- Ramon Salazar (Hospitalet de Llobregat, Spain)
- Takayuki Yoshino (Kashiwa, Chiba, Japan)
LBA32 - Encorafenib plus cetuximab with or without binimetinib for BRAF V600E–mutant metastatic colorectal cancer: Expanded results from a randomized, 3-arm, phase III study vs the choice of either irinotecan or FOLFIRI plus cetuximab (BEACON CRC) (ID 4491)
- Josep Tabernero (Barcelona, Spain)
Abstract
Background
Encorafenib (ENCO) + binimetinib (BINI) + cetuximab (CETUX) significantly improved overall survival (OS, HR:0.52, P < 0.0001) and objective response rates (ORR, 26% vs 2%, P < 0.0001) in patients (pts) with BRAFV600E metastatic colorectal cancer (mCRC) compared with current standard of care. This analysis focuses on the triplet ((ENCO+CETUX+BINI) and doublet (ENCO+CETUX) arms.
Methods
The BEACON CRC study was a randomized, 3-arm, phase 3 study which evaluated triplet or doublet vs. investigator’s choice of irinotecan or FOLFIRI + CETUX in 665 pts with BRAFV600E mCRC. The triplet vs doublet efficacy comparison was a secondary endpoint (not formally powered). Analyses included efficacy (OS, ORR, depth of response, and progression-free survival [PFS]), multivariate modeling, safety, and quality of life (QOL) assessments (EORTC QOL Questionnaire (QLQ C30), Functional Assessment of Cancer Therapy Colon Cancer, EuroQol 5D 5L, and Patient Global Impression of Change).
Results
224 and 220 pts were randomized to triplet and doublet, respectively. Median overall survival for triplet and doublet was 9.0 (95%CI: 8.0, 11.4) and 8.4 months (95%CI: 7.5, 11.0), respectively (HR:0.79 [95%CI: 0.59, 1.06]). ORR was 26% (95%CI: 18%, 35%) for triplet and 20% (95%CI: 13%,29%) for doublet. For pts with 1 prior therapy, ORR was 34% (95%CI: 23, 47) for triplet and 22% (95%CI: 14, 33) for doublet. Waterfall plots indicated that depth of response favored triplet. Grade 3+ adverse events (AE) were 58% in triplet and 50% in doublet. Rates of discontinuation due to an AE were similar (triplet: 7%; doublet: 8%), with median relative dose intensity maintained for both arms. There were no differences in QOL across 4 instruments. Some toxicities occurred less frequently with the triplet.
Conclusions
In BEACON CRC, triplet and doublet showed encouraging activity in BRAFV600E mCRC. Data suggest that the triplet offers improved efficacy vs doublet with some additional manageable toxicity and no impact on overall QOL. Further follow-up will better define the relative benefits of the regimens.
Clinical trial identification
NCT02928224.
Editorial acknowledgement
Editorial assistance was provided by JD Cox and Mayville Medical Communications, with funding from Array Biopharma.
Legal entity responsible for the study
Array BioPharma Inc.
Funding
Array BioPharma Inc.
