High major pathologic response (MPR) rates occurred in patients with resectable mismatch repair–proficient (pMMR) and mismatch repair–deficient (dMMR) colorectal cancer (CRC) who were treated with neoadjuvant botensilimab (AGEN-1181) plus balstilimab (AGEN-2034) in the phase 2 NEST-1 trial (NCT05571293).

2025 ASCO Gastrointestinal Cancer Symposium

 showed that the complete MPR rate among patients classified as having microsatellite stable (MSS) disease treated with 2 balstilimab doses (NEST-1) vs up to 4 balstilimab doses (NEST-2) were 14% (95% CI, 0.4%-58%) and 40% (95% CI, 16%-68%), respectively. Additionally, among patients with microsatellite instability-high (MSI-H) CRC, the complete MPR rate was 75% (95% CI, 19%-99%). Additionally, the median days to surgery among patients treated in the NEST-1 arm, NEST-2 arm, and the MSI-H cohort were 29 (range, 21-37), 57 (range, 45-104), and 46 (34-78), respectively.

Additionally, an MPR of 90% or greater occurred in 29% (95% CI, 4%-71%) of the NEST-1 arm, 47% (95% CI

 21%-73%) of the NEST-2 arm, and 100% (95% CI, 40%-100%) of patients with MSI-H disease. MPR of 50% or greater occurred in 57%, 60%, and 100% of the respective groups.

Median progression-free survival (PFS) was 18.2 months (IQR, 16.9-19.23) in the NEST-1 arm and 8.98 months (IQR, 8.07-9.37) in the NEST-2 arm. Additionally, circulating tumor DNA (ctDNA)–positive status was reported in 9 of 16 patients.

“Neoadjuvant BOT/BAL is safe and effective. We observed high MPR rates in both MSS and MSI-H CRC with no recurrences to date,” Erika Hissong, MD, gastrointestinal pathologist in the Department of Pathology and Laboratory Medicine at Weill Cornell Medicine, wrote in the study with coinvestigators.

 “The [MPR] rate improved with extended time to surgery.”

The study examined the combination checkpoint inhibitor (CPI) therapy in patients with MSI-H and MSS localized CRC. A total of 24 patients were enrolled on study, including 10 in the NEST-1 arm and 14 in the NEST-2 arm; there was a total of 4 patients identified as having dMMR disease, including 3 NEST-1 patients and 1 NEST-2 patient.

Patients in the NEST-1 arm received 1 dose of botensilimab at 75 mg and 2 doses of balstilimab at 240 mg 2 weeks apart, followed by surgery. In the NEST-2 arm, patients received the same botensilimab regimen and received the same balstilimab dose but for up to 4 doses 2 weeks apart, followed by surgery.

Patients 18 years and older with cytologically, histologically, or clinically confirmed adenocarcinoma of the colon or rectal and no plans for neoadjuvant radiation for rectal cancer were eligible for enrollment on the NEST trial.

The median patient age was 64 (IQR, 46-73) across all arms, 57 (IQR, 35-69) for NEST-1, and 69 (IQR, 59-75) for NEST-2. The male to female ratio was 13:11, 5:5, and 8:6 in respective arms. Most patients were White (n = 12, 5, and 7, respectively) and non-Hispanic (n = 21, 9, and 12, respectively). Additionally, 10 patients had a clinical stage of T1/T2, and 14 had a clinical stage of III or greater.

In the NEST-1 arm, there was a single grade 2 instance of fever and single grade 3 instances of fatigue and colitis or diarrhea. Additionally, the NEST-2 arm had 3 grade 2 instances of colitis or diarrhea, 2 grade 2 instances of fever, and single grade 2 instances of fatigue, anemia, nausea, and myositis. Additionally, there were 2 grade 3 instances of colitis or diarrhea in this arm.

A total of 7 patients did not complete the 4 cycles of balstilimab in the NEST-2 cohort. There were no grade 4 adverse events (AEs) or unresolved immune-mediated AEs. Furthermore, no delays in surgery due to immune-mediated AEs were observed.

Hissong E, Jafari D, Khan S, et al. Neoadjuvant botensilimab (BOT) plus balstilimab (BAL) in resectable mismatch repair proficient (pMMR) and deficient (dMMR) colorectal cancer (CRC). 

 2025;43(suppl 4):207. doi:10.1200/JCO.2025.43.4_suppl.207

Combination immunotherapy in colorectal cancer (NEST-1). ClinicalTrials.gov. Updated August 20, 2024. Accessed January 27, 2024. https://bit.ly/3CrbWaf

Articles

Neoadjuvant botensilimab and balstilimab therapy demonstrated high major pathologic response (MPR) rates in patients with resectable mismatch repair–proficient (pMMR) and mismatch repair–deficient (dMMR) colorectal cancer (CRC) in the phase 2 NEST-1 trial. The study revealed significant MPR rates in both microsatellite stable (MSS) and microsatellite instability-high (MSI-H) CRC, with no recurrences reported. Median progression-free survival (PFS) varied between trial arms, and the therapy was deemed safe with manageable adverse events. The trial included 24 patients, with distinct dosing regimens for NEST-1 and NEST-2 arms.

The combination of botensilimab plus balstilimab elicited high major pathologic response rates with extended time to surgery in resectable colorectal cancer.



Neoadjuvant Botensilimab Plus Balstilimab Yields High MPR Rates in CRC

Frailty and elder age may contribute to worsened postoperative outcomes, regardless of following enhanced recovery after surgery (ERAS) protocols in patients undergoing major gynecologic oncology surgery, according to retrospective data presented at the 

Data from the study revealed that patients 65 years of age or older, accounting for 23% of the population, had a significant association with higher modified frailty index (mFI) scores compared with those classified as non-elderly (

.001). Patients classified as elderly were more like to be identified as mFI 4 (1.20% vs 0.12%), mFI 3 (6.00% vs 1.83%), mFI 2 (34.80% vs 15.40%), or mFI 1 (41.60% vs 29.30%) vs nonelderly patients.

