bluuebunny/crossref_metadata_2025 huggingface dataset:
Adagrasib (Ada) + cetuximab (Cetux) for
KRAS
G12C
-mutated metastatic colorectal cancer (mCRC): Longer follow-up analysis from KRYSTAL-1.
Authors: Yaeger Rona , Uboha Nataliya V. , Klempner Samuel J. , Bekaii-Saab Tanios S. , Sabari Joshua K. , Barve Minal A. , Saltzman Joel N. , Peguero Julio Antonio , Paulson Andrew Scott , Jänne Pasi A. , Pelster Meredith , Cruz-Correa Marcia , Kim Amy Min Kyung , Hu Nan , Ahmad Harris A. , Kopetz Scott
Published: January 2025

131

Background:
KRAS
G12C
mutations occur in 3%–4% of CRC cases and are associated with poor prognosis. In the phase 1/2 KRYSTAL-1 study (NCT03785249), at a median follow-up of 11.9 months (mo), Ada (irreversible inhibitor of
KRAS
G12C
) in combination with Cetux (anti-EGFR antibody) demonstrated promising clinical activity (objective response rate [ORR] of 34% per blinded independent central review [BICR] and 43% per investigator [INV]) and was well tolerated in patients (pts) with previously treated
KRAS
G12C
-mutated mCRC. Based on these findings, Ada + Cetux was granted accelerated approval in the United States for these pts. Here, we present longer-term follow-up analyses from this study.
Methods:
Adults with previously treated
KRAS
G12C
-mutated mCRC and ECOG performance status of 0 or 1 were treated with Ada (600 mg BID) in combination with Cetux (400 mg/m
2
followed by 250 mg/m
2
QW or 500 mg/m
2
Q2W) until disease progression, unacceptable toxicity, withdrawal of consent, or death, in separate phase 1 and phase 2 cohorts. Primary endpoints were safety (phase 1) and ORR per BICR (phase 2). Secondary endpoints were duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety (phase 2).
Results:
A total of 94 pts received Ada + Cetux. The median number of prior lines of systemic therapy was 3 (range, 1–9); 23 pts (24%) had received ≥ 4 prior lines of systemic therapy. The most frequent sites of metastases at baseline were the lung (71%) and liver (64%). At a median follow-up of 20.4 mo, ORR per INV was 43% (95% CI 32–53) and all were partial responses; median DOR was 5.9 (95% CI 5.5–7.6) mo. Disease control rate per INV was 86% (95% CI 78–92). Median PFS per INV was 6.9 (95% CI 5.9–7.4) mo; 6- and 12-mo PFS rates were 61% and 19%, respectively. Median OS was 16.0 (95% CI 13.3–18.8) mo; 6- and 12-mo OS rates were 88% and 66%, respectively. Any-grade treatment-related adverse events (TRAEs) were reported in 100% of pts, 28% of which were grade 3/4. TRAEs led to discontinuation in 10% of pts. Efficacy analyses by BICR, subgroup analyses, and additional safety results will be presented.
Conclusions:
In heavily pretreated pts with

KRAS
G12C

-mutated mCRC, Ada + Cetux continued to demonstrate clinically meaningful activity and tolerable safety with longer follow-up. These updated results are consistent with those from the primary analysis and constitute the longest duration of follow-up for dual
KRAS
G12C
/EGFR blockade in this setting. Efficacy of second-line Ada + Cetux vs chemotherapy in
KRAS
G12C
-mutated mCRC is being investigated in the phase 3 KRYSTAL-10 study (NCT04793958).
Clinical trial information: NCT03785249
.
Longitudinal ctDNA measurements for treatment response monitoring in patients with metastatic colorectal cancer undergoing systemic therapy: The ORCA trial.
Authors: van Steijn Denise , Laliotis George , Spickard Erik Anthony , Schraa Suzanna J. , van der Baan Frederieke H , Punt Cornelis J. A. , van den Broek Daan , Sharma Shruti , Sethi Himanshu , Liu Minetta C. , Jurdi Adham A , Kok Niels FM , Koopman Miriam , Vink Geraldine R , Fijneman Remond
Published: January 2025

220

Background:
Precise monitoring of treatment response may support and improve treatment decision-making in patients with metastatic colorectal cancer (mCRC). The PLCRC-ORCA study aimed to explore the clinical applicability of personalized ctDNA testing for treatment response monitoring in patients with mCRC.
Methods:
The prospective, observational ORCA study is a substudy of the Prospective Dutch ColoRectal Cancer cohort (PLCRC). After informed consent, blood samples were collected before initiating first line of treatment (baseline) and subsequently every 8-9 weeks during routine clinical care. ctDNA levels were analyzed using a clinically validated, personalized, tumor-informed 16-plex PCR NGS assay (Signatera™, Natera, Inc).
Results:
The majority of patients (45/49) had blood samples collected at both baseline and the first on-treatment time point. At baseline, 43/45 (95.6%) patients were ctDNA-positive with a median concentration of 63.5 mean tumor molecules per mL (MTM/mL; range 0.08 to 16,200). In a multivariate linear regression model including metastatic site at baseline and resection status of the primary tumor, ctDNA levels at baseline were lower in patients with metastatic disease limited to the lung (n = 4; p < 0.001) or peritoneum (n = 6; p = 0.002) compared to patients with liver-limited metastases. Moreover, primary tumor resection was independently associated with lower levels of ctDNA at baseline (p = 0.05). At the first measurement on-treatment, 13/45 patients (28.9%) were ctDNA-negative and 32/45 (71.1%) patients were ctDNA-positive with ctDNA levels ranging from 0.04 to 318 MTM/mL. Reduction in ctDNA levels relative to baseline was observed in 42/45 (85.7%) patients while two patients exhibited increased ctDNA levels. One patient had undetectable ctDNA levels at baseline and on treatment. Among the 30 patients with detectable but reduced ctDNA levels on treatment, the median ctDNA levels decreased 55-fold (95% CI: 26–600).
Conclusions:
The levels of ctDNA in patients with mCRC are influenced by the metastatic site and are lowest among patients with metastases limited to the lung and peritoneum. Our data suggest that clinical applications of ctDNA testing for treatment response monitoring should take the baseline ctDNA levels into account when interpreting ctDNA dynamics. Correlation of ctDNA status with radiological treatment response is underway and will be reported during the conference.
The use of liquid biopsy comprehensive genomic profiling to identify the molecular landscape of patients with metastatic colorectal cancer who are candidates for anti-EGFR rechallange therapy: Findings from the CAVE-2 GOIM trial.
Authors: Napolitano Stefania , Boscolo Bielo Luca , Martini Giulia , Pietrantonio Filippo , Pisconti Salvatore , Sartore-Bianchi Andrea , Blasi Livio , Tortora Giampaolo , Zaniboni Alberto , Pinto Carmine , Santabarbara Giuseppe , Avallone Antonio , Leo Silvana , Lotesoriere Claudio , Latiano Tiziana , Zampino M. Giulia , Martinelli Erika , Troiani Teresa , Ciardiello Fortunato , Ciardiello Davide
Published: January 2025

