The advent of immunotherapy in the management of BC treatment was thought to herald a new era of treatment management for the most common form of gynecological malignancy in women in the United States. With the development of biomarkers, research has found that prognostic and chemotherapy response is associated with immune infiltration in BC.

The utilization of immune checkpoint inhibitors in other cancers spurred the investigation into the use of immunotherapy for BC with rapid growth occurring in the early 2010s. However, as of December 2023, only one immunotherapy drug, pembrolizumab, has been approved for use in the management of BC.

Pembrolizumab is indicated for the treatment of patients with high-risk, early-stage, triple-negative BC (TNBC) in combination with chemotherapy as neoadjuvant treatment and then continued as a single agent as adjuvant treatment after surgery. It is also indicated in combination with chemotherapy in the treatment of locally recurrent unresectable or metastatic TNBC whose tumors express programmed death ligand 1 as determined by an FDA-approved test.

Given this limited role of immunotherapy in BC, researchers undertook a study to survey immunotherapy trials in BC and to assess what fraction of trials met their prespecified completion time points for reporting outcomes.

Using the search terms pembrolizumab, camrelizumab, nivolumab, toripalimab, sintilimab, tisletizumab, cemiplimab, spartalizumab, dostarlimab, pucotenlimab, balstilimab, carilizumab, retifanlimab, serplulimab, atezolizumab, durvalumab, avelumab, TQB2450, pacmilimab, erfonrilimab, and envafolimab appearing with cancer vaccine, CAR-T, immunomodulators, adoptive T-cell therapy, and immunotherapy, researchers identified BC immunotherapy trials listed on ClinicalTrial.gov in April 2023. The reporting analysis was restricted to trials with primary study completion dates up to November 30, 2022.

The FDA requires that clinical trials posted on ClinicalTrial.gov have their study results posted within 1 year of its primary completion date, which is defined as “the date on which the last participant was examined or received an intervention to collect final data for the primary outcome measure, this term refers to the date on which data collection is completed for all the primary outcome measures.”

The authors searched the Clinicaltrials.gov website, Google Scholar, PubMed, and LARVOL CLIN, which is a platform that curates 10 years of historical clinical trial data focusing on immune-oncology, for immunotherapy trials for BC. A trial was considered reported if results were available either on ClinicalTrial.gov or if an abstract or manuscript about the therapeutic agent was available. Data on sample size, trial design, study phase, disease setting (i.e., neoadjuvant, adjuvant, or metastatic), site, primary endpoint, lead sponsor, primary completion data, and results were extracted in December 2023. Trials were categorized as positive or negative depending on whether primary endpoints were met or not met. Focus was placed on randomized trials.

Attempts to standardize the method for data extraction were not successful, resulting in studies being manually filtered and data extracted for each trial. Additionally, four trials were excluded from analysis because accrual was never started and five randomized trials were eliminated from further review because they had a noncomparative design or had endpoints other than efficacy (e.g., were dose-finding studies).

The investigators reported that 331 immunotherapy trials were launched between January 2004 and April 2023 targeting to enroll 48,844 patients. Almost three-quarters of these trials were phase II trials (73.1%) and, less commonly, phase I and III (14.2% and 12.7%, respectively). Nearly two-thirds of trials (64%) were for metastatic disease; 28.5% were for neoadjuvant treatment, and 7.5% were as adjuvant therapy. Over three-quarters of the trials (76.1%) were for triple-negative BC with less than one-quarter exclusively studying estrogen-positive or HER-2 (ERBBB2)-positive BC patients (23.9%). Only about 2% of trials were National Institutes of Health–funded. The pharmaceutical industry funded about one-quarter (24.2%), and the rest were funded by other funding sources. Most trials were combination studies with chemotherapy, immunotherapy, or targeted therapies. The majority of phase II and III trials (168/284; 59.2%) were nonrandomized.

Primary completion dates were not yet met in 62.5% (207/331) of trials at the time of analysis. Additionally, 120 trials (36.3%) had a primarily completion date up to November 30, 2022. Of these, 25% (30 trials) had not reported results including 31.8% of phase I, 23.6% of phase II, and 22.2% of phase III trials. Among these 30 unreported trials, four had been terminated. Single-center studies were significantly more likely (35.2%) than multicenter studies (15.0%) to have unreported results. The vast majority of the unreported single-center clinical trials were based in the U.S. (42%).

The authors pointed out that despite the FDA’s requirements on publishing study results on ClinicalTrial.gov in a timely manner, only 74 trials (61.7%) had updated this website with study results and an additional 16 trials had published their research in the literature. Among these 90 trials, only 52.2% yielded positive results (N = 47). The majority of phase II trials (N = 68) were negative (54.4%). Almost three-quarters of negative trial results (74.4%) were reported in a manuscript compared with only 55.3% of positive results that were published.

After excluding the five randomized trials without clinical efficacy data, of the remaining 19 randomized trials, 89.5% had negative results. Among these negative results were four of the six randomized phase III trials, which had included 4,189 patients.

These results are disappointing and show that even the best preclinical models are unlikely to capture the variability in human antitumor immunity. This paper serves as a call to action that the early identification of the immunotherapy-sensitive BC subpopulation should focus on the use of human biomarkers to increase the chances of success in phase III trials. Pharmacists need to read studies on immunotherapy therapy treatments for BC with a critical lens and should help their BC patients have realistic expectations should they enroll in one of these trials.

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