Clin Oncol Research Articles

Abstract PO4-20-05: An open label phase III randomized trial to evaluate the efficacy of Post-chemotherapy Axillary Conservation Surgery in breast cancer (PACS)

Abstract Background- Axillary lymph nodes (ALN) status is the most important prognostic factor in breast cancer. Traditionally, a complete axillary lymph node dissection (ALND) has been standard of care for those patients who have a positive node pre-chemotherapy. However, lately axillary conservation is paving its way in the post-chemotherapy setting as well to avoid significant morbidity of ALND. Most sentinel node biopsy studies have failed to achieve the desired false negative rate(FNR). (Boughey JC et al, JAMA. 2013 Oct; Kuehn T et al, Lancet Oncol. 2013; Boileau JF et al, J Clin Oncol. 2015 Jan).We previously reported a low FNR of low axillary sampling (LAS) in the post-chemotherapy setting. (Parmar et al, JCO-GO, 2021) We are conducting a phase III, randomised controlled trial of LAS versus complete ALND in post-chemotherapy negative (ypN0) axilla. Aims and objectives- The primary objective is to assess the non-inferiority of LAS in patients who are rendered ypN0 by pre-operative chemotherapy with disease-free survival as primary end point. The secondary objectives are comparing the morbidity of ALND (lymphedema, paraesthesia, and shoulder dysfunction) in the LAS and ALND arms, and to evaluate the impact on overall survival, local, regional, and distant recurrence free survival and quality of life. Trial design- This is a prospective, open label, randomised, phase III trial where histologically proven, non-metastatic, cT1-4,N0-2 breast cancer patients who are rendered ycN0 after pre-operative systemic chemotherapy are being accrued. Patients with prechemo N3 disease, inflammatory breast cancer, recurrent disease, pregnancy associated breast cancer are being excluded from the study. The chemotherapy regimens and surgical assessment is as per standard institutional protocols. After obtaining informed consent, patients undergo LAS during surgery and lymph nodes(LN) are sent for frozen section analysis. If any LN is found to be involved, a complete ALND is carried out. If the staging procedure is negative, then patients are randomised into 2 groups- observation v/s complete ALND. Stratification factors are T stage, N stage, Hormone receptor status, Her2 receptor status and number of chemotherapy cycles taken. Morbidity assessment is done with- Constans shoulder score, arm volumetry, paraesthesia assessment, and a QOL questionnaire- Self-reported Breast cancer Lymphedema Symptom Experience Index (BCLSEI). A baseline assessment pre-surgery is followed by 6 monthly morbidity assessments and regular oncologically relevant follow-up up to 5 years. A two-sided log-rank test with an overall sample size of 2316 with a 10% dropout rate (1158 in ALND and 1158 in LAS group) achieves 80% power at a 0.05 significance level to detect a hazard ratio of 1.16 (upper limit of non-inferiority) when the proportion surviving in the control group is 0.71. An interim analysis will be carried out at 25% events and conditional power will be calculated. If the conditional power is below 20%, then the study will be discontinued for futility. The study has been approved by Institutional Ethics Committee (CTRI/2022/07/044461) Expected Study and Results- We started accrual in February 2023 and have screened 63 and randomized 45 patients until now. Ours is a first large randomised prospective study in the post-chemotherapy axillary management setting which will help us understand the efficacy of axillary conservation surgery in patients who are node negative post neoadjuvant chemotherapy. In future, lesser morbid procedures than LAS like targeted axillary dissection can be tested in the same trial. However, LAS as a technique of axillary conservation suits resource constraints and high volume setting such as ours. Citation Format: Shalaka Joshi, Jessicka Shah, Pallavi Daphale, Rohini Hawaldar, Anuradha Daptardar, Ayushi Sahay, Tanuja Shet, Palak Popat, Tabassum Wadasadawala, Nita Nair, Vani Parmar, Bipin Bandre, Shabina Siddique, Vaibhav Vanmali, Sudeep Gupta, Rajendra Badwe. An open label phase III randomized trial to evaluate the efficacy of Post-chemotherapy Axillary Conservation Surgery in breast cancer (PACS) [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 PO4-20-05.

Abstract PO5-20-04: A Phase II Study of Ribociclib and Endocrine Treatment of Physician’s Choice for Locoregional Recurrent, Resected Hormone Receptor Positive HER2 Negative Breast Cancer (RaPhLRR Study)

Abstract Background Hormone receptor positive (HR+) breast cancer (BC) is the most common subtype of BC (70-80%). This subset tends to have good prognosis, therefore most patients with localized disease have excellent long-term survival, approaching 100% 5-year relative survival. However, 10% of patients experience loco-regional recurrence (LRR) within 5 year of final surgical management of the primary disease-well within the typical treatment window of adjuvant endocrine therapy. Few studies exists to guide the systemic treatment of patients who have suffered LRR of HR+ HER2 - BC. The randomized controlled CALOR trial demonstrated no benefit to systemic cytotoxic chemotherapy for this subgroup of patients and persistent high rate of subsequent recurrences (50% within 10 years on LRR event). There is no standard of care for managing this patient population. The combination of ribociclib and endocrine therapy (ET) (fulvestrant and aromatase inhibitors) is FDA approved for management of unresectable recurrences and metastatic HR+HER- BC (MONALEESA trials). CDK4/6 inhibitors have been investigated in early BC setting too, several trials showing positive results (monarchE, NATALEE). Data is needed to investigate their use in patients with LRR. Trial design This is a multicenter, single arm phase II study to evaluate efficacy and safety of ribociclib and ET in patients with LRR of HR+HER2- BC. Treatment includes ribociclib for 36 months, 600 mg daily for 21 days, 28-day cycle plus physician’s choice ET for 60 months (fulvestrant or AIs). Ribociclib dose was chosen based on approved dose in metastatic BC. Eligibility Criteria Patients ≥ 18 of age, with LRR of BC (ipsilateral breast, axilla, regional lymph nodes, chest wall), histologically confirmed estrogen receptor positive and/or progesterone receptor positive, HER 2 negative. Patients must have adequate local treatment for LRR (surgery and/or radiation) with negative microscopic margins, no evidence of distant metastatic disease. Prior treatment with neo-adjuvant and adjuvant chemotherapy and ET is allowed, no prior CDK 4/6 inhibitor in the last 12 months. Pre and post-menopausal women are allowed. Patient must enroll within 6 months of the last local therapy. Specific aims Primary objective: to estimate subsequent recurrence-free survival (RFS) at 3 years for ribociclib when administered with ET in patients with HR + HER2- BC with adequately resected local recurrence. Secondary objectives: to estimate distant metastasis-free survival and overall survival, to evaluate safety and tolerability, to identify predictors of LRR. Correlative analysis will explore prognostic and predictive biomarkers of treatment with ribociclib and ET and potential molecular mechanisms of resistance to treatment. Statistical Methods From previous published data (J Clin Oncol. 2018 Apr 10;36(11):1073-1079), we assume that patients receiving standard of-care management following recurrence would have a recurrence free survival (RFS) rate of 80% at 3 years and that treatment with ribociclib + ET will increase it by 7%. We wish to have at least 80% power at that significance level of 0.0487 to correctly detect that improvement in RFS rate at 3 years from 80 to 87%. Because only an improvement in RFS rate is of clinical interest, we have a directional hypothesis, and have used a 1-sided alpha. Using a one-sample survival study design, with assumed accrual duration of 3-years and additional follow-up time of 3 years, the minimum sample size requirement is N=180 patients. Target accrual The minimum sample size requirement is N=180 patients. A bigger sample size of N=200 patients will achieve a power of at least 84%. Current accrual is 6/200. This study will be open at up to 35 sites. Contact information The study is being administered through the HCRN, it can be identified as BRE20-468, NCT05467891, ocdanciu@uic.edu Citation Format: Oana Danciu, Nancy Chan, Kari Wisinski, Trish Millard, Kathleen Kemmer, Sneha Phadke, Zhengjia Chen, Ana Cuesta Fernandez, Melanie Clark, Alison Conlin, Coral Omene, Sima Ehsani, Stephanie Dublis, Vijayakrishna K. Gadi. A Phase II Study of Ribociclib and Endocrine Treatment of Physician’s Choice for Locoregional Recurrent, Resected Hormone Receptor Positive HER2 Negative Breast Cancer (RaPhLRR Study) [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 PO5-20-04.

