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.

Background

Rucaparib has antitumour activity in BRCA-mutant or BRCA wild-type/genomic loss of heterozygosity (LOH) high associated OC. ARIEL3 evaluated rucaparib vs placebo as maintenance treatment in pts with recurrent platinum-sensitive OC.

Methods

Eligible pts received ≥2 prior platinum-based therapies, had platinum-sensitive OC (disease progression ≥6 mo after penultimate platinum), and achieved a complete response (RECIST v1.1) or partial response (RECIST v1.1 or Gynecologic Cancer InterGroup CA-125 criteria) to their most recent platinum. All responses required CA-125 to be less than the upper limit of normal. Pts were randomised 2:1 to receive oral rucaparib 600 mg BID or placebo. Investigator-assessed progression-free survival (PFS) (primary endpoint) was assessed in a step-down procedure for 3 nested groups: (1) BRCA mutant (deleterious germline or somatic BRCA mutation); (2) homologous recombination deficient (BRCA mutant or BRCA wild-type/LOH high); and (3) intent-to-treat population. PFS was also assessed by blinded independent central review (key secondary endpoint) and LOH status in pts with BRCA wild-type OC (exploratory endpoint).

Results

Data are presented for the rucaparib and placebo groups, respectively. ARIEL3 enrolled 564 pts (375 and 189 in each group). PFS data are summarised in the Table. The most common grade 3 or higher treatment-emergent AEs were anaemia (18.8% and 0.5%) and alanine/aspartate aminotransferase increase (10.5% and 0%). At the visit cutoff date (15 Apr 2017), 13.4% and 1.6% of pts discontinued due to treatment-emergent AEs (excluding disease progression); 1.6% and 1.1% of pts died due to AEs (including disease progression).Table:

LBA40_PR

Conclusions

Rucaparib significantly improved PFS vs placebo in all primary analysis groups of pts with platinum-sensitive, recurrent OC. Improvement in PFS was observed in non-nested subgroups of pts with BRCA wild-type OC (both LOH high and LOH low).

Clinical trial identification

NCT01968213

Legal entity responsible for the study

Clovis Oncology, Inc.

Funding

Clovis Oncology, Inc.

Disclosure

J. Ledermann: Advisory Role: Clovis Oncology. A.M. Oza: Consulting or Advisory Role: Amgen, Verastem, Clovis Oncology, Immunovaccine Travel, Accommodations, Expenses: AstraZeneca Honoraria: WebRx. D. Lorusso: Consulting or Advisory Role: AstraZeneca, Clovis Oncology, Roche, PharmaMar Travel, Accommodations, Expenses: Roche, PharmaMar. A. Oaknin: Consulting or Advisory Role: PharmaMar, Clovis Oncology, Roche, AstraZeneca N. Colombo: Advisory board: Roche, AstraZeneca, Tasaro, Pharmamar, Clovis, Advaxis J. Weberpals: Research support: Abbvie, AstraZeneca. A. Leary: Advisory board: Clovis Oncology, Pfizer, Pharmamar, Gamamabs, Merus. R. Holloway: Speaker’s Bureau honoraria: Astra Zeneca, Clovis, Tesaro. D.M. O\'Malley: Research support: Clovis Oncology Advisory Board: Janssen, Eisai. T. Cameron, L. Maloney, S. Goble, K.K. Lin, H. Giordano: Employment: Clovis Oncology Stock and Other Ownership Interests: Clovis Oncology. J. Sun: Stock and Other Ownership Interests: Foundation Medicine. R. Coleman: Research support: AstraZeneca, Roche/Genentech, Janssen, Oncomed, Millennium, Esperance, Abbvie. All other authors have declared no conflicts of interest.

Background

The highly selective poly(ADP-ribose) polymerase (PARP) 1/2 inhibitor niraparib (ZEJULA™) concentrated in the tumor vs plasma in preclinical studies, delivering ≥90% durable PARP inhibition, and showed significantly longer progression-free survival vs placebo in patients (pts) with recurrent OC following complete (CR) or partial response (PR) to platinum-based chemotherapy (PBC) regardless of germline BRCA mutation (gBRCAmut) or homologous recombination deficiency (HRD) status in the phase 3 ENGOT-OV16/NOVA trial. Quality of life (QoL) measures are important to determine the benefit of drug therapy in this population. We evaluated patient-reported outcomes (PROs) associated with QoL and individual patient-reported symptoms using the Functional Assessment of Cancer Therapy-Ovarian Symptoms Index (FOSI) and European Quality of Life Scale 5-Dimensions (EQ-5D-5L) in ENGOT-OV16/NOVA pts treated with niraparib vs placebo.

