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ROLE OF MAINTENANCE THERAPY IN ADVANCED CRC

ROLE OF MAINTENANCE THERAPY IN ADVANCED CRC. Cigdem Usul Afsar, MD, Assoc. Prof Acıbadem Mehmet Ali Aydınlar University Department of Internal Medicine and Medical Oncology Acıbadem Bakırkoy Hospital. Presentatıon PLAN. Preface/Introduction Anti-VEGFR based maintenance therapies (Phase 3)

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ROLE OF MAINTENANCE THERAPY IN ADVANCED CRC

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  1. ROLE OF MAINTENANCE THERAPY IN ADVANCED CRC Cigdem Usul Afsar, MD, Assoc. Prof Acıbadem Mehmet Ali Aydınlar University Department of Internal Medicine and Medical Oncology Acıbadem Bakırkoy Hospital

  2. Presentatıon PLAN • Preface/Introduction • Anti-VEGFR based maintenance therapies (Phase 3) • Anti-EGFR based maintenance therapies (Phase 2) • Factors affecting response to MT • Tumor sidedness and RAS/RAF mutation status • Alternative Maintenance Strategies and Ongoing Trials • Take Home Messages

  3. PREFACE • Goal of palliative therapy is to: -extend a patient’s life and -maintain the quality of life as long as possible, using the least amount of treatment necessary to control the disease. The use of oxaliplatin-based first-line therapy has early-on led to trials investigating Stop-and-Go strategies to prevent cumulative neurotoxicity.

  4. Introductıon • Interest in the use of maintenance therapy (MT) approach after first-line treatment of unresectable, metastatic CRC is growing. • Intensive first line therapy------followed by less intensive therapy until progression (in patients with good response to initial treatment)

  5. No irinotecan, no oxaliplatin Maughan et al. Lancet 2003

  6. Antı-vegfr based therapıes

  7. CAIRO 3 Study • Open-label, phase 3, multicenter RCT • 558 patients with metastatic CRC and with stable disease or better after first-line treatment with CapeOx/bevacizumab • Maintenance therapy with capecitabine/bevacizumab vs observation • After first progression, both groups took CapeOx/beva again until 2nd progression (PFS2) • Median follow-up: 48 months, PFS2(primary endpoint) was higher in the maintenance arm (11.7vs 8.5 months) HR=0.67, p 0.0001 • 54 % patients received CapeOx/beva the 2nd time • QoL good, hand-foot syndrome (23 %) during maintenance • OS: NS trend towards improved OS (21.6 vs 18.1 months), HR=0.83, p=0.06 Simkens LH, et al. Maintenance treatment with capecitabine and bevacizumab in metastatic colorectal cancer (CAIRO3): a phase 3 randomised controlled trial of the Dutch Colorectal Cancer Group. Lancet 2015; 385(9980): 1843-52.

  8. AIO 0207 TrIal • Open-label, non-inferiority, randomized phase 3 trial • 472 patients whose disease did not progress on induction FOLFOX/beva or CapeOx/beva • Fluoropyrimidine/beva maintenance or bevacizumab maintenance or no maintenance • After first progression, re-introduction of primary therapy • Primary endpoint: time to failure (time from randomization to second progression, death and initiation of new drug treatment) • Median follow-up: 17 months, median TTF was 6.4 m (no treatment)-6.9 m (FP/beva)-6.1 m (beva), BEVA alone was NONINFERIOR • Only 1/3 received re-induction CT- interpreting the RESULTS, OS was NS (secondary endpoint) Hegewisch-Becker S, et al. Maintenance strategies after first-line oxaliplatin plus fluoropyrimidine plus bevacizumab for patients with metastatic colorectal cancer (AIO 0207): a randomised, non-inferiority, open-label, phase 3 trial. Lancet Oncol 2015; 16(13): 1355-69.

  9. While either MT was superior to observation in patients with RAS/BRAF wild-type tumours, only maintenance with FP+beva was superior to observation in those with RAS/BRAF mutant tumours.

  10. PRODIGE 9 TrIal • Randomized phase 3 trial • Following 12 cycles of induction CT with FOLFIRI/beva, during CT-free intervals, observation or bevacizumab maintenance • Median tumor control duration was 15 months (in both groups) • PFS=9.2 vs 8.9 m, OS=21.7-22 m (beva vs no treatment) • BEVA MAINTENANCE DID NOT IMPROVE OUTCOMES Aparicio T, and PRODIGE 9 Investigators. Bevacizumab Maintenance Versus No Maintenance During Chemotherapy-Free Intervals in Metastatic Colorectal Cancer: A Randomized Phase III Trial (PRODIGE 9). J Clin Oncol 2018; 36(7): 674-81.

