American Society of Clinical Oncology ASCO 2019 Geissler

American Society of Clinical Oncology (ASCO) 2019 Geissler M, et al. VOLFI: m. FOLFOXIRI + panitumumab versus FOLFOXIRI as first-line treatment in patients with RAS wild-type metastatic colorectal cancer (m. CRC): final results of a randomized phase II trial of the AIO (AIO-KRK -0109) Modest DP, et al. Tumor dynamics with fluorouracil/folinic acid, irinotecan and oxaliplatin (FOLFOXIRI) plus panitumumab (pmab) or FOLFOXIRI alone as initial treatment of RAS wildtype metastatic colorectal cancer (m. CRC) –central radiologic review of VOLFI: a randomized, open label, phase-2 study (AIO KRK 0109) Click the box to view the associated poster/presentation data. SC-EU-PANITUMUMA-00288 Amgen (Europe) Gmb. H, 6343 Rotkreuz, Switzerland © 2019 Amgen Inc. All rights reserved

Geissler M, et al. VOLFI: m. FOLFOXIRI + panitumumab versus FOLFOXIRI as first-line treatment in patients with RAS wild-type metastatic colorectal cancer (m. CRC): final results of a randomized phase II trial of the AIO (AIO-KRK-0109) Michael Geissler 1, Jorge Riera Knorrenschild 2, Andrea Tannapfel 3, Jobst Greeve 4, Axel Florschuetz 5, Sven Wessendorf 1, Thomas Seufferlein 6, Stephan Kanzler 7, Swantje Held 8, Thomas Ettrich 6, Volker Heinemann 9, Petra Büchner. Steudel 10, Anke Reinacher-Schick 11, Uwe Martens 12, Dominik Modest 9 1 Klinikum Esslingen, Cancer Center Esslingen, Esslingen am Neckar, Germany, 2 Universitätsklinikum Gießen und Marburg, Germany, 3 Institut für Pathologie der Ruhr-Universität Bochum, Germany, 4 St. Vincenz-Krankenhaus, Paderborn, Germany, 5 Städtisches Klinikum Dessau, Germany, 6 Universitätsklinikum Ulm Zentrum für Innere Medizin, Ulm, Germany, 7 Leopoldina-Krankenhaus der Stadt Schweinfurt, Germany, 8 Clin. Assess Gmb. H, Leverkusen, Germany, 9 Klinikum der Universität München, Comprehensive Cancer Center CCC, Munich, Germany, 10 Universitätsklinikum Halle, Germany, 11 Klinikum der Ruhr-Universität Bochum, Germany 12 SLK-Kliniken Heilbronn, Germany Abstract 3511 American Society of Clinical Oncology (ASCO) 2019 May 31 - June 04, 2019, Chicago, IL

Geissler M, et al. VOLFI: m. FOLFOXIRI + panitumumab versus FOLFOXIRI as first-line treatment in patients with RAS wild-type metastatic colorectal cancer (m. CRC): final results of a randomized phase II trial of the AIO (AIO-KRK-0109) Introduction § Triplet chemotherapy using the FOLFOXIRI protocol results in high ORR and OS rates in fit patients (ECOG 0 -1) with m. CRC (1). § Combining the FOLFOXIRI chemotherapy with anti-VEGF (bevacizumab) or anti-EGFR (panitumumab, cetuximab) m. Abs further increased the effectivity in terms of ORR and OS in single arm phase II trials. § So far, no randomized clinical trial has evaluated the superiority of combining FOLFOXIRI plus either anti-VEGF or anti-EGFR m. Ab compared to FOLFOXIRI alone. § The VOLFI trial investigated a modified FOLFOXIRI chemotherapy protocol together with anti-EGFR therapy [panitumumab (P)]. Primary endpoint was first presented at ESMO 2017 + ASCO 2018 (3). ECOG = Eastern Cooperative Oncology Group; EGFR = epidermal growth factor receptor; FOLFOXIRI = 5 -fluorouracil, leucovorin, oxaliplatin, irinotecan; m. Ab = monoclonal antibody; m. CRC = metastatic colorectal cancer; ORR = objective response rate; OS = overall survival; VEGF = vascular endothelial growth factor. 1. Falcone A. et al. , J Clin Oncol 2007, 13: 1670 -1676. 2. Simon R. , Control Clin Trials 1989; 10: 1 -10. 3. Geissler M. et al. , ESMO 2017, A 475 O + ASCO 2018, A 3509

