This was a Phase 1/2, open-label, multicenter, single-arm study of combination therapy with
ensartinib, an anaplastic lymphoma kinase (ALK) inhibitor, and durvalumab, an anti-programmed
cell death ligand 1 (PD-L1) antibody, in subjects with ALK-rearranged (ALK-positive)
non-small cell lung cancer (NSCLC). Primary study objectives were to determine the
recommended combination dose (RCD) and safety and tolerability of the combination. Further
objectives were to evaluate the clinical efficacy and biologic activity of the combination.
Prior to initiation of combination therapy with ensartinib plus durvalumab, subjects were
enrolled sequentially to receive ensartinib monotherapy (orally once daily) during a
pre-immunotherapy Run-in Period for one to two 28-day cycles. The purpose of the Run-in
Period was to determine whether any safety signals might compromise combination therapy and
to determine the effect of ALK inhibitor therapy on the immune tumor microenvironment. For
subjects with no dose-limiting toxicity (DLT) during the Run-in Period, combination therapy
was then initiated during a dose-finding phase using a standard 3 + 3 design until
determination of the RCD, which was defined as the highest dose level at which ≤ 1 of 6
subjects (i.e., < 33%) experienced DLTs during the first 2 cycles of combination treatment.
A fixed dose of durvalumab (1500 mg by intravenous [IV] infusion every 4 weeks) was
administered in all cohorts. Ensartinib dosing started at 200 mg, with subsequent cohorts
receiving a reduced (150 mg) or escalated (225 mg) ensartinib dose depending upon observed
toxicity. The study was then designed to include an expansion phase, in which the RCD cohort
would be expanded to a total of 20 subjects.
Subjects were monitored for safety (including immune-related adverse events), disease status
(using the Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1 and
immune-related RECIST), and biologic activity (peripheral blood assays and immunological
changes in the tumor microenvironment) for the duration of study participation.
Inclusion Criteria:
1. Histologic confirmation of metastatic NSCLC. Subjects must have had confirmed ALK
rearrangement as assessed by immunohistochemistry. Subjects may have had prior therapy
with ALK inhibitors (other than ensartinib) or been ALK inhibitor naïve. ALK inhibitor
naïve subjects were informed of the availability of approved ALK inhibitors.
2. Measurable disease according to RECIST 1.1, defined as ≥ 1 lesion that could be
accurately measured in ≥ 1 dimension (longest diameter to be recorded for non-lymph
node lesions, shortest diameter to be recorded for lymph node lesions). Each lesion
must have been ≥ 10 mm when measured by computed tomography, magnetic resonance
imaging, or caliper measurement by clinical examination or ≥ 20 mm when measured by
chest x-ray.
3. Willing to provide a fresh pre-treatment biopsy; however, if subject was ALK inhibitor
naïve, either archival or pre-treatment biopsy was acceptable.
4. Asymptomatic subjects with surgically treated brain metastases must have been ≥ 14
days post surgery at the time of first dosing, while clinically stable with no
requirement for steroids. Asymptomatic subjects with radiation-treated brain
metastases may have entered the study immediately after completion of the radiation
(and been off steroids, if applicable). Symptomatic subjects (those experiencing
headache, seizure etc.), must have been relieved from all symptoms of their central
nervous system disease, and must have completed radiation and been off steroids prior
to first dosing (anti seizure medicine permitted).
5. Laboratory parameters for vital functions should have been in the normal range.
Laboratory abnormalities that were not clinically significant were generally
permitted, except for the following laboratory parameters, which must have been within
the ranges specified, regardless of clinical significance:
- Hemoglobin: ≥ 9 g/dL
- Neutrophil count: ≥ 1.5 x 10^9/L
- Platelet count: ≥ 100,000/mm^3
- Serum creatinine: ≤ 1.5 x institutional upper limit of normal (ULN), OR
creatinine clearance: ≥ 50 mL/min (by Cockcroft-Gault formula)
- Serum total bilirubin: ≤ 1.5 × ULN (except for subjects with Gilbert's syndrome
who were allowed after consultation with their physician)
- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT): ≤ 2.5 x ULN
- Alkaline phosphatase: ≤ 2.5 x ULN
6. Eastern Cooperative Oncology Group Performance Status ≤ 2.
7. Age ≥ 18 years.
8. Able and willing to provide valid written informed consent.
9. Able and willing to comply with the protocol for the duration of the study including
undergoing treatment and scheduled visits and examinations including follow-up.
10. Body weight > 30 kg.
Exclusion criteria:
1. Treatment with an investigational agent within 4 weeks of starting treatment, and any
prior drug-related toxicity (except alopecia) should have recovered to Grade 1 or
less.
2. Prior treatment with anti-PD-1, PD-L1 (including durvalumab), or cytotoxic
T-lymphocyte-associated antigen-4 (CTLA-4), or ensartinib (X-396).
3. Active, suspected or prior documented autoimmune disease (including but not restricted
to inflammatory bowel disease, celiac disease, Wegner's granulomatosis, Hashimoto's
thyroiditis, rheumatoid arthritis, systemic lupus, scleroderma and its variants,
multiple sclerosis, myasthenia gravis). Vitiligo, residual hypothyroidism due to
autoimmune condition only requiring hormone replacement, psoriasis not requiring
systemic treatment, or conditions not expected to recur in the absence of an external
trigger were permitted.
