Anti-epidermal Growth Factor Receptor Research Articles

Genome-wide DNA methylation status is a predictor of the efficacy of anti-EGFR antibodies in the second-line treatment of metastatic colorectal cancer: Translational research of the EPIC trial

PurposeThe genome-wide DNA methylation status (GWMS) predicts of therapeutic response to anti-epidermal growth factor receptor (EGFR) antibodies in treating metastatic colorectal cancer. We verified the significance of GWMS as a predictive factor for the efficacy of anti-EGFR antibodies in the second-line treatment of metastatic colorectal cancer.MethodsClinical data were obtained from a prospective trial database, and a genome-wide DNA methylation analysis was performed. GWMS was classified into high-methylated colorectal cancer (HMCC) and low-methylated colorectal cancer (LMCC). The patients were divided into subgroups according to the treatment arm (cetuximab plus irinotecan or irinotecan alone) and GWMS, and the clinical outcomes were compared between the subgroups.ResultsOf the 112 patients, 58 (51.8%) were in the cetuximab plus irinotecan arm, and 54 (48.2%) were in the irinotecan arm; 47 (42.0%) were in the HMCC, and 65 (58.0%) were in the LMCC group regarding GWMS. Compared with the LMCC group, the progression-free survival (PFS) was significantly shortened in the HMCC group in the cetuximab plus irinotecan arm (median 1.4 vs. 4.1 months, p = 0.001, hazard ratio = 2.56), whereas no significant differences were observed in the irinotecan arm. A multivariate analysis showed that GWMS was an independent predictor of PFS and overall survival (OS) in the cetuximab plus irinotecan arm (p = 0.002, p = 0.005, respectively), whereas GWMS did not contribute to either PFS or OS in the irinotecan arm.ConclusionsGWMS was a predictive factor for the efficacy of anti-EGFR antibodies in the second-line treatment of metastatic colorectal cancer.

Temporal dynamics of RAS mutations in circulating tumor DNA in metastatic colorectal cancer: clinical significance of mutation loss during treatment

PurposeIn metastatic colorectal cancer (mCRC), RAS mutation loss may occur during the standard-of-care regimen. In this study, we aimed to investigate the temporal dynamics of the RAS gene and its clinical significance.MethodsThis was a retrospective, single-center study that included 82 patients with tissue RAS-mutant (RAS-MT) mCRC who underwent circulating tumor DNA (ctDNA) RAS monitoring between January, 2013–April, 2023. Patients were analyzed for the rate of change over time to acquired RAS mutation loss (aRAS-ML) and clinicopathological factors. The prognostic relevance of mutation loss was assessed.ResultsaRAS-ML was detected in 33 (40.2%) patients, 32 of whom had a mutation loss in the first ctDNA RAS assay. Patients with a RAS mutation detected in the first assay had a median time of 8 months until the second ctDNA RAS assay, with 4.5% cases newly converted to aRAS-ML; no new conversions were detected at the third assay. The aRAS-ML group exhibited more single-organ metastases in the target organ during ctDNA measurement (aRAS-ML: 84.8% vs. RAS-MT: 59.2%, p = 0.02). Of the 33 patients with aRAS-ML, seven (21.2%) received anti-epidermal growth factor receptor (EGFR) therapy, with a median progression-free survival of 8 months. Multivariate analysis revealed that persistent ctDNA RAS mutation was an independent prognostic factor for overall survival (hazard ratio: 2.7, 95% confidence interval: 1.1–6.3, p = 0.02).ConclusionThe rate of ctDNA mutation loss in patients with RAS-MT mCRC decreases over time. Therefore, using a ctDNA RAS assay early in treatment will assist in challenging the use of EGFR regimens.

Rechallenge with Anti-EGFR Treatment in RAS/BRAF wt Metastatic Colorectal Cancer (mCRC) in Real Clinical Practice: Experience of the GITuD Group.

There are few third- and fourth-line therapeutic options for metastatic colorectal cancer (mCRC). In RAS/BRAF wild-type (wt) mCRC previously treated with anti-epidermal growth factor receptor (anti-EGFR) (first-line) and relapsed after a good response, retreatment with anti-EGFR (rechallenge) emerges as a therapeutic alternative. The aim was to show the activity and safety of anti-EGFR rechallenge in RAS/BRAF wt mCRC in real-world practice. A multicenter, retrospective, observational study (six hospitals of the Galician Group of Research in Digestive Tumors) was conducted. Adult patients with RAS/BRAF wt mCRC, evaluated by liquid biopsy, were included. They received anti-EGFR rechallenge (cetuximab, panitumumab) as monotherapy, or combined with chemotherapy, in third- or subsequent lines. Efficacy (overall response rate [ORR], disease control rate [DCR], overall survival [OS], and progression-free survival [PFS]) and safety (incidence of adverse events [AEs]) were assessed. Thirty-one patients were analyzed. Rechallenge (median 6 cycles [range 1-27], mainly cetuximab [80.7%]), started at a median anti-EGFR-free time of 18.4 months (1.7-37.5months) after two (38.7%) or more (61.3%) lines of treatment; 64.5% of patients received a full dose. Median OS and PFS were 9.8 months (95% confidence interval [CI] 8.2-11.4) and 2.6 months (95% CI 1.7-3.4), respectively. ORR was 10%, and DCR was 30%. The most common AEs were diarrhea (35.5%), anemia (29%), emesis (6.4%), and neutropenia (6.4%); <5% grade ≥3; 48.4% of patients reported anti-EGFR-related skin toxicity (grade >1). Hypomagnesemia required supplements in 29% of patients. Dose delays (≥3 days) and reduction (≥20%) were reported in 11 (35.5%) and seven patients (22.6%), respectively. In RAS/BRAF wt mCRC patients, an anti-EGFR rechallenge provides a feasible therapeutic option with clinical benefit (survival) and a manageable safety profile.

