Dataset Information

Safety and efficacy of panitumumab in combination with trifluridine/tipiracil for pre-treated patients with unresectable, metastatic colorectal cancer with wild-type RAS: The phase 1/2 APOLLON study.

ABSTRACT:

Background

We aimed to assess the safety and efficacy of combination treatment with panitumumab plus trifluridine/tipiracil (FTD/TPI) in patients with wild-type RAS metastatic colorectal cancer (mCRC) who were refractory/intolerant to standard therapies other than anti-epidermal growth factor receptor therapy.

Methods

APOLLON was an open-label, multicentre, phase 1/2 trial. In the phase 1 part, 3 + 3 de-escalation design was used to investigate the recommended phase 2 dose (RP2D); all patients in the phase 2 part received the RP2D. The primary endpoint was investigator-assessed progression-free survival (PFS) rate at 6 months. Secondary endpoints included PFS, overall survival (OS), overall response rate (ORR), disease control rate (DCR), time to treatment failure (TTF), and safety.

Results

Fifty-six patients were enrolled (phase 1, n = 7; phase 2, n = 49) at 25 Japanese centres. No dose-limiting toxicities were observed in patients receiving panitumumab (6 mg/kg every 2 weeks) plus FTD/TPI (35 mg/m² twice daily; days 1-5 and 8-12 in a 28-day cycle), which became RP2D. PFS rate at 6 months was 33.3% (90% confidence interval [CI] 22.8-45.3). Median PFS, OS, ORR, DCR, and TTF were 5.8 months (95% CI 4.5-6.5), 14.1 months (95% CI 12.2-19.3), 37.0% (95% CI 24.3-51.3), 81.5% (95% CI 68.6-90.8), and 5.8 months (95% CI 4.29-6.21), respectively. Neutrophil count decreased (47.3%) was the most common Grade 3/4 treatment-emergent adverse event. No treatment-related deaths occurred.

Conclusion

Panitumumab plus FTD/TPI exhibited favourable anti-tumour activity with a manageable safety profile and may be a therapeutic option for pre-treated mCRC patients.

SUBMITTER: Kato T

PROVIDER: S-EPMC8213662 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:ImportanceCurrent third-line therapies for patients with metastatic colorectal cancer (MCRC) have limited efficacy. Rechallenge with epidermal growth factor receptor (EGFR) inhibitors for RAS wild-type (WT) MCRC may be valuable for these patients.ObjectiveTo compare the anti-EGFR monoclonal antibody panitumumab plus standard-of-care trifluridine-tipiracil with trifluridine-tipiracil alone as third-line therapy for RAS WT MCRC.Design, setting, and participantsThis phase 2 randomized clinical trial (RCT) was conducted in 7 Italian centers from June 2019 to April 2022. Patients with refractory RAS WT MCRC who had a partial or complete response to first-line chemotherapy plus an anti-EGFR monoclonal antibody and an anti-EGFR drug-free interval of 4 or more months during second-line therapy were included.InterventionsPatients were randomized 1:1 to receive panitumumab plus trifluridine-tipiracil or trifluridine-tipiracil alone.Main outcomes and measuresThe primary end point was progression-free survival (PFS). Circulating tumor DNA (ctDNA) extended sequence variation analysis was performed in a subgroup of patients.ResultsOf 62 included patients, 31 received panitumumab plus trifluridine-tipiracil (19 [61.3%] male; median age, 65 years [range, 39-81 years]) and 31 received trifluridine-tipiracil alone (17 [54.8%] male; median age, 66 years [range, 32-82 years]). The primary end point was met. Median PFS was 4.0 months (95% CI, 2.8-5.3 months) in the panitumumab plus trifluridine-tipiracil arm vs 2.5 months (95% CI, 1.4-3.6 months) in the trifluridine-tipiracil only (hazard ratio [HR], 0.48; 95% CI, 0.28-0.82; P = .007). Pretreatment plasma RAS/BRAF WT ctDNA identified patients obtaining prolonged clinical benefit with panitumumab plus trifluridine-tipiracil compared with trifluridine-tipiracil, with PFS rates at 6 months of 38.5% vs 13.0% and at 12 months of 15.4% vs 0%. A ctDNA liquid-biopsy extended mutation analysis by FoundationOne Liquid CDx (profiling 324 genes) was performed in a subgroup of patients with baseline plasma RAS/BRAF WT ctDNA; in 15 of 23 patients (65.2%) whose tumors were WT for KRAS, NRAS, BRAFV600E, EGFR, ERBB2, MAP2K1, and PIK3CA, median PFS was 6.4 months (95% CI, 3.7-9.2 months). Within this group of 15 patients, 2 (13.3%) had partial response, 11 (73.3%) had stable disease, and 2 (13.3%) had disease progression as best response.Conclusions and relevanceIn this RCT, third-line treatment with the anti-EGFR monoclonal antibody panitumumab plus the standard-of-care trifluridine-tipiracil resulted in improved PFS compared with treatment with trifluridine-tipiracil alone among patients with refractory RAS WT MCRC. The findings support the clinical utility of liquid biopsy-guided anti-EGFR rechallenge therapy for refractory RAS WT MCRC.Trial registrationClinicalTrials.gov Identifier: NCT05468892.

Project description:BackgroundInitial systemic therapy for patients with metastatic colorectal cancer (mCRC) is usually based on two- or three-drug chemotherapy regimens with fluoropyrimidine (5-fluorouracil (5-FU) or capecitabine), oxaliplatin and/or irinotecan, combined with either anti-VEGF (bevacizumab) or, for RAS wild-type (WT) tumors, anti-EGFR antibodies (panitumumab or cetuximab). Recommendations for patients who are not eligible for intensive combination therapies are limited and include fluoropyrimidine plus bevacizumab or single agent anti-EGFR antibody treatment. The use of a monochemotherapy concept of trifluridine/ tipiracil in combination with monoclonal antibodies is not approved for first-line therapy, yet. Results from the phase II TASCO trial evaluating trifluridine/ tipiracil plus bevacicumab in first-line treatment of mCRC patients and from the phase I/II APOLLON trial investigating trifluridine/ tipiracil plus panitumumab in pre-treated mCRC patients suggest favourable activity and tolerability of these new therapeutic approaches.MethodsFIRE-8 ( NCT05007132 ) is a prospective, randomized, open-label, multicenter phase II study which aims to evaluate the efficacy of first-line treatment with trifluridine/tipiracil (35 mg/m2 body surface area (BSA), orally twice daily on days 1-5 and 8-12, q28 days) plus either the anti-EGFR antibody panitumumab (6 mg/kg body weight, intravenously on day 1 and 15, q28 days) [arm A] or (as control arm) the anti-VEGF antibody bevacizumab (5 mg/kg body weight, intravenously on day 1 and 15, q28 days) [arm B] in RAS WT mCRC patients. The primary objective is to demonstrate an improved objective response rate (ORR) according to RECIST 1.1 from 30% (control arm) to 55% with panitumumab. With a power of 80% and a two-sided significance level of 0.05, 138 evaluable patients are needed. Given an estimated drop-out rate of 10%, 153 patients will be enrolled.DiscussionTo the best of our knowledge, this is the first phase II trial to evaluate the efficacy of trifluridine/tipiracil plus panitumumab in first-line treatment of RAS WT mCRC patients. The administration of anti-EGFR antibodies rather than anti-VEGF antibodies in combination with trifluridine/tipiracil may result in an increased initial efficacy.Trial registrationEU Clinical Trials Register (EudraCT) 2019-004223-20 . Registered October 22, 2019, ClinicalTrials.gov NCT05007132 . Registered on August 12, 2021.