Additionally, elderly patients were more likely to experience longer length of stays (LOS). Incidence ratio rates (IRR) for LOS in elderly and nonelderly patients, respectively, were 0.924 (95% CI, 0.64-1.34; 

 = .632) in those with mFI 1, 1.45 (95% CI, 1.01-2.11) vs 1.37 (95% CI, 1.12-1.67) in those with mFI 2, 2.40 (95% CI, 1.37-4.18) vs 1.17 (95% CI, 0.69-1.98; 

 = .561) in those with mFI 3, and 3.91 (95% CI, 1.39-11.01) vs 0.78 (95% CI, 0.09-6.79; 

Furthermore, across all age groups, higher mFI scores were associated with higher non-home discharge rates. Odds ratios (OR) for non-home discharge in all patients were 1.97 (95% CI, 0.62-6.26; 

 = .25) in mFI 1 vs mFI 0, 5.16 (95% CI, 1.78-15.1) in mFI 2 vs mFI 0, 6.78 (95% CI, 1.26-36.5) in mFI 3 vs mFI 0, and 31.6 (95% CI, 2.79-358) in mFI 4 vs mFI 0.

“Despite ERAS protocols, the elderly and frail undergoing major gynecologic oncology surgery have worse postoperative outcomes in terms of LOS and non-home discharge,” Bailey Widstrom, DO, from the Department of Obstetrics, Gynecology and Reproductive Services at the University of Texas Health Science Center at Houston, McGovern Medical School, wrote in the poster with study coinvestigators. “Elderly patients are more likely to have a higher frailty index, making them even more vulnerable postoperatively. Frailty evaluation, especially functional status, should be incorporated into preoperative planning and patient counseling.”

The institutional review board–approved retrospective study assessed 1070 patients with gynecologic cancer who underwent major gynecologic surgery from January 2019 to December 2023. Patients were assigned to the ERAS protocol for gynecologic oncology and were assigned an mFI-5 score based on 5 factors, functional status, diabetes, history of chronic obstructive pulmonary disease (COPD), history of congestive heart failure (CFS), and hypertension.

Patients in the total study cohort and elderly patients had a median age of 53 years (range, 10-91) vs 70 years (range, 66-91). Most patients were either White (46.6% vs 49.2%) or Black (24.7% vs 25.2%), most were not Hispanic (89.8% vs 90.8%), and 9.2% vs 4.8% were smoking at baseline. Patients in the respective groups primarily had an American Society of Anesthesiologists (ASA) classification of III (65.4% vs 77.6%) or II (27.4% vs 12.8%), had malignant disease (52.9% vs 78.4%), and underwent either robotic (52.1% vs 58.0%) or open (42.1% vs 34.8%) operative approaches.

The study end points included LOS, incidence of emergency room visits, hospital readmissions, non-home discharges, and severity of postoperative complications.

Perioperative morbidity in elderly patients and non-elderly patients, respectively, included 5.2% vs 1.6% undergoing non-home discharge (

 .001), 8.4% vs 11.6% undergoing emergency department visits (

 = .156), and 7.6% vs 7.9% undergoing readmission (

 .866). Additionally, the Clavien-Dindo surgical complication grade rates in each group included 10.8% vs 8.2% with grade 1 complications, 16.9% vs 15.8% with grade 2 complications, 4.4% vs 3.9% with grade 3 complications, 3.6% vs 3.7% with grade 4 complications, and 0.8% vs 0.6% with grade 5 complications (

Widstrom B, Schulz M, Cervantes J, et al. The impact of frailty on surgical outcomes in gynecologic oncology surgery with ERAS protocols. Presented at:  2025 SGO Winter Meeting; January 30 – February 1, 2025; Whistler, British Columbia, Canada.

Frailty and advanced age negatively impact postoperative outcomes in major gynecologic oncology surgeries, even with ERAS protocols. A study of 1070 patients revealed that those aged 65 and older had higher modified frailty index (mFI) scores, longer hospital stays, and increased non-home discharge rates compared to younger patients. The study emphasized the importance of incorporating frailty evaluations into preoperative planning. Despite ERAS protocols, elderly patients experienced worse outcomes, highlighting the need for tailored perioperative management strategies to improve recovery and reduce complications in this vulnerable population.

Postoperative outcomes may be worse among patients with gynecologic cancers who are elderly or frail.

Retrospective Analysis Shows Frailty Leads to Worsened Outcomes After Surgery in Gynecologic Cancers

Synchronous vs metachronous metastatic status did not appear to impact survival outcomes with subsequent systemic therapy among patients with 

 V600E–mutant colorectal cancer (CRC) who underwent primary tumor resection, although this patient population was generally associated with poor prognosis, according to findings from a real-world, retrospective, observational study presented during the 

With a median follow-up of 43 months (95% CI, 29-61), 28 (57%) patients received chemotherapy, which included 14 with synchronous tumor locations and 14 with metachronous tumor locations. Data showed a median time to treatment change (TTC) of 11.5 months (95% CI, 8-17) for frontline therapy.

Investigators reported a median overall survival (OS) of 17 months (95% CI, 11-not available [NA]) across the overall population, 15 months (95% CI, 8-NA) for patients with synchronous tumors, and 18 months (95% CI, 11-NA) for those with metachronous tumors. Based on univariate analysis, factors that correlated with OS outcomes included metastasectomy (

 = .002), distant lymph node metastases (

 = .012), and Charlson Comorbidity Index (

Factors that correlated with OS per multivariate analysis included having a metastasectomy (

 = .02) and an ECOG performance status of 2 (

“Real-world data confirm that patients with 

-V600E mutant [metastatic] CRC have poor clinical outcomes,” Arwa Ahmed, of the Division of Medical Oncology in the Department of Medicine at the University of Ottawa, wrote with study coauthors.

 “Our analysis suggests that synchronous metastatic status did not seem to impact survival of [patients with] 

-V600E mutant [metastatic] CRC with resected primary tumor. Future analysis will assess the impact of mismatch repair [MMR] and microsatellite instability [MSI] on these findings.”

