CAVE-2 (Cetuximab-AVElumab) mCRC: A Phase II Randomized Clinical Study of the Combination of Avelumab Plus Cetuximab as a Rechallenge Strategy in Pre-Treated RAS/BRAF Wild-Type mCRC Patients
IntroductionImmunotherapy has limited efficacy in metastatic colorectal cancer (mCRC). Understanding mechanisms mediating immune resistance in microsatellite stable (MSS) colorectal tumors remains an ongoing challenge. Novel combination immunotherapy-based approaches have been developed under the ra...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-06-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2022.940523/full |
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| author | Stefania Napolitano Giulia Martini Davide Ciardiello Davide Ciardiello Massimo Di Maio Nicola Normanno Antonio Avallone Erika Martinelli Evaristo Maiello Teresa Troiani Fortunato Ciardiello |
| author_facet | Stefania Napolitano Giulia Martini Davide Ciardiello Davide Ciardiello Massimo Di Maio Nicola Normanno Antonio Avallone Erika Martinelli Evaristo Maiello Teresa Troiani Fortunato Ciardiello |
| author_sort | Stefania Napolitano |
| collection | DOAJ |
| description | IntroductionImmunotherapy has limited efficacy in metastatic colorectal cancer (mCRC). Understanding mechanisms mediating immune resistance in microsatellite stable (MSS) colorectal tumors remains an ongoing challenge. Novel combination immunotherapy-based approaches have been developed under the rationale of overcoming immune resistance and developing effective immune response against colorectal tumor cells. Preclinical studies have demonstrated that cetuximab may modulate immune response to cancer cells. In this scenario, the inhibition of PD-L1 with IgG1 MAb avelumab in combination with anti-EGFR IgG1 monoclonal antibody cetuximab could be a strategy for potentiating antitumor activity. The CAVE phase II single-arm clinical trial provided the first evidence of clinical activity of combining cetuximab plus avelumab in 77 patients with RAS wild-type (WT) mCRC. This combination had a good toxicity profile, with a low rate of common grade 3 adverse events.Patients and MethodsBased on results obtained with the CAVE clinical trial, here we describe the design and rationale for the phase II, randomized CAVE 2 clinical study of the combination of avelumab plus cetuximab as a rechallenge strategy in pre-treated RAS, BRAF WT mCRC patients treated in first line with chemotherapy in combination with cetuximab and who have had a clinical benefit (complete or partial response) from treatment. A total of 173 patients will be randomized (2:1) to cetuximab + avelumab (115) or cetuximab as a single agent (58). The primary endpoint is overall survival. Key secondary endpoints include overall response rate, progression-free survival, and safety. For each patient, before treatment, a blood sample will be obtained and analyzed for circulating free tumor DNA according to NGS (Foundation/Roche), to identify RAS/BRAF WT patients to be enrolled. The same procedure will be performed at the progression of the disease. Additional blood/plasma, tumor, and fecal samples will be collected and centrally stored for additional translational studies.DiscussionThis study will provide the rationale to test immunotherapy-based combinations in the clinical setting, offering new opportunities for RAS WT mCRC patients.Clinical Trial Registration[https://clinicaltrials.gov/ct2/show/NCT05291156], identifier [NCT05291156]. |
| first_indexed | 2024-12-12T14:18:03Z |
| format | Article |
| id | doaj.art-c73ea4fc55a04ed89b22a3faeda777f5 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-12T14:18:03Z |
| publishDate | 2022-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-c73ea4fc55a04ed89b22a3faeda777f52022-12-22T00:21:52ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2022-06-011210.3389/fonc.2022.940523940523CAVE-2 (Cetuximab-AVElumab) mCRC: A Phase II Randomized Clinical Study of the Combination of Avelumab Plus Cetuximab as a Rechallenge Strategy in Pre-Treated RAS/BRAF Wild-Type mCRC PatientsStefania Napolitano0Giulia Martini1Davide Ciardiello2Davide Ciardiello3Massimo Di Maio4Nicola Normanno5Antonio Avallone6Erika Martinelli7Evaristo Maiello8Teresa Troiani9Fortunato Ciardiello10Oncologia Medica, Dipartimento di Medicina di Precisione, Università degli Studi della Campania “L. Vanvitelli”, Napoli, ItalyOncologia Medica, Dipartimento di Medicina di Precisione, Università degli Studi della Campania “L. Vanvitelli”, Napoli, ItalyOncologia Medica, Dipartimento di Medicina di Precisione, Università degli Studi della Campania “L. Vanvitelli”, Napoli, ItalyOncologia Medica, Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, ItalyDipartimento di Oncologia, Università di Torino, Azienda Ospedaliera Mauriziana, Torino, ItalyBiologia Cellulare e Bioterapie, Istituto Nazionale per lo Studio e la Cura dei Tumori “Fondazione Giovanni