Dataset Information

Phase II Single-Arm Study of Palbociclib and Cetuximab Rechallenge in Patients with KRAS/NRAS/BRAF Wild-Type Colorectal Cancer.

ABSTRACT:

Background

Cetuximab is often administered to patients with KRAS wild-type (KRAS-WT) metastatic colorectal cancer (mCRC), although resistance inevitably develops. We hypothesized that co-inhibition of the epidermal growth factor receptor (EGFR) with cetuximab and downstream cyclin-dependent kinases (CDK) 4/6 with palbociclib would be effective for anti-EGFR rechallenge in KRAS-WT mCRC.

Methods

We designed a single-arm, Simon's 2-stage, phase II trial of cetuximab and palbociclib in KRAS-WT mCRC treated with ≥2 prior lines of therapy. We report here on cohort B rechallenging patients with anti-EGFR-based therapy who had disease control of at least 4 months on prior anti-EGFR therapy. Primary endpoint was disease control rate (DCR) at 4 months.

Results

Ten evaluable patients were enrolled in this cohort. The 4-month DCR was 20%, which did not fulfill the prespecified 4-month DCR rate to continue. Median progression-free survival was 1.8 months and median overall survival was 6.6 months. Three patients had stable disease, although overall response rate was 0%. Most common treatment-related grades 3-4 adverse events were lymphopenia and leukopenia.

Conclusion

Selection of patients for anti-EGFR rechallenge using clinical criteria alone was insufficient to identify response to palbociclib + cetuximab. Additional biomarkers are needed to select anti-EGFR rechallenge and circulating tumor DNA (ctDNA) analysis is planned for samples collected in this study. (ClinicalTrials.gov Identifier: NCT03446157).

SUBMITTER: Sorah JD

PROVIDER: S-EPMC10249423 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Phase II Single-Arm Study of Palbociclib and Cetuximab Rechallenge in Patients with KRAS/NRAS/BRAF Wild-Type Colorectal Cancer.

Sorah Jonathan D JD Moore Dominic T DT Reilley Matthew J MJ Salem Mohamed E ME Triglianos Tammy T Sanoff Hanna K HK McRee Autumn J AJ Lee Michael S MS

The oncologist 20221201 12

<h4>Background</h4>Cetuximab is often administered to patients with KRAS wild-type (KRAS-WT) metastatic colorectal cancer (mCRC), although resistance inevitably develops. We hypothesized that co-inhibition of the epidermal growth factor receptor (EGFR) with cetuximab and downstream cyclin-dependent kinases (CDK) 4/6 with palbociclib would be effective for anti-EGFR rechallenge in KRAS-WT mCRC.<h4>Methods</h4>We designed a single-arm, Simon's 2-stage, phase II trial of cetuximab and palbociclib i ...[more]

PMID: 36288238

Similar Datasets

Project description:ImportanceBased on a small retrospective study, rechallenge with cetuximab-based therapy for patients with KRAS wild-type metastatic colorectal cancer (mCRC) who were previously treated with the same anti-epidermal growth factor receptor-based regimen might be efficacious. Recent data suggest the role of liquid biopsy as a tool to track molecular events in circulating tumor DNA (ctDNA).ObjectiveTo prospectively assess the activity of cetuximab plus irinotecan as third-line treatment for patients with RAS and BRAF wild-type mCRC who were initially sensitive to and then resistant to first-line irinotecan- and cetuximab-based therapy.Design, setting, and participantsMulticenter phase 2 single-arm trial conducted from January 7, 2015, to June 19, 2017. Liquid biopsies for analysis of ctDNA were collected at baseline. Main eligibility criteria included RAS and BRAF wild-type status on tissue samples; prior first-line irinotecan- and cetuximab-based regimen with at least partial response, progression-free survival of at least 6 months with first-line therapy, and progression within 4 weeks after last dose of cetuximab; and prior second-line oxaliplatin- and bevacizumab-based treatment.InterventionsBiweekly cetuximab, 500 mg/m2, plus irinotecan, 180 mg/m2.Main outcomes and measuresOverall response rate according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary end points included progression-free survival and overall survival and, as an exploratory analysis, RAS mutations in ctDNA.ResultsTwenty-eight patients (9 women and 19 men; median age, 69 years [range, 45-79 years]) were enrolled. Six partial responses (4 confirmed) and 9 disease stabilizations were reported (response rate, 21%; 95% CI, 10%-40%; disease control rate, 54%; 95% CI, 36%-70%). Primary end point was met because lower limit of 95% CI of response rate was higher than 5%. RAS mutations were found in ctDNA collected at rechallenge baseline in 12 of 25 evaluable patients (48%). No RAS mutations were detected in samples from patients who achieved confirmed partial response. Patients with RAS wild-type ctDNA had significantly longer progression-free survival than those with RAS mutated ctDNA (median progression-free survival, 4.0 vs 1.9 months; hazard ratio, 0.44; 95% CI, 0.18-0.98; P = .03).Conclusions and relevanceThis is the first prospective demonstration that a rechallenge strategy with cetuximab and irinotecan may be active in patients with RAS and BRAF wild-type mCRC with acquired resistance to first-line irinotecan- and cetuximab-based therapy. The evaluation of RAS mutational status on ctDNA might be helpful in selecting candidate patients.Trial registrationClinicalTrials.gov Identifier: NCT02296203.