Abstract PO1-18-12: Trial in progress: Open-label, randomized, multicenter, phase 3, ELAINE 3 study of the efficacy and safety of lasofoxifene plus abemaciclib for treating locally advanced or ER+/HER2- metastatic breast cancer with an ESR1 mutation

Abstract Background: Patients with estrogen receptor-positive (ER+) metastatic breast cancer (BC) may develop resistance to endocrine therapy (ET), particularly following treatment with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i), potentially driven by a mutation in the ERa-coding gene, ESR1. Lasofoxifene, an oral, next-generation ET and ER breast antagonist, had potent activity in mBC xenograft models expressing ESR1 mutations, either as a single agent or combined with a CDK4/6i. Subsequently, two phase 2 studies evaluated lasofoxifene in women with ER+/HER2- metastatic BC and an ESR1 mutation who had disease progression on previous ET and CDK4/6i. The ELAINE 1 trial showed numerically greater progression-free survival (PFS, median ~6 vs 4 months; P=0.138), objective response rate (ORR, 13% vs 3%; P=0.124), and clinical benefit rate (CBR, 37% vs 22%; P=0.117) with lasofoxifene monotherapy versus the ER degrader fulvestrant, with a favorable safety profile (Goetz MP, et al. Ann Oncol. 2022;33:S1387). The single-arm, ELAINE 2 trial demonstrated that lasofoxifene combined with abemaciclib was well tolerated with a median PFS of ~13 months, ORR of 56%, and CBR of 66% (Damodaran S, et al. J Clin Oncol. 2023;41:suppl 16; abstr 1057). Based on these data, the phase 3, registrational, ELAINE 3 trial was initiated. Methods: ELAINE 3 (NCT05696626) is an open-label, phase 3, multicenter study evaluating the efficacy, safety, and tolerability of lasofoxifene plus abemaciclib versus fulvestrant plus abemaciclib. Key inclusion criteria are pre- and postmenopausal women and men aged ≥18 years; ER+/HER2-, locally advanced and/or metastatic BC (measurable and/or non-measurable disease); ≥1 acquired ESR1 mutation; progression on an aromatase inhibitor plus palbociclib or ribociclib as their first hormonal treatment for advanced/metastatic BC; and ≤1 line of chemotherapy in the advanced/metastatic setting. Patients will be randomized 1:1 to receive lasofoxifene 5 mg/day plus abemaciclib 150 mg BID, or fulvestrant 500 mg IM on days 1, 15, and 29, then 4 weekly plus abemaciclib 150 mg BID. Treatment will continue until progression, death, unacceptable toxicity, or withdrawal from the study. The primary endpoint is PFS; key secondary endpoints are ORR, overall survival, CBR, duration of response, and time to response. Time to cytotoxic chemotherapy, quality of life, and safety will also be evaluated. Blood samples for circulating tumor DNA (ctDNA) will be collected at screening, at weeks 4 and 8 and every 8 weeks thereafter, and at the final visit for genomic analyses. Outcomes with lasofoxifene/abemaciclib and fulvestrant/abemaciclib will be compared using a stratified Cox proportional hazards model and stratified logrank test. Expected PFS is ≥10.3 months for lasofoxifene/abemaciclib and 7 months for fulvestrant/abemaciclib (PFS hazard ratio of 0.68 at final analysis). The target sample size is 400, to achieve 90% power with a one-sided type I error rate of 0.025 after 285 PFS events. Full recruitment is expected to occur over 18 months at 125 global sites. Citation Format: Matthew Goetz, Seth Wander, Thomas Bachelot, Gerald Batist, Javier Cortés, Massimo Cristofanilli, Giuseppe Curigliano, Alexandre de Nonneville, Einav Nili-Gal Yam, Komal Jhaveri, Cynthia Ma, Heather Parsons, Hope Rugo, Sarah Sammons, Daniel Stover, Chris Twelves, Aditya Bardia, Paul V. Plourde, David J Portman, Senthil Damodaran. Trial in progress: Open-label, randomized, multicenter, phase 3, ELAINE 3 study of the efficacy and safety of lasofoxifene plus abemaciclib for treating locally advanced or ER+/HER2- metastatic breast cancer with an ESR1 mutation [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 PO1-18-12.

Abstract PO1-02-02: Update of RSClin with extended TAILORx follow-up and development and validation of a new tool for risk of late distant recurrence

Abstract Background: RSClin® (Sparano et al J Clin Oncol 2020, PMID 33306425) is an educational tool that estimates the 10-year risk of distant recurrence (DR) and the absolute benefit of chemotherapy in HR-positive, HER2-negative, node-negative early breast cancer. The RSClin tool integrates the Recurrence Score® (RS) result with the clinical-pathological features tumor grade, tumor size and patient age using patient-specific meta-analysis (PSMA) applied to the NSABP B-14, TAILORx and NSABP B-20 studies. Approximately 3 years of additional follow-up data have accumulated in the TAILORx study since the RSClin tool was developed, including 50% more DR events in the RS 11-25 group (375 vs. 250), and 46% more DR events in the overall population (561 vs. 384). Methods: The RSClin tool estimates were updated to include the extended follow-up data from TAILORx. As before, the PSMA included 10,004 women with hormone-receptor positive, HER2-negative, node-negative breast cancer from the NSABP B-14 (n=577) trial receiving endocrine therapy (ET) alone and the TAILORx trial receiving ET alone (n=4854) or chemotherapy (CT) plus ET (n=4573). The baseline risk estimate used TAILORx event rates with ET alone. Since there was evidence of differing hazard ratios in years 0-5 versus 5+, models using time-varying effects were used. A patient-specific estimator of absolute CT benefit was computed by combining a PSMA estimate of the individualized relative CT effect from the TAILORx and NSABP B-20 (n=550 HER2-negative) trials with risk estimates for ET alone. Similar methods were used to develop and validate a new tool for assessing the risk of late DR (from year 5 to 10) in patients who survive DR-free for 5 years on ET alone after surgery. External validation of DR risk estimation was performed in an independent cohort of 1098 women enrolled in the Clalit Health Service registry. Results: With the updated data, the model integrating RS result with clinical-pathological features was more informative for DR risk than either RS result alone or the clinical-pathological features alone, both for 10-year DR risk and for late DR risk (likelihood ratio tests, each p≤.001). The updated 10-year RSClin risk estimates are similar to the existing RSClin tool risk estimates with slightly lower risk estimates for very high RS results and more precise estimates for mid-range RS results. The updated chemotherapy effect estimates are slightly lower than for the existing RSClin. The updated RSClin tool 10-year risk estimates were strongly associated with DR risk in the independent Clalit registry (Cox regression p< .001) and closely approximated the observed DR risk (Lin concordance 0.87). The new tool’s late DR risk estimates beyond 5 years were strongly associated with late DR risk in the Clalit registry (Cox regression p=.002) and closely approximated the observed late DR risk (Lin concordance 0.92). Conclusions: The RSClin tool 10-year DR risk estimates have been updated to incorporate extended follow-up data from the TAILORx study. A new tool for assessing late DR risk has been developed and validated that provides more prognostic information than either clinical-pathological features or genomic risk used individually. Citation Format: Joseph Sparano, Michael Crager, Robert Gray, Gong Tang, Jess Hoag, Frederick Baehner, Charles Geyer, Steven Shak, Norman Wolmark, Salomon Stemmer. Update of RSClin with extended TAILORx follow-up and development and validation of a new tool for risk of late distant recurrence [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 PO1-02-02.

