Cetuximab Arm 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.

Cetuximab plus FOLFOXIRI versus cetuximab plus FOLFOX as conversion regimen in RAS/BRAF wild-type patients with initially unresectable colorectal liver metastases (TRICE trial): A randomized controlled trial.

It remains unclear whether intensification of the chemotherapy backbone in tandem with an anti-EGFR can confer superior clinical outcomes in a cohort of RAS/BRAF wild-type colorectal cancer (CRC) patients with initially unresectable colorectal liver metastases (CRLM). To that end, we sought to comparatively evaluate the efficacy and safety of cetuximab plus FOLFOXIRI (triplet arm) versus cetuximab plus FOLFOX (doublet arm) as a conversion regimen (i.e., unresectable to resectable) in CRC patients with unresectable CRLM. This open-label, randomized clinical trial was conducted from April 2018 to December 2022 in 7 medical centers across China, enrolling 146 RAS/BRAF wild-type CRC patients with initially unresectable CRLM. A stratified blocked randomization method was utilized to assign patients (1:1) to either the cetuximab plus FOLFOXIRI (n = 72) or cetuximab plus FOLFOX (n = 74) treatment arms. Stratification factors were tumor location (left versus right) and resectability (technically unresectable versus ≥5 metastases). The primary outcome was the objective response rate (ORR). Secondary outcomes included the median depth of tumor response (DpR), early tumor shrinkage (ETS), R0 resection rate, progression-free survival (PFS), overall survival (not mature at the time of analysis), and safety profile. Radiological tumor evaluations were conducted by radiologists blinded to the group allocation. Primary efficacy analyses were conducted based on the intention-to-treat population, while safety analyses were performed on patients who received at least 1 line of chemotherapy. A total of 14 patients (9.6%) were lost to follow-up (9 in the doublet arm and 5 in the triplet arm). The ORR was comparable following adjustment for stratification factors, with 84.7% versus 79.7% in the triplet and doublet arms, respectively (odds ratio [OR] 0.70; 95% confidence intervals [CI] [0.30, 1.67], Chi-square p = 0.42). Moreover, the ETS rate showed no significant difference between the triplet and doublet arms (80.6% (58/72) versus 77.0% (57/74), OR 0.82, 95% CI [0.37, 1.83], Chi-square p = 0.63). Although median DpR was higher in the triplet therapy group (59.6%, interquartile range [IQR], [50.0, 69.7] versus 55.0%, IQR [42.8, 63.8], Mann-Whitney p = 0.039), the R0/R1 resection rate with or without radiofrequency ablation/stereotactic body radiation therapy was comparable with 54.2% (39/72) of patients in the triplet arm versus 52.7% (39/74) in the doublet arm. At a median follow-up of 26.2 months (IQR [12.8, 40.5]), the median PFS was 11.8 months in the triplet arm versus 13.4 months in the doublet arm (hazard ratio [HR] 0.74, 95% CI [0.50, 1.11], Log-rank p = 0.14). Grade ≥ 3 events were reported in 47.2% (35/74) of patients in the doublet arm and 55.9% (38/68) of patients in the triplet arm. The triplet arm was associated with a higher incidence of grade ≥ 3 neutropenia (44.1% versus 27.0%, p = 0.03) and diarrhea (5.9% versus 0%, p = 0.03). The primary limitations of the study encompass the inherent bias in subjective surgical decisions regarding resection feasibility, as well as the lack of a centralized assessment for ORR and resection. The combination of cetuximab with FOLFOXIRI did not significantly improve ORR compared to cetuximab plus FOLFOX. Despite achieving an enhanced DpR, this improvement did not translate into improved R0 resection rates or PFS. Moreover, the triplet arm was associated with an increase in treatment-related toxicity. ClinicalTrials.gov Identifier: NCT03493048.

Genome-wide DNA methylation status to predict the efficacy of modified (m)-FOLFOXIRI plus cetuximab as initial treatment for RAS wild-type metastatic colorectal cancer: A biomarker study of the DEEPER trial (JACCRO CC-13AR).

152 Background: Genome-wide DNA methylation status (GWMS) has been shown to be a predictor of therapeutic response to anti-EGFR antibody therapies. This study investigated the association between GWMS and clinical outcomes of first-line chemotherapy with anti-EGFR or anti-VEGF antibody agents for metastatic colorectal cancer (mCRC). Methods: Tumor tissues of mCRC patients registered in the JACCRO CC-13AR (clinical trial number: UMIN000018412) were analyzed for GWMS and were classified into low-methylated colorectal cancer (LMCC) and high-methylated colorectal cancer (HMCC). Clinical data were obtained from the randomized phase II trial, DEEPER trial (JACCRO CC-13) [NCT02515734], in which patients were randomly assigned to m-FOLFOXIRI plus cetuximab (CET) arm and m-FOLFOXIRI plus bevacizumab (BEV) arm for treatment. Progression-free survival (PFS), overall survival (OS), depth of response (DpR), and response rate (RR) were analyzed according to GWMS for each treatment arm. Results: One hundred thirty-seven out of 227 patients enrolled in the JACCRO CC-13AR were analyzed. Of these, 122 (89.1%) and 15 (10.9%) were classified in the LMCC and HMCC, respectively; 66 were assigned to the CET arm including 7 HMCCs, and 54 were assigned to the BEV arm including 8 HMCCs. In the CET arm, PFS and OS of the LMCC were significantly longer than those of the HMCC (median PFS 14.3 vs. 4.0 months, hazard ratio [HR] 0.11, 95% CI: 0.05–0.29, P<0.01; median OS 42.7 vs. 13.6 months, HR 0.04, 95% CI: 0.01–0.13, P<0.01). There were no differences in DpR and RR between the LMCC and the HMCC (median DpR 58.1% vs. 46.7%, P=0.45), although RR of the LMCC was numerically higher than that of the HMCC (71.2% vs. 42.9%, P=0.13). In contrast, in the BEV arm, there were no differences in PFS, DpR, and RR between the two groups (median PFS 16.1 vs. 12.2 months, P=0.08; median DpR 48.3% vs. 53.9%, P=0.99; RR 73.0% vs. 75.0%, P=0.91). However, OS of the LMCC was significantly longer than that of the HMCC (median OS 48.9 vs. 24.2 months, HR 0.39, 95% CI: 0.16–0.95, P=0.03). Conclusions: This study showed that GWMS may be a prognostic marker for initial treatment in RAS wild-type mCRC. Also, GWMS correlates to the survival outcomes of m-FOLFOXIRI plus CET as initial treatment for RAS wild-type mCRC. Clinical trial information: 000018412 .

