colon cancer: asco poster review -...
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Alfonso De Stefano MD, PhD
SC Oncologia Clinica Sperimentale Addome
Colon cancer: ASCO poster review
255 poster examined: my selection
• Clinical Practice
• Translational & new Biomarkers
• Immunotherapy
• TIPs
255 poster examined: my selection
• Clinical Practice
• Translational & new Biomarkers
• Immunotherapy
• TIPs
Bekaii-Saab et al. ASCO GI 2018 #611
REDOS trial: regorafenib dosing strategy
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
Nakamura et al. ASCO GI 2018 #729
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
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
SAPPHIRE trial: a fixed strategy for OXA plus anti-EGFR
Van Cutsem et al. ASCO GI 2018 #627
BEACON trial: efficacy and safety in BRAFV600 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
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 BRAFV600E 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
BEACON trial: efficacy and safety in BRAFV600 pts
VELOUR trial biomarkers update: Impact of RAS, BRAF, and sidedness on aflibercept activity. Pratyaksha Wirapati , Valentina Pomella, Ben Vandenbosch, Peter Kerr, Evaristo Maiello, Grahame Mark Jeffery, Razvan-Ovidiu D. Curca, Meinolf Karthaus, John A. Bridgewater, Anca C. Mihailov, Igor Kiss, Sandra Merino, Joseph James McKendrick, Zacharenia Saridaki, Xavier JA Sagaert, Sabine Tejpar. Swiss Institute of Bioinformatics, Lausanne, Switzerland; University of Leuven, Leuven, Belgium; Almac Diagnostics, Craigavon, Northern Ireland; U.O. Oncologia, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy; Christchurch Hospital, Christchurch, NZ; County Emergency County Hospital Alba Iulia, Romania; Klinikum Neuperlach, Dept Hematology and Oncology, Städt. Klinikum München, Germany, Germany; University College London Cancer Institute, London, United Kingdom; C.F. Clinical Hospital Cluj-Napoca, Romania; Masaryk Memorial Cancer Institute, Brno, Czech Republic; Hospital Universitari de Sant Joan de Reus, Tarragon, Spain; Monash University Melbourne Australia; Asklepios Oncology Unit, Heraklion, Crete, Greece; University Hospitals Leuven Dept of Pathology, Leuven, Belgium; University Hospital Leuven, KUL, Leuven, Belgium. Contact: [email protected]
ABSTRACT Background: Addition of (ziv)-aflibercept (A) to FOLFIRI in second-line therapy for metastatic colorectal cancer (CRC) has been shown to be beneficial in phase III VELOUR trial (NCT00561470). A retrospective follow-up study (NCT01754272) was undertaken to acquire tumor samples for biomarker analyses and identify subgroups of patients with differential treatment effects. The primary results assessing efficacy according to well-established CRC subgroups defined by RAS, BRAF status and sidedness are reported here. Methods: Tissue specimens were collected for 666 patients from 1226 ITT pts. Suitable specimens were assayed for somatic mutation using NGS targeting extended RAS and BRAF genes. NGS assays with no missing values were obtained for 482 pts. Affymetrix gene chip technology was used for whole-transcriptome profiling; sidedness was extracted from available pathological reports. Differences between subgroups were assessed by interaction analysis. Results: The treatment effects on overall survival (OS) for the 482 pts is still significant HR = 0.80 (CI 0.65-0.99), and similar to the ITT (n = 1226) results (HR = 0.82, CI 0.71-0.93). Two established ways of defining mutations (traditional KRAS exon 2 and extended RAS using NGS) show a trend for a differential effect across mutation groups.(see table for OS). Interestingly, BRAF mutants (which are all RAS wild type) show a trend for better outcome Same is seen for PFS and RR. Sidedness did not affect efficacy (HR: 0.83 (0.63- 1.1) for left and HR: 0.83 (0.54-1.3) for right) Conclusions: None of the mutations subgroup results shows significant interaction, although the ratios of treatment HR favor RAS wild types. Similar trends were observed in published trials with bevacizumab or ramucirumab.
INTRODUCTION and METHODS
• The phase 3 VELOUR trial showed that aflibercept added to FOLFIRI significantly improved overall survival [OS], PFS and ORR compared with FOLFIRI alone [median OS: 13.50 vs 12.06 months (HR=0.817; IC95%: 0.713-0.937; p=0.0032); median PFS: 6.90 vs 4.67 months (HR=0.758; IC95%: 0.661-0.869; p=0.00007); ORR: 19.8% vs 11.1% (p˂0.001)] in mCRC patients previously treated with an oxaliplatin-containing regimen.1
• A follow-up non-interventional study (NCT01754272) was undertaken to acquire archived tumor materials, with the purpose of identifying subgroups of patients with differential treatment effects.