Abstract PO2-14-09: Baseline genomic alterations and the activity of lasofoxifene (LAS) plus abemaciclib (Abema) in patients with ER+/HER2- metastatic breast cancer (mBC): the ELAINE 2 study

Abstract Introduction: Estrogen receptor-positive (ER+)/HER2-negative (HER2-) breast cancers commonly acquire constitutively active mutations in the ERα-encoding gene (ESR1), resulting in endocrine therapy (ET) resistance. In the phase 2, ELAINE 2 study (NCT04432454), LAS (a breast ER antagonist) combined with Abema provided a median progression-free survival (PFS) of ~13 months (mos) and clinical benefit rate (CBR) of 66% in patients with endocrine-resistant, ER+/HER2- mBC and ESR1 mutations (mESR1; Damodaran. J Clin Oncol 2023;41:suppl16;1057). Our objective was to describe baseline genomic alterations co-occuring with mESR1 and treatment responses to LAS plus Abema in patients with these concurrent genomic alterations. Methods: Women (age ≥18 yrs) with ER+/HER2- mBC that progressed after prior ET and CDK4/6 inhibitor (CDK4/6i) with an mESR1 detected in blood using the Sysmex-Inostics SafeSeq circulating tumor DNA (ctDNA) test were enrolled in ELAINE 2. Oral LAS 5 mg/day and Abema (provided by Eli Lilly and Co) 150 mg BID were taken until disease progression, death, unacceptable toxicity, or withdrawal. The Guardant360 CDx test was used to identify and describe baseline genomic alterations in ctDNA (including mESR1). Median PFS and CBR were assessed in patients with mESR1 and co-existing baseline genomic alterations. For patients who withdrew before disease progression, their last observation time was used as the progression time for PFS estimation. Data were summarized descriptively with no formal hypothesis testing. Results: Of the 29 patients (median age 60 yrs) enrolled, mutations in ESR1 were identified in 26 by Guardant360; all these 26 patients had received prior CDK4/6i, 21 (81%) prior fulvestrant, and 12 (46%) prior chemotherapy for mBC. Alterations in 39 genes were concurrently identified with mESR1, including TP53 mutations (n=11), PIK3CA mutations (n=8), CCND1 amplifications (n=6), and FGFR1 amplifications (n=5); co-amplification of CCND1 and FGFR1 was identified in 3 patients. LAS plus Abema treatment was associated with a CBR of 73% and a median PFS of 12.9 mos in the 26 patients with mESR1 (Table). CBRs were 63% in the co-occurring PIK3CA mutation subgroup and 64% in the TP53 mutation subgroup; median PFS times were 7.8 and 8.3 mos, respectively. All patients in the CCND1 and FGFR1 amplification subgroups achieved clinical benefit (CBR 100%) and the median PFS was 16.6 mos for both subgroups. In patients with mESR1 and co-alterations in ≥2 other genes of interest (PIK3CA, FGFR1, CCND1, TP53, ERBB2, CCNE1, or RB1), CBR was 83% and median PFS was 16.6 mos. Conclusion: Using Guardant360 ctDNA profiling from patients in ELAINE 2, we demonstrate that other baseline genomic alterations are frequently detected concurrently with mESR1 in the endocrine resistant setting, but without apparent compromise on the efficacy of LAS plus Abema. These results should be interpreted with caution considering the small numbers of patients and the exploratory nature of the analysis. The ELAINE 2 study suggests the potential of LAS plus Abema for treating ESR1-mutated, ER+/HER2- mBC in the post-CDK4/6i setting. This will be further evaluated in the larger, registrational, phase 3, ELAINE 3 study (NCT05696626) that compares LAS plus Abema with fulvestrant plus Abema. Table. Treatment response by genomic alterations concurrent with ESR1 mutations (n=26). aFor patients who withdrew before disease progression, the last observation time was used as the progression time for PFS estimation. bOther genes of interest include PIK3CA, FGFR1, CCND1, TP53, ERBB2, CCNE1, or RB1. CBR, clinical benefit rate; mPFS, median progression-free survival. Citation Format: Senthil Damodaran, Massimo Cristofanilli, Matthew Goetz, Ciara O'Sullivan, Gary Riordan, Hope Rugo, Daniel Stover, Seth Wander, Dominic Carroll, Paul V. Plourde, David J Portman, Einav Nili-Gal Yam. Baseline genomic alterations and the activity of lasofoxifene (LAS) plus abemaciclib (Abema) in patients with ER+/HER2- metastatic breast cancer (mBC): the ELAINE 2 study [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 PO2-14-09.

Abstract PO5-14-11: Leveraging a pharmacokinetic/pharmacodynamic (PK/PD) model to guide dose optimization of palbociclib (palbo) in combination with vepdegestrant

Abstract Background: Vepdegestrant is a potent, selective, orally bioavailable PROteolysis TArgeting Chimeric (PROTAC) estrogen receptor (ER) degrader. A phase 3 study will evaluate the combination of vepdegestrant and palbo in participants with ER+, human epidermal growth factor receptor negative (HER2[-]) advanced/metastatic breast cancer (NCT05909397). The recommended starting dose of palbo is 125 mg once daily for 3 weeks followed by 1 week off treatment for each 28-day cycle in combination with aromatase inhibitors or fulvestrant.1 Neutropenia is the most frequently reported adverse event for patients receiving palbo in clinical trials.1 When co-administered with vepdegestrant in a phase 1b cohort of the first-in-human phase 1/2 study (NCT04072952), higher rates of medically manageable neutropenia and increased palbo concentrations were observed compared with historical studies of palbo administered with letrozole or fulvestrant.1 Reduced starting doses of palbo (100 mg, 75 mg) are planned to mitigate increased rates of Grade 4 neutropenia while maintaining similar palbo exposure when combined with vepdegestrant. The analysis objective was to leverage a PK/PD model to simulate palbo exposure and neutropenia taking into consideration the dose modification and management for hematologic toxicities provided in the palbo prescribing information.1 Methods: A Monte-Carlo simulation platform2 was utilized to monitor absolute neutrophil count (ANC) in 1000 patients with weekly monitoring over 4 cycles (112 days) of palbo administration. Simulated ANC was determined using a semi-mechanistic model of chemotherapy-induced myelosuppression as previously described.3 Palbo dose modification methods included both dose hold and reduction based on an individual’s ANC and thresholds for Grade 3 (< 1000 mm3) or Grade 4 (< 500 mm3) neutropenia. Simulated neutropenia and exposures from palbo starting doses of 100 mg and 75 mg in the presence of a 25%, 49%, and 67% increase in typical exposure were compared to a palbo starting dose of 125 mg in the absence of increased exposure (historical reference). Average concentration is calculated as the cumulative area under the curve divided by the simulation duration. Results: After a 4-cycle simulation, the 100 mg starting dose of palbo simulated across varying levels of increased exposure resulted in similar Grade 4 neutropenia incidence and average concentration compared to the reference simulation (< 12% difference). The 75 mg starting dose of palbo simulated across varying levels of increased exposure resulted in lower Grade 4 neutropenia incidence as well as lower average concentration compared to the reference simulation (Table 1). Conclusion: The PK/PD model simulation allows for relative comparison of Grade 4 neutropenia incidence and average palbo concentration between the planned reduced starting doses of palbo in the context of increased exposure relative to standard palbo dosing, i.e., without vepdegestrant. This simulation indicates a reduced dose of palbo (100 mg) in combination with vepdegestrant produces similar incidence of Grade 4 neutropenia and comparable average palbo concentration compared to historical reference providing additional support for the study lead-in of NCT05909397. Citations: 1. IBRANCE® (Palbociclib) [Package Insert]. New York, US: Pfizer, Inc. 2. Jermain et al. ACOP13 2023. 3. Friberg et al. J Clin Oncol 2002. Table 1. 4-cycle simulation results comparing reduced starting doses of palbociclib in the presence of increased typical exposure to a reference standard palbociclib dosing in the absence of increased exposure Citation Format: Brian Jermain, Derek Yang, Weiwei Tan, Julia Perkins-Smith, Justin Hoffman, Jason Williams. Leveraging a pharmacokinetic/pharmacodynamic (PK/PD) model to guide dose optimization of palbociclib (palbo) in combination with vepdegestrant [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 PO5-14-11.

Abstract PO5-07-03: Integrating mechanism-based and data-driven modeling to predict the response of triple negative breast cancer to therapy

