Combination Arm Research Articles

Dose-expansion part of a phase 1b global study of E7386 in combination with lenvatinib (LEN) in patients (pts) with hepatocellular carcinoma (HCC) and other solid tumors including endometrial cancer (EC).

TPS3169 Background: E7386, a first-in-class anticancer agent, inhibits protein-protein interaction between β-catenin and the CREB-binding protein, thus modulating Wnt/β-catenin signaling. E7386 is being tested in combination with LEN in the open-label global phase 1b Study 102. The dose-escalation part of Study 102 determined the recommended dose of E7386 + LEN in pts with HCC and other solid tumors. Here we describe the ongoing dose-expansion part in pts with HCC or EC. Methods: Eligible pts ≥18 years old should have an ECOG PS of 0-1 and a confirmed diagnosis of advanced, unresectable, or recurrent solid tumor. Pts with HCC will have a Child-Pugh score of A and a categorization of BCLC Stage B (not amenable to locoregional therapy or refractory to locoregional therapy, and not amenable to a curative treatment) or Stage C. Pts with HCC should also have received 1 prior immuno-oncology (IO)-based regimen and have progressed on/after prior treatment with IO therapy. If ineligible for IO therapy, pts should not have received prior systemic therapy; pts who previously received LEN are ineligible. In the EC subpart, pts should have disease progression after receiving prior platinum-based chemotherapy (PBT) and an IO-based therapy for EC. Pts may have received 1 additional line of PBT if given in the neoadjuvant/adjuvant setting, but not exceeding 3 lines of therapies. Pts with EC who are ineligible for IO therapy may have received only 1 prior systemic therapy including PBT. Pts who have received prior LEN therapy will be eligible if they meet protocol-specified criteria. Pts with HCC (n≈60) will be randomized in a 2:1 ratio into 1 of 2 treatment arms and will receive either the combination E7386 + LEN or LEN monotherapy in 28-day cycles. E7386 will be administered at 100 mg BID in the combination arm and LEN will be administered QD at 8 mg (if body weight <60 kg) or 12 mg (if body weight ≥60 kg) in both arms. Pts with HCC will be stratified by geographical region (Western Europe and North America vs Japan vs other countries). Pts with EC (n≈30) will receive only the combination E7386 120 mg BID + LEN 14 mg QD. The expansion part of Study 102 aims to assess safety and tolerability (primary endpoints), and pharmacokinetics and preliminary efficacy (secondary endpoints), of E7386 in combination with LEN for pts with HCC and EC. Efficacy of LEN monotherapy will be assessed for HCC (secondary endpoint). Tumors will be assessed by investigator per RECIST v1.1 every 8 weeks from the date of the first dose. Adverse events will be monitored and recorded for up to 30 days after the last dose or until initiation of a new anticancer therapy, whichever occurs first. Study sites will include the United States, France, Republic of Korea, Japan, and Taiwan. As of February 5, 2024, 46 pts with HCC and 16 pts with EC have enrolled. Clinical trial information: NCT04008797 .

A phase I trial of intratumoral STX-001: A novel self-replicating mRNA expressing IL-12 alone or with pembrolizumab in advanced solid tumors.

TPS2696 Background: STX-001 is a multi-mechanistic lipid nanoparticle encapsulated synthetic self-replicating mRNA, engineered to express the IL-12 cytokine for an extended duration when administered intratumorally. A murine surrogate of STX-001 induces deep durable responses in multiple preclinical solid tumor models. This Phase 1 open-label, multi-center first-in-human dose-escalation trial evaluates the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antitumor activity of STX-001 alone, or in combination with pembrolizumab in patients with treatment refractory advanced cancers. Methods: Approximately 30 adults ≥18 years of age with histologically confirmed advanced solid tumors that are refractory to standard treatments will be enrolled. The study will consist of two arms, an STX-001 monotherapy arm and an STX-001 + pembrolizumab combination arm, enrolling approximately 15 patients each. Key eligibility criteria include ECOG status 0 or 1, a tumor lesion amendable to injection, and confirmed prior disease progression. STX-001 will be administered every 3 weeks (q3w) for 3 doses and then every 6 weeks (q6w) for a further 3 doses. Tumor biopsies will be obtained at baseline and after the first STX-001 administration. Primary endpoints will include safety and maximum tolerated dose (MTD), with secondary endpoints encompassing pharmacokinetics and preliminary efficacy as measured by RECIST 1.1. To determine the MTD, this study will employ the Bayesian optimal interval (BOIN) design, with the 3 + 3 design run-in and a recommended phase 2 dose (RP2D) will be determined. Tumor response will be assessed using RECIST 1.1 criteria. Exploratory pharmacodynamic analyses will assess tumor-infiltrating lymphocytes and STX-001 mRNA in baseline and on-treatment biopsies, evaluate inflammatory cytokine profiles in plasma, determine immune activation in circulating immune cells, and measure circulating tumor DNA (ctDNA) for molecular response assessment. Clinical trial information: NCT06249048 .

An open-label, placebo-controlled, randomized phase II trial of camrelizumab combined with or without apatinib or capecitabine in the treatment of previously treated advanced pancreatic cancer.