Geissler M, et al. VOLFI: m. FOLFOXIRI + panitumumab versus FOLFOXIRI as first-line treatment in patients with RAS wild-type metastatic colorectal cancer (m. CRC): final results of a randomized phase II trial of the AIO (AIO-KRK-0109) Methods: Study Design m. CRC non-resectable 1 st-line WT RAS age ≥ 18 yrs ECOG PS 0 -1 N = 96 m. FOLFOXIRI + panitumumab 6 mg/kg Q 2 W N = 63 R 2: 1 randomization period 6/2011 -1/2017 § Open-label, 2: 1 randomized phase II study § Study population: 1 st-line non-resectable m. CRC Irinotecan 150 mg/m 2, oxaliplatin 85 mg/m 2, LV 200 mg/m 2, 5 -FU 3000 mg/m 2 CIV FOLFOXIRI Q 2 W N = 33 Irinotecan 165 mg/m 2, oxaliplatin 85 mg/m 2, LV 200 mg/m 2, 5 -FU 3200 mg/m 2 CIV 5 -FU = 5 -fluorouracil; CIV = continuous infusion; ECOG PS = Eastern Cooperative Oncology Group performance status; FOLFOXIRI = 5 fluorouracil, leucovorin, oxaliplatin, irinotecan; LV = leucovorin; m. CRC = metastatic colorectal cancer; m. FOLFOXIRI = modified FOLFOXIRI; Q 2 W = every 2 weeks; R = randomization; RAS = rat sarcoma viral oncogene homolog; WT = wild type.

Geissler M, et al. VOLFI: m. FOLFOXIRI + panitumumab versus FOLFOXIRI as first-line treatment in patients with RAS wild-type metastatic colorectal cancer (m. CRC): final results of a randomized phase II trial of the AIO (AIO-KRK-0109) Methods: Study Design (cont. ) § Sample size calculations and statistical design according to Simon-2 -stage methods (1). § Strata: § Cohort 1: Definitively unresectable metastatic disease with a focus on symptomatic patients and/or large tumor load (n=43 arm A, n=22 arm B). § Cohort 2: Chance of secondary resection with curative intent (n=20 arm A, n=11 arm B). § Primary endpoint: ORR (RECIST 1. 1). § Secondary endpoints: PFS, OS, DCR, secondary resection rate of metastases, toxicity, QL (QLQ-C 30), time to recurrence (cohort 2). DCR = disease control rate; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; QL = quality of life; QLQ-C 30 = 30 -item quality of life questionnaire-core 30; RECIST = Response Evaluation Criteria In Solid Tumors. 1. Simon R. , Control Clin Trials. 1989; 10: 1 -10.

Geissler M, et al. VOLFI: m. FOLFOXIRI + panitumumab versus FOLFOXIRI as first-line treatment in patients with RAS wild-type metastatic colorectal cancer (m. CRC): final results of a randomized phase II trial of the AIO (AIO-KRK-0109) Results Table 1: Tumor Mutation Status (n=20 BRAF status unknown) m. FOLFOXIRI + P N = 50 FOLFOXIRI N = 26 Total RAS/BRAF WT 43 (86. 0) 17 (65. 4) 60 (78. 9) BRAF mut (V 600 E) 7* (14. 0) 9** (34. 6) 16 (21. 1) N (%) *1 patient with BRAF D 594 N **1 patient with BRAF G 469 A BRAF = B-Raf proto-oncogene; FOLFOXIRI = 5 -fluorouracil, leucovorin, oxaliplatin, irinotecan; m. FOLFOXIRI = modified FOLFOXIRI; mut = mutant; P = panitumumab; RAS = rat sarcoma viral oncogene homolog; WT = wild type.

Geissler M, et al. VOLFI: m. FOLFOXIRI + panitumumab versus FOLFOXIRI as first-line treatment in patients with RAS wild-type metastatic colorectal cancer (m. CRC): final results of a randomized phase II trial of the AIO (AIO-KRK-0109) Results: Secondary Resection Rate Full Analysis Set Cohort 1 Cohort 2 N=65 N=31 P=0. 08 OR=7. 80 95% CI 0. 42 – 145. 2 P=0. 05 OR=5. 25 95% CI 1. 07 – 25. 8 N=96 100 90 90 90 80 80 80 70 70 70 60 50 40 33. 3 30 20 12. 1 Resection Rate (%) 100 Resection Rate (%) P=0. 02 OR=3. 63 95% CI 1. 13 – 11. 67 60 50 40 30 20 10 10 0 0 60 50 36. 4 40 30 20 14. 0 m. FOLFOXIRI + panitumumab 75. 0 0 10 0 FOLFOXIRI CI = confidence interval; FOLFOXIRI = 5 -fluorouracil, leucovorin, oxaliplatin, irinotecan; m. FOLFOXIRI = modified FOLFOXIRI; OR = odds ratio.

