Colon cancer: ASCO poster review. Alfonso De Stefano MD, PhD SC Oncologia Clinica Sperimentale Addome

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1 Colon cancer: ASCO poster review Alfonso De Stefano MD, PhD SC Oncologia Clinica Sperimentale Addome

2 255 poster examined: my selection Clinical Practice Translational & new Biomarkers Immunotherapy TIPs

3 255 poster examined: my selection Clinical Practice Translational & new Biomarkers Immunotherapy TIPs

4 REDOS trial: regorafenib dosing strategy Bekaii-Saab et al. ASCO GI 2018 #611

5 REDOS trial: results Conclusions - A strategy with weekly dose escalation of Regorafenib from 80 mg to 160mg/day was found to be superior to a starting dose of 160 mg/day - A trend for improved OS was seen in the dose escalation arm - At 2-wks from initiation of therapy, the dose escalation strategy did not appear to compromise QOL unlike the standard dose administration - These results potentially establish a new standard for optimizing regorafenib dosing through a dose escalation strategy

6 SAPPHIRE trial: a fixed strategy for OXA plus anti-egfr Endpoints - Primary: PFS at 9 months - Secondary: PFS, OS, RR, TTF, safety Nakamura et al. ASCO GI 2018 #729

7 SAPPHIRE trial: a fixed strategy for OXA plus anti-egfr Conclusions - 5FU/LV plus panitumumab combination therapy maintained the efficacy after 6 fixed cycles of mfolfox6 plus panitumumab - combination therapy and did not increase the incidence of peripheral neuropathy - mfolfox6 plus panitumumab combination therapy with fixed OXA cycles can be a useful treatment option for patients with unresectable, advanced/recurrent CRC Nakamura et al. ASCO GI 2018 #729

8 BEACON trial: efficacy and safety in BRAF V600 pts Background The Safety Lead-In (SLI) of the BEACON CRC phase 3 study assessed the safety and efficacy of the combination of the BRAF inhibitor encorafenib (ENCO) + MEK inhibitor binimetinib (BINI) + anti-egfr antibody cetuximab (CETUX) in pts with BRAF -mutant mcrc after 1 or 2 prior regimens. Objectives Evaluate the association of CEA and CA19-9 changes while on treatment with clinical outcomes in pts from the SLI. Update on safety profile and efficacy of the triplet therapy Van Cutsem et al. ASCO GI 2018 #627

9 BEACON trial: efficacy and safety in BRAF V600 pts Conclusions - No difference in CEA and CA 19.9 from baseline to nadir in pts with DCR - With additional FUP, triple combination ENCO-BINI-CET continues to be generally well tolerated and to yield promising antitumor activity: - Common side effects were GI toxicities and skin rash (typical for BRAF, MEK and EGFR inhibitors) - ORR: 48% in BRAF V600E mcrc (with 3CR) - PFS: 8 months (similar between who received 1 or 2 lines) - Prolonged SD (>6months) was observed in 9 of 15 (60%) pts without a confirmed ORR

10 eft and HR: 0.83 ( ) for right) ignificant interaction, although the ratios of treatment HR ed trials with bevacizumab or ramucirumab. ODS FOLFIRI significantly improved overall survival [OS],.50 vs months (HR=0.817; IC95%: ; 95%: ; p= ); ORR: 19.8% vs 11.1% liplatin-containing Background regimen. 1 undertaken - In RAISE to trial acquire the archived addition tumor of RAM materials, to with rential treatment effects. FOLFIRI improved mos in 2 nd line rticipating centers world-wide were collected in a lity Objectives and quantity were assayed using next-generation.-based Report on the efficacy mutations, results the patients according were to classified "), other KRAS and NRAS mutations ("newras"), BRAF ntioned RAS/BRAF or BRAF status mutations ("WT"). criptome profiling. Here we present the results of two ere derived on external datasets and applied to "wild-type-like", based on cutoff that puts 55% of the based on the frequencies of respective mutations in L et al. JNCI. 2005;97:981-9; Kubicka S et al. Ann Oncol. 2013;24: ; Obermannova et al. Ann Oncol ;27: summary of published KRAS biomarker studies and VELOUR data Pairwise comparisons for several ways to define m BRAF mutant versus others for OS. The treatment magnitude and direction is consistent to those of o treatment effects of aflibercept on BRAF mutants. VEGFR2 blockage in BRAF mutants: analysis from RAISE Figure 1. : Treatment effects on OS and PFS, subgrouped by DNA mutation models stratified by ECOG status and prior bevacizumab were used to obt Conclusions Wirapati et al. ASCO 2017 # RAISE demonstrated that the addition of RAM to FOLFIRI improved pts outcome regardless of RAS mutation status - The noteworthy signal for pts with BRAF mutant tumor is encouraging, particularly due to their poor prognosis, and did not appear to depend on VEGF-D levels, based on very limited data; this will require further confirmation in other clinical trials Figure 2. :Kaplan-Meier curves for OS and PFS, subgrouped by DNA mu for detailed survival analysis. Yoshino et al. ASCO GI 2018 #622

