LBA8 - A randomised phase III trial of induction chemotherapy followed by chemoradiation compared with chemoradiation alone in locally advanced cervical cancer: The GCIG INTERLACE trial

Background

Locally advanced cervical cancer (LACC) is treated with chemoradiation (CRT). However, many patients relapse and die from metastatic disease. A feasibility study demonstrated a good response rate to short course weekly induction chemotherapy (IC) delivered before standard CRT and the INTERLACE trial investigated whether this approach improves both progression free survival (PFS) and overall survival (OS).

Methods

Women with squamous, adeno or adenosquamous carcinoma FIGO (2008) stage IB1 node positive,IB2,II,IIIB, IVA were eligible. Patients were randomised (1:1) to receive either CRT alone (5 cycles weekly cisplatin) or IC (6 weeks carboplatin AUC2 and paclitaxel 80mg/m²) followed by the same CRT in week 7. Mandated minimum total EQD2 dose 78Gy to Point A with 3D brachytherapy recommended. All centres underwent radiation quality assurance. Primary endpoints were PFS (target hazard ratio [HR] 0.65) and OS (target HR 0.65-0.70).

Results

500 patients were recruited from 32 centres in 5 countries (Nov 2012-Nov 2022). Median age 46 (range 24-78) years. Stage distribution was: IB1/2; 9%, II;77%, IIIB;11% and IVA;3%. 57% were node negative and 82% squamous subtype. Arms were balanced. 92% of IC patients had 5/6 cycles carboplatin/paclitaxel. Median interval from IC to CRT was 7 days. 84% (IC/CRT) vs. 89% (CRT alone) had 4/5 cycles cisplatin. In the CRT arm 92% and 89% completed external beam and brachytherapy respectively; corresponding figures in the IC/CRT arm were 97% and 95%. The median overall treatment time for CRT was 45 days in both arms. Grade ≥3 adverse events were seen in 59% (IC/CRT) vs. 48% (CRT alone). Median follow up 64 months. 5 year PFS rate is 73% with IC/CRT and 64% with CRT alone (HR 0.65; 95%CI:0.46-0.91, p=0.013). The corresponding 5-year OS rates are 80% and 72% (HR 0.61:95%CI:0.40-0.91, p=0.04).

Conclusions

Induction chemotherapy followed by CRT significantly improves PFS and OS in LACC and should be considered a new standard of care. INTERLACE recruited patients from diverse health care settings demonstrating that IC followed by CRT is feasible in all countries.

Clinical trial identification

EudraCT: 2011-001300-35.

Editorial acknowledgement

Legal entity responsible for the study

Trial Sponsor: University College London Trial Sponsor reference: UCL 11/0034.

Funding

Cancer Research UK.