Methods

A mixed-effects growth-curve model adjusted for baseline demographic values and 3 stratification factors was constructed to model the relationship between treatment and PRO score for each measure. The relationship between health status and PROs was evaluated through a cross-sectional analysis of adjusted EQ-5D-5L health utility index (HUI) scores. A disutility analysis of hematologic adverse events was conducted at different time points.

Results

No significant difference in mean PRO scores was observed between niraparib and placebo arms in either cohort. Adjusted HUI scores were similar in both arms at baseline, but average adjusted HUI pre-progression scores trended higher in the niraparib arm (0.812 vs 0.803 in gBRCAmut cohort; 0.845 vs 0.828 in non-gBRCAmut cohort). Hematologic toxicities had no detrimental effect on pts’ overall health utility.

Conclusions

These data suggest pts with recurrent OC treated with niraparib following CR or PR to PBC can continuously maintain their QoL while on treatment.

Clinical trial identification

NCT01847274

Legal entity responsible for the study

TESARO, Inc.

Funding

TESARO, Inc.

Disclosure

A.M. Oza: Consulting/Advisory: Amgen, Verastem, Clovis Oncology, Immunovaccine; Travel, Accommodations, Expenses: AstraZeneca; Honoraria: WebRx. U.A. Matulonis: Consulting/Advisory: Merck KGaA, AstraZeneca, Immunogen, Tesaro, Genentech. S. Malander: Honoraria: AstraZeneca, Roche. J. Sehouli: Honoraria: Roche, AstraZeneca, Tesaro, PharmaMar; Consulting/Advisory: Clovis Oncology, Roche, AstraZeneca, Tesaro, Novocure Research; Funding: Amgen, Novartis, Lilly, Bayer. J.M. del Campo: Speakers’ Bureau: Roche, MSD Oncology, PharmaMar, Boehringer Ingelheim. S. Banerjee: Travel, Accommodations, Expenses: AstraZeneca, Clovis Oncology. G. Scambia: Honoraria: Roche, AstraZeneca, PharmaMar Consulting/Advisory: Roche, AstraZeneca, PharmaMar Speakers’ Bureau: Roche, AstraZeneca, PharmaMar; Travel, Accommodations, Expenses: Roche, AstraZeneca, PharmaMar. J.S. Berek: Consulting/Advisory: Atara Biotherapeutics. A.V. Tinker: Consulting/Advisory: AstraZeneca. F. Hilpert: Honoraria: Roche, AstraZeneca, Novartis, Medac, MSD, PharmaMar; Consulting/Advisory: PharmaMar, Roche, AZ, MSD; Travel, Accommodations, Expenses: AZ, Roche, PharmaMar. I. Palacio Vázquez: Research Funding: Novartis, Tesaro; Expert Testimony: AstraZeneca; Travel, Accommodations, Expenses: Roche, PharmaMar. V. D’hondt: Travel, Accommodations, Expenses: Amgen. B. Benigno: Honoraria: AstraZeneca, Insys Therapeutics; Research funding: Tesaro. D.M. Provencher: Consulting or Advisory Role: AstraZeneca; Speakers\' Bureau: AstraZeneca. S. Hudgens: Consulting/Advisory: Tesaro; Research Funding: Tesaro. S. Agarwal: Employment: TESARO, Inc. Stock: TESARO, Inc. M.R. Mirza: Consulting or Advisory Role: Clovis Oncology, AstraZeneca, Tesaro. All other authors have declared no conflicts of interest.

Background

PankoMab-GEX (PMG) is a glyco-engineered humanized monoclonal antibody recognizing the carbohydrate-induced tumor-associated epitope mucin 1 (TA-MUC1). A phase I study showed safety and tolerability of PMG in patients with TA-MUC1 positive advanced solid malignancies. The aim of the present phase 2 study is to evaluate the efficacy and safety of maintenance therapy with PMG compared to placebo in patients with recurrent ovarian, fallopian tube or primary serous peritoneal cancer.

Methods

In this placebo-controlled phase 2 study PMG was given as switch maintenance therapy, after response or absence of tumor progression following chemotherapy (CT) in tumors that are TA-MUC1 positive on archival tissue. Stratification criteria are ‘resistance’ (progression-free survival (PFS) 0 - < 6 months) vs. ‘partial sensitivity‘(PFS 6-12 months) to the most recent platinum-based CT; number of prior CT lines (2 vs. 3-5); response or stable disease after last CT. Patients were randomized 2:1 to receive intravenous PMG (500mg and 1 week later a dose of 1700mg) or placebo (Pl) repeated every 3 weeks until tumor progression or toxicity. Primary endpoint is PFS by immune related response criteria (irRC) based on modified RECIST 1.1. Secondary endpoints include PFS and PFS at 6 months by RECIST, safety, overall response rate, CA125 progression; overall survival; QoL; pharmacokinetics.