Geissler M, et al. VOLFI: m. FOLFOXIRI + panitumumab versus FOLFOXIRI as first-line treatment in patients with RAS wild-type metastatic colorectal cancer (m. CRC): final results of a randomized phase II trial of the AIO (AIO-KRK-0109) Results: Objective Response Rate Full Analysis Set by Tumor Sidedness Left N=78 P=0. 021 OR=4. 52 1. 30 – 15. 72 N=96 P=0. 004 OR=4. 47 95% CI 1. 61 – 12. 38 100 87. 3 90 100 90. 6 90 80 60. 6 ORR (%) 60 RAS/BRAF wt BRAF mut N=60 N=16 P=0. 081 P=0. 041 OR=3. 36 OR=21. 0 0. 90 – 12. 55 1. 50 – 293. 25 100 80 70 Right N=18 P=0. 345 OR=3. 89 0. 54 – 27. 89 70 85. 7 86. 0 80 68. 0 70. 0 ORR (%) 90 by Genotype 60 70 50 50 40 40 30 30 30 20 20 20 10 10 10 0 m. FOLFOXIRI + panitumumab 64. 7 60 50 37. 5 40 22. 2 FOLFOXIRI BRAF = B-Raf proto-oncogene; CI = confidence interval; FOLFOXIRI = 5 -fluorouracil, leucovorin, oxaliplatin, irinotecan; m. FOLFOXIRI = modified FOLFOXIRI; mut = mutant; OR = odds ratio; ORR = objective response rate; RAS = rat sarcoma viral oncogene homolog; wt = wild type.

Geissler M, et al. VOLFI: m. FOLFOXIRI + panitumumab versus FOLFOXIRI as first-line treatment in patients with RAS wild-type metastatic colorectal cancer (m. CRC): final results of a randomized phase II trial of the AIO (AIO-KRK-0109) Results: Objective response rate, subgroups BRAF = B-Raf proto-oncogene; ECOG = Eastern Cooperative Oncology Group; FOLFOXIRI = 5 -fluorouracil, leucovorin, oxaliplatin, irinotecan; m. FOLFOXIRI = modified FOLFOXIRI; P = panitumumab; RAS = rat sarcoma viral oncogene homolog.

Geissler M, et al. VOLFI: m. FOLFOXIRI + panitumumab versus FOLFOXIRI as first-line treatment in patients with RAS wild-type metastatic colorectal cancer (m. CRC): final results of a randomized phase II trial of the AIO (AIO-KRK-0109) Results: Progression free survival m. FOLFOXIRI + panitumumab: 9. 7 mo (95% CI 8. 5 -11. 8) FOLFOXIRI: 9. 7 mo (95% CI 7. 8 -11. 8) HR: 1. 071 (95% CI 0. 69 -1. 66), p=0. 76 CI = confidence interval; CTX = chemotherapy; HR = hazard ratio; FOLFOXIRI = 5 -fluorouracil, leucovorin, oxaliplatin, irinotecan; m. FOLFOXIRI = modified FOLFOXIRI; P = panitumumab.

Geissler M, et al. VOLFI: m. FOLFOXIRI + panitumumab versus FOLFOXIRI as first-line treatment in patients with RAS wild-type metastatic colorectal cancer (m. CRC): final results of a randomized phase II trial of the AIO (AIO-KRK-0109) Results: Median PFS, subgroups Months (95% CI) m. FOLFOXIRI + P FOLFOXIRI ITT Cohort 1 Cohort 2 RAS/BRAF WT BRAF mut Left sided Right sided 9. 7 (8. 5 – 11. 8) 8. 7 (7. 2 – 9. 7) 12. 6 (10. 8 – 17. 1) 12. 0 (9. 6 – 13. 0) 6. 5 (3. 5 – 7. 2) 10. 8 (9. 4 – 12. 3) 6. 3 (3. 5 – 9. 3) 9. 7 (7. 8 – 11. 8) 10. 4 (7. 8 – 13. 1) 8. 7 (4. 0 – 22. 1) 10. 7 (8. 7 – 13. 3) 6. 1 (2. 4 – 10. 5) 10. 5 (7. 7 – 13. 3) 8. 5 (6. 2 – 13. 1) BRAF = B-Raf proto-oncogene; CI = confidence interval; FOLFOXIRI = 5 -fluorouracil, leucovorin, oxaliplatin, irinotecan; ITT = intent to treat; mut = mutant; m. FOLFOXIRI = modified FOLFOXIRI; P = panitumumab; PFS = progression-free survival; RAS = rat sarcoma viral oncogene homolog; WT = wild type.