Abstract Introduction Neoadjuvant chemotherapy (NAC) is the standard-of-care (SOC) for patients with locally advanced triple-negative breast cancer (TNBC) [1]. Unfortunately, only about half of TNBC patients achieve a pathological complete response (pCR) at the completion of NAC [2]. With the recent FDA approval of immunotherapy, the response rate improved by about 8% [3]. To try to further improve NAC response rates, we build upon methods that predict treatment response to optimize interventions and outcomes. Our previous studies have demonstrated that excellent predictive accuracy of TNBC response to NAC was achieved through calibrating mechanism-based models to both pre- and on- treatment imaging data [4]. However, by requiring on-treatment imaging data, therapy optimization can only occur after a patient begins NAC. Here, our goal is to relax the requirement of on-treatment imaging data such that we can predict, and potentially optimize, a patient’s response to NAC before initiating it. We will accomplish this through combining data-driven approaches with mechanism-based modeling to obtain spatiotemporal predictions of tumor response prior to NAC. More specifically, we integrate a reaction-diffusion equation based mathematical model with a U-Net based convolutional neural network (CNN). Methods The reaction-diffusion equation models the development of tumor cellularity over time as the sum of tumor cell diffusion, controlled by a fixed diffusivity, and tumor cell proliferation, controlled by a calibrated net proliferation rate. The net proliferation rate implicitly accounts for both proliferative and drug induced death effects. We calibrated the net proliferation rates in this model on a patient-specific basis for 128 patients from the ARTEMIS trial (NCT02276443) using three imaging timepoints – pre- (V1), post two cycles (V2), and post four cycles (V3) of A/C. We then employed a CNN to characterize the relationship between the calibrated net proliferation rates and the pre-treatment imaging data. The CNN takes pretreatment imaging inputs of the apparent diffusion coefficient map, percent enhancement maps from the dynamic contrast enhanced MRI timecourse, and precontrast T1 map. The CNN outputs an estimate of the calibrated net proliferation rate which can be used to run the mathematical model forward in time to predict cellularity maps at V2/3. In training the CNN, our loss considers both the concordance correlation coefficient (CCC) and the normalized root mean square error (NRMSE). We calculated loss on the net proliferation rate predictions as NRMSE with a CCC penalty to aid in characterizing the non-Gaussian distribution of the net proliferation rate. We calculated loss on the cellularity predictions as the CCC between predicted and measured voxel-wise cellularity. The CNN was trained using the Adam optimizer and a fivefold cross validation with a withheld test set of 26 patients. Results Using the CNN predictions to forward run the mechanism-based model in time to V3 we calculated change in total tumor cellularity and volume from V1 to V3. In the test cohort, we obtained CCC values between the predicted and measured changes of 0.95 and 0.91 for cellularity and volume, respectively. Discussion and summary Through integrating mechanistic modeling and deep learning, we can accurately predict the spatiotemporal development of TNBC response to NAC using only pretreatment imaging data. We will build upon these results by expanding our model to include separate proliferation and drug induced death terms to allow for therapy intervention and optimization. Additionally, we will incorporate other pretreatment data types including genetic data. [1] Liedtke et al., J of Clin Oncol, 2008. [2] Spring et al., Clin Cancer Res, 2020. [3] Schmid et al., NEJM, 2020. [4] Wu et al., Cancer Res, 2022. Citation Format: Casey Stowers, Chengyue Wu, Sidharth Kumar, Zhan Xu, Clinton Yam, Jong Bum Son, Jingfei Ma, Jonathan Tamir, Gaiane Rauch, Thomas Yankeelov. Integrating mechanism-based and data-driven modeling to predict the response of triple negative breast cancer to therapy [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 PO5-07-03.

Abstract PO2-06-11: A phase II randomized trial of gemcitabine plus cisplatin(GP) vs gemcitabine plus carboplatin (GC) as the first-line treatment for patients with metastatic triple-negative breast cancer

Abstract Background: Triple-negative breast cancer (TNBC) is an aggressive disease with limited treatment options and poor prognosis. Gemcitabine plus carboplatin (GC) is one of the classic chemotherapeutic regimens for patients with metastatic triple-negative breast cancer(mTNBC) and also a backbone regimen for chemoimmunotherapy, with a median progression-free survival (PFS) of 4.6 months in the first-line (O'Shaughnessy J, et al. J Clin Oncol 2014). Gemcitabine plus cisplatin (GP) has also demonstrated promising efficacy and safety in the first-line phase III trial of mTNBC, with a median PFS of 7.7 months (Hu XC, et al. Lancet Oncol 2015). To further investigate the superiority between carboplatin and cisplatin when combined with gemcitabine, a prospective phase II study was conducted to directly compare the efficacy and safety of GP with GC in the first-line treatment for patients with mTNBC (NCT02341911). Methods: Patients with untreated mTNBC were randomized 1:1 to receive gemcitabine (1250 mg/m2, D1,8) plus cisplatin (75 mg/m2, D1) or gemcitabine (1000mg/m2, D1,8) plus carboplatin (area under the curve 2 mg × min/mL, D1,8) every 21 days until disease progression or intolerable toxicity. The stratification factors included visceral metastasis (yes or no) and the number of metastatic sites (1, 2, or ≥3). The primary endpoint was PFS and secondary endpoints included overall response rate (ORR), overall survival (OS), and safety. Results A total of 150 mTNBC patients were enrolled. After a median follow-up of 49.1 months (IQR 31.3-70.7), PFS events had been recorded in 55 (73.3%) of 75 patients in the GP group and 59 (78.7%) of 75 patients in the GC group. PFS was numerically longer in the GP group than in the GC group, though not significantly (median, 7.8 months [95% CI 7.2–8.4] vs. 6.9 months [95% CI 6.4–7.4]; HR, 0.93; 95% CI 0.64–1.34; P = 0.689; stratified HR, 0.84; 95% CI 0.58–1.23; P = 0.375). Median OS was 20.7 months (95%CI 17.9-23.5) in GP group and 20.9 months (95%CI 15.3-26.5) in GC group, HR, 1.13; 95% CI 0.77–1.67; P = 0.537; stratified HR, 1.03; 95% CI 0.70–1.52; P = 0.886). The ORR of GP and GC was 49.3% and 41.3% in the intent-to-treat population. Dose reduction occurred in 30(40.0%) patients in the GP group and 38 (50.7%) patients in the GC group. Grade 3 and 4 hematological AEs, including leucopenia, neutropenia, anemia, and thrombocytopenia were slightly higher in the GC group. Grade 3 and 4 non-hematological AEs, including nausea, vomiting, and hearing toxicity, were more common in the GP group. No treatment-related deaths were reported. Conclusions Cisplatin was not associated with a survival advantage over carboplatin when combined with gemcitabine as a first-line treatment for patients with mTNBC, though numerically longer PFS and higher ORR was observed. The safety profiles of the two combinations were different but the adverse events were manageable. Citation Format: Chengcheng Gong, Yannan Zhao, Leiping Wang, Jun Cao, Zhonghua Tao, Ting Li, Mingchuan Zhao, Haitao Miao, Juan Jin, Xichun Hu, Biyun Wang. A phase II randomized trial of gemcitabine plus cisplatin(GP) vs gemcitabine plus carboplatin (GC) as the first-line treatment for patients with metastatic triple-negative 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 PO2-06-11.

Abstract 1960: CFON-026 is a potent non-covalent BTK inhibitor suitable for combination therapy with covalent BTK inhibitors for early eradication of resistance mutations

Abstract Bruton’s Tyrosine Kinase (BTK) inhibitor drugs are a mainstay in the treatment of CLL, WM and MCL. They are not curative because of the emergence of BTK inhibitor resistance mutations in as much as 67% of relapsed patients (in CLL) [1]. Frequently observed mutations include BTKC481S, which abrogates covalent binding of irreversible drugs such as acalabrutinib, ibrutinib and zanubrutinib, and BTKT474I and BTKV416L which both abrogate binding of the non-covalent inhibitor drug pirtobrutinib [1, 2]. To combat resistance, third generation BTK inhibitors are needed, which must 1. bind to unique regions in the tumor driving kinases that are not marred by resistance mutations, 2. have sufficient potency for sustained inhibition of BTK signaling, and 3. be sufficiently selective to afford efficacious doses and suitable for a combination regimen. We have developed a platform called Energetically Privileged Ligands (EPriLs), based on a macrocycle scaffold that binds non-covalently in the kinase ATP pocket. Their unique binding mode involves connecting the N-terminal and C-terminal lobes of the general kinase fold in a continuous β-sheet, in this way avoiding hotspots for kinase inhibitor resistance mutations. The potent binding of the macrocycle ensures a very long residence time. Using the EPriL platform, we have developed CFON-026, a next generation non-covalent BTK inhibitor with a covalent-like residence time as demonstrated by surface plasmon resonance (SPR) and cellular washout experiments. The biochemical binding KD to BTKWT, determined by SPR, is 0.14 nM. CFON-026 binds mutants with KDs of 0.4 nM (BTKC481S) and and 1.8 nM (BTKT474I). X-ray crystal structures of CFON-026 bound to BTKWT and BTKT474I confirm the unique binding mode and water network around the active site. CFON-026 inhibits the growth of the BTK dependent cell lines TMD8 and Rec-1 with IC50s of 0.45 nM and 1.7 nM, respectively. CFON-026 is very active on TMD8 variants containing endogenous BTK inhibitor resistance mutations (BTKC481S, BTKV416L, BTKT474I and BTKL528W, IC50 range 1-100 nM). CFON-026 has favorable metabolic stability, pharmacokinetic properties, and safety characteristics, and induces complete tumor regression in a TMD8 xenograft model. Since BTK resistance mutations can be detected diagnostically 12-18 months before clinical relapse, CFON-026 could be applied as combination partner to prolong progression free survival on first line BTK inhibitor therapy. Experiments with mixed populations of BTK mutant cell lines, to model a heterogenous tumor, show that CFON-026 can deepen the efficacy of ibrutinib, acalabrutinib and zanubrutinib. In conclusion, CFON-026 is a novel EPriL-based non-covalent BTK inhibitor that could enhance and prolong responses of existing covalent BTK inhibitor therapy. [1] Woyach et al., J Clin Oncol (2017). [2] Wang et al., N. Eng J Med (2022). Citation Format: Jos de Man, Michelle Muller, Joost C.M. Uitdehaag, Freek van Cauter, Sander van Gemert, Milan Hoffmann, Yvonne G.T.H. van Mil, Winfried R. Mulder, Martine B.W. Prinsen, Jan Gerard Sterrenburg, Diep Vu, Joeri de Wit, Erik Ensing, Rogier C. Buijsman. CFON-026 is a potent non-covalent BTK inhibitor suitable for combination therapy with covalent BTK inhibitors for early eradication of resistance mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1960.