• Methods: Archived tissue specimens (FFPE blocks) from participating centers world-wide were collected in a centralized pathology facility. Specimens with suitable quality and quantity were assayed using next-generation sequencing (NGS) targeted at KRAS, NRAS and BRAF genes. Based on the mutations, the patients were classified into four groups (with no overlap): KRAS exon 2 ("KRASex2"), other KRAS and NRAS mutations ("newRAS"), BRAF V600E ("BRAF") and double wild-type absent in all aforementioned RAS or BRAF mutations ("WT").
• Affymetrix gene chip technology was used for whole-transcriptome profiling. Here we present the results of two signatures: the "BRAF-like" and "RAS-like signatures, that were derived on external datasets and applied to VELOUR. Patients are dichotomized into "mutant-like" or "wild-type-like", based on cutoff that puts 55% of the patient as "KRAS-mutant-like" and 7% "BRAF-mutant-like“, based on the frequencies of respective mutations in DNA data.
RESULTS
Definition of VELOUR Biomarker population
CONCLUSIONS
• This retrospective biomarker analyses tested RAS and BRAF defined patient subgroups for differential treatment effects.
• Our data suggest that aflibercept could have a specific beneficial effect in BRAF mutant patients. This is the first randomized trial with an antiangiogenic drug to show a BRAF biomarker/drug interaction. BRAFmut pt numbers remain small and these results need further validation in similar trials to inform clinical practice
• RAS defined subgroups show no significant interaction, although the ratios of treatment HR favor RAS wild types. Similar trends were observed in published trials with bevacizumab or ramucirumab for KRAS mut and merit further investigation.
• Left versus right side origin of tumors has no effect on aflibercept efficacy. For OS: left HR = 0.86 [0.64 – 0.15], right HR = 0.85 (0.53 -1.35), interaction p-value = 0.96. For PFS: left HR = 0.74 (0.46 – 1.00), right HR = 0.70 (0.42 – 1.15), interaction p-value = 0.69.
ACKNOWLEDGMENTS
Figure 1. : Treatment effects on OS and PFS , subgrouped by DNA mutations. (*) indicates significant p-value (0.05 for HR, 0.1 for interaction). Cox regression models stratified by ECOG status and prior bevacizumab were used to obtain HR and interaction tests.
• The treatment effects on overall survival for the biomarker subpopulation (n=482, or 39.3% of original ITT, n=1226) is still significant ( HR=0.80 (CI 0.65-0.99), p = 0.043), and similar to the ITT results (HR=0.82, (CI 0.71-0.93), p = 0.0031). Pretreatment rates with bevacizumab and patient demographics are similar except for fewer samples from America in the biomarker group.
• Figure 1 shows summary results of treatment effects on OS under various subgroupings. The treatment effect of the original trial is shown on the first line (ITT:all). The second line shows the summaries of the subset where DNA data are available versus those that are not, showing that the biomarker subset has representative baseline HR. The subsequent subdivisions ("mutation", "KRAS" and so on) are all pertaining to those with DNA available. The vertical dashed line is aligned with the HR of the samples with available DNA.
• In the comparison of the four mutation classes, we see the trend of WT and BRAF mut having better HR than the total, while newRAS and KRASex2 are worse, as also reflected by the differences in the median survival. However, the confidence intervals are wide (none of the subgroups are significant on its own) and the global interaction test is also not significant (p = 0.22).
• Pairwise comparisons for several ways to define mutation groups also show no significant interaction except for BRAF mutant versus others for OS. The treatment HR’s for BRAF are not significant due to small number, but the magnitude and direction is consistent to those of other studies. The Kaplan-Meier curves in figure 2 highlight the treatment effects of aflibercept on BRAF mutants.
• For RAS mutants, there is a consistent trend of quantitative reduction of effects, although the interaction tests are not significant. The ratio of OS hazard ratios (RoHR) of mutant relative to wild-type for KRASex2 is 1.21 (95%CI: 0.74 – 1.96; p=0.45), and 1.39 (95%CI: 0.90 – 2.13; p= 0.13) for extRAS respectively, indicating a potential loss of 20 to 40% of the positive aflibercept effect, not reaching statistical significance.
• Similar studies have been reported for KRAS exon2 and other antiangiogenic drugs, summarized in figure3 Additional exploratory results
• Although RAS mutations are a validated biomarker for anti-EGFR therapy, not RAS mutation itself but some associated characteristic may drive the association observed here . Further investigation is needed to pinpoint the optimal definition for the subgroup with reduced efficacy. We complemented our DNA analysis by RNA based characterization of RAS and BRAF likeness which captures downstream pathway activation regardless of mutation status. RNA profiling showed 78% concordance between the KRAS-like signature and extended-RAS status; while 91% agreement is found between BRAF-like and BRAF mutation status.
• Fig 4. Of note the subset of patients available for this RNA signature, (n=439, with only n=363 overlapping with the subset with available DNA data) is not representative any more of the ITT in terms of treatment effects: HR in the population with RNA samples available is 0.92 (95%CI: 0.74 – 1.16) versus HR=0.82 (95%CI: 0.71 -0.93) in the ITT population. Thus, caution must be exercised not to interpret the treatment effects as absolute, but only to observe the relative effect sizes between RNA subgroups.
