit: Pixel-Shot - stock.adobe.com

To do so, the researchers manually identified breast cancer immunotherapy trials in April 2023 using various search terms such as pembrolizumab and atezolizumab. They extracted various features from eligible trials, including sample size, design, primary completion date, and results.

Because the FDA requires trials to report results in ClinicalTrials.gov within 1 year of the primary completion date, the researchers restricted their reporting analysis to trials with primary study completion dates up to November 30, 2022. The researchers considered a trial to be reported if the results were available on ClinicalTrial.gov, or as an abstract or manuscript.

Therefore, they retrieved outcome reports for eligible studies through ClinicalTrials.gov or by searching PubMed, Google Scholar, and LARVOL CLIN using the National Clinical Trial (NCT) number. The researchers categorized a trial as positive or negative based on whether it met its primary endpoint.

Between January 2004 and April 2023, 331 breast cancer immunotherapy trials were launched, aiming to gather 48,844 patients. Of these trials, 47 (14.2%), 242 (73.1%), and 42 (12.7%) were phase 1, 2, and 3 trials, respectively; the researchers noted that 168 of the 248 phase 2 and 3 trials were nonrandomized. Also, 94 (28.5%), 25 (7.5%), and 212 (64%) trials were conducted in the neoadjuvant, adjuvant, and metastatic disease settings, respectively.

At the time of their analysis, 207 trials were yet to met their primary completion dates, including 84 randomized trials. Conversely, 120 trials, which enrolled 10,830 patients, had primary completion dates up to November 30, 2022. Of these trials, 30 (25%) did not report results, namely 7 phase 1 trials (31.8%), 21 phase 2 trials (23.6%), and 2 phase 3 trials (22.2%). In particular, single-center studies (n = 19/54; 35.2%; P = .02) were significantly more likely to be unreported vs multicenter studies (n = 9/60; 15.0%; P = .02).

On the other hand, of the 90 trials that reported results, 47 (52.2%) were positive and 43 (47.8%) were negative. However, when considering the 68 reported phase 2 trials, the researchers found that 31 (45.6%) were positive and 37 (54.4%) were negative.

Despite regulations, only 74 trial results were reported in ClinicalTrials.gov, while the other 16 were presented in published research. More specifically, 26 of 47 positive trials (55.3%) and 32 of 43 negative trials (74.4%) were reported in a manuscript.

Lastly, of the 19 eligible randomized trials, 17 (89.5%) had negative results, including 4 of the 6 phase 3 trials. Because of the small number of positive trials, the researchers found no statistically significant association between trial features and positive vs negative results.

“Trials that are unable to produce results or fail to translate into successful phase [3] trials represent inefficiency in the clinical trial system and increase drug development costs; the results of this study suggest that the many single-center, small, unrandomized phase [2] trials appear to be low yield,” the authors wrote.

The researchers acknowledged their limitations, including their reliance on ClinicalTrials.gov as their primary data source. They explained that some trials may have been overlooked as other sources could host trial information not captured on ClinicalTrials.gov; this may affect the generalization of their findings. Despite their limitations, the researchers suggested ways to increase trial efficacy.

“More selective initiation of phase [2] trials, grounded in preclinical and biomarker observations and with optimal statistical designs for early efficacy assessment, is needed to increase trial efficacy,” the authors concluded.

Reference

1. Mariani M, Viale G, Galbardi B, et al. Completion rate and positive results reporting among immunotherapy trials in breast cancer, 2004-2023. JAMA Netw Open. 2024;7(7):e2423390. doi:10.1001/jamanetworkopen.2024.23390
2. Vonderheide RH, Domchek SM, Clark AS. Immunotherapy for breast cancer: what are we missing?. Clin Cancer Res. 2017;23(11):2640-2646. doi:10.1158/1078-0432.CCR-16-2569
3. Galluzzi L, Buqué A, Kepp O, Zitvogel L, Kroemer G. Immunological effects of conventional chemotherapy and targeted anticancer agents. Cancer Cell. 2015;28(6):690-714. doi:10.1016/j.ccell.2015.10.012