Abstract 936: Targeted proteomics and next-generation sequencing (NGS) for biomarker discovery in metastatic colorectal cancer (mCRC)

Abstract Background: Multi-omics analysis is widely used in cancer diagnosis, prognosis and prediction of treatment response. Here we introduce the use of targeted proteomics coupled with NGS as tools to assess oncogenic alterations along with quantitative protein expression in patients with mCRC. Our proteomics panel included proteins that are antibody drug conjugates (ADCs) targets (ERBB 1-4, TROP2, CEACAM5 etc.) as well as proteins involved in sensitivity to ADC payload (SLFN11, drug efflux pump, TOP1 etc.). Methods: The HORIZON III trial (NCT00384176) evaluated FOLFOX + bevacizumab or cediranib as first-line treatment in patients with mCRC (Schmoll J Clin Oncol 2012). In the current analysis, a subset of samples from the HORIZON III trial were assessed for molecular alterations using NGS and proteomics. Pre-existing HER2 IHC scores were used as previously referenced (Cecchi J Clin Oncol 2023). Samples were processed (n=135) with an automated extraction and library preparation method, then sequenced with both a Whole Exome and targeted-custom gene panel. NGS analysis had a success rate of 116/135 samples (87.3%). Absolute quantitation of protein targets was performed using parallel reaction monitoring (PRM) mass spectrometry after collecting tumor epithelial cells by laser microdissection and punch biopsies (n=60) followed by trypsin digestion. Results: The NGS analysis showed that patients had mutated RAS (50%), BRAF (10%), PIK3CA (16%), and TMB-H (18%) and MSI-H (5%) status. A distinguished pattern of mutual exclusivity among KRAS, NRAS, and BRAF mutations is evident. The HER2-positive patients were wildtype RAS, BRAF, and PIK3CA, MSS and TMB-L. Samples that were IHC HER2-positive matched those with NGS ERBB2 amplification. Using PRM, nearly all the evaluable samples had detectable HER2. HER2 IHC 3+ sample showed the highest protein expression at 30,000 amol/ug (equivalent to 1M receptors/cell). Within the HER2-negative patients, HER2 protein expression showed broad dynamic range. CEACAM5 and HER2 are the only ADC targets that reached the level of 1M receptors/cell. Highest TROP2 protein expression is 5 times lower than the highest HER2 value. Conclusions: Our preliminary findings for this cohort indicate the benefit of the use of multi-modal methodologies to inform better strategies for patient stratification and precision medicine, though further assessment of proteogenomic characteristics is needed. This data may inform future clinical development and guide patient eligibility to clinical trials and possible treatment sequencing for ADCs. Citation Format: William J. Kelly, Barrett Nuttall, Marlon Rebelatto, Marcus Schick, Armin Meier, Steve Sweet, Beom-Jun Kim, David Chain, Yeoun Jin Kim, Zhongwu Lai, Ying Wang, Todd H. Creasy, Ramya Gurrapu, Sakshi Gulati, Alice Barkell, Brian Dougherty, Danielle Carroll, Fabiola Cecchi. Targeted proteomics and next-generation sequencing (NGS) for biomarker discovery in metastatic colorectal cancer (mCRC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 936.

Abstract 6468: Nodular lymphocyte predominant hodgkin lymphoma: A national cancer database analysis with focus on hispanics

Abstract Background:Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare and distinct subtype of Hodgkin Lymphoma.(PMID 26149294) 80% manifest at early stages, with a male and black race predilection.(PMID 26149195) Previous analysis have shown similar survival of Hispanics (HI) compared to Non-Hispanics (NH).(J Clin Oncol 10.1200/JCO.2023.41.16_suppl.e19512) This National Cancer Database (NCDB) analysis aims to clarify how sociodemographic factors affect presentation and survival in HI vs NH patients with NLPHL. Methods:Data were analyzed on NLPHL patients in the United States reported to the NCDB 2004-2019. Demographic and treatment characteristics were compared between ethnic groups. Kaplan-Meier and Cox regression analyses were used to compare overall survival (OS) between HI and NH populations. Multivariate analysis and propensity score matching was performed. Results:Of 5517 of NLPHL patients, 379 were HI, and 4904 NH. Male gender and white race predominated for both. HI were diagnosed at a younger median age of 44 years (y) vs 48 y for NH, p=0.001. Most patients were diagnosed between years 2016-2019. Stage I predominated for both, p<0.001. As to Charlson-Deyo score ≥2, both HI and NH had 4%. Private insurance as primary payer was the most prevalent type for HI (53%) and NH (65%). HI had a higher percentage of unknown/uninsured, 12% vs 6% for NH, p<0.001. In relation to census median income (2008-2012), the most prevalent bracket for HI (27%) was $48,000-$62,000, and for NH (35%) was >$63,000. Regarding median income of <$38,000, HI were 29% vs 16% for NH, p<0.001. For median distance in miles (mi) between the patient’s residence and the hospital that reported the case (great circle distance), HI lived at a median of 6.3mi, vs NH at median of 9.5mi. Majority of HI (56%) were treated at Academic/Research programs; while most of NH (39%) were treated at Comprehensive Community Cancer programs, p<0.001. On survival analysis, the survival probability at 2, 5 and 10 y for HI was 96%, 92%, 86%, vs for NH was 96%, 92%, 84%, respectively. The median survival time wasn’t reached for both HI and NH, and no statically significant difference was seen, p=0.57. On multivariate analysis, HI was not associated with worse OS (HR 0.76, CI 0.44-1.31, p=0,33). The propensity matched analysis confirmed not reached OS on both cohorts. Conclusion:NLPHL is a disease that affects young males, at early stages, for both HI and NH. Unlike previous studies, in this analysis white race predominates; which could be explained by the increase in reported cases over years. Despite HI having more uninsured population with lower median income quartiles, this wasn’t a barrier to access care at academic/research programs. Although no difference in OS was seen among ethnicities, there is a tendency that might favor HI. More studies are needed to determine if specific demographic factors truly influence survival in NLPHL. Citation Format: Esteban Toro Velez, Daniel Rosas, Carolina Velez-Mejia, Qianqian Liu, Joel Michalek, Adolfo Enrique Diaz Duque. Nodular lymphocyte predominant hodgkin lymphoma: A national cancer database analysis with focus on hispanics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6468.

