Adding cetuximab to paclitaxel and carboplatin for first-line treatment of carcinoma of unknown primary (CUP): results of the Phase 2 AIO trial PACET-CUP.
Journal
British journal of cancer
ISSN: 1532-1827
Titre abrégé: Br J Cancer
Pays: England
ID NLM: 0370635
Informations de publication
Date de publication:
02 2021
02 2021
Historique:
received:
25
05
2020
accepted:
15
10
2020
revised:
01
10
2020
pubmed:
26
11
2020
medline:
15
7
2021
entrez:
25
11
2020
Statut:
ppublish
Résumé
Patients with carcinoma of unknown primary (CUP) have a dismal prognosis, even when treated with multi-agent chemotherapy. We hypothesised that adding the epidermal growth-factor receptor (EGFR) inhibitor cetuximab to standard first-line chemotherapy with paclitaxel and carboplatin would improve PFS and RR in unfavourable CUP. This open-labelled, multicentre Phase 2 study included patients with unfavourable, untreated adeno- or undifferentiated CUP. Patients were randomised to receive either paclitaxel/carboplatin (group A) or paclitaxel/carboplatin plus cetuximab (group B) every 3 weeks for a maximum of 6 cycles followed by cetuximab maintenance in group B. The primary endpoint was PFS in the two groups. Secondary endpoints were RR, toxicity and overall survival (OS). One-hundred-and-fifty patients were randomised (group A = 72, group B = 78). The median PFS and OS for all patients were 3.8 and 8.1 months (95% confidence interval (CI): 2.9-4.8 and 6.8-9.5). There was no significant difference in PFS (3.7 vs 4.6 months, HR 0.98) or OS (8.1 vs 7.4, HR 1.1) between the two treatment groups. Response rate tended to be better for chemotherapy plus cetuximab compared to chemotherapy alone (22% vs 15%). Adverse events grade ≥3 were comparable between the two groups, except for significantly increased skin toxicity in the cetuximab arm. Cetuximab plus paclitaxel/carboplatin did not improve PFS, OS and RR in metastatic CUP compared to paclitaxel/carboplatin alone. Addition of cetuximab resulted in additional skin toxicity. The study was registered at clinicaltrials.gov as NCT00894569.
Sections du résumé
BACKGROUND
Patients with carcinoma of unknown primary (CUP) have a dismal prognosis, even when treated with multi-agent chemotherapy. We hypothesised that adding the epidermal growth-factor receptor (EGFR) inhibitor cetuximab to standard first-line chemotherapy with paclitaxel and carboplatin would improve PFS and RR in unfavourable CUP.
METHODS
This open-labelled, multicentre Phase 2 study included patients with unfavourable, untreated adeno- or undifferentiated CUP. Patients were randomised to receive either paclitaxel/carboplatin (group A) or paclitaxel/carboplatin plus cetuximab (group B) every 3 weeks for a maximum of 6 cycles followed by cetuximab maintenance in group B. The primary endpoint was PFS in the two groups. Secondary endpoints were RR, toxicity and overall survival (OS).
RESULTS
One-hundred-and-fifty patients were randomised (group A = 72, group B = 78). The median PFS and OS for all patients were 3.8 and 8.1 months (95% confidence interval (CI): 2.9-4.8 and 6.8-9.5). There was no significant difference in PFS (3.7 vs 4.6 months, HR 0.98) or OS (8.1 vs 7.4, HR 1.1) between the two treatment groups. Response rate tended to be better for chemotherapy plus cetuximab compared to chemotherapy alone (22% vs 15%). Adverse events grade ≥3 were comparable between the two groups, except for significantly increased skin toxicity in the cetuximab arm.
CONCLUSIONS
Cetuximab plus paclitaxel/carboplatin did not improve PFS, OS and RR in metastatic CUP compared to paclitaxel/carboplatin alone. Addition of cetuximab resulted in additional skin toxicity.
