Completion Rate and Positive Results Reporting Among Immunotherapy Trials in Breast Cancer, 2004-2023

Key Points Question What fraction of immunotherapy trials launched since 2004 have reported an outcome and translated into positive phase III randomized trials, and what features are associated with failure to report results? Findings In this cross-sectional study of 331 immunotherapy breast cancer trials, 25% of the 120 trials with a primary completion date before December 2022 failed to report their outcomes (31.8%, 23.6%, and 22.2% of phase I, II, and III trials, respectively), and 89% of the 19 randomized trials reported negative results. Single-center studies were significantly more likely to be unreported. Meaning Trials that are unable to produce results or fail to translate into successful phase III 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 II trials appear to be low yield.


Introduction
The modern era of cancer immunotherapy started with the demonstration of the remarkable singleagent efficacy of ipilimumab in metastatic melanoma in 2010. 1 Historically, breast cancer was considered not to be an immunogenic cancer. 2Nevertheless, extensive biomarker research has established the prognostic and chemotherapy response predictive value of immune infiltration in breast cancer, [3][4][5][6] and preclinical studies have suggested that immune cell activation mediates chemotherapy effect and provide antitumor immune surveillance. 7These observations motivated launching many immunotherapy trials in the early 2010s in breast cancer that leveraged clinical experience with immune checkpoint inhibitors in other cancer types.However, as of December 2023, there is only 1 immunotherapy drug, pembrolizumab, that is approved for the treatment of breast cancer in the US under 2 distinct indications; as first-line therapy in combination with chemotherapy for programmed death ligand 1 (PD-L1)-positive (Combined Positive Score [CPS] score 10 or above) metastatic triple negative breast cancer (mTNBC), 8 and as neoadjuvant therapy in combination with chemotherapy followed by adjuvant pembrolizumab for stage II/III TNBC. 9In Europe, atezolizumab is also available as first-line therapy in combinations with nab-paclitaxel for PD-L1-positive (Immune Cell [IC] score 1% or higher) mTNBC. 10This indicates surprisingly low societal and pharmaceutical industry return on the large number of trials conducted in this clinical space in the past 15 years.The goal of our analysis was to survey immunotherapy trials in breast cancer and assess what fraction of trials that met their prespecified completion time points have reported outcomes.We also examined what trial features were associated with failure to report results, and what fraction of completed and reported randomized trials met their primary end point.III [including phase II/III]), disease setting (neoadjuvant, adjuvant, or metastatic), site (single-center [defined as trial conducted at only 1 institution] or multicenter), primary end point, lead sponsor (industry, National Institute of Health [NIH], others), primary completion date, and results were extracted for each trial in December 2023.The database is available as an Excel table (eTable in Supplement 2).According to Food and Drug Administration (FDA) legislation, trials are required to report results in ClinicalTrials.govwithin 1 year of primary completion date that 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."We therefore restricted our reporting analysis to trials with primary study completion dates up to November 30, 2022.Outcome reports for these studies were retrieved from the ClinicalTrials.govwebsite and, via the National Clinical Trial (NCT) number, from Google Scholar, PubMed, and LARVOL CLIN. 11A trial was considered reported if results were posted on ClinicalTrial.gov or reported as an abstract or manuscript.Four trials never started accrual (NCT03554109, NCT03872505, NCT04088032, NCT04249167) and were excluded from the reporting analysis.We categorized trials that reported outcome as positive or negative based on whether the study met its primary end point.We then focused on randomized trials that reported outcome and excluded from this analysis 5 randomized trials (NCT02622074, NCT03167619, A single author (M.M.) performed the data abstraction.Although we attempted to use a standardized method for data extraction, we soon recognized its failure to capture the entirety of the reported study status and the quality of the study.Therefore, as described previously, we decided to manually filter, check the reporting status, and extract the results of each trial.

JAMA Network Open | Oncology
This was an analysis of publicly available aggregate trial data; thus, institutional review board approval and informed consent was not required per the Common Rule.This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

Statistical Analysis
Associations between trial reporting outcomes and trial features of interest were tested using Fisher Of the 19 randomized trials that reported outcome excluding 5 randomized trials that had noncomparative designs or had end points other than efficacy (as described in Methods section), 17 (89.5%) had negative results, including 4 of the 6 randomized phase III trials (Table 2).The negative randomized trials combined enrolled 4189 patients.Due to the small number of positive trials (2 of 19 trials), no statistically significant association was found between trial features and positive vs negative results (Table 2).

Discussion
A total of 46 844 patients with breast cancer participated in 331 immunotherapy trials in the past 20 years, leading to a single drug approval under 2 separate indications in the US.Two hundred and seven trials have not yet met their primary completion dates, including 84 randomized trials, and new approvals will likely occur in the coming years.However, 120 trials had primary completion dates before December 2022 and 30 of these have not posted or published results.This is consistent with earlier studies that reported only around 40% 1-year reporting compliance across all trials, as well as

Cancer vaccine
Autologous whole cell-cancer GM-CSF gene-transfected breast cancer vaccine

Oncolytic virus Hydroxychloroquine
Imprime PGG oncology trials, in ClinicalTrials.gov;sponsors running many trials (eg, industry) were significantly more likely to be compliant than smaller sponsors. 12,13In our breast cancer focused immunotherapy trials analysis, we also found that single-center trials (typically smaller phase I/II trials) were significantly less likely to report results than multicenter studies.

