Search

129 Background: Rechallenge therapy with epidermal growth factor receptor (EGFR) inhibitors in chemo-refractory metastatic colorectal cancer (mCRC) is an emerging therapeutic approach. Trifluridine-tipiracil is approved for treatment of chemo-refractory mCRC patients. Methods: Chemo-refractory RAS WT mCRC patients, that had a major response (partial or complete response) to first-line chemotherapy plus an anti-EGFR monoclonal antibody and had an-anti-EGFR drug-free interval during second-line therapy of four or more months were randomized in a phase II trial to assess the addition of the anti-EGFR monoclonal antibody panitumumab to trifluridine-tipiracil as third-line rechallenge therapy. The primary endpoint was progression free survival (PFS). Baseline plasma was analyzed for circulating free tumor (ct) DNA by using Biocartis Idylla platform to detect mutations in KRAS, NRAS, BRAF ( V600E) and EGFRextracellular domain ( S492R). In 24 patients with baseline RAS/BRAF wild type (WT) ctDNA, Foundation One liquid CDx (324 gene profiling) was also performed before treatment and at disease progression. Results: 62 patients were treated with trifluridine-tipiracil (31 patients, arm A) or with trifluridine-tipiracil plus panitumumab (31 patients, arm B). As of September 16, 2022, 1 patient in arm A and 2 patients in arm B were on treatment. The primary endpoint was met. Median PFS (mPFS) was 4 months in arm B versus 2.5 months in arm A [hazard ratio (HR): 0.48; 95% CI 0.28-0.82; P = 0.007]. Baseline plasma RAS/BRAF WT ctDNA was found in 23/31 patients in Arm A and in 26/31 patients in Arm B. In this group, mPFS was 4.5 months in Arm B versus 2.6 months in Arm A (HR: 0.48; 95% CI 0.26-0.89; P = 0.019). Disease control (major responses plus stable disease) was higher for patients in Arm B compared to Arm A (81% versus 48%), whereas disease progression was the best response in 19% versus 52% patients, respectively. PFS rates at 6 and 12 months were 38.5% and 15.4% in arm B versus 13% and 0% in arm A. At disease progression, Foundation One liquid CDx detected several mutations within the EGFR pathway, which could correlate with cancer cell resistance to panitumumab. Conclusions: This is the first prospective randomized trial which evaluated anti-EGFR monoclonal antibody (panitumumab) in addition to standard of care (trifluridine-tipiracil) as third-line rechallenge therapy in chemo-refractory RASWT mCRC patients. Baseline liquid biopsy allows selection of RAS/BRAF WT ctDNA patients who could have a relevant clinical benefit. Clinical trial information: NCT05468892 .

TPS731 Background: The immune system plays a crucial role in modulating response to monoclonal antibodies therapy in cancer. Novel immunecheckpoint inhibitors have demonstrated potent efficacy alone and in combinations with cytotoxic agents in several cancers. In this regard, avelumab in combination with cetuximab might be a relevant rechallenge strategy in RAS wild-type (WT) metastatic colorectal cancer (mCRC) patients treated in first-line with chemotherapy (CT) in combination with anti-EGFR drugs and who achieved a complete or partial response. Methods: CAVE Colon is a single arm, multi-center phase II study designed to evaluate the efficacy of avelumab and cetuximab in pre-treated RAS WT mCRC patients. Eligible patients: pathologically confirmed RAS WT mCRC treated with a first-line CT in combination with an anti-EGFR agent with a major response achieved (complete or partial), who have progressed to a second line therapy, and received no prior immunotherapy. Primary endpoint is overall survival, secondary endpoint are overall response rate according to RECIST 1.1, progression free survival and safety profile. The current study seeks to demonstrate a median OS of 11 months (alternative hypothesis) by the experimental combination for comparison with historical median OS 8.0 (null hypothesis) with standard third line treatments, which correspond to an improvement of OS at six months from 40% to 57%. It was estimated that it would be needed to enroll 66 patients to achieve a 80% power with a one-sided 5% level test. The accrual period will be 18 months and the total duration of the study will be 36 months. Considering a potential drop-out of approximately 15% of patients, a total of 75 patients will be recruited. Seven patients have been enrolled and started treatment to date (September 15, 2018) with avelumab 10 mg/kg q14 as a one-hour i.v. infusion and cetuximab at 400 mg/m2 over two-hour and subsequently 250 mg/m2 q 14 as one-hour i.v. infusion until disease progression or unacceptable toxicity. EudraCT number: 2017-004392-32. This study is partially supported by Merck KgA, Darmstadt, Germany. Results: N/A. Conclusions: N/A. Clinical trial information: EudraCT number: 2017-004392-32.

e15018 Background: A high neutrophil/lymphocyte ratio (NLR) in peripheral blood has been shown to be a strong negative prognostic factor in several types of tumors, such as colorectal, breast, panc...