According to the study authors, approximately 20% of patients with CRC present with metastatic disease requiring management with systemic therapy,

 and the median OS of patients who receive systemic treatment exceeds 30 months.

 V600E-mutant disease confers a worse prognosis, investigators aimed to assess if metastatic status synchronous tumors or metachronous tumors could predict survival in patients with resected 

 V600E-mutated metastatic CRC before the time in which BRAF and EGFR inhibitors became more prominent in the field.

Investigators of this retrospective observational study assessed adult patients with advanced 

 V600E-mutant metastatic CRC who underwent treatment prior to March 31, 2021, at the Ottawa Hospital Cancer Centre. The main end points were OS and TTC, which served as a surrogate for progression-free survival.

Data collection involved the use of electronic medical records, with investigators analyzing information via RED CAP. Additionally, survival outcomes were determined via Kaplan Meier curves, and univariate analyses were conducted with proportional Cox modeling.

Overall, investigators identified 71 patients with 

 V600E-mutant metastatic CRC. Of these patients, 49 had their primary tumors resected.

The median age of patients with resected tumors was 69 years at diagnosis and 72 years at the time of metastatic disease diagnosis. Most patients were female (53%). Additionally, a majority of patients had an ECOG performance status of 1 (47%) followed by 0 (35%), 2 (12%), and 3 (6.1%).

Most patients in the analysis had a Charlston score of less than 5 (90%) and lived inside a metropolitan area (61%). Regarding histology, most patients had adenocarcinoma (69%) followed by mucinous adenocarcinoma (27%) and signet-ring cell carcinoma (4.1%). Most patients had poorly differentiated disease (48%) and stage IV tumors (41%). Data showed that 51% of patients received adjuvant chemotherapy and that most had MMR proficient tumors (39%).

Ahmed AA, Marginean H, Alghamdi A, et al. Impact of synchronous vs metachronous primary tumor resection on prognosis of BRAF-V600E mutant metastatic colorectal cancer (mCRC). 

 2025;43(suppl 4):304. doi:10.1200/JCO.2025.43.4_suppl.304

Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, et al. Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. 

 2013;49(6):1374-403. doi:10.1016/j.ejca.2012.12.027.

Hamers PAH, Elferink MAG, Stellato RK, et al. Informing metastatic colorectal cancer patients by quantifying multiple scenarios for survival time based on real-life data. 

 2021;148(2):296-306. doi:10.1002/ijc.33200.

Patients with BRAF V600E-mutant metastatic colorectal cancer (CRC) who underwent primary tumor resection showed no significant difference in survival outcomes between synchronous and metachronous metastatic statuses. The study, with a median follow-up of 43 months, reported a median overall survival (OS) of 17 months. Factors such as metastasectomy and ECOG performance status were correlated with OS. The study highlighted the poor prognosis of this patient population and suggested future analyses to explore the impact of mismatch repair and microsatellite instability on survival outcomes.

Patients with BRAF V600E-mutant metastatic colorectal cancer experience poor clinical outcomes, according to real-world data.
 

BRAF V600E-Mutant Metastatic CRC Confers Poor Survival Outcomes Regardless of Synchronous vs Metachronous Status

Overall survival (OS) outcomes were associated with baseline geriatric assessment (GA) vulnerabilities and quality of life (QOL) scores in patients with metastatic pancreatic adenocarcinoma (PDAC) treated with chemotherapy, according to data from the phase 2 ECOG-ACRIN EA2186 (GIANT) trial (NCT04233866) presented at the 

Data from the presentation revealed a correlation between GA/QOL and OS related to 4 significant factors through multivariate analysis: Instrumental Activities of Daily Living (IADL) scale (HR, 0.85; 

.029), and Functional Assessment of Cancer Therapy–Hepatobiliary (FACT-HEP; HR, 0.99; 

.026). Furthermore, white blood cell counts (HR, 0.29; 

.012) all significantly correlated with grade 3 toxicity incidence in a multi-variate analysis.

“The GIANT study was the first elderly-specific clinical trial [evaluating chemotherapy in vulnerable adults with metastatic pancreatic cancer], and it does show us what real outcomes vulnerable patients have with these treatments. Baseline [GA] and [QOL] scores clearly affect outcomes,” Efrat Dotan, MD, executive medical director of the Ann B. Barshinger Cancer Institute at Lancaster General Health of the University of Pennsylvania, stated in the presentation.

 “There is a strong correlation based on nutritional status, [IADL] function, depression, and every single one of the [QOL] measures. This is the first prospective study to evaluate [these measures] strongly. We hope that supportive care and management of these vulnerabilities will help improve outcomes of these patients and help us select who can derive benefit [from chemotherapy].”

Patients 70 years or older with untreated metastatic PDAC were selected to undergo a screening GA. Patients who were identified as vulnerable, or having mild to moderate GA abnormalities, were then given a complete geriatric and QOL assessment before being randomly assigned to receive either modified gemcitabine plus nab-paclitaxel or 5-flouorouracil (5FU) plus leucovorin and liposomal irinotecan every 2 weeks. Treatment continued until disease progression or intolerance; disease evaluation, a modified GA, and a QOL assessment were performed every 8 weeks.

Patients in the gemcitabine/nab-paclitaxel arm received intravenous gemcitabine and nab-paclitaxel separately over 30 minutes on day 1 of every 14-day cycle.

 Those in the alternative arm received intravenous fluorouracil over 46 hours starting day 1, as well as intravenous leucovorin over 90 to 120 minutes and intravenous liposomal irinotecan over 90 minutes on day 1 of every 14-day cycle.

For the gemcitabine/nab-paclitaxel (n = 88) and 5FU/liposomal irinotecan arms (n = 88) of the analysis, most patients had an ECOG performance status of 1 (64.8% vs 62.5%; 

.974). Additionally, screening vulnerability consisted of 36.4% and 36.4% for age, 28.4% and 36.4% for co-morbidities, 41.4% and 49.4% for cognition, and 20.7% and 18.4% for IADL in the respective arms. Furthermore, most patients had 1 vulnerability domain (60.9% vs 49.4%), with 6.9% and 11.5% of the respective arm having 3 or more domains.

