ICON8 investigated the safety and efficacy of weekly dose dense chemotherapy (q1w) in patients with epithelial ovarian cancer (EOC) compared to standard three weekly chemotherapy (q3w). ICON8 had co-primary outcomes of progression free (PFS) and overall survival (OS). Mature OS and updated PFS results are reported here.

Background: Neoadjuvant carboplatin-paclitaxel (CT) with delayed primary surgery (DPS) after 3 cycles is a standard-of-care option for women with bulky FIGO stage IIIc-IV EOC. However, radiological and biochemical response to neoadjuvant CT has not been prospectively evaluated nor compared with DPS outcome and progression-free survival (PFS). Methods: ICON8 is a phase III randomised trial that compared standard 3-weekly CT with 2 dose-dense weekly CT regimens. Patients could enter after primary surgery or receive neoadjuvant treatment with planned DPS. Radiological response to neoadjuvant CT was evaluated using RECIST v1.1. Serum CA125 was measured 3-weekly per protocol and evaluated using GCIG criteria. Results: 779 patients entered ICON8 with planned DPS after neoadjuvant CT. DPS was performed in 602 (536 after 3-4 cycles; 65 after 5/6 cycles; data missing 1). RECIST and CA125 response data were available for 531 and 726 respectively. No differences in response were noted between trial arms, so a combined analysis was performed. Best RECIST response (RR) pre-DPS was 61% (CR 4%, PR 57%, SD 33%, PD 6%). Median pre-operative change in marker lesions was -14.5% in patients with SD. GCIG CA125 response rate was 84%, including 71% (123/173) in patients with RECIST SD. Comparison of surgical feasibility, cytoreductive outcomes and PFS with ORR are presented in the table.Table: 943PDDPS Outcome by RECIST GroupPD N = 32SD N = 177PR/CR N = 322Total N = 531Surgery not performed8 (31%)28 (17%)28 (9%)64 (13%)Inoperable03 (2%)5 (2%)8 (2%)Debulked to no visible residual disease14 (54%)69 (42%)166 (54%)249 (50%)Debulked to ≤ 1cm residual disease2 (8%)41 (25%)74 (25%)117 (23%)Debulked to > 1cm residual disease2 (8%)24 (15%)34 (11%)60 (12%)Surgical outcome missing6121533Median PFS (months)5.014.716.4 Open table in a new tab Conclusions: RR to neoadjuvant CT in ICON8 was 61% and was not improved by dose-dense CT. PD is rare following neoadjuvant CT and SD by RECIST incorporates many women with definite reduction in disease burden. GCIG CA125 criteria overestimate response compared to RECIST. Both PFS and complete/optimal debulking rates were similar in SD and CR/PR groups, reinforcing that patients with SD should be offered DPS. Clinical trial identification: ISRCTN: ISRCTN10356387; EudraCT: 2010-02209-16. Legal entity responsible for the study: University College London. Funding: Cancer Research UK. Disclosure: A.R. Clamp: Research grants, travel expenses and advisory board: AstraZenenca, I.A. McNeish: Advisory boards: AstraZeneca, Clovis Oncology, Tesaro, Takeda. All other authors have declared no conflicts of interest.

Background: For several decades, standard first-line chemotherapy for EOC has been carboplatin (C) and paclitaxel (T), administered 3-weekly (q3w). The JGOG3016 trial reported clinically significant lengthening of PFS and overall survival in Japanese women using dose-dense weekly (q1w) T but with increased toxicity. ICON8 is a 3-arm trial, comparing standard q3w CT with dose-dense q1w regimens in a predominantly European patient group. Methods: Eligible women with FIGO stage IcG3- IV EOC were randomised 1:1:1 to Arm 1 (standard) - q3w C AUC5/6 + q3w T 175mg/m2; Arm 2 - q3w C AUC5/6 + q1w T 80mg/m2; Arm 3 - q1w C AUC2 + q1w T 80 mg/m2. Patients entered ICON8 after immediate primary surgery (IPS), or received neo-adjuvant chemotherapy with planned delayed primary surgery (DPS). Primary intention to treat analysis compared arm 2v1 and arm 3v1 using methods for data with non-proportional hazards. Results: 1566 women were randomised Jun 2011-Nov 2014. Median age- 62 years, 72% serous histology, 93% ECOG performance status 0/1. 48% had IPS, 50% planned DPS, 2% inoperable. 72%, 60%, 63% completed 6 cycles protocol-defined treatment in arms 1, 2, 3. Completion rate for 6 cycles platinum was 88% (90%; 89%; 85%). Paclitaxel dose-intensification was achieved (median total dose T (mg/m2)-1011; 1234; 1274). Grade (G) 3/4 toxicity (predominantly uncomplicated low neutrophils) was seen in 42%; 63%; 53% patients. Incidence of G3/4 febrile neutropenia (4%; 6%; 3%) and ≥G2 sensory neuropathy (28%; 25%; 23%) were similar across arms. At Feb 2017, 64% patients had experienced disease progression. No significant increase in PFS was observed with either weekly treatment (log-rank arm 2v1 p = 0.45; arm 3v1 p = 0.56, non-proportionality p = 0.02, restricted mean survival time=24.4; 24.9; 25.3 months in arms 1, 2, 3, median PFS- 17.9; 20.6; 21.1months, HR = 0.92 arm 2v1, HR = 0.94 arm 3v1). Conclusions: Although weekly dose-dense chemotherapy can be delivered successfully as first-line EOC treatment without substantial toxicity increase, it does not significantly improve PFS compared to standard 3-weekly CT. Clinical trial identification: ISRCTN: ISRCTN10356387 EUDRACT: 2010-022209-16 CTA: 2010-022209-16 ENGOT: OV-13 MREC: 11/LO/0043 Legal entity responsible for the study: Medical Research Council Clinical Trials Unit at University College London Funding: Cancer Research UK; Medical Research Council Disclosure: All authors have declared no conflicts of interest.