  11. SAKK 41/06 TrIal • Randomized, phase 3, non-inferiority • CT+beva in first line therapy, beva alone as maintenance therapy • Primary endpoint: TTP was not met (4.1 for beva arm-2.9 m for nom) HR=0.74 • OS=NS (25.4-23.8 m), HR=0.83, p=0.2 • NONINFERIORITY WAS NOT DEMONSTRATED Koeberle D, et al. Bevacizumab continuation versus no continuation after first-line chemotherapy plus bevacizumab in patients with metastatic colorectal cancer: a randomized phase III non-inferiority trial (SAKK 41/06). Ann Oncol 2015; 26(4): 709-14.

  12. GERCOR DREAM (OPTIMOX 3) TrIal • Open-label, phase 3, randomized trial • Patients with metastatic CRC without disease progression on beva-based CT, maintenance with beva or beva+erlotinib • ITT analysis, PFS was 5.4 vs 4.9 m (HR=0.81, p=0.06) and OS was 24.9 vs 22.1 m (HR=0.79, p=0.04) • SURVIVAL ADVANTAGE WITH COMBINATION THERAPY Tournigand C, et al. Bevacizumab with or without erlotinib as maintenance therapy in patients with metastatic colorectal cancer (GERCOR DREAM; OPTIMOX3): a randomised, open-label, phase 3 trial. Lancet Oncol 2015; 16(15): 1493-505.

  13. NORDIC ACT 2 TrIal • K-ras wild type • Beva vs beva/erlotinib maintenance, metronomic capecitabine • No difference in PFS or OS Hagman H, et al. A randomized study of KRAS-guided maintenance therapy with bevacizumab, erlotinib or metronomic capecitabine after first-line induction treatment of metastatic colorectal cancer: the Nordic ACT2 trial. Ann Oncol 2016; 27(1): 140-7.

  14. METAANALYSIS • 3 randomized trials (682 patients) • Beva/erlotinib maintenance significantly increases PFS (HR=0.79, p=0.002) and OS (HR=0.78, p=0.006) • Manageable toxicity Xu W, et al. Survival Benefit and Safety of Bevacizumab in Combination with Erlotinib as Maintenance Therapy in Patients with Metastatic Colorectal Cancer: A Meta-Analysis. Clin Drug Investig 2017; 37(2): 155-65.

  15. RandomIzed ClInIcal TrIal • Initial FOLFOX or CapeOx • Maintenance capecitabine vs observation • PFS=6.4-3.4 m (HR=0.54, p  0.001) • OS: NS but there is difference (HR=0.85, p=0.22) • Acceptable toxicity with capecitabine Luo HY, et al. Single-agent capecitabine as maintenance therapy after induction of XELOX (or FOLFOX) in first-line treatment of metastatic colorectal cancer: randomized clinical trial of efficacy and safety. Ann Oncol 2016; 27(6): 1074-81.

  16. Tumor sIdedness and RAS/BRAF status • The beneficial effect of maintenance treatment (FU/beva) on PFS2 was not significantly influenced by tumor sidedness or RAS/BRAF mutational status. • Nevertheless, this appealed to be less pronounced in patients with RAS mutant tumors who also did not derive a statistically significant benefit from MT in terms of OS in contrast to those with RAS/BRAF wild-type or BRAF mutant tumors. • More recently, data from 414 patients (87.7%) showed that the impactof maintenance strategies on PFS was independent of the location of theprimary tumour (i.e., right vs left colon) Reinacher-Schick A, et al. Impact of the Localization of the Primary Tumor and RAS/BRAF Mutational Status on Maintenance Strategies After First-line Oxaliplatin, Fluoropyrimidine, and Bevacizumab in Metastatic Colorectal Cancer: Results From the AIO 0207 Trial. Clin Colorectal Cancer 2018; 17(4): e733-e739. Goey KKH, et al. Reporting of patient characteristics and stratification factors in phase 3 trials investigating first-line systemic treatment of metastatic colorectal cancer: A systematic review. Eur J Cancer 2018; 96: 115-24.