Geissler M, et al. VOLFI: m. FOLFOXIRI + panitumumab versus FOLFOXIRI as first-line treatment in patients with RAS wild-type metastatic colorectal cancer (m. CRC): final results of a randomized phase II trial of the AIO (AIO-KRK-0109) Results: Progression free survival, subgroups BRAF = B-Raf proto-oncogene; ECOG = Eastern Cooperative Oncology Group; FOLFOXIRI = 5 -fluorouracil, leucovorin, oxaliplatin, irinotecan; m. FOLFOXIRI = modified FOLFOXIRI; P = panitumumab; RAS = rat sarcoma viral oncogene homolog.

Geissler M, et al. VOLFI: m. FOLFOXIRI + panitumumab versus FOLFOXIRI as first-line treatment in patients with RAS wild-type metastatic colorectal cancer (m. CRC): final results of a randomized phase II trial of the AIO (AIO-KRK-0109) Results: Overall survival m. FOLFOXIRI + panitumumab: 35. 7 mo (95% CI 27. 6 -43. 8) FOLFOXIRI: 29. 8 mo (95% CI 19. 8 -39. 9) HR: 0. 67 (95% CI 0. 41 -1. 11), p=0. 12 CI = confidence interval; CTX = chemotherapy; HR = hazard ratio; FOLFOXIRI = 5 -fluorouracil, leucovorin, oxaliplatin, irinotecan; m. FOLFOXIRI = modified FOLFOXIRI; P = panitumumab.

Geissler M, et al. VOLFI: m. FOLFOXIRI + panitumumab versus FOLFOXIRI as first-line treatment in patients with RAS wild-type metastatic colorectal cancer (m. CRC): final results of a randomized phase II trial of the AIO (AIO-KRK-0109) Results: Median Overall Survival, subgroups Months (95% CI) m. FOLFOXIRI + P FOLFOXIRI ITT Cohort 1 Cohort 2 RAS/BRAF WT BRAF mut Left sided Right sided 35. 7 (27. 6 – 43. 8) 24. 7 (13. 3 – 39. 9) 52. 0 (35. 2 – ) 43. 5 (35. 7 – 53. 3) 8. 0 (7. 7 – 22. 4) 39. 9 (32. 7 – 52. 0) 11. 5 (7. 7 – ) 29. 8 (19. 8 – 39. 9) 28. 3 (13. 9 – 37. 7) 41. 7 (10. 7 – 44. 4) 35. 3 (17. 7 – 41. 7) 9. 0 (2. 7 – 13. 9) 35. 3 (14. 3 – 41. 8) 22. 0 (12. 9 – 41. 7) CI = confidence interval; FOLFOXIRI = 5 -fluorouracil, leucovorin, oxaliplatin, irinotecan; ITT = intent to treat; mut = mutant; P = panitumumab; PFS = progression-free survival; RAS = rat sarcoma viral oncogene homolog; WT = wild type.

Geissler M, et al. VOLFI: m. FOLFOXIRI + panitumumab versus FOLFOXIRI as first-line treatment in patients with RAS wild-type metastatic colorectal cancer (m. CRC): final results of a randomized phase II trial of the AIO (AIO-KRK-0109) Results: Overall survival, subgroups BRAF = B-Raf proto-oncogene; ECOG = Eastern Cooperative Oncology Group; FOLFOXIRI = 5 -fluorouracil, leucovorin, oxaliplatin, irinotecan; m. FOLFOXIRI = modified FOLFOXIRI; P = panitumumab; RAS = rat sarcoma viral oncogene homolog.