221

Background:
In the era of precision medicine, biomarker guided therapies are necessary for patients with chemorefractory metastatic colorectal cancer (mCRC). Circulating tumor DNA (ctDNA) comprehensive genomic profiling (CGP) may contribute to the development of more effective treatments.
Methods:
CAVE-2 GOIM trial (ClinicalTrials.gov ID: NCT05291156) is the first randomized phase II study to assess the efficacy of avelumab plus cetuximab compared to cetuximab alone as rechallenge strategy in pre-treated plasma ctDNA
RAS, BRAF
WT mCRC patients. Before being enrolled in the trial, patients were selected by baseline plasma ctDNA analysis by Foundation One Liquid CDx (F1L CDx) 324 genes to identify ctDNA
RAS/BRAF
WT cases.
Results:
As of July 31th 2024, 229 (out of approximately 310) patients have been screened. A total of 1562 pathogenic variants (PV) were detected, with
TP53
(86.0%),
APC
(84.2%),
DNMT3A
(30.5%) representing the most common altered genes. In these anti-EGFR pretreated patients different acquired mechanisms of resistance were observed. In particular, 72/229 (31.4%) patients had
RAS
or

BRAF
V600E

PV (102
KRAS
, 21
NRAS
and 8

BRAF
V600E

mutations, respectively). Additionally, in these 72 patients, multiple

RAS/BRAF
V600E

gene alterations (median of 1 PV, range 1-7) were observed in 41.6% cases.
MAPK, RTK
, and
PI3K/AKT/mTOR
PV were detected in 43.2%, 24.5% and 24.5% patients, respectively. Of note, the variant allele frequency of resistant PV was lower than other gene alterations, suggesting a high tumor heterogeneity as a consequence of the development and/or expansion of EGFR-inhibitor resistant cancer cell sub-clones. All patients were assessed for tumor mutational burden (TMB). Median TMB was 6 (IQR 4-10) mut/Mb, with 29.6% cases showing a TMB ≥10 mut/Mb. Finally, a total of 258 actionable genomic alterations were detected in 52,4% of patients according to the ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT). Eighty-one tier I alterations were detected in 32.3% patients, which included TMB high (29,7%),

BRAF
V600E

(3,5%),

KRAS
G12C

(6,5%), and
RET
fusions (0,4%).
Conclusions:
These findings support liquid biopsy-based GCP for individualized therapeutic choices in chemorefractory mCRC. Up-dated final analyses of the entire screened patient population of the CAVE-2 GOIM trial will be presented.
Clinical trial information: NCT05291156
.
TP53
Y220C mutations in colorectal carcinoma (CRC): A genomic landscape study.
Authors: Parekh Deevyashali , Ross Jeffrey S. , Srivastava Nimisha , Jamaspishvili Tamara , Basnet Alina
Published: January 2025

239

Background:
Inactivating genomic alteration (GA) of the TP53 tumor suppressor gene leads to inactivation of p53 protein and is currently the most frequently associated GA across all cancers. Colorectal cancer is a common and lethal subtype of cancer, in the top 5 for incidence, prevalence and cancer-related deaths worldwide. TP53 is the second most frequent GA identified in clinically advanced CRC. It has been postulated that GA in TP53 not only affects the molecular biology of malignant cells but also impacts the tumor microenvironment in CRC. This GA is currently untargetable by approved drugs however, recently a novel approach designed to revert to wild type functioning of TP53 inactivated by Y220C base substitution has gained significant clinical interest.
Methods:
67,301 cases of clinically advanced CRC underwent hybrid capture based comprehensive genomic profiling to assess all classes of GA. Cases were sequenced to a mean coverage depth of 650X with microsatellite instability (MSI) status and tumor mutation burden (TMB) determined from the sequencing data and PD-L1 expression measured by immunohistochemistry using the DAKO tumor proportional staining system (low positive set at 1-49% staining and high positive set at ≥50% staining).
Results:
422 (0.6%) of the CRC featured the
TP53
Y220C GA (Y220C+). When compared with the CRC that were
TP53
Y220C negative (Y220C-), the Y220C+ cases were of similar age, gender and number of GA per tumor. The Y220C- cases has significantly higher frequencies of MSI status (6.1% vs 2.2%; p=.0007) and TMB levels greater >10 mutations/Mb (8.7% vs 4.7%; p=.004). The Y220C+ featured lower frequencies of GA in
PIK3CA
(12.9% vs 18.6%; p=.002),
BRAF
(8.8% vs 10.1%; NS) and
PTEN
(7.4% vs 8.3%, NS) and a higher frequency of
ERBB2
amplification (5.0% vs 2.7%; p=.004). GA in
APC
,
KRAS
,
NRAS
,
BRCA2
,
EGFR
and
MET
were similar in both Y220C+ and Y220C- CRC. PD-L1 low expression was similarly infrequent (12.1% to 16.7% range) in both groups.
Conclusions:
The potentially targetable
TP53
Y220C short variant mutation is uncommon in clinically advanced CRC but is associated with unique genomic and biomarker characteristics. Further research might elucidate subpopulations or CRC subtypes with a greater frequency of this mutation who might benefit from a novel targeted therapy.