11 TAS102: patients characteristics in EAP Pts aged 18 yo with confirmed diagnosis of mcrc - Receipt of 2 prior regimens of standard ChT - Refractory, intolerant or not candidate for those ChTs - ECOG PS of 0 or 1 - Adequate organ function FTD/TPI 35 mg/m 2 BID on days 1-5 and 8-12 of each 28-days cycle Main characteristics (pts: 300) Gender Age PS RAS status M 196 F 104 <65y y Mut 164 WT 88 Right 81 Conclusions - Analysis of the baseline characteristics shows Primary a patient site population that appears to be broadly Left 193 similar to that enrolled in the RECOURSE trial (pretreated pts still candidate to additional anticancer cht) - Optimal treatment sequencing for mcrc pts receiving cht beyond 2 nd line is not yet established - Preliminary prospective safety, efficacy and QoL results from pts treated with FTD/TPI upcoming Price et al. ASCO GI 2018 #761

12 TAS102: QoL at baseline in EAP Pts aged 18 yo with confirmed diagnosis of mcrc - Receipt of 2 prior regimens of standard ChT - Refractory, intolerant or not candidate for those ChTs -CONCLUSIONS ECOG PS of 0 or 1 - Adequate organ function - The symptoms associated with mcrc may affect patient QoL. - This analysis of baseline QoL from a real-world EAP shows that some heavily pretreated patients with advanced mcrc can have an impaired QoL despite having an ECOG PS of 0- FTD/TPI 35 mg/m 2 BID on days 1-5 and of each 28-days cycle - The EORTC QLQC-30 scores indicated impaired QoL in various domains, including gastrointestinal-related adverse events (nausea, vomiting, constipation, diarrhea), loss of appetite, insomnia, pain and fatigue QoL measured at BL, every 4 wks during treatment, and at treatment discontinuation - The majority of patients indicated a level of pain that was either moderate (60%) or extreme (7%) in the EQ-5D, and approximately one third of patients indicated some impact on usual activities - There is a relationship between ECOG PS at baseline and health-related QoL. Falcone et al. ASCO GI 2018 #803

13 TAS102: safety in elderly patients Background patients enrolled in the EAP in the USA and treated according to registrative schedule Objective - evaluation of tolerability and safety profile in elderly pts ( 65 years) Results Population - Median age was 58 years (377 pts were aged < 65 years, 172 were 65 years) - no data on prior lines of treatment Treatment - Median duration of treatment was similar between elderly and younger subgroups (9.7 vs 9.6 weeks) - Dose reduction was applied in 25.6% of elderly pts and 19.9% of younger pts - Hematologic toxicity was the main cause of dose reduction (20.3% vs 13.0%) - Treatment discontinuation due to PD in 77.3% vs 75.6% Mayer et al. ASCO GI 2018 #752

14 TAS102: safety in elderly patients Conclusions - This analysis shows that the safety of FTD/TPI in pts aged 65yo was similar to that seen in pts aged <65yo - Overall, FTD/TPI was well tolerated in both subgroups with a slightly lower difference rate of total AEs and serious AEs in elderly compared with younger pts - These data demonstrate that FTD/TPI can be used in elderly pts and provides clinicians with another option for elderly pts with mcrc progressing after standard treatments Mayer et al. ASCO GI 2018 #752

15 Bev + CT vs CT according to PTL: efficacy outcomes Background - Based on results by Loupakis et al (JNCI, 2015) which found that primary tumour location has a strong prognostic effect on patients with mcrc Objective - An exploratory subgroup analysis of 2 pivotal phase 3 studies was performed to evaluate the efficacy of bev+ct according to tumour location Loupakis et al. ASCO GI 2018 #726

16 Bev + CT vs CT according to PTL: efficacy outcomes Conclusions - This retrospective exploratory subgroup analysis of 2 pivotal phase 3 studies indicates that the effect of bev is independent of tumour location - Similar PFS and OS improvements were observed when pts were stratified according to baseline characteristics - These results build upon the Loupakis et al study, which found that primary tumour location has a strong prognostic effect on patients with mcrc Loupakis et al. ASCO GI 2018 #726