• The BRAF-like and KRAS-like groups show differential effects similar to the corresponding DNA mutations (more efficacy in KRAS-WT-like and BRAF-mutant-like). Significant interactions are seen for KRAS-like status for all OS, PFS and ORR. BRAF-like signature shows trends in the same direction, but lack significant due to very small (7%) mutant-like subgroup. Further validation of this is needed.
Figure 4 : Treatment effects on OS and PFS, subgrouped by RNA signatures
• Sanofi supported this ISS • We thank all the investigators and patients of the original trial and particularly those investigators that contributed to sample
collection
Figure 2. :Kaplan-Meier curves for OS and PFS , subgrouped by DNA mutations. `ext.RAS` is a pool of KRAS exon 2 and new RAS mutation. See figure 1 for detailed survival analysis.
Lack of sufficient RNA extraction quality
control 33 pts
1. Van Cutsem E et al. J Clin Oncol. 2012 Oct 1;30(28):3499-506
Abstract 3538
median PS
Ince WL et al. JNCI. 2005;97:981-9; Kubicka S et al. Ann Oncol. 2013;24:2342-2349; Obermannova et al. Ann Oncol. 2016 ;27:2082-2090.
Figure 3. summary of published KRAS biomarker studies and VELOUR data
Wirapati et al. ASCO 2017 #3538
Background - In RAISE trial the addition of RAM to
FOLFIRI improved mOS in 2nd line Objectives - Report efficacy results according to
RAS/BRAF status
Yoshino et al. ASCO GI 2018 #622
Conclusions - 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
VEGFR2 blockage in BRAF mutants: analysis from RAISE
Price et al. ASCO GI 2018 #761
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/m2 BID on days 1-5 and 8-12 of each 28-days cycle
Main characteristics (pts: 300)
Gender M 196
F 104
Age <65y 150
≥65y 150
PS 0 117
1 173
RAS status Mut 164
WT 88
Primary site Right 81
Left 193
Conclusions - Analysis of the baseline characteristics shows a patient population that appears to be broadly similar to that enrolled in the RECOURSE trial (pretreated pts still candidate to additional anti-cancer cht) - Optimal treatment sequencing for mCRC pts receiving cht beyond 2nd line is not yet established - Preliminary prospective safety, efficacy and QoL results from pts treated with FTD/TPI upcoming
Falcone et al. ASCO GI 2018 #803
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 - ECOG PS of 0 or 1 - Adequate organ function
FTD/TPI 35 mg/m2 BID on days 1-5 and 8-12 of each 28-days cycle
QoL measured at BL, every 4 wks during treatment, and at treatment discontinuation
CONCLUSIONS - 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 0-1
- 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
- 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.
Mayer et al. ASCO GI 2018 #752
TAS102: safety in elderly patients
Background - 549 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
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
Bev + CT vs CT according to PTL: efficacy outcomes
Loupakis et al. ASCO GI 2018 #726
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
Bev + CT vs CT according to PTL: efficacy outcomes
Loupakis et al. ASCO GI 2018 #726
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
Zhang et al. ASCO GI 2018 #603
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 III, CEA positive colon cancer pts and thus potentially identifying the optimal timing to increase survivorship
Results On a cohort of 19180 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.
Time to chemo in CEA + pts
Conclusions - Delays in receiving adjuvant chemotherapy had a negative linear association on
survival - Adjuvant therapy should be considered as soon as patient’s clinical condition
permits
255 poster examined: my selection
Clinical Practice Translational & new Biomarkers Immunotherapy TIPs
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
Clinicopathological characteristics and HER2 status in mCRC
Sartore Bianchi et al. ASCO GI 2018 #581
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.
Clinicopathological characteristics and HER2 status in mCRC
Raghav et al. ASCO GI 2018 #661
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
Detection and description of ERBB2 amplification using cfDNA
Zhi-Yu Chen et al. ASCO GI 2018 #714
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.
Dynamic monitoring HER2 amp of ctDNA in mCRC pts treated with Cet
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
Sinicrope et al. ASCO GI 2018 #614
Role of Immunoscore in low and high risk subsets of stage III pts in NO147 trial
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
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 T1-3N1 pts and 68% vs 54% in T4 or N2 pts
Sinicrope et al. ASCO GI 2018 #614
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
Role of Immunoscore in low and high risk subsets of stage III pts in NO147 trial
255 poster examined: my selection
Clinical Practice Translational & new Biomarkers Immunotherapy TIPs
Boland et al. ASCO GI 2018 #834
Cetuximab + Pembrolizumab in mCRC pts: a phase Ib trial
Bendell et al. ASCO GI 2018 #870TPS
Immunotherapy in RASmut 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
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
Immunotherapy in RASmut pretreated MSS pts
Yoshino et al. ASCO GI 2018 #881TPS
TRUSTY trial: TAS102 + bev in 2nd line for mCRC
Grazie!