Early identification and treatment of occult metastatic disease in stage III colon cancer (SU2C ACT3 clinical trial).

148 Background: Despite adjuvant chemotherapy, nearly 30% of patients with Stage III colon cancer (CC) will recur. We are performing a randomized clinical trial using a plasma-only circulating tumor DNA (ctDNA) platform after adjuvant therapy for patients with ctDNA-positive Stage III CC. Methods: Patients (pts) with Stage III CC are eligible for prescreening, including tumor tissue profiling by next-generation sequencing. Pts are screened 3-6 weeks after adjuvant chemotherapy. At screening blood is collected for ctDNA analysis with a CLIA-certified sequencing panel (Reveal, Guardant Health). A baseline CT scan is required to confirm lack of metastases. Pts with undetectable ctDNA (-) at screening undergo surveillance with imaging, labs and ctDNA testing every 3 months (Arm 3). ctDNA-detectable (+) pts who are biomarker-negative are randomized to 1:1 to FOLFIRI (Arm 1) or active surveillance (Arm 2). ctDNA+ pts with an actionable biomarker (biomarker-positive) are given 6 months biomarker-directed therapy as follows: V600E/MSS- encorafenib, binimetinib and cetuximab (Arm 5), HER2 amplified trastuzumab/pertuzumab (arm 6), and MSI-H nivolumab (Arm 4). Primary outcome is ctDNA clearance in Arms 1 and 2, 1-month after completion of additional adjuvant therapy or surveillance. Secondary outcomes include RFS and OS in Arms 1 and 2, ctDNA clearance and RFS/OS in the other arms. An interim analysis is planned after 13 patients are enrolled in Arm 1 and primary outcome will be assessed after 50 patients’ complete treatment/surveillance in Arms 1 and 2. Results: From 4/16/2020 through 9/8/2023, 147 patients were screened, 66 screen failed. Pre-screening as well as active ongoing enrollment is underway. To date, 73 patients have enrolled (46 male and 27 female). 53 (72.6%) were white. 10 (13.7%) patients were noted to be ctDNA+ within 6 weeks of completion of adjuvant therapy: 4 in Arm 1; 5 in Arm 2; 1 in Arm 4. 63 pts were ctDNA- and in Arm 3. Conclusions: In this ctDNA guided trial, with single time-point testing, only 13.7% of pts were ctDNA+ after adjuvant chemotherapy. 90% of ctDNA+ patients did not have an actionable biomarker. Strict windows for eligibility and enrollment initially restricted eligibility but these were adjusted to increase eligibility. To mitigate the low positivity rate and allow us to meet our accrual goals in arm 1 and 2, the protocol was amended to allow for entry into the ctDNA+ arms at any time during the first 3 years after completion of adjuvant therapy as opposed to within 6 weeks of completion of adjuvant therapy. The lessons learnt would have implications for other ctDNA-driven clinical trials. Clinical trial information: NCT03803553. Patient distribution in the SU2C ACT3 study. Total Screened Pre-Screening Screen Fail Enrolled Off Study ctDNA Treatment Arm + - Arm 1 Arm 2 Arm 3 Arm 4 Arm 5 Arm 6 147 8 66 73 10 10 63 4 5 63 1 0 0

Palbociclib + cetuximab versus cetuximab in patients with CDKN2A-altered, anti-PD-1 resistant, HPV-negative head and neck squamous cell carcinoma (HNSCC): A phase 3 trial.

TPS6103 Background: Cell cycle deregulation is ubiquitous in HNSCC. In HPV-negative HNSCC, the most common genomic cell-cycling alteration involves CDKN2A, which results in loss of p16 expression, hyper-activation of CDK4/6-cyclin D1, unrestrained cell cycling and tumor progression. The modest antitumor activity of cetuximab in HPV-negative HNSCC may be due to unregulated cell-cycling events downstream of EGFR. In cell-line, xenograft, and PDX models of HPV-negative HNSCC, selective CDK4/6 inhibition arrested cell cycling and inhibited tumor growth. CDKN2A alterations were predictive of efficacy. Palbociclib, a selective CDK4/6 inhibitor, in combination with an EGFR inhibitor synergistically reduced the viability of HPV-negative HNSCC cell lines. An exploratory analysis of a double-blind, randomized, phase 2 trial (PALATINUS) showed that overall survival (OS) was numerically superior in patients with CDKN2A altered, HPV-negative recurrent/metastatic (RM) HNSCC treated with palbociclib + cetuximab vs those treated with placebo + cetuximab (median 9.7 vs 4.6 months, HR 0.38); however, OS was similar between the two treatment arms in patients without CDKN2A-altered disease. Also, the TAPUR trial showed that palbociclib decreased target lesions in 25% of patients with CDKN2A-altered HN cancers. These data provide justification for a randomized trial of palbociclib + cetuximab vs cetuximab in patients with CDKN2A-altered, HPV-negative RM-HNSCC. Enrollment was limited to patients with anti-PD-1 resistant disease, since current treatments fail to improve OS in these patients. Methods: The primary aim of this open-label, phase 3 trial is to determine the OS of patients with CDKN2A-altered (mutation or deletion), anti-PD-1 resistant, HPV-negative HNSCC treated with palbociclib + cetuximab (Arm 1) vs cetuximab (Arm 2). Eligibility also requires 1-3 lines of prior therapy and no cetuximab for RM disease. Patients are randomized (2:1) to Arms 1 or 2, stratified by prior platinum or cetuximab (if given with curative-intent therapy). Patients receive 28-day cycles of palbociclib 125 mg/d orally on days 1-21 + cetuximab 400 mg/m2 IV cycle 1 day 1, then 250 mg/m2 weekly (Arm 1) or cetuximab (Arm 2). Tumor response is assessed using RECIST 1.1. A two-stage sequential design, including one interim and a final analysis, was planned. We hypothesized that the median OS of Arm 1 will be 9.7 months and of Arm 2 4.6 months. O'Brien-Fleming method was used to calculate the sample size at each stage and derive the boundaries of two-sided hypothesis with early stopping to reject or accept H0 (HR = 1). Assuming 22 months enrollment and 12 months follow-up, 66 patients (Arm 1: 44; Arm 2: 22) will be enrolled in the first stage. If the study continues, an additional 15 patients will be enrolled (total Arm 1: 54; Arm 2: 27) which achieves 80% power at a two-sided α 0.05. Clinical trial information: NCT04966481 .

