Panitumumab and RAS, Diagnostically-useful Gene Mutation for mCRC

Conditions

Colorectal Cancer

Keywords

Metastatic colorectal cancer, Panitumumab, mFOLFOX6, Bevacizumab

Brief summary

The purpose of this study is to verify the efficacy of mFOLFOX6 + panitumumab combination therapy and mFOLFOX6 + bevacizumab combination therapy in first-line treatment of chemotherapy-naive patients with KRAS/NRAS wild-type, incurable/unresectable, advanced/recurrent colorectal cancer.

Detailed description

The purpose of this study is to verify the efficacy of mFOLFOX6 + panitumumab combination therapy and mFOLFOX6 + bevacizumab combination therapy in first-line treatment of chemotherapy-naive patients with KRAS/NRAS wild-type, incurable/unresectable, advanced/recurrent colorectal cancer. This study will enroll a total of approximately 800 participants (400 per group). Participants will be randomized to either the mFOLFOX6 + panitumumab arm (Group P) or mFOLFOX6 + bevacizumab arm (Group B) at 1:1 ratio at the time of registration. Group P and Group B treatment regimen shown below should be administered once every two weeks, following dose, schedule and route of administration. Group P; mFOLFOX6 + panitumumab combination therapy, once every two weeks OXA: 85 mg/m2/day 1 l-LV: 200 mg/m2/day 1 5-FU iv: 400 mg/m2/day 1 5-FU civ: 2400 mg/m2/day 1-3 panitumumab: 6 mg/kg Group B; mFOLFOX6 + bevacizumab combination therapy, once every two weeks OXA: 85 mg/m2/day 1 l-LV: 200 mg/m2/day 1 5-FU iv: 400 mg/m2/day 1 5-FU civ: 2400 mg/m2/day 1-3 bevacizumab: 5 mg/kg This trial is conducted by multicenter and is scheduled for 12 months as whole administration period.

Kentaro Yamazaki, Riu Yamashita, Takayuki Yoshino, Kohei Shitara, Jun Watanabe et al. (19 authors)

Journal of Clinical Oncology2026-05-27

10.1200/jco.2026.44.16_suppl.3573

Acquired gene alteration patterns and post-progression survival: PARADIGM study analysis.

Hiroyuki Uetake, Riu Yamashita, Kohei Shitara, Takayuki Yoshino, Jun Watanabe et al. (20 authors)

Journal of Clinical Oncology2024-06-013 citations

10.1200/jco.2024.42.16_suppl.3507

Abstract 5844: Landscapes of acquired EGFR and VEGF resistance alterations in colorectal cancer: findings from the PARADIGM biomarker study

Katsuya Tsuchihara, Riu Yamashita, Takayuki Yoshino, Kohei Shitara, Jun Watanabe et al. (24 authors)

Cancer Research2024-03-22

10.1158/1538-7445.am2024-5844

Baseline ctDNA gene alterations as a biomarker of survival after panitumumab and chemotherapy in metastatic colorectal cancer

Kohei Shitara, Kei Muro, Jun Watanabe, Kentaro Yamazaki, Hisatsugu Ohori et al. (31 authors)

Nature Medicine2024-02-1285 citations

10.1038/s41591-023-02791-w

First-line (1L) panitumumab (PAN) vs bevacizumab (BEV) in patients (pts) with HER2 amplification (HER2amp+), RAS wild type (WT) metastatic colorectal cancer (mCRC) according to tumor sidedness.

Eiji Oki, Kei Muro, Jun Watanabe, Kohei Shitara, Kentaro Yamazaki et al. (20 authors)

JCO Global Oncology2023-08-01

10.1200/go.2023.9.supplement_1.53

Efficacy of panitumumab in patients with left-sided disease, MSS/MSI-L, and RAS/BRAF WT: A biomarker study of the phase III PARADIGM trial.

