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

Martinelli, Erika; Martini, Giulia; Famiglietti, Vincenzo; Troiani, Teresa; Napolitano, Stefania; Pietrantonio, Filippo; Ciardiello, Davide; Terminiello, M.; Borrelli, C.; Vitiello, Pietro Paolo; Braud, Filippo de; Morano, Federica; Avallone, Antonio; Normanno, Nicola; Nappi, Anna; Maiello, Evaristo; Latiano, Tiziana Pia; Falcone, Alfredo; Cremolini, Chiara; Rossini, Daniele; Santabarbara, Giuseppe; Pinto, Carmine; Santini, Daniele; Cardone, Claudia; Zanaletti, N.; Liello, Alessandra Di; Renato, Daniela; Esposito, Lucia; Marrone, Francesca; Ciardiello, Fortunato

doi:10.1001/jamaoncol.2021.2915

Cited by 106 publications

(126 citation statements)

References 27 publications

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“…The main patient characteristics are listed in Table S1 . ITT population survival outcomes have been previously described [ 5 ].…”

Section: Resultsmentioning

confidence: 99%

“…Patients enrolled in the study had: histologically confirmed mCRC with RAS ( NRAS and KRAS , exon 2, 3 and 4) WT tumors, obtained a complete (CR) or partial response (PR) during a first-line treatment with an anti-EGFR-based regimen and should have progressed, and received at least one subsequent line of therapy with an interval of more than 4 months from last dose of the anti-EGFR drug. Additional inclusion and exclusion criteria are described in the full protocol available online [ 5 ].…”

Section: Methodsmentioning

confidence: 99%

“…Different studies have shown promising activity of reintroduction of anti-epidermal growth factor receptor (EGFR) drugs in patients with RAS wild-type ( RAS WT) metastatic colorectal cancer (mCRC), that obtained clinical benefit by first-line therapy with anti-EGFR drugs, then became resistant and progressed to second-line treatment [ 1 , 2 , 3 , 4 , 5 , 6 ]. This treatment strategy is called rechallenge.…”

Section: Introductionmentioning

confidence: 99%

“…CAVE mCRC is a single-arm phase II study, in which 77 patients with refractory RAS WT mCRC received cetuximab plus the immune checkpoint inhibitor (ICI) avelumab, as rechallenge strategy [ 5 ]. In the intention-to-treat population (ITT population) the primary endpoint was met, with an improvement in median overall survival (mOS) [ 5 ]. The highest benefit was observed in patients with RAS, BRAF, and EGFR wild-type tumor assessed by basal plasma circulating tumor DNA (ctDNA) analysis [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

“…In the intention-to-treat population (ITT population) the primary endpoint was met, with an improvement in median overall survival (mOS) [ 5 ]. The highest benefit was observed in patients with RAS, BRAF, and EGFR wild-type tumor assessed by basal plasma circulating tumor DNA (ctDNA) analysis [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

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Skin Toxicity as Predictor of Survival in Refractory Patients with RAS Wild-Type Metastatic Colorectal Cancer Treated with Cetuximab and Avelumab (CAVE) as Rechallenge Strategy

Ciardiello

Famiglietti

Napolitano

et al. 2021

Cancers

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The single-arm phase II CAVE mCRC trial evaluated the combination of cetuximab plus avelumab as rechallenge strategy in RAS wild-type (WT) metastatic colorectal cancer (mCRC) patients, with clinical response to first-line anti-EGFR-based chemotherapy, who progressed and received a subsequent line of therapy. The correlation of skin toxicity (ST) and different clinico-molecular variables with overall survival (OS), progression-free survival (PFS) and response rate (RR) was assessed at univariate and multivariate analysis. A total of 33/77 (42.9%) patients experienced grade 2–3 ST and displayed median OS (mOS) of 17.8 months (CI 95%, 14.9–20.6); whereas 44/77 (57.1%) patients with grade 0–1 ST exhibited mOS of 8.2 months (CI 95%, 5.5–10.9), (hazard ratio (HR), 0.51; CI 95%, 0.29–0.89; p = 0.019). Median PFS (mPFS) was 4.6 months (CI 95%, 3.4–5.7) in patients with grade 2–3 ST, compared to patients with grade 0–1 ST with mPFS of 3.4 months (CI 95%, 2.7–4.1; HR, 0.49; CI 95%, 0.3–0.8; p = 0.004). Grade 2–3 ST (HR, 0.51; CI 95%, 0.29–0.89; p = 0.019) and RAS/BRAF/EGFR WT circulating tumor DNA (ctDNA) (HR, 0.50; CI 95%, 0.27–0.9; p = 0.019) had a statistically significant effect on OS at univariate analysis. At the multivariate analysis, RAS/BRAF/EGFR WT ctDNA status maintained statistical significance (HR, 0.49; CI 95%, 0.27–0.9; p = 0.023), whereas there was a trend towards ST grade 2–3 (HR, 0.54; CI 95%, 0.29–1.01; p = 0.054). Skin toxicity is a promising biomarker to identify patients with mCRC that could benefit of anti-EGFR rechallenge.