ICON8 is a randomised GCIG phase III 3-arm trial comparing 6 cycles of standard 3-weekly (q3w) carboplatin/paclitaxel with weekly (q1w) dose-dense treatment. Patients had immediate primary surgery (IPS) or neo-adjuvant chemotherapy and delayed primary surgery (DPS) after 3 cycles. Two interim analyses were planned: 1A, first 50 patients (pts) in each arm; 1B, first 50 DPS pts in each arm, ICON8 being the first trial of dose-dense treatment with DPS. 1566 women were randomised between Jun 2011 and Nov 2014 to: Arm 1 - q3w carboplatin AUC5/6 + paclitaxel 175mg/m2; Arm 2 - q3w carboplatin AUC5/6 + q1w paclitaxel 80mg/m2; Arm 3 - q1w carboplatin AUC2 + paclitaxel 80 mg/m2. The interim safety analyses included 237 patients. Feasibility was measured by completion of protocol treatment, safety by the rate of any G3+ toxicity experienced per patient. Stage 1A analysis included 85 IPS and 65 DPS pts, median age 59 years and 64% stage IIIC/IV disease. Stage 1B included 87 further DPS pts (total DPS = 152), median age 62 years, 92% stage IIIC/IV. Protocol treatment completion was lower than expected but >80% 1A and >75% 1B pts received 6 cycles of platinum chemotherapy. Increased paclitaxel dose intensity was achieved (see table). Most common reason for not completing protocol treatment was toxicity. G3+ toxicity was more frequent in arms 2 and 3, mainly due to uncomplicated neutropenia.Tabled 1Stage 1AStage 1AStage 1AStage 1BStage 1BStage 1BArm 1 n = 50Arm 2 n = 50Arm 3 n = 50Arm 1 n = 50Arm 2 n = 52Arm 3 n = 50FeasibilityProtocol treatment completion, N(%) P-value (compared to arm 1)39 (78%) -29 (58%) 0.0329 (58%) 0.0329 (58%) -34 (65%) 0.4725 (50%) 0.426 cycles platinum chemotherapy, N(%) P-value (compared to arm 1)44 (88%) -46 (92%) 0.5140 (80%) 0.2340 (80%) -46 (88%) 0.2739 (78%) 0.81Carboplatin dose intensity (AUC/week) median1.791.861.831.821.781.77Paclitaxel dose intensity (mg/m2/weed) median53.564.167.851.365.567.9ToxicityG3/4+ Toxicity, N(%)17 (35%)29 (58%)24 (48%)24 (50%)33 (63%)23 (46%)G3/4+ Uncomplicated neutropenia, N(%)4 (8%)16 (32%)11 (22%)5 (10%)19 (37%)13 (26%)G3/4+ Febrile neutropenia, N(%)2 (4%)1 (2%)1 (2%)1 (2%)3 (6%)0G3/4+ Thrombocytopenia, N(%)2 (4%)2 (4%)1 (2%)2 (4%)3 (6%)1 (2%)G2+ Sensory neuropathy, N(%)12 (25%)15 (30%)9 (18%)16 (33%)6 (12%)5 (10%) Open table in a new tab Completion of 6 cycles of platinum chemotherapy was high; however, protocol-defined q1w regimens were frequently modified. Protocol treatment completion differed significantly between arms in stage 1A, but not 1B, perhaps reflecting q3w paclitaxel toxicity in DPS patients. Rates of clinically relevant toxicity were acceptable, and despite aggressive dosing thresholds febrile neutropenia was rare. No dose modifications were implemented following stage 1A/1B analyses, but early use of G-CSF was recommended. PFS results are expected in Q2 2017, OS in 2018.