Pretreatment BMI was 25.6 (range, 15.7-44.1) across cohorts, including 25.9 (range, 17.9-44.1) in the gemcitabine arm and 24.7 (range, 15.7-43.8) in the 5FU arm (

.046). Additionally, the median weight loss was 14.0 lbs (range, 0-95), including 14.5 lbs (0-62) in the gemcitabine arm and 12.6 lbs (range, 0-95) in the 5FU arm (

.812). For the QOL FACT-HEP score, with scores ranging from 0 to 180, the median patient score was 130.5 (range, 74-175), including 129.5 (range, 74-172) in the gemcitabine arm and 132.5 (range, 77-175) in the 5FU arm.

The primary end point of the study was OS. Key secondary end points included progression-free survival (PFS) and objective response rate (ORR). Furthermore, additional secondary end points included QOL and toxicities of interest for older adults.

The median OS in the gemcitabine arm was 4.7 months (95% CI, 4.1-7.4) vs 4.4 months (95% CI, 3.1-8.9) in the 5FU arm (HR, 1.12; 95% CI, 0.76-1.66; 

= .72). Additionally, median PFS was 3.0 months (95% CI, 1.9-4.3) and 2.4 months (95% CI, 1.9-3.7) in each respective arm (HR, 1.10; 95% CI, 0.79-1.53; 

.58). An additional OS analysis revealed that patients who received 4 or more weeks of treatment had a median OS of 8.0 months (95% CI, 5.9-10.0) across cohorts.

Dotan E, Catalano PJ, Lenchik L, et al. Effect of baseline geriatric and quality of life assessments on treatment outcomes in ECOG-ACRIN EA2186 (GIANT): A randomized phase II study of gemcitabine and nab-paclitaxel compared with 5-fluorouracil, leucovorin, and liposomal irinotecan in older patients with treatment-naïve metastatic pancreatic cancer. 

 2025;43(suppl 4):676. doi:10.1200/JCO.2025.43.4_suppl.676

Comparing two treatment combinations, gemcitabine and nab-paclitaxel with 5-fluorouracil, leucovorin, and liposomal irinotecan for older patients with pancreatic cancer that has spread. ClinicalTrials.gov. Updated December 30, 2024. Accessed January 24, 2025. https://tinyurl.com/233xark8

Baseline geriatric assessment (GA) vulnerabilities and quality of life (QOL) scores significantly impact overall survival (OS) in elderly patients with metastatic pancreatic adenocarcinoma (PDAC) undergoing chemotherapy. The phase 2 ECOG-ACRIN EA2186 (GIANT) trial highlighted correlations between GA/QOL and OS, emphasizing factors like nutrition, depression, and functional status. The study compared gemcitabine/nab-paclitaxel with 5-fluorouracil, leucovorin, and liposomal irinotecan, revealing similar OS and progression-free survival (PFS) outcomes. The findings underscore the importance of supportive care and management of vulnerabilities to improve treatment outcomes.

Overall survival data were linked with baseline geriatric assessment and QOL scores in patients with metastatic pancreatic ductal adenocarcinoma.

OS With Chemotherapy Is Linked With Baseline Geriatric, QOL Factors in Metastatic Pancreatic Cancer

A real-world retrospective cohort study showed that the median overall survival (OS) with frontline FOLFIRINOX (leucovorin calcium, fluorouracil, irinotecan hydrochloride, and oxaliplatin) in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) was numerically lower than the median OS that was previously shown with frontline NALIRIFOX (liposomal irinotecan, 5-fluorouracil [5-FU], leucovorin, and oxaliplatin) in this population in the phase 3 NAPOLI 3 trial (NCT04083235).

The real-world findings, which were presented at the 

2025 ASCO Gastrointestinal Cancers Symposium

, demonstrated that treatment with FOLFIRINOX in a trial-aligned cohort of patients who met the eligibility criteria for the NAPOLI 3 trial (n = 219) elicited a median OS of 9.1 months (95% CI, 7.8-10.9) compared with 11.1 months (95% CI, 10.0-12.1) with NALIRIFOX in NAPOLI 3. Furthermore, the median OS was 9.0 months (95% CI, 8.5-9.3) for all-comer patients with mPDAC treated with first-line FOLFIRINOX between January 1, 2014, and February 29, 2024 (n = 3271). An additional trial-aligned cohort of patients treated with modified FOLFIRINOX (mFOLFIRINOX; n = 154) experienced a median OS of 8.6 months (95% CI, 7.3-10.5).

“[The] NALIRIFOX regimen in the NAPOLI 3 trial showed numerically improved OS compared to [FOLFIRINOX], including [mFOLFIRINOX], in the real-world setting,” Paul Cockrum, PharmD, director of American Oncology HEOR at Ipsen Pharma, wrote with coauthors in the study.

 “Analyses adjusting for baseline characteristics are warranted and will provide further insights for the comparative efficacy of the 2 regimens.”

The real-world analysis used de-identified, patient-level, longitudinal data from the Flatiron Electronic Health Record collected between January 1, 2014, and February 29, 2024, to construct the 3 cohorts for the study. All adult patients identified with confirmed diagnoses of mPDAC on or after January 1, 2014, who were treated with first-line FOLFIRINOX encompassed the all-comer cohort of the analysis. A second, trial-aligned cohort included members of the all-comer cohort who met the NAPOLI 3 trial eligibility criteria.

A third cohort included a subgroup of patients in the second cohort who were treated with mFOLFIRINOX. mFOLFIRINOX in the third cohort was defined as an initial dose of 150 mg/m

 or lower of irinotecan or an initial cumulative dose of 2720 mg/m

 or lower of 5-FU during the first cycle. 

