Failure Of Fluoropyrimidine Research Articles

A phase II study of TAS-102 (FTD/TPI) in combination with ramucirumab (RAM) in advanced, refractory gastric (GC) or gastroesophageal junction (GEJ) adenocarcinomas (GEAs).

302 Background: The RAINBOW trial established the standard of care for treatment of metastatic GEAs with ramucirumab and paclitaxel after failure of fluoropyrimidine and platinum-based chemotherapy. While the combination achieved an objective response rate (ORR) of 28%, the incidence of any grade neuropathy was 46%. Therefore, there is an unmet need for novel treatment combinations that minimize the long-term toxicity of neuropathy. In a recently published Asian study, the combination of RAM+TAS-102 showed good disease control and acceptable toxicity profile. Methods: This was a single arm, single institution phase II trial using the combination of TAS-102 plus RAM in refractory GEAs. Patients (pts) received RAM 8mg/kg intravenously on day 1 and 15, and TAS-102 35mg/m2 orally twice daily on days 1-5 and days 8-12 every 28-day cycle. The primary endpoint was 6-months overall survival (OS) rate and secondary endpoints were progression free survival (PFS), ORR and safety profile. The trial was registered at www.clinicaltrials.gov (NCT03686488). Results: At data cut-off of August 15, 2021, 23 pts were enrolled. Baseline demographics are as follows: median age of 62 years (range: 23-74), median lines of prior therapy of 1 (1: 14 pts vs ≥2: 9 pts) and location of primary tumor (GEJ:19 vs GC: 4). 6-month OS rate was 56.2%. Median OS was 6.2 month (95% CI: 5.4-7.0) and median PFS was 4.9 months with median observation of 2.3 months. Of 17 evaluable pts defined as more than one baseline imaging, 1 (6%) had partial response (PR) and 15 (88%) had stable disease (RECIST v1.1). Eleven pts came off the study due to progression of disease, 8 for toxicities and 4 for consent withdrawal. Most common treatment-emergent adverse events (TEAEs) were diarrhea (39%), fatigue (39%) and hypertension (39%). Total 11 pts (48%) experienced grade 3 and 4 TEAEs, and most common Gr3 and 4 TEAEs were neutropenia (17%) and anemia (13%). Conclusions: The combination of RAM and TAS-102 showed very similar disease control rate as the study in Asia. The combination has now shown modest activity in advanced GEAs and should be investigated further now in the context of patients receiving immunotherapy-based treatment as first-line treatment. A randomized phase II study is currently enrolling patients with ramucirumab and TAS-102 or paclitaxel. Clinical trial information: NCT03686488.

Radiosensitisation and enhanced tumour growth delay of colorectal cancer cells by sustained treatment with trifluridine/tipiracil and X-rays.

Trifluridine/tipiracil (FTD/TPI; marketed as Lonsurf®) has shown clinically relevant activity after fluoropyrimidine failure in colorectal cancer and may thus be of increased efficacy compared with current standard capecitabine chemoradiation. Here we investigated the colorectal cancer cell lines HT29, HCT116, SW48 and Caco-2 to provide a preclinical rationale for FTD/TPI-based chemoradiation treatment. All lines incorporated similar amounts of FTD, irrespective of treatment concentration and duration, then arrested in S phase, showed persistent γH2AX induction and eventually underwent endoreplication, resulting in polyploidy. Clonogenic assays performed for four combined treatment schedules demonstrated additivity for treatments given within 6h of each other. However, 24h FTD/TPI treatment prior to irradiation caused 1.6-2.4 fold radiosensitisation. Combined in vivo treatment was well tolerated and caused a marked tumour growth delay, similar to capecitabine radiochemotherapy regimes. Prolonged S phase arrest, persistent γH2AX signalling, endoreplication and polyploidy may contribute to the cytotoxicity of FTD/TPI. The strong radiosensitising effect observed in vitro after prolonged treatment with FTD/TPI and equivalence with capecitabine-based chemoradiation in vivo support a daily fractionated combined regime of FTD/TPI and radiation in rectal cancer treatment. This is now being tested in a phase I/II clinical trial (NCT04177602).

Combined PD-1 inhibition (Pembrolizumab) and CCR5 inhibition (Maraviroc) for the treatment of refractory microsatellite stable (MSS) metastatic colorectal cancer (mCRC): First results of the PICCASSO phase I trial.