Disclosure
J. Tabernero: Advisory / Consultancy: Bayer; Advisory / Consultancy: Boehringer; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: MSD; Advisory / Consultancy: Merck Serono; Advisory / Consultancy: Novartis; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Taiho; Advisory / Consultancy: Merrimack; Advisory / Consultancy: Peptomyc; Advisory / Consultancy: Rafael Pharmaceuticals; Advisory / Consultancy: Symphogen; Advisory / Consultancy: Chugai Pharma; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Merus; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Seattle Genetics; Advisory / Consultancy: Array BioPharma; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: BeiGene. A. Grothey: Honoraria (self): Elsevier; Honoraria (self): Aptitude Health; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Genentech; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bayer; Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Eli Lilly; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Boston Biomedical; Advisory / Consultancy, Travel / Accommodation / Expenses: Amgen; Advisory / Consultancy, Research grant / Funding (institution): Array BioPharma; Advisory / Consultancy: Guardant Health; Advisory / Consultancy, Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Eisai; Travel / Accommodation / Expenses: MSD; Travel / Accommodation / Expenses: Boehringer Ingelheim. E. Van Cutsem: Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): Eli Lilly; Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy, Research grant / Funding (institution): Servier; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Celgene; Advisory / Consultancy: MSD; Advisory / Consultancy, Research grant / Funding (institution): Merck KGaA; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: AstraZeneca; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Ipsen; Research grant / Funding (institution): Merck. R. Yaeger: Research grant / Funding (institution), Travel / Accommodation / Expenses: Array BioPharma; Research grant / Funding (institution): GSK; Research grant / Funding (institution): Novartis; Speaker Bureau / Expert testimony: Sysmex; Research grant / Funding (institution): Symphogen; Licensing / Royalties: Biocartis. H. Wasan: Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (institution): Merck KGaA; Honoraria (self), Speaker Bureau / Expert testimony: Celgene; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Sirtex Medical; Honoraria (self): Array BioPharma; Honoraria (self), Advisory / Consultancy: Shire; Honoraria (self): Genentech; Honoraria (self), Advisory / Consultancy: ERYTECH Pharma; Advisory / Consultancy: Roche; Advisory / Consultancy: Incyte; Speaker Bureau / Expert testimony: Servier; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): MSD. T. Yoshino: Research grant / Funding (institution): Chugai Pharma; Research grant / Funding (institution): Sanofi; Research grant / Funding (institution): Sumitomo Dainppon; Research grant / Funding (institution): GSK. J. Desai: Advisory / Consultancy, Research grant / Funding (institution): Eli Lilly; Advisory / Consultancy, Research grant / Funding (institution): Bionomics; Advisory / Consultancy: Eisai; Advisory / Consultancy, Research grant / Funding (institution): BeiGene; Advisory / Consultancy: Ignyta; Research grant / Funding (institution): Roche; Research grant / Funding (institution): GSK; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Ipsen. F. Ciardiello: Advisory / Consultancy, Research grant / Funding (institution): Genentech; Advisory / Consultancy, Research grant / Funding (institution): Merck KGaA; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): Amgen; Advisory / Consultancy: Pfizer; Research grant / Funding (institution): Servier; Research grant / Funding (institution): Symphogen; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Ipsen. N. Steeghs: Research grant / Funding (institution): AstraZeneca/MedImmune; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): GSK; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Blueprint Medicines; Research grant / Funding (institution): AB Science; Research grant / Funding (institution): Deciphera; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Merus; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Incyte. H. Arkenau: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): GSK; Research grant / Funding (institution): Servier; Research grant / Funding (institution): Astellas; Research grant / Funding (institution): Array BioPharma; Research grant / Funding (institution), Travel / Accommodation / Expenses: Iovance; Full / Part-time employment: SCRI. A. Gollerkeri: Full / Part-time employment: Pfizer Inc.. M. Pickard: Full / Part-time employment: Pfizer Inc.. K. Maharry: Full / Part-time employment: Pfizer Inc.. J.L. Christy-Bittel: Full / Part-time employment: Pfizer Inc.. L. Anderson: Full / Part-time employment: Pfizer Inc.. S. Kopetz: Shareholder / Stockholder / Stock options: MolecularMatch; Research grant / Funding (institution), Shareholder / Stockholder / Stock options: Navire ; Advisory / Consultancy: Roche; Advisory / Consultancy, Research grant / Funding (institution): Genentech; Advisory / Consultancy, Research grant / Funding (institution): EMD Serono; Advisory / Consultancy: Merck; Advisory / Consultancy: Karyopharm; Advisory / Consultancy: Amal Therapeutics; Advisory / Consultancy: Symphogen; Advisory / Consultancy: Holy Stone; Advisory / Consultancy, Research grant / Funding (institution): Biocartis; Advisory / Consultancy, Research grant / Funding (institution): Amgen; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Boehringer Ingelheim; Research grant / Funding (institution): Sanofi; Research grant / Funding (institution): Guardian Health; Research grant / Funding (institution): Array BioPharma; Research grant / Funding (institution): MedImmune. All other authors have declared no conflicts of interest.