Targeting KRAS Oncogene for Patients With Colorectal Cancer: A New Step Toward Precision Medicine.

KRAS mutations are common driver oncogenes associated with the development of several solid tumors. KRAS oncogene has been considered a highly challenging target for drug development because of structural features, including the lack of deep groove on its catalytic unit. However, by leveraging cysteine residues, covalent KRAS inhibitors irreversibly trap KRAS G12C mutants in their inactive GDP-bound state. These agents have resulted in significant clinical responses among patients with KRAS G12C-mutant solid tumors, including patients with colorectal cancer (CRC). Other allele-specific inhibitors of KRAS oncogene and panKRAS and panRAS inhibitors are also currently being investigated in clinical trials. This review article overviews recent clinical progress on KRAS G12C targeting for the management of patients with KRAS G12C-mutant CRC and provides an update on other RAS targeting approaches. We also discuss the unique biological features of RAS-mutant CRC, which require the combination of KRAS inhibitors and anti-epidermal growth factor receptor therapy, and elaborate on resistance mechanisms and novel therapeutic avenues that may define future treatment paradigms of patients with RAS-mutant CRC.

Abstract PO1-19-11: Phase 3 Study of Tucatinib or Placebo in Combination With Trastuzumab and Pertuzumab as Maintenance Therapy for HER2+ Metastatic Breast Cancer (HER2CLIMB-05, Trial in Progress)

Abstract Background The current first-line (1L) standard of care (SOC) for human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (MBC) is trastuzumab (T) plus pertuzumab (P) and a taxane. Despite advances in 1L SOC, most patients progress during maintenance therapy with T+P. Tucatinib is a tyrosine kinase inhibitor (TKI) approved in combination with T and capecitabine for adults with HER2+ MBC, with and without brain metastases (BM). In HER2CLIMB, addition of tucatinib significantly prolonged progression-free survival (PFS) and overall survival (OS) in patients with HER2+ MBC and was well tolerated. Adding tucatinib also reduced the risk of disease progression or death in patients with untreated and/or active BM (Murthy et al. NEJM 2020, Curigliano et al. Ann Oncol 2022). HER2CLIMB-05 investigates whether adding tucatinib to 1L SOC as maintenance therapy will extend PFS while maintaining quality of life (QOL). Methods HER2CLIMB-05 (NCT05132582) is a phase 3, randomized, double-blind study evaluating tucatinib plus T+P as maintenance therapy for HER2+ MBC. Approximately 650 patients will be enrolled. Eligible patients will have advanced HER2+ disease, no progression on 4–8 cycles of prior 1L SOC, Eastern Cooperative Oncology Group Performance Status of 0 or 1, and no or asymptomatic BM. Exclusion criteria include prior treatment with anti-HER2 and/or anti-epidermal growth factor receptor TKI (prior SOC for early BC is permitted) or inability to undergo contrast magnetic resonance imaging of the brain. Patients will be randomized 1:1 to receive either tucatinib or placebo twice daily, with T+P once every 21 days. Patients with hormone receptor-positive disease may receive endocrine therapy. The primary endpoint is investigator-assessed PFS. Secondary endpoints include OS, time to deterioration of health-related QOL, central nervous system PFS, safety, and pharmacokinetic (PK) parameters. PFS and OS will be compared using a two-sided stratified log-rank test between treatment groups. Time-to-event endpoints will be summarized using the Kaplan–Meier method. PK and safety data will be summarized using descriptive statistics. Enrollment is ongoing in Austria, Chile, Greece, Italy, Japan, Poland, Portugal, Spain, the US, and several other European, APAC, and LATAM countries. This abstract was previously presented at ESMO-BC 2022, FPN (Final Publication Number): 415, by Veronique Dieras (reused with permission). Citation Format: Erika Hamilton, Junji Tsurutani, Giuseppe Curigliano, Miguel Martín, Ciara O'Sullivan, Joo Hyuk Sohn, Konstantinos Tryfonidis, Libero Santarpia, Shan Yang, Véronique Diéras. Phase 3 Study of Tucatinib or Placebo in Combination With Trastuzumab and Pertuzumab as Maintenance Therapy for HER2+ Metastatic Breast Cancer (HER2CLIMB-05, Trial in Progress) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-19-11.

Real-World Evidence of FOLFIRI Combined with Anti-Angiogenesis Inhibitors or Anti-EGFR Antibodies for Patients with Early Recurrence Colorectal Cancer After Adjuvant FOLFOX/CAPOX Therapy: A Japanese Claims Database Study.