3010 Background: Checkpoint inhibition using PD-1/PD-L1 inhibitors does not show clinically relevant activity in MSS/pMMR (Mismatch Repair Proficient) colorectal cancer. Previous work showed that inhibition of CCR5 (C-C chemokine receptor type 5) leads to a macrophage re-polarization towards M1 macrophages within the tumor microenvironment which directly affects immune cell infiltrates. The current phase I trial explores a combined modification of the innate immune system (by CCR 5 blockade) and the adaptive immune system (by PD-1 inhibition) in the treatment of MSS CRC. Methods: 20 patients with metastatic MSS/pMMR colorectal cancer with failure of fluoropyrimidines, oxaliplatin, irinotecan, VEGF antibodies and EGFR antibodies (in ras WT patients) received pembrolizumab 200 mg q21d and maraviroc 300 mg bid cont. for 8 cycles, followed by pembrolizumab monotherapy for a maximum of 24 additional cycles. Imaging was performed every nine weeks (RECIST and irRECIST criteria). Primary endpoint was the feasibility rate (rate of patients receiving the protocol treatment during the core treatment without special event: treatment-related Grade ≥ 3 immune-related abnormalities, treatment-related Grade ≥ 4 AEs or any toxicity-related premature withdrawal of treatment). Secondary endpoints included safety/toxicity, ORR, PFS and OS. Results: 20 patients were enrolled. The median number of applied cycles was 3.5 for pembrolizumab and 3.5 for maraviroc. Two patients completed the core treatment period with pembrolizumab and started maintenance treatment. The feasibility rate was 94.7% (90% CI 77.4 to 99.7%), with one patient experiencing a special event. Except this grade 4 event (hyperglycemia) no ≥ 3 treatment-related toxicities were observed. According to irRECIST criteria one patient showed a partial response and one a stable disease as best response, resulting in an irDCR of 10.5%. Median PFS according to irRECIST was 2 months (CI 95%, 2 to 3), median OS 9 months (CI 95%, 6 to 20). Conclusions: Therapy with pembrolizumab and maraviroc was feasible and showed a beneficial toxicity pattern. Clinical activity in MSS CRC patients was limited, however prolonged disease stabilizations were observed in single patients and overall survival was higher than expected in this heavily pretreated population. Clinical trial information: NCT03274804 .

Reverce: Randomized phase II study of regorafenib followed by cetuximab versus the reverse sequence for metastatic colorectal cancer patients previously treated with fluoropyrimidine, oxaliplatin, and irinotecan.

557 Background: The optimal treatment sequence in current standard care for patients (pts) with anti-EGFR antibodies-naïve metastatic colorectal cancer (mCRC) is cetuximab (C) followed by regorafenib (R). The objective of this randomized phase II trial is to evaluate efficacy and safety of the therapeutic sequence of R followed by C compared with that of C followed by R for mCRC pts. Methods: Pts with KRAS exon 2 wild-type mCRC after failure of fluoropyrimidine, oxaliplatin, and irinotecan were randomized to receive sequential treatment with R followed by C ± irinotecan (R-C arm) or reverse sequence (C ± irinotecan followed by R; C-R arm). The primary endpoint was OS. Key secondary endpoints included PFS with initial treatment (PFS1), PFS with second treatment (PFS2), safety, and QOL. The exploratory endpoint was serial biomarker analyses including oncogenic alterations from ctDNA or multiple serum proteins. Results: Between November 2013 and September 2016, 101 pts (51 in the R-C arm and 50 in the C-R arm) were randomized and eligible for efficacy analysis. Baseline characteristics were well-balanced in both arms. Bevacizumab had been previously administered in 96% and 98% pts in R-C and C-R, respectively. Sequential treatment was succeeded in 86% pts in both arms. After a median follow-up of 29.0 months with 81 death events, median OS in R-C and C-R were 17.4 and 11.6 months, respectively (stratified logrank P = 0.0293), with a hazard ratio (HR) of 0.61 for OS (95% CI, 0.39–0.96). HR for PFS1 (R in R-C versus C in C-R) was 0.97 (95% CI, 0.61–1.54), whereas that for PFS2 (C in R-C versus R in C-R) was 0.29 (95% CI, 0.17–0.50). No unexpected safety signals were observed in both arms. OS results in RAS/RAF wild type populations with ctDNA analysis at study entry (n = 86) were similar to those of overall population. Conclusions: This was the first randomized study to compare the two therapeutic sequences of R and C for mCRC, suggesting R followed by C is the preferred sequence. Comparable PFS1 and remarkable PFS2 improvement may lead to a longer OS in R-C sequence. The results of detailed biomarker analysis would be also reported. Clinical trial information: UMIN000011294.