Kentaro Yamazaki, Kei Muro, Jun Watanabe, Kohei Shitara, Hisatsugu Ohori et al. (20 authors)

Journal of Clinical Oncology2023-06-014 citations

10.1200/jco.2023.41.16_suppl.3508

Panitumumab vs Bevacizumab Added to Standard First-line Chemotherapy and Overall Survival Among Patients With RAS Wild-type, Left-Sided Metastatic Colorectal Cancer

Jun Watanabe, Kei Muro, Kohei Shitara, Kentaro Yamazaki, Manabu Shiozawa et al. (28 authors)

JAMA2023-04-18219 citations

10.1001/jama.2023.4428

Panitumumab (PAN) plus mFOLFOX6 versus bevacizumab (BEV) plus mFOLFOX6 as first-line treatment in patients with RAS wild-type (WT) metastatic colorectal cancer (mCRC): Results from the phase 3 PARADIGM trial.

Takayuki Yoshino, Jun Watanabe, Kohei Shitara, Hirofumi Yasui, Hisatsugu Ohori et al. (20 authors)

Journal of Clinical Oncology2022-06-0866 citations

10.1200/jco.2022.40.17_suppl.lba1

Rationale for and Design of the PARADIGM Study: Randomized Phase III Study of mFOLFOX6 Plus Bevacizumab or Panitumumab in Chemotherapy-naïve Patients With RAS (KRAS/NRAS) Wild-type, Metastatic Colorectal Cancer

Takayuki Yoshino, Hiroyuki Uetake, Katsuya Tsuchihara, Kohei Shitara, Kentaro Yamazaki et al. (17 authors)

Clinical Colorectal Cancer2017-01-2412 citations

10.1016/j.clcc.2017.01.001

PARADIGM study: A multicenter, randomized, phase III study of mFOLFOX6 plus panitumumab or bevacizumab as first-line treatment in patients with RAS (KRAS/NRAS) wild-type metastatic colorectal cancer.

Kei Muro, Hiroyuki Uetake, Katsuya Tsuchihara, Kohei Shitara, Kentaro Yamazaki et al. (16 authors)

Journal of Clinical Oncology2016-05-203 citations

10.1200/jco.2016.34.15_suppl.tps3625

PARADIGM study: A multicenter, randomized, phase III study of 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) plus panitumumab or bevacizumab as first-line treatment in patients with RAS (KRAS/NRAS) wild-type metastatic colorectal cancer.

Takayuki Yoshino, Hiroyuki Uetake, Katsuya Tsuchihara, Kohei Shitara, Kentaro Yamazaki et al. (16 authors)

Journal of Clinical Oncology2016-02-015 citations

10.1200/jco.2016.34.4_suppl.tps776

Interventions

DRUGoxaliplatin (OXA), levofolinate calcium (l-LV), 5-FU, panitumumab

oxaliplatin (OXA), levofolinate calcium (l-LV), panitumumab: intra-venous infusion 5-FU: bolus and continuous intra-venous infusion

DRUGoxaliplatin (OXA), levofolinate calcium (l-LV), 5-FU, bevacizumab

oxaliplatin (OXA), levofolinate calcium (l-LV), bevacizumab: intra-venous infusion 5-FU: bolus and continuous intra-venous infusion

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

20 Years to 79 Years

Healthy volunteers

No

Inclusion criteria

1. Investigator and subinvestigator judge a candidate is understand clinical trial and comply this protocol. Investigator is those who participate in conducting a study and oversight the study duties at a site. 2. Patients who have given written consent to take part in the study after detailed explanation of the study prior to enrollment 3. Aged ≥20 to \<80 years at the time of informed consent 4. Patients with unresectable adenocarcinoma originating in the large intestine (excluding carcinoma of the appendix and anal canal cancer) 5. Patients with lesion(s) that can be evaluated. It is not essential to be evaluated the tumor according to the RECIST ver. 1.1. 6. Patients who have not received chemotherapy for colorectal cancer. Patients who experience relapse more than 24 weeks (168 days) after the final dose of perioperative adjuvant chemotherapy with fluoropyrimidine agents may be enrolled. Patients who have received perioperative adjuvant chemotherapy including oxaliplatin are excluded. 7. Patients classified as KRAS/NRAS wild-type by KRAS/NRAS testing. KRAS/NRAS test will be performed using the in vitro diagnostic listed in the National Health Insurance. Patients with no mutation in any of the codons shown below are considered wild type. It is not considered wild type if either of the codons are not evaluable or not tested. KRAS: EXON2 (codon 12, 13), EXON3 (codon 59, 61), EXON4 (codon 117, 146) NRAS：EXON2 (codon 12, 13), EXON3 (codon 59, 61), EXON4 (codon 117, 146) 8. Patients who satisfy the following criteria for the major organ function in tests performed within 14 days prior to enrollment * Neutrophil count ≥ 1.5×10\^3/µL * Platelet count ≥ 1.0×10\^4/µL * Hemoglobin ≥ 9.0 g/dL * Total bilirubin ≤ 2.0 mg/dL * AST ≤ 100 IU/L (≤ 200 IU/L if liver metastases are present) * ALT ≤ 100 IU/L (≤ 200 IU/L if liver metastases are present) * Serum creatinine ≤ 1.5 mg/dL * PT-INR \< 1.5 (\< 3.0 for patients treated with oral warfarin) * Satisfies at least one of these conditions 1. Urine protein (dip stick method) ≤ 1+ 2. UPC (urine protein creatinine) ratio ≤ 1.0 3. Urinary protein ≤ 1000 mg/ 24hours 9. ECOG performance status (PS) of 0 or 1 10. Life expectancy of ≥ 3 months (90 days) after enrollment

