Neoadjuvant and adjuvant pembrolizumab in advanced high-grade serous carcinoma: the randomized phase II NeoPembrOV clinical trial.
Humans
Antibodies, Monoclonal, Humanized
/ therapeutic use
Female
Middle Aged
Aged
Neoadjuvant Therapy
/ methods
Carboplatin
/ therapeutic use
Antineoplastic Combined Chemotherapy Protocols
/ therapeutic use
Paclitaxel
/ therapeutic use
Chemotherapy, Adjuvant
/ methods
Adult
Ovarian Neoplasms
/ drug therapy
Cystadenocarcinoma, Serous
/ drug therapy
Progression-Free Survival
Cytoreduction Surgical Procedures
Neoplasm Staging
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
16 Jul 2024
16 Jul 2024
Historique:
received:
24
02
2023
accepted:
18
03
2024
medline:
17
7
2024
pubmed:
17
7
2024
entrez:
16
7
2024
Statut:
epublish
Résumé
This open-label, non-comparative, 2:1 randomized, phase II trial (NCT03275506) in women with stage IIIC/IV high-grade serous carcinoma (HGSC) for whom upfront complete resection was unachievable assessed whether adding pembrolizumab (200 mg every 3 weeks) to standard-of-care carboplatin plus paclitaxel yielded a complete resection rate (CRR) of at least 50%. Postoperatively patients continued assigned treatment for a maximum of 2 years. Postoperative bevacizumab was optional. The primary endpoint was independently assessed CRR at interval debulking surgery. Secondary endpoints were Completeness of Cytoreduction Index (CCI) and peritoneal cancer index (PCI) scores, objective and best response rates, progression-free survival, overall survival, safety, postoperative morbidity, and pathological complete response. The CRR in 61 pembrolizumab-treated patients was 74% (one-sided 95% CI = 63%), exceeding the prespecified ≥50% threshold and meeting the primary objective. The CRR without pembrolizumab was 70% (one-sided 95% CI = 54%). In the remaining patients CCI scores were ≥3 in 27% of the standard-of-care group and 18% of the investigational group and CC1 in 3% of the investigational group. PCI score decreased by a mean of 9.6 in the standard-of-care group and 10.2 in the investigational group. Objective response rates were 60% and 72%, respectively, and best overall response rates were 83% and 90%, respectively. Progression-free survival was similar with the two regimens (median 20.8 versus 19.4 months in the standard-of-care versus investigational arms, respectively) but overall survival favored pembrolizumab-containing therapy (median 35.3 versus 49.8 months, respectively). The most common grade ≥3 adverse events with pembrolizumab-containing therapy were anemia during neoadjuvant therapy and infection/fever postoperatively. Pembrolizumab was discontinued prematurely because of adverse events in 23% of pembrolizumab-treated patients. Combining pembrolizumab with neoadjuvant chemotherapy is feasible for HGSC considered not completely resectable; observed activity in some subgroups justifies further evaluation to improve understanding of the role of immunotherapy in HGSC.
Identifiants
pubmed: 39013870
doi: 10.1038/s41467-024-46999-x
pii: 10.1038/s41467-024-46999-x
doi:
Substances chimiques
pembrolizumab
DPT0O3T46P
Antibodies, Monoclonal, Humanized
0
Carboplatin
BG3F62OND5
Paclitaxel
P88XT4IS4D
Types de publication
Journal Article
Clinical Trial, Phase II
Randomized Controlled Trial
Multicenter Study
Langues
eng
Sous-ensembles de citation
IM
Pagination
5931Subventions
Organisme : Merck (Merck & Co., Inc.)
ID : NA
Informations de copyright
© 2024. The Author(s).
