Durvalumab versus placebo with chemoradiotherapy for locally advanced cervical cancer (CALLA) : a randomised, double-blind, phase 3 trial
Copyright © 2023 Elsevier Ltd. All rights reserved..
BACKGROUND: Concurrent chemoradiotherapy has been the standard of care for locally advanced cervical cancer for over 20 years; however, 30-40% of treated patients have recurrence or progression within 5 years. Immune checkpoint inhibition has improved outcomes for patients with PD-L1 positive metastatic or recurrent cervical cancer. We assessed the benefit of adding durvalumab, a PD-L1 antibody, with and following chemoradiotherapy for locally advanced cervical cancer.
METHODS: The CALLA randomised, double-blind, phase 3 trial included 105 hospitals across 15 countries. Patients aged at least 18 years with previously untreated locally advanced cervical cancer (adenocarcinoma, squamous, or adenosquamous; International Federation of Gynaecology and Obstetrics [FIGO] 2009 stage IB2-IIB lymph node positive, stage ≥III any lymph node status) and WHO or Eastern Cooperative Oncology Group performance status of 0 or 1 were randomly assigned (1:1) through an interactive web response system using a permuted block size of 4 to receive durvalumab (1500 mg intravenously once every 4 weeks) or placebo with and following chemoradiotherapy, for up to 24 cycles. Chemoradiotherapy included 45 Gy external beam radiotherapy at 5 fractions per week concurrent with intravenous cisplatin (40 mg/m2) or carboplatin (area under the concentration-time curve 2) once weekly for 5 weeks, followed by image-guided brachytherapy (high-dose rate, 27·5-30 Gy or low-dose/pulse-dose rate, 35-40 Gy). Randomisation was stratified by disease stage status (FIGO stage and node status) and geographical region. Chemoradiotherapy quality was continuously reviewed. The primary endpoint was progression-free survival, assessed by the investigator using Response Evaluation Criteria in Solid Tumors, version 1.1, in the intention-to-treat population. Safety was assessed in patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03830866.
FINDINGS: Between Feb 15, 2019, and Dec 10, 2020, 770 women were randomly assigned (385 to durvalumab and 385 to placebo; median age 49 years [IQR 41-57]). Median follow-up was 18·5 months (IQR 13·2-21·5) in the durvalumab group and 18·4 months (13·2-23·7) in the placebo group. At data cutoff, median progression-free survival had not been reached (95% CI not reached-not reached) for either group (HR 0·84; 95% CI 0·65-1·08; p=0·17); 12-month progression-free survival was 76·0% (71·3-80·0) with durvalumab and 73·3% (68·4-77·5) with placebo. The most frequently reported grade 3-4 adverse events in both groups were anaemia (76 [20%] of 385 in the durvalumab group vs 56 [15%] of 384 in the placebo group) and decreased white blood cells (39 [10%] vs 49 [13%]). Serious adverse events occurred for 106 (28%) patients who received durvalumab and 89 (23%) patients who received placebo. There were five treatment-related deaths in the durvalumab group (one case each of urinary tract infection, blood loss anaemia, and pulmonary embolism related to chemoradiotherapy only; one case of endocrine disorder related to durvalumab only; and one case of sepsis related to both durvalumab and chemoradiotherapy). There was one treatment-related death in the placebo group (pneumonia related to chemoradiotherapy).
INTERPRETATION: Durvalumab concurrent with chemoradiotherapy was well tolerated in participants with locally advanced cervical cancer, however it did not significantly improve progression-free survival in a biomarker unselected, all-comers population. Concurrent durvalumab plus chemoradiotherapy warrants further exploration in patients with high tumoral PD-L1 expression. Rigorous monitoring ensured high chemoradiotherapy compliance with advanced technology and allowed patients to receive optimal care.
