Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Amivantamab · 15 trials · 5 indications
OS is defined as time from the date of randomization to the date of death due to any cause.
ORR is defined as the percentage of randomized participants achieving a confirmed best overall response (BOR) of partial response (PR) or complete response (CR) by BICR using RECIST version 1.1 .
PFS is defined as the time from randomization until the date of objective disease progression or death (due to any cause), whichever comes first, as assessed by BICR using response evaluation criteria in solid tumors (RECIST) version (v)1.1. Participants who have not progressed or have not died at the time of analysis will be censored at their last evaluable RECIST v1.1 assessment date.
PFS was defined as the time from randomization until the date of objective disease progression based on BICR using RECIST version 1.1 or death (by any cause) in the absence of progression, whichever came first. Participants who have not progressed or have not died at the time of analysis were censored at the time of the latest date of their last evaluable RECIST version 1.1 assessment. Pharmacodynamic: Sum of diameters increased by greater than or equal to (\>=)20 percent (%) and \>=5 millimeter (mm) from nadir (including baseline if it was smallest sum).
MPR is defined as less than or equal to (\<= ) 10 percent (%) residual cancer cells in the surgical specimen, per independent centralized pathology review.
PFS is defined as the time from the date of first dose of any study treatment until the date of objective disease progression or death, whichever occurs first according to response evaluation criteria in solid tumors (RECIST) version (v) 1.1 as assessed by the investigator.
Number of participants with Grade \>= 2 DAEIs within 12 weeks after initiation of anticancer treatment based on National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE) Version (v) 5.0 will be reported. DAEIs includes rash, dermatitis acneiform, pruritus, skin fissures, acne, folliculitis, erythema, eczema, rash maculo-papular, skin exfoliation, skin lesion, skin irritation, dermatitis, rash erythematous, rash macular, rash popular, rash pruritic, rash pustular, dermatitis contact, dermatitis exfoliative generalized, drug eruption, dyshidrotic eczema, eczema asteatotic and paronychia. As per NCI CTCAE v 5.0, severity scale ranges from Grade 1 (mild) to Grade 5 (death). Grade 1= mild, Grade 2= moderate, Grade 3= severe, Grade 4= life-threatening, and Grade 5= death related to adverse event.
Percentage of participants with IRRs at Cycle 1 Day 1 was reported. IRRs were defined as IRR events with onset time within 24 hours of the start of the first amivantamab infusion and prior to the start of amivantamab infusion on Cycle 1 Day 2. IRR included chills, dyspnea, flushing, nausea, chest discomfort, vomiting, tachycardia, hypotension, and fever. IRRs that occurred on Cycle 1 Day 2 pre-infusion were considered under Cycle 1 Day 1.
ORR based on INV will be reported. ORR is defined as the percentage of participants who achieve a complete response (CR) or partial response (PR), based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as determined by investigator.
An AE is any untoward medical occurrence in a participant participating in a clinical study that does not necessarily have a causal relationship with the pharmaceutical/ biological agent under study.
An AE is any untoward medical occurrence in a participant participating in a clinical study that does not necessarily have a causal relationship with the pharmaceutical/ biological agent under study. Severity of AEs will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. Severity scale ranges from Grade 1 (Mild) to Grade 5 (Death). Grade 1= Mild, Grade 2= Moderate, Grade 3= Severe, Grade 4= Life-threatening and Grade 5= Death related to adverse event.
Number of participants with abnormalities in clinical laboratory values (which includes serum chemistry, hematology, coagulation, urinalysis, and serology) will be reported.
Number of participants with laboratory values abnormalities which includes serum chemistry, hematology, coagulation, urinalysis, and serology) by severity will be reported. Severity of laboratory values abnormalities will be graded according to the NCI-CTCAE version 5.0. Severity scale ranges from Grade 1 (Mild) to Grade 5 (Death). Grade 1= Mild, Grade 2= Moderate, Grade 3= Severe, Grade 4= Life-threatening and Grade 5= Death related to adverse event.
An AE is any untoward medical occurrence in a clinical study participant administered a pharmaceutical (investigational or non-investigational) product. An AE does not necessarily have a causal relationship with the treatment. An assessment of severity grade will be made by the investigator according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 defined as follows: Grade 1 (mild; asymptomatic or mild symptoms; intervention not indicated); Grade 2 (moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living \[ADL\]); Grade 3 (severe or medically significant but not immediately life threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL); Grade 4 (life-threatening consequences; urgent intervention indicated); Grade 5 (Death related to adverse event).
DLT is defined as drug related adverse events and includes unacceptable non-hematologic toxicity, hematologic toxicity, pulmonary toxicity, or elevations in hepatic enzymes suggestive of drug-induced liver injury of Grade 3 or higher. Toxicities will be graded for severity according to the NCI-CTCAE, version 5.0.
ORR is defined as the percentage of participants who achieve either a confirmed partial response (PR) or complete response (CR), using Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 by investigator review. Confirmatory analysis may be performed using Blinded Independent Central Review (BICR).