Abstract 1971: Olverembatinib, a novel multikinase inhibitor, demonstrates superior antitumor activity in succinate dehydrogenase (SDH)-deficient neoplasms

Abstract SDH deficiency, characterized by loss of SDHB, occurs in many tumors including paraganglioma, pheochromocytoma, renal, and gastrointestinal stromal tumor (GIST). Olverembatinib, a novel multikinase inhibitor, targets a broad spectrum of kinases and has promising efficacy in SDH-deficient GIST (Qiu H et al. J Clin Oncol. 2023). Here, we assessed antitumor effects of olverembatinib in preclinical models of SDH-deficient cancers and explored potential mechanisms of action (MOA). Antiproliferation assays were conducted using CellTiter-Glo®. MOA analyses were performed using western blotting. In vivo activity was evaluated using an SDHB knock-out [KO])-derived mouse xenograft model. Olverembatinib had superior antiproliferative activity (vs other approved TKIs) in SDH-deficient cell lines (IC50, 0.129-5.132 μM), including Jurkat clone E6-1 (SDHB mutation [mut]), OS-RC-2 (SDHA and SDHB mut), RKO (SDHA mut), and rat pheochromocytoma PC12 cells with SDHB KO (PC12#5F7) (Table 1). In PC12#5F7 cells, olverembatinib decreased HIF-1α, HIF-2α, VEGFA, and FGFR1 protein levels and inhibited phosphorylation of FGFR1, IGF-1R, SRC, AKT, and ERK1/2. Increased cleavage of caspase-3 and PARP-1 was observed, suggesting induction of apoptosis. In PC12#5F7 (SDHB KO)-derived xenograft models, olverembatinib demonstrated dose-dependent antitumor activity at 10 and 20 mg/kg (QOD), with tumor growth inhibition rates of 27.4% and 52.2%, respectively. At 20 mg/kg, olverembatinib showed superior efficacy vs ponatinib (10 mg/kg) and rogaratinib (50 mg/kg). Results from western blot analyses were similar in both tumor tissues and cell lines. Olverembatinib exerts promising antitumor effects in SDH-deficient neoplasms and can modulate multiple signal pathways involved in angiogenesis, apoptosis, proliferation, and survival. The results provide a preclinical rationale for future development of olverembatinib in SDH-deficient cancers. Table 1. Antiproliferation activity of TKIs in SDH-deficient cell lines IC50 μM, mean ± SD Cell lines Acute lymphoblastic leukemia Renal cell carcinoma Colon cancer Rat pheochromocytoma carcinoma Jurkat, clone E6-1 OS-RC-2 RKO PC12 PC12#5F7 SDH status* SDHB: missense_variant, p.A15T SDHA: missense_variant, p.G184R; SDHB: stop gained, p.W218Ter SDHA: missense_variant, p.P279S SDHB competent SDHB exon 2+3 KO (heterozygote) by CRISPR-Cas9 Compound Olverembatinib (KIT, PDGFR, SRC, VEGFR, FGFR, FLT-3, RET) 0.149 ± 0.04 0.135 ± 0.083 0.129 ± 0.136 9.600 ± 1.407(n = 4) 5.132 ± 1.950 Imatinib (KIT, PDGFR) > 10 > 10 > 10 > 10 > 10 Ripretinib (KIT, PDGFR) 1.559 ± 0.294 8.781 ± 1.725 1.247 ± 0.933 > 10 > 10 Avapritinib (PDGFRA exon 18 mut) > 8.071 ± 2.728 > 10 ± 0 > 10 ± 0 > 10 > 10 Ponatinib (KIT, PDGFR, VEGFR, FGFR) 2.136 ± 2.107 0.809 ± 0.443 0.274 ± 0.241 > 10 8.537 ± 3.553 Dasatinib (KIT, SRC, PDGFR, FGFR) 2.025 ± 0.644 0.029 ± 0.003 0.382 ± 0.320 > 10 > 10 Sunitinib (VEGFR) 4.289 ± 0.280 > 5.099 ± 0.207 3.789 ± 0.385 > 10 > 10 Regorafenib (VEGFR) > 10 5.110 ± 0.588 2.145 ± 0.812 > 10 > 10 Sorafenib (VEGFR) > 10 3.581 ± 0.255 3.875 ± 0.170 > 10 > 10 Pazopanib (VEGFR, FGFR) > 10 > 10 > 10 > 10 > 10 Rogaratinib (FGFR) > 10 > 10 > 10 > 10 > 10 Infigratinib (FGFR) 4.581 ± 0.342 3.166 ± 0.791 2.374 ± 2.311 > 10 > 10 Pemigatinib (FGFR) 4.642 ± 1.842 > 10 > 10 > 10 > 10 *From CrownBio database. Citation Format: Yan Xiong, Eric Liang, Ping Min, Huidan Yu, Bingxing Wu, Guoqin Zhai, Dajun Yang, Yifan Zhai. Olverembatinib, a novel multikinase inhibitor, demonstrates superior antitumor activity in succinate dehydrogenase (SDH)-deficient neoplasms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1971.

A Phase II Study of Rucaparib Monotherapy in Nonmetastatic, Hormone-Sensitive Prostate Cancer Demonstrating "BRCAness" Genotype (ROAR).

Both germline and somatic BReast CAncer gene (BRCA) mutations are poor prognostic markers in men with localized or metastatic prostate cancer. For instance, men with these mutations often are diagnosed with prostate cancer earlier and develop metastatic disease earlier compared with those who do not harbor similar mutations. Patients with germline alterations typically have more advanced disease and shorter overall survival (Castro E, Goh C, Olmos D, et al. Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. J Clin Oncol. 2013;31(14):1748-1757. doi:10.1200/JCO.2012.43.1882). The risk of disease progression to metastatic disease is significant in patients with this genotype of prostate cancer. The percentage of patients free from metastatic disease was 90%, 72%, and 50%, respectively, compared with 97%, 94%, and 84% at 3, 5, and 10 years for patients with intact DNA repair (P < .001) (Castro E, Goh C, Leongamornlert D, et al. Effect of BRCA mutations on metastatic relapse and cause-specific survival after radical treatment for localised prostate cancer. Eur Urol. 2015;68(2):186-193. doi: 10.1016/j.eururo.2014.10.022). DNA damage repair non-BRCA mutations include alterations in genes such as ATM, CHEK2, PALB2, and RAD51. While less common than BRCA mutations, they have emerged as significant prognostic markers in prostate cancer. These BRCAness mutations are associated with a higher risk of aggressive disease and poorer survival outcomes. Given the debilitating physical and psychological side effects of androgen deprivation therapy (ADT) in relatively younger men with prostate cancer, delaying ADT in these men may be an attractive strategy. Given the proven efficacy of polyadenosine diphosphate-ribose polymerase (PARP) inhibitors in the castration-resistant prostate cancersetting, PARP inhibitor monotherapy in a nonmetastatic castration-sensitive (nmCSPC) setting has the potential to delay metastasis and delay the onset of ADT related symptoms. This is a single-arm, single-center, open-label, phase II trial to assess the efficacy of rucaparib in patients with high-risk biochemically recurrent (BCR) nmHSPC, which was defined as PSA doubling time of <9 months, demonstrating a "BRCAness" genotype (BRCA1/2 and other homologous recombination repair mutations). A total of 15 patients were intended to be enrolled, with an expected enrollment duration of 12 months. Patients were given rucaparib 600mg orally twice daily and were allowed to remain on study treatment until PSA progression defined by Prostate Cancer Working Group 3, with 2 years of follow-up after study treatment. We anticipated a total of 2-3 years until completion of the clinical trial. The primary endpoint was to assess the PSA progression-free survival (PSA-PFS). The secondary endpoints of the study were safety, the proportion of patients with a PSA 50% response (PSA 50), and an undetectable PSA. A 4-week treatment duration comprised one cycle. The study started enrolling in June 2019 and was prematurely terminated in June 2022 after the accrual of 7 patients because of changing standard of care treatments with the introduction of next-generation scans, eg, prostate-specific membrane antigen positron emission tomography (PSMA-PET). Seven patients were enrolled in the study with the following pathogenic alterations: ATM (n = 3), BRCA2 (n = 2), BRCA1 (n = 1), BRIP1 (n = 1), and RAD51 (n = 1). The median duration of follow-up was 18 months. A median of 20 cycles (range 4-42) was completed, median PSA-PFS was 35.37 months (95% CI, 0-85.11 months). In total, 2 patients achieved PSA50; both also achieved nadir PSA as undetectable. Grade ≥ 3 adverse events (AEs) were anemia and rash (in 1 patient each). No dose-limiting toxicities or severe AEs were seen. Rucaparib demonstrated acceptable toxicity and efficacy signal as an ADT-sparing approach in patients with biochemically recurrent nonmetastatic prostate cancer. It is currently challenging to understand the optimal value of systemic therapy in this disease setting due to the rapidly changing standard of care. Additionally, there are relatively few patients with BRCAness who present with nonmetastatic hormone-sensitive prostate cancer (ClinicalTrials.gov Identifier: NCT03533946).

Glioblastoma Cells Use an Integrin- and CD44-Mediated Motor-Clutch Mode of Migration in Brain Tissue.