Références
Vergote, I. et al. European Organization for Research and Treatment of Cancer-Gynaecological Cancer Group; NCIC Clinical Trials Group. Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer. N. Engl. J. Med. 363, 943–953 (2010).
doi: 10.1056/NEJMoa0908806
pubmed: 20818904
Vergote, I. et al. EORTC; MRC CHORUS study investigators. Neoadjuvant chemotherapy versus debulking surgery in advanced tubo-ovarian cancers: pooled analysis of individual patient data from the EORTC 55971 and CHORUS trials. Lancet Oncol. 19, 1680–1687 (2018).
doi: 10.1016/S1470-2045(18)30566-7
pubmed: 30413383
Kehoe, S. et al. Primary chemotherapy versus primary surgery for newly diagnosed advanced ovarian cancer (CHORUS): an open-label, randomised, controlled, non-inferiority trial. Lancet 386, 249–257 (2015).
doi: 10.1016/S0140-6736(14)62223-6
pubmed: 26002111
Fagotti, A. et al. Phase III randomised clinical trial comparing primary surgery versus neoadjuvant chemotherapy in advanced epithelial ovarian cancer with high tumour load (SCORPION trial): final analysis of peri-operative outcome. Eur. J. Cancer 59, 22–33 (2016).
doi: 10.1016/j.ejca.2016.01.017
pubmed: 26998845
Fagotti, A. et al. Randomized trial of primary debulking surgery versus neoadjuvant chemotherapy for advanced epithelial ovarian cancer (SCORPION-NCT01461850). Int. J. Gynecol. Cancer 30, 1657–1664 (2020).
doi: 10.1136/ijgc-2020-001640
pubmed: 33028623
González-Martín, A. et al. ESMO Guidelines Committee. Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann. Oncol. 34, 883–848 (2023).
doi: 10.1016/j.annonc.2023.07.011
Wright, A. A. et al. Neoadjuvant chemotherapy for newly diagnosed, advanced ovarian cancer: Society of Gynecologic Oncology and American Society of Clinical Oncology clinical practice guideline. J. Clin. Oncol. 34, 3460–3473 (2016).
doi: 10.1200/JCO.2016.68.6907
pubmed: 27502591
Rodrigues, M. et al. Real-world clinical outcomes of patients with de novo advanced high-grade epithelial ovarian cancer eligible to niraparib maintenance in France. Ann. Oncol. 32, S725–S772 (2021).
doi: 10.1016/j.annonc.2021.08.1188
Vergote, I. et al. Clinical research in ovarian cancer: consensus recommendations from the Gynecologic Cancer InterGroup. Lancet Oncol. 23, e374–e384 (2022).
doi: 10.1016/S1470-2045(22)00139-5
pubmed: 35901833
pmcid: 9465953
Colombo, N. et al. ESMO-ESGO Ovarian Cancer Consensus Conference Working Group. ESMO-ESGO consensus conference recommendations on ovarian cancer: pathology and molecular biology, early and advanced stages, borderline tumours and recurrent disease. Ann. Oncol. 30, 672–705 (2019).
doi: 10.1093/annonc/mdz062
pubmed: 31046081
Rouzier, R. et al. Efficacy and safety of bevacizumab-containing neoadjuvant therapy followed by interval debulking surgery in advanced ovarian cancer: results from the ANTHALYA trial. Eur. J. Cancer 70, 133–142 (2017).
doi: 10.1016/j.ejca.2016.09.036
pubmed: 27914243
Garcia, Y. et al. Efficacy and safety results from GEICO 1205, a randomized phase II trial of neoadjuvant chemotherapy with or without bevacizumab for advanced epithelial ovarian cancer. Int J. Gynecol. Cancer 29, 1050–1056 (2019).
doi: 10.1136/ijgc-2019-000256
Liu, J. et al. Improved efficacy of neoadjuvant compared to adjuvant immunotherapy to eradicate metastatic disease. Cancer Discov. 6, 1382–1399 (2016).
doi: 10.1158/2159-8290.CD-16-0577
pubmed: 27663893
Palazón, A. et al. The HIF-1α hypoxia response in tumor-infiltrating T lymphocytes induces functional CD137 (4-1BB) for immunotherapy. Cancer Discov. 2, 608–623 (2012).