Phase III FIRE-4 study (AIO KRK-0114): Influence of baseline liquid biopsy results in first-line treatment efficacy of FOLFIRI/cetuximab in patients with tissue RAS-WT mCRC.

3507 Background: FIRE-4 (AIO KRK-0114) is performed in RAS wild-type (wt) mCRC patients. This randomized study tests the efficacy of early switch maintenance during 1st-line therapy (part 1) and re-challenge with cetuximab (part 2) in later-line treatment. In part 1, arm A patients continued FOLFIRI/Cet until progression or intolerable toxicity. In arm B, patients received FOLFIRI/Cet for 8-12 cycles, after which maintenance therapy with 5-FU/FA plus bevacizumab (5-FU/Bev) was applied. The first randomization evaluates the question if an early switch from cetuximab to bevacizumab may prolong PFS. Within the translational protocol, serial baseline liquid biopsy were taken to analyze RAS and BRAF mutations. Methods: Within this randomized, controlled, open-label phase-III study, patients received FOLFIRI (irinotecan plus 5-FU/FA) plus cetuximab at the standard dosing schedule. In arm A, FOLFIRI plus cetuximab was continued until progression or intolerable toxicity. In arm B, patients received 8 cycles of FOLFIRI plus cetuximab (in case of tumor response) or 12 cycles (in case of stable disease) followed by maintenance with 5-FU/FA plus bevacizumab (5mg/kg) until disease progression or intolerable toxicity. Overall survival after second randomization (part 2) is evaluated as a primary endpoint. Liquid Biopsies were analyzed by RAS BEAMing and BRAF ddPCR technology. Results: From August 2015 to January 2021, 673 patients were randomized, and liquid biopsies of 540 patients were evaluable at baseline. Of those, 70 (13%) were RAS mutant and 38 (7%) BRAFV600E mutant at baseline. Patients with a detectable RASmut had a significant shorter PFS and OS when compared to RASwt patients (PFS: 9.0mo vs. 11.5mo; p < 0.001; OS: 22.1mo vs 33.6mo; p < 0.001). Whereas, for RASwt patients no difference for both arms with respect to PFS and OS could be observed, RASmut patients (n = 70) had a clear trend towards shorter survival in the standard FOLFIRI cetuximab arm (PFS: 6.4mo vs. 10.1mo, p = 0.54; OS: 24.9mo vs. 16.3mo, p = 0.10). Patients with a BRAF mutation in liquid biopsy had median survival times as expected for BRAF mutant patients (PFS = 5.5mo; OS = 12.0mo). In the standard arm, with a continuous administration of cetuximab, the conversion rate from RASwt to RASmut was significantly higher at progression than in the switch maintenance arm. Conclusions: Liquid biopsy detected RAS mutation in 13% of patients deemed RASwt based on tissue analyses. These patients show outcome characteristics expected for RAS mutant patients (median PFS of 9.0 months and median OS of 22 months). The study thus shows the clinical relevance of liquid biopsy in the verification of RAS mutational status. Clinical trial information: NCT02934529 .

Radiotherapy-Dose Escalated for Large Volume Primary Tumors-And Cetuximab with or without Induction Chemotherapy for HPV Associated Squamous Cell Carcinoma of the Head and Neck-A Randomized Phase II Trial.

Eligible patients in this multicenter, randomized, controlled, phase 2 trial had p16-positive locoregionally advanced SCCHN. Patients were randomized in a 1:1 ratio to either RT with cetuximab (arm B) versus the same regimen preceded by two cycles of taxotere/cisplatin/5-FU (arm A). The RT dose was escalated to 74.8 Gy for large volume primary tumors. Eligibility criteria included patients of 18-75 years, an ECOG performance status 0-1, and adequate organ functions. From January 2011 to February 2016, 152 patients, all with oropharyngeal tumors were enrolled, 77 in arm A and 75 in arm B. Two patients, one in each group, withdrew their consent after randomization, leaving 150 patients for the ITT analysis. PFS at 2 years was 84.2% (95% CI 76.4-92.8) in arm A and 78.4% (95% CI 69.5-88.3) in arm B (HR 1.39, 95% CI 0.69-2.79, p = 0.40). At the time of analysis, there were 26 disease failures, 9 in arm A and 17 in arm B. In arm A, 3 patients had local, 2 regional, and 4 distant relapses as first sites of recurrence, and in arm B, 4, 4, and 9 relapses in corresponding sites. Eight out of 26 patients with disease progression had salvage therapy and 7 were alive NED (no evidence of disease), at 2 years. Locoregional control was 96% in arm A and 97.3% in arm B and OS 93% and 90.5%, respectively. Local failure as first site of recurrence was low, in 4.6% of patients and was similar for T1/T2 and T3/T4 tumors (n.s). Nevertheless, out of 7 patients with primary local failures, 4 were treated with the escalated RT dose. Toxicity was low and similar in the treatment arms. There was one fatal event in arm A where the combined effects of the drugs used in chemotherapy and cetuximab could not be ruled out. PFS, locoregional control and toxicity did not differ between the two arms, OS was high, and there were few local relapses. In arm B, more than twice as many patients had distant metastasis as the first site of relapse compared to arm A. The response to IC was found to define 29% of patients in arm A who did not have a tumor relapse during follow-up. An escalated dose of 74.8 Gy could mitigate the negative impact of large tumor volume but for some patients, even this intensified treatment was insufficient.