160 Background: HER2 overexpression in GC is reported in 20% of cases; it is considered a negative prognostic factor with a positive predictive value of response to trastuzumab. We reviewed our case records analyzing its clinical significance. Methods: We retrospectively collected the data for patients (pts.) with histologically confirmed GC and tumor specimens. Results: From June 2011 to December 2012 we analyzed HER2 status in 76 pts with metastatic GC. (M/F 50/26, median age 64 years, ECOG performance status 0/1/2 = 59/12/5, G1/G2/G3 = 6.6%/22.4%/71%). In 36.8% of pts. gastric body was the primary tumor site. HER-2 overexpression was observed in 13 pts (17.1%). HER2-positive group had the following characteristics: M/F = 10/3, median age 63 years; Lauren’s histotype: 75% intestinal and 25% diffuse; G1/G2/G3 = 15.4%/30.8%/53.8%; T3-T4 tumors and N+ disease were observed in 46.1% respectively; the primary tumor site was: proximal 38.4%, distal 61.6%. 46.1% of pts with metastatic disease received a first line CT with a median progression free survival (mPFS) of 5 months (range, 3-7) and a median overall survival (mOS) of 9 months (range, 3-23). In HER2-negative group, (N= 63, M/F = 40/23, median age 64 years), 92.1% of pts. Lauren’s histotype: 45.5% intestinal and 54.5% diffuse; G1/G2/G3 = 4.8%/20.6%/74.6%; metastatic disease: 55.5%. T3-T4 tumors were assessed in 65.1% of pts and N+ disease in 61.9%. The primary tumor location was: proximal 38.1%, distal 61.9%. 57.1% with advanced disease received a first line CT with a mPFS of 5.5 months (range, 2-30) and a mOS of 10 months (range, 2-67). No statistically significant differences for mPFS (p: 0.08) and mOS (p: 0.06) were observed between HER2 positive and HER2 negative metastatic patients. Conclusions: According to our experience, HER2 overexpression doesn’t seem to correlate with a worse prognosis. In particular, it is not correlated with a worse histology and higher stage at diagnosis. Furthermore, no differences in terms of mPFS and mOS were observed between HER2 positive and HER2 negative metastatic pts.

e14565 Background: Cetuximab in combination with standard doublet chemotherapy is an effective treatment in KRAS wt mCRC patients (pts). The present study investigated a treatment strategy of cetuximab in combination with FOLFOX4 as a second line therapy for KRAS wt mCRC pts treated in first line with cetuximab plus FOLFIRI. Methods: KRAS wt m CRC pts were treated in first line with cetuximab plus FOLFIRI and at progression were randomized (1:1) to receive FOLFOX alone (Arm A) or in combination with cetuximab (Arm B). Primary endpoint for each treatment line was progression-free survival (PFS), with secondary endpoints overall survival (OS), response rate (RR), disease control rate and safety. 221 events would be required to statistically differentiate PFS between the two arms with 80% power for the second line treatment. Here we report the results of first line cetuximab plus FOLFIRI treatment. Results: From July 2009, 344 pts were enrolled: 58% males, median age 63 years (range, 20-81 years), ECOG performance status, 0 (85%); 1 (15%); synchronous metastasis (75%). For the 319 evaluable patients, median PFS was 10 months; overall response rate (ORR) was 55% with 47% partial responses (PR), 8% complete responses (CR) and 35% stable disease (SD) for a disease control rate (DCR) of 90%. The most common grade 3/4 adverse events were: skin reactions (15%), diarrhea (9%) and neutropenia (6%). As of January 31 2013, 118 pts have progressed and have been enrolled in second line treatment (58 Arm A; 60 Arm B). Conclusions: The results of first line treatment with cetuximab plus FOLFIRI confirm in a multicenter trial in prospectively selected KRAS wt mCRC pts the efficacy and tolerability of this combination. The randomized second line part of the study is currently ongoing. Multiple gene next generation sequencing to characterize a 24 genes mutation profile is currently ongoing. Clinical trial information: 2009-014041-81.

3039 Background: AEE788 is an oral inhibitor with potent activity against multiple tyrosine kinases including EGFR, HER2, and VEGFR2. This phase 1 study was to assess the safety, pharmacokinetics (...