Cancer Trials Research Articles

Updates on the Management of Colorectal Cancer in Older Adults

Colorectal cancer (CRC) poses a significant global health challenge. Notably, the risk of CRC escalates with age, with the majority of cases occurring in those over the age of 65. Despite recent progress in tailoring treatments for early and advanced CRC, there is a lack of prospective data to guide the management of older patients, who are frequently underrepresented in clinical trials. This article reviews the contemporary landscape of managing older individuals with CRC, highlighting recent advancements and persisting challenges. The role of comprehensive geriatric assessment is explored. Opportunities for treatment escalation/de-escalation, with consideration of the older adult’s fitness level. are reviewed in the neoadjuvant, surgical, adjuvant, and metastatic settings of colon and rectal cancers. Immunotherapy is shown to be an effective treatment option in older adults who have CRC with microsatellite instability. Promising new technologies such as circulating tumor DNA and recent phase III trials adding later-line systemic therapy options are discussed. Clinical recommendations based on the data available are summarized. We conclude that deliberate efforts to include older individuals in future colorectal cancer trials are essential to better guide the management of these patients in this rapidly evolving field.

Management of patients with diffuse intrinsic pontine glioma in Australia and New Zealand: Australian and New Zealand Children's Haematology/Oncology Group position statement.

The main mission of the Australian and New Zealand Children's Haematology and Oncology Group (ANZCHOG) is to develop and facilitate local access to the world's leading evidence-based clinical trials for all paediatric cancers, including brain tumours, as soon as practically possible. Diffuse intrinsic pontine gliomas (DIPGs) - a subset of a larger group of tumours now termed diffuse midline glioma, H3K27-altered (DMG) - are paediatric brain cancers with less than 10% survival at two years. In the absence of any proven curative therapies, significant recent advancements have been made in pre-clinical and clinical research, leading many to seek integration of novel therapies early into standard practice. Despite these innovative therapeutic approaches, DIPG remains an incurable disease for which novel surgical, imaging, diagnostic, radiation and systemic therapy approaches are needed. All patients with DIPG should be discussed in multidisciplinary neuro-oncology meetings (including pathologists, neuroradiologists, radiation oncologists, neurosurgeons, medical oncologists) at diagnosis and at relapse or progression. Radiation therapy to the involved field remains the local and international standard of care treatment. Proton therapy does not yield a superior survival outcome compared with photon therapy and patients should undergo radiation therapy with the available modality (photon or proton) at their treatment centre. Patients may receive concurrent chemotherapy or radiation-sensitising agents as part of a clinical trial. Biopsy should be offered to facilitate consideration of experimental therapies and eligibility for clinical trial participation. After radiation therapy, each patient should be managed individually with either observation or considered for enrolment on a clinical trial, if eligible, after full discussion with the family. Re-irradiation can be considered for progressive disease. Every child diagnosed with DIPG should be offered enrolment on a clinical trial where available. Access to investigational drugs without biological rationale outside the clinical trial setting is not supported. In case of potentially actionable target identification with molecular profiling and absence of a suitable clinical trial, rational targeted therapies can be considered through compassionate access programs.

Abstract PO3-27-08: Geographic Distribution and Accessibility of Clinical Trials for Advanced-Stage Breast Cancer in the United States: A Focus on Rural and Minority Health Disparities

Abstract Background: Our research examines the geographical distribution and accessibility of clinical trials for metastatic breast cancer patients in the U.S., spotlighting the challenges faced by rural communities and minority groups. Prior research indicated nearly half of these patients would have to commute over an hour to reach a trial site. [1] Our study provides a refreshed perspective on this issue, offering a more comprehensive analysis. Methods: Utilizing the ClinicalTrials.gov portal, we identified active interventional clinical trials for metastatic breast cancer patients as of November 25, 2022. We obtained distinct zip codes linked to these trials and, using 2020 census data, estimated the proportion of the U.S. populace residing within specific distances from these sites. Our analysis encompassed ethnicity, and other socio-economic parameters. Using GIS software, we also developed illustrative maps to visually represent the U.S. clinical trial accessibility landscape. Results: The majority of Americans diagnosed with metastatic breast cancer have clinical trials within their reach. A significant 81.8% of the U.S. populace resides within a 30-mile radius of a relevant clinical trial site. However, there is significant variation among ethnic groups, especially among American Indians, where 56.5% live within 30 miles of a clinical trial site. Conclusions: While a commendable 81.8% of the U.S. population resides within 30 miles of a metastatic breast cancer clinical trial site, our data underscores the uneven geographical spread of these trials. Our findings underscore the need for strategic initiatives to ensure clinical trials are within reach for every individual, irrespective of their location or background. Reference: 1. Galsky MD, Stensland KD, McBride RB, Latif A, Moshier E, Oh WK, Wisnivesky J. Geographic accessibility to clinical trials for advanced cancer in the United States. JAMA Intern Med. 2015 Feb;175(2):293-5. PMID: 25437434. Map of 30-, 60-, and 120-mile buffers from clinical trial sites open to patients with metastatic breast cancer. The U.S. Population living withing 30-, 60-, and 120-miles of an open clinical trial site for patients with metastatic breast cancer. Citation Format: Emily Westergard, Abigail Swenson, Zachary Schroeder, Wade Swenson. Geographic Distribution and Accessibility of Clinical Trials for Advanced-Stage Breast Cancer in the United States: A Focus on Rural and Minority Health Disparities [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-27-08.

Abstract PS01-09: Early Results of a Phase I Pre-Operative Single Fraction Ablative Trial for Early Stage Breast Cancer