  17. Factors affectIng response to MT • Performance status: WHO PS 1 associated with OS benefit from MT (CAIRO3) • Site of primary tumor:Colon tumours associated with OS benefit from MT (CAIRO3) • Previous treatment for primary tumor: Synchronous metastases with resected primary tumour associated with PFS2and OS benefit from MT (CAIRO3) • Number of metastatic sites: > 1 metastatic sites associated with no PFS benefit from addition of erlotinibto bevacizumab maintenance (DREAM/OPTIMOX 3) • Platelets:≥400,000 platelets associated with OS detriment from intermittentchemotherapy(MRC COIN), patients with elevated PLT benefitted more than those with normal PLT (PFS2) from FP/beva MT (CAIRO 3 and AIO 0207)

  18. Factors affectIng response to MT • KRAS/ NRAS/ BRAF: RAS mutations associated with lack of OS benefit from MT (CAIRO3) and RAS/RAF mutations associated with lack of TFP benefit from MT with bevacizumab alone (AIO 0207) • Prognostic score: High GERCOR prognostic score associated with no PFS benefit from additionof erlotinib to bevacizumab maintenance (DREAM/OPTIMOX 3) and high Köhne prognostic score associated with TCD and OS benefit frommaintenance bevacizumab (PRODIGE 9) • Response to induction therapy: Partial or complete response to induction chemotherapy associated with PFS2and OS benefit from MT (CAIRO3) Morano F, Sclafani F. Duration of first-line treatment for metastatic colorectal cancer: Translating the available evidence into general recommendations for routine practice. Crit Rev Oncol Hematol 2018; 131: 53-65.

  19. The role of maIntenance bevacIzumab In metaanalysIs • While PFS was longer with beva plus FP (HR 0.45, p < 0.0001) and beva alone (HR=0.72, p = 0.0001) compared with observation, no statistically significant improvement in OS was found with either maintenance strategy (HR=0.92, p = 0.31 and HR 0.85, p = 0.14, respectively) (Stein et al., 2016). • The meta-analysis by Tamburini et al included the same studies and confirmed these findings (Tamburini et al., 2016). • In addition, by pooling data from two other trials (Díaz-Rubio et al., 2012; Yalcin et al., 2013), it showed no difference between continuation of CT and bevacizumab-based maintenance treatment in terms of TFS and OS.

  20. Antı-egfr based therapıesClinical trials with anti-EGFR monoclonal antibodies

  21. NORDIC VII • Median PFS was 7.9 and 7.5 m among patients with KRASwild-type tumours and 9.2 and 7.2 months among patients with KRASmutant tumours. • Median OS was 19.7 m in the continuous and20.3 m in the intermittent treatment arm and survival estimatesdid not change significantly in the analysis by KRAS status. • Also, overallstudy findings did not change when mutational analysis was extendedto NRAS and BRAF. Toxicity was overall similarbetween arms.

  22. Clinical trials with anti-EGFR monoclonal antibodies • Phase II COIN-B trial: 130 patients with KRAS exon 2–3 wild-type tumours who hadachieved at least stable disease after 12 weeks of FOLFOX plus cetuximab (primary analysis cohort) were randomised to treatment break ormaintenance cetuximab. • Further 12 weeks ofFOLFOX plus cetuximab (followed by another treatment break ormaintenance cetuximab) were planned upon tumour progression. • Theprimary endpoint of the studywas failure-free survival rate at 10 months. Thiswas 50% in the intermittent cetuximab arm and 52% in the continuouscetuximab arm (median failure-free survival 12.2 and 14.3 months,respectively). • A higher numerical difference in favour of the continuoustreatment was reported for the group of patients with KRAS/NRAS/BRAF wild-type tumours. • The incidence of grade ≥3 toxicities did notappear to be significantly influenced by the treatment strategy.

  23. Phase II MACRO-2 trial: 193 patients with KRASexon 2 wild-type tumours were treated with mFOLFOX plus cetuximabuntil progressive disease or the same treatment for 16 weeks followedby maintenance cetuximab (Aranda et al., 2018). • The study had a non-inferiority design and maintenance single agent cetuximab was shownto be noninferior to continuation of FOLFOX plus cetuximab in terms of9-month PFS (60% vs 72%, p non inferiority = 0.0502). • Other outcomemeasures were reported to be similar between arms while continuingFOLFOX until progressive disease was associated with an increased riskof grade ≥3 neuropathy (15% vs 2%).