Pascale”—Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Napoli, ItalyOncologia Medica, Istituto Nazionale per lo Studio e la Cura dei Tumori “Fondazione Giovanni Pascale”—IRCCS, Napoli, ItalyOncologia Medica, Dipartimento di Medicina di Precisione, Università degli Studi della Campania “L. Vanvitelli”, Napoli, ItalyOncologia Medica, Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, ItalyOncologia Medica, Dipartimento di Medicina di Precisione, Università degli Studi della Campania “L. Vanvitelli”, Napoli, ItalyOncologia Medica, Dipartimento di Medicina di Precisione, Università degli Studi della Campania “L. Vanvitelli”, Napoli, ItalyIntroductionImmunotherapy has limited efficacy in metastatic colorectal cancer (mCRC). Understanding mechanisms mediating immune resistance in microsatellite stable (MSS) colorectal tumors remains an ongoing challenge. Novel combination immunotherapy-based approaches have been developed under the rationale of overcoming immune resistance and developing effective immune response against colorectal tumor cells. Preclinical studies have demonstrated that cetuximab may modulate immune response to cancer cells. In this scenario, the inhibition of PD-L1 with IgG1 MAb avelumab in combination with anti-EGFR IgG1 monoclonal antibody cetuximab could be a strategy for potentiating antitumor activity. The CAVE phase II single-arm clinical trial provided the first evidence of clinical activity of combining cetuximab plus avelumab in 77 patients with RAS wild-type (WT) mCRC. This combination had a good toxicity profile, with a low rate of common grade 3 adverse events.Patients and MethodsBased on results obtained with the CAVE clinical trial, here we describe the design and rationale for the phase II, randomized CAVE 2 clinical study of the combination of avelumab plus cetuximab as a rechallenge strategy in pre-treated RAS, BRAF WT mCRC patients treated in first line with chemotherapy in combination with cetuximab and who have had a clinical benefit (complete or partial response) from treatment. A total of 173 patients will be randomized (2:1) to cetuximab + avelumab (115) or cetuximab as a single agent (58). The primary endpoint is overall survival. Key secondary endpoints include overall response rate, progression-free survival, and safety. For each patient, before treatment, a blood sample will be obtained and analyzed for circulating free tumor DNA according to NGS (Foundation/Roche), to identify RAS/BRAF WT patients to be enrolled. The same procedure will be performed at the progression of the disease. Additional blood/plasma, tumor, and fecal samples will be collected and centrally stored for additional translational studies.DiscussionThis study will provide the rationale to test immunotherapy-based combinations in the clinical setting, offering new opportunities for RAS WT mCRC patients.Clinical Trial Registration[https://clinicaltrials.gov/ct2/show/NCT05291156], identifier [NCT05291156].https://www.frontiersin.org/articles/10.3389/fonc.2022.940523/fullmCRCrechallengecetuximabavelumabphase II trial |
| spellingShingle | Stefania Napolitano Giulia Martini Davide Ciardiello Davide Ciardiello Massimo Di Maio Nicola Normanno Antonio Avallone Erika Martinelli Evaristo Maiello Teresa Troiani Fortunato Ciardiello CAVE-2 (Cetuximab-AVElumab) mCRC: A Phase II Randomized Clinical Study of the Combination of Avelumab Plus Cetuximab as a Rechallenge Strategy in Pre-Treated RAS/BRAF Wild-Type mCRC Patients Frontiers in Oncology mCRC rechallenge cetuximab avelumab phase II trial |
| title | CAVE-2 (Cetuximab-AVElumab) mCRC: A Phase II Randomized Clinical Study of the Combination of Avelumab Plus Cetuximab as a Rechallenge Strategy in Pre-Treated RAS/BRAF Wild-Type mCRC Patients |
| title_full | CAVE-2 (Cetuximab-AVElumab) mCRC: A Phase II Randomized Clinical Study of the Combination of Avelumab Plus Cetuximab as a Rechallenge Strategy in Pre-Treated RAS/BRAF Wild-Type mCRC Patients |
| title_fullStr | CAVE-2 (Cetuximab-AVElumab) mCRC: A Phase II Randomized Clinical Study of the Combination of Avelumab Plus Cetuximab as a Rechallenge Strategy in Pre-Treated RAS/BRAF Wild-Type mCRC Patients |
| title_full_unstemmed | CAVE-2 (Cetuximab-AVElumab) mCRC: A Phase II Randomized Clinical Study of the Combination of Avelumab Plus Cetuximab as a Rechallenge Strategy in Pre-Treated RAS/BRAF Wild-Type mCRC Patients |
| title_short | CAVE-2 (Cetuximab-AVElumab) mCRC: A Phase II Randomized Clinical Study of the Combination of Avelumab Plus Cetuximab as a Rechallenge Strategy in Pre-Treated RAS/BRAF Wild-Type mCRC Patients |
| title_sort | cave 2 cetuximab avelumab mcrc a phase ii randomized clinical study of the combination of avelumab plus cetuximab as a rechallenge strategy in pre treated ras braf wild type mcrc patients |
| topic | mCRC rechallenge cetuximab avelumab phase II trial |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2022.940523/full |
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