LBA33 - Lefitolimod vs standard of care (SOC) for patients with metastatic colorectal cancer (mCRC) responding to first-line standard treatment: Results from the randomized phase III IMPALA trial (ID 5016)
- Ramon Salazar (Hospitalet de Llobregat, Spain)
Abstract
Background
The TLR9 agonist lefitolimod broadly activates the innate and adaptive immune system. Based on encouraging data from the randomized phase II IMPACT trial, lefitolimod was evaluated in this phase III trial as switch maintenance treatment in patients with mCRC who have responded to first-line therapy.
Methods
The international, multicenter, open-label phase III IMPALA trial was conducted including the AIO, TTD and GERCOR cooperative groups and recruited 549 patients across 8 European countries. Patients who had an objective response to any standard first-line induction therapy (5FU/FA or CAPE, plus OX or IRI, alone or plus antiVEGF or antiEGFR) were randomized to receive either lefitolimod monotherapy (experimental arm) or local standard of care (control arm). After first progression, patients started re-induction therapy, with those in the experimental arm continuing lefitolimod on top.
Results
Demographics and baseline characteristics were well balanced between the study arms. Median duration of follow up was 35 months. The primary endpoint overall survival (OS) was not met: median OS was 22.0 and 21.9 months in the lefitolimod and control group, respectively (p = 0.2765; HR = 1.12; 95% CI 0.91 - 1.38). Progression free survival, event-free rates, pre-defined sub-group analyses including molecular and immunological parameters for OS did also not indicate a benefit. In comparison with the control arm treatment with lefitolimod was generally well tolerated. Rates of grade 3, 4 and 5 toxicities were 6.3, 1.9 and 0%, respectively and no new safety signals or autoimmune events were identified while immune activation was confirmed in peripheral blood.
Conclusions
Lefitolimod did not show superiority to standard of care as a single agent maintenance treatment in patients with mCRC. Limited add-on toxicity confirmed the favorable safety and tolerability profile of lefitolimod. Hence, and given its mode of action, lefitolimod will be evaluated in combination with other anti-cancer immunotherapies.
Clinical trial identification
NCT02077868.
Legal entity responsible for the study
Mologen AG.
Funding
Mologen AG.
Disclosure
D. Cunningham: Advisory / Consultancy: Celgene; Advisory / Consultancy: MedImmune; Advisory / Consultancy: Bayer; Advisory / Consultancy: 4SC; Advisory / Consultancy: Clovis; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Janssen; Advisory / Consultancy: Merck. R. Salazar: Advisory / Consultancy: VCN-BCN; Advisory / Consultancy: Agendia; Advisory / Consultancy: Guardant Health; Advisory / Consultancy, Research grant / Funding (institution): Roche Diagnostics; Advisory / Consultancy: Ferrer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Prizer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Advisory / Consultancy: Ipsen; Advisory / Consultancy, Speaker Bureau / Expert testimony: Amgen; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): Roche Farma; Advisory / Consultancy: Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD; Speaker Bureau / Expert testimony: AZD; Speaker Bureau / Expert testimony: Celgene; Leadership role, Shareholder / Stockholder / Stock options: Sace Medhealth; Research grant / Funding (institution): Novartis Farmaceutica; Research grant / Funding (institution): PsiOxus Therapeutics Ltd; Research grant / Funding (institution): VCN Biosciences; Research grant / Funding (institution): Mologen. A. Sobrero: Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck; Advisory / Consultancy, Speaker Bureau / Expert testimony: Amgen; Advisory / Consultancy, Speaker Bureau / Expert testimony: BMS; Advisory / Consultancy, Speaker Bureau / Expert testimony: Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony: Celgene; Advisory / Consultancy, Speaker Bureau / Expert testimony: Sanofi; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bayer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Takeda. M.P. Ducreux: Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Celgene; Research grant / Funding (self): Chugai; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy: Merck Serono; Honoraria (self), Advisory / Consultancy: Novartis; Research