Oxaliplatin-containing adjuvant regimens (folinic acid, fluorouracil, and oxaliplatin/capecitabine and oxaliplatin [FOLFOX/CAPOX]) are used after curative resection of colorectal cancer (CRC). However, real-world evidence regarding treatment sequences and outcomes in patients with early recurrence CRC after adjuvant chemotherapy is limited. We aimed to describe the patient characteristics, treatment sequence, and overall duration of second-line (2L) therapy in patients with early recurrence CRC who received adjuvant chemotherapy (FOLFOX/CAPOX) followed by folinic acid, fluorouracil, and irinotecan (FOLFIRI) + anti-angiogenesis drugs (AA) or FOLFIRI + anti-epidermal growth factor receptor (EGFR) antibodies. This retrospective study analyzed Japanese administrative data from November 2014 to March 2023 of adult patients who underwent CRC resection surgery, started FOLFOX/CAPOX ≤3 months (mo) after surgery, and had early CRC recurrence. Early recurrence was defined as initiation of FOLFIRI+AA or FOLFIRI+anti-EGFR antibodies as 2L therapy, ≤12 mo of discontinuing adjuvant chemotherapy. Patient characteristics, treatment sequence, median time to treatment discontinuation (mTTD), i.e., duration between the start and end dates of 2L therapy (Kaplan-Meier method), and factors associated with 2L time to treatment discontinuation constituted the study outcomes (Cox regression model). Subgroup analyses were performed for timing of early CRC recurrence (≤6 mo and 6-12 mo) and tumor sidedness. Among the 832 selected patients (median age [minimum-maximum] 67 (24-86) years, 56.4% male), CAPOX (71.3%) was more commonly used than FOLFOX (28.7%) as adjuvant therapy. FOLFIRI+AA (72.5%) was used more commonly than FOLFIRI+anti-EGFR antibodies (27.5%) in 2L. AA and anti-EGFR antibodies groups had similar mTTD: 6.2 mo (95% confidence interval 5.8, 6.9) and 6.1 mo (95% confidence interval 5.2, 7.4). Age ≥70 years showed significant association with shorter 2L treatment duration (hazard ratio 1.2, 95% confidence interval 1.0, 1.4; p = 0.03). The AA cohort's mTTD was numerically shorter in the ≤6 mo recurrence subgroup compared with the 6-12 mo recurrence subgroup (6.1 mo vs 8.1 mo); the anti-EGFR antibodies cohort had similar mTTD (5.8 mo vs 6.2 mo). The AA and anti-EGFR antibodies cohorts also had similar mTTD in the left-sided CRC subgroup (6.5 mo vs 6.2 mo), but not in the right-sided subgroup (5.6 mo vs 3.9 mo). This is the first administrative data-based real-world evidence on treatment sequence and outcomes for patients with early recurrence CRC treated with FOLFIRI+AAs or FOLFIRI+ anti-EGFR antibodies after adjuvant FOLFOX/CAPOX therapy in Japan. Both regimens had similar TTD, but relapse timing and tumor sidedness may influence their efficacy.

Monitoring ctDNA RAS Mutational Status in Metastatic Colorectal Cancer: A Trial Protocol of RAS-trace and RAS-trace-2 Studies.

Spatial and temporal heterogeneities of RAS and other molecular genes should be considered in the treatment of metastatic colorectal cancer (mCRC) treated with anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs); acquired RAS mutation is sometimes observed at disease progression of treatment with the anti-EGFR mAb. At the same time, discrepancy of RAS status from tissues and circulating tumor DNA (ctDNA) in the same patient is sometimes observed. Based on this, we commenced two observational studies to clarify these heterogeneities of RAS and BRAF in mCRC, using next generation sequencing from liquid biopsy. RAS-trace study is an observational study to monitor ctDNA RAS/BRAF/PIK3CA status every 4-12 weeks using the Plasma-SeqSensei™ CRC RUO Kit (Sysmex Inostics GmbH) in mCRC with RAS/BRAF wild-type (wt) on tumor tissue. The primary endpoint was the time to the acquired RAS mutations. A total of 42 patients has been accrued. RAS-trace-2 study is also an observational study aimed at comparing the efficacy of the anti-EGFR mAb in ctDNA RAS/BRAF wt with ctDNA RAS or BRAF mutant mCRC patients, whose RAS/BRAF are wt in tumor tissue. The primary endpoint was progression-free survival in patients with ctDNA RAS/BRAF wt and RAS or BRAF mutant. A total of 240 patients will be accrued over 2 years. These trials will help us understanding the clinical significance of spatial and temporal heterogeneities of RAS, BRAF and other genes, while optimizing the anti-EGFR mAb treatment strategies in mCRC.

Chinese expert consensus on maintenance treatment with anti-EGFR monoclonal antibody for RAS wild-type metastatic colorectal cancer (2024 edition)

For patients with metastatic colorectal cancer (mCRC) who achieve disease control during first-line standard therapy, post-induction strategies should emphasize on quality of life improvement while maintaining disease control. Chemotherapy combined with anti-epidermal growth factor receptor (EGFR) monoclonal antibody is the standard first-line treatment for RAS wild-type mCRC patients. After anti-EGFR-based first-line induction therapy achieves at least stable disease, anti-EGFR-based maintenance treatment could maintain disease control while keeping a good safety profile. Based on research evidence and clinical practice, the Chinese expert consensus on anti-EGFR-based maintenance strategy for RAS wild-type mCRC aims to futher clarify the treatment timing, regimen options, adverse reaction management and follow-up strategy, providing standardized guidance to maximize the clinical benefit in RAS wild-type mCRC.