CRC
TP53
Y220C+(422 Cases)

CRC
TP53
Y220C-(66,879 Cases)

P Value

Gender
41.2% F/ 58.8% M
44.4% F/55.6% M
NS

Median Age (range)
62 (23-89+)
61 (8-89+)
NS

GA/tumor
6.1
6.5
NS

TP53
non-Y220C GA

16.1%
75.7%
<.0001

PIK3CA

12.9%
18.6%
.002

ERBB2

6.2% (5.0% amp)
5.1% (2.7% amp)
.004 (amp)

MSI High
2.2%
6.1%
.0007

TMB > 10 mut/Mb
4.7%
8.7%
.004

PD-L1 Low (1-49%TPS)/ PD-L1 High (>50% TPS)
16.7% (132 cases)/2.3%
12.1% (20,759 cases)/1.4%
NS
Prognostic implications and therapeutic response in GNAS-mutated colorectal adenocarcinoma: A retrospective cohort analysis.
Authors: Polani Faran , Swain Whitney Rose , Se Bobby , Randall Jamie , Cannon Timothy Lewis
Published: January 2025

244

Background:
GNAS, a key regulator of the G-protein signaling pathway, is frequently mutated in colorectal adenocarcinomas and other malignancies. Despite its role in tumorigenesis, GNAS mutations remain understudied, with no established targeted therapies. Exploring the impact of GNAS alterations on therapeutic response and outcomes in colorectal cancer (CRC) is crucial for developing effective treatment strategies.
Methods:
We reviewed 531 CRC cases from our institutional Molecular Tumor Board database, identifying 8 patients with GNAS mutations. The prevalence ofGNASmutations in our cohort was 1.5%, which aligns with reported rates of 2-5% in various CRC cohorts. Comprehensive clinicopathologic data, including tumor histology, staging, treatment outcomes, and response rates, were analyzed. A detailed evaluation was conducted on stage IV patients to assess their response, progression-free survival (PFS), and overall survival (OS) in comparison to historical stage IV CRC benchmarks.
Results:
The cohort included 8 patients with a median age of 61 years (range: 33-73 years), with balanced gender representation (50% male, 50% female). The racial distribution was 50% Black or African American, 25% White, and 12.5% Asian or Pacific Islander. The majority of patients (62.5%) were diagnosed at stage IV, with primary tumor sites predominantly in the sigmoid colon and cecum. Among the 5 stage IV patients, while no patients achieved a complete or partial response, 3 exhibited stable disease, resulting in a 60% disease control rate (including stable disease). The median progression-free survival (mPFS) was 9 months, reflecting the duration of disease control before progression, while the median overall survival (mOS) was 15 months. These outcomes are notably lower than historical benchmarks for stage IV CRC, where response rates typically range from 40-50% with mOS of 20-24 months, highlighting the potentially adverse prognostic impact of GNAS mutations.
Conclusions:
Patients with GNAS-mutated colorectal adenocarcinoma appear to represent a unique subset with poorer therapeutic outcomes, even when achieving stable disease. The observed disease control in the absence of objective responses underscores the complexity of treating GNAS-mutated tumors and highlights the urgent need for targeted therapies tailored to this molecular subtype. Further research into the biological mechanisms underlying GNAS mutations and their impact on CRC treatment resistance is warranted to improve patient outcomes.
Serial monitoring of circulating tumor DNA as a marker of response to immune checkpoint blockade in MSI-H gastrointestinal tumors.
Authors: Higbie Victoria , LaPelusa Michael Brian , Shah Preksha , Childress Merrida , Gasco Amaya , An Amy , Bent Alisha Heather , Kee Bryan K. , Kopetz Scott , Le Phat , Morris Van K. , Pant Shubham , Parseghian Christine , Shen John Paul Y.C. , Wolff Robert A. , Overman Michael J.
Published: January 2025

273

Background:
Microsatellite instability- high (MSI-H) tumors have high rates of response to immune checkpoint blockade (ICB) with prolonged durability of response. However, predicting who will have a response is difficult and there are limitations to radiographic evaluation of response. As circulating tumor DNA (ctDNA) offers a noninvasive approach to monitoring response and therapeutic efficacy, we sought to correlate ctDNA change with response to ICB in MSI-H gastrointestinal (GI) tumors.
Methods:
We conducted a retrospective study of MSI-H GI patients receiving ICB who underwent serial ctDNA sequencing. Tissue-informed ctDNA monitoring utilized comprehensive genomic profiling results of pre-treatment tumor tissue from a clinical trial assay based on FoundationOne CDx, a variant selection algorithm to exclude non-tumor variants, and multiplex PCR of up to 16 patient-specific variants to detect and quantify ctDNA. ctDNA changes were correlated with radiographic response.
Results:
A total of 20 patients with MSI-H tumors were evaluated including 17 colon, 2 small bowel, and 1 pancreatic. For 12 patients, it was the first exposure to ICB whereas 8 had previously progressed and were being rechallenged with ICB. Response was seen in 9 patients with a best overall response (BOR) of complete response (CR) in 4 and partial response (PR) in 5 while 5 showed stable disease (SD) and progression (PD) in 6. All patients had baseline ctDNA samples and at least 1 serial ctDNA after ICB initiation (median number of samples was 3). The mean time from baseline to first on-treatment sample was 30 days (range 13-64 days). 4 patients had undetectable ctDNA levels at baseline and remained undetectable on treatment. Of the 16 that had detectable ctDNA at baseline, 11 had a decrease in ctDNA levels at 1st on-treatment sample and 5 had an increase. The mean percent change of ctDNA at 1st on-treatment for those who had a response (CR + PR) was a 76% decrease while the mean percent change for those with SD was a 7% increase and for those with PD a 72% increase (p=0.05). Of the 6 patients with BOR of PD, 5 had an increase in ctDNA and 1 had undetectable levels at baseline. Of the 5 patients with BOR of SD, 2 had a decrease, 1 had an increase, and 2 were undetectable at baseline. Duration of SD did not correlate with initial ctDNA response.
Conclusions:
Early ctDNA change correlated with response in MSI-H GI tumors suggesting that serial ctDNA monitoring may provide early indication of response even prior to radiographic evaluation.
Pan-cancer microsatellite instability testing using a multiplex assay including long mononucleotide repeats.
Authors: Deming Dustin A. , Bacher Jeff , Vyazunova Irina , Albrecht Dawn , Buratti Madeleine , Ruelle Laura , Pasch Cheri , Snow Santina , Matkowskyj Kristina , Sappenfield Ryan , Halberg Richard
Published: January 2025