Impact of genetic variants involved in the lipid metabolism pathway on progression free survival in patients receiving bevacizumab-based chemotherapy in metastatic colorectal cancer: a retrospective analysis of FIRE-3 and MAVERICC trials.

Antiangiogenic drug (AAD)-triggered oxygen and nutrient depletion through suppression of angiogenesis switches glucose-dependent to lipid-dependent metabolism. Blocking fatty acid oxidation can enhance AAD-mediated anti-tumor effects in colorectal cancer (CRC). Therefore, we hypothesised that genetic variants in the lipid metabolism pathway may predict clinical outcomes [overall response rate (ORR), overall survival (OS) and progression-free survival (PFS)] in metastatic CRC (mCRC) patients receiving bevacizumab-based first-line treatment. Genomic DNA from blood samples of patients enrolled in FIRE-3 (a global, randomised, open-label, phase 3 trial, between 2007-6-23 and 2012-9-19, discovery cohort: FOLFIRI/bevacizumab arm, n=107; control cohort: FOLFIRI/cetuximab arm, n=129) and MAVERICC (a global, randomised, open-label, phase II study, between 2011-8 and 2015-7, in United States, Canada, Estonia, Ireland, Switzerland, Norway, and Portugal. Validation cohort: FOLFIRI/bevacizumab arm, n=163) trials, was genotyped using the OncoArray-500K beadchip panel. The impact on OS and PFS of 17 selected SNPs in 7 genes involved in the lipid metabolism pathway (CD36, FABP4, LPCAT1/2, CPT1A, FASN, ACACA) was analysed using Kaplan-Meier curves, the log-rank test for univariate analyses and likelihood ratio tests of Cox proportional hazards regression parameters for multivariable analyses. ORR and SNP associations were evaluated using Chi-square or Fisher's exact tests. In the discovery cohort, patients with FASN rs4485435 any C allele (n=21) showed significantly shorter PFS (median PFS: 8.69 vs 13.48 months) compared to carriers of G/G (n=62) in multivariable (HR=2.87; 95%CI 1.4-5.9; p=0.00675) analysis. These data were confirmed in the validation cohort in multivariable analysis (HR=2.07, 95%CI: 1.15-3.74; p=0.02), but no association was observed in the cetuximab cohort of FIRE-3. In the comparison of bevacizumab vs cetuximab arm in FIRE-3, a significant interaction was shown with FASN rs4485435 (p=0.017) on PFS. Our study demonstrates for the first time, to our knowledge, that FASN polymorphisms may predict outcome of bevacizumab-based treatment in patients with mCRC. These findings support a possible role of the lipid metabolism pathway in contributing to resistance to anti-VEGF treatment. This work was supported by the National Cancer Institute [P30CA 014089 to H.-J.L.], Gloria Borges WunderGlo Foundation, Dhont Family Foundation, Victoria and Philip Wilson Research Fund, San Pedro Peninsula Cancer Guild, Ming Hsieh Research Fund, Eddie Mahoney Memorial Research Fund, Shanghai Sailing Program (22YF1407000), China National Postdoctoral Program for Innovative Talents (BX20220084), China Postdoctoral Science Foundation (2022M710768), National Natural Science Foundation of China (82202892).

Phase III FIRE-4 study (AIO KRK-0114): Evaluation of first-line treatment efficacy of FOLFIRI/cetuximab in patients with RAS-WT mCRC receiving the first cycle of treatment with chemotherapy only.

100 Background: FIRE-4 (AIO KRK-0114) is performed in RAS wild-type (wt) mCRC patients. This randomized study tests the efficacy of early switch maintenance during 1st-line therapy (part 1) and re-challenge with cetuximab (part 2) in later-line treatment. In part 1, all patients received first-line induction treatment with FOLFIRI plus cetuximab (FOLFIRI/Cet). In arm A, patients were randomized to continue FOLFIRI/Cet until progression or intolerable toxicity. In arm B, patients received FOLFIRI/Cet for 8-12 cycles, after which maintenance therapy with 5-FU/FA plus bevacizumab (5-FU/Bev) was applied. The first randomization evaluates the question if an early switch from cetuximab to bevacizumab during maintenance therapy may prolong PFS. The study protocol explicitly allowed a first cycle of chemotherapy to be applied before randomization. Methods: Within this randomized, controlled, open-label phase-III study, patients received FOLFIRI (irinotecan plus 5-FU/FA) plus cetuximab every two weeks at the standard dosing schedule. In arm A, FOLFIRI plus cetuximab was continued until progression or intolerable toxicity. De- and re-escalation was allowed according to the local standard of care. In arm B, patients received 8 cycles of FOLFIRI plus cetuximab (in case of tumor response) or 12 cycles (in case of stable disease) followed by maintenance with 5-FU/FA plus bevacizumab (5mg/kg) until disease progression or intolerable toxicity. Overall survival after second randomization (part 2) is evaluated as a primary endpoint. Here, we report PFS in first-line (part 1) as a secondary study endpoint of the study. Other secondary endpoints included ORR, OS, safety, and tolerability. Results: From August 2015 to January 2021, 672 patients were randomized, and 656 patients were assigned to treatment in 120 German and 10 Austrian centers (327 arm A and 329 in arm B). Of those, 205 patients received one cycle of FOLFIRI alone before randomization. In both arms, ORR was comparable for patients receiving cetuximab from the first cycle when compared to those receiving one cycle of chemotherapy only (arm A: 58.7% vs 62.9% (p = 0.54), arm B 60.2% vs 55.6% (p = 0.48). PFS was also not influenced in both arms (arm A: 10.8mo vs. 10.6mo (p = 0.91); arm B 11.2mo vs. 11.4mo (p = 0.62)). Preliminary results suggest that also OS (event rate 38.3%) was not influenced by one cycle applied without cetuximab (arm A: 33.7 mo vs. 29.1 mo (p = 0.20); arm B: 35.6 mo vs. 28.9 mo (p = 0.13)). Conclusions: Application of one initial cycle with chemotherapy alone did not influence the efficacy of a first-line strategy of FOLFIRI plus cetuximab. If RAS mutational analysis is not timely available, a start with FOLFIRI alone adding cetuximab in cycle 2 seems to be safe with respect of overall efficacy. Clinical trial information: NCT02934529 .