Analysis of RAS/BRAF mutations in a randomized phase II WJOG6510G study of panitumumab plus irinotecan versus cetuximab plus irinotecan in chemorefractory metastatic colorectal cancer.

624 Background: A randomized phase II WJOG6510G study demonstrated non-inferiority of panitumumab (Pmab) plus irinotecan (IRI) to cetuximab (Cmab) plus IRI in terms of progression-free survival (PFS) in wild-type (WT) KRAS exon 2 metastatic colorectal cancer (mCRC). Here, we performed exploratory analyses of updated survival data using KRAS exon 2 and RAS/BRAF statuses. Methods: In this trial, patients with WT KRAS exon 2 mCRC who progressed after failure of fluoropyrimidine, IRI, and oxaliplatin were randomized to receive Pmab or Cmab in combination with IRI. An independent central laboratory performed RAS/BRAF testing using a PCR-reverse sequence specific oligonucleotide method which can detect 48 types of KRAS/NRAS and 34 types of BRAF mutations. Results: In the ITT population, patient characteristics included the following (Pmab/Cmab): number 61/59; male 69%/63%; median age 64 y/64 y; ECOG PS 0 62%/54%; left-sided primary tumor 85%/88%; multiple sites of metastases 51%/66%. At the time of updated analysis, 113 (94%) and 117 (98%) out of 120 patients had OS and PFS events, respectively. Median PFS was 5.42 months in the Pmab arm and 4.27 months in the Cmab arm (HR 0.674, unstratified log-rank p = 0.035). Median overall survival (OS) was 14.85 months in the Pmab arm and 11.53 months in the Cmab arm (HR 0.675, p = 0.037). In 83 patients, RAS/BRAF tests revealed 19 patients (23%) with RAS and 4 patients (5%) with BRAF mutations (two with V600E, two with non-V600E). Patients with RAS and BRAF mutations did not respond to the treatments. In the RAS WT population, a better PFS trend was observed for Pmab treatment (median 6.06 months vs. 5.26 months, HR 0.629, p = 0.08); however, OS was similar in both arms (median 14.85 months vs. 11.26 months, HR 0.818, p = 0.449). Conclusions: In this analysis, a modest survival benefit was found to be associated with Pmab plus IRI compared to Cmab plus IRI in WT KRAS exon2 mCRC, which warrants further evaluation in the WT RAS population. The number of analytic cases of RAS/BRAF status will be updated in the presentation. Clinical trial information: UMIN000006643.

5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) as a third-line chemotherapy treatment in metastatic gastric cancer, after failure of fluoropyrimidine, platinum, anthracycline, and taxane.

Studies on the effects of third-line chemotherapy (CT) in advanced gastric cancer (GC) patients are still scarce. The aim of this study was to evaluate the efficacy and safety of the modified 5-fluorouracil, leucovorin, and irinotecan (mFOLFIRI) regimen as a third-line CT in metastatic GC patients, after failure of fluoropyrimidine, platinum, anthracycline, and taxane. After failure of first- and second-line therapies, 42 patients received third-line FOLFIRI (180 mg/m² irinotecan and 400 mg/m² leucovorin administered concomitantly as a 90-minute intravenous (IV) infusion on day 1, followed by a 400 mg/m² 5-fluorouracil IV bolus then 2600 mg/m² continuous infusion over 46 hours), between January 2009 and December 2015. FOLFIRI was administered for a median of 6 cycles (range 4-12 cycles). Eight patients achieved partial response, while 13 patients showed stable disease, resulting in the overall response rate (ORR) of 19% and disease control rate (DCR) of 50%. The most frequent grade 3-4 hematological and non-hematological toxicities were neutropenia (14.2%) and diarrhea (7.1%). The median progression-free survival (PFS) and overall survival (OS) from the start of third-line CT were 3.8 months (95% confidence interval [CI], 3.0-4.5) and 6.8 months (95% CI, 5.6-7.9), respectively. According to the multivariate analysis, two factors were independently predictive of the poor OS: >2 regions of metastasis (relative risk [RR], 2.6; 95% CI, 1.3-5.4) and a high level of carcinoembryonic antigen [CEA] (RR, 3.4; 95% CI, 1.6-7.4). In conclusion, FOLFIRI was well tolerated as third-line CT and showed promising PFS and OS in advanced GC patients, after failure of fluoropyrimidine, platinum, anthracycline, and taxane.