The median age on the index date of the trial-aligned cohort was 65.0 years (interquartile range [IQR], 59.0-71.0) compared with 64.0 years (IQR, 58.0-70.0) across all-comers and 65.5 years (IQR, 60.0-72.0) in the mFOLFIRINOX cohort. Furthermore, male patients accounted for 54.3%, 57.9%, and 55.8% of each cohort; 66.7%, 64.8%, and 64.9% of patients in these respective cohorts were White; and the respective median times from metastatic diagnosis to index date were 3.0 weeks (IQR, 2.0-4.6), 3.0 weeks (IQR, 1.9-4.7), and 3.0 weeks (IQR, 2.0-4.4).

All patients in the trial-aligned and mFOLFIRNOX cohorts, as well as 82.9% of those in the all-comer cohort, had a known ECOG performance status. Additionally, 53.0% of patients in the trial-aligned cohort, 34.7% of all-comers, and 50.0% of those in the mFOLFIRNOX cohort had an ECOG performance status of 0. Data showed that 7.8%, 11.3%, and 9.7% of patients in these respective cohorts were previously treated with surgery, and 10.5%, 13.8%, and 12.3% of these patients, respectively, were treated with prior chemotherapy.

The phase 3 NAPOLI 3 trial enrolled treatment-naive patients with mPDAC to receive either NALIRIFOX or nab-paclitaxel (Abraxane) plus gemcitabine.

 Patients in the NALIRIFOX arm received 50 mg/m

 of fluorouracil sequentially as a continuous intravenous infusion over 46 hours on days 1 and 15 of a 28-day cycle. Those in the standard-of-care cohort received 125 mg/m

of gemcitabine intravenously on days 1, 8, and 15 of a 28-day cycle.

In the NALIRIFOX arm, the median patient age was 64.0 years (range, 20-85), most patients were male (53%), and most patients were White (82%). Most patients on trial had an ECOG performance status of 1 (58%), 3 or more metastatic sites (39%), liver metastases (80%), and a baseline CA 19-9 level of 37 U/mL or higher (84%). Additionally, 6% of patients had undergone any previous anticancer therapy, including a surgical procedure (5%), chemotherapy (4%), and radiotherapy (3%). 

Cockrum P, Chang R, Yu L, et al. Overall survival (OS) of patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) treated with first-line (1L) FOLFIRINOX (FFX): bridging the gap between the NAPOLI 3 trial and real-world practice. 

2025;43(suppl 4):690. doi:10.1200/JCO.2025.43.4_suppl.690

Wainberg ZA, Melisi D, Macarulla T, et al. NALIRIFOX versus nab-paclitaxel and gemcitabine in treatment-naive patients with metastatic pancreatic ductal adenocarcinoma (NAPOLI 3): a randomised, open-label, phase 3 trial. 

 2023;402(10409):1272-1281. doi:10.1016/S0140-6736(23)01366-1

A retrospective cohort study compared the median overall survival (OS) of patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) treated with frontline FOLFIRINOX versus NALIRIFOX. The study found that NALIRIFOX demonstrated a numerically higher median OS than FOLFIRINOX in both trial-aligned and real-world settings. The analysis utilized de-identified patient data from the Flatiron Electronic Health Record, focusing on patients treated between 2014 and 2024. The study suggests further analyses adjusting for baseline characteristics to better understand the comparative efficacy of these regimens.

The median OS with frontline FOLFIRINOX was numerically lower than that seen with frontline NALIRIFOX in patients with metastatic PDAC.

First-Line FOLFIRINOX Fails to Improve OS vs First-Line NALIRIFOX in Metastatic PDAC

The addition of evorpacept (ALX148) to trastuzumab (Herceptin), paclitaxel, and ramucirumab (Cyramza; TRP) yielded more durable responses and favorable survival outcomes compared with TRP alone in patients with HER2-positive gastric or gastroesophageal junction (GEJ) cancer, particularly among those with confirmed HER2-positive disease by circulating tumor DNA (ctDNA) or fresh biopsy, according to results from the phase 2/3 ASPEN-06 trial (NCT05002127) presented at the 

Efficacy findings from the trial revealed that the confirmed objective response rate (ORR) was 41.3% (95% CI, 29.0%-54.4%) in the evorpacept combination arm vs 26.6% (95% CI, 16.3%-39.1%) with TRP alone. In the respective arms, 1.6% and 1.6% of patients achieved a complete response, and 39.7% and 25.0% achieved a partial response. Additionally, the median duration of response (DOR) was 15.7 months (95% CI, 7.7-not reached [NR]) with evorpacept plus TRP and 9.1 months (95% CI, 5.3-NR) with TRP alone.

The median progression-free survival (PFS) was 7.5 months (95% CI, 5.5-12.9) with the investigational regimen and 7.4 months (95% CI, 4.6-9.0) with TRP alone (HR, 0.77; 95% CI, 0.49-1.20). Additionally, HER2–positive expression confirmed via fresh biopsy conferred bolstered antitumor benefit, with an ORR of 59.1% (95% CI, 36.4%-79.3%) in the evorpacept arm vs 23.1% (95% CI, 9.0%-43.6%) in the TRP arm and a median DOR of 15.7 months (95%, 4.0-NR) vs 14.5 months (95% CI, 7.4-NR), respectively.

“[Evorpacept plus] TRP showed promising activity for patients with HER2–positive gastric and GEJ cancer with a response rate above 41.3% compared with 26.6% with TRP alone,” Kohei Shitara, MD, director of the Department of Gastrointestinal Oncology at National Cancer Center Hospital East in Kashiwa, Japan, said in the oral presentation.

 “The benefit of [evorpacept] was especially [observed] in patients with confirmed HER2–positive [expression] in fresh biopsy or ctDNA, in that its mode of action was able to enhance the activity of trastuzumab. This efficacy, as well as acceptable safety profile, support the further development of [evorpacept plus] TRP in patients with gastric and GEJ cancers.”

The intent-to-treat (ITT) population included patients with HER2–positive gastric or GEJ cancer who progressed on 2 or 3 previous lines of HER2-directed therapy (n = 127). Patients were randomly assigned 1:1 to receive either evorpacept in combination with TRP (n = 63) or TRP without evorpacept (n = 64).