Extensive molecular profiling of squamous cell anal carcinoma in a phase 2 trial population: Translational analyses of the “CARACAS” study

BackgroundMolecular characteristics of squamous cell anal carcinoma (SCAC) are poorly explored. Immune checkpoint inhibitors showed limited activity in phase I/II trials, but predictive and prognostic biomarkers are lacking. Patients and methodsIn the phase II randomised trial CARACAS (NCT03944252), avelumab alone (Arm A) or with cetuximab (Arm B) was tested in pre-treated advanced SCAC , with overall response rate being the primary end-point. On pre-treatment tumour tissue samples, we assessed Human papillomavirus status, programmed-death ligand 1 (PD-L1) expression, mismatch repair proteins expression, tumour mutational burden (TMB) and comprehensive genomic profiling by FoundationOne CDx. Tumour-infiltrating lymphocytes were characterised on haematoxylin-eosine-stained samples. Primary objective was to describe response to immunotherapy in the CARACAS trial population according to molecular and histological characteristics. Secondary objectives were to assess progression-free survival (PFS) and overall survival (OS) according to molecular biomarkers. ResultsHigh PD-L1 (>40 with combined positive score) was significantly more frequent in patients with disease control (p = 0.0109). High TMB (>10 mutations per megabase) was related to better OS (hazard ratio (HR) = 0.09; 95%confidence interval (CI) 0.01–0.68; p = 0.019) and PFS (HR = 0.44; 95%CI = 0.15–1.27; p = 0.129). High expression of PD-L1 conferred longer OS (HR = 0.46; 95%CI = 0.19–1.08; p = 0.075) and PFS (HR = 0.42; 95%CI = 0.20–0.92; p = 0.03). Neither OS (HR = 1.30; 95%CI = 0.72–2.36; p = 0.39) or PFS (HR = 1.31; 95%CI = 0.74–2.31; p = 0.357) was affected by high (>1.2) Tumour-infiltrating lymphocytes count. High TMB and PD-L1identified patients were with significantly better OS (HR = 0.33; 95%CI = 0.13–0.81; p = 0.015) and PFS (HR = 0.48; 95%CI = 0.23–1.00; p = 0.015). ConclusionsTo our knowledge, TranslaCARACAS is the first study to document prognostic role of TMB and PD-L1 in advanced SCAC patients treated with immune checkpoint inhibitors.

Safety of Nivolumab Added to Chemoradiation Therapy Platforms for Intermediate and High-Risk Locoregionally Advanced Head and Neck Squamous Cell Carcinoma: RTOG Foundation 3504

Programmed death-1 immune checkpoint blockade improves survival of patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC), but the benefits of addition to (chemo)radiation for newly diagnosed patients with HNSCC remain unknown. We evaluated the safety of nivolumab concomitant with 70 Gy intensity modulated radiation therapy and weekly cisplatin (arm 1), every 3-week cisplatin (arm 2), cetuximab (arm 3), or alone for platinum-ineligible patients (arm 4) in newly diagnosed intermediate- or high-risk locoregionally advanced HNSCC. Patients received nivolumab from 2 weeks prior to radiation therapy until 3 months post-radiation therapy. The primary endpoint was dose-limiting toxicity (DLT). If ≤2 of the first 8 evaluable patients experienced a DLT, an arm was considered safe. Secondary endpoints included toxicity and feasibility of adjuvant nivolumab to 1 year, defined as all 7 additional doses received by ≥4 of the first 8 evaluable patients across arms. Of 39 patients (10 in arms 1, 3, 4 and 9 in arm 2), 72% had T3-4 tumors, 85% had N2-3 nodal disease, and 67% had >10 pack-years of smoking. There were no DLTs in arms 1 and 2, 1 in arm 3 (mucositis), and 2 in arm 4 (lipase elevation and mucositis in 1 and fatigue in another). The most common grade ≥3 nivolumab-related adverse events were lipase increase, mucositis, diarrhea, lymphopenia, hyponatremia, leukopenia, fatigue, and serum amylase increase. Adjuvant nivolumab was feasible as defined in the protocol. Concomitant nivolumab with the 4 tested regimens was safe for patients with intermediate- and high-risk HNSCC, and subsequent adjuvant nivolumab was feasible as defined (NCT02764593).

Evaluating the time toxicity of cancer treatment in the CCTG CO.17 randomized clinical trial (RCT).