A phase Ib/II study of second-line therapy with panitumumab, irinotecan and everolimus (PIE) in metastatic colorectal cancer (mCRC) with KRAS wild type (WT): Biomarker substudy.

643 Background: Inhibition of mTOR in addition to EGFR may overcome upstream resistance to EGFR inhibitors in CRC. This phase Ib/II study evaluated the efficacy and safety of irinotecan, panitumumab and everolimus (Townsend et al. ESMO 2016).These are the results of the biomarker substudy. Methods: Patients with KRAS exon 2 WT mCRC after failure of fluoropyrimidine based therapy received IV irinotecan (200mg/m2) and panitumumab (6mg/kg) 2 weekly. Everolimus dose was 5mg orally alternate days for dose level 1/expansion, and 5mg daily for level 2. Survival outcomes were calculated using Kaplan-Meier method. DNA was isolated from FFPE tumour sections for whole exome sequencing. Reads were mapped to hg19 reference genome and variants called using GATK tool. RAS/RAF mutations (MT) identified were correlated with response (Fishers exact test), progression free survival (PFS) and overall survival (OS). Filtering for variants in genes associated with progressive disease (PD) was performed. Results: 48 patients were enrolled. 33 had adequate tissue and outcome data for analysis (29 dose level 1, 4 level 2). Median age 63 yrs (41-82), M/F 23/10, ECOG 0/1 17/16. 14 (42%) had partial response (PR), 15 (45%) stable disease (SD) as best response. Median PFS was 5.3 ms and OS 11.1 ms. Three patients had RAS MTs (KRAS exon 2 G12V, KRAS exon 3 Q61H, NRAS exon 2 G12D) and 5 BRAF V600E MT. 2/3 RAS MT had SD and 1/3 PR. 3/5 BRAF MT had SD and 2/5 PD. 13/25 all WT had PR (52%) and 10/25 (40%) SD. BRAF V600E was associated with poorer PFS v WT (median 2.7 v 6.1 ms; P < 0.0001). In all WT patients median PFS was 5.8 ms and OS 12.2 ms. In exploratory analysis 4 patients were heterozygous for PPP1R17 L12V variant (rs3735422) which correlated with PD in 3/4 (P = 0.003) and worse PFS (P = 0.0001). On multivariate analysis (COX regression) BRAF V600E MT and PPP1R17 L12V remained associated with worse PFS (p = 0.005 & p = 0.001 respectively). Conclusions: No responses were seen in patients with BRAF MT. One of 3 with RAS MT had a PR suggesting mTOR inhibition may overcome resistance in this group however this may represent purely a chemotherapy effect. PPP1R17 L12V variant should be validated in larger cohorts. Clinical trial information: NCT01139138.

HER2 Amplification and Cetuximab Efficacy in Patients With Metastatic Colorectal Cancer Harboring Wild-type RAS and BRAF

BackgroundCetuximab has shown clinical benefit in patients with metastatic colorectal cancer (mCRC) harboring wild-type RAS. Human epidermal growth factor receptor 2 (HER2) amplification may be a mechanism of cetuximab resistance. We evaluated the association between HER2 amplification and cetuximab efficacy in patients with mCRC harboring wild-type RAS and BRAF. Patients and MethodsBetween December 2003 and June 2013, we identified 142 patients with mCRC whose tumors harbored both wild-type exons 2, 3, and 4 in KRAS and NRAS, and wild-type exon 15 in BRAF using high throughput sequencing (OncoMap version 4.0). All patients received cetuximab after oxaliplatin, irinotecan, and fluoropyrimidine failure. HER2 status was determined using immunohistochemistry and silver in situ hybridization (SISH) and correlated with cetuximab efficacy. ResultsOf 142 RAS and BRAF wild-type tumors, we observed 7 cases (4.9%) of HER2 amplification by SISH. After a median follow-up of 13.2 months (range, 1.4-78.1 months), median progression-free survival (PFS) was significantly different according to HER2 status: 3.1 months in patients with HER2 amplification compared with 5.6 months in those with non-amplified HER2 (hazard ratio, 2.73; 95% confidence interval, 1.18-6.31; P = .019). Overall survival (OS) was not significantly different between groups, although there was a tendency towards shorter OS in patients with HER2-amplified tumors (hazard ratio, 1.31; 95% confidence interval, 0.61-2.82; 10.1 vs. 13.5 months; P = .488). ConclusionsHER2 amplification is predictive of shorter PFS after cetuximab treatment in patients with mCRC harboring wild-type RAS and BRAF. Further study is warranted for this patient population.