Abstract Objective(s): To explore the impact of pre-operative single fraction stereotactic ablative partial breast irradiation (SPBI) dose escalation (30, 34, or 38Gy) on toxicity and tumor response for early-stage hormone receptor (HR)+ breast cancer in an interim analysis of an expanded cohort phase I dose escalation study (NCT04040569). Methods: Eligible patients (pts) have < 3 cm, HR+, Her2 -, cN0 invasive breast carcinomas not requiring chemotherapy. Patients are treated on either MR LINAC, robotic radiosurgery, or cobalt stereotactic breast units. Endocrine therapy is started two weeks after SPBI. Surgery is completed 2-12 months after SPBI. The primary objective is to escalate single fraction SPBI to an ablative dose without exceeding maximum tolerable dose (MTD). Secondary endpoints include pathologic complete response (pCR), local control, toxicity, cosmesis, and distant disease-free survival. Near complete response (nCR) is defined as RCB 1 and Miller-Payne 4/5. Dose limiting toxicity (DLT) is defined as grade ≥3 toxicity or any grade 4/5 toxicity attributed to SPBI. Each dose cohort enrolls 7-15 pts. Dose escalation is permitted if 0/7, 2/9, ≤3/12, or ≤4/15 patients experienced a DLT within 90 days of SPBI. MTD is exceeded if more DLTs occur in any cohort. Results: From 12/2019 to 6/2023, 11 and 15 pts were treated with 30Gy and 34Gy, respectively. Rates of pCR/nCR are 37.5% for 30Gy versus 92.8% 34 Gy (p=0.01). At 30Gy, 8/11 pts (73%) underwent surgery with a median 4.3 (range 2.8-5.9) month interval from SPBI to surgery: 0/8 (0%) had a pCR and 3/8 (37.5%) had a nCR. At dose level 34Gy, 14/15 pts (93%) underwent surgery with a median 7.3 (range 5.9-12) month interval from SPBI to surgery: 6/14 (42.8%) had a pCR while 7/14 (50%) had a nCR. Of the 8 pts with a nCR, 50% had only 1-3mm of residual disease. The mean ki67 for the entire cohort was 12.0% +/- 6.9% at diagnosis and decreased to 1.4 +/-2.3% at surgery. 13/14 (92.8%) pts with residual disease had a ki67 < 3% after surgery and SPBI. There were 33 acute grade 1; 2 acute grade 2 (breast pain and dermatitis); and 10 late grade 1 [1 grade 2 (breast pain), and 1 grade 3 (slow healing wound) in an uncontrolled diabetic] toxicities. Conclusion: First study to show pre-operative SPBI up to 34Gy in a single fraction was safe and effective for early-stage HR+ breast cancer. Escalating the dose has achieved a dramatic improvement in pCR/nCR (92.8%) suggesting this is an exciting approach for potentially eliminating tumor with radiation/endocrine therapy alone in early stage breast cancer and potentially paving a path towards non-surgical management in highly selected patients. Citation Format: Asal Rahimi, A Marilyn Leitch, Baṣak Dogan, Prasanna Alluri, Deborah Farr, Mona Arbab, Stephen Seiler, Nathan Kim, Rachel Wooldridge, Nisha Unni, Chika Nwachukwu, Ina Patel, You Zhang, David Parsons, Anvy Nguyen, Howard E Morgan, Heather McArthur, Sunati Sahoo, Robert Timmerman. Early Results of a Phase I Pre-Operative Single Fraction Ablative Trial for Early Stage Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS01-09.

Abstract PO5-25-11: Appropriate use of interventional cohort studies with threshold-crossing designs for de-escalation trials in breast cancer

Abstract For some populations of patients with early breast cancer (BC), clinical outcomes have improved such that the focus has shifted to identifying aspects of therapy that can be reduced or omitted to spare patients toxicity without compromising outcomes. For example, in patients with HER2+ disease, introduction of HER2-targetted therapy significantly reduced event rates but at increased exposure to toxicity. For those with a pathological complete response (pCR) to neo-adjuvant anti-HER2 therapy, the absolute gain from continued adjuvant therapy is likely to be small and the event rate sufficiently low such that any deviation from the expected prognosis would be sufficient to infer failure of a reduced treatment strategy. Previous studies would usually adopt a non-inferiority (NI) trial randomising patients between standard of care (SOC) and reduced therapy. The reduced therapy would be declared non-inferior if the difference between the groups does not exceed a pre-agreed NI margin. Some populations, such as those described, have a very low rate of recurrence and thus large sample sizes are required to gain sufficient power resulting in several issues. In these situations, threshold-crossing designs, also known as interventional cohort studies (ICS), provide an alternative to traditional NI trials. In ICS, a single cohort is recruited and receives the reduced therapy. The event rate is compared to a pre-defined fixed threshold, above which recurrence rates would be considered unacceptable. When conducted appropriately, such studies are statistically and logistically efficient, and should be considered definitive. ICS can be used when 1. A stable background of SOC exists with robust data from which an appropriate crossing-boundary can be defined. Critically, the historical control population used to define the boundary must closely reflect the study population and those seen in clinical practice. 2. The event rate is sufficiently low and consequently has low variability, so a concurrent control group is not required because an accurate estimate of the event rate with SOC already exists. 3. The primary endpoint of interest is reliable, sensitive to treatment and timely to allow early stopping if interim analyses indicate an issue. The well-defined excellent prognosis of patients with HER2+ BC who have a pCR to contemporary neo-adjuvant therapy, coupled with the pattern of relapse rates dropping off rapidly after 3 years, makes this an appropriate setting for implementing such designs. Three recently initiated studies testing reduced therapy in this patient population, HER2-RADiCAL (NIHR131362), CompassHER2 (NCT04266249) and DECRESCENDO (NCT04675827), all have an ICS design. An ICS approach is also valid for trials testing avoidance of radiotherapy in very low-risk populations, where the absolute benefit is likely low and occurrence of late local events is salvageable so as not to impact on overall survival, such as in PRIMETIME (ISRCTN 41579286). In contrast, there are several settings where these designs should not be used. For example, in the assessment of systemic therapy in ER+ HER2- BC the recurrence rate is constant beyond 3 years meaning events cannot be picked up in a timely manner and a fixed threshold defined at 3/5 years would not allow preclusion of a later drop-off in efficacy. It would also be premature to use ICS in TNBC following immunotherapy as outcome data is not yet sufficiently mature to accurately define a suitable threshold. Finally, if relapse rates are not sufficiently low, natural variation in control group incidence rates would prevent setting a suitable fixed threshold. We will discuss the key requirements and design features for using ICS to efficiently evaluate avoidance of treatment in BC and highlight the importance of patient involvement in the development of such trials. Citation Format: Holly Tovey, Laura Finneran, Lucy Kilburn, Iain Macpherson, Andrew Wardley, Hilary Stobart, Lesley Turner, Mairead MacKenzie, Charlotte Coles, Cliona Kirwan, Judith Bliss. Appropriate use of interventional cohort studies with threshold-crossing designs for de-escalation trials in breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-25-11.

Abstract PO1-03-07: Revisiting the potential of pathological complete response as a surrogate for long-term survival outcomes in triple-negative breast cancer at the trial-level