DLTs are specific adverse events and are defined as any of following: Any high grade (Grade 3, 4 or 5) non-hematologic toxicity with exceptions such as: Grade 3 fever resolved in \<=48 hours, anorexia; Grade 3 nausea, vomiting or diarrhea, or constipation Grade 3 fatigue; rash that improves to Grade \<; transient electrolyte abnormalities; symptoms of IRRs that are attributable to amivantamab or docetaxel; Tumor flare; hematologic toxicity (Grade 4 anemia or neutropenia, Febrile neutropenia; Grade 3 or 4 thrombocytopenia associated with bleeding or requiring transfusion); pulmonary toxicity (confirmed any grade pulmonary toxicity, including pneumonitis or interstitial lung disease \[ILD\]), liver enzyme elevation (ALT or AST elevation\>=Grade 3 persisting \>=7 days); or treatment delay greater than (\>) 28 days due to unresolved toxicity.
ORR is defined as the percentage of participants who achieve either a confirmed partial response (PR) or complete response (CR), using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
ORR is defined as the proportion of participants who achieve either a partial response (PR) or complete response (CR), as defined by investigator assessment using Response Criteria in Solid Tumors (RECIST) version 1.1.
Number of participants with DLTs will be reported. A DLT is defined as any of the following: treatment delay of greater than (\>) 28 days due to unresolved toxicity, non-hematologic toxicity of Grade 3 or higher, hematologic toxicity of Grade 4 neutropenia persisting for \>7 days or Grade 3 or higher thrombocytopenia with clinically significant bleeding or neutropenic fever of any grade, and liver enzyme elevation.
An AE is any untoward medical occurrence in a participant participating in a clinical study that does not necessarily have a causal relationship with the pharmaceutical/ biological agent under study. TEAEs are defined as AEs with onset or worsening on or after date of first dose of study treatment. Severity of TEAEs will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. Severity scale ranges from Grade 1 (mild) to Grade 5 (death). Grade 1= mild, Grade 2= moderate, Grade 3= severe, Grade 4= life-threatening, and Grade 5= death related to adverse event.
The participants who achieve MPR at the time of surgery.
ORR is defined as the percentage of participants who achieve either a partial response (PR) or complete response (CR), as defined by investigator assessment using Response Criteria in Solid Tumors (RECIST) version 1.1.
Number of participants with DLT will be assessed. The DLTs are specific adverse events and are defined as any of the following: high grade non-hematologic toxicity, or hematologic toxicity.
Number of participants with DLT by severity will be assessed. The DLTs are specific adverse events and are defined as any of the following: high grade non-hematologic toxicity, or hematologic toxicity. Toxicities will be graded for severity according to the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0, graded as Grade 1: mild, Grade 2: moderate, Grade 3: severe, Grade 4: life-threatening, and Grade 5: death related to adverse event.
An AE is any untoward medical occurrence in a participant participating in a clinical study that does not necessarily have a causal relationship with the pharmaceutical/ biological agent under study. Severity of AEs will be graded according to the NCI CTCAE version 5.0. Severity scale ranges from Grade 1 (Mild) to Grade 5 (Death). Grade 1: mild, Grade 2: moderate, Grade 3: severe, Grade 4: life-threatening and Grade 5: death related to adverse event.
Number of participants with laboratory values abnormalities, which includes serum chemistry, hematology, coagulation, and urinalysis, will be reported.
Number of participants with vital signs including temperature, heart rate, respiratory rate, and blood pressure (systolic and diastolic) and oxygen saturation, abnormalities will be reported.
An AE is any untoward medical occurrence in a participant taking part in a in a clinical study that does not necessarily have a causal relationship with the pharmaceutical/ biological agent under study. Severity of AEs will be graded according to the NCI-CTCAE version 5.0. Severity scale ranges from Grade 1 (Mild) to Grade 5 (Death). Grade 1: mild, Grade 2: moderate, Grade 3: severe, Grade 4: life-threatening and Grade 5: death related to adverse event.
Number of participants with laboratory values abnormalities, which includes serum chemistry, hematology, coagulation, and urinalysis, will be reported.
Number of participants with vital signs including temperature, heart rate, respiratory rate, and blood pressure (systolic and diastolic) and oxygen saturation, abnormalities will be reported.
The Dose Limiting Toxicity (DLT) is based on drug related adverse events and includes unacceptable hematologic toxicity, non-hematologic toxicity of Grade 3 or higher, or elevations in hepatic enzymes suggestive of drug-induced liver injury.
An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.
Overall response rate (ORR) is defined as the percentage of participants who achieve either a CR or PR as per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1). CR: disappearance of all target lesions and non-target lesions. All lymph nodes must be non-pathological in size (\< 10 mm short axis) and normalisation of tumour marker levels; PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters and Persistence of one or more non-target lesion(s) and/or maintenance of tumour marker level above the normal limits.
DOR will be calculated as time from initial response of CR (disappearance of all target lesions and non-target lesions. All lymph nodes must be non-pathological in size (\[\<\] 10 \[mm\] short axis) and normalisation of tumour marker levels) or PR (at least a 30 \[%\] decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters and persistence of one or more non-target lesion(s) and/or maintenance of tumour marker level above the normal limits or durable stable disease (neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum diameters while on study and persistence of one or more non-target lesion(s) and/or maintenance of tumour marker level above the normal limits) to progressive disease (PD) or death due to underlying disease, whichever comes first, only for participants who achieve CR or PR.