grant / Funding (self): Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Roche; Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (self), Advisory / Consultancy: Servier; Spouse / Financial dependant: Sandoz. E. Van Cutsem: Advisory / Consultancy: Astellas; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): Celgene; Advisory / Consultancy: Incyte; Advisory / Consultancy, Research grant / Funding (institution): Lilly; Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy, Research grant / Funding (institution): Merck Serono; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy, Research grant / Funding (institution): Servier; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Ipsen. C. Tournigand: Advisory / Consultancy: Bayer; Advisory / Consultancy: BMS; Advisory / Consultancy: MSD; Advisory / Consultancy: Roche; Advisory / Consultancy: Sanofi. V. Molnar: Full / Part-time employment: Mologen AG. M. Starke: Full / Part-time employment: Mologen AG. M. Baumann: Leadership role: Mologen AG. E. Wiegert: Advisory / Consultancy: Mologen AG. M. Schmidt: Full / Part-time employment: Mologen AG. D. Arnold: Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self): Amgen; Advisory / Consultancy: MSD; Advisory / Consultancy: Merck Serono; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Honoraria (self), Advisory / Consultancy: Servier; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Honoraria (self), Travel / Accommodation / Expenses: Sanofi; Honoraria (self), Advisory / Consultancy: Terumo; Honoraria (self): Astellas; Honoraria (self): Biocompatibles; Honoraria (self), Advisory / Consultancy: Sirtex; Advisory / Consultancy: Boston Scientific; Honoraria (self): ArtTempi Media; Honoraria (self): PRiME Oncology; Honoraria (self): TRM Oncology; Advisory / Consultancy: IQVIA / Quintiles; Advisory / Consultancy: FlatIron. All other authors have declared no conflicts of interest.
524O - Next-generation sequencing (NGS) in metastatic colorectal cancer (mCRC): Novel mutated genes and their effect on response to therapy (Alliance) (ID 4878)
- Federico Innocenti (Chapel Hill, US, United States of America)
Abstract
Background
CALGB (Alliance)/SWOG 80405 was a randomized phase III trial that found no difference in overall survival (OS) in first-line mCRC Patients (pts) treated with bevacizumab (Bev) or cetuximab (Cet) combined with the same chemotherapy. By applying NGS to tumour DNA collected from pts in the trial, we aimed to discover novel mutated genes associated with differential response to therapy with the biologics and prognosis.
Methods
Primary tumour DNA from 520 pts was profiled for somatic gene mutations. Mutations in 426 genes were determined by NGS (FoundationOne). OS was the primary endpoint, both as a time-to-event and a categorical (<20 or ≥ 20 months) variable. Cox proportional hazard models (hazard ratio, HR) and logistic regression (odds ratio, OR) were used, respectively, adjusted by MSI status, BRAF V600E, all RAS mutations, arm, gender, and age. Interactions between mutated genes and treatment (Bev versus Cet) on OS were tested.
Results
In Bev-treated pts, tumours with mutated IGF1 (6%) conferred worse OS than WT tumours (HR 2.8 [1.5-5.2], p = 0.0009), and tumours with mutated KDR (11%) conferred worse OS than WT tumours (OR 4.4 [1.6-12.3], p = 0.004). In Cet-treated pts, tumours with mutated FANCD2 (6%) conferred worse OS than WT tumours (HR 2.7 [1.4-5.3], p = 0.004), and tumours with mutated APC (74%) conferred better OS than WT tumours (OR 0.3 [0.1-0.6], p = 0.0009). RNF43-mutated tumours (12%) and SMARCA4-mutated tumours (6%) conferred worse OS in Cet-treated pts than Bev-treated pts (interaction p-value 0.002 and 0.0009, respectively). In all patients in the study, FANCI-mutated tumours (4%) conferred worse OS than WT tumours (HR 2.0 [1.2-3.3], p = 0.005; OR 5.0 [1.9-14.8], p = 0.002). The full set of NGS results will be presented, including the mutational map of tumour location.
Conclusions
To our knowledge, this is the largest and most comprehensive NGS analysis of somatic DNA mutations in tumours from mCRC pts treated with standard of care therapy. It provides novel gene candidates affecting response to Bev and Cet, each combined with chemotherapy, as well as mutated genes affecting the prognosis of patients. If validated in other phase III studies, these results may be used to guide treatment decisions in pts with mCRC.