Geissler M, et al. VOLFI: m. FOLFOXIRI + panitumumab versus FOLFOXIRI as first-line treatment in patients with RAS wild-type metastatic colorectal cancer (m. CRC): final results of a randomized phase II trial of the AIO (AIO-KRK-0109) Summary § AIO-KRK 0109 (VOLFI) is the first randomized trial investigating FOLFOXIRI vs. FOLFOXIRI + any m. Ab, here panitumumab. § 1 st-line treatment with m. FOLFOXIRI + P resulted in significantly higher ORR compared to FOLFOXIRI. § The addition of P to FOLFOXIRI resulted in high ORR in left and right sided as well as BRAF mutated m. CRC. § For the first time, this study demonstrates that P improves secondary resection rates also in combination with a triplet regimen correlating with high percentage of early tumor shrinkage (85. 7%) and depth of response (58. 9%), Modest et al. ASCO 2019, A 3530. § PFS was in the expected range with no difference in PFS between both arms suggesting that PFS might be a suboptimal endpoint to assess the efficacy of EGFR-targeted antibodies in m. CRC. § Median OS was numerically longer in the panitumumab-based study arm as compared to FOLFOXIRI alone (HR 0. 67), but the trial was not powered to detect statistically significant differences. § While there was a strong signal towards prolonged OS with panitumumab in cohort 2 with potentially resectable metastases (HR 0. 41), there was no signal in right sided and BRAF mutant disease (small patient numbers). § m. FOLFOXIRI + P has relevant, but manageable gastrointestinal toxicity and should be used in ECOG 0 -1 patients only. Compared to the GONO FOLFOXIRI protocol, both the irinotecan and the 5‑FU dose should be reduced. 5 -FU = 5 -fluorouracil; BRAF = B-Raf proto-oncogene; ECOG = Eastern Cooperative Oncology Group; EGFR = epidermal growth factor receptor; FOLFOXIRI = 5 -fluorouracil, leucovorin, oxaliplatin, irinotecan; GONO = Gruppo Oncologico Nord Ovest; HR = hazard ratio; m. Ab = monoclonal antibody; m. CRC = metastatic colorectal cancer; m. FOLFOXIRI = modified FOLFOXIRI; ORR = objective response rate; OS = overall survival; P = panitumumab; PFS = progression-free survival.

Geissler M, et al. VOLFI: m. FOLFOXIRI + panitumumab versus FOLFOXIRI as first-line treatment in patients with RAS wild-type metastatic colorectal cancer (m. CRC): final results of a randomized phase II trial of the AIO (AIO-KRK-0109) Conclusions In conclusion, this four-drug regimen may represent a valuable treatment option in fit patients with high tumor load and/or chance of secondary resection of metastases. Future studies are required to confirm the trend towards improved overall survival.

Slide intentionally left blank

Modest DP, et al. Tumor dynamics with fluorouracil/folinic acid, irinotecan and oxaliplatin (FOLFOXIRI) plus panitumumab (pmab) or FOLFOXIRI alone as initial treatment of RAS wildtype metastatic colorectal cancer (m. CRC) –central radiologic review of VOLFI: a randomized, open label, phase-2 study (AIO KRK 0109) D. P. Modest 1, 2, D. Noerenberg 3, M. Seidensticker 3, J. Ricke 3, U. M. Martens 4, J. Riera-Knorrenschild 5, J. Greeve 6, A. Florschütz 7, S. Wessendorf 8, T. Ettrich 9, S. Kanzler 10, S. Held 11, P. Buechner-Steudel 12, J. Atzpodien 13, V. Heinemann 1, 2, A. Tannapfel 14, A. C. Reinacher-Schick 15, M. Geissler 8 1 Department of Medicine III & Comprehensive Cancer Center, Hospital of the university (LMU), München, Germany; 2 German Cancer Consortium (DKTK); German Cancer Research Centre (DKFZ), Heidelberg, Germany; 3 Department of Radiology, Hospital of the university (LMU), München, Germany; 4 SLK-Kliniken Heilbronn, Klinik für Innere Medizin, Heilbronn, Germany; 5 Universitätsklinik Marburg, Germany; 6 St. Vincenz-Krankenhaus Paderborn, Germany; 7 Stadtisches Klinikum Dessau, Germany; 8 Klinikum Esslingen, Department of Hematology/Oncology, Esslingen, Germany; 9 Universitätsklinikum Ulm Klinik für Innere Medizin I, Ulm, Germany; 10 Leopoldina Krankenhaus, Schweinfurt, Germany; 11 Clin. Assess Gmb. H, Leverkusen, Germany; 12 Universitätsklinik und Poliklinik für Innere Medizin I, Universitätsklinikum Halle (Saale), Halle, Germany; 13 Franziskus-Hospital Harderberg, Georgsmarienhütte (Saale), Germany; 14 Pathologisches Institut der Ruhr Universität Bochum, Germany; 15 St. Josef-Hospital, Klinikum der Ruhr-Universität Bochum, Germany Abstract 3530 American Society of Clinical Oncology (ASCO) 2019 May 31 - June 04, 2019, Chicago, IL