Abstract Background: Pathological complete response (pCR) has been used as a primary endpoint in neoadjuvant clinical trials for non-metastatic breast cancer and as a surrogate endpoint for long-term survival outcomes. The U.S. Food and Drug Administration (FDA) accepted pCR as a surrogate endpoint for the approval of new drugs in the neoadjuvant setting in high-risk early-stage breast cancer. However, though the Collaborative Trials in Neoadjuvant Breast Cancer (CTNeoBC) pooled analysis in 2014 showed that at the patient level achieving pCR was associated with longer overall survival (OS) and event-free survival (EFS), at the trial-level the association between high pCR rate and better OS and EFS outcomes was weak (coefficient of difference [R2]; 0.03 and 0.24, respectively) among all subtypes of breast cancer. A recent study reported that this association at the trial-level was similarly weak among Human Epidermal Growth Factor Receptor-2 (HER-2) positive breast cancer (R2; 0.02 and 0.23, respectively). However, the potential surrogacy of pCR rate for OS and EFS in triple-negative breast cancer (TNBC) in the neoadjuvant setting has not been well studied in a comprehensive manner. Moreover, because of significant advances in systemic treatment strategies in TNBC over the past decade including a combination of immune checkpoint inhibitors (ICIs) with conventional cytotoxic agents, the trial-level surrogacy needs to be reassessed in recently published neoadjuvant clinical trials for TNBC. Our primary objective is to assess the association between pCR rate and survival outcomes in neoadjuvant clinical trials for TNBC by collecting data from articles published after the CTNeoBC article in 2014. Methods: We performed a systematic literature search based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines in the PubMed, Cochrane Library, and Web of Science databases. Articles published between January 1, 2014, and March 31, 2023, were searched. We included only randomized control trials of neoadjuvant treatments for clinical stage I-III TNBC that compared two or more regimens followed by curative intent breast surgery. The selected trials had data for odds ratio (OR) for pCR and hazard ratios (HRs) either for OS or for EFS or disease-free survival (DFS). We excluded trials including estrogen receptor positive, progesterone receptor-positive, or HER-2 positive diseases, and those without data enough to obtain ORs for pCR, HRs for OS, EFS, or DFS. Unpublished data as a full article was also excluded. If EFS could not be obtained from the articles, DFS was used in place of EFS. Two independent investigators (TY and TF) searched and extracted data. Any disagreement was resolved by discussion with the third author (ZZ). A linear regression model on a logarithmic scale weighted by the sample size of each trial was performed and the R2 was used to assess the trial-level association between OR for pCR and HRs for OS or EFS. Results: We identified eight trials with a total of 2,926 patients. Three of the eight trials used ICIs in the intervention arm. One trial did not provide OS data and was not included in the OS analysis. In four trials, EFS was not available and DFS was used for EFS analysis. The R2 was 0.191 (95% confidence interval [CI], 0.165 to 0.218) for OS and 0.193 (95% CI, 0.167 to 0.219) for EFS. Conclusions: Similarly to the previous reports, our findings suggest that the surrogacy of the pCR rate for OS and EFS in recent neoadjuvant clinical trials for TNBC is weak. At this moment, there is no strong evidence to support using pCR as a surrogate for long-term survival outcomes in neoadjuvant clinical trials for TNBC. Citation Format: Toru Yoshino, Zao Zhang, Ryota Sato, Stanley Lipkowitz, Takeo Fujii. Revisiting the potential of pathological complete response as a surrogate for long-term survival outcomes in triple-negative breast cancer at the trial-level [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-03-07.

Abstract PO5-17-04: Tolerability of pertuzumab in older adults with HER2 positive breast cancer: A single institution experience

Abstract Background: Tumor HER2 over-expression occurs in 10 to 15% of older adults with breast cancer (BC). Combination HER2-directed therapy (pertuzumab and trastuzumab) with chemotherapy (CT) is the standard treatment for early and advanced HER2-positive bc. However, a study of more than 1,300 Medicare beneficiaries showed that about half of patients (pts) aged 65 or older with stage I to III HER2 positive bc did not receive trastuzumab-based therapy. This is likely due to concern for tolerability as older women remain underrepresented in clinical trials of breast cancer making it difficult to extrapolate tolerability of these agents in these patients. In the Neosphere and TRYPHAENA studies, the mean age of pts were 49.8 and 50.6 years, respectively. We examined the real-world tolerability of pertuzumab in combination with trastuzumab and systemic ct in women over the age of 65 with HER2 positive bc. Methods: An IRB approved retrospective review of medical records was conducted evaluating pts over the age of 65 with early or advanced HER2 positive bc treated at The Ohio State University Comprehensive Cancer center from January 1, 2015 to May,1 2020. Descriptive statistics (means, standard deviations, medians and ranges for continuous variables and frequencies and percents for categorical variables) were used to summarize disease and patient characteristics for pts enrolled in this study and treated with pertuzumab. The total number of planned and completed cycles of treatment as well as the number of treatment delays and dose reductions were also summarized using frequencies and percentages. The same descriptive statistics were used to summarize the number of grade II or IV toxicities and pathologic complete response (pCR) in the neoadjuvant setting. Results: A total of 71 pts met inclusion criteria. Mean age was 76 years (SD 4.1). Of these pts, 62 had stage I-III disease and 9 had metastatic disease. Additionally, 68% (48/71) had estrogen positive (ER) disease whereas 32% (23/71) had ER negative disease. Neoadjuvant systemic therapy was provided to 81% (50/62) of non-metastatic pts and 19% (12/62) received adjuvant therapy. The median number of completed neoadjuvant cycles (ct plus trastuzumab and pertuzumab) was 5.4 (SD 1.5). Among those who received pertuzumab with systemic ct in the neoadjuvant setting, 46% (23/50) of pts achieved a pCR (56% for ER negative disease and 41% for ER positive disease) The median number of completed adjuvant cycles (ct plus trastuzumab and pertuzumab) was 4.9 (SD 2.0). Pts with stage I to III disease completed a mean of 8.6 (SD 5.0) targeted therapy cycles (pertuzumab/trastuzumab). Pts with metastatic disease had a median of 5.7 (SD 1.0) cycles of ct plus trastuzumab and pertuzumab and received a mean of 34.4 (SD 36.0) cycles of maintenance pertuzumab. Treatment delay by 7 or more days occurred in 11% (8/71) of pts whereas 25% (18/71) of pts discontinued pertuzumab early. Pertuzumab termination occurred due to toxicity in 44% (8/18), metastasis in 11% (2/18), and other causes in 44% (8/18) of cases. For toxicities, 2% (1/51) of patients reported grade 3 pain, 25% (2/8) reported grade 3 fatigue, and 12% reported grade 4 diarrhea (1/8) (Table 1). Conclusions: Our study showed that pertuzumab was well tolerated in older pts with bc in the real-world setting. However, 25 % of pts still discontinued pertuzumab early which illustrates the importance of identifying pts who are at higher risk for toxicities prior to starting treatment. Table 1 Reported adverse events in patients age 65 and older receiving pertuzumab Citation Format: Nicole Williams, Austin Warmbier, Dureti Doto, Marilly Palettas, Julie Stephens, Dionisia Quiroga, Kai Johnson, Ashley Pariser, Mathew Cherian, Sagar Sardesai, Daniel Stover, Margaret Gatti-Mays, Robert Wesolowski, Bhuvana Ramaswamy. Tolerability of pertuzumab in older adults with HER2 positive breast cancer: A single institution experience [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-17-04.