Clinical benefit rate is defined as the percentage of participants achieving complete response (CR): disappearance of all target lesions and non-target lesions. All lymph nodes must be non-pathological in size (less than \[\<\] 10 millimeter \[mm\] short axis) and normalisation of tumour marker levels or partial response (PR): at least a 30 percent (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters and persistence of one or more non-target lesion(s) and/or maintenance of tumour marker level above the normal limits or durable stable disease (neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum diameters while on study and persistence of one or more non-target lesion(s) and/or maintenance of tumour marker level above the normal limits.
Ctrough is the observed serum concentration immediately prior to the next administration.
The AUCtau is the area under the serum concentration-time curve during a dose interval time period (tau)
| Arm | Type | Description |
|---|---|---|
| Arm A: Pembrolizumab, Amivantamab, Carboplatin | EXPERIMENTAL | Participants will receive pembrolizumab, amivantamab and carboplatin. |
| Arm B: Pembrolizumab, 5-Flurouracil (5-FU), Carboplatin or Cisplatin | ACTIVE_COMPARATOR | Participants will receive pembrolizumab, 5-FU and carboplatin or cisplatin (platinum therapy). |
| Arm A: Amivantamab + FOLFIRI | EXPERIMENTAL | Participants will receive amivantamab along with FOLFIRI (consisting of 5-fluorouracil, leucovorin calcium \[folinic acid\] or levoleucovorin, and irinotecan) as a chemotherapy regimen for 28-days treatment cycles and will continue to receive the treatment until radiographic disease progression or other discontinuation criteria are met. |
| Arm B: Cetuximab or Bevacizumab + FOLFIRI | ACTIVE_COMPARATOR | Participants will receive either cetuximab or bevacizumab along with FOLFIRI as a chemotherapy regimen for 28-days treatment cycles and will continue to receive the treatment until radiographic disease progression or other discontinuation criteria are met. |
| Arm A: Amivantamab in Combination With Chemotherapy | EXPERIMENTAL | Participants will receive amivantamab in combination with chemotherapy (mFOLFOX6 \[chemotherapy consisting of 5-fluorouracil, leucovorin calcium (folinic acid) or levoleucovorin, and oxaliplatin\] or FOLFIRI \[chemotherapy consisting of 5-fluorouracil, leucovorin calcium (folinic acid) or levoleucovorin, and irinotecan hydrochloride\]) for 28-days treatment cycles and will continue to receive the treatment until radiographic disease progression or other discontinuation criteria are met. |
| Arm B: Cetuximab in Combination With Chemotherapy | ACTIVE_COMPARATOR | Participants will receive cetuximab in combination with chemotherapy (mFOLFOX6 or FOLFIRI) for 28-days treatment cycles and will continue to receive the treatment until radiographic disease progression or other discontinuation criteria are met. |
| Arm A: Amivantamab + Chemotherapy | EXPERIMENTAL | Participants will receive pemetrexed 500 milligram per meter square (mg/m\^2) intravenous (IV) infusion (with vitamin supplementation) on Day 1 of each 21-day cycle, in combination with carboplatin for up to 4 cycles, and then as maintenance monotherapy until disease progression. Carboplatin area under the concentration-time curve 5 milligram per milliliter (mg/mL) per minute (AUC 5) will be administered as IV infusion on Day 1 of each 21 day cycle, for up to 4 cycles. Participants will receive amivantamab 1400 mg (1750 mg if body weight is \>=80 kilogram \[kg\]) by IV infusion once weekly up to Cycle 2 Day 1, then 1750 mg (2100 mg if body weight is \>=80 kg) on Day 1 of each 21-day cycle, starting with Cycle 3. Following the primary analysis for efficacy, the study will transition to an OLE phase and participants will continue to receive the amivantamab plus chemotherapy in OLE phase. Participants who completed OLE period will enter LTE period and continue to receive same treatment. |
| Arm B: Chemotherapy Alone | EXPERIMENTAL | Participants will receive pemetrexed 500 mg/m\^2 IV infusion (with vitamin supplementation) on Day 1 of each 21-day cycle, in combination with carboplatin for up to 4 cycles, and then as maintenance monotherapy until disease progression. Carboplatin AUC 5 IV infusion will be administered on Day 1 of each 21-day cycle for up to 4 cycles. Following the primary analysis for efficacy, the study will transition to an OLE phase and participants will either continue to receive the chemotherapy or cross over to amivantamab in OLE phase. Participants who completed OLE period will enter LTE period and continue to receive same treatment. |
| Treatment Arm A (Open-label): Amivantamab and Lazertinib | EXPERIMENTAL | Participants will receive amivantamab 1050 milligram (mg) intravenously (IV) for body weight less than (\<) 80 kilogram (kg) and 1400 mg for body weight greater than or equal to (\>=) 80 kg in 28-day cycles: once weekly in Cycle 1 (with a split dose on Days 1-2), and then every 2 weeks in subsequent cycles. Lazertinib will be administered 240 mg (80\*3) orally once daily. |