A short interval between bevacizumab and anti-epithelial growth factor receptor therapy interferes with efficacy of subsequent anti-EGFR therapy for refractory colorectal cancer.

Both bevacizumab and anti-epithelial growth factor receptor (EGFR) agents (e.g. cetuximab and panitumumab) are sequentially used for metastatic colorectal cancer (mCRC). Their co-administration as a first-line treatment does not improve outcome, indicating that there are negative interactions between these agents. A long-term pharmacokinetics study demonstrated serum persistence of bevacizumab following termination of bevacizumab 6 months after the last administration. This prompted us to investigate the impact of short intervals between bevacizumab and anti-EGFR antibody on the efficacy of subsequent anti-EGFR therapy. We retrospectively reviewed consecutive patients with KRAS exon 2 wild-type mCRC who underwent anti-EGFR therapy after the failure of fluoropyrimidines, oxaliplatin and irinotecan. We divided patients into two groups (Group A: the interval between bevacizumab and anti-EGFR agent< 6 months; Group B: the interval >6 months). Of the 114 included patients (median age, 63 years), 78 (68%) were male. Most patients (88%) were treated with cetuximab plus irinotecan. Groups A and B consisted of 74 and 40 patients, respectively. There were no significant differences in patient characteristics. Group B patients had significantly longer progression-free survival (4.2 vs. 6.6 months; HR, 0.65; 95% CI, 0.43-0.98; P = 0.038) and longer overall survival (11.6 vs. 14.3 months; HR, 0.63; 95% CI, 0.41-0.98, P = 0.039). The response rate was 24.3% in Group A and 47.5% in Group B (P = 0.012). A short interval between bevacizumab and anti-EGFR antibody treatment may interfere with the efficacy of subsequent anti-EGFR therapy.

P2-8-20 - Salvage line CPT-11 after failure of fluoropyrimidine and paclitaxel-based chemotherapy in advanced gastric cancer

P2-8-20 - Salvage line CPT-11 after failure of fluoropyrimidine and paclitaxel-based chemotherapy in advanced gastric cancer

Phase II study of everolimus as a salvage treatment after failure of fluoropyrimidine and platinum in patients with metastatic gastric cancer positive for pS6Ser240/4 expression.

4057 Background: Everolimus is a macrolide derivative of rapamycin which inhibits mTOR. Our previous phase II study in 2nd line setting showed that everolimus had no significant activity with 1.7 m...

O1-17-5 - Irinotecan as a Third-Line Treatment of Advanced Gastric Cancer After Failure of Fluoropyrimidine, Platinum, and Taxanes

Background: Oral fluoropyrimidine plus platinum regimen as a first-line and weekly paclitaxel monotherapy as a second-line were one of Japanese standard care for advanced gastric cancer. The irinotecan monotherapy has become a common practice as a third-line chemotherapy, though there are few reports regarding the efficacy. The aim of this study was to evaluate the efficacy and safety of irinotecan as a third-line chemotherapy in patients refractory or intorelant to first-line oral fluoropyrimidine plus platinum and second-line taxane.Methods: We retrospectively analyzed 52 patients received irinotecan as a third-line chemotherapy at the National Cancer Center Hospital, between February 2008 and December 2013.Results: The characteristics of the 52 patients were as follows: median age, 65 years (range, 41 to 78); male/female, 41/11; PS 0/1/2, 2/40/10; number of metastatic sites 1/ ≥ 2, 14/38; and peritoneal metastasis; yes/no, 30/22. The median number of irinotecan administration was three (rage, 1 to 25), and 25 patients (48%) had initial dose reduction. Among the 32 patients who had measurable lesions by RECISTv1.1 criteria, one patient achieved confirmed partial response and six patients had stable disease. The overall response rate was 3% and the disease control rate was 21%. The median progression-free survival was 2.3 months (95% confidence interval [CI], 1.8 to 2.8) and median overall survival was 4.0 months (95% CI, 2.5 to 5.5). The adverse events of grade 3/4 included neutropenia in 14 patients (27%), febrile neutropenia in six patients (12%), anorexia in six patients (12%), and diarrhea in three patients (6%), respectively.Conclusion: Irinotecan would be reasonably well tolerated as a third-line therapy regimen for patients with advanced gastric cancer, however the efficacy might be limited.