e16324 Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the few cancer types that have essentially no clinical benefit from immune checkpoint inhibitors therapy, combined immunotherapy is expected to solve this dilemma. We conducted a randomized open-label, placebo-controlled phase II trial evaluating the efficacy of camrelizumab combined with apatinib or capecitabine in the treatment of patients with previously treated metastatic PDAC (ChiCTR1900024095). Methods: Eligible patients (n = 30) were randomized 1:1:1 to receive camrelizumab (200 mg q2w) combined with apatinib (250mg qd, d1-28, q4w) or capecitabine (1000 mg/m2, bid d1-14, q3w), or placebo plus capecitabine (1000 mg/m2, bid d1-14, q3w) until disease progression or unacceptable toxicity. Tumor response was assessed every 8 weeks according to RECISTv1.1. Primary endpoints were investigator-assessed 6-month overall survival (OS) rate. Secondary endpoints were progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), duration of response (DoR) and safety. Data cutoff date for the prespecified interim OS and final PFS analysis was Oct 30, 2022. Results: In the primary endpoint analysis, camrelizumab combined treatment showed improved 6-month OS rates, whether in the camrelizumab-apatinib arm (83.3% versus 33.3%, p = 0.1189) or in the camrelizumab-capecitabine arm (100% versus 33.3%, p = 0.0098), compared placebo-capecitabine, respectively. Median PFS was 5.4 months, HR 0.58, [95% confidence interval (CI), 0.21–1.59] in the camrelizumab-apatinib arm , 3.1 months HR 0.98, [95%CI, 0.35–2.77] in the camrelizumab-capecitabine arm , and 2.6 months in the placebo-capecitabine, respectively. The ORR and DCR were 0% and 66.7% in the camrelizumab-apatinib arm, 40% and 50% in the camrelizumab-capecitabine arm, 0% and 44.4% in the placebo-capecitabine, respectively. PR was observed in two patients receiving camrelizumab-capecitabine treatment. The median DoR were 5.3 months in the camrelizumab-apatinib arm, 4.3 months in the camrelizumab-capecitabine arm, and 2.1 months in the placebo-capecitabine arm. Treatment-related adverse event rates were slightly increased in camrelizumab combined arms. Incidences of grade ≥3 treatment-related adverse events were comparable between the three groups (20%、 10% vs 0%), with reactive cutaneous capillary endothelial proliferation (10%) as the most common one in Camrelizumab combinations. Conclusions: Camrelizumab combined treatment showed improved 6-month OS vs conventional capecitabine monotherapy, with a manageable safety profile. These analyses revealed combined immunotherapy could be used as a new option for posterior line treatment in previously treated metastatic PDAC. Clinical trial information: ChiCTR1900024095.

The role and the place of physical training in the system of military education of officers of the armed forces of the Republic of Korea

The article devoted to the system of military education of commissioned officers in the Armed Forces of the Republic of Korea, which provides the basic needs in qualified specialists in all types of armed forces and troops branches, and also allows maintaining the staffing of the armed forces and their reserve components at the level necessary to solve the tasks facing before the state. Considerable attention in educational process is paid to combat, operational and physical training, as well as to the study of foreign languages. Operational and combat training in the Armed Forces is aimed to improve the ways and methods of managing troops in all types of defensive and offensive operations, achieving high combat capability, mastering the techniques of modern combined arms combat, and acquiring the necessary tactical, special and shooting training skills for the military personnel. Physical training in the Armed Forces of the Republic of Korea is one of the main ways to develop the personality of a future commander. This requires theoretical knowledge in the field of physical education, the ability to apply them in practice, the ability to manage the process of physical education of troops, as well as personal physical qualities and spiritual strength. At regular classes, commissioned officers study physical training management, physical training pedagogy, martial arts (taekwondo), which is the most widespread form of martial arts in the Armed Forces of the Republic of Korea.

BE-WEL trial (breast: evaluation of weight and exercise for lymphoedema) testing weight control and exercise programmes for women with breast cancer related lymphoedema: a feasibility trial

PurposeA combined body weight loss and upper body/arm exercise programme is a potential strategy for managing Breast cancer related lymphoedema (BCRL), but there is limited data on the best method for delivery or its potential efficacy.MethodsFifty-seven women with overweight/obesity and BCRL were randomised to a 12 week supervised (n = 12) or home-based combined weight loss and upper body/arm exercise programme (n = 16), a home-based upper-body arm exercise only programme (n = 17) or standard care (n = 12). Primary outcomes were uptake, retention and changes in weight and change in Relative Arm Volume Increase (RAVI) using analysis of covariance (ANCOVA).ResultsSixteen percent of women invited joined the study and 49 completed the trial (85% retention). Reductions in weight occurred in the supervised and home-based weight control and exercise programmes; Mean (95% CI) change compared to standard care − 1.68 (− 4.36 to − 1.00), − 2.47(− 4.99 to − 0.04) Kg. Reductions in perometer assessed RAVI were seen in the supervised and home-based combined weight control and arm exercise groups and the weight stable home-based arm exercise only group: mean (95% CI) change compared to standard care − 2.4 (− 5.0 to + 0.4),− 1.8 (− 4.3 to + 0.7), − 2.5(− 4.9 to − 0.05)%.ConclusionWomen with BCRL and overweight and obesity engaged in diet and exercise weight loss programmes. Both weight loss/arm exercise programmes led to modest changes in weight and BCRL. Comparable reductions in BCRL were reported in the weight stable group undertaking arm exercise only. The independent and combined effects of weight loss and exercise on BCRL need further study.Trial registrationISRCTN86789850 https://doi.org/10.1186/ISRCTN86789850, registered 2011.

Tip of the Spear: Developing Predictive Military Planning Tools Using Hidden Markov Models

The evolution of the modern battlefield is increasingly complex as new technologies emerge. However, the nature of the battlefield still can be explained by Baron De Jomini’s “Grand Tactics.” Military planners’ success is in their ability to develop synergy through layering effects of a complex system at a decisive point on the battlefield. Synergistic effects require subject matter experts (SME) working in planning cells to integrate systems and units in time and space. These planning cells have large footprints and become prioritized in the opposition’s targeting cycle. Without these SMEs, planners are unable to identify the latent variables to achieve the massing of forces at the decisive point. This paper explores the application of Hidden Markov Models (HMMs) to enhance existing Correlation of Forces and Means (COFM) calculators as predictive tools in military planning. Current tools focus on a 3 to 1 force ratio for an offensive operation. They get improved through applying a force equivalent factor. The force equivalent factors are scalars that adjust relative combat power from a single main battle tank to a mechanized infantry vehicle. These tools lack the ability to identify the physics of the battlefield in time and space. The utilization of wargames during planning and training provides a venue for serious games to improve planning tools. It allows a visualization of target pairing and dynamics that a linear equation would miss. This study employs scenarios generated in OneSAF, ranging from simple platoon-level ambushes to combined arms maneuver featuring rotary wing assets requiring a shaping effort to ensure favorable COFMs. The focus of the research lies in leveraging HMMs to establish a time-series indicator of success probability using potentially observable data, with an emphasis on communication dynamics. In this study, we examine observable communication by data generated through both visual and direct contact. Through observation of contact from the friendly and opposition forces will provide a predictor of the hidden state of relative advantage, in time and space. With the data generated by the OneSAF simulation, the HMM determines the states of the operation and probability of success while minimizing required presence inside the units.