| Treatment Arm B (Double-blind): Osimertinib+Placebo Lazertinib | ACTIVE_COMPARATOR | Participants will receive osimertinib 80 mg orally once daily plus matching placebo of lazertinib 240 mg (80\*3) orally once daily. |
| Treatment Arm C (Double-blind): Lazertinib+Placebo Osimertinib | EXPERIMENTAL | Participants will receive lazertinib 240 mg (80\*3) orally once daily plus matching placebo of osimertinib 80 mg orally once daily. |
| Cohort 1: Amivantamab plus Lazertinib | EXPERIMENTAL | Participants will receive amivantamab in combination with lazertinib. |
| Cohort 2: Amivantamab plus Carboplatin and Pemetrexed | EXPERIMENTAL | Participants will receive amivantamab in combination with carboplatin and pemetrexed. |
| Cohort 1: Amivantamab and Lazertinib | EXPERIMENTAL | Participants will receive Amivantamab in combination with Lazertinib orally in 28-day cycles until disease progression, withdrawal of consent, death, or the investigator decides to discontinue treatment, whichever comes first. |
| Cohort 2: Amivantamab and Chemotherapy | EXPERIMENTAL | Participants will receive Amivantamab in combination with chemotherapy (carboplatin and pemetrexed) intravenous (IV) infusion in 21-day cycles until disease progression, withdrawal of consent, death, or the investigator decides to discontinue treatment, whichever comes first. |
| Arm A: Enhanced Dermatologic Management | EXPERIMENTAL | Participants will receive enhanced dermatologic management to reduce toxicities in skin and nail with doxycycline tablet or minocycline capsule, clindamycin topical lotion, chlorhexidine topical solution, and noncomedogenic skin moisturizer during background anticancer treatment of advanced or metastatic epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) with amivantamab intravenously (Dose 1 for body weight \[BW\] less than 80 kilograms \[kg\] and Dose 2 for BW greater than or equal to \[\>=\] 80 kg as IV infusion \[Arm A\]) until documented disease progression using Response Evaluation Criteria in Solid Tumors version 1.1). |
| Arm B: Standard-of-Care Dermatologic Management | ACTIVE_COMPARATOR | Participants will receive standard care for dermatologic management according to local practice to reduce dermatologic toxicities in skin and nail during background anticancer treatment of advanced or metastatic EGFR-mutated NSCLC with amivantamab administered as IV infusion plus lazertinib, dose and dosing schedule as same as experimental arm. |
| Sub-study: Cohort A: Ruxolitinib | EXPERIMENTAL | Participants enrolled in Arms A and B of the main study who experience new-onset or persistent specific DAEIs (Grade greater than or equal to \[\>=\] 2, as defined by National Cancer Institute Common Terminology Criteria for Adverse Events \[NCI-CTCAE\] v5.0) will be enrolled and receive reactive treatment with ruxolitinib in the sub-study. Participants in the sub-study will continue to receive amivantamab and lazertinib. |
| Sub-study: Cohort B: Tacrolimus | EXPERIMENTAL | Participants enrolled in Arms A and B of the main study who experience new-onset or persistent specific DAEIs (Grade \>= 2, as defined by NCI-CTCAE v5.0) will be enrolled and receive reactive treatment with tacrolimus in the sub-study. Participants in the sub-study will continue to receive amivantamab and lazertinib. |
| Amivantamab Subcutaneous (SC) Expansion Cohort: Standard Schedule | EXPERIMENTAL | Participants will receive modified enhanced dermatologic management with oral doxycycline or minocycline, zinc gluconate and noncomedogenic skin moisturizer during background anticancer treatment of advanced or metastatic EGFR mutated NSCLC with amivantamab SC and lazertinib as per standard schedule. If a participant develops a dermatologic adverse event of interest (DAEI) they will receive early intervention as follows: for facial (ruxolitinib), for scalp (oral propranolol and clobetasol), for paronychia (chlorhexidine in addition to timolol) until documented disease progression using Response Evaluation Criteria in Solid Tumors version 1.1. |
| Amivantamab SC Expansion Cohort: Modified Schedule | EXPERIMENTAL | Participants will receive modified enhanced dermatologic management with oral doxycycline or minocycline, zinc gluconate and noncomedogenic skin moisturizer during background anticancer treatment of advanced or metastatic EGFR mutated NSCLC with amivantamab SC and lazertinib as per modified schedule. If a participant develops a DAEI they will receive early intervention as follows: for facial (ruxolitinib), for scalp (oral propranolol and clobetasol), for paronychia (chlorhexidine in addition to timolol) until documented disease progression using Response Evaluation Criteria in Solid Tumors version 1.1. |
| Background Anti-cancer Therapy with Amivantamab Plus Lazertinib | EXPERIMENTAL | Participant will receive following treatments in 4 different cohorts prior to administration of combination therapy of IV Amivantamab and oral Lazertinib (anti-cancer regimen): dexamethasone dose-1 in Cohort A; dexamethasone dose-2 in Cohort A2; montelukast in Cohort B; and methotrexate in Cohort C. |