Cetuximab for the treatment of cutaneous squamous-cell carcinoma in kidney transplant recipients – A retrospective cohort study

Background: Kidney transplant recipients are at high risk of developing cutaneous squamous cell carcinoma (cSCC) due to prolonged immunosuppression. While most lesions can be managed with local therapy, a subset of patients develop advanced cSCC that is unresectable, recurrent or metastatic. Immune check point inhibitors (ICI) and chemotherapy may jeopardize the transplanted kidney. Cetuximab, an anti-epidermal growth factor receptor antibody, has demonstrated efficacy in advanced cSCC, but data regarding efficacy and safety in solid organ transplant recipients is lacking. Methods: This retrospective cohort study analyzed kidney transplant recipients diagnosed with locally advanced or metastatic cSCC who were treated with cetuximab. Results: Seventeen patients were included in the analysis. The median age was 57 years at the time of kidney transplantation and 62 years at diagnosis of index lesion. Cetuximab was administered with radiation therapy as a radiosensitizer in 58.8% of patients, as monotherapy in 17.6% of patients, and with chemotherapy in 23.5% of patients. Importantly, no detrimental impacts on kidney graft function were observed. The main toxicites were grade 1–2 skin reactions and electrolyte imbalance. Of the 10 patients receiving cetuximab with chemoradiotherapy as a radiosesnitizer, 2 were treated with definitive intent, 7 of them in the adjuvantsetting, and 1 for palliative pourpose. Over half of these patients achieved a complete response (37.29%) or no recurrence after resection (23.5%). Median time to disease progression was 10 months. Conclusions: This novel study suggests cetuximab has a reasonable safety profile and potential efficacy in kidney transplant recipients with advanced cSCC, without impairing allograft function. Further prospective research with larger sample sizes is warranted to confirm these findings. Cetuximab should be investigated as a systemic treatment option for this high-risk population of solid organ transplant recipientss with recurrent, metastatic, or unresectable cSCC.

Anti-EGFR Rechallenge in Patients With Refractory ctDNA RAS/BRAF wt Metastatic Colorectal Cancer

The available evidence regarding anti-epidermal growth factor receptor (EGFR) inhibitor rechallenge in patients with refractory circulating tumor DNA (ctDNA) RAS/BRAF wild-type (wt) metastatic colorectal cancer (mCRC) is derived from small retrospective and prospective studies. To evaluate the efficacy of anti-EGFR rechallenge in patients with refractory ctDNA RAS/BRAF wt mCRC. This nonrandomized controlled trial used a pooled analysis of individual patient data from patients with RAS/BRAF wt ctDNA mCRC enrolled in 4 Italian trials (CAVE, VELO, CRICKET, and CHRONOS) and treated with anti-EGFR rechallenge between 2015 and 2022 (median [IQR] follow-up, 28.1 [25.8-35.0] months). Patients received anti-EGFR rechallenge therapy, including cetuximab plus avelumab, trifluridine-tipiracil plus panitumumab, irinotecan plus cetuximab, or panitumumab monotherapy. Overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and disease control rate (DCR) were calculated. Exploratory subgroup analysis evaluating several clinical variables was performed. Safety was reported. Overall, 114 patients with RAS/BRAF wt ctDNA mCRC (median [IQR] age, 61 [29-88] years; 66 men [57.9%]) who received anti-EGFR rechallenge as experimental therapy (48 received cetuximab plus avelumab, 26 received trifluridine-tipiracil plus panitumumab, 13 received irinotecan plus cetuximab, and 27 received panitumumab monotherapy) were included in the current analysis. Eighty-three patients (72.8%) had received 2 previous lines of therapy, and 31 patients (27.2%) had received 3 or more previous lines of therapy. The ORR was 17.5% (20 patients), and the DCR was 72.3% (82 patients). The median PFS was 4.0 months (95% CI, 3.2-4.7 months), and the median OS was 13.1 months (95% CI, 9.5-16.7 months). The subgroup of patients without liver involvement had better clinical outcomes. The median PFS was 5.7 months (95% CI, 4.8-6.7 months) in patients without liver metastasis compared with 3.6 months (95% CI, 3.3-3.9 months) in patients with liver metastasis (hazard ratio, 0.56; 95% CI, 0.37-0.83; P = .004). The median OS was 17.7 months (95% CI, 13-22.4 months) in patients without liver metastasis compared with 11.5 months (95% CI, 9.3-13.9 months) in patients with liver metastasis (hazard ratio, 0.63; 95% CI, 0.41-0.97; P = .04). Treatments showed manageable toxic effects. These findings suggest that anti-EGFR rechallenge therapy has promising antitumor activity in patients with refractory ctDNA RAS/BRAF wt mCRC. Within the limitation of a subgroup analysis, the absence of liver metastases was associated with significant improved survival. ClinicalTrials.gov Identifiers: NCT02296203; NCT04561336; NCT03227926; NCT05468892.

First Line Chemotherapy in Metastatic Colorectal Cancers: A Review

Colorectal cancer (CRC) is a common malignancy detected. Approximately, 22% of CRCs are metastatic at initial diagnosis, and about 70% of patients will eventually develop metastatic relapse. Metastatic colorectal cancer is a disease with poor prognosis whose treatment is always palliative chemotherapy. Today, thanks to the knowledge of molecular biology and the discoveries of new pathways, we have managed to increase survival to around 40 months which can increase thanks to the use of surgery and locoregional treatments. The choice of chemotherapy in these patients therefore depends on the characteristics of the molecular profile and includes, in fit patients, chemotherapy with the addition of targeted therapies. In this article, we examine the most recent data from randomized clinical trials supporting the use of chemotherapy triplets or doublets as well as the addition of bevacizumab or anti-epidermal growth factor receptor (EGFR) agents.