Disclosure

M. McCormack: Other, Personal, Advisory Board: GSK, Eisai, AstraZeneca; Other, Personal and Institutional, Coordinating PI: Roche. L. Farrelly: Financial Interests, Institutional, Other, Research Grant, Institutional, Financial interest, Grant for a UCL-academic sponsored clinical trial: MSD, AstraZeneca, Autolus, Boehringer Ingelheim, GRAIL Inc, Novartis, Pfizer, Roche, Takeda; Financial Interests, Institutional, Other, Takeda: Janssen; Financial Interests, Institutional, Other, Research Grant for commercially sponsored trial through the ENGOT Network: Clovis, Seagen, Immunogen, GSK, Novartis, Aravive. C. Kent: Financial Interests, Personal, Speaker, Consultant, Advisor: Janssen; Financial Interests, Personal, Advisory Board: Clovis; Non-Financial Interests, Personal, Leadership Role, trustee of prostaid Charity: Prostaid Charity. E. Hudson: Financial Interests, Personal, Other, Advisory boards, lecture fees and travel: GSK/Tesaro, Clovis; Financial Interests, Personal, Other, Advisory boards, s and travel: Roche. T. Mathews: Non-Financial Interests, Personal, Leadership Role, NIHR gynae subspeciality lead for gynae research for South/West Yorkshire and Humber side: NIHR. J. Forrest: Non-Financial Interests, Personal, Other, Trsutee FORCE cancer support charity: FORCE cancer support charity; Financial Interests, Institutional, Other, PI EngotCx 11 Trial: Marke Sharpe & Dohme; Financial Interests, Institutional, Other, PI Engot Cx 12 Tria: Seagan. R. Bhana: Financial Interests, Personal, Other, All related to sponsorships for conferences, meetings and courses and market research or teaching sponsorshipAll related to sponsorships for conferences, meetings and courses and market research or teaching sponsorship: Pfizer; Financial Interests, Personal, Other, All related to sponsorships for conferences, meetings and courses and market research or teaching sponsorship: Astellas, Novartis, MSD, Jannsen, Takeda, Eisai, BMS, Clovis, AstraZeneca, GSK, Boston scientific, Palette Life Sciences, Varian, EUSA pharma. H. Stobart: Non-Financial Interests, Personal, Membership or affiliation: Independent Cancer Patients' Voice. A. Mukhopadhyay: Other, Personal, Other, Honoraria for being DSMB member 2023: Canariabio; Financial Interests, Personal, Licencing Fees or royalty for IP, Royalty payment one off in 2019 through Newcastle University: Clovis Oncology; Financial Interests, Institutional, Funding, esearch funding to KolGoTrg for conducting the HPV screening study PRECERCA 2023: Cepheid Global; Non-Financial Interests, Personal, Leadership Role, Project lead- PRECERCA study ( prevention of cervical cancer) - POint of care HPV testing for tea garden workers in Himalayan foothills: N/A; Non-Financial Interests, Personal, Leadership Role, Director: Kolkata Gynecoloy Oncology Trials and Translational Research Group. A.M. Hacker: Financial Interests, Institutional, Other, Research Grant, Institutional, Financial interest, Grant for a UCL-academic sponsored clinical trial: MSD, AstraZeneca, Autolus, Boehringer Ingelheim, GRAIL Inc, Jannsen, Novartis, Pfizer, Roche, Takeda; Financial Interests, Institutional, Other, Research Grant for commercially sponsored trial through the ENGOT Network: Clovis, Seagen, Immunogen, GSK, Novartis, Aravive. A. Hackshaw: Financial Interests, Personal, Advisory Board, AH is an investigator for an academic study (SUMMIT) sponsored by UCL that is funded by GRAIL, Inc.; has received one honorarium for an advisory board meeting for GRAIL, Inc; received a consulting fee from Evidera Inc (for one GRAIL-initiated project).: GRAIL Inc; Financial Interests, Personal, Other, For delivering general education/training in clinical trials.: AbbVie, Boehringer Ingelheim, Clovis, Ipsen, Takeda, AstraZeneca, Daiichi Sankyo, Merck Serono, MSD, UCB, Kyowa Kirin, Servier, Sobi, Pfizer, Roche; Financial Interests, Personal, Stocks/Shares, Shares were sold in 2020: Illumina, Thermo Fisher; Financial Interests, Institutional, Research Grant, Grant for a UCL-academic sponsored clinical trial: Roche, MSD, Autolus, AstraZeneca, Boehringer Ingelheim, GRAIL Inc, Takeda, Pfizer, Novartis, Bristol Myers Squibb, Janssen; Non-Financial Interests, Principal Investigator, Co-lead academic investigator for an observational study sponsored and conducted by Roche. Unpaid/no honoraria for this role.: Roche; Non-Financial Interests, Advisory Role, AH is on the scientific advisory board for Adela Bio and receives no payments/honoraria for this but has share options available.: Adela Bio; Non-Financial Interests, Advisory Role, Unpaid member of advisory board: Navio. J.A. Ledermann: Financial Interests, Personal, Advisory Board, Advisory Board and Speaker Fees: AstraZeneca, Clovis Oncology, GSK; Financial Interests, Personal, Advisory Board: Artios Pharma, Eisai, Merck/MSD, VBL Therapeutics, Bristol Myers Squibb, Nuvation, Ellipses, Immunogen, Miltenyi, Novocure, Immagene; Financial Interests, Personal, Invited Speaker, Speaker Fees: Neopharm; Financial Interests, Personal, Other, Independent Data Monitoring Committee: Mersana; Financial Interests, Personal, Other, IDMC: Sutro Bio, Mersana; Financial Interests, Institutional, Research Grant, Clinical Research University: AstraZeneca, MSD/Merck; Non-Financial Interests, Leadership Role, Vice President ( 2019-2021): European Society of Gynaecological Oncology; Non-Financial Interests, Officer, Chair Gynaecological Clinical Practice Guidelines: ESMO; Other, Associate Editor: Therapeutic Advances in Medical Oncology: Sage Publishing. All other authors have declared no conflicts of interest.