| Cohort 1(Exon19del/Exon21 L858R NSCLC, 1L, Previously Untreated): Amivantamab (Q2W) + Lazertinib | EXPERIMENTAL | Participants with treatment-naive locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring an epidermal growth factor receptor (EGFR) exon 19 deletion (exon19del) or exon 21 leucine 858 to arginine substitution (exon 21 L858R) mutation, will receive amivantamab SC-CF injection, 1600 milligrams (mg) or 2240 mg if body weight is greater than or equal to (\>=) 80 kilograms (kg), on Cycle 1 Days 1, 8, 15, and 22 and on Days 1 and 15 of each subsequent 28-day cycle, starting with Cycle 2, along with lazertinib 240 mg orally once daily. Eligible participants will be given an option to enter long-term extension (LTE) phase and may continue to receive access to study treatment(s) within the study by transferring to the Drug Access (DA)-LTE Phase. |
| Cohort 2(Exon20 NSCLC,1L, Previously Untreated): Amivantamab (Q3W) + Chemotherapy | EXPERIMENTAL | Participants with treatment-naive locally advanced or metastatic NSCLC harboring an EGFR exon20ins mutation will receive Amivantamab SC-CF injection 1600 mg or 2240 mg if body weight is \>=80 kg on Cycle 1 Day 1, 2400 mg or 3360 mg if body weight is \>=80 kg on Cycle 1 Day 8 and 15 and on Day 1 of each subsequent 21-day cycle, starting with Cycle 2 along with pemetrexed 500 milligrams per meter square (mg/m\^2) as intravenous (IV) infusion (with vitamin supplementation) on Day 1 of each 21-day cycle and IV infusion carboplatin area under the concentration-time curve 5 milligrams per milliliters (mg/mL) per minute (AUC 5) maximum 750 mg on Day 1 of each 21-day cycle, for up to 4 cycles. Eligible participants will be given an option to enter LTE phase and may continue to receive access to study treatment(s) within the study by transferring to the DA-LTE Phase. |
| Cohort 3(Exon19del/Exon21 L858R NSCLC,2L,Post Osimertinib):Amivantamab(Q3W)+Lazertinib+Chemotherapy | EXPERIMENTAL | Participants with locally advanced or metastatic NSCLC harboring an EGFR exon19del or exon 21 L858R mutation who have experienced disease progression on or after treatment with a third-generation EGFR TKI (osimertinib), will receive amivantamab SC-CF injection 1600 mg or 2240 mg if body weight is \>=80 kg on Cycle 1 Day 1, 2400 mg or 3360 mg if body weight is \>=80 kg on Cycle 1 Day 8 and 15 and on Day 1 of each subsequent 21-day cycle starting with Cycle 2; in combination with IV infusion carboplatin area under the concentration-time curve 5 mg/mL per minute (AUC 5) maximum 750 mg on Day 1 of each 21-day cycle, for up to 4 cycles; and pemetrexed 500 mg/m\^2 as an IV infusion (with vitamin supplementation) on Day 1 of each 21-day until disease progression. Lazertinib 240 mg orally once daily starting Cycle 5 Day 1 when carboplatin is complete or sooner if carboplatin discontinued earlier than Cycle 4. Eligible participants will be given an option to enter LTE phase and DA-LTE Phase. |
| Cohort 3b(Exon19del/Exon21 L858R NSCLC, 2L, Post Osimertinib): Amivantamab (Q3W)+Chemotherapy | EXPERIMENTAL | Participants with locally advanced or metastatic NSCLC harboring an EGFR exon19del or exon 21 L858R mutation who have experienced disease progression on or after treatment with a third-generation EGFR TKI (osimertinib), will receive amivantamab SC-CF injection 1600 mg or 2240 mg if body weight is \>=80 kg on Cycle 1 Day 1, 2400 mg or 3360 mg if body weight is \>=80 kg on Cycle 1 Day 8 and 15 and on Day 1 of each subsequent 21-day cycle starting with Cycle 2; in combination with IV infusion carboplatin area under the concentration-time curve 5 mg/mL per minute (AUC 5) maximum 750 mg on Day 1 of each 21-day cycle, for up to 4 cycles; and pemetrexed 500 mg/m\^2 as an IV infusion (with vitamin supplementation) on Day 1 of each 21-day until disease progression. Eligible participants will be given an option to enter LTE phase and may continue to receive access to study treatment(s) within the study by transferring to the DA-LTE Phase. |
| Cohort 4(Previously Treated with Amivantamab IV): Switch from Amivantamab IV to SC-CF (Q2W) | EXPERIMENTAL | Participants who were previously on amivantamab IV once every 2 weeks (Q2W) regimen as part of standard of care, for at least 8 weeks, either as monotherapy or combination with lazertinib, will receive amivantamab SC-CF injection 1600 mg and 2240 mg if body weight is greater than or equal to 80 kg. Participants who continue to benefit from study treatments, as determined by their investigator, may shift to the drug access (DA)-LTE phase. |