Abstract PO3-06-13: A novel stable 6-aryl-2-benzoyl-pyridine colchicine-binding site inhibitor targeting microtubules (60c) is effective against taxane-resistant, metastatic breast cancer

Abstract Background: Improving survival for patients diagnosed with metastatic disease and treating spontaneous chemoresistance remain major clinical challenges in treating breast cancer. Triple negative breast cancer (TNBC), characterized by a lack of therapeutically targetable receptors (ER/PR/HER2), is an aggressive subtype of breast cancer. TNBC therapy relies on a combination of systemically administered chemotherapies, including microtubule-targeting agents (MTAs) like paclitaxel (taxane class) or eribulin (vinca class); however, there are currently no FDA approved MTAs that bind to the colchicine-binding site. Approximately 70% of patients who initially respond to paclitaxel, a first-line MTA, will develop taxane resistance (TxR) within 6 months. We have previously reported that an orally bioavailable colchicine-binding site inhibitor (CBSI), sabizabulin (formerly known as Veru-111), not only inhibits TNBC tumor progression but also treats pre-established metastatic disease in a taxane-refractory PDX model, HCI-10-Luc2. Sabizabulin is currently in phase II/III trials for advanced prostate cancer. To further improve potency and metabolic stability, we created next-generation derivatives of the sabizabulin scaffold, including 60c. Results: 60c shows improved potency compared to sabizabulin against taxane-sensitive and TxR TNBC models, inhibiting proliferation and clonogenicity at low nanomolar concentrations, and inducing apoptosis in a dose-dependent manner. In vivo, 60c therapy significantly suppressed primary tumor growth and lung metastasis in an orthotopic MDA-MB-231-TxR xenograft model without gross toxicity, and with equivalent efficacy to combrestatin A4 phosphate (CA-4P), another CBSI in clinical trials. In the taxane-refractory HCI-10-Luc2 PDX model, 60c significantly suppressed both the growth of the primary tumor (by ~3.5 fold) and the expansion of pre-established axillary metastases (by ~26 fold) whereas paclitaxel had no effect. Analysis of total photon flux of organs excised at study endpoint showed that 60c had distinct anti-metastatic tropism as compared to sabizabulin. Whereas 60c completely suppressed metastases to the spleen (0/9 mice had signal), and significantly reduced metastatic burden in the leg bones (only 3/9 mice had signal) and in the kidney (only 2/9 mice had signal), 60c had no statistically significant effect on liver metastases. In contrast, we had previously reported that sabizabulin strongly repressed liver metastases in the same PDX model (0 mice with detectable liver metastases), with less potent effects on bone. Unlike 60c, sabizabulin showed no improvement relative to the vehicle control for spleen and kidney metastases. Together, our data positions 60c as a promising candidate for TNBC therapy, particularly for patients with TxR disease. Our results also suggest that different CBSI scaffolds may preferentially inhibit metastasis to specific organs, which requires further investigation. Citation Format: Damilola Oluwalana, Kelli Hartman, Raisa Krutilina, Hao Chen, Hilaire Playa, Shanshan Deng, Deanna Parke, Duane Miller, Tiffany Seagroves, Wei Li. A novel stable 6-aryl-2-benzoyl-pyridine colchicine-binding site inhibitor targeting microtubules (60c) is effective against taxane-resistant, metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-06-13.

Abstract PO1-03-03: STEEP criteria v2.0 validation: A multi-trial analysis using GEICAM and TRIO adjuvant trials to evaluate surrogate endpoints for overall survival

Abstract Background: Standardized definitions of efficacy endpoints are needed to improve clinical trial designs, data reporting and interpretation of results, and to allow cross-trial comparisons. STEEP (Standardized Definitions for Efficacy Endpoints) criteria were proposed in 2007 by an expert panel from the National Cancer Institute (NCI) to provide common definitions for clinical trials in early breast cancer (BC). Invasive disease-free survival (IDFS) was selected as a candidate surrogate endpoint for overall survival (OS) in adjuvant trials and has been widely used in the last 15 years. Advances in BC systemic treatment led to review these criteria (STEEP v2.0), with the definition of a new modified endpoint: invasive BC-free survival (IBCFS). IBCFS excludes second primary non-breast invasive cancers from IDFS which may better detect efficacy effects when the toxicity profile of the intervention is well-known and the risk of second primary cancer is small. Methods: We proposed a multi-trial analysis of 8 adjuvant chemotherapy (CT) trials from GEICAM and TRIO to evaluate the different surrogate endpoints defined in the STEEP v2.0. Trial-level surrogacy was assessed through correlation between the ln hazard ratio (HR) of OS and the ln HR of the different studied endpoints across trials. The correlation was estimated by the weighted, by trial size, least squares regression (WLS) line and evaluated comparing the R2 values between OS and the corresponding endpoint tested. Primary analyses evaluated the correlation of OS with IDFS/IBCFS. Secondary analyses evaluated the correlation of OS with other STEEP v2.0 endpoints (distant disease-free survival [DDFS], distant relapse-free survival [DRFS], recurrence-free survival [RFS], recurrence-free interval [RFI] and distant recurrence-free interval [DRFI]) and explored the surrogacy between OS and all endpoints in specific groups of patients (pts) according to their risk of relapse: hormone receptors positive (HR+)/HER2-negative (HER2-) pts with intermediate/high and high-risk and triple negative (TN) pts. Results: A total of 14,473 pts were included. Median age was 50 years (range, 20–82). All were female, and 51.8% were postmenopausal. With a median follow-up of 115 months (range, 0.0–188) we found 2,504 OS events, 4,146 IDFS events (60.9% being distant recurrences) and 3,810 IBCFS events (62.4% being distant recurrences). For each trial, HR of OS, IDFS and IBCFS indicated same conclusions. If HR< 1 for OS, it was also for IDFS and IBCFS and the same was true when HR >1. R2 results of the weighted linear correlations between the ln HR of OS versus (vs) IDFS and OS vs IBCFS were 0.86 and 0.89, respectively. Confidence intervals (CI) at 95% were both overlapping. All other efficacy endpoints showed strong correlation with OS in the overall analysis. R2 values for HR+/HER2- intermediate/high and high-risk pts were 0.89 (OS vs IDFS) and 0.84 (OS vs IBCFS). For TN pts the correlations were weaker, being 0.63 (OS vs IDFS) and 0.73 (OS vs IBCFS). All WLS R2 values are described in the table. Conclusions: All tested STEEP v2.0 endpoints were strongly correlated with OS (R2 close to 1), meaning that their use as surrogate endpoints for adjuvant CT trials is appropriate. Notably, no differences were found between them in this multi-trial analysis. Therefore, none of them is more appropriate than other to discriminate the value of a new intervention vs comparator in adjuvant CT studies with mature data and long-term follow-up. Table: Citation Format: Sara López-Tarruella, Marina Pollan, Ander Urriticoechea, Eva Carrasco, Gonzalo Spera, Miguel Martín, Begoña Bermejo, Linnea Chap, Manuel Ruíz - Borrego, John Crown, Jose Angel García-Sáenz, Arlene Chan, Angel Guerrero, Valerie Bee, Lourdes Calvo, Rodrigo Fresco, Andrea Blasco, Andrés Hernando, Dennis Slamon. STEEP criteria v2.0 validation: A multi-trial analysis using GEICAM and TRIO adjuvant trials to evaluate surrogate endpoints for overall survival [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-03-03.