  24. VALENTINO trial:Randomised phase II studywhich aimed to demonstrate non-inferiority of maintenance treatmentwith single agent panitumumab compared to panitumumab plus LV5FUafter 8 cycles of induction therapy with FOLFOX plus panitumumab inpatients with RAS wild-type tumours. • The primary endpoint was 10-month PFS rate. A total of 227 patients were included and the studyfailed to reject the null hypothesis as the upper limit of the 90% confidence interval of the HR (1.946) crossed the pre-defined non-inferiority boundary (1.515). • The rate of PFS at 10 months was 52.8% inthe panitumumab arm versus 62.8%in the panitumumab plus LV5FUarm (median PFS 10.2 and 13.0 months, respectively). • An increasedincidence of grade 3/4 adverse events, especially diarrhoea,mucositis,neutropenia and skin rash, was reported among patients randomised tothe combination arm.

  25. Alternative maintenance strategies and ongoing clinical trials • Enzastaurin: negative (PKC, PI3K/AKT inh) • Axitinib: 6m-PFS benefit • Phase 2 Macbeth trial: 8 cycles (m)FOLFOXIRI+cetux----maintenance cetux or beva (RAS/BRAF wild type, 116 patients)-PFS=11.2 (c)-9.3 m (b), HR=0.78 and 14-10.7 m ( 1 cycle MT)-HR=0.63 • IMPACT trial: lefitolimod (MGN1703) maintenance,a synthetic, covalently-closedDNA molecule which induces activation of the innate, immune-medi-ated, anti-cancer response by activating the toll-like receptor 9 (TLR9), because of slow recruitment closed prematurely, 6m-PFS was better (HR=0.55, p=0.04)-----Phase 3 IMPALA results awaiting Grávalos C, et al. A Randomized Phase II Study of Axitinib as Maintenance Therapy After First-line Treatment for Metastatic Colorectal Cancer. Clin Colorectal Cancer 2018; 17(2): e323-e329.

  26. The case for maıntenance therapy • Clear evidence that tumor control is prolonged in first-line when maintenance strategies are used. • MT with FP+VEGFi has good clinical rationale and exhibits limited side effects. • Maintenance strategies can mitigate toxicities from first-line therapy, in particular, when oxaliplatin is used as component of upfront therapy. • Maintenance setting can be used for drug development.

  27. The results of comprehensive molecular analyses and identificationof actionable tumour genetic aberrations in CRC have recentlyprompted the design of clinical trials where standard induction CT is followed by a switch to maintenance targeted therapies • The FOCUS-4 is a molecularly-stratified, multi-arm, multi-stage,double-blind, randomised trial sponsored by the UK MRC. • In this study,patients who achieve stable disease or better after 16 weeks of CT are assigned to one of several molecular cohorts where theyare randomly allocated to placebo or a novel targeted drug based on theresults of tumour molecular tests. • Six molecular cohorts are currentlyopen, these being defined by the presence of BRAF mutation (active MT: BRAF + EGFR ± MEK inhibitors), PI3KCA mutation (active MT: aspirin), KRAS/NRAS mutation(active MT: AKT + MEK inhibitors), pTEN expressionin the absence of BRAF, PI3KCA and RAS mutation (active MT: HER1,2,3 inhibitors), loss of the protein H3K36me3 or doubleRAS/TP53 mutation (active MT: WEE1 inhibitor), orlack of targetable alterations (active MT: capecitabine). • The adaptive design of the study allows the implementation ofadditional molecular cohorts should new targetable biomarkers emergein the near future. The primary outcome measure is PFS. • MODUL trial: biomarker driven maintainance treatment

  28. KEY MESSAGES-I • When oxaliplatin-basedregimens (without targeted agents) are used,discontinuing treatment after 12 weeks maybe detrimental for survival, whereas continuing treatment beyond12 weeks with a de-escalated (oxaliplatin-free) regimen may maintain a satisfactory oncological outcome while significantly reducingthe incidence of severe peripheral sensory neuropathy as well asother toxicities. • When first line treatment consists of an oxaliplatin-based regimenplus bevacizumab, switching to a de-escalated, maintenance regimen including a fluoropyrimidine plus bevacizumab after 18 or 24weeks appears to be as effective as, but less toxic than, continuationof induction treatment until progression, while the same strategycould be more effective, but possibly more toxic, than completediscontinuation of induction treatment. • The available studies do notseem to suggest any benefit from single agent bevacizumab whengiven as MTafter 18–24 weeks of inductiontreatment (either oxaliplatin- or irinotecan-based).

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