Abstract PO2-14-06: CIRCULATING TUMOR DNA DYNAMICS IN THE FIRST TREATMENT LINE OF THE SONIA TRIAL

Abstract Background and objective: CDK4/6 inhibitors (CDK4/6i) improve the outcome of patients with ER+/HER2- advanced breast cancer when added to endocrine therapy in the first line or second line of treatment. The recently reported SONIA trial shows no difference in progression free survival after two lines of treatment (PFS2), overall survival (OS) or quality of life benefit of CDK4/6i in first-line compared to second-line, while adverse events are substantially higher when CDK4/6i is added in the first-line. However, a subgroup of patients shows early progression on endocrine mono-treatment and not all patients respond equally well to CDK4/6i. This highlights the need for early response markers during the first weeks of treatment to reduce unnecessary toxicity while providing the most optimal care. In this SONIA side study, we aim to investigate whether we could identify patients who will progress rapidly during first line of therapy by using circulating tumor DNA (ctDNA) dynamics. Methods: Blood samples were obtained from patients included in the SONIA trial in both the first line CDK4/6i + aromatase inhibitor (AI) combination arm (arm A) and the first line AI monotherapy arm (arm B) at three time points: before start, after two weeks and after three months of first line treatment. Cell free DNA (cfDNA) was isolated from all samples and subsequently baseline cfDNA was sequenced with the Oncomine™ Breast cfDNA Assay v2 (Thermofisher), a focused NGS panel of 10 genes. Dedicated dPCR assays were used to track an identified driver mutation over time. Results: Blood samples of 332 patients (206 in arm A and 126 in arm B) before start of first line treatment and after two weeks of treatment were obtained. At baseline, in 142 of the 332 (42.7%) patients at least one somatic mutation was detected. In 30 patients two or more mutations were identified, in which case the mutation with the highest variant allele frequency (VAF) was followed over time. The most frequently mutated genes were PIK3CA (102 patients (30.7% of the total included cohort)), TP53 (32 patients (9.6%)), SF3B1 (8 patients (2.4%) and ESR1 (6 patients (1.8%)). The median observed VAF at baseline was 4.1% (IQR: 1.5%-13.1%). Of the 142 patients with detectable ctDNA at baseline, 141 patients and 100 patients, respectively, had blood samples taken after 2 weeks and after 3 months of treatment. After two weeks, the VAF of the tracked mutation was increased in 15.2% (14/92) of the patients in arm A and in 18.4% (9/49) of the patients in arm B. At the same time 40.2% (37/92) of the patients in arm A and 34.7% (17/49) of the patients in arm B had cleared ctDNA. No difference was observed between the arms for both an increase in VAF (P=0.63, Chi-square test) and ctDNA clearance (P=0.52, Chi-square test). After 3 months an increased VAF of the tracked mutation compared to baseline was observed in 6.3% (4/64) of the patients in arm A and 8.3% (3/36) of the patients in arm B. At this timepoint 59.4% (38/64) of the patients in arm A and 61.1% (22/36) of the patients in arm B had cleared ctDNA. No difference was observed between the arms for both ctDNA clearance (P=0.86, Chi-square test) and increase in VAF (P=0.70, Chi-square test) after three months. Conclusions: ctDNA was detected at baseline in almost half of the patients in the SONIA study. Compared to baseline, a decreasing number of patients had an elevation of the VAF of the tracked mutation and an increasing number of patients showed ctDNA clearance from 2 weeks to 3 months after start of treatment. There was no difference between the two arms observed regarding ctDNA dynamics. Interestingly, irrespective of treatment arm, about 1/3rd of patients remained ctDNA-positive even after 3 months of treatment. Associations of these ctDNA data with the clinical outcome data are currently being evaluated and will be presented at the meeting. Citation Format: Elisabeth M Jongbloed, Stefania Stella, Lotte van Bergen, Corine Beaufort, Jean Helmijr, Vanja de Weerd, Frans Erdkamp, Joan Heijns, Yvonne Kamm, Anne-Marie van Riel, Quirine van Rossum-Schornagel, Maurice Jansen, Inge RHM Konings, Gabe Sonke, John WM Martens, Agnes Jager, Saskia M Wilting. CIRCULATING TUMOR DNA DYNAMICS IN THE FIRST TREATMENT LINE OF THE SONIA TRIAL [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 PO2-14-06.

Abstract PO3-20-04: A first-in-human study of the highly selective PI3Kα inhibitor RLY-5836 in patients with advanced breast cancer and other solid tumors

Abstract Background: Oncogenic activation of PI3Kα is a common driver event in solid tumors. Although PI3Kα is a validated therapeutic target, there is no approved highly selective inhibitor that targets mutant PI3Kα. Alpelisib, a non-selective orthosteric PI3Kα inhibitor, is approved in combination with fulvestrant for patients with PIK3CA-mutant, ER+, HER2– advanced breast cancer. Inhibition of wild-type PI3Kα causes hyperglycemia, limiting the tolerability, dosing, and efficacy of alpelisib. RLY-5836 is the second allosteric, selective pan-mutant PI3Kα inhibitor under clinical investigation. It is molecularly distinct with differentiated pharmaceutical properties compared to RLY-2608. This first-in-human study aims to further explore the tolerability and efficacy of highly selective PIK3CA-mutant inhibition as monotherapy and in combination treatment. Methods: This multicenter, open-label study is designed to evaluate the safety, maximum tolerated dose (MTD), recommended Phase 2 dose (RP2D), pharmacokinetics (PK) and preliminary anti-tumor efficacy of RLY-5836 as a single agent and in various combinations. A Bayesian Optimal Interval design is used for dose escalation, followed by a dose expansion part. As monotherapy, RLY-5836 will be investigated in pts with advanced solid tumors harboring a PIK3CA mutation (Arm 1) per local assessment (blood and/or tumor). In pts with PIK3CA-mutant, HR+, HER2– advanced or metastatic breast cancer, RLY-5836 combination arms will include anti-estrogen therapy with or without CDK4/6 inhibition: fulvestrant (Arm 2), and fulvestrant + CDK4/6 inhibitor(s) (Arms 3–5). RLY-5836 is administered orally, continuously in 28-day cycles until disease progression or study discontinuation. Enrollment criteria include age ≥18 years, ECOG PS 0–1, and measurable disease (Arm 1) or evaluable disease (Arms 2–5) per RECIST version 1.1. Participants in the combination arms are required to have received prior treatment with ≥1 CDK4/6 inhibitor and ≥1 anti-estrogen therapy. Prior treatment with a PI3Kα inhibitor is an exclusion criterion for the dose expansion parts of all arms. Planned overall sample size is ~220 pts (~145 pts for the dose escalation, and ~15 pts in each dose expansion arm). Primary endpoints are the MTD, RP2D and overall safety profile of RLY-5836, either as a single agent or in combination. The MTD will be determined as the dose with a dose-limiting toxicity rate closest to the target toxicity rate (30%) in Cycle 1. Secondary endpoints include PK and efficacy parameters. Statistical analyses will be descriptive. This study (NCT05759949) is enrolling in the United States. For further information, please contact clinicaltrials@relaytx.com. Funding source: This study is funded by Relay Therapeutics, Cambridge, MA, United States. Citation Format: Andreas Varkaris, Steven Isakoff, Cesar A. Perez, Bert O'Neil, Erika Hamilton, Erin Conlin, Gege Tan, Xiaoyan Li, Alison Timm, Ramin Samadani, Erika Puente-Poushnejad, Eunice Kwak, Brenton G. Mar, Alison M. Schram. A first-in-human study of the highly selective PI3Kα inhibitor RLY-5836 in patients with advanced breast cancer and other solid tumors [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 PO3-20-04.