FUNDING: AstraZeneca.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:24 |
|---|---|
| Enthalten in: |
The Lancet. Oncology - 24(2023), 12 vom: 26. Dez., Seite 1334-1348 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Monk, Bradley J [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
28X28X9OKV |
|---|
| Anmerkungen: |
Date Completed 04.12.2023 Date Revised 27.02.2024 published: Print ClinicalTrials.gov: NCT03830866 Citation Status MEDLINE |
|---|
| doi: |
10.1016/S1470-2045(23)00479-5 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM365309885 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM365309885 | ||
| 003 | DE-627 | ||
| 005 | 20240229170457.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/S1470-2045(23)00479-5 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1310.xml |
| 035 | |a (DE-627)NLM365309885 | ||
| 035 | |a (NLM)38039991 | ||
| 035 | |a (PII)S1470-2045(23)00479-5 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Monk, Bradley J |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Durvalumab versus placebo with chemoradiotherapy for locally advanced cervical cancer (CALLA) |b a randomised, double-blind, phase 3 trial |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 04.12.2023 | ||
| 500 | |a Date Revised 27.02.2024 | ||
| 500 | |a published: Print | ||
| 500 | |a ClinicalTrials.gov: NCT03830866 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 Elsevier Ltd. All rights reserved. | ||
| 520 | |a BACKGROUND: Concurrent chemoradiotherapy has been the standard of care for locally advanced cervical cancer for over 20 years; however, 30-40% of treated patients have recurrence or progression within 5 years. Immune checkpoint inhibition has improved outcomes for patients with PD-L1 positive metastatic or recurrent cervical cancer. We assessed the benefit of adding durvalumab, a PD-L1 antibody, with and following chemoradiotherapy for locally advanced cervical cancer | ||
| 520 | |a METHODS: The CALLA randomised, double-blind, phase 3 trial included 105 hospitals across 15 countries. Patients aged at least 18 years with previously untreated locally advanced cervical cancer (adenocarcinoma, squamous, or adenosquamous; International Federation of Gynaecology and Obstetrics [FIGO] 2009 stage IB2-IIB lymph node positive, stage ≥III any lymph node status) and WHO or Eastern Cooperative Oncology Group performance status of 0 or 1 were randomly assigned (1:1) through an interactive web response system using a permuted block size of 4 to receive durvalumab (1500 mg intravenously once every 4 weeks) or placebo with and following chemoradiotherapy, for up to 24 cycles. Chemoradiotherapy included 45 Gy external beam radiotherapy at 5 fractions per week concurrent with intravenous cisplatin (40 mg/m2) or carboplatin (area under the concentration-time curve 2) once weekly for 5 weeks, followed by image-guided brachytherapy (high-dose rate, 27·5-30 Gy or low-dose/pulse-dose rate, 35-40 Gy). Randomisation was stratified by disease stage status (FIGO stage and node status) and geographical region. Chemoradiotherapy quality was continuously reviewed. The primary endpoint was progression-free survival, assessed by the investigator using Response Evaluation Criteria in Solid Tumors, version 1.1, in the intention-to-treat population. Safety was assessed in patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03830866 | ||