Dosing in the evorpacept arm consisted of 30 mg/kg of intravenous evorpacept twice weekly, 6 mg/kg then 4 mg/kg of trastuzumab twice weekly, 8 mg/kg of ramucirumab twice weekly, and 80 mg/m

 of paclitaxel on days 1, 8, and 15 of a 28-day cycle. Dosing in the TRP only arm consisted of the same dosing without evorpacept.

The median ages of patients in the investigational and control arms were 64 years (range, 34-81) and 63 years (range, 31-86), respectively. Patients were primarily Asian (49.2% vs 48.4%), or White (30.2% vs 29.7%), and most patients had an ECOG performance status of 1 (52.4% vs 57.8%). Furthermore, the most common type of cancer in either arm was gastric (76.2% vs 68.8%), most patients received second-line therapy (77.8% vs 68.8%), and most patients had a HER2 status of IHC 3+ (82.5% vs 82.8%).

The phase 2 primary efficacy end point was ORR over an assumed historical control of 30% and over internal control.

 Secondary end points included DOR, PFS, and overall survival.

Among patients with HER2-positive disease confirmed via fresh biopsy or ctDNA positivity, the confirmed ORR was 48.9% (95% CI, 34.1%-63.9%) in the evorpacept arm vs 24.5% (95% CI, 13.3%-38.9%) in the TRP only arm. Additionally, the median DOR in this subgroup was 15.7 months (95% CI, 7.7-NR) vs 9.1 months (95% CI, 3.5-NR), respectively.

Among those with a HER2-positive fresh biopsy (n = 48), the median PFS was 9.5 months (95% CI, 5.4-19.5) with evorpacept plus TRP vs 7.1 months (95% CI, 2.9-9.1) with TRP alone (HR, 0.62; 95% CI, 0.28-1.36). Of those with a HER2-positive biopsy or ctDNA positivity (n = 96), the median PFS was 7.5 months (95% CI, 5.5-14.7) and 6.7 months (95% CI, 4.0-9.0) in each respective arm (HR, 0.64; 95% CI, 0.39-1.07).

The most common grade 3 treatment-emergent adverse events (TEAEs) in the investigational and control arms included decreased neutrophil counts (both 19.0%), anemia (22.2% vs 17.5%), neutropenia (17.5% vs 11.1%), and hypertension (9.5% vs 6.3%). There were 11 grade 5 TEAEs, 2 of which were related to treatment and included individual occurrences of esophageal perforation and pneumopathy.

Shitara K, Wainberg Z, Tabernero J, et al. Final analysis of the randomized phase 2 part of the ASPEN-06 study: A phase 2/3 study of evorpacept (ALX148), a CD47 myeloid checkpoint inhibitor, in patients with HER2–overexpressing gastric/gastroesophageal cancer (GC). 

 2025;43(suppl 4):332. doi:10.1200/JCO.2025.43.4_suppl.332

A study of evorpacept (ALX148) in patients with advanced HER2+ gastric cancer (ASPEN-06). ClinicalTrials.gov Updated September 19, 2024. Accessed January 23, 2025. https://tinyurl.com/yzf33xdk

Evorpacept, when added to trastuzumab, paclitaxel, and ramucirumab, demonstrated improved response rates and survival outcomes in HER2-positive gastric or gastroesophageal junction cancer compared to the standard regimen. The ASPEN-06 trial showed a higher objective response rate and longer duration of response with the evorpacept combination, particularly in patients with confirmed HER2-positive status via ctDNA or fresh biopsy. The investigational regimen also exhibited a favorable safety profile, supporting its further development. The trial included patients who had progressed on previous HER2-directed therapies, with dosing regimens specified for both study arms.

Evorpacept plus TRP produced superior ORR, DOR, and PFS outcomes vs TRP alone in patients with HER2-positive gastric or gastroesophageal junction cancer.

Evorpacept Plus TRP Generates Superior Antitumor Responses, Survival Outcomes in HER2+ Gastric/GEJ Cancer  

An ancillary analysis of the phase 3 NRG/RTOG 9804 (NCT00003857) and ECOG-ACRIN E5194 (NCT00002934) trials showed that tamoxifen (Soltamox) was associated with a reduced risk of 15-year ipsilateral breast recurrence (IBR) in patients with good-risk ductal carcinoma in situ (DCIS) treated without radiation therapy (RT). Data were presented at the 

2024 San Antonio Breast Cancer Symposium (SABCS)

Findings showed that treatment with tamoxifen elicited a statistically significant reduction in 15-year overall IBR by 11.4% (95% CI, 7.9%-15.5%) with tamoxifen vs 19.0% (95% CI, 15.3%-22.9%) without it (HR, 0.52; 95% CI, 0.35-0.77; 

 = .001). The 15-year risk of DCIS IBR was not significantly impacted by tamoxifen (5.5%) compared with those who did not receive it (8.1%; HR, 0.61; 95% CI, 0.34-1.08). For those with invasive IBR, there was a significant reduction with tamoxifen use (6.0%) compared with those who did not (11.5%; HR, 0.47; 95% CI, 0.27-0.80; 

 = .005). A non-significant reduction was also observed with contralateral breast events (CBE; 8.1%; HR, 0.61; 0.34-1.08; 

“Tamoxifen reduced the HR––or trended toward reducing the HR––across all subsets of patients, suggesting a broad benefit in the patients included in this analysis,” Jean Wright, MD, professor and chair of Radiation Oncology at the University of North Carolina, said in an oral presentation at SABCS. “We now have more thorough data to present to patients who are considering radiation therapy with respect to their endocrine therapy decision... Our data shows that it is important to evaluate the impact of endocrine therapy [for patients] who do not receive radiation therapy.”

Patients in the ancillary analysis of the NRG/RTOG and ECOG-ACRIN E5194 trials were included if they were considered to have “good risk” DCIS after breast-conserving surgery (BCS). “Good risk” was defined as a DCIS size of 2.5 cm or smaller, grade 1 or 2, and a margin greater than or equal to 3 mm. The use of tamoxifen was tracked in both trials, with both assessing tamoxifen alone on IBR in patients defined as “good risk” not receiving radiation therapy.