Comparison of acute glucose responses following combined arm and leg cycling in non and pre-diabetic males

Prolonged and chronic sedentary behavior contributes to negative metabolic health conditions. Recent research has shown that a single bout of combined arm and leg cycling (CALC) can improve acute glucose metabolism in non-diabetic college aged adults. If a short bout of CALC can improve glucose metabolism in individuals that are non-diabetic then one could hypothesize that a short bout of CALC may improve glucose metabolism in individuals that are pre-diabetic. We hypothesized that short bouts of CALC would result in a greater decrease in the 60-min total (tAUC) area under the curve in pre-diabetic compared to non-diabetic males. PURPOSE: To compare acute glucose responses following a short bout of CALC in non and pre-diabetic males. METHODS: College age males were recruited for this trial. Diabetes status was based upon a fasting blood glucose measurement taken after an overnight 12 hour fast. Participants completed three randomized experimental trials. Two of the experimental trials consisted of a 1-min (1M) or 5-min (5M) bout of CALC at a self-selected pace. The third trial was a non-exercise control (CON) trial. Immediately following both exercise trials and during the CON trial, participants completed a 60-min oral glucose tolerance test. A 2-way (diabetes status vs trial) repeated measures ANOVA was done to determine if there were any significant differences between the two groups and the three trials for the tAUC during the 60-min OGTT. RESULTS: A total of 18 college age males completed this study. Fasting blood glucose was 94.0 ± 3.7 and 108.1 ± 4.6 mg/dl for the non (n=8, 21.4 ± 2.4 yrs) and pre-diabetics (n = 10, 22.6 ± 3.9 yrs) participants respectively. There was a significant interaction between trials and diabetes status (p = 0.04) for tAUC. Follow-up analysis showed that within the pre-diabetic group, tAUC was significantly lower in the 5-min trial compared to the CON trial (113.7 ± 22.5 mg/dl, p > 0.001). Within the pre-diabetic group, the tAUC for the 1M trial was not significantly different from the CON or 5M trials. Within the non-diabetic group, there were no significant differences in tAUC between the three trials. CONCLUSIONS: The results of this study indicate that a 5M bout of CALC done at a self-selected pace may have the ability to acutely improve glucose metabolism in college age pre-diabetic males when compared to non-diabetic males. Supported by a SIUE Graduate School Research Grant for Graduate Students, the School of Education, Health, and Human Behavior Dean's Grant, and the Undergraduate Research and Creative Activities Program. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Impact of cash transfer programs on healthcare utilization and catastrophic health expenditures in rural Zambia: a cluster randomized controlled trial.

Nearly 100 million people are pushed into poverty every year due to catastrophic health expenditures (CHE). We evaluated the impact of cash support programs on healthcare utilization and CHE among households participating in a cluster-randomized controlled trial focusing on adolescent childbearing in rural Zambia. The trial recruited adolescent girls from 157 rural schools in 12 districts enrolled in grade 7 in 2016 and consisted of control, economic support, and economic support plus community dialogue arms. Economic support included 3 USD/month for the girls, 35 USD/year for their guardians, and up to 150 USD/year for school fees. Interviews were conducted with 3,870 guardians representing 4,110 girls, 1.5-2 years after the intervention period started. Utilization was defined as visits to formal health facilities, and CHE was health payments exceeding 10% of total household expenditures. The degree of inequality was measured using the Concentration Index. In the control arm, 26.1% of the households utilized inpatient care in the previous year compared to 26.7% in the economic arm (RR = 1.0; 95% CI: 0.9-1.2, p = 0.815) and 27.7% in the combined arm (RR = 1.1; 95% CI: 0.9-1.3, p = 0.586). Utilization of outpatient care in the previous 4 weeks was 40.7% in the control arm, 41.3% in the economic support (RR = 1.0; 95% CI: 0.8-1.3, p = 0.805), and 42.9% in the combined arm (RR = 1.1; 95% CI: 0.8-1.3, p = 0.378). About 10.4% of the households in the control arm experienced CHE compared to 11.6% in the economic (RR = 1.1; 95% CI: 0.8-1.5, p = 0.468) and 12.1% in the combined arm (RR = 1.1; 95% CI: 0.8-1.5, p = 0.468). Utilization of outpatient care and the risk of CHE was relatively higher among the least poor than the poorest households, however, the degree of inequality was relatively smaller in the intervention arms than in the control arm. Economic support alone and in combination with community dialogue aiming to reduce early childbearing did not appear to have a substantial impact on healthcare utilization and CHE in rural Zambia. However, although cash transfer did not significantly improve healthcare utilization, it reduced the degree of inequality in outpatient healthcare utilization and CHE across wealth groups. https://classic.clinicaltrials.gov/ct2/show/NCT02709967, ClinicalTrials.gov, identifier (NCT02709967).