CLINICAL TRIAL REGISTRATION
The study was registered at clinicaltrials.gov as NCT00894569.
Identifiants
pubmed: 33235314
doi: 10.1038/s41416-020-01141-8
pii: 10.1038/s41416-020-01141-8
pmc: PMC7884392
doi:
Substances chimiques
Carboplatin
BG3F62OND5
Paclitaxel
P88XT4IS4D
Cetuximab
PQX0D8J21J
Banques de données
ClinicalTrials.gov
['NCT00894569']
Types de publication
Clinical Trial, Phase II
Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
721-727Références
Rassy, E. & Pavlidis, N. The currently declining incidence of cancer of unknown primary. Cancer Epidemiol. 61, 139–141 (2019).
doi: 10.1016/j.canep.2019.06.006
Pavlidis, N. & Pentheroudakis, G. Cancer of unknown primary site. Lancet. 379, 1428–1435 (2012).
doi: 10.1016/S0140-6736(11)61178-1
Conway, A.-M., Mitchell, C., Kilgour, E., Brady, G., Dive, C. & Cook, N. Molecular characterisation and liquid biomarkers in carcinoma of unknown primary (CUP): taking the ‘U’ out of ‘CUP.’. Br. J. Cancer 120, 141–153 (2019).
doi: 10.1038/s41416-018-0332-2
Jones, W., Allardice, G., Scott, I., Oien, K., Brewster, D. & Morrison, D. S. Cancers of unknown primary diagnosed during hospitalization: a population-based study. BMC Cancer 17, 85 (2017).
doi: 10.1186/s12885-017-3083-1
Varghese, A. M., Arora, A., Capanu, M., Camacho, N., Won, H. H., Zehir, A. et al. Clinical and molecular characterization of patients with cancer of unknown primary in the modern era. Ann. Oncol. 28, 3015–3021 (2017).
doi: 10.1093/annonc/mdx545
Hainsworth, J. D., Rubin, M. S., Spigel, D. R., Boccia, R. V., Raby, S., Quinn, R. et al. Molecular gene expression profiling to predict the tissue of origin and direct site-specific therapy in patients with carcinoma of unknown primary site: A prospective trial of the Sarah cannon research institute. J. Clin. Oncol. 31, 217–223 (2013).
doi: 10.1200/JCO.2012.43.3755
Briasoulis, E., Kalofonos, H., Bafaloukos, D., Samantas, E., Fountzilas, G., Xiros, N. et al. Carboplatin plus paclitaxel in unknown primary carcinoma: a Phase II Hellenic Cooperative Oncology Group Study. J. Clin. Oncol. 18, 3101–3107 (2000).
doi: 10.1200/JCO.2000.18.17.3101
Greco, F. A. Cancer of unknown primary site: improved patient management with molecular and immunohistochemical diagnosis. Am. Soc. Clin. Oncol. Educ. B. 33, 175–181 (2013).
doi: 10.1200/EdBook_AM.2013.33.175
Huebner, G., Link, H., Kohne, C. H., Stahl, M., Kretzschmar, A., Steinbach, S. et al. Paclitaxel and carboplatin vs gemcitabine and vinorelbine in patients with adeno- or undifferentiated carcinoma of unknown primary: a randomised prospective phase II trial. Br. J. Cancer 100, 44–49 (2009).
doi: 10.1038/sj.bjc.6604818
Yoon, H. H., Foster, N. R., Meyers, J. P., Steen, P. D., Visscher, D. W., Pillai, R. et al. Gene expression profiling identifies responsive patients with cancer of unknown primary treated with carboplatin, paclitaxel, and everolimus: NCCTG N0871 (alliance). Ann. Oncol. 27, 339–344 (2016).
doi: 10.1093/annonc/mdv543
Hainsworth J. D., Daugaard G., Lesimple T., Hübner G., Greco F. A., Stahl M. J. et al. Paclitaxel/carboplatin with or without belinostat as empiric first-line treatment for patients with carcinoma of unknown primary site: a randomized, phase 2 trial. Cancer 121, 1654–1661 (2015).