In the combined treatment analysis, 878 patients with “good risk” DCIS were included, 378 (43%) of whom received tamoxifen. Across both trials, the median age was 59 years (range, 28-88), with 80% of patients 50 years or older. Furthermore, 89% of patients were White.

Most patients had a DCIS margin width between 3 and 9 mm (n = 534, 61%) whereas only 19% had a margin width of 10 mm or greater (n = 169, 19%; 

 .0001). Additionally, 48% (n = 421) of patients had a pathologic size of 5 mm or smaller vs 35% (n = 310) between 6 and 10 mm, and 17% (n = 145) had a pathologic size greater than 10 mm (

Furthermore, most patients had DCIS nuclear grade 2 (n = 496, 56%), with a subset of patients initially classified as low or intermediate grade upgraded to grade 3 (n = 110, 13%) after subsequent pathology review was conducted in the ECOG-ACRIN E5194 study (

Subgroup analysis revealed a notably high benefit in patients with a margin width of 10 mm or greater, at an IBR of 5.4% (95% CI, 1.3%-14.1%) with tamoxifen vs 24.3% (95% CI, 15.0%-34.8%) without. Furthermore, patients with a pathologic size greater than 10 mm saw a notable benefit with tamoxifen, with an IBR of 14.4% (95% CI, 5.0%-28.4%) with the agent vs 29.7% (95% CI, 19.8%-40.2%) without it.

Wright JL. Impact of tamoxifen only after breast conservation surgery for “good risk” duct carcinoma in situ: results from the NRG oncology/RTOG 9804 and ECOG-ACRIN E5194 trials. Presented at: San Antonio Breast Cancer Symposium 2024; December 10-13, 2024; San Antonio, TX. Abstract GS2-02

Tamoxifen significantly reduces the risk of 15-year ipsilateral breast recurrence (IBR) in patients with good-risk ductal carcinoma in situ (DCIS) who do not receive radiation therapy. The analysis of phase 3 NRG/RTOG 9804 and ECOG-ACRIN E5194 trials demonstrated a reduction in overall IBR and invasive IBR with tamoxifen use. Subgroup analysis highlighted greater benefits in patients with larger margin widths and pathologic sizes. These findings provide valuable data for patients considering endocrine therapy without radiation, emphasizing the importance of evaluating tamoxifen's impact in this context.

Tamoxifen reduced the risk of invasive ipsilateral breast recurrence in patients with good-risk ductal carcinoma in situ.

Tamoxifen Reduces Ipsilateral Breast Recurrence in Good-Risk Ductal CIS

CAR T Cells in R/R Non-Hodgkin Lymphoma | 

Transposon-engineered BAFF ligand–based CAR T cells (LMY-920) induced responses with a tolerable safety profile among 3 patients with relapsed/refractory B-cell non-Hodgkin lymphoma (NHL), according to data from a phase 1 trial (NCT05312801) presented at the 

Data from the trial reveal that a single grade 1 cytokine release syndrome (CRS) event was reported among the 3 patients, with no immune effector-cell associated neurotoxicity syndrome (ICANS) incidence reported. Additionally, a complete response was observed in one patient with transformed follicular lymphoma. A mixed response, characterized by a decrease in FDG uptake and a decrease in size of all lesions, and stable disease were recorded among 2 other patients with mantle cell lymphoma (MCL). Furthermore, one grade 2 incident of COVID-19 infection was observed in a 55-year-old patient with MCL.

“In terms of safety, it was quite good. [There were] low rates of low-grade CRS among 3 patients, no ICANS was observed, the standard hematologic toxicity [one would] expect from the lymphodepleting regimen [was observed], and [there was] little other relevant toxicity,” Matthew Spear, MD, chief medical officer at Denovo Biopharma, said in a presentation of the study findings. “The efficacy was quite remarkable. [The first] patient [had] diffuse large B-cell lymphoma [and achieved] a complete response with resolution of all FDG avidity on PET scan.”

Investigators of the phase 1 study enrolled 3 patients with histologically confirmed B-cell NHL who had relapsed after 2 or more lines of therapy, were refractory to prior chemotherapy, or had progressive disease at 12 or fewer months following autologous stem cell transplantation (ASCT). All patients were assigned to receive 1 x 106 BAFF CAR T-cells/kg in a 3+3 dose escalation. Prior to treatment, patients underwent lymphodepletion with fludarabine at 30 mg/m2 and cyclophosphamide at 500 mg/m2 once daily for 3 days.

Among the patients enrolled, ages varied from 55 to 81 years, and they received 2 to 4 prior lines of therapy. The 2 patients with MCL had 

 mutations, one of whom had prior Bruton tyrosine kinase inhibitor therapy and ASCT.

The primary end point of the study was assessing the recommended phase 2 dose of LMY-920. Key secondary end points included toxicity, disease response, duration of response, progression-free survival, overall survival, and incidence of anti-LMY-920 antibodies.

“Overall, [this study is] somewhat interesting in that this is the first of its kind CAR T-cell therapy testing patients using a BAFF-ligand to target NHL. It is also a transposon engineer target system, which are still relatively uncommon in the CAR T-cell field,” Spear said in the presentation. “Safety and efficacy at this point are looking good. This could be extrapolated farther, and that is perhaps the most interesting aspect of the system.”

Key inclusion criteria of the study included having more than 2 weeks since prior radiation or systemic therapy at time of leukapheresis; an absence of central nervous system lymphoma; and adequate pulmonary, cardiac, liver and renal function.

Key exclusion criteria included having a history of allogenic hematopoietic stem cell transplantation, uncontrolled incurrent illness, and other active malignancies, active hepatitis B or C infection, and a history of autoimmune disease with requirement of immunosuppressive medication within 6 months of treatment initiation.

Clinical trials evaluating LMY-920 in B-cell related multiple myeloma and systemic lupus erythematosus are ongoing. Additionally, an allogenic version of the BAFF CAR-T cell inhibitor is being developed.