Oral arsenic plus imatinib versus imatinib solely for newly diagnosed chronic myeloid leukemia: a randomized phase 3 trial with 5-year outcomes

PurposeThe synergistic effects of combining arsenic compounds with imatinib against chronic myeloid leukemia (CML) have been established using in vitro data. We conducted a clinical trial to compare the efficacy of the arsenic realgar–indigo naturalis formula (RIF) plus imatinib with that of imatinib monotherapy in patients with newly diagnosed chronic phase CML (CP-CML).MethodsIn this multicenter, randomized, double-blind, phase 3 trial, 191 outpatients with newly diagnosed CP-CML were randomly assigned to receive oral RIF plus imatinib (n = 96) or placebo plus imatinib (n = 95). The primary end point was the major molecular response (MMR) at 6 months. Secondary end points include molecular response 4 (MR4), molecular response 4.5 (MR4.5), progression-free survival (PFS), overall survival (OS), and adverse events.ResultsThe median follow-up duration was 51 months. Due to the COVID-19 pandemic, the recruitment to this study had to be terminated early, on May 28, 2020. The rates of MMR had no significant statistical difference between combination and imatinib arms at 6 months and any other time during the trial. MR4 rates were similar in both arms. However, the 12-month cumulative rates of MR4.5 in the combination and imatinib arms were 20.8% and 10.5%, respectively (p = 0.043). In core treatment since the 2-year analysis, the frequency of MR4.5 was 55.6% in the combination arm and 38.6% in the imatinib arm (p = 0.063). PFS and OS were similar at five years. The safety profiles were similar and serious adverse events were uncommon in both groups.ConclusionThe results of imatinib plus RIF as a first-line treatment of CP-CML compared with imatinib might be more effective for achieving a deeper molecular response (Chinadrugtrials number, CTR20170221).

The therapeutic effect of radiotherapy combined with systemic therapy compared to radiotherapy alone in patients with simple brain metastasis after first-line treatment of limited-stage small cell lung cancer: a retrospective study

PurposeWe aimed to compare the therapeutic effect of radiotherapy (RT) plus systemic therapy (ST) with RT alone in patients with simple brain metastasis (BM) after first-line treatment of limited-stage small cell lung cancer (LS-SCLC).MethodsThe patients were treated at a single center from January 2011 to January 2022. BM only without metastases to other organs was defined as simple BM. The eligible patients were divided into RT alone (monotherapy arm) and RT plus ST (combined therapy arm). Univariate and multivariate Cox proportional hazards analyses were used to examine factors associated with increased risk of extracranial progression. After 1:1 propensity score matching analysis, two groups were compared for extracranial progression-free survival (ePFS), PFS, overall survival (OS), and intracranial PFS (iPFS).Results133 patients were identified and 100 were analyzed (monotherapy arm: n = 50, combined therapy arm: n = 50). The ePFS of the combined therapy was significantly longer than that of the monotherapy, with a median ePFS of 13.2 months (95% CI, 6.6–19.8) in combined therapy and 8.2 months (95% CI, 5.7–10.7) in monotherapy (P = 0.04). There were no statistically significant differences in PFS (P = 0.057), OS (P = 0.309), or iPFS (P = 0.448). Multifactorial analysis showed that combined therapy was independently associated with better ePFS compared with monotherapy (HR = 0.617, P = 0.034); more than 5 BMs were associated with worse ePFS compared with 1–5 BMs (HR = 1.808, P = 0.012).ConclusionsCompared with RT alone, combined therapy improves ePFS in patients with simple BM after first-line treatment of LS-SCLC. Combined therapy and 1–5 BMs reduce the risk of extracranial recurrence.

Abstract CT137: Efficacy and immunological outcomes of non-fucosylated anti-CTLA-4 (BMS-986218) + degarelix acetate vs. degarelix acetate alone in men with high-risk localized prostate cancer (Neo-Red-P)

Abstract Background: Men with high-risk localized prostate cancer are at significant risk for disease recurrence and there is currently no role for neoadjuvant therapy. Although androgen deprivation therapy (ADT) is immunomodulatory and can increase CD8 T cell infiltration, these effects are counterbalanced by the expansion of suppressive regulatory T cells (Tregs). We therefore designed a correlative-rich clinical trial for men with high-risk localized prostate cancer to test whether BMS-986218 - a novel afucosylated anti-CTLA-4 antibody optimized for antibody-dependent cell-mediated cytotoxicity (ADCC) - depletes Tregs and augments response to ADT. Methods: Neo-Red-P is a single-center, two-arm, open-label pilot study assessing degarelix (ADT) versus ADT + anti-CTLA-4-NF (BMS-986218) in patients with treatment naïve high-risk localized prostate cancer. Key eligibility criteria included histologically confirmed adenocarcinoma with Gleason sum of ≥4+3 and clinical stage T1c-T3bN0M0. All patients received degarelix (ADT; 240mg SQ) 2 weeks before radical prostatectomy (RP). Patients were randomized to Arm A (ADT only), or Arm B (ADT + BMS-986218 [20mg IV] 2 doses Q2w starting 3 weeks before RP). The primary endpoint was the safety and feasibility of neoadjuvant BMS-986218 in prostate cancer. Secondary endpoints included the pathologic complete response rate, rate of undetectable PSA at 12 months, PSA response rate (>50% decrease pre-RP), and time-to-PSA recurrence. Fresh tumor specimens were collected at RP for single-cell RNA-sequencing, cytometry by time-of-flight, next-generation sequencing, and multiplex immunofluorescence. A treatment naïve cohort of matching demographic and pathological characteristics was collected for comparative analysis (n=14). Results: Between February 26, 2020, and November 15, 2022, 24 patients were enrolled. Severe treatment-related adverse events (TRAE; Grade ≥ 3) were rare in both arms; 0% in the ADT alone arm and 4% in the combination arm, suggesting a tolerable safety profile with the addition of BMS-986218. In the combination arm, 54% of subjects achieved a 50% reduction in PSA versus 33% in the ADT alone arm. In the ADT alone arm, 80% of patients had an undetectable PSA at 12 months, with a median recurrence-free survival of 1.61 years (IQR: 1.50-1.99 years). In the combination group, 75% had an undetectable PSA at 12 months, with a median recurrence-free survival of 1.82 years (IQR: 0.89-2.07 years). The overall recurrence rate in patients treated with combination therapy was 25% (3 of 12 patients) versus 20% (2 of 10 patients) in the ADT alone arm. Correlative studies suggest that aCTLA4-NF mitigates ADT-induced Treg accumulation through enhanced Fc receptor activity and augmented CTL activation, indicating an enhanced anti-tumor response with combination therapy. Conclusions: The neoadjuvant combination of ADT + aCTLA-4-NF (BMS-986218) is feasible, well tolerated, and induces significant remodeling of the immune TME through enhanced Fc receptor and CTL activity. Rates of disease recurrence following surgery were low in this high-risk population, warranting further investigation of combination immuno-hormonal therapy in the neoadjuvant setting for high-risk prostate cancer. Clinical Trial Information: NCT04301414 Citation Format: Patrick J. McCann, Casey R. Ager, Aleksandar Z. Obradovic, Matthew G. Chaimowitz, Samuel Pan, Caroline J. Laplaca, Parin Shah, Renu K. Virk, Christopher B. Anderson, Catherine S. Spina, Karie D. Runcie, Mark N. Stein, Charles G. Drake, Matthew C. Dallos. Efficacy and immunological outcomes of non-fucosylated anti-CTLA-4 (BMS-986218) + degarelix acetate vs. degarelix acetate alone in men with high-risk localized prostate cancer (Neo-Red-P) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT137.