Modest DP, et al. Tumor dynamics with fluorouracil/folinic acid, irinotecan and oxaliplatin (FOLFOXIRI) plus panitumumab (pmab) or FOLFOXIRI alone as initial treatment of RAS wildtype metastatic colorectal cancer (m. CRC) –central radiologic review of VOLFI: a randomized, open label, phase-2 study (AIO KRK 0109) Background The VOLFI trial demonstrated improved objective response rate (ORR) with the addition of pmab to modified triplet chemotherapy with FOLFOXIRI in a 2: 1 (63 patients FOLFOXIRI plus pmab; 33 patients FOLFOXIRI) randomized, controlled, phase II trial in patients with untreated RAS wildtype m. CRC. Patients and Methods Radiologic images from the study were centrally examined according to RECIST 1. 1. We further assessed early tumor shrinkage (=ETS: 20% shrinkage of tumor diameter at first re-assessment) and depth of response (=Dp. R: maximum shrinkage of lesions defined as relation of smallest tumor diameter to baseline). Moreover, time to Dp. R was calculated (randomisation to depth of response image). The trial is registered with Clinical. Trials. gov, NCT 01328171. FOLFOXIRI = 5 -fluorouracil, leucovorin, oxaliplatin, irinotecan; m. CRC = metastatic colorectal cancer; pmab = panitumumab; RAS = rat sarcoma viral oncogene homolog; RECIST = Response Evaluation Criteria In Solid Tumors.

Modest DP, et al. Tumor dynamics with fluorouracil/folinic acid, irinotecan and oxaliplatin (FOLFOXIRI) plus panitumumab (pmab) or FOLFOXIRI alone as initial treatment of RAS wildtype metastatic colorectal cancer (m. CRC) –central radiologic review of VOLFI: a randomized, open label, phase-2 study (AIO KRK 0109) Results Images were available for 88 of 96 patients (91. 7%), 86 patients (89. 6%) had at least one follow-up image and were included in the central review. According to central review, objective response rates were 89. 2% vs 66. 7% with FOLFOXIRI plus pmab vs FOLFOXIRI alone (P=0. 02). ETS was also significantly more frequent (Fisher’s exact test; P=0. 01) and Dp. R (Wilcoxon test; P= 0. 004) significantly greater with pmab as compared to chemotherapy alone. See table for details. Time to Dp. R was similar in the pmab- vs chemotherapy alone arm (3. 9 (95% confidence interval 2. 8 -4. 7) vs. 4. 2 (95% CI 3. 6 -5. 7) months, respectively. P=0. 63). CI = confidence interval; Dp. R = depth of response; ETS = early tumor shrinkage; FOLFOXIRI = 5 -fluorouracil, leucovorin, oxaliplatin, irinotecan; pmab = panitumumab.

Modest DP, et al. Tumor dynamics with fluorouracil/folinic acid, irinotecan and oxaliplatin (FOLFOXIRI) plus panitumumab (pmab) or FOLFOXIRI alone as initial treatment of RAS wildtype metastatic colorectal cancer (m. CRC) –central radiologic review of VOLFI: a randomized, open label, phase-2 study (AIO KRK 0109) Conclusion In this central review, pmab significantly improves ORR, the rate of ETS and also Dp. R when added to a m. FOLFOXIRI regimen. Our findings underline the potential of this highly active regimen in patients with RAS wildtype m. CRC that need to achieve early and profound shrinkage of the tumor. Additional analysis including molecular subgroups and tumor sidedness will be shown at the meeting. Dp. R = depth of response; ETS = early tumor shrinkage; m. CRC = metastatic colorectal cancer; m. FOLFOXIRI = modified 5 -fluorouracil, leucovorin, oxaliplatin, irinotecan; ORR = objective response rate; RAS = rat sarcoma viral oncogene homolog.

Modest DP, et al. Tumor dynamics with fluorouracil/folinic acid, irinotecan and oxaliplatin (FOLFOXIRI) plus panitumumab (pmab) or FOLFOXIRI alone as initial treatment of RAS wildtype metastatic colorectal cancer (m. CRC) –central radiologic review of VOLFI: a randomized, open label, phase-2 study (AIO KRK 0109) Consort diagram BRAF = B-Raf proto-oncogene; FOLFOXIRI = 5 -fluorouracil, leucovorin, oxaliplatin, irinotecan; m. ITT = modified intent to treat; RAS = rat sarcoma viral oncogene homolog.