290

Background:
Microsatellite instability (MSI)/mismatch repair deficiency (dMMR) testing is a critical component of molecular testing for gastrointestinal cancers, among others. These analyses are important for the identification of patients with lynch syndrome and eligibility for treatment with immunotherapy. The current standard of care testing can identify most cases, however improved identification of MSI-H status is needed for non-colorectal cancers and for cancers with alterations outside MLH1/PMS2. A recent analysis indicated the potential for improved MSI-H detection with a multiplex assay including long mononucleotide repeats (LMR).
Methods:
Patients were selected based on MSI status, MMR gene variants, or the presence of a high tumor mutation burden and consented for participation as part of an IRB-approved protocol (UW15068). Formalin-fixed tissue slides were annotated by a pathologist for tumor and normal tissue. Slides were scraped and DNA isolated. The LMR MSI Analysis System (Promega, Madison, WI) and the OncoMate MSI Dx Analysis System (Promega) were performed on cancer DNA and normal tissue DNA when available per the manufacturer’s protocols. Instability of microsatellites and the MSI score were reported and correlated with clinical MMR immunohistochemistry (IHC) and commercial next-generation sequencing (NGS).
Results:
A total of 96 cancer samples were tested across 94 patients with over 20 different cancer types, including lung, colon, rectal, gynecologic, and esophagogastric cancers. Tumors from 20 patients were known to have microsatellite instability based on clinical NGS testing. 27 cases were found to be MSI-H based on the OncoMate assay. All of these cases were also MSI-H per the LMR assay and an additional 3 cases were found to be MSI-H using only the LMR assay. Of these 3 cases all were microsatellite stable by NGS. This number includes 1 colorectal and 2 esophagogastric cancer cases. One of the cases was found to have loss of MSH6 by IHC with an MSH6 mutation (MSH6 L1061fs). One of the cases was MMR intact by IHC, though did have a MSH6 exon 7 splice acceptor alteration that failed NGS calling quality control. The last case did not have MMR IHC performed, no detected MMR gene alterations, and a tumor mutation burden of 6.3 mutations per megabase.
Conclusions:
In this limited dataset, the utility of various methods for determination of MSI, dMMR, and TMB including PCR, IHC, and NGS were demonstrated using a patient cohort spanning solid tumor types. Promising results were observed with the LMR MSI Analysis System. These findings need to be further validated in a larger dataset and correlated with the response to immunotherapeutics.
Impact of synchronous vs metachronous primary tumor resection on prognosis of BRAF-V600E mutant metastatic colorectal cancer (mCRC).
Authors: Ahmed Arwa Isameldin , Philips William , Marginean Horia , Asmis Timothy R. , Vickers Michael M. , Lo Bryan , Goodwin Rachel Anne
Published: January 2025

304

Background:
The goal of this study is to evaluate if resection of the primary tumor in synchronous versus metachronous metastatic disease predicts survival of BRAF-V600E mCRC in the era prior to combination BRAF/EGFR inhibitors.
Methods:
This is a retrospective study of patients treated at the Ottawa Hospital Cancer Centre with BRAF-V600E mutation mCRC who did not receive combination BRAF/anti-EGFR therapy, diagnosed with colorectal cancer prior to March 31, 2021. Demographic, clinical, pathologic and cancer characteristics were abstracted from electronic medical records. Outcomes of interest included median duration of therapy and overall survival (OS).
Results:
71 patients were included with a median age of 70 years:, 37 (52%) were females, 49 (69%)had right-sided tumors and 19 (27%) were mismatch repair deficient (dMMR). The primary tumor was unresected in 22 (30%) and resected in 49 (70%), completely resected in 44 (62%), and partially resected in 5 (7%) patients. Overall, median OS was 12.9 months 95% CI (8.4, 19) with 17 months 95% CI (11, —) mOS in patients with resected primary and 6.3 95% CI (4.8, 15) months in patients with unresected primary, HR 2.48 95% CI (1.42, 4.32), p=0.001. In univariate analysis: signet ring cell (p=0.007), good performance status (p<0.001), distant lymph nodes (p<0.001), peritoneal metastasis (p=0.008), metasetectomy (p=0.002), Charlston Comorbidity Index (p=0.003) were significant prognostic factors. Synchronous versus metachronous primary tumour was not a significant prognostic factor.
Conclusions:
Real world data confirms that patients with BRAF-V600E mutant mCRC have poor clinical outcomes. Our analysis suggests that resection of the primary tumor did not seem to impact on survival of BRAF-V600E mutant mCRC patients. This suggests that prognosis is dictated by the systemic disease and not complications of the primary tumour itself.

Of the patients with unresected primary tumour (n=21), 6 were synchronous.

