A multicentre single-arm phase II trial of amivantamab, lazertinib plus bevacizumab in patients with EGFR-mutant advanced NSCLC with progression on previous third generation EGFR TKI

The third-generation EGFR-TKIs osimertinib is currently the preferred
first-line treatments for patients with metastatic, EGFR-mutant NSCLC.
Osimertinib or lazertinib (for Korea) are also indicated upon disease
progression after first-line therapy with a first- or second-generation
EGFR-TKI when the T790M resistance mutation is documented. The standard
treatment following progression on osimertinib or lazertinib is platinum and
pemetrexed.
Mechanisms of acquired resistance to third-generation EGFR-TKIs in the
first-line setting include C797S mutation (7%) and MET amplification (7-66%).
MET amplification is a mechanism of acquired resistance following treatment
with a third-generation EGFR-TKI in the first- or second-line setting.
Amivantamab (JNJ-61186372), is an anti-EGFR-MET bispecific antibody that
targets activating and resistance mutations of EGFR, as well as the MET
pathway. Amivantamab monotherapy, has shown a response rate of 19% in
chemo-naïve patients post osimertinib treatment.
Lazertinib is an oral, third-generation, EGFR-TKI being developed for the
treatment of NSCLC. It is a brain-penetrant, irreversible EGFR-TKI that targets
the T790M mutation and activating EGFR-mutations exon 19 deletion and L858R,
while sparing wild type-EGFR. Lazertinib is approved in Korea for the treatment
of patients with EGFR T790M-mutant advanced NSCLC who have previously received
EGFR-TKI therapy.
The combination of amivantamab plus lazertinib after osimertinib appears to
have higher activity and response durability compared to the Amivantamab
monotherapy, with potentially improved CNS protection.
Increased VEGF is associated with resistance to EGFR inhibition and resistance
to EGFRTKI may be associated with increased tumour and stromal VEGF levels.
Furthermore, dual inhibition of both the VEGFR and the EGFR pathway can
abrogate resistance to EGFR-TKIs and anti-angiogenic agents may increase
intra-tumour uptake of anti-cancer drugs by altering tumour vessel physiology.

This study has been transitioned to CTIS with ID 2024-512288-29-00 check the CTIS register for the current data.

The aim of this prospective single-arm phase II study is to evaluate the
efficacy of amivantamab and bevacizumab added to continued treatment with a
third-generation EGFRTKI (osimertinib or lazertinib), for patients with
EGFR-mutant advanced NSCLC, progressing on prior treatment on osimertinib or
lazertinib.

Single-arm phase II trial, aiming to evaluate the efficacy of amivantamab,
lazertinib and bevacizumab in patients with EGFRmutant advanced NSCLC and
progression on previous treatment with a third-generation EGFR-TKI, based on
the primary endpoint of ORR.

The patients will be given three different drugs called amivantamab, lazertinib
and bevacizumab until disease progression or unacceptable toxicity. Amivantamab
and bevacizumab are given by infusion once every 3 weeks.
The Amivantamab dose given varies according to each patient*s body weight. It
is 1750 mg for patients below 80 kg (in cycle1: 350 mg on day 1, 1050 mg on day
2, 1400 mg on day 8, 1400 mg on day 15, In cycle 2: 1400 mg on day 1, From
cycle 3 on: 1750 mg on day 1).
A bevacizumab dose of 15 mg per kilogram body weight will be given once every 3
weeks by infusion.
Lazertinib is an oral drug which is given in 3x 80 mg tablets to be taken once
a day.
Furthermore, the following study procedures/assessments will be performed:
Physical examination (including body weight, temperature, pulse rate and blood
pressure measurements), questions about general wellbeing to assess performance
or activity level, blood and urine tests, Radiological scans by CT and MRI of
the brain, cardiac function tests (ECG and LVEF), lung cancer biopsy.