A salvage treatment with combination of docetaxel and epirubicin in patients with recurrent or metastatic gastric cancer after fluoropyrimidine failure.

e15081 Background: For patients with recurrent or metastatic gastric cancer (GC), second-line chemotherapy is considered as standard in practice with various regimens. While docetaxel and epirubicin are one of the most commonly used agents in GC, the feasibility of the combination has not been evaluated. Methods: In this phase II trial, patients with recurrent or metastatic GC who had failed to fluoropyrimidine-based chemotherapy were recruited. Docetaxel (50 mg/m2) and epirubicin (50 mg/m2) were administered every 3 weeks. The primary end-point was disease control rate (DCR) and the secondary end-points were OS, PFS and toxicities. As there is a notion that anthracycline is effective in HER2-positive breast cancer, we also analyzed the efficacy according to HER2 status in GC patients. Results: From Sep 2012 to Oct 2013, a total of 22 patients were enrolled. The median age was 51 (range 33-70) and M:F ratio was 15:7. Five patients were HER2 positive and they all had progressed after anti-HER2 treatment. O...

Association of bevacizumab-free interval with efficacy of anti-EGFR therapy in patients with metastatic colorectal cancer.

610 Background: Both bevacizumab (Bev) and anti-EGFR agents are sequentially used for metastatic colorectal cancer (mCRC). Some basic studies reported the interaction between Bev and anti-EGFR agents in vivo. Therefore we hypothesized the shorter Bev-free interval may lead to poor outcome of anti-EGFR therapy. The aim of this study is to examine the association of the interval between last Bev administration and initial anti-EGFR agents with efficacy of anti-EGFR therapy. Methods: We retrospectively reviewed consecutive mCRC patients who underwent combination therapy of anti-EGFR agents and irinotecan after failure of fluoropyrimidines, oxaliplatin, irinotecan, and Bev at a single institution. We divided patients in two groups (group A: the interval between Bev and anti-EGFR agents &lt;6M, group B: ≥6M). Results: A total of 114 patients constituted the cohort of analysis. The median age was 63; 78 (68%) patients were male. Most patients (N=100, 88%) were treated with cetuximab, and 14 patients were panitumumab. Seventy-four patients were group A and 40 patients group B, respectively. There was no significant difference in patient characteristics. Response rate was 24.7% in group A, and 50.0% in group B (p=0.0072). The patients in group B have significantly longer progression free survival (4.2 vs. 6.6 M, HR 0.65, 95% CI 0.43- 0.98, p=0.042) and longer overall survival (11.6 vs. 14.3 M, HR 0.62, 95% CI 0.39- 0.97, p=0.038). Conclusions: The short interval (&lt;6M) between last Bev and anti-EGFR agents may interfere with the efficacy of anti-EGFR therapy.

Panitumumab (pmab) in patients (pts) with chemorefractory metastatic colorectal cancer (mCRC): Final analysis from a community-based, observational study (VECTOR) in Germany.

550 Background: Pmab monotherapy significantly improves progression-free survival versus best supportive care in pts with chemorefractory KRAS wild-type (WT) mCRC. This study evaluated the efficacy and safety of pmab in routine clinical practice in Germany. Methods: To ensure a representative sample, eligibility criteria were largely unrestricted. Consenting pts were &gt;18 years old, had histologically confirmed KRAS WT mCRC, &gt;4 weeks pmab therapy, failure of fluoropyrimidine-, oxaliplatin- and irinotecan-containing chemotherapy (CTx) regimens, and women of child-bearing age received contraception. Predefined endpoints were overall response rate (ORR; investigator`s assessment) and skin toxicity (NCI Common Terminology Criteria for Adverse Events v3.0). Results: A total of 428 pts were included in the full analysis set. At the start of pmab therapy, median age was 69 (range 22-89) years, 268 pts (63%) were male and 343 (80%) had an ECOG performance status of 0-1. Overall, 400 pts (93%) had undergone prior surgery and 154 (36%) had received ≥1 cycle of adjuvant CTx. Pts had received a median of 3 cycles (range: 1‑12) of prior CTx for mCRC. The most common regimens were FOLFOX/FOLFIRI ±antibody therapy; 65% of regimens were given with palliative, 32% with curative/palliative and 3% with curative intent. The median pmab dose was 6 mg/kg (range 2.4-7.2) q2w for a median of 8 (range 2‑45) cycles, with 143 pts (33%) receiving &gt;10 cycles. The ORR during pmab therapy was 20% (complete response: n=7 [2%]; partial response: n=77 [18%]); disease control (including stable disease) was achieved in 261 pts (61%). Skin reactions occurred in 324 pts (67%) with 52% experiencing a maximum grade ≥2. Most pts had some type of rash (48% acne, 5% desquamation, 4% hand-foot skin reaction, 1% erythema multiforme). Overall, 21% of pts had other toxicities. Three serious adverse drug reactions (infection/fever; thrombosis/embolism; erythema multiforme) and two grade 1 infusion reactions were reported. Conclusions: In this observational study, pmab monotherapy had efficacy at least as good as was seen in the randomised pmab trial and safety was also similar.

