| Eligibility |
Inclusion Criteria:
1. Have a histologically or cytologically confirmed diagnosis of incurable Stage IIIB,
IIIC, IVA, IVB (American Joint Committee on Cancer [AJCC], version 8) non-squamous
NSCLC. Postoperative recurrence is acceptable if the disease is not curable.
2. Have documentation of tumor activating EGFR mutation, specifically either exon 19
deletion or exon 21 L858R.
3. Have investigator determined radiographic disease progression per RECIST 1.1 after
treatment with EGFR-TKI therapy:
1. Participants previously treated with 1st or 2nd generation EGFR TKI (eg,
erlotinib/afatinib/gefitinib) are required to have confirmed documented absence
of EGFR T790M mutation.
2. Participants with confirmed acquired T790M mutation after 1st or 2nd generation
EGFR-TKI (eg, erlotinib/afatinib/gefitinib) are required to have osimertinib TKI
treatment failure prior to enrollment.
3. Participants previously failed osimertinib TKI treatment as 1st line therapy are
eligible regardless of their EGFR T790M mutation status.
4. Participants treated with a combination of EGFR TKIs and antibodies targeting the
VEGF pathway will also be eligible.
4. Have measurable disease per RECIST 1.1.
5. Be male or female = 20 years of age inclusive, at the time of signing the informed
consent form (ICF).
6. Have a life expectancy of at least 3 months.
7. Have an ECOG performance status of 0 or 1 within 7 days prior to the first dose of
study intervention but before registration.
8. A male participant must agree to use a contraception during the treatment period.
9. A female participant is eligible to participate if she is not pregnant, not
breastfeeding
10. The participant provides written informed consent for the study.
11. Have adequate organ function.
12. Have adequately controlled blood pressure (BP) with or without antihypertensive
medications, defined as BP = 150/90 mmHg and no change in antihypertensive medications
within 1 week prior to registration.
Exclusion Criteria:
1. Has known untreated central nervous system (CNS) metastases and/or carcinomatous
meningitis. Participants with previously treated brain metastases may participate
provided they are radiologically stable, clinically stable, and have not required
steroids for at least 14 days prior to the first dose of study intervention.
2. Has history of (noninfectious) pneumonitis that required systemic steroids or current
pneumonitis/interstitial lung disease.
3. Radiographic evidence of intratumoral cavitations, encasement, or invasion of a major
blood vessel. Additionally, the degree of proximity to major blood vessels should be
considered because for exclusion because of the potential risk of severe hemorrhage
associated with tumor shrinkage/necrosis after lenvatinib therapy (in the chest, major
blood vessels include the main pulmonary artery, the left and right pulmonary
arteries, the 4 major pulmonary veins, the superior or inferior vena cava, and the
aorta).
4. Has a known history of an additional malignancy, except if the participant has
undergone potentially curative therapy with no evidence of that disease of that
disease recurrence for at least 3 year since initiation of that therapy.
5. Has an autoimmune disease that has required systemic treatment in the past 2 years
(ie, with use of disease-modifying agents, corticosteroids, or immunosuppressive
drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is allowed.
6. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
(doses exceeding 10 mg daily of prednisone equivalent) or any other form of
immunosuppressive therapy within 7 days prior the first dose of study intervention.
7. Has had an allogeneic tissue/solid organ transplant.
8. Has a known history of human immunodeficiency virus (HIV) infection. HIV testing is
not required unless mandated by the local health authority.
9. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg]
reactive or HBV-DNA detected) or known active Hepatitis C virus (HCV antibody
reactive).
10. Has a history of a gastrointestinal condition or procedure that in the opinion of the
investigator may affect oral drug absorption.
11. Has active hemoptysis (at least 0.5 tsp of bright red blood) within 2 weeks prior to
the first dose of study intervention.
12. Has significant cardiovascular impairment within 12 months prior to the first dose of
study intervention, including history of congestive heart failure greater than New
York Heart Association (NYHA) Class II, unstable angina, myocardial infarction,
cerebrovascular accident (CVA)/stroke, or cardiac arrhythmia associated with
hemodynamic instability.
13. Has a known history of active tuberculosis.
14. Has an active infection requiring systemic therapy.
15. Has had major surgery within 3 weeks prior to first dose of study interventions.
Note: Adequate wound healing after major surgery must be assessed clinically,
independent of time elapsed for eligibility.
16. Has known psychiatric or substance abuse disorders that would interfere with the
participant's cooperation to meet with the requirements of the study.
17. Previously had a severe hypersensitivity reaction to treatment with a monoclonal
antibody or has s known sensitivity to any component of lenvatinib or pembrolizumab,
or as applicable, carboplatin, or pemetrexed.
18. A women of childbearing potential (WOCBP) who has a positive urine pregnancy test
within 72 hours prior to registration. If the urine test is positive or cannot be
confirmed as negative, a serum pregnancy test will be required.
19. Has preexisting = Grade 3 gastrointestinal or non-gastrointestinal fistula.
Prior/Concomitant Therapy
20. Has received prior systemic cytotoxic chemotherapy for their metastatic NSCLC. Note:
Prior treatment with chemotherapy and/or radiation as part of neoadjuvant/adjuvant
therapy is allowed as long as therapy was completed at least 6 months prior to the
diagnosis of metastatic NSCLC.
21. Has received prior treatment with pembrolizumab or any other anti-PD-1, anti-PD-L1,
anti-PD-L2 agent, with lenvatinib or any other RTKi, or with an agent directed to
another stimulatory or co-inhibitory T cell receptor (eg, CTLA-4, OX-40, CD137, GITR).
22. Has received radiotherapy within 14 days prior to the first dose of study intervention
or received lung radiation therapy of > 30 Gy within 6 months prior to the first dose
of study intervention.
23. Has received systemic steroid therapy (in doses exceeding 10 mg daily of prednisone
equivalent) within 7 days prior to the first dose of study intervention.
24. Has received a live vaccine within 30 days prior to the first dose of study
intervention. Examples of live vaccines include, but are not limited to, the
following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, and
Bacillus Calmette-Guerin (BCG). Seasonal influenza vaccines for injection are
generally killed virus vaccines and are allowed.
25. Is currently participating and receiving study therapy or has participated in a study
of an investigational agent and received study therapy or used an investigational
device within 4 weeks prior to the first dose of study intervention.
Note: Participants who have entered the follow-up phase of an investigational study
may participate as long as it has been > 4 weeks after the last dose of the previous
investigational agent.
26. Participants with proteinuria > 1+ on urinalysis will undergo 24-hour urine collection
for quantitative assessment of proteinuria. Participants with urine protein = 1 g/24
hours will be ineligible.
27. Has a prolongation of QTc interval (calculated using Fridericia's formula) of > 480
msec.
28. Has left ventricular ejection fraction (LVFE) below 50% as determined by multigated
acquisition scan (MUGA) or echocardiogram (ECHO).
29. Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the study, interfere with the participant's ability
to participate for the full duration of the study, or make it not in the best interest
of the participant to participate, in the opinion of the treating investigator.
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