The objective of this trial is to evaluate safety (in terms of grade >=2 pneumonitis, requiringmedical treatment) and efficacy (in terms of PFS) in patients with synchronous oligometastatic EGFR-mutant NSCLC treated with osimertinib and locally…
ID
Source
Brief title
Condition
- Respiratory and mediastinal neoplasms benign (excl mesotheliomas)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
- Proportion of patients with grade >=2 pneumonitis, requiring medical
treatment, by
month 18
- Hierarchically tested: Progression-free survival
Secondary outcome
- Overall survival
- Pattern of disease progression
- Distant progression free survival
- Objective response rate
- Duration of response
- Adverse events according to CTCAE v5.0
- Symptom-specific and global quality of life
Background summary
Targeting EGFR mutation has fundamentally changed the treatment of metastatic
NSCLC.
Several randomised phase III studies have compared first-generation (erlotinib
or gefitinib) or
second-generation (afatinib) EGFR-targeting TKIs with standard platinum-based
chemotherapy and all reported significantly improved objective response rates
(ORR) and
progression-free survival (PFS). For patients with TKI resistance development by
T790M mutation, which is the resistance mechanism in about 50% of the patients,
osimertinib
is superior compared to platinum-based chemotherapy with significant and
clinically relevant
improved ORR and PFS. On longer follow-up, first-line osimertinib was also
associated with improved survival.
Integration of local therapy into a multimodality treatment is a promising
strategy to overcome
the limitations of EGFR-targeting TKIs alone, despite patients suffering from a
metastatic
stage of disease. This is based on the observations that disease progression
under EGFR targeting TKI most frequently occurs at the original sites of
metastatic disease and that the majority of patients show disease progression
in a limited number of metastatic lesions, a
situation defined as oligoprogression. Early imaging-based detection of
oligoprogressive disease sites and their local ablation
combined with continuation of TKI is one strategy to overcome this resistance
development:
metastatic sites with acquired resistance to EGFR-targeting TKI are eradicated
by locally
ablative treatment, irrespective of the underlying resistance mechanism,
whereas nonprogressing and EGFR-sensitive sites are continuously targeted and
controlled by TKI therapy. There is a clinical need to evaluate locally
ablative therapy in oligo-metastatic EGFR-mutant NSCLC patients and
simultaneously a strong rationale that this population might benefit in
particular from a combined modality treatment: the benefit of locally ablative
therapy is expected to be largest in situations of effective systemic therapies
to control locally untreated microscopic disease which is true for EGFR
targeting.
Study objective
The objective of this trial is to evaluate safety (in terms of grade >=2
pneumonitis, requiring
medical treatment) and efficacy (in terms of PFS) in patients with synchronous
oligometastatic EGFR-mutant NSCLC treated with osimertinib and locally ablative
radiotherapy
to all cancer sites
Study design
Single-arm, multicentre phase II trial evaluating the safety (in terms of
grade >=2 pneumonitis, requiring medical treatment) and efficacy (in
terms of progression-free survival) of osimertinib and locally ablative
stereotactic radiotherapy in patients with synchronous oligo-metastatic
EGFR-mutant NSCLC.
Intervention
All patients will be treated with Osimertinib, 80 mg once daily p.o., until
progression or unacceptable toxicity. Locally ablative radiotherapy (SBRT) will
be delivered to the primary tumour and to all metastatic sites. SBRT will be
delivered using risk-adapted SBRT with a maximum of 5 SBRT fractions.
Depending on tumour size and anatomical location in relationship to critical
serial organs at
risk, SBRT will either be delivered immediately (SBRT to start within 4 weeks
after start of
osimertinib treatment) or after the 2-month restaging (SBRT to start within 4
weeks after
restaging).
The decision when to start SBRT is at the discretion of the local radiotherapy
team.
Furthermore, the following study procedures/assessments will be performed:
medical examination (measurement of body weight, temperature, pulse, blood
pressure and checking the eyes for redness and other symptoms), general
well-being questions to determine performance or activity level, blood and
urine tests, cardiac function tests (ECG and LVEF), quality of life
questionnaires, radiologic scans (FDG-PET-CT, MRI and CT), lung cancer biopsy
(if disease progression).
Study burden and risks
The study procedures and tests can be found in the protocol (pages 19-21).
- Possible side effects of osimertinib: Sudden difficulty in breathing along
with a cough or fever ('interstitial lung disease'), watery eyes, sensitivity
to light, eye pain, red eyes, or vision changes, ring-shaped skin reactions,
Stevens-Johnson syndrome (reddish flat dots or round spots, often with a
central blister on the body, peeling skin, ulcers of the mouth, throat, nose,
genitals and eyes You may also develop fever and flu-like symptoms, diarrhea,
skin and nail problems, stomatitis, decline of white blood cell count, anaemia,
inflammation of the blood vessels in the skin, decrease of red blood cell
production (aplastic anaemia).