248 Background: Most individual treatments for advanced cancer are associated with modest survival benefits. The time spent in pursuing these treatments can be substantial. We have previously developed a pragmatic and patient-centered metric of these time costs, which we term ‘’time toxicity’’, as any day with physical healthcare system contact. This includes outpatient visits (e.g., for bloodwork, scans, infusions, urgent care), emergency room visits, and overnight stays in a healthcare facility. Herein we sought to assess time toxicity in a completed RCT. Methods: We conducted a secondary analysis of the Canadian Cancer Trials Group CO.17 RCT that evaluated weekly cetuximab infusions vs supportive care alone in 572 patients with advanced colorectal cancer. CO.17 recruited participants in Canada, Australia and New Zealand. Initial results reported a 6-week improvement in median overall survival (OS) with cetuximab (6.1 vs 4.6 months, p = 0.005). Subsequent analyses reported that OS benefit was restricted to and significantly more in patients with K-ras wild-type tumors. We calculated patient-level time toxicity by analyzing treatment, follow-up, and resource utilization forms. We considered a day without physical healthcare contact as a ‘’home day’’. Thus, for a patient, OS was time toxic days + home days. We compared medians of time measures across arms, and stratified results by K-ras status. Results: In the overall population, median time toxic days were higher in the cetuximab arm (28, vs 10, p < 0.001), although median home days were not statistically different (140, vs 121, p = 0.09). The proportion of time toxic days (time toxic days/OS) were significantly more with cetuximab (18%, vs 6%, p < 0.001). Of the 28 time toxic days in the overall cetuximab arm, 14 (50%) were protocol-related (e.g., scheduled infusions etc). Stratified results are in the table. Conclusions: Time toxicity can be extracted through secondary analyses of RCTs. In CO.17, despite an overall OS-benefit with cetuximab, home days were statistically similar across arms. In the K-ras-mutated group, cetuximab was associated with numerically similar OS but more time toxic days. In the K-ras-wild type group, cetuximab was associated with higher home days. Thus, time toxicity data need not always be sobering. Time toxicity measures can supplement traditional survival endpoints in RCTs to guide patient-oncologist decision-making. Cooperative group RCTs are well positioned for such analyses. Clinical trial information: NCT00079066. [Table: see text]

Pathological Evaluation of Resected Colorectal Liver Metastases: mFOLFOX6 Plus Bevacizumab versus mFOLFOX6 Plus Cetuximab in the Phase II ATOM Trial.

Simple SummaryWe compared the pre-planned histopathological responses, such as tumor regression grade (TRG), modified TRG, and dangerous halo (DH) of resected liver metastases, in patients who received modified FOLFOX6 plus bevacizumab and modified FOLFOX6 plus cetuximab for liver-limited colorectal metastases from the ATOM trial. We clarified the difference between bevacizumab and cetuximab in terms of histological response. TRG is a useful marker for determining prognosis in both treatments. We also showed, for the first time, that DH is associated with prognosis.We compared the preplanned histopathological responses of resected liver metastases from patients who received modified FOLFOX6 plus bevacizumab or modified FOLFOX6 plus cetuximab for liver-limited colorectal metastases in the ATOM trial. Fibrosis and viable tumor cells in tumor regression grade (TRG), infarct-like necrosis in modified TRG (mTRG), and dangerous halo (DH) were assessed. Fifty-five patients (28 and 27 patients in the bevacizumab and cetuximab arms, respectively) were divided into the low (viable tumor cells ≤ 50%) and high (>50%) TRG or mTRG groups. DH was characterized as absent/rare or focal/diffuse. Compared to the bevacizumab arm, the cetuximab arm was more effective, with respect to low TRG (13 vs. 23 patients) and absent/rare DH (14 vs. 19 patients), respectively. Low mTRG was similarly observed in both arms. Low TRG/mTRG and absent/rare DH showed better relapse-free survival (RFS) than high TRG/mTRG and focal/diffuse DH. In the bevacizumab arm, a significant difference in RFS existed between the low and high TRG groups, while in the cetuximab arm, for TRG, mTRG, and DH, the low and absent/rare groups demonstrated significantly longer RFS than the high and focal/diffuse groups, respectively. TRG could estimate RFS in patients who underwent liver metastasectomy after bevacizumab or cetuximab chemotherapy.

A Systematic Review of Conversion to Resectability in Unresectable Metastatic Colorectal Cancer Chemotherapy Trials.

Metastasectomy in patients with metastatic colorectal cancer (mCRC) confers a significant survival benefit. We hypothesized that conversion to resectability (C2R) correlates with superior overall survival (OS) in patients with unresectable mCRC. A prospectively registered systematic review (PROSPERO CRD42015024104) of randomized clinical trials published after 2003 was conducted. Exposure of interest was C2R with a primary outcome of OS. Clinical trials were classified based on difference in C2R between study arms (<2%, 2% to 2.9%, ≥3%). Generalized estimating equations were used to measure associations while adjusting for multiple observations from the same trial. Of 2902 studies reviewed, 30 satisfied selection criteria (n=13,618 patients). Median C2R was 7.3% (interquartile range [IQR]: 5% to 12.9%), with maximum C2R in the FOLFOX/FOLFIRI+cetuximab arm (28.6%). The median difference in C2R between 2 arms of the same study was 2.3% (IQR: 1.3% to 3.4%) with a maximum difference of 15.4% seen in FOLFOX/FOLFIRI+cetuximab versus FOLFOX/FOLFIRI. Median OS for the entire patient cohort was 20.7 months (IQR: 18.9 to 22.7 mo), with a between group difference of 1.3 months (IQR: -1.2 to 3.6 mo). The median survival difference between the 2 study arms with <2% C2R difference was 0.8 months versus 1.6 months with ≥3% C2R rates . Increasing C2R had an incremental dose-effect response on OS ( P =0.021), and higher response rates correlated with C2R rates ( P =0.003). C2R occurs infrequently and variably in clinical trials enrolling patients with unresectable mCRC. Prioritization of chemotherapeutic agents that enhance C2R might improve OS of patients.