| Cohort 5(Exon19del/Exon21 L858R NSCLC, 1L, Previously Untreated): Amivantamab (Q4W) + Lazertinib | EXPERIMENTAL | Participants with treatment-naïve locally advanced or metastatic NSCLC harboring an EGFR Exon19del or Exon 21 L858R mutation will receive amivantamab SC-CF induction with 1,600 mg (or 2,240 mg if BW \>=80 kg) on Cycle 1 Days 1, 8, 15, and 22, starting with Cycle 2 on Day 1 of each next 28-day cycle, amivantamab SC-CF (160 mg/mL co-formulated with rHuPH20) by manual injection at 3,520 mg (or 4,640 mg if BW \>=80 kg); along with lazertinib 240 mg by mouth once daily from Cycle 1 Day 1. Eligible participants will be given an option to enter LTE phase and may continue to receive access to study treatment(s) within the study by transferring to the DA-LTE Phase. |
| Cohort6(Exon19del/Exon21L858R,NSCLC1L,PreviouslyUntreated):Amivantamab(Q2W)+Lazertinib+Anticoagulant | EXPERIMENTAL | Participants with treatment-naive locally advanced or metastatic NSCLC harboring an EGFR Exon19del or Exon 21 L858R mutation treated will receive will receive amivantamab SC-CF injection, 1600 milligrams (mg) and 2240 mg if body weight is greater than or equal to (\>=) 80 kilograms (kg), on Cycle 1 Days 1, 8, 15, and 22 and on Days 1 and 15 of each subsequent 28-day cycle, starting with Cycle 2, along with lazertinib 240 mg orally once daily from Cycle 1 Day 1. Participants will additionally take prophylactic anticoagulation with a direct oral anticoagulant (DOAC) or a low molecular weight heparin (LMWH) for the first four months of study treatment (from Day 1 through Day 120) with the combination of amivantamab and lazertinib. Eligible participants will be given an option to enter LTE phase and may continue to receive access to study treatment(s) within the study by transferring to the DA-LTE Phase. |
| Cohort 7(Exon19del/Exon21 L858R NSCLC,2L,Post Amivantamab+Lazertinib):Amivantamab(Q3W)+Chemotherapy | EXPERIMENTAL | Participants with locally advanced or metastatic NSCLC harboring an EGFR exon19del or exon 21 L858R mutation who have experienced disease progression on or after the combination of amivantamab and lazertinib will receive amivantamab SC-CF injection 1600 mg or 2240 mg if body weight is \>=80 kg on Cycle 1 Day 1, 2400 mg or 3360 mg if body weight is \>=80 kg on Cycle 1 Day 8 and 15 and on Day 1 of each subsequent 21-day cycle starting with Cycle 2; in combination with IV infusion carboplatin area under the concentration-time curve 5 mg/mL per minute (AUC 5) maximum 750 mg on Day 1 of each 21-day cycle, for up to 4 cycles; and pemetrexed 500 mg/m\^2 as an IV infusion (with vitamin supplementation) on Day 1 of each 21-day until disease progression. Eligible participants will be given an option to enter LTE phase and may continue to receive access to study treatment(s) within the study by transferring to the DA-LTE Phase. |
| Phase 1: Combination Dose Selection | EXPERIMENTAL | Participants will receive amivantamab along with olomorasib to determine the RP2CD of the combination therapy until disease progression, significant toxicity, or until another criterion for discontinuation of study treatment is met. Eligible participants may have the option to transfer to a long-term extension (LTE) phase for continued access to study treatments. |
| Phase 2: Expansion | EXPERIMENTAL | Participants will receive amivantamab and olomorasib combination therapy at the RP2CD determined in Phase 1 until disease progression, significant toxicity, or until another criterion for discontinuation of study treatment is met. Eligible participants may have the option to transfer to LTE phase for continued access to study treatments. |
| Phase 1 (Combination Dose Selection) | EXPERIMENTAL | Participants will receive amivantamab intravenous (IV) infusion administered based on body weight from Cycle 1 Day 1, Day 2, and subsequent doses on Days 8 and 15, and then on Day 1 of each 21-day treatment cycle. Docetaxel will be administered on Day 2 of Cycle 1 (before Day 2 amivantamab infusion) and then on Day 1 of each 21-day treatment cycle, thereafter. Doses will be escalated or de-escalated based on the dose limiting toxicities (DLTs) and the recommended Phase 2 combination dose (RP2CD) will be determined. Participants will continue study treatment until disease progression, unacceptable toxicity, or until another criterion for discontinuation of study treatment is met. |
| Phase 2 (Dose Expansion) | EXPERIMENTAL | Participants will receive amivantamab in combination with docetaxel in 2 cohorts (Cohort A \[adenocarcinoma\] and Cohort B \[squamous\]) at the RP2CD determined in Phase 1. Participants will continue study treatment until disease progression, unacceptable toxicity, or until another criterion for discontinuation of study treatment is met. |
| Cohort 1: Amivantamab Monotherapy (Dose Expansion) | EXPERIMENTAL | Participants will receive subcutaneous injection of amivantamab monotherapy 1600 milligrams (mg) (2240 mg, if body weight \>=80 kilograms \[kg\]) on Cycle 1 Day 1 and 2400 mg (3360 mg, if body weight \>=80 kg) once every week (q1w) for the remainder of Cycle 1 (Days 8 and 15), and every 3 weeks (q3w) from Cycle 2 onwards. |