Metastatic status
Primary Tumor Resected
Primary Tumor unresected
Total

Synchronous
23
22
45

Metachronous
26
0
26

Total
49
22
71
Comprehensive analysis of Native Hawaiians and other Pacific Islanders with early-onset colorectal cancer.
Authors: Tanariyakul Manasawee , Acoba Jared David
Published: January 2025

31

Background:
Rates of early-onset colorectal cancers (EOCRC) are increasing in Hawaii across all racial groups. Although previous studies have shown that Native Hawaiians have a higher mortality rate compared to other racial groups, the adjustment for sociodemographic factors have been limited. Our objective is to perform a comprehensive analysis of outcomes among patients with EOCRC in a racially diverse population accounting for tumor factors and patient sociodemographics.
Methods:
Patients diagnosed with EOCRC between 2000 and 2022 in Hawaii. Overall survival of Asians, Whites, and Native Hawaiian or Other Pacific Islanders (NHOPI) were calculated using the Kaplan-Meier method. Cox proportional hazard regression models assessed survival predictors adjusting for clinical and sociodemographic factors.
Results:
We included 379 patients in the final analysis. NHOPI had higher prevalence of underinsured status and higher histopathology grade compared to Whites and Asians. In unadjusted Cox regression, NHOPI race, underinsured status, grade, and stage were prognostic for survival. After adjusting for confounders, underinsured status, grade, and stage remained prognostic, but race was not significantly associated with survival.
Conclusions:
This study concludes that while NHOPI patients with EOCRC demonstrated poorer survival outcomes compared to other racial groups, this disparity was largely explained by the large percentage of underinsured NHOPI patients. Addressing treatment disparities in underinsured or uninsured is essential to improve survival outcomes.

Univariate and multivariate analysis of survival.

Univariate
Multivariate

HR (95% CI)
p-value
HR (95% CI)
p-value

Insurance

Private Insurance
-
-
-
-

Underinsured & Uninsured
1.865 (1.331-2.612)
<0.001
1.843 (1.285-2.643)
<0.001

Race

White
-
-
-
-

Asian
1.179 (0.746-1.865)
0.48
0.936 (0.585-1.496)
0.781

NHOPI
2.005 (1.231-3.265)
0.005
1.051 (0.714-1.547)
0.8

Age at diagnosis
0.996 (0.967-1.025)
0.771
1.002 (0.971-1.034)
0.901

Histopathology grade

Grade 1&2
-
-
-
-

Grade 3&4
2.785 (1.958-3.963)
<0.001
2.278 (1.571-3.303)
<0.001

Stage

Stage 1
-
-
-
-

Stage 2
1.104 (0.49-2.487)
0.81
1.028 (0.451-2.342)
0.948

Stage 3
3.255 (1.666-6.359)
<0.001
2.873 (1.447-5.706)
0.003

Stage 4
14.851 (7.499-29.41)
<0.001
12.778 (6.283-25.987)
<0.001

Unknown
3.738 (1.506-9.275)
0.004
3.008 (1.189-7.608)
0.02

Sex

Male
-
-
-
-

Female
0.812 (0.587-1.123)
0.22
0.852 (0.609-1.194)
0.352

Microsatellite status

Stable
-
-

Unstable
0.481 (0.148-1.562)
0.204

Not done/Unknown
1.08 (0.737-1.582)
0.739

Time to Treatment

Less than 1 month
-
-
-
-

More than 1 month
1.221 (0.863-1.727)
0.26
1.123 (0.784-1.609)
0.527

Location of Tumors

Right
-
-
-
-

Left
1.239 (0.76-2.02)
0.391
1.466 (0.886-2.425)
0.137

Rectal
1.391 (0.86-2.249)
0.178
1.211 (0.738-1.986)
0.449

NHOPI: Native Hawaiians and Other Pacific Islanders; HR: Hazard Ratio; CI: Confidence Interval.
Incidence trends, demographic disparities, and survival outcomes of gastrointestinal malignancies in young adults: A focus on stomach and pancreatic cancers.
Authors: Modi Shivani , Dourado Claudia M , Rathod Malay
Published: January 2025

339

Background:
The incidence of gastrointestinal (GI) cancers has been rising among younger populations. While prior research has highlighted the increasing incidence of colorectal cancer (CRC) in adolescents and young adults (AYA), defined as individuals aged 15-39, there is less focus on non-CRC GI malignancies, such as stomach and pancreatic cancers, within this age group. This study aims to further elucidate the incidence, mortality, and demographic disparities in the AYA population for stomach and pancreatic cancers compared to older populations (>50 years old).
Methods:
Data was extracted from the SEER database spanning from 2000 to 2020. Demographic, clinical, and secondary cancer characteristics were summarized across the sample, stratified by cancer type. Overall survival (OS) and disease-specific survival (DSS) were analyzed using the Kaplan-Meier method, with comparisons performed via the log-rank test. Univariate and multivariate analyses were conducted to identify predictors of survival outcomes.
Results:
We identified 19,983 AYA patients diagnosed with non-CRC GI malignancies (including esophageal, stomach, small intestine, anal, hepatobiliary, and pancreatic cancers) between 2000 and 2020. Among these patients, the majority were male (58%), White (47%), and resided in metropolitan areas (90%). The median age at diagnosis was 38 years. Pancreatic cancer was 20% more common in the AYA group compared to those over 50 years old (12%), while stomach cancer was also more prevalent in the AYA group (27% vs. 17%). Survival outcomes were significantly better in the AYA group, with a median OS of 24 months compared to 9 months in the older population, and a median DSS of 52 months versus 13 months (p<0.001). Predictors of worse OS and DSS included male sex, African American race, income below $45,000/year, lack of surgical intervention, and delayed initiation of treatment.
Conclusions:
The incidence of stomach and pancreatic cancers is notably higher in the AYA population compared to older adults, with AYA patients demonstrating better overall and disease-specific survival outcomes. However, certain demographic factors, such as male sex, African American race, and lower income, are associated with worse survival, underscoring the need for targeted interventions to address these disparities. Early diagnosis and timely treatment are critical to improving outcomes in this younger population.
Nimotuzumab combined with chemotherapy plus immunotherapy as first-line treatment for advanced esophageal squamous cell carcinoma.
Authors: Han Quanli , Wang Qi , Cui Zhi , Deng Muhong , Ma Yue , Pang Fang
Published: January 2025

