Neuroblastoma RAS viral oncogene homolog

Progressive disease

Gene

Panitumumab

Cetuximab

Microsatellite

Adverse effect

Colorectal cancer

Response Evaluation Criteria in Solid Tumors

Clinical trial

Biochemistry

Phases of clinical research

Microsatellite instability

Pembrolizumab

Progression-free survival

Internal medicine

Clinical endpoint

Chemotherapy

KRAS

Oncology

Medicine

Chemistry

Immunotherapy

Gastroenterology

Allele

Cancer

Avelumab

JAMA Oncology

<h3>Importance</h3> Rechallenge therapy with anti–epidermal growth factor receptor (EGFR) drugs has been suggested in patients with chemo-refractory<i>RAS</i>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. <h3>Objective</h3> To assess the efficacy and safety of cetuximab rechallenge therapy plus avelumab. <h3>Design, Setting, and Participants</h3> This single-arm, multicenter phase 2 trial enrolled patients from August 2018 to February 2020. Eligible patients with<i>RAS</i>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<i>KRAS, NRAS, BRAF,</i>and<i>EGFR-S492R</i>mutation analysis was done. <h3>Interventions</h3> Patients received avelumab (10 mg/kg every 2 weeks) and cetuximab (400 mg/m<sup>2</sup>and, subsequently, 250 mg/m<sup>2</sup>weekly) until disease progression or unacceptable toxic effects. <h3>Main Outcomes and Measures</h3> The primary end point was OS. Secondary end points were progression-free survival (PFS), overall response rate (ORR), and safety. <h3>Results</h3> Seventy-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 K<i>RAS, NRAS, BRAF,</i>and<i>EGFR-S492R</i>variations was feasible. Forty-eight patients had WT disease, whereas 19 had mutations. Patients with<i>RAS/BRAF</i>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;<i>P</i> = .02). The mPFS was 4.1 months (95% CI, 2.9-5.2 months) in<i>RAS/BRAF</i>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;<i>P</i> = .004). <h3>Conclusions and Relevance</h3> The findings of this single-arm phase 2 trial suggest that cetuximab plus avelumab is an active, well tolerated rechallenge therapy in<i>RAS </i>WT mCRC. Plasma ctDNA analysis before treatment may allow selection of patients who could benefit. <h3>Trial Registration</h3> ClinicalTrials.gov Identifier:NCT04561336

Cetuximab Rechallenge Plus Avelumab in Pretreated Patients With <i>RAS</i> Wild-type Metastatic Colorectal Cancer

Cetuximab Rechallenge Plus Avelumab in Pretreated Patients With RAS Wild-type Metastatic Colorectal Cancer