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“…The main patient characteristics are listed in Table S1 . ITT population survival outcomes have been previously described [ 5 ].…”

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Skin Toxicity as Predictor of Survival in Refractory Patients with RAS Wild-Type Metastatic Colorectal Cancer Treated with Cetuximab and Avelumab (CAVE) as Rechallenge Strategy

Ciardiello

Famiglietti

Napolitano

et al. 2021

Cancers

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Anti-EGFR Rechallenge in Patients With Refractory ctDNA RAS/BRAF wt Metastatic Colorectal Cancer

Ciardiello,

Martinelli,

Troiani

et al. 2024

JAMA Netw Open

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ImportanceThe available evidence regarding anti–epidermal growth factor receptor (EGFR) inhibitor rechallenge in patients with refractory circulating tumor DNA (ctDNA) RAS/BRAF wild-type (wt) metastatic colorectal cancer (mCRC) is derived from small retrospective and prospective studies.ObjectiveTo evaluate the efficacy of anti-EGFR rechallenge in patients with refractory ctDNA RAS/BRAF wt mCRC.Design, Setting, and ParticipantsThis nonrandomized controlled trial used a pooled analysis of individual patient data from patients with RAS/BRAF wt ctDNA mCRC enrolled in 4 Italian trials (CAVE, VELO, CRICKET, and CHRONOS) and treated with anti-EGFR rechallenge between 2015 and 2022 (median [IQR] follow-up, 28.1 [25.8-35.0] months).InterventionPatients received anti-EGFR rechallenge therapy, including cetuximab plus avelumab, trifluridine-tipiracil plus panitumumab, irinotecan plus cetuximab, or panitumumab monotherapy.Main Outcomes and MeasuresOverall survival (OS), progression-free survival (PFS), overall response rate (ORR), and disease control rate (DCR) were calculated. Exploratory subgroup analysis evaluating several clinical variables was performed. Safety was reported.ResultsOverall, 114 patients with RAS/BRAF wt ctDNA mCRC (median [IQR] age, 61 [29-88] years; 66 men [57.9%]) who received anti-EGFR rechallenge as experimental therapy (48 received cetuximab plus avelumab, 26 received trifluridine-tipiracil plus panitumumab, 13 received irinotecan plus cetuximab, and 27 received panitumumab monotherapy) were included in the current analysis. Eighty-three patients (72.8%) had received 2 previous lines of therapy, and 31 patients (27.2%) had received 3 or more previous lines of therapy. The ORR was 17.5% (20 patients), and the DCR was 72.3% (82 patients). The median PFS was 4.0 months (95% CI, 3.2-4.7 months), and the median OS was 13.1 months (95% CI, 9.5-16.7 months). The subgroup of patients without liver involvement had better clinical outcomes. The median PFS was 5.7 months (95% CI, 4.8-6.7 months) in patients without liver metastasis compared with 3.6 months (95% CI, 3.3-3.9 months) in patients with liver metastasis (hazard ratio, 0.56; 95% CI, 0.37-0.83; P = .004). The median OS was 17.7 months (95% CI, 13-22.4 months) in patients without liver metastasis compared with 11.5 months (95% CI, 9.3-13.9 months) in patients with liver metastasis (hazard ratio, 0.63; 95% CI, 0.41-0.97; P = .04). Treatments showed manageable toxic effects.Conclusions and RelevanceThese findings suggest that anti-EGFR rechallenge therapy has promising antitumor activity in patients with refractory ctDNA RAS/BRAF wt mCRC. Within the limitation of a subgroup analysis, the absence of liver metastases was associated with significant improved survival.Trial RegistrationClinicalTrials.gov Identifiers: NCT02296203; NCT04561336; NCT03227926; NCT05468892

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Panitumumab Plus Trifluridine-Tipiracil as Anti–Epidermal Growth Factor Receptor Rechallenge Therapy for Refractory RAS Wild-Type Metastatic Colorectal Cancer

et al. 2023

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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

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

Cited by 106 publications

References 27 publications

Skin Toxicity as Predictor of Survival in Refractory Patients with RAS Wild-Type Metastatic Colorectal Cancer Treated with Cetuximab and Avelumab (CAVE) as Rechallenge Strategy

Skin Toxicity as Predictor of Survival in Refractory Patients with RAS Wild-Type Metastatic Colorectal Cancer Treated with Cetuximab and Avelumab (CAVE) as Rechallenge Strategy

Anti-EGFR Rechallenge in Patients With Refractory ctDNA RAS/BRAF wt Metastatic Colorectal Cancer

Panitumumab Plus Trifluridine-Tipiracil as Anti–Epidermal Growth Factor Receptor Rechallenge Therapy for Refractory RAS Wild-Type Metastatic Colorectal Cancer

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