The Safety and Effectiveness of Bevacizumab in Metastatic Colorectal Cancer With Unresectable Metastases: A Real-Life Study From the South of Morocco.

Background Colorectal cancer constitutes a significant public health challenge, despite remarkable strides made in the last two decades, particularly in the medical management of metastatic stages. Notable progress has been achieved through targeted therapies such as anti-epidermal growth factor receptors or anti-angiogenic antibodies, as well as advancements in surgical approaches for hepatic metastases. This study seeks to assess the efficacy and safety of bevacizumab plus chemotherapy in individuals with metastatic colorectal cancer. Methodology This is an observational, cross-sectional, retrospective study of all patients who were followed up for metastatic colorectal cancer with unresectable metastases and were treated with bevacizumab in combination with standard chemotherapy from January 2010 until December 2019 in the medical oncology department of the Centre Hospitalier Universitaire (CHU) Souss-Massa of Agadir. Results Of the total 162 cases, 117 (72%) had metastatic disease, and 45 (28%) progressed to metastatic disease after initial treatment. The median age of the patients was 55 years (range = 23-79 years) with a sex ratio of 1.1 (M/F). The tumor was located in the left colon in 135 (83.3%)patients. The results represented adenocarcinoma in 137 (84.6)cases and mucinous subtype in 23 (14.19) cases. The three most common sites of metastasis were the liver (99, 61.1), peritoneum (67, 41.3), and lung (33, 20.3). In the first line, allpatients received bi-chemotherapy plus bevacizumab, i.e., fluorouracil, oxaliplatin, and leucovorin in 34 (20.9%) patients; capecitabine plus oxaliplatin in 88 (54.3%) patients; leucovorin, fluorouracil, and irinotecan in 17 (10.4%) patients; andcapecitabine plusirinotecan in 23 (14.1%) patients. Response after first-line treatment was progression in 74 (45.7) cases, stability in 42 (25.9) cases, partial response in 35(21.6) cases, and complete response in 11 (6.8) cases. Nine (6%) patients were able to benefit from surgical resection of metastatic lesions. Overall, 77 (47%)patients received second-line chemotherapy, i.e., 5-FU with irinotecan in 40 (51.8%)cases or with oxaliplatin in 30(38.8%) cases. Two patients developed undesirable side effects under bevacizumab (hypertension). The median progression-free survival and median overall survival of the study cohort were 9 months and 14 months, respectively. Nevertheless, patients who underwent primary tumor resection (p = 0.048), those with right‑sided tumors (p = 0.022), those who received a higher number of treatment cycles (p = 0.020), and those who received maintenance treatment (p = 0.001) had a longer median overall survival. Conclusions Chemotherapy combination with bevacizumab is considered as the cornerstone of metastatic colorectal cancer treatment in our region. With the new healthcare and social security systems, easier access to expensive treatments and molecular pathology tests is currently available. It is important to highlight that real-world data can offer valuable insights into the daily clinical practice of medical oncology.

Abstract 3264: Characterization of EGFR ectodomain mutation in acquired resistance to cetuximab in colorectal cancer

Abstract Colorectal cancer (CRC) remains the second leading cause of cancer-related deaths in the United States (US). Individuals with surgically unresectable stage four CRC have a five-year overall survival rate of 13%. Targeting of the receptor tyrosine kinase (RTK), EGF receptor (EGFR) with therapeutic monoclonal antibodies (cetuximab, panitumumab) is approved for use in wild-type (WT) KRAS/NRAS/BRAF (RAS/RAF) advanced CRC. However, these antibodies as a single agent have response rates of 12-17% and expected progression-free survivals of only 3-4 months. Accordingly, resistance may be present at the outset (de novo resistance) or develop during treatment (acquired resistance). Here, we report the identification of an EGFR ectodomain missense mutation acquired in vitro in response to treatment with anti-epidermal growth factor receptor (EGFR) antibody cetuximab. Using 2D and 3D drug sensitivity assays, our results demonstrate that this EGFR ectodomain mutation in addition to being resistant to cetuximab and panitumumab, also could not be targeted by the oligoclonal antibody cocktail MM-151. To determine whether this EGFR ectodomain mutation is necessary and sufficient to impart cetuximab resistance, we engineered CRC lines to inducibly overexpress mutant EGFR and showed that this was sufficient to induce cetuximab resistance. Further structural, and functional characterization is underway for this ectodomain mutation that confers resistance to cetuximab and will be shared during the meeting. These findings necessitate the need for additional treatment strategies for a subset of subjects with mCRC who do not respond to treatment with cetuximab/panitumumab and MM-151. Citation Format: Neeraj Joshi, Ramona Graves Deal, Galina Bogatcheva, James N. Higginbotham, Marisol Ramirez, Benjamin P. Brown, Qi Liu, Jens Meiler, Bhuminder Singh. Characterization of EGFR ectodomain mutation in acquired resistance to cetuximab in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3264.