17 Time to chemo in CEA + pts Background - Positive serum CEA levels are associated with inferior survival in pts with advanced non metastatic colon cancer - It is not fully elucidated whether this prognostic factors can inform the optimal timing of adjuvant chemotherapy after surgery - This study was aimed to determine the relationship between onset of adjuvant cht and rate of survival in stage Conclusions III, CEA positive colon cancer pts and thus potentially identifying the optimal timing to increase Results On a cohort of pts, a positive CEA was significantly associated with worse survival (+49.7%) For every ten-day delay in receiving adjuvant treatment there was a 1.6% increased risk of death. - Delays in receiving adjuvant chemotherapy had a negative linear association on survival survivorship - Adjuvant therapy should be considered as soon as patient s clinical condition permits Zhang et al. ASCO GI 2018 #603

18 255 poster examined: my selection Clinical Practice Translational & new Biomarkers Immunotherapy TIPs

19 Clinicopathological characteristics and HER2 status in mcrc Objectives - To develop and validate a new diagnostic model indentifying predictive clinicopathological characteristics for HER2 amplification in mcrc pts - to determine and confirm the independent predictive role of HER2 amplification for response to anti-egfr therapy and OS Sartore Bianchi et al. ASCO GI 2018 #581

20 Clinicopathological characteristics and HER2 status in mcrc Conclusions - HER2 amplification was more frequently detected among pts with distal carcinomas, higher primary tumor grading and superior metastatic burden. None of the main clinicopathological features was predicitive for HER2 amplification. - Testing of HER2 should be offered to all mcrc pts candidate to an antiegfr based treatment as less likely to respond and it is not possible to predict it on the basis of clinicopathological features. Sartore Bianchi et al. ASCO GI 2018 #581

21 Detection and description of ERBB2 amplification using cfdna Conclusions - In one of the largest series of CRC pts with ctdna NGS, HER2amp was detected in 5% of mcrc pts, a prevalence comparable to tissue based testing - Co-existing RAS mutations were uncommon, while PIK3CA and ERBB2 mutation were seen in a sizeable number of HER2amp - These findings may have implications for anticipated innate/acquired resistance mechanism to HER2-targeting therapies currently under evaluation for CRC Raghav et al. ASCO GI 2018 #661

22 Dynamic monitoring HER2 amp of ctdna in mcrc pts treated with Cet Conclusions Plasma HER2 amplification detected by ddpcr was showed changing over time and would predict resistance to cetuximab based treatment. Average 2 months lead time was observed and need to validate in a further study. Zhi-Yu Chen et al. ASCO GI 2018 #714

23 Role of Immunoscore in low and high risk subsets of stage III pts in NO147 trial Background and objectives - Immune biomarkers may provide further risk stratification in low (T3-N1) and high risk (T4 or N2) pts - To determine if the immunoscore can prognostically stratify stage III colon cancer pts between low and high risk groups Results - Higher immunoscore group was related with prolonged DFS - High vs low immunoscore was significantly associated with better 3- year DFS rates of 91% vs 77% in T 1-3 N 1 pts and 68% vs 54% in T 4 or N 2 pts Methods - Patients grouped into low and high risk according to pathological stage - Immuno staining of CD3 + and CD8 + T-cells and CD20 + B-cells determined in core tumour and invasive margin, categorized into 4 levels and dichotomized in high (2-3-4) and low (0-1) groups Sinicrope et al. ASCO GI 2018 #614

24 Role of Immunoscore in low and high risk subsets of stage III pts in NO147 trial Conclusions - Immunoscore is prognostic in stage III colon cancer pts and provides validation in a phase III clinical trial cohort and is strongly prognostic within low and high risk T and N subsets defined in the IDEA study - These data underscore limitations of T and N staging and demonstrate the ability of immune biomarkers to further refine prognostication Sinicrope et al. ASCO GI 2018 #614

25 255 poster examined: my selection Clinical Practice Translational & new Biomarkers Immunotherapy TIPs

26 Cetuximab + Pembrolizumab in mcrc pts: a phase Ib trial Boland et al. ASCO GI 2018 #834

27 Immunotherapy in RAS mut pretreated MSS pts Background - RAS mutation play a role in reducing immune cell infiltration and contribute to immuno escape mechanism - Efficacy of anti-pd1 and PD-L1 not proven in MSS disease - Preclinical models show a sinergistic action of MEK inhibitors on anti- PD1 with an increased and durable response in RAS mut - Combination of anti-pd1 with anti CTLA4 has higher activity than single agent Bendell et al. ASCO GI 2018 #870TPS

28 Immunotherapy in RAS mut pretreated MSS pts Objectives - Phase 1b: determine MTD and recommended phase 2 dose of BINI + NIVO +/- IPI - Phase 2: assess the antitumour activity, safety and pharmacokinetis (PK) of BINI + NIVO +/- IPI Bendell et al. ASCO GI 2018 #870TPS

29 TRUSTY trial: TAS102 + bev in 2 nd line for mcrc Yoshino et al. ASCO GI 2018 #881TPS

30 Grazie!