Molecular target therapies
Our examination of breast cancer immunotherapy trials across all phases revealed a numerically higher number (47) of positive trials compared with negative (43) ones.However, for some phase I and II trials reported only as abstracts, the statistical criteria for success were not provided.
Consequently, these trials were considered positive if they reported tolerability and numerical  efficacy results within the range of expected benefit rates from existing therapies in the given disease setting.
5][16] In this cross-sectional study of immunotherapy trials for breast cancer, it is noteworthy that there were numerically more negative trials reported as manuscripts (74%) compared with positive ones (55%).This could be due to the relatively early reporting of the results, and perhaps the manuscripts are still in preparation.However, Krzyzanowska et al 17 reported that within 5 years after presentation at the meeting, 26% of randomized phase 3 oncology trials remain unpublished.Additionally, breast cancer had the highest unpublished rate at 36%, while lung cancer the lowest at 16%.The reasons behind this phenomenon are known and may affect all levels of the publication system, from the authors to the journals, and represents a break in what may be described as an implicit contract between investigators and trial participants that exerts a negative impact on the research community. 18High-quality research, acknowledgment of conflicts of interest, and publishing trial results regardless of their outcomes are all established strategies to minimize publication bias. 19venty-three percent of the trials conducted since 2004 were phase II studies (242 trials); results from these trials are supposed to guide phase III trial design to maximize the chance for positive outcome.Disappointingly, 89.5% of the completed randomized immunotherapy trials yielded negative results.1][22] Recognizing that these same issues continue to plague modern immunotherapy trials, the Society for Immunotherapy of Cancer (SITC) recently published a detailed framework to maximize the value and success of phase III trials in immuno-oncology. 23Many currently tested drug combinations are empirical and development of more human-relevant preclinical immunotherapy models are needed to generate better rationale for combination therapies and define the clinical niche where these might shine. 24Even the best preclinical models are unlikely to capture the variability in human antitumor immunity and therefore early identification of the treatment sensitive subpopulation through biomarker discovery is essential to increase the chance of success in phase III trials. 21,25Observing efficacy in patient populations that progressed on, or not sensitive to, current immunotherapy modalities also bodes well for future success in larger trials. 26

Limitations
We acknowledge several limitations in our that are important for properly interpreting our findings.First, the data extraction from ClinicalTrials.gov was performed manually, which involved a thorough review and curation of each trial's reported outcomes.While this approach allowed for detailed scrutiny of results, it inherently carries the risk of inaccuracies and potential biases in trial results interpretation to define positive or negative studies.
Second, our reliance on ClinicalTrials.govas the primary source of trial data might have resulted in some trials being overlooked.ClinicalTrials.gov is a comprehensive registry, but it is not exhaustive.
Other registries and sources could host information on trials that were not captured in our database, which might affect the generalizability of our findings.
Third, our analysis was restricted to trials with primary study completion dates before December 2022.This cutoff may exclude significant data from trials that concluded around or after this date but have not yet reported results.This time limitation might lead to an underrepresentation of more recent trials, which could influence the observed trends and conclusions regarding the effectiveness and reporting rates of immunotherapy trials in breast cancer.

Conclusions
The findings of this study suggest that the large number of immunotherapy trials being run have yielded modest clinical impact.Single-center studies commonly fail to report outcome, and the many phase II studies that have been conducted have not translated into many successful phase III trials.
More selective initiation of phase II trials, grounded in preclinical and biomarker observations and with optimal statistical designs for early efficacy assessment, is needed to increase trial efficiency.

Figure 1 .
Figure 1.Overview of Immuno-Oncology Trials in Breast Cancer Opened Between 2004 and April 2023

Figure 2 .
Figure 2. Landscape of Anti-PD-1 and Anti-PD-L1 Combination Trials in Breast Cancers

Figure 3 .
Figure 3. Evolution of Types of Immunotherapy Trials in Breast Cancer 100 Completion Rate and Positive Results Reporting in Breast Cancer Immunotherapy Trials

Table 1 .
Trial Features Associated With Not Reporting Results for Trials That Had Primary Completion Dates Before December 2022 Completion Rate and Positive Results Reporting in Breast Cancer Immunotherapy Trials a P values were calculated with Fisher test comparing reported vs unreported trials.JAMA Network Open | OncologyJAMA Network Open.2024;7(7):e2423390.doi:10.1001/jamanetworkopen.2024.23390(Reprinted) July 19, 2024 6/10 Downloaded from jamanetwork.comby guest on 08/05/2024

Table 2 .
Trial Features Associated With Positive vs Negative Results in Randomized Trials That Had Primary Completion Dates Before December 2022 a P values were calculated with Fisher test.b Co-primary end points are counted separately.c Others include safety, tumor-infiltrating lymphocytes increase, clinical benefit rate, and circulating tumor DNA clearance.