Abstract 5844: Landscapes of acquired EGFR and VEGF resistance alterations in colorectal cancer: findings from the PARADIGM biomarker study

Abstract Introduction: Resistance mechanisms to anti-epidermal growth factor receptor (EGFR) treatment, such as panitumumab (PAN), in patients (pts) with metastatic colorectal cancer (mCRC) depend on the diversity of acquired gene alterations and clonal variation. To explore resistance mechanisms and emerging genomic alterations during PAN treatment, we analyzed the circulating cell-free DNA (cfDNA) samples from the PARADIGM trial (NCT02394795), which demonstrated survival benefits of PAN over bevacizumab (BEV), an anti-vascular endothelial growth factor (VEGF) antibody, in combination with first-line chemotherapy in pts with RAS wild-type (WT) mCRC. Methods: cfDNA from blood samples were obtained pre- and post-treatment and analyzed for gene alterations using the custom PlasmaSELECT-R 91 PGDx panel (NCT02394834). We analyzed the landscapes of acquired alterations and their association with functional pathways in mCRC according to The Cancer Genome Atlas signaling classification. Result: Among the enrolled 802 pts, 390 discontinued treatment due to progressive disease, of which 276 (70.8%) had evaluable pre- and post-treatment cfDNA samples (PAN, n=126; BEV, n=150). Though the proportion of pts with acquired alterations in any of 30 RTK-RAS-related genes was similar in PAN vs BEV (44.4% vs 42.7%), known EGFR resistance-related genes were observed more frequently in PAN compared with BEV: KRAS (19.1 vs 2.7%), NRAS (9.5 vs 2.7%), BRAF (11.1 vs 0.7%), MAP2K1 (5.6 vs 0.7%), and EGFR (5.6 vs 3.3%). These acquired mutations clustered at hotspots within those genes in the PAN group, unlike in the BEV group. Furthermore, the co-occurrence rates of acquired alterations among the RTK-RAS pathway of the individual cases were higher in PAN (25.4%) vs BEV (9.3%), suggesting an increased subclonal complexity in PAN. There were few acquired alterations predominantly observed in BEV, and their biological significance remains unclear. Conclusion: These results suggest that PAN treatment, compared with BEV, more commonly induces multiple resistant subclones in specific pathways under selective treatment pressure. Our findings provide valuable insight for further investigations into the mechanisms of acquired and resistance associated with PAN and BEV. Citation Format: Katsuya Tsuchihara, Riu Yamashita, Takayuki Yoshino, Kohei Shitara, Jun Watanabe, Hirofumi Yasui, Hisatsugu Ohori, Manabu Shiozawa, Kei Muro, Kentaro Yamazaki, Eiji Oki, Takeo Sato, Takeshi Naitoh, Yoshito Komatsu, Takeshi Kato, Kazunori Yamanaka, Ikuo Mori, Masamitsu Hihara, Junpei Soeda, Kouji Yamamoto, Kiwamu Akagi, Atsushi Ochiai, Victor E. Velculescu, Hiroyuki Uetake. Landscapes of acquired EGFR and VEGF resistance alterations in colorectal cancer: findings from the PARADIGM biomarker study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5844.

Trifluridine-Tipiracil (Lonsurf)

&#x0D; CADTH recommends that Lonsurf be reimbursed by public drug plans in combination with bevacizumab for the treatment of metastatic colorectal cancer (mCRC) in adults who have been previously treated with or are not candidates for available therapies, including fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapies; anti–vascular endothelial growth factor (anti-VEGF) biological agents; and, if positive for RAS wild-type disease, anti-epidermal growth factor receptor (anti-EGFR) agents, if certain conditions are met.&#x0D; Lonsurf should be covered for use in adults with histologically confirmed adenocarcinoma that cannot be surgically removed or has spread to other parts of the body and if the patient’s disease progressed or the patient was intolerant to a maximum of 2 prior chemotherapy regimens. Eligible patients should have good overall health (performance status) and no unstable neurologic issues related to the central nervous system (CNS) or need increasing doses of steroids to control CNS disease.&#x0D; Lonsurf should be reimbursed in combination with bevacizumab. It should be prescribed by doctors who specialize in diagnosing and treating patients with mCRC. Lonsurf plus bevacizumab should be stopped if the disease worsens or the patient has severe side effects. The cost of Lonsurf should be reduced.&#x0D;

Development of PET Radioisotope Copper-64-Labeled Theranostic Immunoliposomes for EGFR Overexpressing Cancer-Targeted Therapy and Imaging.

Combining standard surgical procedures with personalized chemotherapy and the continuous monitoring of cancer progression is necessary for effective NSCLC treatment. In this study, we developed liposomal nanoparticles as theranostic agents capable of simultaneous therapy for and imaging of target cancer cells. Copper-64 (64Cu), with a clinically practical half-life (t1/2 = 12.7 h) and decay properties, was selected as the radioisotope for molecular PET imaging. An anti-epidermal growth factor receptor (anti-EGFR) antibody was used to achieve target-specific delivery. Simultaneously, the chemotherapeutic agent doxorubicin (Dox) was encapsulated within the liposomes using a pH-gradient method. The conjugates of 64Cu-labeled and anti-EGFR antibody-conjugated micelles were inserted into the doxorubicin-encapsulating liposomes via a post-insertion procedure (64Cu-Dox-immunoliposomes). We evaluated the size and zeta-potential of the liposomes and analyzed target-specific cell binding and cytotoxicity in EGFR-positive cell lines. Then, we analyzed the specific therapeutic effect and PET imaging of the 64Cu-Dox-immunoliposomes with the A549 xenograft mouse model. In vivo therapeutic experiments on the mouse models demonstrated that the doxorubicin-containing 64Cu-immunoliposomes effectively inhibited tumor growth. Moreover, the 64Cu-immunoliposomes provided superior in vivo PET images of the tumors compared to the untargeted liposomes. We suggest that nanoparticles will be the potential platform for cancer treatment as a widely applicable theranostic system.