Genetic variants involved in the cGAS-STING pathway predict outcome in patients with metastatic colorectal cancer: Data from FIRE-3 and TRIBE trials

BackgroundThe activation of stimulator of interferon genes (STING) was reported to enhance cetuximab-mediated natural killer cell activation and dendritic cell maturation. Polymorphisms in genes in the cyclic GMP-AMP synthase (cGAS)-STING pathway may affect innate immune response. Therefore, we hypothesised that genetic variants in the cGAS-STING pathway may predict the efficacy of cetuximab-based treatment in patients with metastatic colorectal cancer. MethodsGenomic DNA from blood samples of patients enrolled in FIRE-3 (cetuximab arm, n = 129; bevacizumab arm, n = 107) and TRIBE (bevacizumab arm, n = 215) was genotyped using the OncoArray-500K bead chip panel. Seven selected single nucleotide polymorphisms in 3 genes (cGAS, STING and interferon B1 (IFNB1)) were analysed for the association with overall survival and progression-free survival. ResultsIn the cetuximab cohort, patients with STING rs1131769 any T allele showed significantly shorter overall survival (36.3 versus 56.1 months) than carriers of C/C in both univariate [hazard ratio (HR) = 2.08; 95% confidence interval (CI): 1.06–4.07; P = 0.03] and multivariate (HR = 2.98; 95% CI: 1.35–6.6; P = 0.0085) analyses; patients carrying IFNB1 rs1051922 G/A and A/A genotype showed a significantly shorter progression-free survival than carriers of G/G allele in both univariate (G/A versus G/G, 10.2 versus 14.1 months, HR = 1.84; 95% CI 1.23–2.76; A/A versus G/G, 10.7 versus 14.1 months, HR = 2.19; 95% CI 0.97–4.96; P = 0.0077) and multivariate analyses (G/A versus G/G, HR = 2; 95% CI 1.22–3.3; A/A versus G/G, HR = 2.19, 95% CI 0.92–5.26, P = 0.02). These associations were not observed in the bevacizumab arm of FIRE-3 or TRIBE. ConclusionThese results suggest for the first time that germline polymorphisms in STING and IFNB1 genes may predict the outcomes of cetuximab-based treatment in patients with metastatic colorectal cancer.

P-90 First-line anti-EGFR agents (panitumumab or cetuximab) plus chemotherapy in patients with metastatic colorectal cancer: Onco-colon Turkey study subgroup analysis

The guidelines support the use of the epidermal growth factor receptor (EGFR) inhibitors panitumumab or cetuximab for the treatment of metastatic colorectal cancer (mCRC) on significant clinical benefits in patients with wild-type RAS. We assessed the efficacy and toxicity of panitumumab versus cetuximab in Onco-Colon Turkey registry patients. Patients with wild-type RAS mCRC treated with fluorouracil-oxaliplatin- and irinotecan-based chemotherapies in first-line setting were evaluated to either panitumumab or cetuximab including combinations. The efficacy of cetuximab vs panitumumab on overall survival (OS) and progression-free survival (PFS) and safety profile when combined with chemotherapy regimen was compared retrospectively. From January 2016 to March 2019, 1065 patients were recorded in Onco-Colon Turkey Registry, and 316 (47.4%) and 351(52.6%) patients were received the panitumumab and cetuximab as anti-EGFR treatment in first-line setting, respectively. The panitumumab was used more commonly with a combination regimen containing oxaliplatin (74.9%), while the cetuximab was used more in contingency with a combination regimen containing irinotecan (50.4%) (p=0.000). The median PFS was 11.6 months in the panitumumab arm and 11.0 months in the cetuximab arm, (p=0.270), and median OS was 26.5 and 27.6 months (p = 0.726), respectively. The overall response rate was 58.4% in panitumumab arm and 51.4% in cetuximab arm (p=0.138). The incidence of acneiform rash and thrombocytopenia was higher in the panitumumab arm (p=0.011 and 0.045) and the incidence of nausea/vomiting was higher in the cetuximab arm (p=0.013). Our findings show that panitumumab is similar to cetuximab and that these agents provide equal progression-free and overall survival benefit in this population of patients with wild-type RAS. Both agents had toxicity profiles that were to be expected.

Recurrence pattern after chemoradiotherapy for HPV-associated oropharyngeal squamous cell carcinoma with respect to induction chemotherapy and escalated radiation dose-results from a prospective randomized phase II study.

6074 Background: Patients with HPV associated squamous cell carcinoma of the oropharynx have a favorable outcome with respect to tumor control and overall survival (OS) after treatment with chemoradiotherapy (CRT). The leading cause of death in these patients is reported to be peripheral metastases. Because of the favorable outcome for these patients, the medical community tries to find methods to ameliorate treatment intensity, mainly in order to reduce long term morbidity. However, between 10 and 15 % of patients relapse locally in the primary tumor as first site of disease failure. Methods: In this multicentre, randomized, controlled, phase II trial 152 patients with locoregionally advanced oropharyngeal cancer were randomized in a 1:1 ratio to either radiotherapy with cetuximab (arm B) versus the same regimen preceded by 2 cycles of induction chemotherapy (IC) with taxotere/cisplatin/5-FU (arm A). To decrease risk of local failure, an escalated radiation (RT) dose of 74.8 Gy was delivered to T3/T4 tumors and to T2 tumors &gt; 3 cm in the base of tongue. Eligibility criteria included patients 18-75 years, ECOG performance status 0-1 and adequate organ functions. Primary endpoint of the study was to compare PFS between the treatment arms, secondary objectives were recurrence pattern, locoregional control, OS and toxicity. Results: PFS at 2 years was 84.2% (95%CI 76.4-92.8) in arm A and 78.4 (95%CI 69.5-88.3) in arm B (p = 0.20). At the time of analysis there were 26 disease failures, 9 in arm A and 17 in arm B. In arm A there were 3 local, 2 regional and 4 distant relapses as first site of recurrence, and in arm B 4, 4 and 9 relapses in corresponding sites. Local relapse rate as first site of failure was low, i.e. in 4.7%. Local failures constituted 7 relapses out of all 26 (27%), and in 4 of these local failures (57%), the escalated dose was given. In arm B, patients who had no IC, there were more than twice as many patients who had distant metastases as first site of relapse compared to arm A (n.s.). No patient who had a response to IC in the primary tumor or in regional lymph nodes, respectively, measured with CT or MRI, of either CR+CR or CR+PR, had any recurrence, local, regional or distant. So, IC could identify 22 out of 73 evaluable patients (30%) in arm A, who never had any recurrence during follow up. Conclusions: A high incidence of distant metastases as first site of failure is recognized while local failure rate is low. However, despite a high RT dose of 74.8 Gy, delivered to the primary tumor, relapses can appear in this site. Radiological response of tumor to IC could identify patients with no tumor relapse, at least within the first years of follow up, possible candidates for de-escalation treatment protocols. Clinical trial information: 2009-013438-26.

