Abstract
Background
Materials and Methods
Results
Conclusion
Keywords
Abbreviations:
ACT (Appropriate comparative therapy), AE (Adverse event), AESI (Adverse event of special interest), BIRC (Blinded Independent Central Review Committee), BOR (Best overall response), BRAF (V-raf murine sarcoma viral oncogene homolog B1), CEA (Carcinoembryonic antigen), CI (Confidence interval), CRC (Colorectal cancer), CRP (C-reactive protein CTCAE, Common Terminology Criteria for Adverse Events), DOR (Duration of response), ECOG (Eastern Cooperative Oncology Group), EGFR (Epidermal growth factor receptor), EMA (European Medicines Agency), EORTC (European Organisation for Research and Treatment of Cancer), EQ-5D (European Quality of Life 5 Dimensions questionnaire), ESMO (European Society for Medical Oncology), FACT-C (Functional Assessment of Cancer Therapy-Colon cancer), FACT-G (Functional Assessment of Cancer Therapy-General), FOLFIRI (Folinic acid, fluorouracil, and irinotecan), G-BA (German Federal Joint Committee), HRstrat (Stratified hazard ratio), HRunstrat (Unstratified hazard ratio), HTA (Health Technology Assessment), IQWiG (Institute for Quality and Efficiency in Health Care), IRI (Irinotecan), LS (Least square), MAPK (Mitogen-activated protein kinase), mCRC (Metastatic colorectal cancer), MMRM (Mixed model for repeated measures), mOS (Median overall survival), MSI (Microsatellite instability), n.c. (Not calculable), n.r. (Not reached), ORR (Overall response rate), OR (Odds ratio), OS (Overall survival), PCR (Polymerase chain reaction), PFS (Progression free survival), PFS2 (Progression free survival 2), PGIC (Patient Global Impression of Change), PPE (Palmar-plantar erythrodysesthesia), PS (Performance status), REML (Restricted Maximum Likelihood), SAE (Serious adverse event), SOC (System organ class), TFST (Time to first subsequent therapy), TSST (Time to second subsequent therapy), TTR (Time to response), VAS (Visual analog scale)Introduction
World Health Organization – International Agency for Research on Cancer (IARC). All cancers. Available at: https://gco.iarc.fr/today/fact-sheets-cancers. Accessed: May 24, 2021.
World Health Organization – International Agency for Research on Cancer (IARC). Colorectal cancer. Available at: https://gco.iarc.fr/today/fact-sheets-cancers. Accessed: May 24, 2021.
Cancer Research UK Bowel cancer incidence statistics. Available at: https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/bowel-cancer/survival#heading-Zero. Accessed: May 24, 2021.
Cancer Research UK Bowel cancer incidence statistics. Available at: https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/bowel-cancer/incidence#heading-Three. Accessed: February 24, 2021.
American Cancer Society. Available at: https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/colorectal-cancer-facts-and-figures/colorectal-cancer-facts-and-figures-2017-2019.pdf. Accessed: May 24, 2021.
Cancer Research UK Bowel cancer incidence statistics. Available at: https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/bowel-cancer/incidence#heading-Three. Accessed: February 24, 2021.
Merck Sharp & Dohme B.V. KEYTRUDA Summary of Product Information. Available at: https://www.ema.europa.eu/en/documents/product-information/keytruda-epar-product-information_en.pdf. Accessed: August 11, 2021.
Bristol-Myers Squibb Pharma EEIG. OPDIVO Summary of Product Information. Available at: https://www.ema.europa.eu/en/documents/product-information/opdivo-epar-product-information_en.pdf. Accessed: August 11, 2021.
Bristol-Myers Squibb Pharma EEIG. YERVOY Summary of Product Information. Available at: https://www.ema.europa.eu/en/documents/product-information/yervoy-epar-product-information_en.pdf. Accessed: August 11, 2021.
Leitlinienprogramm Onkologie (Deutsche Krebsgesellschaft, Deutsche Krebshilfe, AWMF): S3-Leitlinie Kolorektales Karzinom, Langversion 2.1, 2019, AWMF Registrierungsnummer: 021/007OL. Available at: http://www.leitlinienprogramm-onkologie.de/leitlinien/kolorektales-karzinom/. Accessed: September 29, 2021.
German Federal Joint Committee (G-BA). Overview on Regulatory Documents Concerning the Early Value Asessment of Drugs. Available at: https://www.g-ba.de/downloads/17-98-4977/Fruehe-Nutzenbewertung_Gesetzesauftraege.pdf. Accessed: May 20, 2020.