Results

From 2014 to 2016, 216 pts were randomized to PMG (n = 151) or placebo (Pl) (n = 65) (see demographics in table 1). No difference was observed for the primary endpoint of PFS by irRC (median 15.3 and 15.0 weeks for PMG and Pl respectively) [HR: 0.958 (95% CI: 0.690-1.331) p = 0.7988]. No advantage for PMG over Pl was observed for all other secondary efficacy endpoints and subgroup analysis by stratification factors. PMG was well tolerated, with grade 1-2 infusion related reactions being the most common AE.Table:

LBA41 Patient Demographics

Conclusions

This study shows that PMG switch maintenance does not improve outcome in ovarian cancer TA-MUC1 positive patients.

Clinical trial identification

: NCT01899599

Legal entity responsible for the study

Glycotope GmbH

Funding

Glycotope GmbH

Disclosure

U. De Giorgi: Speaker honorarium or travel support from Astellas, Janssen-Cilag and Sanofi-Aventis. N. Colombo: Attended advisory board meetings for Astra Zeneca, Roche, Pharmamar, Tesaro, Clovis, Pfizer, Advaxis. All other authors have declared no conflicts of interest.

Background

There are limited therapeutic options available for patients (pts) with relapsed, recurrent, and/or metastatic cervical cancer. Historic data indicate dismal outcome with ORR of 0-15% and a median OS of 6-8 months (Mo). Tisotumab vedotin (Tv) is an antibody-drug conjugate (ADC) composed of a Tissue Factor specific human IgG1 monoclonal antibody conjugated to a microtubule disrupting agent Monomethyl Auristatin E (MMAE) and is being tested in an ongoing Ph I/IIa dose-escalation study (NCT02001623) in pts with locally advanced and/or metastatic solid tumors. Here, we present initial data on the pre-planned 30 pt expansion cohort in relapsed, recurrent, or metastatic cervical cancer.

Methods

Key eligibility criteria included recurrent or metastatic cervical cancer with at least 1 prior line of therapy, adequate liver and kidney function and ECOG 0-1. Tv was given as 2 mg/kg q3w until progression. Efficacy and toxicity were assessed according to RECIST 1.1 and CTCAE 4.03.

Results

Thirty pts were enrolled. Median age was 43 (21-73), median prior lines 2 (1-5). Twenty-nine pts had previously received cisplatin, 28 a taxane and 19 also bevacizumab. Preliminary efficacy data for 19 pts were available at time of submission. Ten pts (33%) experienced Gr 3 TEAE(s) related to GI (2 pts), anemia (2 pts), infections (1 pt), neuropathy (1 pt), bleeding (1 pt), other (7 pts). No Gr 4 or 5 AEs were reported. The toxicity profile appeared to be consistent with MMAE-based ADCs, including peripheral neuropathy and neutropenia with an identified compound-specific toxicity of conjunctivitis for which prophylactic management was introduced. Seven of the 19 pts (37%) evaluable for efficacy obtained a clinical response; hereof, 6 were confirmed at time of submission. With a mean follow-up of 5.5 Mo for the 7 responders, 5 remain on trial with none of the responders having relapsed. Full efficacy data for all 30 pts will be available at time of presentation.

Conclusions

Preliminary data demonstrated a manageable safety profile and encouraging efficacy (ORR 37%) in relapsed, recurrent or metastatic cervical cancer. Our findings in a high unmet medical need population warrant further investigation.

Clinical trial identification

NCT02001623, released November 14, 2013

Legal entity responsible for the study

Genmab A/S

Funding

Genmab A/S

Disclosure

E. Dean: Employee of The Christie NHS Foundation Trust and The University of Manchester during this research but currently employed by AstraZeneca. The Christie NHS Foundation Trust received institutional commercial income for the conduct of the research. J. de Bono: Employed by The institute of Cancer Research, have served on Genmab Advisory Board, have served as advisor on advisory boards for multiple industry partners incl. AstraZeneca, Daiichi-Sankyo, Genentech, GSK, Merck, Pfizer, Sanofi, Taiho a.o. M. Johnson: Lilly Serono Kadmon Janssen Mirati Therapeutics Genmab Pfizer AstraZeneca Genentech/Roche Novartis Checkpoint Therapeutics Array BioPharma Regeneron Abbvie Merrimack Tarveda Astellas, Otsuka, Genentech/Roche, Boehringer-Ingelheim. S. Lisby, L. Basse: Employed by Genmab and hold shares in the company. R. Coleman: Member of Genmab\'s Advisory Board for Tisotumab vedotin. D.S. Hong: Research/Grant Funding: Bayer, Lilly, Genentech, LOXO, Pfizer, Amgen, Mirati, Ignyta, Merck, Daichi-Sanko, Eisai; Travel, Accommodations, Expenses: MiRNA, LOXO; Consulting Role: Bayer, Baxter, Guidepoint Global Other: Oncoreseponse (founder). All other authors have declared no conflicts of interest.