Irinotecan combined with 5-fluorouracil and leucovorin third-line chemotherapy after failure of fluoropyrimidine, platinum, and taxane in gastric cancer: treatment outcomes and a prognostic model to predict survival

The aim of this study was to evaluate the activity and safety of the combination chemotherapy of 5-fluorouracil (5-FU), leucovorin, and irinotecan (FOLFIRI regimen) after failure of fluoropyrimidine, platinum, and taxane in gastric cancer (GC) and to evaluate the prognostic factors for survival. Patients received biweekly FOLFIRI chemotherapy as third-line treatment. The FOLFIRI-1 consisted of irinotecan (180 mg/m(2) in a 2-h infusion) on day 1, and then leucovorin (200 mg/m(2) in a 2-h infusion) and 5-FU (a 400 mg/m(2) bolus, followed by 600 mg/m(2) in a 22-h continuous infusion) on days 1 and 2. FOLFIRI-2 consisted of irinotecan (180 mg/m(2) in a 2-h infusion) on day 1, and then leucovorin (400 mg/m(2) in a 2-h infusion) and 5-FU (a 400 mg/m(2) bolus, followed by 2400 mg/m(2) in a 46-h continuous infusion) on day 1. A total of 158 patients were included. The overall response rate was 9.6 % in patients with measurable lesions. The median progression-free survival (PFS) and overall survival (OS) were 2.1 months [95 % confidence interval (CI), 1.7-2.5] and 5.6 months (95 % CI, 4.7-6.5), respectively. The major grade 3/4 toxicity was myelosuppression (36.7 %). Good performance status (PS), fewer metastatic sites, and longer duration from the first-line to third-line chemotherapy were independent prognostic factors affecting both PFS and OS. The FOLFIRI regimen showed antitumor activity and tolerable toxicity profiles against advanced GC in the third-line setting. Patients with good PS, fewer metastatic sites and longer previous treatment duration might have the maximal benefit from third-line chemotherapy.

P-0061 Docetaxel Monotherapy as a Second-Line Salvage Treatment in Advanced Gastric Cancer: Experience of 40 Patients with Prognostic Factor Analysis

IntroductionFluoropyrimidine (F) and platinum (P) combination chemotherapy has been widely used as a first-line treatment of advanced gastric cancer (AGC). Docetaxel has been considerable promise against this disease. We want to investigate the efficacy and safety of docetaxel monotherapy as salvage chemotherapy for AGC in clinical practice and determine the prognostic factors in these patients. MethodsWe retrospectively reviewed the medical records of patients with AGC for whom fluoropyrimidine and platinum had previously failed and who had received docetaxel salvage monotherapy between March 2005 and December 2011. Docetaxel was administered at a dose of 75 mg/m(2) intravenously every 3 weeks with dexamethasone prophylaxis. ResultsA total of 40 patients received 133 cycles of docetaxel with a median of three cycles per patient (range 1-6). The median age was 63 years (range 38-78 years). The objective response rate was 10%, with 4 partial responses, with response duration of 1.1, 2.2, 2.6 and 7.1 months respectively. An additional 4 patients achieved stable disease. The median time to progression (TTP) for all patients was 1.9 months [95% confidence interval (CI), 1.2-2.7] and the median overall survival (OS) from the start of docetaxel chemotherapy was 4.1 months (95% CI, 3.6-4.6). Grade 3/4 neutropenia and febrile neutropenia occurred in 15% of patients and anemia occurred in 12.5%. The incidence of non-hematologic toxicities of grade 3 or worse was asthenia 25%, anorexia 12.5%, diarrhea 2.5% and stomatitis 2.5%. Multivariate analysis showed that the Eastern Cooperative Oncology Group (ECOG) performance status (0 or 1 versus 2) was an independent prognostic factor for both TTP and OS. Number of metastatic sites was a predictor for better TTP. ConclusionDocetaxel 75 mg/m(2) is relatively active against AGC as a second-line salvage treatment after failure of fluoropyrimidine and platinum combination chemotherapy in general clinical practice. The toxicity profile is moderate. Further investigation in salvage therapy is needed, in order to improve survival and provide palliation of symptoms.

