The management of advanced nonsmall cell lung cancer (NSCLC) has gone a definitive
change over time with the discovery of small-molecule inhibitors. In 2004, the first
initial description of actionable mutation of epidermal growth factor receptor (EGFR)
was provided, and since then, almost 10 actionable mutations have been identified.[1] These include EGFR, anaplastic lymphoma kinase (ALK), ROS, MET, rearranged during
transfection (RET), Kirsten rat sarcoma viral oncogene (KRAS), raf murine sarcoma
virus oncogene homolog B (BRAF), and many others. After the development of the drugs
against these receptors, these were approved by US Food and Drug Administration (FDA)
for used against NSCLC with the receptor mutations.
The most common receptor tyrosine kinase mutations in adenocarcinoma lung are as follows:[2]
-
KRAS mutation in 25% of cases of NSCLC
-
EGFR mutation—10 to 30%
-
MET amplification or MET exon 14 mutation—5%
-
ALK mutation—3 to 7% cases
-
BRAF mutations—2 to 4%
-
Rest others: RET rearrangements, MEK1 mutation, FGFR1 amplification, Her2 mutation,
ROS1 rearrangements, and NRAS mutation occur in 1% each
-
The majority are still unknown—40%.
The drugs are very effective for patients with actionable mutant NSCLC with the response
rates of 60 to 85% in the first-line setting. The main barrier is the development
of resistance after a few months of treatment, which limits the duration of response
to ~1 to 2 years for most of the drugs.[3]
Anaplastic Lymphoma Kinase Rearrangements
Anaplastic Lymphoma Kinase Rearrangements
ALK being the first reported oncogene in NSCLC in 2007 is usually found fused to echinoderm
microtubule-associated protein-like 4 (EML4) gene, leading to its permanent activation,
and hence, leading to cellular proliferation. The other fusion loci are TFG, KIF5B,
and KLC1.[4]
[5]
[6]
[7]
[8]
It is detected in 3 to 7% cases of NSCLC and seen in younger patients who are light
or never smokers, and their presentation is usually at the advanced stage.[8] Since 2007, small-molecule ALK tyrosine kinase inhibitors (TKIs) are being developed
and are found to be highly sensitive in ALK-rearranged NSCLC.
Diagnostic tools for targeted mutation in carcinoma lung:[9]
-
Fluorescence in situ hybridization (FISH) analysis: It is the gold standard technique
for ALK mutation testing. Vysis ALK break apart FISH probe kit manufactured by Abbot
was approved by FDA for the use in 2011. The probe has two fluorophores-red binding
to 3′ end of ALK gene and green binding to 5′ end. When the translocation is seen,
the probe shows separated red and green fluorophores, or has loss of the green signal,
but we have to examine 15% or more cells for the mutation to be labeled as positive.
The demerits of FISH are as follows: (1) costly, (2) it requires expert and experienced
pathologist for interpretation, (3) provides information only about the translocation
of ALK gene and not about the fusion partners, and (4) is time-consuming. However,
it is very accurate and detects all the ALK rearrangements.
-
Immunohistochemistry (IHC): ALK can be readily identified by IHC, but the protein
levels in NSCLC are lower compared with anaplastic large-cell lymphoma that makes
it difficult to attempt. The antibodies commonly used are D5F3, ALK clone ZAL4, and
5A4, and in India, we are commonly using D5F3 antibodies. It is still not a preferred
method because of the problems faced during tissue preparation, antibody choice, signal
enhancement systems, and the optimal scoring system, which are not standardized as
yet. It is helpful because of low cost, easy to be performed and interpreted by pathologist,
quick results and with the background histological information.
Other problem with IHC is the discordant results went compared with FISH, which are
in the range of 1 to 10%. This problem may be due to intrachromosomal translocations
that are not detected on FISH and the patients are labeled as IHC+/FISH-ve. These
patients when treated with crizotinib show similar objective response rate (ORR) and
disease control rate as compared with FISH positive patient in PROFILE 1001 trial.
Hence, IHC+/FISH-ALK-positive patients can still be treated with ALK TKIs.[10]
-
Polymerase chain reaction (PCR) by either reverse transcriptase or 5′ rapid amplification
of cDNA ends-PCR helps finding out the fusion protein when specific primers are added.
It helps in identifying DNA from a diluted sample with good sensitivity and specificity.
However, PCR fails to identify unknown fusions or novel fusions affected by sample
contamination and quality of sample.
-
Next-generation sequencing: The technique of genomic profiling of the sample DNA to
identify the ALK mutation or fusions missed by FISH. It can identify complex rearrangements
in the genome and helps in identifying the mutations in patients who are IHC positive
and FISH negative. It helps in the diagnosis of driver mutations not identified by
other methods, but is time-consuming and costly.
-
Exon-array profiling can be used for the detection of alk-eml4 fusion by the expression
of transcripts at 3′ and 5′ end of ALK gene. The details of ALK inhibitors are given
with evidence in [Table 1].