344

Background:
Esophageal squamous cell carcinoma (ESCC) is the primary type of esophageal cancer with poor prognosis in China. Chemotherapy plus immunotherapy as first-line standard treatment has limited benefit in advanced ESCC patients. Nimotuzumab, a humanized anti-EGFR antibody, exhibited favorable efficacy in advanced ESCC with good safety profile. We explored the efficacy and safety of nimotuzumab as first-line therapy for patients with advanced ESCC.
Methods:
In this retrospective study, patients were aged ≥ 18 years with histologically diagnosed advanced ESCC, ECOG of 0-3, given nimotuzumab (400 mg, Q3W) combined with chemotherapy (paclitaxel: 300-400mg and platinum: 400-500mg or tegafur: 60mg/bid, Q3W) plus immunotherapy (PD-(L)1: 200-240 mg, Q3W). They assigned into two groups: metastasis group and locally advanced group. The primary endpoint was overall survival (OS). Secondary endpoints were progression-free survival (PFS), objective response rate (ORR) and safety.
Results:
As of July 2024, 58 patients were enrolled (metastasis group: n=20, locally advanced group: n=38). The median age was 59.5 years (range: 44-80). The median follow-up was 32.59 months (95% CI: 23.0, 36.7). The ORR was 74.1% (95% CI: 0.6, 0.8). Survival analysis showed that the 1-year OS was 79.16% (95% CI: 64.5, 88.3) and 2-year OS was 57.38% (95% CI: 41.3, 70.5), 1-year PFS and 2-year PFS was 64.41% (95% CI: 49.4, 76.0) and 32.80% (95% CI: 19.7, 46.5), respectively. The median OS (mOS) was 31.01months, the median PFS (mPFS) was 17.84 months. Nimotuzumab plus chemotherapy and immunotherapy displayed a favorable survival outcomes both in metastasis group and locally advanced group with OS (1-year OS: 77.76% and 80.37%; 2-year OS: 62.21% and 55.91%) and PFS (1-year PFS: 53.46% and 69.99%; 2-year PFS: 25.06% and 36.66%), the mOS was not reached and 31.01 months, mPFS was 18.27 months and 16.69 months, respectively. There were 74.1% patients occurred grade 1-2 adverse events (AEs), and 13.8% occurred grade 3-5 AEs. The most common AEs included nausea (60.3%), myelosuppression (51.7%), leukopenia (41.4%), thrombocytopenia (29.3%), and neutropenia (24.1%). No serious treatment-related AEs or death recorded.
Conclusions:
This study demonstrated a favorable survival profile and acceptable toxicity in first-line treatment of advanced ESCC patients with nimotuzumab regimen. Further prospective study needed to certify in order to benefit more patients.
Association between adjuvant component of perioperative chemotherapy and survival outcomes in resected gastric cancer (GC).
Authors: Sreeram Aravind , Yeh Celine , Toumbacaris Nicolas , Capanu Marinela , Shimada Shoji , Gu Ping , Janjigian Yelena Y. , Ilson David Herman , Strong Vivian E. , Ku Geoffrey Yuyat
Published: January 2025

378

Background:
Perioperative chemotherapy is the standard of care for resectable GC but many patients do not proceed to or complete adjuvant chemotherapy (AC). It remains unclear whether AC following neoadjuvant chemotherapy (NAC) improves survival.
Methods:
Patients with GC who received NAC and underwent curative-intent gastrectomy from 2006-2022 were identified from an institutional database. Patients with mismatch repair-deficient/microsatellite instability-high tumors, GEJ tumors, M1 disease, neoadjuvant radiotherapy, total neoadjuvant intent treatment, incomplete NAC (<66% of planned cycles), and incomplete data were excluded. A lymph node ratio (LNR) risk cutoff was determined using maximally selected rank statistics. Kaplan-Meier analysis with log-rank tests were used to compare overall survival (OS) and disease-free survival (DFS). Cox proportional hazards regression models were used to identify independent predictors of OS and DFS. All analyses were performed in R statistical software.
Results:
Of 340 patients included, 264 (78%) received AC. Most common reasons for incomplete AC were postoperative complications (20%), poor performance status (16%), minimal pathologic response to NAC (14%), patient choice (14%), and NAC toxicity (9%). Median follow-up was 6.4 years. In the overall cohort, there was no significant difference in OS (median 10 vs. 8.3 years; p=0.14) or DFS (7.0 vs. 7.5 years; p=0.12) between AC and non-AC groups. In node-negative (ypN-) patients (n=170), there was no association between receipt of AC and OS (12 vs. 10 years; p=0.6) or DFS (12 vs. 10 years; p=0.8). On univariable analysis, lack of AC receipt was not associated with shorter OS (p=0.3) or DFS (p=0.4). In the node-positive (ypN+) cohort (n=170), AC receipt was associated with significantly longer DFS (4.8 vs. 2.7 years; p=0.031) but not OS (5.5 vs. 2.8 years; p=0.071). However, on multivariate analysis, AC only showed a non-significant trend towards longer DFS (HR 0.77 [95% CI 0.49-1.19]; p=0.20). High-risk patients based on LNR (LNR>0.0684; n=112) who received AC (n=87; 78%) had longer OS (p=0.033) and DFS (p=0.014). No such differences were observed in the low risk LNR subgroup (LNR<0.0684; n=227).
Conclusions:
Following NAC, AC was not associated with improved survival in patients with ypN- GC. The association between AC and survival in ypN+ GC remains unclear but LNR may be used to identify patients with ypN+ disease who may benefit from AC. These observations require prospective validation but may have implications for clinical care and future trial design.
Precision medicine and multidisciplinary care in gastric and gastroesophageal junction (G/GEJ) cancers: Challenges and practice gaps in community cancer clinics.
Authors: Strickland Matthew , Sidiropoulos Nikoletta , Vazquez Salgado Alexandra M. , Dewald Ilona , Carter Jeffrey D. , Heggen Cherilyn , McKinnon Kelly
Published: January 2025