Exclusion criteria

1. Radiotherapy received within 4 weeks (28 days) prior to enrollment. Treatments aimed at relieving pain for bone metastases are excluded. 2. Known brain metastasis or strongly suspected of brain metastasis 3. Synchronous cancers or metachronous cancers with a disease-free period of ≤ 5 years (excluding colorectal cancer) excluding mucosal cancers cured or be possibly cured by regional resection (esophageal, stomach, and cervical cancer, non-melanoma skin cancer, bladder cancer, etc.). 4. Body cavity fluid that requires treatment (pleural effusion, ascites, pericardial effusion, etc.) 5. Patients who do not want to use contraception to prevent pregnancy, and women who are pregnant or breast-feeding, or test positive for pregnancy 6. Nonhealing surgical wound (excluding implanted venous reservoirs) 7. Active hemorrhage requiring blood transfusion 8. Disease requiring systemic steroids for treatment (excluding topical steroids) 9. The patient who has placed colonic stent 10. Intestinal resection within 4 weeks prior to enrollment or colostomy within 2 weeks prior to enrollmentt 11. History or obvious and extensive CT findings of interstitial pulmonary disease (interstitial pneumonia, pulmonary fibrosis, etc.) 12. Patients with unstable angina, myocardial infarction, cerebral hemorrhage, arterial thromboembolism such as cerebral infarction, or have history of these desease less than 24 weeks (168 days) before registration (except for lacunar infarction asymptomatic) 13. Serious drug hypersensitivity 14. Local or systemic active infection requiring treatment, or fever indicating infection 15. NYHA class II or higher heart failure or serious heart disease 16. Intestinal paralysis, gastrointestinal obstruction, or uncontrollable diarrhoea (incapacitating symptoms despite adequate treatment) 17. Poorly controlled hypertension 18. Poorly controlled diabetes mellitus 19. Active hepatitis B 20. Known HIV infection 21. Peripheral neuropathy of ≥ Grade 2 by CTCAE (Japanese edition JCOG version 4.03) 22. Other patients judged by the investigator or subinvestigator to be ineligible for enrollment in the study (e.g. Patients who might agree to participate under compulsion).

Design outcomes

Primary

Measure	Time frame	Description
OS in Participants With Left-sided Tumors	Up to approximately 60 months	OS was measured as the time from the date of randomization to the date of death due to any cause. The left-sided tumors were defined as primary tumors occupying a left-sided site include the descending colon, sigmoid colon, and rectum.
Overall Survival (OS) in All Participants	Up to approximately 60 months	OS was measured as the time from the date of randomization to the date of death due to any cause.