German Federal Joint Committee (G-BA). Document template “dossier for value assessment according to §53a SGB V – module 4”. 2019-02-21. Available at: https://www.g-ba.de/downloads/17-98-4825/2019-02-21_Anl2_6_Modul4.pdf. Accessed: May 20, 2020.
Institute for Quality and Efficiency in Health Care (IQWiG). General Methods - Version 5.0. Available at: https://www.iqwig.de/download/General-Methods_Version-5-0.pdf. Accessed: October 7, 2020.
Materials and Methods
Statistical Analysis
Results
Characteristic | Encorafenib/Cetuximab (n = 220) | Control (n = 221) |
---|---|---|
Sex, n (%) | ||
Male | 114 (52) | 94 (43) |
Female | 106 (48) | 127 (57) |
Median age (range), years | 61 (30-91) | 60 (27-91) |
ECOG PS, n (%) | ||
0 | 112 (51) | 108 (49) |
1 | 104 (47) | 113 (51) |
2 | 4 (2) | 0 (0) |
Location of primary tumor, n (%) | ||
Left colon (includes rectum) | 83 (38) | 68 (31) |
Right colon | 110 (50) | 119 (54) |
Others | 27 (12) | 34 (15) |
≥ 3 organs involved, n (%) | 103 (47) | 98 (44) |
Presence of liver metastases, n (%) | 134 (61) | 128 (58) |
Primary tumor removed, n (%) | ||
Completely resected | 123 (56) | 122 (55) |
Partially resected or unresected | 97 (44) | 99 (45) |
Prior lines of therapy, n (%) | ||
1 | 146 (66) | 145 (66) |
2 | 74 (34) | 76 (34) |
Prior oxaliplatin, n (%) | 210 (95) | 201 (91) |
MSI-H, n (%) | 19 (9) | 12 (5) |
CEA baseline value > 5 mg/L, n (%) | 153 (70) | 178 (81) |
CRP baseline value > 10 mg/L, n (%) | 79 (36) | 90 (41) |
Parameter | LS-Mean [95% CI] | P-value | Hedges'g [95% CI] |
---|---|---|---|
EORTC QLQ-C30 – functional scale | |||
Global health status | 3.92 [0.26; 7.57] | .036 | 0.23 [0.02; 0.44] |
EORTC QLQ-C30 – symptom scales | |||
Diarrhea | -12.61 [-17.75; -7.47] | <.0001 | -0.53 [-0.74; -0.31] |
Nausea/vomiting | -4.62 [-7.75; -1.48] | .004 | -0.31 [-0.52; -0.11] |
Loss of appetite | -6.72 [-12.07; -1.38] | .014 | -0.27 [-0.48; -0.06] |
Constipation | -5.68 [-10.08; -1.28] | .012 | -0.28 [-0.48; -0.07] |
FACT-G | |||
Global health score | 3.78 [1.05; 6.50] | .007 | 0.29 [0.09; 0.50] |
FACT-C | |||
Physical wellbeing | 1.62 [0.70; 2.54] | <.001 | 0.37 [0.16; 0.58] |
BEACON CRC | Dual Blockade Median Months [95% CI] | Control Treatment Median Months [95% CI] | Dual Blockade vs. Control HRstrat [95% CI]; P-value |
---|---|---|---|
OS | 9.3 [8.0; 11.3] | 5.9 [5.1; 7.1] | 0.61 [0.48; 0.77]; <.0001 |
DOR (BIRC) | 5.6 [4.1; 8.3] | 5.6 [2.6; n.c.] | 1.88 [0.40; 8.96]; .4266 |
TTR (BIRC) | n.c. [n.c.; n.c.] | n.c. [n.c.; n.c.] | 10.46 [3.75; 29.15]; <.0001 |
PFS (BIRC) | 4.3 [4.1; 5.5] | 1.5 [1.5; 1.9] | 0.44 [0.35; 0.55]; <.0001 |
PFS2 | 8.3 [7.7; 9.8] | 5.3 [4.6; 6.2] | 0.62 [0.48; 0.78]; <.0001 |
TFST | 5.6 [4.9; 6.6] | 3.0 [2.5; 3.5] | 0.61 [0.49; 0.75]; <.0001 |
TSST | 8.8 [8.0; 10.3] | 5.1 [4.6; 5.8] | 0.60 [0.48; 0.75]; <.0001 |
BEACON CRC | Dual Blockade Median Time to Onset (Months) [95% CI] % Patients | Control Median Time to Onset (Months) [95% CI] % Patients | Dual Blockade vs. Control HRunstrat [95% CI] P-value |
---|---|---|---|
AEs | |||
SAE | 12.0 [5.9; n.c.] 39.8 | 5.2 [3.2; n.c.] 39.9 | 0.65 [0.47; 0.89] .008 |