| 520 | |a FINDINGS: Between Feb 15, 2019, and Dec 10, 2020, 770 women were randomly assigned (385 to durvalumab and 385 to placebo; median age 49 years [IQR 41-57]). Median follow-up was 18·5 months (IQR 13·2-21·5) in the durvalumab group and 18·4 months (13·2-23·7) in the placebo group. At data cutoff, median progression-free survival had not been reached (95% CI not reached-not reached) for either group (HR 0·84; 95% CI 0·65-1·08; p=0·17); 12-month progression-free survival was 76·0% (71·3-80·0) with durvalumab and 73·3% (68·4-77·5) with placebo. The most frequently reported grade 3-4 adverse events in both groups were anaemia (76 [20%] of 385 in the durvalumab group vs 56 [15%] of 384 in the placebo group) and decreased white blood cells (39 [10%] vs 49 [13%]). Serious adverse events occurred for 106 (28%) patients who received durvalumab and 89 (23%) patients who received placebo. There were five treatment-related deaths in the durvalumab group (one case each of urinary tract infection, blood loss anaemia, and pulmonary embolism related to chemoradiotherapy only; one case of endocrine disorder related to durvalumab only; and one case of sepsis related to both durvalumab and chemoradiotherapy). There was one treatment-related death in the placebo group (pneumonia related to chemoradiotherapy) | ||
| 520 | |a INTERPRETATION: Durvalumab concurrent with chemoradiotherapy was well tolerated in participants with locally advanced cervical cancer, however it did not significantly improve progression-free survival in a biomarker unselected, all-comers population. Concurrent durvalumab plus chemoradiotherapy warrants further exploration in patients with high tumoral PD-L1 expression. Rigorous monitoring ensured high chemoradiotherapy compliance with advanced technology and allowed patients to receive optimal care | ||
| 520 | |a FUNDING: AstraZeneca | ||
| 650 | 4 | |a Randomized Controlled Trial | |
| 650 | 4 | |a Clinical Trial, Phase III | |
| 650 | 4 | |a Journal Article | |
| 650 | 7 | |a B7-H1 Antigen |2 NLM | |
| 650 | 7 | |a durvalumab |2 NLM | |
| 650 | 7 | |a 28X28X9OKV |2 NLM | |
| 700 | 1 | |a Toita, Takafumi |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Xiaohua |e verfasserin |4 aut | |
| 700 | 1 | |a Vázquez Limón, Juan C |e verfasserin |4 aut | |
| 700 | 1 | |a Tarnawski, Rafal |e verfasserin |4 aut | |
| 700 | 1 | |a Mandai, Masaki |e verfasserin |4 aut | |
| 700 | 1 | |a Shapira-Frommer, Ronnie |e verfasserin |4 aut | |
| 700 | 1 | |a Mahantshetty, Umesh |e verfasserin |4 aut | |
| 700 | 1 | |a Del Pilar Estevez-Diz, Maria |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Qi |e verfasserin |4 aut | |
| 700 | 1 | |a Limaye, Sewanti |e verfasserin |4 aut | |
| 700 | 1 | |a Godinez, Francisco J Ramirez |e verfasserin |4 aut | |
| 700 | 1 | |a Oppermann Kussler, Christina |e verfasserin |4 aut | |
| 700 | 1 | |a Varga, Szilvia |e verfasserin |4 aut | |
| 700 | 1 | |a Valdiviezo, Natalia |e verfasserin |4 aut | |
| 700 | 1 | |a Aoki, Daisuke |e verfasserin |4 aut | |
| 700 | 1 | |a Leiva, Manuel |e verfasserin |4 aut | |
| 700 | 1 | |a Lee, Jung-Yun |e verfasserin |4 aut | |
| 700 | 1 | |a Sulay, Raymond |e verfasserin |4 aut | |
| 700 | 1 | |a Kreynina, Yulia |e verfasserin |4 aut | |
| 700 | 1 | |a Cheng, Wen-Fang |e verfasserin |4 aut | |
| 700 | 1 | |a Rey, Felipe |e verfasserin |4 aut | |
| 700 | 1 | |a Rong, Yi |e verfasserin |4 aut | |
| 700 | 1 | |a Ke, Guihao |e verfasserin |4 aut | |
| 700 | 1 | |a Wildsmith, Sophie |e verfasserin |4 aut | |
| 700 | 1 | |a Lloyd, Andrew |e verfasserin |4 aut | |
| 700 | 1 | |a Dry, Hannah |e verfasserin |4 aut | |
| 700 | 1 | |a Tablante Nunes, Ana |e verfasserin |4 aut | |
| 700 | 1 | |a Mayadev, Jyoti |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t The Lancet. Oncology |d 2000 |g 24(2023), 12 vom: 26. Dez., Seite 1334-1348 |w (DE-627)NLM117859516 |x 1474-5488 |7 nnns |
| 773 | 1 | 8 | |g volume:24 |g year:2023 |g number:12 |g day:26 |g month:12 |g pages:1334-1348 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/S1470-2045(23)00479-5 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 24 |j 2023 |e 12 |b 26 |c 12 |h 1334-1348 | ||