doi: 10.1158/2159-8290.CD-11-0314
pubmed: 22719018
Sánchez-Paulete, A. R. et al. Cancer immunotherapy with immunomodulatory anti-CD137 and anti-PD-1 monoclonal antibodies requires BATF3-dependent dendritic cells. Cancer Discov. 6, 71–79 (2016).
doi: 10.1158/2159-8290.CD-15-0510
pubmed: 26493961
Webb, J. R., Milne, K., Kroeger, D. R. & Nelson, B. H. PD-L1 expression is associated with tumor-infiltrating T cells and favorable prognosis in high-grade serous ovarian cancer. Gynecol. Oncol. 141, 293–302 (2016).
doi: 10.1016/j.ygyno.2016.03.008
pubmed: 26972336
Topalian, S. L. et al. Neoadjuvant immune checkpoint blockade: A window of opportunity to advance cancer immunotherapy. Cancer Cell 41, 1551–1566 (2023).
doi: 10.1016/j.ccell.2023.07.011
pubmed: 37595586
Monk, B. J. et al. Chemotherapy with or without avelumab followed by avelumab maintenance versus chemotherapy alone in patients with previously untreated epithelial ovarian cancer (JAVELIN Ovarian 100): an open-label, randomised, phase 3 trial. Lancet Oncol. 22, 1275–1289 (2021).
doi: 10.1016/S1470-2045(21)00342-9
pubmed: 34363762
Pujade-Lauraine, E. et al. Avelumab alone or in combination with chemotherapy versus chemotherapy alone in platinum-resistant or platinum-refractory ovarian cancer (JAVELIN Ovarian 200): an open-label, three-arm, randomised, phase 3 study. Lancet Oncol. 22, 1034–1046 (2021).
doi: 10.1016/S1470-2045(21)00216-3
pubmed: 34143970
Moore, K. N. et al. Atezolizumab, bevacizumab, and chemotherapy for newly diagnosed stage III or IV ovarian cancer: placebo-controlled randomized phase III trial (IMagyn050/GOG 3015/ENGOT-OV39). J. Clin. Oncol. 39, 1842–1855 (2021).
doi: 10.1200/JCO.21.00306
pubmed: 33891472
pmcid: 8189598
Kurtz, J.-E. et al. Atezolizumab combined with bevacizumab and platinum-based therapy for platinum-sensitive ovarian cancer: placebo-controlled randomized phase III ATALANTE/ENGOT-ov29 trial. J. Clin. Oncol. 41, 4768–4778 (2023).
doi: 10.1200/JCO.23.00529
pubmed: 37643382
pmcid: 10602539
Varga, A. et al. Pembrolizumab in patients with programmed death ligand 1-positive advanced ovarian cancer: analysis of KEYNOTE-028. Gynecol. Oncol. 152, 243–250 (2019).
doi: 10.1016/j.ygyno.2018.11.017
pubmed: 30522700
Matulonis, U. A. et al. Antitumor activity and safety of pembrolizumab in patients with advanced recurrent ovarian cancer: results from the phase II KEYNOTE-100 study. Ann. Oncol. 30, 1080–1087 (2019).
doi: 10.1093/annonc/mdz135
pubmed: 31046082
Liao, J. B. et al. Pembrolizumab with low-dose carboplatin for recurrent platinum-resistant ovarian, fallopian tube, and primary peritoneal cancer: survival and immune correlates. J. Immunother. Cancer 9, e003122 (2021).
doi: 10.1136/jitc-2021-003122
pubmed: 34531249
pmcid: 8449961
Zsiros, E. et al. Efficacy and safety of pembrolizumab in combination with bevacizumab and oral metronomic cyclophosphamide in the treatment of recurrent ovarian cancer: a phase 2 nonrandomized clinical trial. JAMA Oncol. 7, 78–85 (2021).