Glioblastoma (GBM) is an aggressive malignant brain tumor with 2year survival rates of 6.7% (Stupp et al. in J Clin Oncol Off J Am Soc Clin Oncol 25:4127-4136, 2007; Mohammed et al. in Rep Pract Oncol Radiother 27:1026-1036, 2002). One key characteristic of the disease is the ability of glioblastoma cells to migrate rapidly and spread throughout healthy brain tissue (Lefranc et al. in J Clin Oncol Off J Am Soc Clin Oncol 23:2411-2422, 2005; Hoelzinger et al. in J Natl Cancer Inst 21:1583-1593, 2007). To develop treatments that effectively target cell migration, it is important to understand the fundamental mechanism driving cell migration in brain tissue. Several models of cell migration have been proposed, including the motor-clutch, bleb-based motility, and osmotic engine models. Here we utilized confocal imaging to measure traction dynamics and migration speeds of glioblastoma cells in mouse organotypic brain slices to identify the mode of cell migration. We found that nearly all cell-vasculature interactions reflected pulling, rather than pushing, on vasculature at the cell leading edge, a finding consistent with a motor-clutch mode of migration, and inconsistent with an osmotic engine model or confined bleb-based migration. Reducing myosin motor activity, a key component in the motor-clutch model, was found to decrease migration speed at high doses for all cell types including U251 and 6 low-passage patient-derived xenograft lines (3 proneural and 3 mesenchymal subtypes). Variable responses were found at low doses, consistent with a motor-clutch mode of migration which predicts a biphasic relationship between migration speed and motor-to-clutch ratio. Targeting of molecular clutches including integrins and CD44 slowed migration of U251 cells. Overall we find that glioblastoma cell migration is most consistent with a motor-clutch mechanism to migrate through brain tissue ex vivo, and that both integrins and CD44, as well as myosin motors, play an important role in constituting the adhesive clutch. The online version contains supplementary material available at 10.1007/s12195-024-00799-x.

INSIGHT: A phase 3, randomized, open-label study of ripretinib vs sunitinib in patients with advanced gastrointestinal stromal tumor previously treated with imatinib with KIT exon 11 + 17/18 mutations.

TPS767 Background: Gastrointestinal stromal tumor (GIST) is the most common gastrointestinal sarcoma with approximately 80% of cases driven by KIT mutations. Most patients (pts) with advanced GIST experience disease progression following first-line treatment with imatinib due to KIT secondary resistance mutations occurring most commonly in the ATP-binding pocket (exons 13/14) and/or activation loop (exons 17/18). Sunitinib is approved as second-line therapy for advanced GIST. Ripretinib is a switch-control tyrosine kinase inhibitor approved for pts with GIST who received prior treatment with 3 or more kinase inhibitors, including imatinib. In the phase 3 INTRIGUE study (NCT03673501) in second-line advanced GIST, ripretinib was not superior to sunitinib in terms of progression-free survival (PFS); however, a more favorable safety profile was observed with ripretinib vs sunitinib.1 Exploratory mutational analysis from INTRIGUE using baseline circulating tumor DNA (ctDNA) demonstrated that pts harboring primary KIT exon 11 mutations with secondary resistance mutations exclusively in KIT exons 17/18 derived PFS benefit with ripretinib vs sunitinib (median, 14.2 vs 1.5 months; HR, 0.22; 95% CI, 0.11 to 0.44; nominal P &lt;0.0001).2 Here, we describe a planned phase 3 study for pts with advanced GIST previously treated with imatinib harboring KIT exon 11 + 17/18 mutations. Methods: INSIGHT (NCT05734105) is a phase 3, randomized, open-label study aiming to evaluate the efficacy of ripretinib vs sunitinib in pts with advanced GIST previously treated with imatinib and who harbor KIT exon 11 + 17/18 mutations. Eligible pts must be ≥18 years old with histologically confirmed GIST and co-occurring KIT exon 11 + 17/18 mutations confirmed by ctDNA analysis. Pts must also have advanced disease with ≥1 measurable lesion per modified Response Evaluation Criteria in Solid Tumors (mRECIST) v1.1, radiologic progression on imatinib, and an Eastern Cooperative Oncology Group performance status ≤2. Key exclusion criteria include a KIT exon 9, 13, or 14 mutation confirmed via ctDNA analysis at screening and prior treatment with another line of therapy in addition to imatinib for advanced GIST. A total of 54 pts will be randomized (2:1) to receive ripretinib 150 mg once daily (QD; continuous) or sunitinib 50 mg QD (4 weeks on/2 weeks off) in 6-week cycles. The primary endpoint is PFS by independent radiologic review (IRR) per mRECIST v1.1; key secondary endpoints are objective response rate by IRR using mRECIST v1.1 and overall survival. Safety and patient-reported outcome measures will also be assessed. Pts randomized to the sunitinib arm may cross over to the ripretinib arm upon disease progression. 1. Bauer S et al. J Clin Oncol. 2022. 2. Bauer S et al. J Clin Oncol. 2023; abstract 397784. Clinical trial information: NCT05734105 .

Exploratory analysis of biomarkers of response to durvalumab in advanced HER2-negative oesophago-gastric adenocarcinoma within a phase 2 clinical trial.

384 Background: Advanced oesophago-gastric cancers have showcased varied responses to immunotherapy based on biomarkers such as tumour mutational burden, microsatellite instability, and PD-L1 expression. However, these markers may not fully capture tumour heterogeneity and evolutionary dynamics. Hence, understanding the intricate relationship between immune selection, specifically immune dN/dS,1 and tumour evolution is vital for devising personalized therapeutic strategies. Methods: In our phase 2 open label, multicentre, randomised PLATFORM trial (NCT02678182), patients received maintenance durvalumab post first-line chemotherapy. A survival advantage was not seen with maintenance durvalumab compared to surveillance and exploratory analysis of PD-L1 expression was not associated with improved survival outcomes.2 However, a subset of patients treated with durvalumab experienced durable responses and some experienced incremental radiological responses. A pilot substudy on a selected cohort (n=24) of these patients was designed to explore the potential of immunogenomics evolutionary-based metrics, notably dN/dS, as predictive biomarkers. DNA and RNA from FFPE baseline tumour samples underwent analysis, examining genomic factors including tumour mutational burden, indel signatures, PDL1 status, and immune evasion mechanisms. Furthermore, the evolutionary metric, immune dN/dS, which has implications in tumour immunoediting and its response to immunotherapies, was scrutinized. Results: A dominant indel mutational signature emerged from the analysis. The majority of patients displayed a significantly higher number of indel variants, compared to non-synonymous and synonymous single-nucleotide variants. A recurring observation was dN/dS values consistently above 1, indicating positive selection for non-synonymous somatic variants. Additionally, hypermutation in driver genes, notably TP53 and XIRP2, was detected. One patient, with a unique dN/dS &lt; 1, showcased survival beyond four years without liver metastases. Immune dN/dS &gt; 1 and no evidence of liver metastases displayed the best prognosis after treatment in contrast with those that have immune dN/dS &lt; 1 with or without liver metastases. Conclusions: Immune dN/dS emerges as a promising tool to decode tumour evolutionary mechanisms, providing profound insights into the dynamics of tumour evolution in advanced HER2 negative oesophago-gastric cancer patients receiving durvalumab immunotherapy. This pilot study underscores the potential of this novel immunogenomic approach in improving patient stratification and tailoring therapeutic strategies in cancer immunotherapy. 1. Zapata et al, Nature Genetics, 2023. 2. Fong et al, J Clin Oncol, 2021. Clinical trial information: NCT02678182 .

A randomized, multicenter, open-label, phase 2 study of TRK-950 in combination with ramucirumab and paclitaxel as second-line therapy in patients with CAPRIN-1 positive gastric or gastroesophageal junction (G/GEJ) adenocarcinoma.