Abstract PO4-18-05: Safety and Feasibility of Administration of an Oral Cannabis Preparation in The Preoperative Period in Breast and Oral Cavity Cancer

Abstract Introduction- Cannabis is world’s oldest cultivated medicinal plant. It has potential applications in oncology, in reducing chronic pain, stimulating appetite, alleviating nausea/vomiting, improving overall well-being as well as its anti-cancer properties. We conducted a phase-1 dose escalation study to determine safety of pre-operative oral cannabis in breast and oral cavity squamous cell carcinoma (OC-SCC) with an intent to explore its anticancer potential in the “pre-operative” window. The primary objective was to determine maximum tolerated dose (MTD) and establish dose limiting toxicity (DLT). Secondary objectives were pharmacokinetic profiling and transcriptomic analysis of tumour tissue. Methodology- Primary objective was to determine maximum tolerated dose (MTD) and establish dose limiting toxicity (DLT). Secondary objectives were pharmacokinetic profiling and transcriptomic analysis of tumour tissue. Non-metastatic breast and OC-SCC patients planned for curative surgery were consented after thorough medical and mini-psychiatric evaluation with Brief Psychiatry Rating Scale (BPRS). The investigational product (IP) comprised of a capsule containing 2.5mg of tetrahydrocannabinol (THC) and 2.5mg cannabidiol (CBD) in 100 mg monocrotolyn oil extract of dried leaves of C. sativa. The capsules were manufactured in an Ayurvedic GMP facility. The classical 3+3, phase-1 design used modified Fibonacci sequence for dose escalation, starting with 5mg THC+5mg CBD. Patients received IP once a day for 5 days after breakfast with hemodynamic and psychiatric monitoring and underwent the planned surgery on day-6. Pharmacokinetic samples were collected at predefined time-points and plasma levels of THC, 11-OH-THC, 11-COOH-THC and CBD were determined using a validated LC-MS/MS method. Tumour tissue was collected before 1st dose of cannabis and during surgery for biomarker analysis. Results- A total of 12 patients were enrolled (6-breast, 3-buccal mucosa, and 3-tongue cancers). First 3 patients completed the study without DLT at 5+5mg dose. A DLT was observed at dose level-2 (10+10mg) and therefore additional 3 patients were enrolled at the same dose. Two patients out of six at this dose had DLT (anxiety- grade-3 and somnolence- grade-2) necessitating dose de-escalation in the next cohort. At 7.5+7.5mg dose, all 3 patients tolerated the IP(MTD). Ten patients completed the study protocol. Common adverse effects were headache (2/12, grade-1), heavy head (8/12, grade-1), hypotension (2/12, grade-1 and 3), epigastric discomfort (1/12, grade-1), diarrhoea (1/12, grade-1), hyponatremia (1/12, grade-1), hypertension (1/12, grade-2), anxiety (1/12, grade-2). Pharmacokinetics of both CBD and THC was less than dose proportional. At the MTD (7.5+7.5), day-1 and day-5 AUC0-24 [median (range)] for CBD were 21.75 (12.44–41.44) ng/ml−1*h and 24.85 (13.72–35.93) ng/ml−1*h respectively. Similarly, for THC, day 1 and day 5 AUC0-24 were 11.79 (8.06–70.58) ng/ml−1*h and 68.98 (1.78 – 136.17) ng/ml−1*h, respectively. Significant accumulation of both CBD and THC was observed across all doses from day 1 to 5. A high variability in pharmacokinetics was observed for both constituents (CV Cmax = 101.26% and 117.48%; CV AUC0-24 = 102.50% and 112.37% for CBD and THC respectively. The median half-life of CBD and THC was 2.2 (1.6–10.7) and 1.9 (1.6–2.4) h respectively. There was no correlation observed between drug exposure and toxicity. There was no significant change in BPRS score before and after IP. Conclusion- We report the first phase-1 study of cannabis in breast and OC-SCC cancer in pre-operative setting for its anti-cancer potential. Biomarker analysis is awaited. MTD identified will be further explored in phase 2/3 clinical trials in breast, oral cavity, lung and pancreatic cancer with survival endpoints. Citation Format: Rajendra Badwe, Shalaka Joshi, Shiva Thiagarajan, Vikram Gota, Vaibhav Vanmali, Pallavi Daphale, Jayita Deodhar, Rohan Chaubal, Rohini Hawaldar, Jaya Chitra Aadhi, Saurabh Kumar Gupta, Delzaad Deolaliwala, Anil Bhansali, Siddhant Mistry, Satyajeet Singh, Nita Nair, Vani Parmar, Sudeep Gupta. Safety and Feasibility of Administration of an Oral Cannabis Preparation in The Preoperative Period in Breast and Oral Cavity Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-18-05.

Abstract PO1-17-07: Invasive disease-free survival as a surrogate for overall survival in patients with hormone receptor−positive/human epidermal growth factor receptor 2−negative early breast cancer: a real-world analysis

Abstract Background: Although the goal of treatment is to improve overall survival (OS), in the adjuvant setting, disease-free survival (DFS) is an important endpoint because DFS risk reduction may reduce mortality risk. After introduction of the STEEP criteria, invasive DFS (iDFS) was adopted as an objective, well accepted primary endpoint in early breast cancer (EBC) trials. This analysis evaluated iDFS as a surrogate for OS in the HR+/HER2− EBC adjuvant treatment setting using real-world data. Methods: This retrospective analysis of the ConcertAI Patient360 database contains deidentified electronic medical records of patients (pts) treated at US academic and community oncology clinics from Jan 1, 1995 to Apr 30, 2021. The cohort included pts with AJCC (8th ed.) stage II-III (if IIIB or IIIC, confirmation was required on residual tumor status; pathological and/or clinical staging [pathological stage was prioritized if both existed in the record]) HR+/HER2− EBC who had surgery and initiated adjuvant endocrine therapy (ET); ovarian function suppression was permitted. iDFS (disease recurrence, metastasis, second primary tumor, or death) and OS (death due to any cause) were defined as time between ET start and first qualifying event. Pts not experiencing an event were censored at data cutoff or maximum follow-up (whichever was first) for iDFS and maximum follow-up for OS. Correlation analyses between individual iDFS and OS times were performed using Pearson and Spearman correlations and an iterative multiple imputation (IMI) algorithm. Subgroup analyses were conducted by first ET, menopausal status (imputed as 50 years if missing), stage, nodal status, prior (neo)adjuvant chemotherapy, and prior radiation. Results: In total, 3133 pts were analyzed. Mean (SD) age (index or ET initiation date) was 58.4 (12.4) years; 98.8% of pts were female, 29.9% were premenopausal, 80.9% had stage II disease, 57.1% had nodal involvement, and 41.6% and 48.8% had received (neo)adjuvant chemotherapy and radiation therapy. Overall, 1854 and 653 pts received nonsteroidal aromatase inhibitors and tamoxifen only. The median follow-up time was 55.1 months for iDFS and 68.2 months for OS. The iDFS (1103 events [35.2%]) rates were 88.9% and 73.9% at 2 and 5 years. The OS (554 events [17.7%]) rates were 97.4% and 90.5% at 2 and 5 years. There was a significant and high correlation ( >0.85 based on IQWiG 2011 guidelines) between iDFS and OS in the overall cohort (Pearson 0.91, P< .001; Spearman 0.88, P< .001) with 82% of OS variation explained by iDFS (least square R2=0.82; Table). Results were confirmed by IMI rho (0.83, P< .001), which is interpreted as very strong ( >0.8). Results were consistent among all reported subgroups; Pearson and Spearman correlations exceeded 0.85 and IMI exceeded 0.8, except for pts with stage III disease where correlation remained high (Pearson 0.88, P< .001) or medium/strong (Spearman 0.84, P< .001; IMI 0.79, P< .001) and where most censoring was observed (38.2% of pts). Conclusions: This retrospective cohort analysis demonstrates a very strong pt-level surrogacy between iDFS and OS among pts with HR+/HER2− EBC treated in a real-world, US-based, academic and community setting. The findings complement the trial-level surrogacy from prior analyses using data from randomized controlled trials and support iDFS as a surrogate endpoint for OS in HR+/HER2− EBC trials. Citation Format: Stephanie Graff, Sara Tolaney, Lowell Hart, Pedram Razavi, Wolfgang Janni, Lee Schwartzberg, Andrii Danyliv, Juan Carlos Mora Payan, Ilia Ferrusi, Rishi Rajat Adhikary, Joyce O'Shaughnessy. Invasive disease-free survival as a surrogate for overall survival in patients with hormone receptor−positive/human epidermal growth factor receptor 2−negative early breast cancer: a real-world analysis [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-17-07.