Project description:ImportanceRechallenge therapy with anti-epidermal growth factor receptor (EGFR) drugs has been suggested in patients with chemo-refractory RAS wild-type (WT) metastatic colorectal cancer (mCRC) after initial response to anti-EGFR-based first-line treatment. The association of treatment with cetuximab plus avelumab with overall survival (OS) may be worthy of investigation in this setting.ObjectiveTo assess the efficacy and safety of cetuximab rechallenge therapy plus avelumab.Design, setting, and participantsThis single-arm, multicenter phase 2 trial enrolled patients from August 2018 to February 2020. Eligible patients with RAS WT mCRC had a complete or partial response to first-line chemotherapy plus anti-EGFR drugs, developed acquired resistance, and failed second-line therapy. Baseline circulating tumor DNA (ctDNA) for KRAS, NRAS, BRAF, and EGFR-S492R mutation analysis was done.InterventionsPatients received avelumab (10 mg/kg every 2 weeks) and cetuximab (400 mg/m2 and, subsequently, 250 mg/m2 weekly) until disease progression or unacceptable toxic effects.Main outcomes and measuresThe primary end point was OS. Secondary end points were progression-free survival (PFS), overall response rate (ORR), and safety.ResultsSeventy-seven patients were enrolled (42 men, 35 women; median age, 63 years); 71 had microsatellite stable tumors (MSS), 3 microsatellite instability-high tumors (MSI-H), 3 unknown. The study met the primary end point, with median OS (mOS) of 11.6 months (95% CI, 8.4-14.8 months). Median PFS (mPFS) was 3.6 months (95% CI, 3.2-4.1 months). Common grade-3 adverse events were cutaneous eruption, 11 (14%), and diarrhea, 3 (4%). For 67 of 77 (87%) patients, baseline analysis of plasma circulating tumor DNA (ctDNA) for KRAS, NRAS, BRAF, and EGFR-S492R variations was feasible. Forty-eight patients had WT disease, whereas 19 had mutations. Patients with RAS/BRAF WT ctDNA had mOS of 17.3 months (95% CI, 12.5-22.0 months) compared with 10.4 months (95% CI, 7.2-13.6 months) in patients with mutated ctDNA (hazard ratio [HR], 0.49; 95% CI, 0.27-0.90; P = .02). The mPFS was 4.1 months (95% CI, 2.9-5.2 months) in RAS/BRAF WT patients compared with 3.0 months (95% CI, 2.6-3.5 months) in patients with mutated ctDNA (HR, 0.42; 95% CI, 0.23-0.75; P = .004).Conclusions and relevanceThe findings of this single-arm phase 2 trial suggest that cetuximab plus avelumab is an active, well tolerated rechallenge therapy in RAS WT mCRC. Plasma ctDNA analysis before treatment may allow selection of patients who could benefit.Trial registrationClinicalTrials.gov Identifier: NCT04561336.

Dataset Information

Phase II Single-Arm Study of Palbociclib and Cetuximab Rechallenge in Patients with KRAS/NRAS/BRAF Wild-Type Colorectal Cancer.

Background

Methods

Results

Conclusion

Publications

Phase II Single-Arm Study of Palbociclib and Cetuximab Rechallenge in Patients with KRAS/NRAS/BRAF Wild-Type Colorectal Cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets