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Microsatellite Instability (MSI) status and prognosis in colorectal cancer: Meta-analysis
abstracts
Funding (institution): Sanofi; Advisory / Consultancy: Celgene; Advisory / Consultancy: Lilly; Advisory / Consultancy: Boeringer Ingelheim; Advisory / Consultancy: Merck Serono; Advisory / Consultancy: Amgen; Advisory / Consultancy: Roche. T.J. Ettrich: Advisory / Consultancy: Merck Serono; Advisory / Consultancy, Speaker Bureau / Expert testimony: Sanofi-Aventis; Advisory / Consultancy: Bayer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Novartis; Advisory / Consultancy: Roche; Advisory / Consultancy: Lilly; Speaker Bureau / Expert testimony: Celgene; Travel / Accommodation / Expenses: Ipsen; Research grant / Funding (institution): Servier. A. Ko¨nig: Travel / Accommodation / Expenses: Ipsen. L. Perkhofer: Travel / Accommodation / Expenses: Ipsen. All other authors have declared no conflicts of interest.
582P
Microsatellite Instability (MSI) status and prognosis in colorectal cancer: Meta-analysis
J. Toh1, K. Spring2 Colorectal, Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead, Australia, 2Medical Oncology, Ingham Institute, Liverpool, Australia
1
Background: Microsatellite instability (MSI) is thought to be a marker of immunogenicity and better prognosis in colorectal cancer (CRC). However, the mechanism by which MSI confers a survival advantage is not well known and there is a range of results reported in the literature. Methods: A systematic literature search of original studies was performed on Ovid searching Medline, Embase, Cochrane Library, CINAHL, Clinical Trials databases from inception of database to current. Data extracted included age, stage, MSI-H, MSS and MSI-L, proximal (right) vs. distal (left), colon vs. rectal, BRAF status, type of MSI or IHC test used, incidence of Lynch within cohort. The primary endpoint was survival (overall survival (OS), disease/relapse free survival (DFS) and disease (cancer) specific survival DSS). Statistical analysis was performed using RevMan Ver 5.3 Cochrane Collaboration. Results: From 11,747 studies, 117 met the inclusion criteria (n ¼ 100,257; MSI-H n ¼ 12,263, (MSI-H 12.2%). Overall, MSI was associated with improved OS (OR 0.80 (0.71, 0.91). When stratified by stage, there was no difference in OS in stage I and IV, but a protective effect in stage II (OR 0.69 (0.51, 0.92)) and III (0.70 (0.54, 0.91)) CRC. By age, there was benefit in studies where reported median age < 60 (OR 0.66 (0.54,0.82)) but not 60. There was no difference in OS between MSI-L and MSS. In studies including only mucinous/signet cell/poor differentiation, there was no difference in OS. In both right and left colon, MSI status was associated with improved OS, but not in the rectum. MSI status was associated with improved DFS (HR 0.75 (0.66, 0.84)), but there was no difference in DSS (HR 0.78 (0.60, 1.03)), and this was seen in all stages (I-IV). Conclusions: MSI is associated with improved overall survival in stage II and III colorectal cancer. Improved prognosis is seen in younger patients, in both right and left sided colon cancer, but evidence is limited in rectal cancer. MSI was associated with less relapse, but was not associated with cancer specific survival at any stage. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
v220 | Gastrointestinal Tumours, Colorectal
583P
Choosing the right strategy based on individualized treatment effect predictions: Combination versus sequential chemotherapy in patients with metastatic colorectal cancer
M. Koopman1, J.J. Kwakman2, R.C.M. van Kruijsdijk3, S.G. Elias4, M.T. Seymour5, A.M. Meade6, F. Visseren7, C.J.A. Punt2 1 Medical Oncology, University Medical Center Utrecht, Utrecht, Netherlands, 2Medical Oncology, Amsterdam University Medical Centers, Location AMC, Amsterdam, Netherlands, 3Internal Medicine, University Medical Center Utrecht, Utrecht, Netherlands, 4Department of Epidemiology, Julias Center for Health Sciences and Primary Care, Utrecht, Netherlands, 5Medical Oncology, St. James’s University Hospital Leeds, Leeds, Yorkshire, UK, 6MRC Clinical Trials Unit at UCL, University College London, London, UK, 7Vascular Medicine, University Medical Center Utrecht, Utrecht, Netherlands Background: Translating results from randomized trials to individual patients is challenging since treatment effects may vary due to heterogeneous prognostic characteristics. We aimed to demonstrate model development for individualized treatment effect predictions in cancer patients. We used data from two randomized trials that investigated combination (ComC) versus sequential chemotherapy (SeqC) in unresectable metastatic colorectal cancer (mCRC) patients. Methods: We used data from 803 patients included in CAIRO for prediction model development and internal validation, and data from 1423 patients included in FOCUS for external validation. A Weibull model with prespecified patient and tumour characteristics was developed for a prediction of gain in median overall survival by upfront ComC versus SeqC. Decision curve analysis with net benefit was used. A nomogram was built for estimating the probability of receiving second-line treatment after firstline monochemotherapy. Results: Median predicted gain in overall survival for ComC versus SeqC was 2.3 months (IQR -1.1-3.7 months). A gain in favour of SeqC was found in 231 patients (29%) and a gain of > 3 months for ComC in 294 patients (37%). Patients with benefit from SeqC had metachronous metastatic disease and a left-sided primary tumour. Decision curve analyses showed improvement in net benefit for treating all patients according to prediction-based treatment compared to treating all patients with ComC. Multiple characteristics were identified as prognostic variables that identify patients at risk of never receiving second-line treatment if treated with initial monochemotherapy. External validation showed good calibration with moderate discrimination in both models (C-index 0.66 and 0.65, respectively). Conclusions: We successfully developed individualized prediction models including prognostic characteristics derived from randomized trials to estimate treatment effects in mCRC patients. In times where the heterogeneity of CRC becomes increasingly evident, such tools are an important step towards personalized treatment. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: M. Koopman: Research grant / Funding (institution): Dutch Colorectal Cancer Group; Advisory / Consultancy: Servier. J.J. Kwakman: Honoraria (self), Research grant / Funding (institution): Nordic Pharma; Advisory / Consultancy, Research grant / Funding (institution): Servier. C.J.A. Punt: Research grant / Funding (institution): Dutch Colorectal Cancer Group; Advisory / Consultancy: Servier. All other authors have declared no conflicts of interest.
584P
Noninferiority on overall survival of every-2-weeks vs weekly schedule of cetuximab for first-line treatment of RAS wild-type metastatic colorectal cancer
S. Kasper1, A-L. Cheng2, F. Overkamp3, M. Rouyer4, C. Foch5, F-X. Lamy6, R. Esser5, D. Messinger7, V. Rothe7, W. Chen8, T. Brodowicz9, C.C. Zielinski10 1 Medical Oncology, University Hospital Essen Westdeutsches Tumorzentrum, Essen, Germany, 2Department of Internal Medicine and Oncology, National Taiwan University Cancer Center, Taipei, Taiwan, 3Oncology, Oncologianova GmbH, Recklinghausen, Germany, 4INSERM CIC1401, Bordeaux PharmacoEpi, University of Bordeaux, Bordeaux, France, 5Oncology, Merck Healthcare KGaA, Darmstadt, Germany, 6Global Epidemiology, Merck Healthcare KGaA, Darmstadt, Germany, 7Biostatistics, Prometris GmbH, Mannheim, Germany, 8Biostatistics, Merck Serono, Shanghai, China, 9 Department of Medical Oncology, Internal Medicine 1, General Hospital – Medical University of Vienna, Vienna, Austria, 10Oncology, Comprehensive Cancer Center, Vienna General Hospital and Medical University of Vienna, Vienna, Austria Background: Cetuximab (CET) in combination with chemotherapy is approved for a once-weekly (q1w) schedule at an initial dose of 400 mg/m2, followed by weekly doses of 250 mg/m2, in patients with RAS wild-type (wt) metastatic colorectal cancer (mCRC). However in clinical practice, an off-label schedule of CET 500 mg/m2 every2-weeks (q2w) is frequently used. This pooled analysis of patient-level data aimed to test the noninferiority of the q2w vs q1w schedule on overall survival (OS). Methods: All post-authorization studies with patient-level data available to marketing authorization holder at time of study design, in patients with confirmed RAS wt mCRC who received a first-line treatment with CET q1w or q2w in combination with chemotherapy from 2007 to 2018 were included: 2 non-interventional cohort studies (NIS) (EREBUS, ERBITAG) and 3 clinical trials (CEBIFOX, CECOG/CORE 1.2.002, APEC). Patients were categorized into q1w or q2w groups according to the CET schedule planned at initiation. OS was calculated from first CET infusion until all-cause death and censored at the last date patients were known to be alive. The noninferiority of the
Volume 30 | Supplement 5 | October 2019
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz246.059/5577459 by guest on 24 October 2019
(CAFmC) that enables early prediction of treatment resistance in treatment naı¨ve patients with mCRC receiving bev plus mFOLFOX6. Phase II will prospectively evaluate this CAFmC and randomize between an early replacement of bev by aflibercept or continuation of bev when the CAFmC indicates imminent progress. Methods: In phase I 41 out of 50 patients recruited in 15 centers in Germany and Austria with treatment naı¨ve mCRC under FOLFOX plus bev treatment were evaluable for CAF analysis. 102 different, preselected CAFs were prospectively collected and centrally analyzed in plasma samples (n ¼ 647) obtained prior to treatment and biweekly until radiologic progress determined by CT scan every 2 months. The values of various CAFs were affected by both, chemotherapeutic treatment itself as well as progress. These CAF were excluded from the bioinformatic analysis. Using the remaining CAF we employed a machine learning approach to define a combination of 5 CAF whose change in values/pattern correlated with later progress at least 2 months prior to radiologic progress as determined by CT. Out of various classifiers examined, a random forest classifier provided a CAF set with the highest accuracy. Results: Using the samples described above and a random forest algorithm we established a CAFmC comprising 5 CAF whose specific change in value/pattern over time indicated treatment resistance 3 months prior to radiologic progress with an accuracy of 83%. The CAFmC was established and cross-validated in two cohorts of 26 and 15 patients, respectively. Conclusions: Using advanced bioinformatics we identified a CAFmC that points out treatment resistance to FOLFOX plus Bev in patients with mCRC 3 months prior to radiological progress. A decision process using this marker combination will be evaluated in the randomized phase II of the trial. Clinical trial identification: NCT02331927, 2012-005657-24. Legal entity responsible for the study: Ulm University Hospital. Funding: Sanofi-Aventis. Disclosure: T. Seufferlein: Research grant / Funding (institution): Celgene; Research grant /
Annals of Oncology
Funding (institution): Sanofi; Advisory / Consultancy: Celgene; Advisory / Consultancy: Lilly; Advisory / Consultancy: Boeringer Ingelheim; Advisory / Consultancy: Merck Serono; Advisory / Consultancy: Amgen; Advisory / Consultancy: Roche. T.J. Ettrich: Advisory / Consultancy: Merck Serono; Advisory / Consultancy, Speaker Bureau / Expert testimony: Sanofi-Aventis; Advisory / Consultancy: Bayer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Novartis; Advisory / Consultancy: Roche; Advisory / Consultancy: Lilly; Speaker Bureau / Expert testimony: Celgene; Travel / Accommodation / Expenses: Ipsen; Research grant / Funding (institution): Servier. A. Ko¨nig: Travel / Accommodation / Expenses: Ipsen. L. Perkhofer: Travel / Accommodation / Expenses: Ipsen. All other authors have declared no conflicts of interest.
582P
Microsatellite Instability (MSI) status and prognosis in colorectal cancer: Meta-analysis
J. Toh1, K. Spring2 Colorectal, Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead, Australia, 2Medical Oncology, Ingham Institute, Liverpool, Australia
1
Background: Microsatellite instability (MSI) is thought to be a marker of immunogenicity and better prognosis in colorectal cancer (CRC). However, the mechanism by which MSI confers a survival advantage is not well known and there is a range of results reported in the literature. Methods: A systematic literature search of original studies was performed on Ovid searching Medline, Embase, Cochrane Library, CINAHL, Clinical Trials databases from inception of database to current. Data extracted included age, stage, MSI-H, MSS and MSI-L, proximal (right) vs. distal (left), colon vs. rectal, BRAF status, type of MSI or IHC test used, incidence of Lynch within cohort. The primary endpoint was survival (overall survival (OS), disease/relapse free survival (DFS) and disease (cancer) specific survival DSS). Statistical analysis was performed using RevMan Ver 5.3 Cochrane Collaboration. Results: From 11,747 studies, 117 met the inclusion criteria (n ¼ 100,257; MSI-H n ¼ 12,263, (MSI-H 12.2%). Overall, MSI was associated with improved OS (OR 0.80 (0.71, 0.91). When stratified by stage, there was no difference in OS in stage I and IV, but a protective effect in stage II (OR 0.69 (0.51, 0.92)) and III (0.70 (0.54, 0.91)) CRC. By age, there was benefit in studies where reported median age < 60 (OR 0.66 (0.54,0.82)) but not 60. There was no difference in OS between MSI-L and MSS. In studies including only mucinous/signet cell/poor differentiation, there was no difference in OS. In both right and left colon, MSI status was associated with improved OS, but not in the rectum. MSI status was associated with improved DFS (HR 0.75 (0.66, 0.84)), but there was no difference in DSS (HR 0.78 (0.60, 1.03)), and this was seen in all stages (I-IV). Conclusions: MSI is associated with improved overall survival in stage II and III colorectal cancer. Improved prognosis is seen in younger patients, in both right and left sided colon cancer, but evidence is limited in rectal cancer. MSI was associated with less relapse, but was not associated with cancer specific survival at any stage. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
v220 | Gastrointestinal Tumours, Colorectal
583P
Choosing the right strategy based on individualized treatment effect predictions: Combination versus sequential chemotherapy in patients with metastatic colorectal cancer
M. Koopman1, J.J. Kwakman2, R.C.M. van Kruijsdijk3, S.G. Elias4, M.T. Seymour5, A.M. Meade6, F. Visseren7, C.J.A. Punt2 1 Medical Oncology, University Medical Center Utrecht, Utrecht, Netherlands, 2Medical Oncology, Amsterdam University Medical Centers, Location AMC, Amsterdam, Netherlands, 3Internal Medicine, University Medical Center Utrecht, Utrecht, Netherlands, 4Department of Epidemiology, Julias Center for Health Sciences and Primary Care, Utrecht, Netherlands, 5Medical Oncology, St. James’s University Hospital Leeds, Leeds, Yorkshire, UK, 6MRC Clinical Trials Unit at UCL, University College London, London, UK, 7Vascular Medicine, University Medical Center Utrecht, Utrecht, Netherlands Background: Translating results from randomized trials to individual patients is challenging since treatment effects may vary due to heterogeneous prognostic characteristics. We aimed to demonstrate model development for individualized treatment effect predictions in cancer patients. We used data from two randomized trials that investigated combination (ComC) versus sequential chemotherapy (SeqC) in unresectable metastatic colorectal cancer (mCRC) patients. Methods: We used data from 803 patients included in CAIRO for prediction model development and internal validation, and data from 1423 patients included in FOCUS for external validation. A Weibull model with prespecified patient and tumour characteristics was developed for a prediction of gain in median overall survival by upfront ComC versus SeqC. Decision curve analysis with net benefit was used. A nomogram was built for estimating the probability of receiving second-line treatment after firstline monochemotherapy. Results: Median predicted gain in overall survival for ComC versus SeqC was 2.3 months (IQR -1.1-3.7 months). A gain in favour of SeqC was found in 231 patients (29%) and a gain of > 3 months for ComC in 294 patients (37%). Patients with benefit from SeqC had metachronous metastatic disease and a left-sided primary tumour. Decision curve analyses showed improvement in net benefit for treating all patients according to prediction-based treatment compared to treating all patients with ComC. Multiple characteristics were identified as prognostic variables that identify patients at risk of never receiving second-line treatment if treated with initial monochemotherapy. External validation showed good calibration with moderate discrimination in both models (C-index 0.66 and 0.65, respectively). Conclusions: We successfully developed individualized prediction models including prognostic characteristics derived from randomized trials to estimate treatment effects in mCRC patients. In times where the heterogeneity of CRC becomes increasingly evident, such tools are an important step towards personalized treatment. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: M. Koopman: Research grant / Funding (institution): Dutch Colorectal Cancer Group; Advisory / Consultancy: Servier. J.J. Kwakman: Honoraria (self), Research grant / Funding (institution): Nordic Pharma; Advisory / Consultancy, Research grant / Funding (institution): Servier. C.J.A. Punt: Research grant / Funding (institution): Dutch Colorectal Cancer Group; Advisory / Consultancy: Servier. All other authors have declared no conflicts of interest.
584P
Noninferiority on overall survival of every-2-weeks vs weekly schedule of cetuximab for first-line treatment of RAS wild-type metastatic colorectal cancer
S. Kasper1, A-L. Cheng2, F. Overkamp3, M. Rouyer4, C. Foch5, F-X. Lamy6, R. Esser5, D. Messinger7, V. Rothe7, W. Chen8, T. Brodowicz9, C.C. Zielinski10 1 Medical Oncology, University Hospital Essen Westdeutsches Tumorzentrum, Essen, Germany, 2Department of Internal Medicine and Oncology, National Taiwan University Cancer Center, Taipei, Taiwan, 3Oncology, Oncologianova GmbH, Recklinghausen, Germany, 4INSERM CIC1401, Bordeaux PharmacoEpi, University of Bordeaux, Bordeaux, France, 5Oncology, Merck Healthcare KGaA, Darmstadt, Germany, 6Global Epidemiology, Merck Healthcare KGaA, Darmstadt, Germany, 7Biostatistics, Prometris GmbH, Mannheim, Germany, 8Biostatistics, Merck Serono, Shanghai, China, 9 Department of Medical Oncology, Internal Medicine 1, General Hospital – Medical University of Vienna, Vienna, Austria, 10Oncology, Comprehensive Cancer Center, Vienna General Hospital and Medical University of Vienna, Vienna, Austria Background: Cetuximab (CET) in combination with chemotherapy is approved for a once-weekly (q1w) schedule at an initial dose of 400 mg/m2, followed by weekly doses of 250 mg/m2, in patients with RAS wild-type (wt) metastatic colorectal cancer (mCRC). However in clinical practice, an off-label schedule of CET 500 mg/m2 every2-weeks (q2w) is frequently used. This pooled analysis of patient-level data aimed to test the noninferiority of the q2w vs q1w schedule on overall survival (OS). Methods: All post-authorization studies with patient-level data available to marketing authorization holder at time of study design, in patients with confirmed RAS wt mCRC who received a first-line treatment with CET q1w or q2w in combination with chemotherapy from 2007 to 2018 were included: 2 non-interventional cohort studies (NIS) (EREBUS, ERBITAG) and 3 clinical trials (CEBIFOX, CECOG/CORE 1.2.002, APEC). Patients were categorized into q1w or q2w groups according to the CET schedule planned at initiation. OS was calculated from first CET infusion until all-cause death and censored at the last date patients were known to be alive. The noninferiority of the
Volume 30 | Supplement 5 | October 2019
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz246.059/5577459 by guest on 24 October 2019
(CAFmC) that enables early prediction of treatment resistance in treatment naı¨ve patients with mCRC receiving bev plus mFOLFOX6. Phase II will prospectively evaluate this CAFmC and randomize between an early replacement of bev by aflibercept or continuation of bev when the CAFmC indicates imminent progress. Methods: In phase I 41 out of 50 patients recruited in 15 centers in Germany and Austria with treatment naı¨ve mCRC under FOLFOX plus bev treatment were evaluable for CAF analysis. 102 different, preselected CAFs were prospectively collected and centrally analyzed in plasma samples (n ¼ 647) obtained prior to treatment and biweekly until radiologic progress determined by CT scan every 2 months. The values of various CAFs were affected by both, chemotherapeutic treatment itself as well as progress. These CAF were excluded from the bioinformatic analysis. Using the remaining CAF we employed a machine learning approach to define a combination of 5 CAF whose change in values/pattern correlated with later progress at least 2 months prior to radiologic progress as determined by CT. Out of various classifiers examined, a random forest classifier provided a CAF set with the highest accuracy. Results: Using the samples described above and a random forest algorithm we established a CAFmC comprising 5 CAF whose specific change in value/pattern over time indicated treatment resistance 3 months prior to radiologic progress with an accuracy of 83%. The CAFmC was established and cross-validated in two cohorts of 26 and 15 patients, respectively. Conclusions: Using advanced bioinformatics we identified a CAFmC that points out treatment resistance to FOLFOX plus Bev in patients with mCRC 3 months prior to radiological progress. A decision process using this marker combination will be evaluated in the randomized phase II of the trial. Clinical trial identification: NCT02331927, 2012-005657-24. Legal entity responsible for the study: Ulm University Hospital. Funding: Sanofi-Aventis. Disclosure: T. Seufferlein: Research grant / Funding (institution): Celgene; Research grant /
Annals of Oncology