Clinical trial identification
NCT00265850.
Legal entity responsible for the study
The authors.
Funding
U10CA180821, U10CA180882, U10CA180888 and U10CA180830 (SWOG); Genentech, Eli Lilly & Co., Pfizer, Sanofi.
Disclosure
X. Qu: Shareholder / Stockholder / Stock options, Full / Part-time employment: Genentech. M. Bertagnolli: Research grant / Funding (self): BMS; Research grant / Funding (self): Eli Lilly; Research grant / Funding (self): Roche; Research grant / Funding (self): Sanofi; Research grant / Funding (self): Pfizer; Research grant / Funding (self): Genentech. A. Venook: Research grant / Funding (self), travel: Genentech; Research grant / Funding (self): BMS; Travel / Accommodation / Expenses: Roche. O. Kabbarah: Full / Part-time employment: Genentech; Shareholder / Stockholder / Stock options: Roche. H.J. Lenz: Honoraria (self): Roche; Advisory / Consultancy: Roche; Travel / Accommodation / Expenses: Roche. All other authors have declared no conflicts of interest.
Invited Discussant LBA32, LBA33 and 524O (ID 6686)
- Alfredo Falcone (Pisa, Italy)
LBA34 - MIRACLE: Green tea extract versus placebo for the prevention of colorectal adenomas: A randomized, controlled trial (ID 1890)
- Thomas Seufferlein (Ulm, Germany)
Abstract
Background
Prevention of colorectal adenomas (CA) is likely to prevent colorectal cancer (CRC). Nutri- or chemoprevention of CRC is not yet established. NSAIDs show some benefit but also increase the bleeding risk. Agents with a more favourable benefit/risk ratio are desirable. Preclinical and small clinical trials suggest that epigallocatechingallate (EGCG), a major polyphenol in green tea, has a good safety profile and antineoplastic effects in the large bowel, but there are no data from large trials. MIRACLE enrolled 1001 patients to examine the effect of a three year intake of ECGC on the recurrence of CA after polypectomy.
Methods
Double-blinded, placebo-controlled trial, 41 recruiting German centers, recruitment 12/2011-6/2015. Patients aged 50-80 years who underwent polypectomy within the last 6 months and tolerated EGCG well during a one month run-in were randomized to standardized decaffeinated EGCG (150 mg bid) or placebo for 3 years. Primary endpoint: Incidence of metachronous CA at the 3 year follow-up colonoscopy. Secondary endpoints: Occurrence, number, localization, size, histological subtype of CA, frequency of CRC and biomarker. Strata: Study center and intake of low-dose aspirin (≤100 mg/d).
Results
Clinical parameters were well balanced between the groups. Primary endpoint was analysed in the modified ITT set (modITT; n = 309 patients in EGCG, n = 323 in placebo group giving informed consent and undergoing 3 year follow up colonoscopy in the requested time frame). n = 102 patients in the EGCG and n = 103 in the placebo group were excluded due to missing follow up colonoscopy. Incidence of one or more CA after 3 year of placebo or EGCG 150 mg bid was 55.7 % and 51.1%, respectively (one sided adj. P = 0.077, adj. RR 0.904) in the modITT. In the per protocol set constituting all modITT patients completing the study without major protocol violations the respective figures were 54.3 % in the placebo and 48.3% in the EGCG group (one sided adj. P = 0.058, adj. RR 0.883). There were no safety issues and no major differences in AEs between EGCG and placebo during the randomized phase.
Conclusions
300 mg EGCG per day was well tolerated and showed a trend towards a preventive effect on CA in the large bowel though not statistically significant.
Clinical trial identification
NCT01360320.
Legal entity responsible for the study
Martin-Luther-Universität Halle-Wittenberg, Germany.
Funding
German Cancer Aid (Stiftung Deutsche Krebshilfe).
Disclosure
All authors have declared no conflicts of interest.
Invited Discussant LBA34 (ID 6689)
- Andrew T. Chan (Boston, MA, United States of America)