- Possible side effects of radiation therapy: fatigue, shortness of breath and
dry cough, nausea and vomiting, temporary worsening of the original symptoms,
skin changes on the treated areas, hair loss (temporary/permanent), diarrhea,
difficulty swallowing or pain when swallowing, chest pain / fractured rib (bone
fractures in other treated areas), impaired / limited breathing ability, liver
dysfunction, renal dysfunction, low risk of major bleeding/delayed swallowing
difficulties/bowel damage/damage to heart function/nerve damage/spinal cord
damage
- Blood samples can hurt or cause a blood shed. This may increase the risk of
infection.
- There is a risk of an allergic reaction in radiological examinations that
require injection of a contrasting agent.
Effingerstrasse 33
Bern 3008
CH
Effingerstrasse 33
Bern 3008
CH
Listed location countries
Age
Inclusion criteria
1) Histologically confirmed, treatment naïve EGFR-mutant NSCLC, with
or without T790M resistance mutation.
2) Presence of sensitising EGFR-mutation (exon 19 deletion and/or exon
21 L858R) detected by an accredited laboratory.
3) Synchronous oligo-metastatic stage IV disease (max 5 lesions)
4) Measurable disease as defined according to RECIST v1.1
5) All lesions amenable for radical radiotherapy according to local
judgment
6) ECOG performance status 0-2
7) Adequate haematological, renal and liver function
Exclusion criteria
1) Prior chemotherapy, immunotherapy, radiotherapy or therapeutic
surgery for NSCLC (an exception is the resection and postoperative
radiotherapy of the resection cavity of CNS or adrenal metastases)
2) More than 5 distant oligo-metastases (any second intra-thoracic
lesion will count as a distant metastasis; regional nodal metastases will
not count towards the 5 oligometastases) and more than 2 intra-pulmonary
lesions.
3) Brain metastases not amenable for radiosurgery or neurosurgery
4) Presence of leptomeningeal metastases
5) Symptomatic spinal cord compression
6) Extracranial metastatic locations not amenable for radical
radiotherapy such as malignant ascites, pleural or pericardial effusion,
diffuse lymphangiosis of skin or lung, diffuse bone marrow metastasis,
metastasis invading the GI tract, abdominal masses/abdominal
organomegaly, identified by physical exam that is not measurable by
reproducible imaging techniques
7) Currently receiving, or unable to stop use prior to enrolment or to
receiving the first dose of osimertinib treatment, medications or herbal
supplements known to be potent CYP3A4 inducers. Potent CYP3A4
inducers are contraindicated for the duration of the trial.
8) Any evidence of severe or uncontrolled systemic diseases, including
uncontrolled hypertension and active bleeding diatheses, which in the
investigator's opinion makes it undesirable for the patient to participate
in the trial or which would jeopardise compliance with the protocol.
Patients with a resolved or chronic HBV infection are eligible if they are:
- Negative for HBsAg and positive for hepatitis B core antibody [anti-HBc
IgG],
or
- Positive for HBsAg, negative for HBeAg but for >6 months have had
transaminases levels below ULN and HBV DNA levels below 2000 IU/mL
(i.e., are in an inactive carrier state).
9) Refractory nausea and vomiting, chronic gastrointestinal diseases,
inability to swallow the formulated product or previous significant bowel
resection that would preclude adequate absorption of osimertinib
10) Any of the following cardiac criteria:
- QTcF >470 msec, using the screening clinic ECG machine derived QTc
value (QTcF: corrected QT interval using Fredericia's formula).
- Any clinically important abnormalities in rhythm, conduction or
morphology of resting ECG (e.g., complete left bundle branch block, third
degree heart block or
second degree heart block).
- Any factors that increase the risk of QTc prolongation or risk of
arrhythmic events such as heart failure, hypokalaemia, congenital long
QT syndrome, family history of long QT syndrome or unexplained sudden
death under 40 years of age in first degree relatives or any concomitant
medication known to prolong the QT interval and cause Torsades de
Pointes (TdP).
11) Past medical history of ILD, drug induced ILD, radiation pneumonitis
which required steroid treatment, or any evidence of clinically active ILD
12) Idiopathic pulmonary fibrosis which is a contraindication to lung
radiation
13) History of hypersensitivity to active or inactive excipients of
osimertinib or drugs with a similar chemical structure or class to osimertinib
Design
Recruitment
Medical products/devices used
metc-ldd@lumc.nl
metc-ldd@lumc.nl
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2020-004114-35-NL |
| ClinicalTrials.gov | NCT04908956 |
| CCMO | NL79320.058.22 |