385

Background:
The advent of biomarker-driven therapeutic strategies brings increasing precision to the treatment of G/GEJ cancer, placing biomarker testing at the forefront of patient management. The management of evolving logistics for testing and related decision-making can be challenging, especially in community clinics. As part of a multi-center quality improvement initiative, we evaluated current gaps in biomarker testing and practice patterns including multidisciplinary care for G/GEJ cancers in community oncology centers.
Methods:
Between 5/2024 and 8/2024, oncology team members (N = 60) from 5 US-based community oncology practices completed surveys assessing attitudes, knowledge, competence, practice patterns, challenges, and gaps regarding biomarker testing and multidisciplinary care in G/GEJ cancers.
Results:
Despite practice guidelines, many patients with G/GEJ cancer did not receive testing for recommended biomarkers. While most providers report that biomarkers HER2 (67%) and PD-L1 (62%) are routinely reported in pathology reports, less than half said testing for MSI/MMR, TMB, and BRAF p.V600E were reported, and less than 25% reported analysis of
NTRK1/2/3
,
RET
, CLDN.18.2, and
FGFR2
. Biomarkers most frequently requested if not included in the original pathology work-up were PD-L1 (48%), TMB (32%), and BRAF p.V600E (32%). Top challenges reported by providers in integrating biomarker testing into practice were
prioritizing testing for limited tissue
(38%),
determining whether to begin treatment prior to receipt of molecular testing results
(35%), and
optimizing specimen collection for molecular testing
(27%). Only 23% of providers reported feeling very or extremely comfortable (4/5 on 5-point Likert scale) with interpreting and applying biomarker testing results to treatment decision-making. Additional challenges included turnaround time for biomarker testing, uncertainty interpreting biomarker results, and inconsistent or infrequent multidisciplinary tumor boards. Indeed, some providers (12%) reported not participating in multidisciplinary tumor boards at all, while others reported participating weekly (16%), once or twice a month (21%), every other month (12%), or less frequently (23%). Providers believed
improving test ordering process
(47%),
decreasing testing turnaround time
(42%), and
standardizing panels for biomarker testing
(40%) would be most impactful in implementation of biomarker testing into clinical workflows.
Conclusions:
Although most oncology teams reported use of some form of biomarker testing in treatment of G/GEJ cancer, testing was inconsistent and not as comprehensive as currently recommended. These data will be leveraged to develop multidisciplinary action plans with participating clinics to improve biomarker testing for treatment selection in G/GEJ cancers.
Is treatment delivery of perioperative FLOT therapy in locally advanced OGA associated with recurrence-free survival?
Authors: Sugiyama Keiji , Kumar Sacheen , Chaudry M. Asif , Patel Nikhil , Patel Pranav , Cunningham David , Starling Naureen , Rao Sheela , Fribbens Charlotte Victoria , Chau Ian
Published: January 2025

391

Background:
Although perioperative FLOT therapy is a standard for locally advanced oesophagogastric adenocarcinoma (LA-OGA), completing all cycles, especially in the adjuvant chemotherapy (ACT) phase, is often challenging. This study examined the survival impact of treatment delivery in LA-OGA patients receiving FLOT therapy.
Methods:
423 patients who underwent radical resection at The Royal Marsden Hospital from 2017 to 2023 were screened. Major inclusion criteria included patients with LA-OGA (cT2≤ and Nany or Tany and N+), treated with FLOT (at least one cycle of neoadjuvant chemotherapy) and radical resection, with an ECOG performance status of 0–2. Patients were divided into therapy incomplete (Tx Incomp, less than eight cycles of FLOT) and therapy (Tx comp) groups. We performed univariate and multivariate analyses, as well as propensity score matching (PSM) analysis, to evaluate whether treatment delivery was associated with recurrence-free survival (RFS) and overall survival (OS). Kaplan-Meier curves and restricted mean survival times (RMST) up to 36 months were used to evaluate the survival time. The primary endpoint was the 3-year RFS and OS rate.
Results:
Of the screened patients, 210 met the inclusion criteria, with 79 (38%) in the Tx Incomp and 131 (62%) in the Tx comp group, and 50 (24%) patients did not receive ACT. The median follow-up time was 26.5 months. The 3-year RFS and OS rates in the Tx Incomp and Tx comp groups after PSM were 54% vs 59% (p=0.14) (RMST difference: 4.04 months, p=0.09) and 58% vs 78% (p=0.04) (RMST difference: 6.15 months, p<0.001), respectively. Multivariable analysis showed a significant impact of Tx comp on OS (HR 0.53, 95% CI: 0.32-0.88). In the subgroup of ypN-positive patients, a significant difference of RMST in OS rate was observed between those who started ACT and those who did not start ACT (RMST difference: 7.89 months, p=0.01), whereas no significant difference was found in the ypN-negative group (RMST difference: 0.65 months, p=0.75).
Conclusions:
This study suggests that completing FLOT therapy is associated with better OS. The impact of ACT might differ according to ypN stage.
First-line (1L) nivolumab (NIVO) plus chemotherapy (chemo) vs chemo in patients (pts) with advanced gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma (GC/GEJC/EAC): 5-year (y) follow-up of Chinese pts from CheckMate 649.
Authors: Shen Lin , Bai Yuxian , Lin Xiaoyan , Li Wei , Wang Jufeng , Zhang Xiaochun , Pan Hongming , Bai Chunmei , Bai Li , Cheng Ying , Zhang Jingdong , Zhong Haijun , Ba Yi , Hu Wenwei , Xu Rui-Hua , Guo Weijian , Qin Shukui , Hu Nan , McCraith Stephen , Liu Tianshu
Published: January 2025