Caimi P, Spear MA, Liter J, Largaespada D, Webber BR, Moriarity BS. Phase 1 study of novel transposon-based BAFF CAR-T cells (LMY-920) for treatment of relapsed or refractory NHL. 

 Published online November 5, 2024. doi:10.1136/jitc-2024-SITC2024.0244

Transposon-engineered BAFF ligand–based CAR T cells (LMY-920) demonstrated promising efficacy and a tolerable safety profile in a phase 1 trial involving three patients with relapsed/refractory B-cell non-Hodgkin lymphoma. The trial reported a single grade 1 cytokine release syndrome event and no immune effector-cell associated neurotoxicity syndrome. One patient achieved a complete response, while others showed mixed responses or stable disease. The study aimed to determine the recommended phase 2 dose and assess secondary endpoints like toxicity and disease response. Further trials are ongoing for other B-cell related conditions.

Transposon-engineered BAFF ligand–based CAR T cells induced responses with a tolerable safety profile among 3 patients with relapsed/refractory B-cell NHL.

Transposon-Based BAFF CAR T Cells Show Early Efficacy, Safety in R/R Non-Hodgkin Lymphoma

Lenvatinib (Lenvima) plus pembrolizumab (Keytruda) demonstrated evidence of tumor responses in patients with stage III/IV or recurrent endometrial carcinoma regardless of mismatch repair–proficient (pMMR) status, histology, and prior adjuvant therapy, according to findings from an exploratory analysis of the phase 3 ENGOT-en9/LEAP-001 trial (NCT03884101) presented at the 

Topline results from the study reveal that as of the data cut-off date of October 2, 2023, 55.7% of patients treated with the lenvatinib combination achieved an objective response, including 50.6% of the pMMR population. Furthermore, the median duration of response (DOR) was 16.1 months (range, 1.0+-48.7+) and 23.2 months (1.0+-49.0+), for all-comers and the pMMR population, respectively.

“Clinically meaningful response rates were seen regardless of baseline characteristics including MMR status, histology, and prior adjuvant therapy,” Anna Dańska-Bidzińska, MD, a gynecologist from Warsaw Medical University in Warsaw, Poland, wrote in the presentation with study coinvestigators. “Patients who experienced a response to lenvatinib plus pembrolizumab, especially patients demonstrating a [complete response (CR)], had promising [progression-free survival (PFS)] and [overall survival (OS)].”

Additional data show a median time to objective response of 2.1 months (range, 1.3-26.4) and 2.1 months (1.2-26.4) among all-comers and pMMR patients, respectively. In each respective group, the median duration of treatment exposure for responders was 17.1 months (range, 1.5-48.4) and 19.8 months (1.5-51.5).

Furthermore, Kaplan-Meier PFS estimates by response in the pMMR population was 18.4 months (95% CI, 15.1-26.8) among all responders and 13.9 months (95% CI, 12.3-15.6) among patients with a partial response (PR), and for those with a CR it was not reached ([NR]; 95% CI, 29.1-NR). Among all-comers, it was 27.3 months (95% CI, 20.9-36.8), 15.1 months (95% CI, 12.9-19.4), and NR (95% CI, NR-NR) respectively.

Kaplan-Meier OS estimates by response in the pMMR population was 43.6 months (95% CI, 37.9- NR) among all responders, 37.6 months (95% CI, 30.9-NR) among patients with a PR, and NR (95% CI, 39.5-NR) for those with a CR. Among all-comers, it was NR (95% CI, 47.0-NR), 43.5 months (95% CI, 32.7-NR), and NR (95% CI, NR-NR), respectively.

The phase 3, multicenter, open-label study randomly assigned patients 1:1 with stage III to IV recurrent endometrial carcinoma to receive lenvatinib at 20 mg orally daily until disease progression plus pembrolizumab at 200 mg intravenously every 3 weeks until disease progression or 35 cycles. In the comparator arm, patients received paclitaxel at 175 mg/m

 intravenously plus carboplatin at area under the curve 6 intravenoulsy every 3 weeks for up to 7 cycles.

The study’s dual primary end points were PFS per RECIST v1.1 by blinded independent central review (BICR) and OS. Secondary end points included objective response rate (ORR) per RECIST v1.1 by BICR, safety, and health-related quality of life. Exploratory end points included DOR per RECIST v1.1 by BICR.

Among responders in the lenvatinib combination group, all experienced adverse events (AEs). Any-grade and grade 3 or higher treatment-related AE (TRAE) occurrence was 99.1% and 82.5%, respectively. Discontinuation of lenvatinib, pembrolizumab, or both due to TRAEs occurred in 27.8%, 18.8%, and 3.4% of patients, respectively. Notably, a single treatment-related grade 5 instance of pneumonitis occurred.

“This exploratory analysis from the ENGOT-en9/LEAP-001 study provides evidence of substantial antitumor activity with lenvatinib plus pembrolizumab,” Dańska-Bidzińska and study coinvestigators concluded in the presentation. “Responses among patients in the lenvatinib plus pembrolizumab arm were both deep and durable…AEs among patients who experienced a CR or PR were manageable with dose modifications and supportive care.”

Dańska-Bidzińska A, Makker V, Salutari V, et al. Characterization of tumor responses with lenvatinib plus pembrolizumab in the ENGOT-en9/LEAP-001 study. Presented at the European Society for Medical Oncology (ESMO) Congress 2024. September 13-17, 2024; Barcelona, Spain. Abstract 737P.

Lenvatinib combined with pembrolizumab showed significant tumor response in patients with stage III/IV or recurrent endometrial carcinoma, irrespective of mismatch repair status, histology, or prior therapy. The phase 3 ENGOT-en9/LEAP-001 trial reported a 55.7% objective response rate, with a median duration of response of 16.1 months. Progression-free survival and overall survival were notably promising, especially in complete responders. Adverse events were prevalent but manageable. The study's findings underscore the combination's substantial antitumor activity and potential as a treatment option for this patient population.

Lenvatinib plus pembrolizumab led to tumor responses regardless of mismatch repair–proficient status, histology, and prior adjuvant therapy.

Roman Fabbricatore