The purpose of study is to evaluate the safety, pharmacokinetics, and preliminary efficacy of
Amivantamab as a monotherapy and in combination with lazertinib, and to determine the
recommended Phase 2 dose (RP2D) (monotherapy), recommended Phase 2 combination dose (RP2CD)
(combination therapy), and to determine recommended Phase 2 Dose (RP2q3W) with combination
chemotherapy (Amivantamab in combination with standard of care carboplatin and pemetrexed) in
21 day treatment cycle for participants with advanced non-small cell lung cancer (NSCLC).
This open label (all participants know the identity of the study drug), multicenter (more
than one study site), first-in-human study consists of 2 parts. Part 1 is a Amivantamab
Monotherapy and Combination Dose Escalations and Part 2 Amivantamab Monotherapy and
Combination Dose Expansions. In Part 1, participants with evaluable NSCLC will be enrolled
into cohorts at increasing dose levels of Amivantamab monotherapy, the RP2CD of the
Amivantamab and lazertinib combination which will be administered in 28 day treatment cycles,
and RP2q3W of Amivantamab in combination with standard of care carboplatin and pemetrexed
(chemotherapy combination) which will be administered in 21 day treatment cycles. The dose
will be escalated until the maximum tolerated dose (MTD, or maximum administered dose [MAD],
if no MTD is found) is reached. Part 1 will follow a traditional 3+3 design. At each dose
level, 3 participants will complete Cycle 1. If no dose limiting toxicity (DLT) occurs in
these 3 participants, then escalation will continue in a new cohort of 3 participants. Data
from Part 1 will be used to determine one or more RP2D regimen(s). In Part 2, participants
with documented epidermal growth factor receptor (EGFR) mutations and measurable disease,
whose disease has progressed after previous treatment will be enrolled and receive
Amivantamab at the RP2D determined in Part 1 as a monotherapy at the RP2D regimen(s), or in
combination with lazertinib at the RP2CD regimen. For both parts, the study consists of
following periods: an optional pre-Screening period; a Screening period (up to 28 days prior
to the first dose of study drug); a Treatment period (first dose of study drug until 30(+7)
days after the last dose of study drug or prior to starting any subsequent anti-cancer
treatment, whichever comes first); and a Follow Up period (approximately 6 months). All
participants will be followed for survival in the post-treatment follow-up period until the
end of study and safety will be monitored throughout the study.
Inclusion Criteria:
- Participant must have histologically or cytologically confirmed non-small cell lung
cancer (NSCLC) that is metastatic or unresectable. Participants must have either
progressed after prior standard of care therapy (Cohort C and hepatocyte growth factor
receptor gene [MET]-1: epidermal growth factor receptor [EGFR] tyrosine kinase
inhibitor [TKI]; Cohort D and MET-2: platinum-based chemotherapy) for metastatic
disease, or be ineligible for, or have refused all other currently available
therapeutic options. In cases where participants refuse currently available
therapeutic options, this must be documented in the study records. For Part 1
Chemotherapy Combination Cohort only: Participants must have histologically or
cytologically confirmed NSCLC that is metastatic or unresectable and be eligible for
treatment with combination carboplatin and pemetrexed, in accordance with standard of
care, and be willing to receive additional investigational therapy with Amivantamab
- For Part 1 Combination Dose Escalation with lazertinib only: Participants must have
been diagnosed with EGFR Exon 19del or L858R activating mutation and (a) be treatment
naïve for metastatic disease, without access to third generation TKI in the front-line
setting, or (b) have progressed after front-line treatment with first (erlotinib or
gefitinib) or second generation (afatinib) TKI and are ineligible for Cohort MET-1, or
(c) have been treated with a third generation TKI (eg, osimertinib) in either the
front line or second-line setting, and are not eligible for enrollment in either
Cohort C or MET-1. For Part 1 Chemotherapy Combination Cohort: Participants may be
diagnosed with EGFR mutated or EGFR wild type NSCLC. For Part 2 only: Participants
must also have disease with a previously diagnosed activating epidermal growth factor
receptor (EGFR) mutation (includes both inhibitor sensitive primary mutations such as
Exon 19 deletion and L858R (Cohort C, E, and MET-1), as well as marketed TKI-resistant
mutations such as Exon 20 insertion (Cohort C, D and MET-1) or activating cMet Exon 14
skipping mutation (Cohort MET-2). Documentation of primary activating EGFR or cMet
mutation eligibility by CLIA-certified laboratory (or equivalent) testing is required
- For Part 1: Participant must have evaluable disease. For Part 2: Participant must have
measurable disease according to Response Criteria in Solid Tumors (RECIST) v1.1
- For Part 2: Cohorts A and B: Participants EGFR mutated disease must have most recently
progressed following treatment with a marketed EGFR inhibitor. Exception: In
participants diagnosed with mutations associated with de novo EGFR inhibitor
resistance (for example, Exon 20 insertions), only previous treatment with combination
platinum-based chemotherapy is required. Cohort C: Participants with primary EGFR
mutated disease, with a documented EGFR alteration (example, C797S) mediating
resistance to previous treatment with a third generation EGFR TKI (for example,
osimertinib), in participants with primary Exon 20ins disease, the documented EGFR
alteration may arise following treatment with a TKI with known activity against Exon
20ins disease (for example, poziotinib). Cohort D: participants must have been
previously diagnosed with an EGFR Exon 20 insertion and have not been previously
treated with a TKI with known activity against Exon 20ins disease (exampe,
poziotinib). Cohort MET-1: Participants with documented primary EGFR mutated disease
and documented MET amplification or MET mutation after progression on any EGFR TKI.