Clinical Outcomes of Sorafenib Treatment in Patients With Metastatic Hepatocellular Carcinoma Who Had Been Previously Treated With Fluoropyrimidine Plus Platinum-based Chemotherapy

There has been no report on sorafenib therapy in patients with metastatic hepatocellular carcinoma (HCC) who had been treated with systemic chemotherapy. The objectives of this analysis were to investigate efficacy and safety of sorafenib in these patients and to elucidate risk factors associated with clinical outcomes. We analyzed patients with metastatic HCC who were treated with sorafenib after failure of fluoropyrimidine plus platinum-based chemotherapy between April 2007 and December 2008. Twenty-four patients (male, 79.2%) were included. Median age was 53 years. Chronic hepatitis B was the predominant cause of HCC (79.2%), followed by chronic hepatitis C (4.2%) and alcohol (4.2%). Twenty patients (83.3%) were Child-Pugh A and 4 patients (16.7%) were Child-Pugh B. Median follow-up duration was 11.1 months. No objective response was observed. Fourteen patients (58.3%) had stable disease. The disease control rate was 58.3%. Median progression-free survival was 2.3 months (95% confidence interval, 0.5-4.1) and overall survival was 7.1 months (95% confidence interval, 3.5-10.7). Grade 3 neutropenia was observed in 1.4% and grade 3 anemia in 1.4%. Grade 3 or 4 nonhematologic toxicities were hand-foot syndrome (16.7%), skin rash (8.3%), diarrhea (4.2%), headache (4.2%), and fatigue (4.2%). Four patients (16.7%) discontinued the therapy because of toxicities. Sorafenib had modest efficacy and tolerable toxicity in patients with metastatic HCC who had received fluoropyrimidine plus platinum-based chemotherapy.

Panitumumab: a new frontier of target therapy for the treatment of metastatic colorectal cancer

Panitumumab is a fully human monoclonal IgG2 antibody targeting the EGF receptor (EGFR). This agent represents a new class of drug owing to its fully human nature, and no need for premedication and loading dose. Panitumumab selectively binds to EGFR, blocking the extracellular domain of the receptor, and has not been associated with the formation of any antibodies directed against it. The drug is indicated as monotherapy for the treatment of patients with EGFR-expressing metastatic colorectal carcinoma with non-mutated (wild-type) KRAS after failure of fluoropyrimidine-, oxaliplatin- and irinotecan-containing chemotherapy regimens. The safety profile is favorable and is generally well tolerated; the most common toxicities are skin rashes and diarrhea. Therefore, panitumumab’s hypersensitivity reaction rate is lower when compared with a chimeric monoclonal antibody such as cetuximab. Panitumumab increases the clinician’s repertoire of agents to treat metastatic colorectal carcinoma. The available clinical data are the most promising for a single-agent anti-EGFR monoclonal antibody in this disease at the present time. These new data open different clinical scenarios in metastatic colorectal carcinoma patients and encourage clinicians and basic researchers to investigate new therapeutic approaches for this patient subset.

Panitumumab alkalmazása az áttétes vastag- és végbélrákos betegek kezelésében

In the molecular target treatment strategy of metastatic colorectal cancer patients panitumumab represents a new class of drugs due to its fully human nature, and no need for premedication and loading dose. Panitumumab binds to epidermal growth factor receptor (EGFR) selectively. In registration pivotal studies the analysis of patient subgroups for KRAS status gives strong evidence for the important role of RAS oncogene: median progression-free survival was 16 weeks on panitumumab arm in KRAS wild-type patients (8 weeks in best supportive care), while in KRAS mutant patients panitumumab showed no efficacy, however adverse events were more frequent and severe. According to SmPC, panitumumab is indicated as monotherapy for the treatment of patients with EGFR expressing metastatic colorectal carcinoma with non-mutated (wild-type) KRAS after failure of fluoropyrimidine-, oxaliplatin- , and irinotecan-containing chemotherapy regimens. Adverse events are similar as with other EGFR inhibitors: skin symptoms (rash), lung infiltrates, diarrhoea, ion abnormalities of renal origin. The drug was formerly available via named patient reimbursement, and now is financed by diagnosis-related group (DRG) system.