4. Subjects with clinically significant cardiovascular disease, including:
1. New York Heart Association Class II or higher congestive heart failure.
2. Myocardial infarction, unstable angina, cerebrovascular accident or transient
ischemic attack within 6 months of start of study drug (Day -28).
3. Clinically significant supraventricular or ventricular arrhythmia.
4. QT interval corrected using Fridericia's formula (QTcF) ≥ 450 ms (male) or QTcF ≥
470 ms (female).
5. Clinically uncontrolled hypertension.
5. History of pneumonitis or interstitial lung disease, or any unresolved immune-related
adverse events following prior therapy.
6. Major surgery within 4 weeks of starting treatment (or scheduled for surgery during
the projected course of the study).
7. Women of child bearing potential who were pregnant as evidenced by positive serum
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic
gonadotropin) or nursing.
8. Female subjects of childbearing potential who were sexually active with a
non-sterilized male partner must have used at least one highly effective method of
contraception (see table below) from the time of screening and must have agreed to
continue using such precautions for 90 days after the final dose of investigational
products. Non-sterilized male partners of a female subject must have used male condoms
plus spermicide throughout this period. Cessation of birth control after this point
should have been discussed with a responsible physician. Not engaging in sexual
activity for the total duration of the trial and the drug washout period was an
acceptable practice; however, periodic abstinence, the rhythm method, and the
withdrawal method were not acceptable methods of birth control.
Female subjects should have refrained from breastfeeding throughout the period
described above.
Females of childbearing potential were defined as those who were not surgically
sterile (i.e., bilateral tubal ligation, bilateral oophorectomy, or complete
hysterectomy) or post-menopausal.
Females were considered post-menopausal if they had been amenorrheic for 12 months
without an alternative medical cause. The following age-specific requirements applied:
- Females <50 years of age were considered post-menopausal if they had been
amenorrheic for 12 months or more following cessation of exogenous hormonal
treatments and if they had luteinizing hormone and follicle-stimulating hormone
levels in the post-menopausal range for the institution or underwent surgical
sterilization (bilateral oophorectomy or hysterectomy).
- Females ≥50 years of age were considered post-menopausal if they had been
amenorrheic for 12 months or more following cessation of all exogenous hormonal
treatments, had radiation-induced menopause with last menses >1 year prior to
study entry, had chemotherapy-induced menopause with last menses >1 year prior to
study entry, or underwent surgical sterilization (bilateral oophorectomy,
bilateral salpingectomy or hysterectomy).
Non-sterilized male subjects who were sexually active with a female partner of
childbearing potential must have used male condoms plus spermicide from screening
through 90 days after receipt of the final dose of investigational products. Male
subjects were to refrain from sperm donation throughout this period. Female partners
(of childbearing potential) of a male subject must have used a highly effective method
of contraception (see table below) throughout this period. Cessation of birth control
after this point was to be discussed with a responsible physician. Not engaging in
sexual activity for the total duration of the trial and the drug washout period was an
acceptable practice; however, periodic abstinence, the rhythm method, and the
withdrawal method were not acceptable methods of birth control.
A highly effective method of contraception was defined as one that resulted in a low
failure rate (i.e. less than 1% per year) when used consistently and correctly. Note
that some contraception methods were not considered highly effective (e.g. male or
female condom with or without spermicide; female cap, diaphragm, or sponge with or
without spermicide; non-copper containing intrauterine device; progestogen-only oral
hormonal contraceptive pills where inhibition of ovulation was not the primary mode of
action [excluding Cerazette/desogestrel which was considered highly effective]; and
triphasic combined oral contraceptive pills).
9. Subjects who were immunosuppressed, including those with known immunodeficiency.
10. Active infection including tuberculosis (clinical evaluation that included clinical
history, physical examination and radiographic findings, and tuberculosis testing in
line with local practice), hepatitis B (known positive hepatitis B virus surface
antigen result), hepatitis C, or human immunodeficiency virus (positive 1/2
antibodies). Subjects with a past or resolved hepatitis B virus infection (defined as
the presence of hepatitis B core antibody and absence of hepatitis B virus surface
antigen) were eligible. Subjects positive for hepatitis C antibody were eligible only
if polymerase chain reaction was negative for hepatitis C virus ribonucleic acid.
11. History of severe allergic reactions to any unknown allergens or components of the
study drugs.
12. Other serious illnesses (e.g., serious infections requiring antibiotics, bleeding
disorders).
13. Mental impairment that may have compromised compliance with the requirements of the
study.
14. Lack of availability for immunological and clinical follow-up assessment.
15. Inability to swallow or retain oral medication, presence of active gastrointestinal
disease or other condition that would have interfered significantly with the
absorption, distribution, metabolism, or excretion of ensartinib.
16. Any condition that, in the clinical judgment of the treating physician, was likely to
prevent the subject from complying with any aspect of the protocol or that may have
put the subject at unacceptable risk.
17. History of allogeneic organ transplant.
18. Subjects must not have donated blood while on study and for at least 90 days following
the last durvalumab treatment.