Abstract PO3-09-10: Minority participation in breast cancer therapeutic trials at an NCI-CCC affiliated safety-net system: Advancing equity in clinical research

Abstract Authors: Nasir Qureshi, MBBS Fabian Robles, MS Mai Badran, MBBS Nisha Unni, MD Hsiao C Li, MD Samira Syed, MD Glenda Delgado-Ramos, MD Sangeetha Reddy, MD Heather McArthur, MD Navid Sadeghi, MD Title: Minority participation in breast cancer therapeutic trials at an NCI-CCC affiliated safety-net system: Advancing equity in clinical research. Introduction: Participation of under-represented minorities (URMs) in clinical trials enhances the generalizability of the findings and can also improve clinical outcomes. Multiple factors, such as access, language barrier, distrust, and misconceptions, negatively impact URM enrollments in cancer clinical trials. Here we describe our approach to increase participation of breast cancer URMs in therapeutic trials at an academic-affiliated safety-net system. Methods: Parkland Health (PH) is a large safety-net system in Dallas County, Texas, and is affiliated with the NCI-CCC designated Harold C. Simmons Comprehensive Cancer Center (SCCC) at UT Southwestern. A dedicated team of SCCC research coordinators support the clinical trial operations at PH. In 2020, several steps were taken to increase access and enrollment of URMs in breast cancer trials at PH including review and optimization of the trial portfolio (more trials in curative intent setting), proactive screening, increasing provider awareness, and addition of a bilingual (English/Spanish) patient navigator to the research team. Data for 2018-2019 (pre-intervention) and 2021-2022 (post-intervention) is presented here. Data for 2020 is excluded due to the impact of COVID-19 pandemic on trial operations. Results: Racial and ethnic minorities composed the majority of breast cancer patients at PH (52% Hispanics, 32% Blacks). Ten percent of new patients at PH presented with metastatic disease. In 2018-2019, PH's portfolio included 13 therapeutic trials, 5 of which (38%) were in metastatic setting and 3 required a biomarker. A total of 47 breast cancer patients were enrolled in 11 therapeutic trials at PH, accounting for an average annual accrual rate of 6.1% (7.6% in 2018 and 4.5% in 2019). Accrual to trials in the metastatic setting accounted for 11% (5/47) of enrollments. Two trials in the metastatic setting had zero accruals. In 2021-2022, 16 trials were open at PH, including 7 cooperative group, 4 industry-sponsored (ISTs), and 5 Investigator-Initiated trials (IITs). Five trials (31%) were in metastatic setting and 4 required a genomic biomarker. A total of 87 patients were enrolled in 2021-22, representing an 85% increase in the accruals over the baseline (2018-2019). The annual accrual rates for 2021 and 2022 were 10.5% (43/409) and 10.4% (44/423), respectively. In 2021-22, 63 were enrolled in cooperative group studies, 20 in IITs, and 4 in ISTs. Accrual to trials in the metastatic setting accounted for 6% (5/87) of enrollments. Two studies had zero accruals. The majority of the trial participants (77/87; 89%) belonged to URMs (64 Hispanic, 13 Black). Overall participation rate was 67% (87/129) and was significantly higher in Hispanics compared to Blacks (77% vs 41% - p < 0.001). Among Black patients who declined participation, 42% (8/19) cited lack of interest as the reason, which may reflect distrust or misperceptions regarding clinical trials. Conclusions: The collaboration between academic centers and safety-net systems provides a unique opportunity to promote equity in clinical trials by increasing access and enrollment of URMs. Developing a balanced portfolio that matches the patient population, enhanced screening, and incorporating clinical trial patient navigation at our institution resulted in a sustained increase in the number of URM trial participants. Given the lower participation rate among eligible Black patients, we aim to expand our clinical trial navigation program to better address the distrust and misperceptions regarding clinical trials, as a strategy to further improve trial participation at our institution. Citation Format: Nasir Qureshi, Fabian Robles. Minority participation in breast cancer therapeutic trials at an NCI-CCC affiliated safety-net system: Advancing equity in clinical research [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-09-10.