TPS420 Background: CAPRIN-1 is strongly expressed on the cell membrane of many cancer types including G/GEJ and on cancer stem cells. High expression is associated with enhanced in vitro colony-forming activity and in vivo tumorigenicity. TRK-950 is a first in class humanized antibody targeting CAPRIN-1.1 In the phase I study (NCT02990481), TRK-950 was well tolerated as monotherapy with no DLTs and MTD not reached at doses of 3-30mg/kg IV weekly. Subsequently the Phase 1b demonstrated that TRK-950 was well tolerated with a high potential for synergistic anti-tumor activity when used in combination with standard of care treatment(s) in selected advanced solid tumors (NCT03872947). Specifically, Regimen D which evaluated TRK-950 in combination with Ramucirumab and Paclitaxel in G/GEJ showed a DCR of 100% in all nine patients receiving 10 mg/kg and partial responses were seen in 5/9 (55%) patients. CAPRIN-1 strong expression was observed in 4/9 patients and an ORR of 100% was seen in those patients.2 A Phase II clinical trial in gastric/GEJ cancer patients with strong CAPRIN-1 is now enrolling patients. Methods: The phase II study is a multi-national, open-label, randomized, multicenter study evaluating the efficacy of TRK-950 in combination with ramucirumab (Ram) + paclitaxel (PTX) as compared with Ram + PTX treatment alone in patients with previously treated metastatic G/GEJ adenocarcinoma (NCT06038578). Patients enrolled across 10 sites in Japan, South Korea and the United States are randomized 1:1:1 by the permuted block method to (arm A) TRK-950 5mg/kg plus Ram + PTX, (arm B) TRK-950 10mg/kg plus Ram + PTX or (arm C) Ram + PTX alone. Inclusion criteria include patients with CAPRIN-1 positive (cutoff; 30% at ≥ 2+ staining) advanced/metastatic G/GEJ adenocarcinoma who have received first line therapy. Key exclusion criteria include HER2 positive disease. The primary endpoint is progression free survival (PFS) based on Independent Central Review (ICR) assessment per RECIST v1.1. Key secondary and exploratory endpoints include overall survival (OS), ORR, DoR, and biomarker evaluation. An interim analysis will be performed after 105 patients are randomized in stage 1 to determine the optimal dose of TRK-950 (5mg/kg or 10mg/kg) that will be evaluated in stage 2. In total 146 patients will be enrolled (40 patients in one arm and 53 patients in the other two arms). This study opened in September 2023. 1. Okano F, et al. Cancer Res Commun. 2023 Apr 18;3(4):640-658. 2. Cassier P, et al. J Clin Oncol. 2023 Vol. 41, No. 4, suppl. Clinical trial information: NCT06038578 .

A phase I study of EO-3021 in adult patients with solid tumors likely to express CLDN18.2.

TPS429 Background: Claudin 18 isoform 2 (CLDN18.2) belongs to a family of tight junction proteins with broad expression in gastric and gastroesophageal junction (GEJ), pancreatic, esophageal, and other solid tumors. Expression of CLDN18.2 in normal tissue is limited to the gastric mucosa, making it a promising antibody-drug conjugate (ADC) therapeutic target. Currently, there are no approved therapies targeting CLDN18.2. EO-3021 (also known as SYSA1801) is an ADC comprised of a fully human CLDN18.2 monoclonal antibody (mAb) specifically conjugated at glutamine 295 with a cleavable linker and MMAE with a homogenous drug-to-antibody ratio (DAR) of 2. In preclinical models, EO-3021 selectively delivers a potent cytotoxic MMAE payload directly to cancer cells expressing CLDN18.2, retains antibody-dependent cellular toxicity (ADCC) and complement-dependent cytotoxicity (CDC) activity, and exhibits a bystander effect.1 In an ongoing Phase 1 study in China (NCT05009966), EO-3021 exhibited signs of anti-tumor activity in patients with gastric cancer and had an acceptable safety profile.2 Outside of Greater China, EO-3021 is being evaluated by Elevation Oncology for the treatment of patients with advanced or metastatic solid tumors likely to express CLDN18.2, particularly gastric and GEJ adenocarcinomas. Methods: This is a Phase I, open-label, multi-center, dose escalation and expansion study to investigate the safety, tolerability, pharmacokinetics (PK) and preliminary anti-tumor activity of EO-3021 in patients with solid tumors likely to express CLDN18.2 (NCT05980416). Patients whose tumors have progressed on or after standard therapy, or who are intolerable for available standard therapy are eligible for participation. Approximately 120 patients will be enrolled in this study. There are 4 planned dose levels in the dose finding portion of the study. Patients will receive EO-3021 intravenously (IV) once every three weeks until disease progression or unacceptable toxicity. The expansion cohort will evaluate EO-3021 in patients with gastric/GEJ adenocarcinoma. Provision of tumor samples (archived and fresh biopsy) is required for study enrollment. CLDN18.2 expression in tumor tissue via will be assessed by retrospective evaluation via central immunohistochemistry assay; results will be explored for possible correlation with tumor response. Enrollment in the dose escalation portion of the study began in August 2023. 1. Dan M, et al. Cancer Res. 83, 2023. 2. Wang Y, et al. J Clin Oncol. 41, 2023. Clinical trial information: NCT05980416 .

A phase II trial of CapeOX plus nivolumab for early relapsed HER2-negative gastric cancer (JACCRO GC-11: FirSTAR trial).

TPS423 Background: Fluoropyrimidine-based post-operative chemotherapy is one of the standard adjuvant therapies for curatively resected gastric cancer (GC).1,2 The current standard first-line chemotherapy consists of fluoropyrimidine and oxaliplatin combined with nivolumab in advanced HER2-negative GC patients including cases with a recurrence &gt; 6 months after completion of post-operative chemotherapy, based on the CheckMate 649 and ATTRACTION-4 trials. However, in GC patients with early recurrence during or ≤ 6 months after completion of post-operative 5-FU based chemotherapy, optimal treatments remain to be established. A previous phase II study showed that capecitabine plus cisplatin is an active regimen for early relapsed GC after post-operative S-1 monotherapy.3 This trial aims to investigate the efficacy of capecitabine plus oxaliplatin (CapeOX) plus nivolumab for patients with early relapsed HER2-negative GC. Methods: This is a multicenter single-arm phase II trial. The main eligibility criteria include: histologically confirmed HER2-negative adenocarcinoma of stomach or esophagogastric junction; radiologically diagnosed recurrence during or ≤ 6 months after post-operative chemotherapy with S-1 or S-1 plus docetaxel conducted for stage II/III GC after curative resection; age ≥ 18 years; ECOG performance status 0-1; having measurable lesions according to RECIST ver. 1.1; and adequate oral intake and organ functions. Enrolled patients will receive 21-day cycles of nivolumab with CapeOX at the following dose until disease progression or unacceptable toxicities: capecitabine, 1000 mg/m2 twice per day on day 1-14; oxaliplatin, 130 mg/m2 on day 1; and nivolumab, 360 mg on day 1. The primary endpoint is objective response rate (ORR), and the secondary endpoints include overall survival, progression-free survival, disease control rate, duration of response, and safety. PD-L1 combined positive score will be tested for the association with efficacy. We assume null ORR of 20% and alternative ORR of 32%. With two-sided alpha level of 10% and 80% power, sample size would be calculated as 85. Thus, a total of 92 patients are planned for enrollment within a 2.5-year accrual period. Enrollment opened in March 2023. Clinical trial information: jRCTs031220572. 1. N Engl J Med. 2007;357:1810-20. 2. J Clin Oncol. 2019;37:1296-1304. 3. Gastric Cancer. 2018;21:811-8. Clinical trial information: jRCTs031220572 .

Engaging communities to inform the development of a diverse cohort of cancer survivors: formative research for the eat move sleep study (EMOVES)

BackgroundThere are more than 18 million cancer survivors in the United States. Yet, survivors of color remain under-represented in cancer survivorship research (Saltzman et al. in Contemp Clin Trials Commun 29:100986, 2022; Pang et al. in J Clin Oncol 34:3992–3999, 2016; Lythgoe et al. in Prostate Cancer Prostatic Dis 24:1208–1211, 2021). Our long-term goal is to enroll and follow a cohort of historically under-represented cancer survivors, to better understand modifiable risk factors that influence clinical and quality of life outcomes in these populations. Towards that goal, we describe herein how we applied community-based participatory research approaches to develop inclusive study materials for enrolling such a cohort.MethodsWe implemented community engagement strategies to inform and enhance the study website and recruitment materials for this cohort including: hiring a dedicated engagement coordinator/community health educator as a member of our team; working with the Helen Diller Family Comprehensive Cancer Center Office of Community Engagement (OCE) and Community Advisory Board members; presenting our educational, research, and study recruitment materials at community events; and establishing a community advisory group specifically for the study (4 individuals). In parallel with these efforts, 20 semi-structured user testing interviews were conducted with diverse cancer survivors to inform the look, feel, and usability of the study website.ResultsEngagement with community members was a powerful and important approach for this study’s development. Feedback was solicited and used to inform decisions regarding the study name (eat move sleep, EMOVES), logo, study website content and imagery, and recruitment materials. Based on community feedback, we developed additional educational materials on healthy groceries and portion size in multiple languages and created a study video.ConclusionsIncluding an engagement coordinator as a permanent team member, partnering with the institutional community outreach and engagement resources (i.e., OCE), and allocating dedicated time and financial support for cultivating relationships with stakeholders outside the university were critical to the development of the study website and materials. Our community guided strategies will be tested as we conduct enrollment through community advisor networks and via the state cancer registry.