| Cohort 2: Amivantamab + Pembrolizumab (Dose Expansion Including Safety Run-in) | EXPERIMENTAL | Participants will receive subcutaneous injection of amivantamab 1600 mg (2240 mg, if body weight \>=80 kg) on Cycle 1 Day 1 and 2400 mg (3360 mg, if body weight \>=80 kg) q1w for the remainder of Cycle 1 (Days 8 and 15), and q3w from Cycle 2 onwards, along with intravenous (IV) injection of pembrolizumab 200 mg q3w (on Day 1 of each 21-day cycle). |
| Cohort 3A (Dose Confirmation): Amivantamab + Paclitaxel | EXPERIMENTAL | Participants will receive subcutaneous injection of amivantamab 1600 mg (2240 mg, if body weight \>=80 kg) on Cycle 1 Day 1 and 2400 mg (3360 mg, if body weight \>=80 kg) q1w for the remainder of Cycle 1 (Days 8 and 15), and q3w from Cycle 2 onwards, along with intravenous injection of paclitaxel 175 mg/m\^2 q3w (on Day 1 of each 21-day cycle) in dose confirmation Cohort 3A. The recommended Phase 2 combination dose (RP2CD) of amivantamab will be determined in conjunction with study evaluation team (SET) in this dose confirmation Cohort 3A. |
| Cohort 3B (Dose Expansion): Amivantamab + Paclitaxel | EXPERIMENTAL | Participants will receive subcutaneous injection of amivantamab at the determined RP2CD in addition to intravenous injection of paclitaxel 175 mg/m\^2 q3w (on Day 1 of each 21-day cycle) as confirmed by SET in Cohort 3A. |
| Cohort 4: Amivantamab Monotherapy | EXPERIMENTAL | Participants will receive subcutaneous injection of amivantamab monotherapy 1600 mg (2240 mg, if body weight \>=80 kg) on Cycle 1 Day 1 and 2400 mg (3360 mg, if body weight \>=80 kg) q1w for the remainder of Cycle 1 (Days 8 and 15), and q3w from Cycle 2 onwards. |
| Cohort 5: Pembrolizumab + Amivantamab + Carboplatin (Dose Expansion) | EXPERIMENTAL | Participants will receive subcutaneous injection of amivantamab 1600 mg (2240 mg, if body weight \>=80 kg) on Cycle 1 Day 1 and 2400 mg (3360 mg, if body weight \>=80 kg) q1w for the remainder of Cycle 1 (Days 8 and 15), and q3w from Cycle 2 onwards in addition to intravenous injection of pembrolizumab 200 mg on Day 1 of each cycle, and carboplatin (area under the concentration-time curve \[AUC\] 5 milligram per milliliter \[mg/ml\]\*min) q3w on Day 1 of Cycles 1-6. |
| Cohort 6: Amivantamab + Pembrolizumab | EXPERIMENTAL | Participants will receive subcutaneous injection of amivantamab 1600 mg (2240 mg, if body weight \>=80 kg) on Cycle 1 Day 1 and 2400 mg (3360 mg, if body weight \>=80 kg) q1w for the remainder of Cycle 1 (Days 8 and 15), and q3w from Cycle 2, along with intravenous injection of pembrolizumab 200 mg q3w (on Day 1 of each 21-day cycle) (Neoadjuvant Phase). In the adjuvant phase, pembrolizumab IV (200 mg) will be administered q3w from Adjuvant Cycle 1 Day 1 to Adjuvant Cycle 15 Day 1 and amivantamab SC 2,400 mg (3,360 mg for \>80 kg) will be administered q3w from Adjuvant Cycle 4 Day 1 to Adjuvant Cycle 15 Day 1. |
| Cohorts A, B, and C: Amivantamab Monotherapy | EXPERIMENTAL | Participants with left-sided colorectal cancer (CRC) in Cohort A (no prior anti-epidermal growth factor receptor \[EGFR\] therapy) and in Cohort B (post anti-EGFR therapy), and right-sided CRC in Cohort C (with or without anti-EGFR therapy), will be administered intravenous (IV) infusion of amivantamab 1050 milligrams (mg) if body weight (BW) is less than (\<) 80 kilograms (kg) or 1400 mg if BW is greater than or equal to (\>=) 80 kg, as monotherapy on Days 1 and 15 of Cycle 2 (28-days cycle). |
| Cohorts Ph1b-D and D: Amivantamab+5-Fluorouracil, Leucovorin, and Oxaliplatin (mFOLFOX6) | ACTIVE_COMPARATOR | Participants who are anti-EGFR treatment naïve, have not received oxaliplatin-based chemotherapy in the metastatic setting, will be administered IV infusion of amivantamab 1050 or 700 mg (dose level 0 \[DL0\]) if BW is \<80 kg, or 1400 or 1050 mg (dose de-escalation \[DL-1\]) if BW is \>= 80 kg, on Days -1, -2, 8 and 22 of Cycle 1 and along with mFOLFOX6 SOC chemotherapy on Days 1 and 15 of Cycle 1 and Days 1 and 15 of Cycle 2 (each cycle of 28 days) in Phase 1b dose confirmation Cohort (Cohort Ph1b-D). Participant in Phase 2 Cohort (Cohort D) will receive recommended Phase 2 combination dose (RP2CD) of amivantamab along with mFOLFOX6 SOC chemotherapy determined in Cohort Ph1b-D. |
| Cohorts Ph1b-E and E: Amivantamab+5-Fluorouracil, Leucovorin, and Irinotecan (FOLFIRI) | ACTIVE_COMPARATOR | Participants who are anti-EGFR treatment naïve, have not received irinotecan-based chemotherapy in the metastatic setting, will be administered IV infusion of Amivantamab along with FOLFIRI SOC chemotherapy on Days -1, -2, and 8 of Cycle 1 and Days 1 and 15 of Cycle 2 in Ph1b-E. For Cohort E, RP2CD determined in Ph1b-E will be administered. |
| Cohort F: Amivantamab + mFOLFOX6 | ACTIVE_COMPARATOR | Participant who are treatment-naïve for right-sided unresectable or metastatic CRC. Participants will receive Amivantamab along with mFOLFOX6 SoC chemotherapy. |