Abstract PO1-16-12: The McPeak-Sirois Group Breast Metastases Registry

Abstract Background: In 2020, the McPeak-Sirois Group (MPSG), a Quebec-based breast cancer trials consortium, launched a feasibility pilot project to register prospectively cases of metastatic breast cancer (MBC). This Breast Metastases Registry (BMR) had the following objectives: a) to measure real-world progression-free and overall survival; b) to capture real-world evidence in efficacy of novel therapeutic approaches and c) to facilitate the development of clinical research projects in MBC. Methods: The pilot phase was initiated in three major academic hospitals with the intention of testing the feasibility of building a BMR and to assess barriers before extension to other hospitals in the province of Quebec. Funding was obtained through non-profit organizations and the pharmaceutical industry. The project was approved by a research ethics board and informed consent was obtained from each patient. The main inclusion criteria was a MBC diagnosis at the time of enrolment. Metastatic diseases were considered de novo if the metastatic condition was detected at the same time of the primary disease diagnosis or within the following 4 months. The information in the BMR relates to participants’ health status, including but not limited to hospitalizations, diagnoses, medications, medical procedures and imaging, pathology, genetic and laboratory results. In addition to the prospective data, the registry also captures information retrospective to the date of enrollment. Results: Between July 30, 2021 and April 22, 2023, a total of 427 patients were approached by a research nurse and 423 patients enrolled and 4 refused (99.2% participation rate). Approximately one third of the cohort was diagnosed between 2021-2023 (30.3%) while 69.7% were in 2002-2020 timeframe. The majority was either HR+/HER2- (55.3%) or HER2+ (26.9%). The median age at the time of MBC diagnosis was 57 years (Q1-Q3 range: 47-67 years). We observed that 57.9% of patients had a relapsed MBC while de novo MBC comprised 42.1% of the cohort with the highest percentage in the HER2+ group (59.6%). The median time between primary cancer and metastatic disease in those with relapsed MBC is shorter in triple negative breast cancer (28.9 months) compared to 71.4 months in HR+ disease. Among all lines of treatment for metastatic disease, independently of age at time of MBC diagnosis, 21% of patients participated in a clinical trial. Discussion: The pilot project demonstrated the acceptability and feasibility of building a MBC provincial registry as illustrated by the high participation rate (more than 99%). The next step is to expand the registry to other hospital sites in Quebec, however, the main difficulty is having the necessary manpower (oncology registrars) to ensure data entry. Over one third of the MBC patients presented as de novo disease (and more than half of these with HER2+ disease). This proportion of de novo MBC is unusually high and is likely due to a recruitment bias during the pilot phase as data entry was prioritised for de novo diagnoses over MBC at time of recurrence and patients were recruited at any time in their MBC trajectory and not only at the time of their MBC diagnosis. Clinical trial participation was higher in our cohort compared to the usually reported 5% participation rate. This may be due to recruitment bias but needs to be evaluated further. Conclusion: We have found that recruiting patients in a metastatic cancer registry and collecting their real-world data is not only feasible but well received by patients. The limiting factor for expansion to other hospitals is lack of oncology registrars. At maturity, the BMR will be a unique and powerful resource for breast cancer research and will allow researchers and their collaborators to unite their efforts to better understand how stage IV breast cancer is treated and how management of the disease can be improved. The BMR could also have the potential to improve participation in clinical trials and to stimulate clinical research. Citation Format: Julie Lemieux, Danielle Charpentier, Dominique Johnson, Nathalie Bolduc, Caty Blanchette, Claude Nadon, Sarkis Meterissian. The McPeak-Sirois Group Breast Metastases Registry [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-16-12.

Abstract PO1-10-11: Illuminating Breast Cancer Clinical Trials: Unpublication Rates, Causes , and Recommendations

Abstract Introduction: Breast cancer stands as the most prevalent cancer among women worldwide. Recent years have witnessed remarkable improvements in patient’s outcome, primarily attributed to advancements in management strategies. However, the introduction of novel management approaches necessitates rigorous evaluation through clinical trials, ensuring both their safety and effectiveness. Conducting these trials entails significant financial investments and time commitments, making them susceptible to termination for various reasons. This study aims to investigate the factors that contribute to an increased likelihood of breast cancer clinical trial termination. Methodology: A thorough and extensive exploration of ClinicalTrials.gov was undertaken in order to discover completed clinical trials focused on treating breast cancer from 2000 to 2020. By employing the distinctive National Clinical Trial number (NCT) identifier, trial's status; whether completed or terminated, was determined. Subsequently, a meticulous evaluation was carried out on these trials to ascertain the factors that contributed to their termination. In order to unveil the noteworthy factors linked to publication, a comprehensive analysis encompassing both univariate and multivariate approaches was conducted. Results: During the specified period, a noteworthy number of oncology clinical trials, totaling 9,145, were conducted. Among them, 12.3% (n=1,127) were focused on breast cancer. These breast cancer trials managed to recruit an impressive 2,669,749 patients. However, it is concerning to note that a significant portion, 38.1% (n=429), of the breast cancer trials did not result in published findings, despite enrolling a considerable number of patients (n= 2,397,179). Our comprehensive univariate analysis revealed several significant associations between the characteristics of clinical trials and their likelihood of going unpublished (P< 0.001). Factors such as funding, phase, masking, center type (single vs multi), and country of conduct were all found to have a statistically significant impact on the publication status. Furthermore, our meticulous multivariate analysis demonstrated that certain criteria were associated with higher odds of publication. These included trials that recruited >50 patients, multicenter trials, studies implemented masking, phase-3 trials and those that included low- and middle-income countries (LMIC), Table. Conclusion: Our findings indicate that the unpublication rate of clinical trials was alarmingly high. We identified that the sample size, masking, multicenter involvement and phase of the trial impact significantly on publication rate . This knowledge can be valuable for researchers, funding agencies, and other stakeholders who can prioritize resource allocations and improve patients care. Table: Multivariate analysis, factors that impact publication rate Citation Format: Abdulrahman Alhajahjeh, Ghayda’ Bader, Saji Aweidah, Taima’ Bader, Basil Abdin, Layla El-Amayreh, Hikmat Abdel-Razeq. Illuminating Breast Cancer Clinical Trials: Unpublication Rates, Causes , and Recommendations [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-10-11.

The Benefits and Risks of Receiving Investigational Solid Tumor Drugs in Randomized Trials : A Systematic Review and Meta-analysis.

Many patients participate in cancer trials to access new therapies. The extent to which new treatments produce clinical benefit for trial participants is unclear. To estimate the progression-free survival (PFS) and overall survival (OS) advantage of assignment to experimental groups in randomized trials for 6 solid tumors. ClinicalTrials.gov was searched for trials of investigational drugs with results posted between 2017 and 2021. Investigational drugs were defined as those not yet having full approval from the U.S. Food and Drug Administration for the study indication. Trials were included if they were randomized and tested drugs or biologics. Data extraction was completed by 2 independent reviewers. Data were pooled using a random-effects model. The sample included 128 trials comprising 141 comparisons of a new drug and a comparator. These comparisons included 47 050 patients. The pooled hazard ratio for PFS was 0.80 (95% CI, 0.75 to 0.85), indicating statistically significant benefit for patients in experimental groups. This corresponded to a median PFS advantage of 1.25 months (CI, 0.80 to 1.68 months). The pooled hazard ratio for OS was 0.92 (CI, 0.88 to 0.95), corresponding to a survival gain of 1.18 months (CI, 0.72 to 1.71 months). The absolute risk for a serious adverse event for comparator group patients was 29.56% (CI, 26.64% to 32.65%), with an increase in risk of 7.40% (CI, 5.66% to 9.14%) for patients in experimental groups. Trials in this sample were heterogeneous. Comparator group interventions were assumed to reflect standard of care. Assignment to experimental groups produces statistically significant survival gains. However, the absolute survival gain is small, and toxicity is statistically significantly greater. The findings of this review provide reassuring evidence that patients are not meaningfully disadvantaged by assignment to comparator groups. Canadian Institutes of Health Research.

Beyond clinical trials: real-world impact of immunotherapy on NSCLC in Jordan.