Participants with disease characterized by both MET amplification and EGFR resistance
mutations to prior third generation EGFR TKI will be preferentially enrolled into
Cohort C. Participants may have received or have been intolerant to prior
platinum-based chemotherapy. Cohort MET-2: Participants with documented primary MET
Exon 14 skipping mutation non-small cell lung cancer (NSCLC). Cohort E (combination
Amivantamab and lazertinib): Participants must have been diagnosed with EGFR Exon
19del or L858R activating mutation, and have progressed after first or second-line
treatment with a third generation TKI (eg, osimertinib)
- Participant must have Eastern Cooperative Oncology Group (ECOG) performance status 0
or 1
Exclusion Criteria:
- Participant has uncontrolled inter-current illness, including but not limited to
poorly controlled hypertension, or diabetes, ongoing or active infection, (that is,
has discontinued all antibiotics for at least one week prior to first dose of study
drug), or psychiatric illness/social situation that would limit compliance with study
requirements. Participants with medical conditions requiring chronic continuous oxygen
therapy are excluded. For Part 1 Chemotherapy Combination Cohort only: additionally,
participants with active bleeding diathesis
- Participant has had prior chemotherapy, targeted cancer therapy, immunotherapy, or
treatment with an investigational anticancer agent within 2 weeks or 4 half-lives
whichever is longer, before the first administration of study drug. For agents with
long half-lives, the maximum required time since last dose is 4 weeks. Toxicities from
previous anti-cancer therapies should have resolved to baseline levels or to Grade 1
or less, (except for alopecia [any grade], Grade less than or equal to [<=] 2
peripheral neuropathy, and Grade less than [<] 2 hypothyroidism stable on hormone
replacement). For Part 1 Combination Dose Escalation: Any previous treatment with
systemic anti cancer immunotherapy, including but not limited to anti-PD-1,
anti-PD-L1, and anti-CTLA-4 agents. For Part 1 Chemotherapy Combination Cohort only:
Any previous treatment with systemic anti cancer immunotherapy in the past 3 months or
localized radiotherapy to lung within the past 6 months. For Part 2 only: Cohorts A
and B: Prior treatment with chemotherapy for metastatic disease is not allowed unless
the tumor mutation carries de-novo resistance to EGFR TKI (example, Exon 20
insertions). Cohort C and MET-1: Prior treatment with more than 2 lines of cytotoxic
chemotherapy for metastatic disease (maintenance therapy is not included). Cohort D:
Previous treatment with an EGFR TKI with activity against EGFR Exon 20 insertions
(such as poziotinib). Cohort E (combination Amivantamab and lazertinib): Any previous
treatment in the metastatic setting with other than a first, second, or third
generation EGFR TKI
- Participants with untreated brain metastases. Participants with definitively,
locally-treated metastases that are clinically stable and asymptomatic for at least 2
weeks and who are off or receiving low-dose corticosteroid treatment (<=10 mg
prednisone or equivalent) for at least 2 weeks prior to study treatment are eligible.
Exception: participants with asymptomatic, untreated brain metastases, each less than
1 cm in diameter, may be eligible for Amivantamab and lazertinib combination therapy
in the Part 1 Combination Dose Escalation or Part 2 Combination Expansion Cohort E
- Participant has a history of malignancy other than the disease under study within 3
years before Screening (exceptions are squamous and basal cell carcinomas of the skin
and carcinoma in situ of the cervix, or malignancy that in the opinion of the
investigator, with concurrence with the sponsor's medical monitor, is considered cured
with or minimal risk of recurrence within a year from Screening)
- Participant has not fully recovered from major surgery or significant traumatic injury
prior the first dose of study drug or expects to have major surgery during the study
period or within 6 months after the last dose of study drug