Hainsworth, J. D., Spigel, D. R., Thompson, D. S., Murphy, P. B., Lane, C. M., Waterhouse, D. M. et al. Paclitaxel/carboplatin plus bevacizumab/erlotinib in the first-line treatment of patients with carcinoma of unknown primary site. Oncologist 14, 1189–1197 (2009).
doi: 10.1634/theoncologist.2009-0112
Vermorken, J. B., Mesia, R., Rivera, F., Remenar, E., Kawecki, A., Rottey, S. et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N. Engl. J. Med. 359, 1116–1127 (2008).
doi: 10.1056/NEJMoa0802656
Bokemeyer, C., Bondarenko, I., Makhson, A., Hartmann, J. T., Aparicio, J., De Braud, F. et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J. Clin. Oncol. 27, 663–671 (2009).
doi: 10.1200/JCO.2008.20.8397
Van Cutsem, E., Köhne, C.-H., Hitre, E., Zaluski, J., Chang Chien, C.-R., Makhson, A. et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N. Engl. J. Med. 360, 1408–1417 (2009).
doi: 10.1056/NEJMoa0805019
Ciardiello, F. & Tortora, G. EGFR Antagonists in cancer treatment. N. Engl. J. Med. 358, 1160–1174 (2008).
doi: 10.1056/NEJMra0707704
Pentheroudakis, G., Golfinopoulos, V. & Pavlidis, N. Switching benchmarks in cancer of unknown primary: From autopsy to microarray. Eur. J. Cancer 43, 2026–2036 (2007).
doi: 10.1016/j.ejca.2007.06.023
Fizazi, K., Greco, F. A., Pavlidis, N., Daugaard, G., Oien, K. & Pentheroudakis, G. Cancers of unknown primary site: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 26, v133–v138 (2015).
doi: 10.1093/annonc/mdv305
Therasse, P., Arbuck, S. G., Eisenhauer, E. A., Wanders, J., Kaplan, R. S., Rubinstein, L. et al. New guidelines to evaluate the response to treatment in solid tumors. J. Natl. Cancer Inst. 92, 205–216 (2000).
doi: 10.1093/jnci/92.3.205
Douillard, J.-Y., Oliner, K. S., Siena, S., Tabernero, J., Burkes, R., Barugel, M. et al. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N. Engl. J. Med. 369, 1023–1034 (2013).
doi: 10.1056/NEJMoa1305275
Moran, S., Martínez-Cardús, A., Sayols, S., Musulén, E., Balañá, C., Estival-Gonzalez, A. et al. Epigenetic profiling to classify cancer of unknown primary: a multicentre, retrospective analysis. Lancet Oncol. 17, 1386–1395 (2016).
doi: 10.1016/S1470-2045(16)30297-2
Hayashi, H., Kurata, T., Takiguchi, Y., Arai, M., Takeda, K., Akiyoshi, K. et al. Randomized Phase II trial comparing site-specific treatment based on gene expression profiling with carboplatin and paclitaxel for patients with cancer of unknown primary site. J. Clin. Oncol. 37, 570–579 (2019).
doi: 10.1200/JCO.18.00771
Fizazi K., Maillard A., Penel N. et al. A phase 3 trial of empiric chemotherapy with cisplatin and gemcitabine or systemic treatment tailored by molecular gene expression analysis in patients with carcinomas of an unknown primary (CUP) site (GEFCAPI 04). Present ESMO Congr 2019, Barcelona Spain; LBA15_PR.
Rassy, E., Bakouny, Z., Choueiri, T. K., Van Allen, E. M., Fizazi, K., Greco, F. A. et al. The role of site-specific therapy for cancers of unknown of primary: a meta-analysis. Eur. J. Cancer 127, 118–122 (2020).
doi: 10.1016/j.ejca.2019.12.016