This study aims to evaluate real-world (rw) outcomes of immunotherapy (IO) for advanced stage NSCLC at King Hussein Cancer Center (KHCC) in Jordan. Advanced stage NSCLC patients who received IO at KHCC between 2017 and 2022 were included. The data were retrospectively collected. PFS and OS were estimated for patients with ECOG performance status (ECOG PS) 0-1. Cox regression analyzed predictors of OS in first-line (1L) IO, regardless of performance status. The total number of patients included was 244. Out of those, 160 (65%), 67 (28%), and 17 (7%) patients received IO as 1L, second-line (2L), or third-line or beyond (3L or beyond), respectively. The median age for all patients was 59 years. Male were 88%, and 77% were smokers. The median follow-up time was 12.5 months. The median PFS and OS for 1L IO were 7 [95% CI 5.8 - 10.3] and 11.8 [95% CI 8.8 - 14.4], months, respectively. In the first 3 months after starting 1L IO, 34/160 (21%) patients had died. For those who survived beyond 3 months after starting 1L IO, the median PFS and OS were 11.3 [95% CI 8.3 - 16.5] and 15.4 [95% CI 13.2 - 21] months, respectively. In the Cox regression model of 1L IO patients with any performance status, ECOG PS 2 was predictive of worse OS compared to ECOG PS 0-1 (p= 0.005). This real-world study of advanced-stage NSCLC patients treated with immunotherapy at KHCC reveals outcomes that fall short of those anticipated from clinical trials. The inclusion of Middle Eastern patients in lung cancer trials is essential to ensure adequate representation of various ethnicities in clinical research.

Aspirin vs Placebo as Adjuvant Therapy for Breast Cancer

Observational studies of survivors of breast cancer and prospective trials of aspirin for cardiovascular disease suggest improved breast cancer survival among aspirin users, but prospective studies of aspirin to prevent breast cancer recurrence are lacking. To determine whether aspirin decreases the risk of invasive cancer events among survivors of breast cancer. A011502, a phase 3, randomized, placebo-controlled, double-blind trial conducted in the United States and Canada with 3020 participants who had high-risk nonmetastatic breast cancer, enrolled participants from 534 sites from January 6, 2017, through December 4, 2020, with follow-up to March 4, 2023. Participants were randomized (stratified for hormone receptor status [positive vs negative], body mass index [≤30 vs >30], stage II vs III, and time since diagnosis [<18 vs ≥18 months]) to receive 300 mg of aspirin (n = 1510) or placebo once daily (n = 1510) for 5 years. The primary outcome was invasive disease-free survival. Overall survival was a key secondary outcome. A total of 3020 participants were randomized when the data and safety monitoring committee recommended suspending the study at the first interim analysis because the hazard ratio had crossed the prespecified futility bound. By median follow-up of 33.8 months (range, 0.1-72.6 months), 253 invasive disease-free survival events were observed (141 in the aspirin group and 112 in the placebo group), yielding a hazard ratio of 1.27 (95% CI, 0.99-1.63; P = .06). All invasive disease-free survival events, including death, invasive progression (both distant and locoregional), and new primary events, were numerically higher in the aspirin group, although the differences were not statistically significant. There was no difference in overall survival (hazard ratio, 1.19; 95% CI, 0.82-1.72). Rates of grades 3 and 4 adverse events were similar in both groups. Among participants with high-risk nonmetastatic breast cancer, daily aspirin therapy did not improve risk of breast cancer recurrence or survival in early follow-up. Despite its promise and wide availability, aspirin should not be recommended as an adjuvant breast cancer treatment. ClinicalTrials.gov Identifier: NCT02927249.

The Bayesian Group-Sequential Predictive Evidence Value Design for Phase II Clinical Trials with Binary Endpoints

AbstractIn clinical research, the initial efficacy of a new agent is typically assessed in a phase IIA study. Bayesian group-sequential designs are often based on predictive probability of trial success. In this paper, the novel Bayesian group-sequential predictive evidence value design is introduced, and we prove that the predictive probability approach is a special case of it. A comparison with Simon’s two-stage and competing Bayesian designs based on phase IIA cancer trials is provided. Results show that the novel design can improve operating characteristics such as the false-positive rate, probability of early stopping for futility and expected sample size of the trial. Given these advantages, the predictive evidence value design constitutes an important addition to the biostatistician’s toolbelt when planning a phase IIA trial the Bayesian way, in particular, when small sample sizes and a large probability for early termination under the null hypothesis are desired.

Racial and Ethnic Disparities in European Breast Cancer Clinical Trials.

Breast cancer is the most prevalent female cancer worldwide with known correlations between the race and tumor characteristics of the patients and prognosis. International and US-based studies, however, have reported a disproportionate representation of Black and Hispanic patients in clinical trials. This is the first study assessing race and ethnicity reporting trends and inclusion in European breast cancer trials. The PubMed and ClinicalTrials.gov databases were systematically searched for trials on breast cancer treatment conducted exclusively in Europe between 2010 and 2022. Of the 97 identified trials, race was reported in 10.31%. Multinational participation, but not the study size or trial phase, was significantly associated with higher race reporting trends. These 10 trials featured a White-predominant population, with 1.08% Asian and 0.88% Black patients included. The acquisition of the race and ethnicity data of patients in European trials is lower compared to the U.S. or worldwide studies and does not permit extensive analysis of minority participation. In a limited analysis, the low rates of minority participation are concerning, based on population-based data on minorities in select European countries. These observations should encourage race reporting practices in European breast cancer trials and adequate minority participation to support the generalizability of the results of the studies and promote healthcare equity.

RECIST 1.1 versus clinico-radiological response assessment for locally advanced cervical cancer: implications on interpreting survival outcomes of future trials.

To investigate differences in standard clinico-radiological evaluation versus Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 for reporting survival outcomes in patients with locally advanced cervical cancer treated with chemoradiation and brachytherapy. Between November 2017 and March 2020, patients recruited in cervical cancer trials were identified. MRI at diagnosis and at least one follow-up imaging was mandatory. Disease-free survival and progression-free survival were determined using standard evaluation (clinical examination and symptom-directed imaging) and RECIST 1.1. Agreement between criteria was estimated using κ value. Sensitivity analysis was done to test the sensitivity, specificity, and accuracy of RECIST 1.1 in detecting response to treatment. Sixty-nine eligible patients had at least one target lesion. Thirty-three patients (47.8%) had pathological lymph nodes. Of these 33 patients, RECIST 1.1 classified only 18% (6/33) as 'target nodal lesions' and the remaining nodes as 'non-target'. There were 6 (8.7%) and 8 (11.6%) patients with disease events using RECIST 1.1 and standard evaluation, respectively. The disease-free survival at 12, 18, and 24 months using RECIST 1.1 was 94.2%, 91.2%, 91.2%, and with standard evaluation was 94.2%, 89.7%, and 88.2%, respectively (p=0.58). Whereas, progression-free survival at 12, 18, and 24 months using RECIST 1.1 and standard evaluation were same (94.2%, 91.2%, and 91.2%, respectively). The κ value was 0.84, showing strong agreement in assessing disease-free survival, although an absolute difference of 3% between endpoint assessment methodologies. RECIST 1.1 had a sensitivity of 75% (95% CI 34.91% to 96.81%), specificity of 100% (95% CI 94.13% to 100%), and accuracy of 97.1% (95% CI 89.92% to 99.65%). The study showed 1.5% and 3% difference in disease-free survival at 18 and 24 months and no difference in progression-free survival between RECIST 1.1 and standard evaluation in a patient cohort with low event rate.