Abstract LB090: Predictive genomic biomarkers for atezolizumab plus bevacizumab combination immunotherapy response in liver cancer: Insights from the IMbrave150 trial

Abstract Introduction: Combination immunotherapy regimens, exemplified by atezolizumab plus bevacizumab or sintilimab paired with a bevacizumab biosimilar (IBI305), have become the established standard of care for individuals with inoperable hepatocellular carcinoma (HCC). Despite this advancement, the absence of clear predictive biomarkers and a comprehensive understanding of the mechanisms governing response and resistance to these combined therapies pose challenges. Our aim is to evaluate whether previously defined immune signature scores (ISS) from the TCGA pan-cancer study can identify HCC patients likely to derive enhanced benefit from the combination immunotherapy. Methods: We applied ISS predictor to gene expression data from IMbrave150 clinical trial in which HCC patients were treated with atezolizumab plus bevacizumab or sorafenib and stratify the patients into responders and non-responders (cutoff of 0.5). The significance of the stratification was assessed by multiple statistical approaches using Kaplan-Meier plots, the log-rank test, chi-square tests, and cox regression analysis. Results: In the IMBrave150 trial cohort, data on gene expression and outcomes were accessible for 247 patients who received atezolizumab plus bevacizumab, and 48 patients who received sorafenib. The high ISS demonstrated a significant association with enhanced PFS in the atezolizumab plus bevacizumab group (p=0.003), while no such association was observed in the sorafenib group (p=0.6). Similarly, in the high ISS subgroup, the combination therapy exhibited superior OS (p.0.001) and PFS (p=0.02) compared to sorafenib, but no discernible benefit was noted in the low ISS subgroup (both p>0.7). The OS hazard ratio for the combination versus sorafenib was 0.26 (95% CI 0.14-0.51, p<0.001) among high ISS patients, while it was not statistically significant in low ISS (HR 0.88, p=0.68). Interaction testing confirmed a notable interaction between ISS subtype and treatment benefit, particularly for OS (p=0.01). In the combination arm, the objective response rate was 45.6% in the high ISS group versus 22.8% in the low ISS group. Conclusions: Our study suggests that ISS may serve as a promising predictive biomarker for enhanced therapeutic outcomes in patients undergoing combination immunotherapy for HCC. The identification of such markers is crucial for refining patient stratification and personalized treatment approaches, thereby advancing the effectiveness of current standard-of-care regimens in both early and advanced stage HCC. Further validation studies are warranted to solidify the clinical utility of ISS and its integration into the decision-making process for HCC immunotherapy. Citation Format: Ju-Seog Lee, Sun Young Yim, Seung-Woo Baek, Sung Hwan Lee, BoHwa Sohn, Yun Seong Jeong, Sanghee Kang, Kena Park, Hyewon Park, Sunyoung S. Lee, Ahmed O. Kaseb, Ji Hoon Kim, In-Sun Chu. Predictive genomic biomarkers for atezolizumab plus bevacizumab combination immunotherapy response in liver cancer: Insights from the IMbrave150 trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB090.

Abstract CT163: FIT-001: A phase 1 clinical trial of the farnesyl transferase inhibitor KO-2806 alone or as part of combination therapy for advanced solid tumors

Abstract Background: Farnesyl transferase inhibitors (FTIs) block post-translational modification of RAS and other farnesylated proteins. HRAS-driven tumors are highly sensitive to FTI treatment. Recent clinical trials (NCT03719690, NCT02383927) of the FTI, tipifarnib, in patients with HRAS-mutant (HRAS-m) head and neck squamous cell carcinoma harboring high variant allele frequency mutations (VAF ≥20%), showed objective response rates of up to 50% and favorable long-term outcomes. KO-2806 is a next-generation FTI that has increased potency and improved pharmacokinetic properties. In preclinical studies, KO-2806 has been shown to: (1) enhance tumor growth inhibition of tyrosine kinase inhibitors, including cabozantinib, in multiple clear cell renal cell carcinoma (ccRCC) cell line- and patient-derived xenograft models; and (2) enhance activity of KRAS inhibitors, including adagrasib, in KRAS mutant non-small cell lung cancer (NSCLC), colorectal cancer (CRC), and pancreatic ductal adenocarcinoma (PDAC) mouse models. These preclinical data support clinical investigation of KO-2806 alone and in combination therapy. Study Design: FIT-001 is a first-in-human, multicenter, open-label clinical trial that will evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics (Pd), and preliminary antitumor activity of KO-2806 as monotherapy or in combination therapy in advanced solid tumors (KO-2806-001; NCT06026410). Up to 270 patients will be enrolled in phase 1a and phase 1b combined across 50 sites. Phase 1a will have separate monotherapy and combination dose-escalation arms. As monotherapy, the study will enroll patients with N/K/HRAS alterations in specific solid tumor types, such as NSCLC, CRC, and PDAC, who are refractory to standard-of-care therapies. KO-2806 and cabozantinib will be combined in patients with advanced or metastatic ccRCC who progressed on ≥1 prior line of immunotherapy-based systemic therapy; KO-2806 and adagrasib will be combined in patients with KRAS-G12C mutant locally advanced or metastatic NSCLC who received ≥1 prior systemic therapy. On the basis of emerging data from phase 1a, two Pd cohorts (n≤12) with mandatory pre- and on-treatment tumor biopsies may be enrolled. In each Phase 1b dose expansion, patients will receive the recommended phase 2 dose [RP2D] of KO-2806 with cabozantinib (in ccRCC) or adagrasib (in NSCLC), or will be randomized by dose if 2 potential KO-2806 RP2Ds are identified for a combination. Other combination arms may also be considered. The study began accrual in October 2023. Citation Format: Glenn J. Hanna, Douglas R. Adkins, Jacob S. Thomas, Justine Y. Bruce, Manish R. Patel, Guru Sonpavde, Jason Henry, Nawal Bendris, Zijing Zhang, Amitava Mitra, Amaya Gascó, Andrew Saunders, Stephen Dale. FIT-001: A phase 1 clinical trial of the farnesyl transferase inhibitor KO-2806 alone or as part of combination therapy for advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT163.