Secondary

Measure	Time frame	Description
Response Rate (RR) in All Participants	Up to approximately 60 months	RR was defined as number of participants who achieve Complete Response (CR) and Partial Response (PR) as the best overall response per RECIST version 1.1.The best overall response was CR, followed by PR, stable disease (SD), progressive disease (PD), and not evaluable (NE). CR: disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to \<10 mm. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters as the best overall response after randomization., SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study).
Duration of Response (DOR)	Up to approximately 60 months	DOR means that the period from the day when either CR or PR is first confirmed until the day of documented PD or the day of death due to all causes, whichever occurs earlier.
Progression-Free Survival (PFS) in Participants With Left-sided Tumors	Up to approximately 60 months	PFS was defined as the time from the date of randomization to the earlier of Progressive Disease (PD) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 or death due to any cause. The left-sided tumors were defined as primary tumors occupying a left-sided site include the descending colon, sigmoid colon, and rectum.
Number of Participants With Treatment-emergent Adverse Events (TEAE)	Up to approximately 60 months	Adverse event (AE) was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have a causal relationship with this treatment. A TEAE was defined as an adverse event with an onset that occurred in the treatment period after receiving the protocol treatment.
Number of Participants Treated With Curative Surgical Resection After Chemotherapy	Up to approximately 60 months	Curative surgical resection was defined as complete resection.
Progression-Free Survival (PFS) in All Participants	Up to approximately 60 months	PFS was defined as the time from the date of randomization to the earlier of Progressive Disease (PD) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 or death due to any cause.

Countries

Japan

Participant flow

Recruitment details

Participants took part in the study at 197 investigative sites in Japan from 29 May 2015 to 14 January 2022.

Pre-assignment details

Participants with KRAS/NRAS wild-type, incurable/unresectable, advanced/recurrent colorectal cancer were enrolled and randomized to either the mFOLFOX6 + panitumumab arm (Group P) or mFOLFOX6 + bevacizumab arm (Group B) at 1:1 ratio.

Participants by arm

Arm	Count
Group P; mFOLFOX6 + Panitumumab Combination Therapy OXA: 85 mg/m2/day 1 l-LV: 200 mg/m2/day 1 5-FU iv: 400 mg/m2/day 1 5-FU civ: 2400 mg/m2/day 1-3 panitumumab: 6 mg/kg mFOLFOX6 + panitumumab combination therapy, once every two weeks.	400
Group B; mFOLFOX6 + Bevacizumab Combination Therapy OXA: 85 mg/m2/day 1 l-LV: 200 mg/m2/day 1 5-FU iv: 400 mg/m2/day 1 5-FU civ: 2400 mg/m2/day 1-3 bevacizumab: 5 mg/kg/ mFOLFOX6 + bevacizumab combination therapy, once every two weeks.	402
Total	802

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	92	70
Overall Study	Death	4	5
Overall Study	Lack of Efficacy	181	211
Overall Study	Lost to Follow-up	0	1
Overall Study	Physician Decision	109	93
Overall Study	Withdrawal by Subject	17	26

Baseline characteristics

Characteristic	Group P; mFOLFOX6 + Panitumumab Combination Therapy	Group B; mFOLFOX6 + Bevacizumab Combination Therapy	Total
Age, Customized 64 years old or less	164 Participants	168 Participants	332 Participants
Age, Customized 65 years old or over	236 Participants	234 Participants	470 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0	328 Participants	319 Participants	647 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 1	71 Participants	83 Participants	154 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 2	1 Participants	0 Participants	1 Participants
Medical Complications Had Medical Complications	238 Participants	243 Participants	481 Participants
Medical Complications Had No Medical Complications	162 Participants	159 Participants	321 Participants
Medical History Had Medical History	314 Participants	324 Participants	638 Participants
Medical History Had No Medical History	86 Participants	78 Participants	164 Participants
Number of Participants with Primary Tumor Categorized by Location Left side	312 Participants	292 Participants	604 Participants
Number of Participants with Primary Tumor Categorized by Location Other	4 Participants	7 Participants	11 Participants
Number of Participants with Primary Tumor Categorized by Location Right side	84 Participants	103 Participants	187 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	400 Participants	402 Participants	802 Participants
Race (NIH/OMB) Black or African American	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	0 Participants	0 Participants	0 Participants
Region of Enrollment Japan	400 Participants	402 Participants	802 Participants
Sex: Female, Male Female	148 Participants	134 Participants	282 Participants
Sex: Female, Male Male	252 Participants	268 Participants	520 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	14 / 404	9 / 407
other Total, other adverse events	399 / 404	392 / 407
serious Total, serious adverse events	115 / 404	95 / 407

Outcome results

Primary

OS in Participants With Left-sided Tumors

OS was measured as the time from the date of randomization to the date of death due to any cause. The left-sided tumors were defined as primary tumors occupying a left-sided site include the descending colon, sigmoid colon, and rectum.