Efficacy of FOLFIRI plus cetuximab vs FOLFIRI plus bevacizumab in 1st-line treatment of older patients with RAS wild-type metastatic colorectal cancer: an analysis of the randomised trial FIRE-3

SummaryBackgroundThe evidence on the efficacy of anticancer therapy is limited in older patients with metastatic colorectal cancer (mCRC). This retrospective analysis of phase III FIRE-3 trial assesses the efficacy of FOLFIRI plus either cetuximab or bevacizumab according to the patients’ age and sidedness of primary tumour.MethodsThe study endpoints overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) were compared between younger (<65 years) and older (≥65 years) patients, followed by stratification according to primary tumour sidedness. ORR was compared using Fisher´s exact test, OS and PFS were estimated by the Kaplan–Meier method and compared using the log-rank test. Univariate Cox regression analyses assessed hazard ratios and 95% confidence intervals for OS and PFS.ResultsOverall, older patients with RAS WT tumours had a significantly shorter OS when compared to younger patients (25.9 months vs 29.3 months, HR 1.29; P = 0.02). Also the proportion of right-sided tumours was significantly greater in older patients (27.1% vs 17.9%; P = 0.029). Secondary resection rates were numerically higher in younger patients (25.4% vs. 17.6%, P = 0.068) than in older patients. This was primarily seen in the Cetuximab arm, where older patients underwent less likely resection (13.1% vs. 26%; P = 0.02). Older patients with left-sided tumours showed only a trend towards greater efficacy of cetuximab (HR 0.86; P = 0.38). In patients with right-sided primary tumours, older patients did not appear to benefit from cetuximab in contrast to younger patients (≥65 years: 16.6 months vs 23.6 months, HR 1.1; P = 0.87; <65 years: 21.9 months vs 16.4 months HR 1.5; P = 0.31).ConclusionsIn FIRE-3, OS was generally shorter in older patients in comparison to younger patients. This could be explained by the overrepresentation of right-sided tumours and a lower secondary resection rate in older patients. The efficacy of targeted therapy was dependent on tumour sidedness in older patients with RAS WT mCRC.Clinical trialFIRE-3 (NCT00433927).

The role of germline polymorphisms in genes involved in the antioxidant system to predict the efficacy of cetuximab for patients with metastatic colorectal cancer (mCRC) enrolled in FIRE-3 trial.

143 Background: Reactive oxygen species activate RAS/MAPK signaling either through inactivation of phosphatases or by direct oxidation of kinases. We hypothesized that functional genetic variants in genes involved in the antioxidant system may be associated with the efficacy of cetuximab in mCRC patients. Methods: We analyzed genomic and clinical data from FIRE-3, a phase III trial which compared cetuximab and bevacizumab in combination with FOLFIRI in untreated mCRC patients. Genomic DNA extracted from blood samples was genotyped using an OncoArray (Illumina, Inc., San Diego, CA, USA). Candidate 13 functional single nucleotide polymorphisms (SNPs) ( TXN rs2301242, TXN rs2301241, TXN2 rs4821494, TXN2 rs9619611, TXN2 rs59841625, CAT rs7943316, CAT rs564250, CAT rs11604331, CAT rs1001179, CAT rs769217, GPX4 rs757229, GPX4 rs4807542, and GPX4 rs713041) were tested for association with progression-free survival and overall survival (OS), using log-rank test and Cox proportional hazards model. To confirm the predictive value, the treatment-by-SNP interaction was tested. Results: A total of 236 patients were available for the SNP analyses (cetuximab arm, n = 129; bevacizumab arm, n = 107). In the cetuximab arm, two SNPs were significantly associated with clinical outcomes in univariate analyses: TXN2 rs4821494 (T/T vs any G allele, hazard ratio [HR] on OS = 2.17, 95% confidence interval [CI] = 1.04–4.56, log-rank p = 0.04) and GPX4 rs4807542 (G/G vs any A allele, HR on OS = 2.04, 95% CI = 1.05–3.98, log-rank p = 0.03). Multivariate analysis confirmed the significance in TXN2 rs4821494 (T/T vs any G allele, HR on OS = 2.47, 95% CI = 1.06–5.72, p = 0.03). In the bevacizumab arm, univariate analyses did not detect any significant associations between the SNPs and clinical outcomes. Treatment-by-SNP interaction test showed the significant predictive value of TXN2 rs4821494 in terms of OS ( p = 0.03). Conclusions: TXN2 rs4821494 involved in the antioxidant system may predict the efficacy of cetuximab, in comparing with bevacizumab, in the first-line treatment of mCRC. Our novel findings warrant further validation studies.

Randomized phase II trial of avelumab alone or in combination with cetuximab for patients with previously treated, locally advanced, or metastatic squamous cell anal carcinoma: the CARACAS study

BackgroundNo standard therapies beyond first line are established for advanced squamous cell anal carcinoma (aSCAC). Earlier preliminary data suggest activity of epidermal growth factor receptor (EGFR) inhibition and programmed cell...