Abstract IA020: Microphysiological systems to decipher tumor-stromal interactions in colorectal cancer

Abstract Cancer is a complex adaptive system driven by the intricate interplay between tumor cells and their microenvironment. Among these interactions, cancer-associated fibroblasts (CAFs), the predominant cellular component of the tumor stroma, are frequently linked with an unfavorable prognosis and play an important role in the progression of various cancers. Although extensive literature has underscored the impact of CAFs on cancer cell behaviors such as proliferation and invasion, the stromal influence on phenotypic plasticity in the context of treatment response and metastasis remains largely unexplored. Furthermore, preclinical treatment studies often concentrate on drug-induced changes in tumor cells with little investigation into the impact on surrounding stromal cells. To enhance our comprehension of the intricate and dynamic interactions between cancer cells and their microenvironment, we are utilizing quantitative high-content imaging in conjunction with more physiologically relevant patient-derived model systems, such as organoids and organ-on-chip technologies. Here we will describe our experimental workflows and demonstrate how the incorporation of mathematical modeling enhances our understanding of 3D organoid growth dynamics and facilitates a more detailed examination of drug resistance influenced by tumor plasticity. One illustrative example we will emphasize involves the treatment of CAFs with an anti-epidermal growth factor receptor (EGFR) targeted agent, cetuximab, resulting in an increased secretion of epidermal growth factor (EGF). This heightened EGF secretion was sufficient to render neighboring tumor cells resistant to cetuximab treatment. These efforts aim to increase our understanding of tumor-stromal interactions in cancer evolution, particularly emphasizing the functional and therapeutic potential of CAFs, through the integration of expertise across disciplines. Citation Format: Shannon Mumenthaler. Microphysiological systems to decipher tumor-stromal interactions in colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr IA020.

A phase 1b study of sotorasib combined with panitumumab as second-line treatment of KRAS G12C-mutated colorectal cancer.

128 Background: In the CodeBreaK 101 phase 1b study, sotorasib, a KRASG12C inhibitor, plus panitumumab, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody, showed acceptable safety and promising efficacy for patients with chemorefractory KRAS G12C–mutated metastatic colorectal cancer: an objective response rate (ORR) of 30% and median progression-free survival (PFS) of 5.7 months were observed. Here, we evaluated sotorasib plus panitumumab in the second-line (2L) setting. Methods: CodeBreaK 101 (NCT04185883) subprotocol H includes dose exploration and expansion in multiple cohorts. Patients eligible for the 2L sotorasib plus panitumumab dose-expansion cohort were KRASG12C inhibitor–naïve and had received no more than one prior regimen for metastatic disease. Patients received oral sotorasib at 960 mg daily and IV panitumumab 6 mg/kg every 2 weeks. The primary endpoint was safety. Secondary endpoints included efficacy endpoints. Results: As of May 23, 2023, this cohort was fully enrolled; all 20 patients (50% female, median age 60.0 years) were included in this analysis. All patients received fluoropyrimidine-based treatment and 17 (85%) patients received oxaliplatin-based treatment as first-line therapy. Any-grade treatment-related adverse events (TRAEs) occurred in 19 (95%) patients. The most common any-grade TRAEs were dermatitis acneiform (60%), dry skin (55%), pruritus (45%), and hypomagnesemia (30%). Grade ≥3 TRAEs occurred in 4 (20%) patients and included fatigue, hypomagnesemia, decreased appetite, and rash (5% each). No TRAEs were grade ≥4 or resulted in treatment discontinuation or deaths. Confirmed ORR was 30% (95% CI: 11.9, 54.3). The disease control rate was 90% (95% CI: 68.3, 98.8). At a median follow-up of 11.3 months (95% CI: 5.6, not estimable), median PFS was 8.3 months (95% CI: 4.3, 14.1). Conclusions: This is the first report of safety and efficacy from a 2L cohort evaluating a KRASG12C inhibitor plus an anti-EGFR antibody in KRAS G12C-mutated metastatic colorectal cancer. The toxicities of sotorasib plus panitumumab were consistent with the expected safety profile of the individual agents and with that reported previously for this combination; the ORR was similar to that previously observed for this combination in a more chemorefractory population. The ORR and PFS of sotorasib plus panitumumab compare favorably to current standard approaches in the 2L treatment of metastatic colorectal cancer. Clinical trial information: NCT04185883 .

Real-world evidence of FOLFIRI combined with anti-angiogenesis inhibitors or anti-EGFR antibodies for patients with early recurrence colorectal cancer after adjuvant FOLFOX/CAPOX therapy in Japan: A retrospective observational study using administrative database.