Modest DP, et al. Tumor dynamics with fluorouracil/folinic acid, irinotecan and oxaliplatin (FOLFOXIRI) plus panitumumab (pmab) or FOLFOXIRI alone as initial treatment of RAS wildtype metastatic colorectal cancer (m. CRC) –central radiologic review of VOLFI: a randomized, open label, phase-2 study (AIO KRK 0109) Investigator’s assessed and centrally evaluated response in the VOLFI trial Response assessment ORR (CR + PR); % (95% CI) ORR (cohort II); % (95% CI) CR (%) PR (%) SD (%) PD (%) NE (%) RAS wildtype ITT Central review population m. FOLFOXIRI plus panitumumab (N=63) FOLFOXIRI (N=33) P-value (95% CI) m. FOLFOXIRI plus panitumumab (N=56) FOLFOXIRI (N=30) P-value 87. 3 (76. 5 -94. 4) 60. 6 (42. 1 -77. 1) 0. 004 89. 3 (78. 1 -96. 0) 66. 7 (47. 2 -82. 7) 0. 02 81. 4 (66. 6 -91. 6) 59. 1 (36. 4 -79. 3) 0. 07 86. 8 (71. 9 -95. 6) 61. 9 (38. 4 -81. 9) 0. 047 100. 0 (83. 2 -100) 63. 6 (30. 8 -89. 1) 0. 01 94. 4 (72. 7 -99. 9) 77. 8 (40. 0 -97. 2) 0. 25 - 2 (6. 1) 4 (7. 1) - 55 (87. 3) 18 (54. 5) 46 (82. 1) 20 (66. 7) 5 (7. 9) 10 (30. 3) 3 (5. 4) 9 (30. 0) 2 (3. 2) 1 (3. 0) 3 (5. 4) 1 (3. 3) 1 (1. 6) 2 (6. 1) - - CI = confidence interval; CR = complete remission; FOLFOXIRI = 5 -fluorouracil, leucovorin, oxaliplatin, irinotecan; ITT = intent to treat; m. FOLFOXIRI = modified FOLFOXIRI; NE = not evaluable; ORR = overall response rate, PD = progressive disease; PR = partial remission, RAS = rat sarcoma viral oncogene homolog; SD = stable disease. p values calculated by Fisher’s exact test.

Modest DP, et al. Tumor dynamics with fluorouracil/folinic acid, irinotecan and oxaliplatin (FOLFOXIRI) plus panitumumab (pmab) or FOLFOXIRI alone as initial treatment of RAS wildtype metastatic colorectal cancer (m. CRC) –central radiologic review of VOLFI: a randomized, open label, phase-2 study (AIO KRK 0109) Response parameters ETS = early tumor shrinkage (20% shrinkage of tumor diameter at first re-assessment after study start); FOLFOXIRI = 5 -fluorouracil, leucovorin, oxaliplatin, irinotecan; m. FOLFOXIRI = modified FOLFOXIRI; pmab = panitumumab. p value ETS calculated by Fisher’s exact test.

Modest DP, et al. Tumor dynamics with fluorouracil/folinic acid, irinotecan and oxaliplatin (FOLFOXIRI) plus panitumumab (pmab) or FOLFOXIRI alone as initial treatment of RAS wildtype metastatic colorectal cancer (m. CRC) –central radiologic review of VOLFI: a randomized, open label, phase-2 study (AIO KRK 0109) Response parameters (cont. ) Dp. R = depth of response (relation of shortest tumor diameter to baseline diameter); FOLFOXIRI = 5 -fluorouracil, leucovorin, oxaliplatin, irinotecan; pmab = panitumumab. p value Dp. R calculated by Wilcoxon test.

Modest DP, et al. Tumor dynamics with fluorouracil/folinic acid, irinotecan and oxaliplatin (FOLFOXIRI) plus panitumumab (pmab) or FOLFOXIRI alone as initial treatment of RAS wildtype metastatic colorectal cancer (m. CRC) –central radiologic review of VOLFI: a randomized, open label, phase-2 study (AIO KRK 0109) Waterfall plots of best response All patients (n=86) FOLFOXIRI = 5 -fluorouracil, leucovorin, oxaliplatin, irinotecan; m. FOLFOXIRI = modified FOLFOXIRI; pmab = panitumumab.