Arms acquisition in the Baltic States and transfers to Ukraine: balancing national security

ABSTRACT Three Baltic States (3Bs), like most eastern NATO countries, treat the war in Ukraine as a strong national interest: if Russia is stopped in Ukraine, it will not be capable of inflicting any harm to them. As a result, national decision-makers are making hard choices on which military capabilities need to be transferred to Ukraine and what must remain for national needs. The results indicate that 3Bs Defence Ministers understand the importance of supporting Ukraine with lethal and non-lethal items. 3Bs acquire major arms from various countries with different spending levels and have limited ability for combined procurement opportunities, although they seek to develop similar military capabilities. It is assessed that 3Bs will not deliver newly acquired major arms to Ukraine and will continue delivering reliable legacy systems. Therefore, allocating funds for combined major arms procurements implemented by the third party like the U.K.-led International Fund for Ukraine, is the most viable option to continue supporting Ukraine.

Adjuvant nivolumab, capecitabine or the combination in patients with residual triple-negative breast cancer: the OXEL randomized phase II study

Chemotherapy and immune checkpoint inhibitors have a role in the post-neoadjuvant setting in patients with triple-negative breast cancer (TNBC). However, the effects of nivolumab, a checkpoint inhibitor, capecitabine, or the combination in changing peripheral immunoscore (PIS) remains unclear. This open-label randomized phase II OXEL study (NCT03487666) aimed to assess the immunologic effects of nivolumab, capecitabine, or the combination in terms of the change in PIS (primary endpoint). Secondary endpoints included the presence of ctDNA, toxicity, clinical outcomes at 2-years and association of ctDNA and PIS with clinical outcomes. Forty-five women with TNBC and residual invasive disease after standard neoadjuvant chemotherapy were randomized to nivolumab, capecitabine, or the combination. Here we show that treatment with immunotherapy containing arms (nivolumab or a combination of nivolumab plus capecitabine) leads to an increase in PIS from baseline to week 6 compared with capecitabine alone, meeting the pre-specified primary endpoint. In addition, the presence of circulating tumor DNA (ctDNA) is associated with disease recurrence, with no new safety signals in the combination arm. Our results provide efficacy and safety data on this combination in TNBC and support further development of PIS and ctDNA analyses to identify patients at high risk of recurrence.

Abstract 2630: Identifying most promising combination therapies for immune suppressive breast cancer using a combined in vitro/in vivo approach

Abstract Combining epigenetic therapy with immunotherapy is a promising strategy to address the complexities of cancer biology. However, it's important to note that the field is still evolving, and more research is needed to understand the optimal combinations, timing, and patient populations that will benefit the most from these approaches. We evaluated a combination of two different checkpoint inhibitor therapies (anti-CTLA4 and anti-PD1) with two different hypomethylating agents (5-azacytidine, AZA and Decitabine, DEC) in vitro and in vivo using a mouse breast cancer cell line 4T1 known to be resistant towards checkpoint inhibition (CPi). Beside tumor cell killing and tumor volume measurement, cytokine expression and immune cell phenotyping was determined. In a co-culture assay with autologous T cells and 4T1 cells, antitumor efficacy weas increased in all combination arms using AZA but not in combination with DEC. The combination of AZA with anti-CTLA4 was significantly better than the respective monotherapies (oneway ANOVA, p< 0.001). This effect was observed as well in the combination with anti-PD1 and AZA, however it was less pronounced (oneway ANOVA, p< 0.01). Of note, AZA restored the CTLA4 expression on CD8+ T cells in vitro, which was reduced by co-culture with tumor cells alone. In the follow-up in vivo experiment we focus on the combination of both CPi with AZA on different treatment schedules in the combination arms. The combination of anti-CTLA4 and AZA in a staggered treatment schedule displayed significant efficacy compared to control (oneway ANOVA, p< 0.05). The implantation of 4T1 reduced the number of T cells in bone marrow (BM), peripheral blood (PB) and spleen of the mice, confirming the immune-suppressive nature of the breast cancer line. This effect was restored under treatment with AZA in monotherapy and combination with CPi. Interestingly AZA reduced the number of immunosuppressive MDSC in BM, spleen and in tumor tissue. Vice versa NK cells were increased in BM, spleen and tumor tissue under treatment with AZA. AZA reduced the number of circulation tumor cells in PB and increased as already shown in vitro the percentage of CD8/CTLA4++ in PB. The PCA analysis of 36 mouse cytokines in vivo displayed two main clusters separated mainly by the presence of absence of AZA in the treatment arms. The combination arms which displayed the highest efficacy showed an increase in CXCL1, G-CSF, IL-6, LIF, M-CSF, MCP-1 (CCL2) and MCP-3 (CCL7) and a decrease of IFN-gamma, CXCL2. This is in line with the more inflammatory pattern of the tumor infiltrating lymphocytes in those groups. In summary, we have strong evidence that AZA influences the immune landscape of breast cancer towards a more inflammatory subtype. The combination with CPi was superior to the monotherapy. In addition, our data indicate that the treatment schedule of the combination might have a crucial influence on efficacy. Citation Format: Hannah Silberzahn, Mattias Bleisch, Anne Löhr, Volker Knauff, Kanstantsin Lashuk, Julia B. Schueler. Identifying most promising combination therapies for immune suppressive breast cancer using a combined in vitro/in vivo approach [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 2630.