AE grade ≥ 3-4 | 4.7 [3.9; 6.4] 57.4 | 1.4 [1.1; 2.1] 64.2 | 0.47 [0.36; 0.62] <.001 |
AE leading to treatment discontinuation | n.r. [17.5; n.c.] 12.0 | n.r. [8.1; n.c.] 17.1 | 0.36 [0.21; 0.63] .0002 |
AESI | |||
AESI: Myopathy | n.r. [15.9; n.r.] 16.7 | n.r. [n.r.; n.r.] 2.6 | 4.84 [1.88; 12.48] .0003 |
AESI: PPE | n.r. [n.r.; n.r.] 5.1 | n.r. [n.r.; n.r.] 7.8 | 0.45 [0.20; 1.00] .0439 |
Frequent SAEs Gastrointestinal | 22.8 [22.8; n.r.] 16.7 | n.r. [n.r.; n.r.] 18.1 | 0.58 [0.36; 0.93] .0233 |
Frequent severe AEs Gastrointestinal | 22.8 [22.8; n.c.] 19.4 | 9.4 [4.4; n.c.] 26.9 | 0.40 [0.26; 0.61] <.0001 |
Selected AEs (ie most frequent in the respective SOC) | |||
SOC Gastrointestinal disorders | 0.7 [0.5; 1,1] 81.5 | 0.2 [0.1; 0.3] 82.9 | 0.64 [0.51; 0.80] <.0001 |
Diarrhea | 10.3 [6.4; 18.8] 38.4 | 2.1 [1.1; n.r.] 48.7 | 0.45 [0.33; 0.62] <.0001 |
SOC Skin and subcutaneous tissue disorders | 0.9 [0.7; 1.2] 75.9 | 0.5 [0.4; 0.6] 73.1 | 0.71 [0.57; 0.90] .0050 |
Dermatitis acneiform | n.c. [13.0; n.c.] 30.1 | n.c. [2.8; n.c.] 39.9 | 0.56 [0.40; 0.78] .0006 |
SOC Blood and lymphatic system disorders | n.c. [12.0; n.c.] 23.1 | n.c. [4.1; n.c.] 34.7 | 0.41 [0.28; 0.61] <.0001 |
Neutropenia | n.c. [n.c.; n.c.] 1.4 | n.c. [n.c.; n.c.] 18.7 | 0.05 [0.01; 0.15] <.0001 |
SOC Nervous system disorders | 7.4 [2.6; n.c.] 49.1 | 9.9 [7.7; n.c.] 23.3 | 2.05 [1.44; 2.92] <.0001 |
Headache | n.c. [n.c.; n.c.] 19.9 | n.c. [n.c.; n.c.] 2.6 | 7.27 [2.87; 18.42] <.0001 |
SOC Musculoskeletal and connective tissue disorders | 4.2 2 ,World Health Organization – International Agency for Research on Cancer (IARC). Colorectal cancer. Available at: https://gco.iarc.fr/today/fact-sheets-cancers. Accessed: May 24, 2021. 8 ; Merck Sharp & Dohme B.V. KEYTRUDA Summary of Product Information. Available at: https://www.ema.europa.eu/en/documents/product-information/keytruda-epar-product-information_en.pdf. Accessed: August 11, 2021. 5 ,American Cancer Society. Available at: https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/colorectal-cancer-facts-and-figures/colorectal-cancer-facts-and-figures-2017-2019.pdf. Accessed: May 24, 2021. 2 56.5World Health Organization – International Agency for Research on Cancer (IARC). Colorectal cancer. Available at: https://gco.iarc.fr/today/fact-sheets-cancers. Accessed: May 24, 2021. | NE [4.9; n.c.] 23.3 | 2.09 [1.48; 2.96]; <.0001 |
Arthralgia | n.c. [n.c.; n.c.] 22.7 | n.c. [13.5; n.c.] 1.6 | 10.16 [3.15; 32.79] <.0001 |
SOC Neoplasms benign, malignant and unspecified (incl. cysts and polyps) | n.c. [10.3; n.c.] 29.6 | n.c. [n.c.; n.c.] 2.6 | 9.03 [3.63; 22.50] <.0001 |
SOC Eye disorders | n.c. [15.6; n.c.] 19.9 | n.c. [11.6; n.c.] 4.7 | 2.93 [1.41; 6.09] .0025 |
Discussion
Leitlinienprogramm Onkologie (Deutsche Krebsgesellschaft, Deutsche Krebshilfe, AWMF): S3-Leitlinie Kolorektales Karzinom, Langversion 2.1, 2019, AWMF Registrierungsnummer: 021/007OL. Available at: http://www.leitlinienprogramm-onkologie.de/leitlinien/kolorektales-karzinom/. Accessed: September 29, 2021.