doi: 10.1001/jamaoncol.2020.5945
pubmed: 33211063
Lee, E. K. et al. Combined pembrolizumab and pegylated liposomal doxorubicin in platinum resistant ovarian cancer: a phase 2 clinical trial. Gynecol. Oncol. 159, 72–78 (2020).
doi: 10.1016/j.ygyno.2020.07.028
pubmed: 32771276
Thomas, Q. D. et al. Optimal timing of interval debulking surgery for advanced epithelial ovarian cancer: a retrospective study from the ESME national cohort. Gynecol. Oncol. 167, 11–21 (2022).
doi: 10.1016/j.ygyno.2022.08.005
pubmed: 35970603
Konstantinopoulos, P. A. et al. Single-arm phases 1 and 2 trial of niraparib in combination with pembrolizumab in patients with recurrent platinum-resistant ovarian carcinoma. JAMA Oncol. 5, 1141–1149 (2019).
doi: 10.1001/jamaoncol.2019.1048
pubmed: 31194228
pmcid: 6567832
Le Saux O. et al. Immunomic longitudinal profiling of the NeoPembrOv trial identifies drivers of immunoresistance in high-grade ovarian carcinoma. Nat. Commun. https://doi.org/10.1038/s41467-024-47000-5 (2024).
You, B. et al. CA-125 ELIMination rate constant K (KELIM) is a marker of chemosensitivity in patients with ovarian cancer: results from the phase II CHIVA trial. Clin. Cancer Res. 26, 4625–4632 (2020).
doi: 10.1158/1078-0432.CCR-20-0054
pubmed: 32209570
You, B. et al. Identification of patients with ovarian cancer experiencing the highest benefit from bevacizumab in the first-line setting on the basis of their tumor-intrinsic chemosensitivity (KELIM): the GOG-0218 validation study. J. Clin. Oncol. 40, 3965–3974 (2022).
doi: 10.1200/JCO.22.01207
pubmed: 36252167
pmcid: 9746742
Ferron, G. et al. Neoadjuvant chemotherapy with or without nintedanib for advanced epithelial ovarian cancer: lessons from the GINECO double-blind randomized phase II CHIVA trial. Gynecol. Oncol. 170, 186–194 (2023).
doi: 10.1016/j.ygyno.2023.01.008
pubmed: 36706645
González-Martín, A. et al. PRIMA/ENGOT-OV26/GOG-3012 Investigators: niraparib in patients with newly diagnosed advanced ovarian cancer. N. Engl. J. Med. 381, 2391–2402 (2019).
doi: 10.1056/NEJMoa1910962
pubmed: 31562799
Ray-Coquard, I. et al. PAOLA-1 investigators. Olaparib plus bevacizumab as first-line maintenance in ovarian cancer. N. Engl. J. Med. 381, 2416–2428 (2019).
doi: 10.1056/NEJMoa1911361
pubmed: 31851799
Munari, E. et al. PD-L1 assays 22C3 and SP263 are not interchangeable in non-small cell lung cancer when considering clinically relevant cutoffs: an interclone evaluation by differently trained pathologists. Am. J. Surg. Pathol. 42, 1384–1389 (2018).
doi: 10.1097/PAS.0000000000001105
pubmed: 29901568
Gilly, F. N. et al. Quantitative prognostic indices in peritoneal carcinomatosis. Eur. J. Surg. Oncol. 32, 597–601 (2006).
doi: 10.1016/j.ejso.2006.03.002
pubmed: 16617003
Callens, C. et al. Validation study of the shallowHRDv2 assay for homologous recombination deficiency (HRD) detection in high-grade ovarian carcinomas (HGOC) in the first-line setting, from the phase III PAOLA-1/ENGOT-ov25 trial. Ann. Oncol. 8, 100811–100811 (2023).
A’Hern, R. P. Sample size tables for exact single-stage phase II designs. Stat. Med. 20, 859–866 (2001).
doi: 10.1002/sim.721
pubmed: 11252008