Table 1
Anaplastic lymphoma kinase inhibitors with their properties and evidence
|
Drug
|
Gen
|
Dose
|
RR
|
PFS (months)
|
AEs
|
Evidence
|
|
Abbreviations: AE, adverse effect; AV, atrioventricular; CNS, central nervous system;
CPK, creatine phosphokinase; CYP, cytochrome P450; Gen, generation; ILD, interstitial
lung disease; LFT, liver function test; PFS, progression-free survival; p-gp, glycoprotein-P;
RR, response rate.
|
|
Crizotinib
|
1st
|
250 mg twice a day (with/without food)
|
74% (1st line) 65% (2nd line)
|
10.9 (1st line) 7.7 (2nd line)
|
Visual disturbances Transaminitis
|
PROFILE101417
(1st line)
|
|
|
|
|
|
Nausea/vomiting
Diarrhea/abdominal pain
Cytopenia
Fatigue
Edema
Hypophosphatemia
QTc prolongation
Renal cysts
|
PROFILE100718
(2nd line)
|
|
Ceritinib
|
2nd
|
750 mg fasting or 450 mg with food19
|
72.5% (1st line)
|
26.3 (no brain
mets:1st line)
16.6 (brain
mets:1st line)
5.4 (2nd line)
|
Transaminitis
Nausea/vomiting
Diarrhea/abdominal pain
Cytopenia
Hyperglycemia
Hypophosphatemia
Fatigue
Increased creatinine
QTc prolongation
|
ASCEND-120 ASCEND-521
(both 2nd line)
ASCEND-422
(1st Line)
|
|
Alectinib
|
2nd
|
600 mg twice a day after food
|
92% (1st line)
|
25.7 (1st line) 7.5–11 (2nd line, postcrizotinib)23,24
|
LFT derangement
Cytopenia
Elevated CPK
Hyperglycemia
Hyponatremia Hypophosphatemia
Raised creatinine
Bradycardia
Fatigue
Edema
Constipation
|
J-ALEX
Global ALEX25
(1st line)
|
|
Brigatinib
|
2nd
|
90 mg for 7 days than 180 mg once a day (with/without food)
|
54% in crizotinib refractory
|
12.9 (1st line)
|
Early ILD
Transaminitis
Hyperglycemia
Hypertension
Bradycardia
Fatigue
Nausea
Diarrhea
Headache
Increased CPK
|
ALTA phase II
trial26
|
|
Lorlatinib
|
3rd
|
100 mg once a day (with/without food)
|
46% in heavily pretreated patients
|
11.4 and has high CNS penetration unlike other P-gp
drugs13
|
Hypercholesterolemia
Hypertriglyceridemia
Edema
Neurocognitive dysfunction
Mood lability
Peripheral neuropathy
Second-degree AV block or
Complete heart blocks
Interstitial lung disease
Contraindicated when strong CYP
P450 inducers are used
|
|
Resistance Mechanism
First Generation
Usually, patients experience progression after 1 to 2 years of treatment. About 20
to 30% cases of resistance to first-line ALK inhibitors are due to ALK tyrosine kinase
domain facing steric hindrance at the adenosine 5′-triphosphate binding site (L1196M-analog
of T790M of EGFR). At progression, as only 20 to 30% ALK-positive NSCLC will have
ALK TDK mutations after the use of crizotinib, compared with EGFR where it is in range
of 60%. Hence, the reassessment with repeat biopsy or circulating free DNA is not
required in ALK positive cases progressed on first-line ALK inhibitors.
The other mechanisms are mutation in solvent-exposed kinase region binding site (G1202R)
and 1151Tins, ALK amplification leading to single-crystal fibers amplifications, and
bypass pathways such as EGFR, MET, and KRAS. Even in few cases, histological transformation
may be a cause known as epithelial to mesenchymal transition. Among these ALK mutations,
10% cases are where ALK amplification leads to the resistance to crizotinib.[11]
[12]
Second Generation
In the second-generation, ALK TKI’s most important mechanism is a change in the ALK
kinase domain or the solvent-exposed kinase region.
However, still certain studies have found patients acquiring compound mutations over
time.
Other off-target pathways are the same as the first-generation drugs. The therapy
and sequencing of ALK inhibitors for ALK positive NSCLC are shown in [Fig. 1].
Fig. 1 Therapy for anaplastic lymphoma kinase positive nonsmall cell lung cancer at progression
guided by the next-generation sequencing.[27]
Newer Anaplastic Lymphoma Kinase Small Molecules
Newer Anaplastic Lymphoma Kinase Small Molecules
-
Lorlatinib—Dual ALK and ROS1 inhibitor and active against most of the ALK resistance
mutations. It is even used in the combination when patients are found to be having
compound mutations. This third-generation ALK TKI is a low efflux substrate of P-gp
and hence has high central nervous system (CNS) penetration and activity, even in
highly pretreated patients with >1 ALK TKIs. Lorlatinib showed ORR of 46% and PFS
of 11.4 months in phase I of phase I/II clinical trial and ORR of 42% and PFS of 9.2
months in patient treated with >2 lines of ALK inhibitors.[13] The recommended dose is 100 mg once a day and major Grade 3 adverse effects (AEs)
are hypercholesterolemia, hypertriglyceridemia, and edema that are most commonly seen.
Reversible CNS side effects are neurocognitive disorders, mood lability, and peripheral
neuropathy. Combined mutations have shown to cause resistance to lorlatinib than single-gene
mutations, for example, C1156Y+L1198F. Mutation to third-generation ALK inhibitors
occur due to complex mechanism and not due to acquisition of secondary mutations in
ALK-EM4. These mutations occur due to activation of by-pass mechanisms like loss of
NF2 or EMT, this mechanism is called loss of ALK dependency, and compound mutations.[14]
[15]
-
Ensartinib—Another third-generation molecule with activity against—ALK, ROS1, MET,
AXL. It has good CNS penetration. In phase II trials, responses shown are 77% in crizotinib
naïve and 73% in crizotinib-treated patients.[16] The dose recommended is 225 mg once a day till progression or unacceptable toxicities.
Most common AEs are mild rash, nausea, vomiting, fatigue, and pruritus.
-
Repotrectinib (known as TPX-0005)—It has activity against ALK, ROS, and TRK kinases.
It was specially designed to overcome G1202R mutation but is affective against SRC
amplification and FAC mutations. It is undergoing phase I study at present.
