Negative hyper-selection of metastatic colorectal cancer patients for anti-EGFR monoclonal antibodies: the PRESSING case–control study

Cremolini, Chiara; Morano, Federica; Moretto, Roberto; Berenato, Rosa; Tamborini, Elena; Perrone, Francesco; Rossini, Daniele; Gloghini, Annunziata; Busico, Adele; Zucchelli, Gemma; Baratelli, Chiara; Tamburini, Emiliano; Tampellini, Marco; Sensi, Elisa; Fucà, Giovanni; Volpi, Chiara Costanza; Milione, Massimo; Maïo, Massimo Di; Fontanini, Gabriella; Braud, Filippo de; Falcone, Alfredo; Pietrantonio, Filippo

doi:10.1093/annonc/mdx546

Cited by 82 publications

(85 citation statements)

References 30 publications

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“…Based on results of the CRICKET trial, whereas trifluridinetipiracil or regorafenib do still represent third-line options with the highest levels of evidence for patients with chemorefractory mCRC, anti-EGFR rechallenge could be a tailored strategy for selected patients. Although markers of EGFR dependency are still lacking, patients with RAS and BRAF wild-type left-sided tumors, possibly not showing other molecular mechanisms of intrinsic resistance to EGFR inhibition, 37 who derived clinically meaningful benefit from first-line anti-EGFR-containing therapy, and with undetectable markers of acquired resistance to anti-EGFR monoclonal antibodies in tissue and/or liquid biopsy samples at the time of retreatment, might be the optimal candidates for rechallenge.…”

Section: Discussionmentioning

confidence: 99%

Rechallenge for Patients With RAS and BRAF Wild-Type Metastatic Colorectal Cancer With Acquired Resistance to First-line Cetuximab and Irinotecan

et al. 2019

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IMPORTANCE Based 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). OBJECTIVE To 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 PARTICIPANTS Multicenter 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.INTERVENTIONS Biweekly cetuximab, 500 mg/m 2 , plus irinotecan, 180 mg/m 2 . MAIN OUTCOMES AND MEASURES Overall 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. RESULTS Twenty-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 RELEVANCE This 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 REGISTRATION ClinicalTrials.gov identifier: NCT02296203A, Hazard ratio, 0.44 (95% CI, 0.18-0.98; P = .03). B, Hazard ratio, 0.58 (95% CI, 0.22-1.52; P = .24). Research Original InvestigationRechallenge for Patients With RAS and BRAF Wild-Type mCRC With Resistance to Cetuximab and Irinotecan Additional Contributions: We are grateful to all participating patients, their fa...

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Section: Discussionmentioning

confidence: 99%

Rechallenge for Patients With RAS and BRAF Wild-Type Metastatic Colorectal Cancer With Acquired Resistance to First-line Cetuximab and Irinotecan

et al. 2019

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“…However, despite the significance in multivariant analysis, it did not improve the discrimination of the clinical score, probably because of the small number of BRAF‐mutant patients (11%) and collinearity with other clinical variables. Biomarkers that could actually improve the classification of these patients may be mutations other than BRAF and PIK3CA or nonmutational driver pathways related to anti‐EGFR resistance, located mainly in primary right‐side tumors .…”

Section: Discussionmentioning

confidence: 99%

Prospective Biomarker Study in Advanced RAS Wild-Type Colorectal Cancer: POSIBA Trial (GEMCAD 10-02)

et al. 2019

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“…The trial met its primary endpoint, showing a significantly higher prevalence of negative predictors of benefit from anti-EGFRs among resistant than among sensitive patients, thus opening the way to a new concept of “negative hyperselection” of patients to be treated with this class of drugs. Notably, the PRESSING panel was able to unveil mechanisms of primary resistance in around half of rapidly progressing patients [44]. …”

Section: Looking For Prospective Evidence: the Case-control Pressimentioning

confidence: 99%

“…In the post-hoc analysis of phase III randomized CALGB/SWOG 80405 trial, patients with MSI-high tumor had a clear worse outcome when receiving a cetuximab-based than a bevacizumab-based first-line therapy [67]. Moreover, in the above-mentioned PRESSING study, microsatellite instability was significantly more frequent in anti-EGFR-resistant than sensitive patients, and associated with other predictors of primary resistance and with right-sidedness [44]. …”

Section: New Biomarkers On the Horizon? Focus On Microsatellite Inmentioning

confidence: 99%

“…At the same time, due to the low prevalence of these molecular alterations, conducting proper prospective validation studies or post-hoc analyses of randomized clinical studies aiming to assess the impact of each marker would be unrealistic. Drawing from these considerations and proposing a pragmatic approach to tackle these limitations, an academic prospective case-control study has recently demonstrated the clinical utility of a panel of uncommon genomic alterations, including HER2 and MET amplifications, ALK , ROS1 , NTRK1-3 , and RET fusions, and HER2 , PI3K , PTEN , AKT1 mutations, in predicting intrinsic resistance to anti-EGFR agents in molecularly (i.e., RAS and BRAF wild-type) selected patients [44], thus introducing the concept of “negative hyperselection”. Moreover, these findings were embedded in the debated scenario of right versus left primary location.…”

Section: Levels Of Evidence and Pragmatic Approaches: How To Make mentioning

confidence: 99%

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The Winding Roadmap of Biomarkers Toward Clinic: Lessons from Predictors of Resistance to Anti-EGFRs in Metastatic Colorectal Cancer

Antoniotti

Ongaro

Falcone

et al. 2018

IJMS

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In the evolving molecular landscape of metastatic colorectal cancer, optimizing available tools to select patients to receive anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibodies is a modern challenge of colorectal oncologists. Several molecular biomarkers have been investigated in recent years as potential predictors of resistance to anti-EGFR agents in preclinical and clinical retrospective series. Nevertheless, none of them have been implemented in clinical practice due to the lack of a formal prospective demonstration. Here, we propose a literature review of molecular alterations associated with resistance to anti-EGFRs, underlining the reasons why their roadmap from laboratories to clinics was prematurely halted.

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Negative hyper-selection of metastatic colorectal cancer patients for anti-EGFR monoclonal antibodies: the PRESSING case–control study

Abstract: The investigated panel of genomic alterations allows refining the selection of RAS and BRAF wild-type metastatic colorectal cancer patients candidates for anti-EGFRs, partially explaining and further corroborating the predictive ability of primary tumour sidedness.

Cited by 82 publications

References 30 publications

Rechallenge for Patients With RAS and BRAF Wild-Type Metastatic Colorectal Cancer With Acquired Resistance to First-line Cetuximab and Irinotecan

Rechallenge for Patients With RAS and BRAF Wild-Type Metastatic Colorectal Cancer With Acquired Resistance to First-line Cetuximab and Irinotecan

Prospective Biomarker Study in Advanced RAS Wild-Type Colorectal Cancer: POSIBA Trial (GEMCAD 10-02)

The Winding Roadmap of Biomarkers Toward Clinic: Lessons from Predictors of Resistance to Anti-EGFRs in Metastatic Colorectal Cancer

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