392

Background:
NIVO + chemo demonstrated clinically meaningful survival benefit and an acceptable safety profile vs chemo in previously untreated Chinese pts with advanced GC/GEJC/EAC from CheckMate 649, consistent with the overall study population. 1L NIVO + chemo is currently approved for pts with advanced non-HER2+ GC/GEJC/EAC in China and other countries. We report 5-y results of NIVO + chemo vs chemo in Chinese pts from CheckMate 649.
Methods:
Adults with previously untreated, unresectable advanced or metastatic, non-HER2+ GC/GEJC/EAC were enrolled regardless of programmed death ligand 1 (PD-L1) expression. Randomized pts received NIVO + chemo, NIVO + ipilimumab, or chemo. Dual primary endpoints for NIVO + chemo vs chemo were overall survival (OS) and progression-free survival (PFS) by blinded independent central review (BICR) in pts with PD-L1 combined positive score (CPS) ≥ 5.
Results:
208 Chinese pts were randomized to NIVO + chemo or chemo. At 61-month (mo) minimum follow-up, NIVO + chemo continued to demonstrate OS and PFS benefit vs chemo in pts with PD-L1 CPS ≥ 5 and all randomized pts (Table). 5-y OS rate was 24% with NIVO + chemo vs 8% with chemo in pts with PD-L1 CPS ≥ 5 and 20% vs 7% in all randomized pts. Objective response rate (ORR) was higher and responses were more durable with NIVO + chemo vs chemo in pts with PD-L1 CPS ≥ 5 and all randomized pts (Table). No new safety signals were identified with longer follow-up.
Conclusions:
NIVO + chemo continued to demonstrate clinically meaningful long-term survival benefit, more durable responses, and acceptable safety vs chemo in Chinese pts after 5 y of follow-up, consistent with earlier reports and with the overall study population of pts with advanced non-HER2+ GC/GEJC/EAC. These results further support NIVO + chemo as a standard 1L treatment option for Chinese pts.
Clinical trial information: NCT02872116
.

Efficacy
PD-L1 CPS ≥ 5
All randomized

NIVO + chemo(n = 75)

Chemo
(n = 81)

NIVO + chemo
(n = 99)

Chemo
(n = 109)

mOS (95% CI), mo
15.5(11.9–21.1)
9.6(8.0–12.1)
14.3(11.5–16.5)
10.3(8.1–12.1)

HR (95% CI)
0.57 (0.40–0.82)
0.63 (0.46–0.85)

mPFS
a
(95% CI), mo

8.5(6.0–14.0)
4.3(4.1–6.5)
8.3(6.2–12.4)
5.6(4.2–6.8)

HR (95% CI)
0.51 (0.34–0.76)
0.57 (0.41–0.80)

ORR
a,b
(95% CI), %

68 (56–79)
48 (36–60)
66 (55–76)
45 (35–56)

mDOR
a,c
(95% CI), mo

12.5 (7.2–23.4)
6.9 (3.9–8.5)
12.5 (7.2–17.7)
5.6 (4.4–8.3)

a
Per BICR.

b
In pts with measurable target lesions at baseline.

c
In responders. DOR, duration of response; m, median.
Perioperative adebrelimab combined with chemotherapy for locally advanced resectable esophageal squamous cell carcinoma: A single-arm, open-label, multicenter study.
Authors: Dai Liang , Wu Yaya , Tian Ziqiang , Ma Jianqun , Zhao Changhong , Zhuang Bo , Chen Keneng
Published: January 2025

421

Background:
Neoadjuvant programmed cell death 1 (PD-1) inhibitors combined with chemotherapy have shown promising results in treating locally advanced esophageal squamous cell carcinoma (LA-ESCC). However, relatively little attention has been focused on programmed cell death ligand 1 (PD-L1) blockades. This study aims to evaluate the efficacy and safety of neoadjuvant adebrelimab (anti-PD-L1 antibody) plus chemotherapy followed by adjuvant adebrelimab for resectable LA-ESCC.
Methods:
In this single-arm, multicenter study, patients (pts) with newly diagnosed, locally advanced resectable thoracic ESCC (cT1b-2, N+ or cT3-4a, N0/+) received 2 cycles of neoadjuvant chemoimmunotherapy with adebrelimab (1200 mg), paclitaxel (175 mg/m
2
) and cisplatin (75 mg/m
2
) every 3 weeks, followed by esophagectomy and 16 doses of adebrelimab. The primary endpoints were safety and pathological complete response (pCR) rate. Secondary endpoints included surgery completion rate, R0 resection rate, major pathological response (MPR) rate, event-free survival (EFS) and disease-free survival (DFS). The trial was registered at Chinese Clinical Trial Registry, identifier: ChiCTR2300069179.
Results:
Between May 2023 and January 2024, 36 pts met inclusion criteria, with a median age of 65 years (range: 42-73). Of these, 66.7% (24/36) were classified as stage III-IVa. As of August 1, 2024, the median number of treatment cycles for all pts was 7 (interquartile range, 2-12). The neoadjuvant therapy completion rate was 91.7% (33/36). Thirty-two pts underwent minimally invasive esophagectomy, resulting in an overall surgical resection rate of 88.9% and an R0 resection rate of 90.6%. The pCR rate was 15.6% (5/32) and the MPR rate was 31.2% (10/32). The EFS and DFS outcomes were not mature. During the preoperative treatment period, 35 pts (97.2%) experienced any grade of treatment-related adverse events (TRAEs). Grade 3 or 4 TRAEs occurred in 7 pts (19.4%), and there were no grade 5 TRAEs. The most common grade 3/4 adverse events included neutropenia (11.1%), leukopenia (5.6%), diarrhea (5.6%) and hyponatremia (5.6%). Surgical complications of grade 3/4 were reported in 7 pts (21.9%), with anastomotic fistula (6.3%) being the most common. No perioperative deaths occurred.
Conclusions:
Neoadjuvant adebrelimab combined with chemotherapy and adjuvant adebrelimab demonstrated encouraging clinical efficacy and manageable safety in pts with LA-ESCC. Further study is warranted. Clinical trial information: ChiCTR2300069179.