Abstract 6487: The selective WEE1 inhibitor azenosertib shows synergistic anti-tumor activity with KRASG12C inhibitors in multiple KRASG12C models

Abstract KRASG12C is a potent oncogenic driver which results in downstream hyperactivation of MAPK signaling and unchecked oncogenic growth, while simultaneously increasing replication stress (RS) and accumulation of DNA damage. KRASG12C-specific inhibitors are approved and/or recommended in metastatic non-small cell lung cancer (NSCLC) and colorectal cancer (CRC), and while responses are robust, some patients are inherently resistant, and most responders acquire resistance. Resistance mechanisms include reactivation of MAPK signaling, and cancer cells which escape MAPKi are reported to have high levels of genomic instability. WEE1 is a kinase involved in cell cycle progression, allowing cells to repair damaged DNA before entering the next cell cycle phase. Consequently, inhibition of WEE1 leads to premature cell cycle entry and RS, thereby driving cancer cells through the cell cycle with unchecked accumulation of DNA damage, ultimately resulting in mitotic catastrophe and cell death. We hypothesized that high levels of genomic instability and RS in KRASG12C mutant and KRASG12C inhibitor-resistant tumors present a vulnerability to WEE1 inhibition and provide rationale for combining azenosertib, a novel, selective, and orally bioavailable WEE1 inhibitor, with KRASG12C inhibitors. Here, we report azenosertib in combination with KRASG12C inhibitors as an effective therapeutic strategy for KRASG12C tumors. In vitro combination of azenosertib with multiple KRASG12C inhibitors demonstrated synergistic cell growth inhibition across a panel of KRASG12C cell lines in both 2D and 3D assays. In vivo treatment with azenosertib in KRASG12C inhibitor-sensitive cell line-derived xenograft (CDX) models of NSCLC (NCI-H358, NCI-H2122, NCI-H1792), CRC (SW837, SW1463), and pancreatic cancer (MIA PaCa-2) demonstrated significant monotherapy activity as well as synergistic tumor growth inhibition (TGI) when combined with KRASG12C inhibitors, including tumor regression in some models. Importantly, the KRASG12C inhibitor-resistant SW1573 NSCLC CDX model demonstrated synergistic TGI in the combo arm (84%) when compared against monotherapy azenosertib (31%) or adagrasib (58%). Similarly, treatment of a KRASG12C inhibitor-resistant patient-derived xenograft (PDX) model of CRC resulted in synergistic TGI in the combination arm (61%) relative to monotherapy azenosertib (17%) or adagrasib (2%). Finally, analysis of biomarkers from both in vitro and in vivo tumor samples demonstrated synergistic increases in protein markers of RS, DNA damage, and apoptosis with combination therapy. Taken together, our results suggest that the combination of azenosertib with KRASG12C inhibitors enhances tumor growth inhibition over single agent therapy and may be an effective treatment option for patients with KRASG12C tumors. Citation Format: Nathan M. Jameson, Gabriel Kim, Catherine Lee, Blake Skrable, Alexandra Shea, Monah Abed, Olivier Harismendy, Jianhui Ma, Doris Kim, Mark R. Lackner. The selective WEE1 inhibitor azenosertib shows synergistic anti-tumor activity with KRASG12C inhibitors in multiple KRASG12C models [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 6487.

Abstract 5284: Immune surveillance of chemotherapy-induced mutant subclones in CRC

Abstract Molecular alterations generated by DNA repair deficiencies and DNA damaging agents can be detected by the host immune system and this can restrict cancer growth. We have previously reported that temozolomide (TMZ) is able to induce MMR defects and hypermutability leading to immunotherapy clinical benefit in the subset of CRCs characterized by inactivation of O6-methylguanine methyltransferase (MGMT). We reasoned that combination of chemotherapeutic agents could similarly impair DNA repair function, increase mutational burden and trigger cancer immunogenicity in the larger group of MMR proficient (MMRp)/MGMT wild type (MGMTwt) CRCs. For this reason, we investigated the impact of treatment with TMZ and cisplatin (CDDP), as well as other commonly used cytotoxic agents in CRC such as 5-fluorouracil, irinotecan and oxaliplatin, on the immunogenomic features of murine CRC cells. We performed a two-step experiment: first, murine CRC models were exposed in vitro to chemotherapy agents used alone or in combination in a pulsatile schedule in order to mimic drug exposure in the clinical setting (priming phase); second, the cells were challenged in vivo with subcutaneous injection in immune-deficient and -proficient syngeneic mice (editing phase). Whole exome sequencing (WES) was performed at baseline and after both the priming and the editing phases to identify mutational signatures, predict neoantigens and assess immunoediting. We found that combinatorial treatment of MMRp/MGMTwt CRC cells with CDDP and TMZ causes clonal and subclonal hypermutability, eventually leading to tumor rejection in syngeneic mice. By following the fate of chemotherapy-induced mutations and predicted neoantigens in primed tumors grown in immunocompromised or immunocompetent mice we found that the majority of chemo-induced mutant clones were immunologically deleted in the CDDP-TMZ combination arm. The same effect was not observed when CDDP and TMZ were administered as monotherapy or when CRC cells were primed with the 5-fluorouracil-oxaliplatin-irinotecan (FOLFOXIRI) triplet. Mutational signature profiling of the immunologically deleted mutations was consistent with the previous exposure to chemotherapy in the priming phase. Moreover, the extent of the immunoediting was related to the clonality of the chemo-induced mutations, underlining the relevance of clonal abundance of immunogenic mutations in immune recognition and surveillance. These results indicate that rational combinations of commonly used cytotoxic agents can be exploited to promote cancer cell subclonal and clonal hypermutability. This approach can be used to promote cancer immunogenicity with implications for the design of new chemo-immunotherapy strategies in CRC. Citation Format: Pietro Paolo Vitiello, Paolo Battuello, Rosaria Chilá, Vittorio Battaglieri, Vito Amodio, Gaia Grasso, Federica Di Nicolantonio, Giovanni Crisafulli, Giovanni Germano, Alberto Bardelli. Immune surveillance of chemotherapy-induced mutant subclones in CRC [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 5284.