110 Background: Oxaliplatin-containing regimens (FOLFOX or CAPOX) are the most common adjuvant treatments after curative resection of colorectal cancer (CRC). However, real-world evidence (RWE) of treatment sequence/outcomes for patients with early recurrence CRC after receiving adjuvant chemotherapy are limited. Methods: This retrospective cohort study was based on an administrative database in Japan. The primary objective was to describe the treatment sequence for patients with early recurrence CRC and treated by combination of FOLFIRI and anti-angiogenesis inhibitors (AAIs) or anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) after adjuvant FOLFOX or CAPOX therapy. The study included patients with CRC who underwent surgical resection, started adjuvant chemotherapy ≤3 months (mo) after the first surgery, had early recurrence of CRC (defined as initiation of FOLFIRI + AAIs/anti-EGFR mAbs second line [2L] regimen) within 1 year after adjuvant chemotherapy ended. Patient characteristics at baseline of 2L (60 days prior to 2L initiation) and treatment sequence were summarized descriptively; time to discontinuation (TTD) for adjuvant and 2L therapy were analyzed using Kaplan-Meier method. Cox proportional hazard model was used to identify risk factors associated with TTD of 2L regimen. Results: The cohort included 832 patients: median (range) age was 67 (24-86) years, 56.4% males, 65.5% with left-sided CRC. Most patients received CAPOX (71.3%) as adjuvant therapy. Median (95% CI) duration of adjuvant therapy was 5.4 mo (5.3-5.5). As 2L therapy, 72.5% and 27.5% of patients received FOLFIRI + AAIs (AAIs group) and FOLFIRI + anti-EGFR mAbs (anti-EGFR group), respectively. Median TTD (95% CI) of the AAIs and anti-EGFR groups in 2L were 6.2 mo (5.8-6.9) and 6.1 mo (5.2-7.4), respectively. Among patients with recurrence within 6 mo (72.6%), the median TTD (95% CI) for AAIs and anti-EGFR groups were 6.1 mo (5.5- 6.5) and 5.8 mo (5.1-7.8), respectively. Among patients with recurrence during 6 to 12 mo (27.4%), the median TTD (95% CI) of AAIs and anti-EGFR groups were 8.1 mo (6.1-9.2) and 6.2 mo (4.6-8.0), respectively. Age ≥70 years was negatively associated with TTD of 2L, HR = 1.19 (95% CI: 1.02-1.39); p=0.03. Conclusions: This is the first RWE based on administrative data on treatment sequence/ outcomes for patients with early recurrence CRC treated by FOLFIRI + AAIs/anti-EGFR mAbs after adjuvant FOLFOX/CAPOX therapy in Japan. The treatment outcomes for patients with early recurrence CRC were similar to previous clinical trials in 2L advanced CRC. The results suggested that these two 2L regimens had similar TTD; however, the timing of relapse may influence the efficacy of AAIs and anti-EGFR mAbs.

HGCSG1801: A multicenter, prospective, phase II trial of second-line FOLFIRI plus aflibercept in patients with metastatic colorectal cancer (mCRC) refractory to anti-EGFR antibodies.

113 Background: Aflibercept (AFL) combined with FOLFIRI prolongs overall survival (OS) in patients (pts) with metastatic colorectal cancer (mCRC) who failed a prior oxaliplatin-based regimen. However, there is limited evidence on the efficacy and safety of AFL plus FOLFIRI in RAS / BRAF wild type pts previously treated with anti-epidermal growth factor receptor (EGFR) agents. Therefore, we conducted a phase II trial evaluating the efficacy and safety of AFL plus FOLFIRI in Japanese pts with mCRC failing a prior oxaliplatin-based chemotherapy combined with an anti-EGFR agent. Methods: This was a prospective open-label phase II trial. AFL (4 mg/kg iv) followed by FOLFIRI (irinotecan 180 mg/m2, leucovorin 200 mg/m2 iv, bolus 5-FU 400 mg/m2 and infusional 5-FU 2400 mg/m2/46 h) was given every 2 weeks until progression or unacceptable toxicities. The primary endpoint was progression-free survival (PFS) rate at 6 months; secondary endpoints included OS, PFS, overall response rate (ORR), disease control rate (DCR), adverse events, and relative dose intensity (RDI) for each drug. Given a PFS rate threshold at 6 months of 38.9% and an expected PFS rate of 58.4% with AFL plus FOLFIRI, a sample size of 41 pts was required (two-sided alpha, 0.1; beta, 0.2). Analyses were conducted in the full analysis set (FAS) of pts satisfying eligibility criteria. Results: Forty-three patients were enrolled between November 2019 and October 2022, and 43 were analyzed (median age 68 years (range 27-80); male, 69.8%; ECOG PS 0/1, 72.1%/27.9%; left sided primary tumor, 90.7%). The primary endpoint was met: 6-month PFS rate was 58.7% (90%CI, 45.5%-71.9%). Median PFS and OS were 7.3 months (95%CI, 5.5-11.0 months) and 18.8 months (95%CI, 12.9-26.6 months), respectively. The ORR was 23.3 % (95%CI, 11.8-38.6%) and DCR was 88.4% (95%CI, 74.9- 96.1%). Mean RDI of AFL, irinotecan, bolus 5-FU and infusional 5-FU were 75.3% (SD, 26.2), 50.6% (SD, 12.5), 31.6% (SD, 26.6), and 58.7% (SD, 7.21), respectively. The main grade ≥3 adverse events included hypertension (62.8%), neutropenia (55.8%), leukopenia (25.6%), febrile neutropenia (11.6%), fatigue (9.3%), anorexia (9.3%), proteinuria (9.3%) and diarrhea (7.0%). No deaths and no new safety signals with a causal relation to the study treatment were observed. Conclusions: Results of this prospective phase II study suggest that AFL plus FOLFIRI shows a high response rate and a manageable safety profile in Japanese pts with mCRC who failed a first-line oxaliplatin-based plus anti-EGFR regimen. Clinical trial information: jRCTs011190006 .