Modest DP, et al. Tumor dynamics with fluorouracil/folinic acid, irinotecan and oxaliplatin (FOLFOXIRI) plus panitumumab (pmab) or FOLFOXIRI alone as initial treatment of RAS wildtype metastatic colorectal cancer (m. CRC) –central radiologic review of VOLFI: a randomized, open label, phase-2 study (AIO KRK 0109) Waterfall plots of best response (cont. ) BRAF mutant patients (n=12) BRAF = B-Raf proto-oncogene; FOLFOXIRI = 5 -fluorouracil, leucovorin, oxaliplatin, irinotecan; m. FOLFOXIRI = modified FOLFOXIRI; mut = mutant; pmab = panitumumab.

Modest DP, et al. Tumor dynamics with fluorouracil/folinic acid, irinotecan and oxaliplatin (FOLFOXIRI) plus panitumumab (pmab) or FOLFOXIRI alone as initial treatment of RAS wildtype metastatic colorectal cancer (m. CRC) –central radiologic review of VOLFI: a randomized, open label, phase-2 study (AIO KRK 0109) Waterfall plots of best response (cont. ) Left-sided primary patients (N=70) FOLFOXIRI = 5 -fluorouracil, leucovorin, oxaliplatin, irinotecan; m. CRC = metastatic colorectal cancer; m. FOLFOXIRI = modified FOLFOXIRI; pmab = panitumumab.

Modest DP, et al. Tumor dynamics with fluorouracil/folinic acid, irinotecan and oxaliplatin (FOLFOXIRI) plus panitumumab (pmab) or FOLFOXIRI alone as initial treatment of RAS wildtype metastatic colorectal cancer (m. CRC) –central radiologic review of VOLFI: a randomized, open label, phase-2 study (AIO KRK 0109) Waterfall plots of best response (cont. ) Right-sided primary patients (n=16) FOLFOXIRI = 5 -fluorouracil, leucovorin, oxaliplatin, irinotecan; m. CRC = metastatic colorectal cancer; m. FOLFOXIRI = modified FOLFOXIRI; pmab = panitumumab.

Modest DP, et al. Tumor dynamics with fluorouracil/folinic acid, irinotecan and oxaliplatin (FOLFOXIRI) plus panitumumab (pmab) or FOLFOXIRI alone as initial treatment of RAS wildtype metastatic colorectal cancer (m. CRC) –central radiologic review of VOLFI: a randomized, open label, phase-2 study (AIO KRK 0109) Tumor diameter (medians) @ scheduled tumor assessments FOLFOXIRI = 5 -fluorouracil, leucovorin, oxaliplatin, irinotecan; m. FOLFOXIRI = modified FOLFOXIRI; pmab = panitumumab; RECIST = Response Evaluation Criteria In Solid Tumors. Median tumor diameters in the respective study arms are displayed. Re-assessment numbers correspond to scheduled assessments (1= 8 weeks, 2=16 weeks, …). Progressive disease evaluations were excluded from the plot.

Modest DP, et al. Tumor dynamics with fluorouracil/folinic acid, irinotecan and oxaliplatin (FOLFOXIRI) plus panitumumab (pmab) or FOLFOXIRI alone as initial treatment of RAS wildtype metastatic colorectal cancer (m. CRC) –central radiologic review of VOLFI: a randomized, open label, phase-2 study (AIO KRK 0109) Summary § The central review of radiologic images confirmed the primary endpoint of the trial (investigator assessed objective response rate). § Early tumor shrinkage (-20% tumor diameter @ first reassessment) was significantly more frequent with the addition of panitumumab to m. FOLFOXIRI § Depth of response was significantly greater with the addition of panitumumab to m. FOLFOXIRI = modified 5 -fluorouracil, leucovorin, oxaliplatin, irinotecan.

Modest DP, et al. Tumor dynamics with fluorouracil/folinic acid, irinotecan and oxaliplatin (FOLFOXIRI) plus panitumumab (pmab) or FOLFOXIRI alone as initial treatment of RAS wildtype metastatic colorectal cancer (m. CRC) –central radiologic review of VOLFI: a randomized, open label, phase-2 study (AIO KRK 0109) Conclusions § The addition of panitumumab to m. FOLFOXIRI increases the chance of early and profound shrinkage of RAS wildtype m. CRC § m. FOLFOXIRI plus panitumumab might be a valuable treatment option in fit patients with high tumor load and/or potentially resectable metastatic disease. m. CRC = metastatic colorectal cancer; m. FOLFOXIRI = modified 5 -fluorouracil, leucovorin, oxaliplatin, irinotecan; RAS = rat sarcoma viral oncogene homolog.

Slide intentionally left blank