Pierre Fabre Médicament. BRAFTOVI Summary of Product Information. Available at: https://www.ema.europa.eu/documents/product-information/braftovi-epar-product-information_en.pdf. Accessed: August 24, 2021.
Swissmedic. Swissmedic Journal 12/2020. Available at: https://www.swissmedic.ch/dam/swissmedic/en/dokumente/stab/journal/swissmedic-journal122020.pdf.download.pdf/Swissmedic%20Journal%2012-2020.pdf. Accessed: August 24, 2021.
Federal Joint Committee. Justification to the Resolution of the Federal Joint Committee (G-BA) on an Amendment of the Pharmaceuticals Directive (AM-RL): Annex XII – Benefit Assessment of Medicinal Products with New Active Ingredients According to Section 35a SGB V Encorafenib (New Therapeutic Indication: Metastatic Colorectal Cancer with a BRAF V600E Mutation after Prior Systemic Therapy, in Combination with Cetuximab). Available at: https://www.g-ba.de/bewertungsverfahren/nutzenbewertung/559/#beschluesse. Accessed: August 25, 2021.
Federal Joint Committee. Justification to the Resolution of the Federal Joint Committee (G-BA) on an Amendment of the Pharmaceuticals Directive (AM-RL): Annex XII – Benefit Assessment of Medicinal Products with New Active Ingredients According to Section 35a SGB V Encorafenib (New Therapeutic Indication: Metastatic Colorectal Cancer with a BRAF V600E Mutation after Prior Systemic Therapy, in Combination with Cetuximab). Available at: https://www.g-ba.de/bewertungsverfahren/nutzenbewertung/559/#beschluesse. Accessed: August 25, 2021.
Federal Joint Committee. Justification to the Resolution of the Federal Joint Committee (G-BA) on an Amendment of the Pharmaceuticals Directive (AM-RL): Annex XII – Benefit Assessment of Medicinal Products with New Active Ingredients According to Section 35a SGB V Encorafenib (New Therapeutic Indication: Metastatic Colorectal Cancer with a BRAF V600E Mutation after Prior Systemic Therapy, in Combination with Cetuximab). Available at: https://www.g-ba.de/bewertungsverfahren/nutzenbewertung/559/#beschluesse. Accessed: August 25, 2021.
Federal Joint Committee. Justification to the Resolution of the Federal Joint Committee (G-BA) on an Amendment of the Pharmaceuticals Directive (AM-RL): Annex XII – Benefit Assessment of Medicinal Products with New Active Ingredients According to Section 35a SGB V Encorafenib (New Therapeutic Indication: Metastatic Colorectal Cancer with a BRAF V600E Mutation after Prior Systemic Therapy, in Combination with Cetuximab). Available at: https://www.g-ba.de/bewertungsverfahren/nutzenbewertung/559/#beschluesse. Accessed: August 25, 2021.
Federal Joint Committee. Justification to the Resolution of the Federal Joint Committee (G-BA) on an Amendment of the Pharmaceuticals Directive (AM-RL): Annex XII – Benefit Assessment of Medicinal Products with New Active Ingredients According to Section 35a SGB V Encorafenib (New Therapeutic Indication: Metastatic Colorectal Cancer with a BRAF V600E Mutation after Prior Systemic Therapy, in Combination with Cetuximab). Available at: https://www.g-ba.de/bewertungsverfahren/nutzenbewertung/559/#beschluesse. Accessed: August 25, 2021.
Conclusions
Clinical Practice Points
- •For BRAF V600E mutant metastatic colorectal cancer, encorafenib plus cetuximab is considered the standard of care after any systemic treatment.
- •Within the phase-III BEACON trial, median OS was significantly longer reaching 9.3 (encorafenib + cetuximab) versus 5.9 months (ACT/control) (stratified hazard ratio (HRstrat): 0.61 [95% confidence interval: 0.48-0.77]).
- •The German Health Technology Assessment (HTA) evaluated the BEACON trial with respect to a risk benefit assessment and granted a “hint for a considerable additional benefit,” giving additional reliability of the use of encorafenib plus cetuximab within this patient group.
Compliance With Ethics Guidelines – Ethics Approval and Consent to Participate
Availability of data and materials
Acknowledgments
Declaration of interests
Appendix. Supplementary materials
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