| Part 1:Amivantamab Monotherapy+Combination Dose Escalations | EXPERIMENTAL | The first cohort of participants will receive intravenous (IV) infusions of Amivantamab 140 milligram (mg) as monotherapy. Each subsequent cohort will receive IV infusions of Amivantamab at increased dose level. Dose escalation will continue until maximum tolerated dose is reached or all planned doses are administered. Participants will receive IV infusion of Amivantamab once weekly during cycle 1 and once every 2 weeks during subsequent cycles (duration of each treatment cycle is 28 days). Participants will receive lazertinib and Amivantamab on Cycle 1 Day 1 (C1D1) prior to initiation of Amivantamab (C1D1) at predefined dose levels, based upon observed safety and protocol defined criteria. Lazertinib will be administered daily thereafter, on 28-day Amivantamab treatment cycle. In Chemotherapy Combination Cohort, participants will receive Amivantamab, administered on a 21-day cycle, in combination with standard of care carboplatin and pemetrexed. |
| Part 2:Amivantamab Monotherapy+Combination Dose Expansion | EXPERIMENTAL | Participants will receive IV infusion of Amivantamab as monotherapy at Phase 2 dose (RP2D) regimen or in combination lazertinib at the recommended Phase 2 combination dose (RP2CD) regimen as determined in Part 1. The purpose of dose expansion is to further evaluate safety, tolerability, pharmacokinetic, and to assess preliminary efficacy in monotherapy and combination therapy cohorts. |
| Name | Type | Description |
|---|---|---|
| Amivantamab | BIOLOGICAL | Amivantamab will be administered. |
| Pembrolizumab | BIOLOGICAL | Pembrolizumab will be administered. |
| Carboplatin | DRUG | Carboplatin will be administered. |
| 5-Flurouracil | DRUG | 5-Flurouracil will be administered for over 4-day infusion period. |
| Cisplatin | DRUG | Cisplatin will be administered. |
| Cetuximab | BIOLOGICAL | Cetuximab will be administered. |
| Bevacizumab | BIOLOGICAL | Bevacizumab will be administered. |
| 5-fluorouracil | DRUG | 5-fluorouracil will be administered as chemotherapy regimen. |
| Leucovorin calcium/Levoleucovorin | DRUG | Leucovorin calcium/Levoleucovorin will be administered as chemotherapy regimen. |
| Irinotecan | DRUG | Irinotecan will be administered as chemotherapy regimen. |
| Oxaliplatin | DRUG | Oxaliplatin will be administered as chemotherapy regimen. |
| Irinotecan Hydrochloride | DRUG | Irinotecan hydrochloride will be administered as chemotherapy regimen. |
| Pemetrexed | DRUG | Pemetrexed will be administered as 500 mg/m\^2 IV infusion (with vitamin supplementation) on Day 1 of each 21-day cycle and then as maintenance monotherapy until disease progression in Arm A and will continue the same treatment in OLE phase then in LTE phase. |
| Osimertinib | DRUG | Participants will receive osimertinib capsules orally. |
| Lazertinib | DRUG | Participants will receive lazertinib tablets orally. |
| Placebo | DRUG | Participants will receive matching placebo orally. |
| Chemotherapy: Pemetrexed | DRUG | Pemetrexed will be administered. |
| Chemotherapy: Carboplatin | DRUG | Carboplatin will be administered. |
| Amivantamab IV | DRUG | Amivantamab will be administered. |
| Amivantamab SC | DRUG | Amivantamab will be administered as SC injection. |
| Doxycycline | DRUG | Doxycycline tablet will be administered orally. |
| Minocycline | DRUG | Minocycline capsule will be administered orally. |
| Clindamycin | DRUG | Clindamycin lotion will be used as topical application on the scalp. |
| Chlorhexidine | DRUG | Chlorhexidine solution will be used as topical application on hands and feet. |
| Noncomedogenic skin moisturizer | OTHER | Noncomedogenic skin moisturizer will be used as topical application. |
| Ruxolitinib | OTHER | Ruxolitinib will be used to the affected skin area. |
| Tacrolimus | OTHER | Tacrolimus will be used as topical application to the affected skin area. |
| Zinc gluconate | DRUG | Zinc gluconate tablet will be administered. |
| Propranolol | DRUG | Propranolol tablet will be administered. |
| Timolol | DRUG | Timolol will be used to the affected skin area. |
| Clobetasol | DRUG | Clobetasol shampoo will be used on the scalp. |
| Dexamethasone | DRUG | Dexamethasone will be administered orally. |
| Montelukast | DRUG | Montelukast will be administered orally. |
| Methotrexate | DRUG | Methotrexate will be administered subcutaneously. |
| Direct Oral Anticoagulant (DOAC) | DRUG | DOAC will be administered orally. |
| Low Molecular Weight Heparin (LMWH) | DRUG | LMWH will be administered subcutaneously. |
| Olomorasib | DRUG | Olomorasib will be administered. |
| Docetaxel | DRUG | Docetaxel will be administered as IV infusion. |
| Paclitaxel | DRUG | Paclitaxel will be administered intravenously. |
| Fluorouracil | BIOLOGICAL | Fluorouracil will be administered as intravenous infusion. |
| Leucovorin | BIOLOGICAL | Leucovorin will be administered as intravenous infusion. |
Inclusion criteria: * Be more than or equal to (\>=) 18 years of age (or the legal age of majority in the jurisdiction in which the study is taking place, whichever is greater) * Have histologically or cytologically confirmed recurrent/metastatic (R/M) HNSCC that is considered incurable by local th...