The study procedures and tests can be found in the protocol (pages 18-21)
- Drawing blood can cause pain, redness, swelling or bruising at or near where
the needle enters the vein and can increase the risk of infection.
- There might be a risk of an allergic reaction related to contrast dye during
radiological test.
- Possible serious side effects for amivantamab:
Infusion-related side effects may occur during or shortly after an amivantamab
infusion is given. The most common side effects are nausea, chills, shortness
of breath, flushing, chest discomfort and vomiting. Less common
infusion-related side effects include fever, cough, itching, rash, changes in
blood pressure, fast heart rate and breathing rate, dizziness and decreased
oxygen level in the blood.
Very common (may affect more than 1 in 10 people) side effects are:
Rash, Infection or inflammation of the skin around the fingernail and other
nail problems, Itching, Dry or cracked skin, Infusion-related reactions,
Inflammation of the mouth or mouth sores, Constipation, Nausea, Vomiting,
Diarrhoea, Low levels of a blood protein called albumin (can cause generalized
swelling), Decreased appetite, Decreased blood calcium level that usually does
not cause symptoms but when severe, can cause muscle twitching and/or
contractions, abnormal heart beats or seizures, Decreased levels of potassium
in the blood that usually does not cause symptoms but when severe, can cause
abnormal heart rates that could be serious and life threatening, Tiredness,
Swelling in the hands, feet or limbs, Increased levels of liver enzymes in the
blood that usually does not cause symptoms, but can indicate liver damage,
Dizziness, Muscle aches or pain.
Common (may affect up to 1 in 10 people) side effects are:
Eye problems (such as dry eye, itchy eyes, vision problems, abnormal growth of
eyelashes), Abdominal pain, Inflammation of the lung (can cause sudden
difficulty in breathing, cough or fever), Low levels of magnesium in the blood
(can cause weakness and muscle cramping).
- Possible serious side effects for amivantamab and lazertinib combination
therapy:
Rashes, Toxic epidermal necrolysis, Venous thromboembolism, Lung Inflammation.
Very common (may affect more than 1 in 10 people) side effects are:
Rash, Infection or inflammation of the skin around the fingernail, Dry or
cracked skin, Itching, Infusion-related reactions, Inflammation of the mouth or
mouth sores, Nausea, Constipation, Diarrhoea.
Common (may affect up to 1 in 10 people) side effects are:
Eye problems (dry or itchy eye, vision blurred, visual impairment,
growth/thickening of eyelashes, conjunctivitis that is not infective, corneal
irritation, redness, pain, sensitivity to light, tearing, inflammation,
floaters), Inflammation of the lung, Muscle pain, Heartburn.
- Possible side effects for bevacizumab:
The side effects listed below were seen when bevacizumab was given together
with chemotherapy. This means the side effects may not have been caused by
bevacizumab.
Severe side effects with bevacizumab that may be very common (may affect more
than 1 in 10 people):
high blood pressure, feeling of numbness or tingling in hands or feet,
decreased number of cells in the blood, including white cells that help to
fight against infections (this may be accompanied by fever), and cells that
help the blood to clot, feeling weak and having no energy, tiredness,
diarrhoea, nausea, vomiting and abdominal pain.
Severe side effects with bevacizumab that may be common (may affect up to 1 in
10 people):
perforation of the gut, bleeding, including bleeding in the lungs in patients
with non-small cell lung cancer, blocking of the arteries by a blood clot,
blocking of the veins by a blood clot, blocking of the blood vessels of the
lungs by a blood clot, blocking of the veins of the legs by a blood clot, heart
failure, problems with wound healing after surgery, redness, peeling,
tenderness, pain, or blistering on the fingers or feet, decreased number of red
cells in the blood, lack of energy, stomach and intestinal disorder, muscle and
joint pain, muscular weakness, dry mouth in combination with thirst and/or
reduced or darkened urine, inflammation of the moist lining of mouth and gut,
lungs and air passages, reproductive, and urinary tracts, sores in the mouth
and the tube from the mouth to the stomach, which may be painful and cause
difficulty swallowing, pain, including headache, back pain and pain in the
pelvis and anal regions, localised pus collection, infection, and in
particular infection in the blood or bladder, reduced blood supply to the brain
or stroke, sleepiness, nose bleed, increase in heart rate (pulse), blockage in
the gut or bowel, abnormal urine test (protein in the urine),
shortness of breath or low levels of oxygen in the blood, infections of the
skin or deeper layers under the skin, fistula: abnormal tube-like connection
between internal organs and skin or other tissues that are not normally
connected, including connections between vagina and the gut in patients with
cervical cancer.
Severe side effects with bevacizumab of unknown frequency:
serious infections of the skin or deeper layers under the skin, especially if
you had holes in the gut wall or problems with wound healing, allergic
reactions (the signs may include difficulty breathing, facial redness, rash,
low blood pressure or high blood pressure, low oxygen in your blood, chest
pain, or nausea/vomiting), a negative effect on a woman*s ability to have
children, a brain condition with symptoms including seizures (fits), headache,
confusion, and changes in vision (Posterior Reversible Encephalopathy Syndrome
or PRES), symptoms that suggest changes in normal brain function (headaches,
vision changes, confusion, or seizures), and high blood pressure, an
enlargement and weakening of a blood vessel wall or a tear in a blood vessel
wall (aneurysms and artery dissections), clogging of a very small blood
vessel(s) in the kidney, abnormally high blood pressure in the blood vessels of
the lungs which makes the right side of the heart work harder than normal, a
hole in the cartilage wall separating the nostrils of the nose, a hole in the
stomach or intestines, an open sore or hole in the lining of the stomach or
small intestine (the signs may include abdominal pain, feeling bloated, black
tarry stools or blood in your stools (faeces) or blood in your vomit), bleeding
from the lower part of the large bowel, lesions in the gums with an exposed jaw
bone that does not heal and may be associated with pain and inflammation of the
surrounding tissue, hole in the gall bladder (symptoms and signs may include
abdominal pain, fever, and nausea/vomiting).
Very common side effects with bevacizumab that were not severe (may affect more
than 1 in 10 people):
constipation, loss of appetite, fever, problems with the eyes (including
increased production of tears), changes in speech, change in the sense of
taste, runny nose, dry skin, flaking and inflammation of the skin, change in
skin colour, loss of body weight, nose bleeds.
Common side effects with bevacizumab that were not severe (may affect up to 1
in 10 people):
voice changes and hoarseness.
Patients older than 65 years may have an increased risk of having the following
side effects with bevacizumab:
blood clot in the arteries which can lead to stroke or heart attack, reduction
in the number of white blood cells and cells that help the blood to clot,
diarrhoea, sickness, headache, fatigue, high blood pressure.