ALK INHIBITORS IN ALK NSCLC

1. ALK INHIBITORS NSCLC

2. CANCER RELATED DEATH WORLDWIDE.
-NSCLC ACCOUNTS FOR ABOUT 85% OF LUNG
CANCER.
-UNFORTUNTLY, ABOUT 75% OF NSCLC ARE
DIAGNOSED LATE WITH METASTATIC DISEASE,
WITH 5 YEARS SURVIVAL RATE IS ONLY 5 %.
-SMOKING,TOGEATHER WITH OTHER
CARCINOGENS E.G “ CHROMIUM, ARSENIC ,
NICKLE, RADON” STILL THE MOST COMMON
CAUSE.
-AND , WE ALL NOW KNOW THAT THERE ARE

3. “GLOBOCAN 2020”

9. 8TH
6T
H

11. -LUNG CANCER IN LAUNGUAGE OF
NUMBERS:
A.WORLDWIDE:
.MOST COMMON CANCER IN MALES WORLDWIDE
.MOST COMMON CAUSE OF CANCER RELATED DEATH IN MALES
WORLDWIDE
. 3RD MOST COMMON CANCER IN WOMEN WORLDWIDE
.2ND MOST COMMON CAUSE OF CANCER RELATED DEATH IN
WOMEN WORLDWIDE
B. JORDANIAN:
.3RD MOST COMMON CANCER IN BOTH SEXES AND MOST COMMON
CANCER IN JORDANIAN MALES
.MOST COMMON CANCER ELATED DEATH IN JORDANIAN MALES
C. LUNG CANCER:

13.  44 YEARS OLD FEMALE PATIENT
HOUSEWIFE, MARRRIED WITH 3 OFF-SPRINGS
NEITHER SMOKER , NOR ALCOHOLIC
HYPOTHYROIDISM ON L.TYROXIN
NEGATIVE FAMILY HISTORY FOR LUNG OR
OTHER CANCERS
NO NKDA AND NOT ON OTHER MEDICATIONS

14. -HISTORY OF COVID-19 INFECTION 4 MONTHS
PRIOR TO PRESENTATION , COVID-19 RELATED
RESPIRATORY SYMPTOMS IMRPOVED GRADUALLY
BUT DIDN’T DISAPPERED, PATIENT MAINLY HAD
RESIDUAL SHORTNESS OF BREATH AND EASY
FATIGUE
.SHE SOUGHT HELP AT PULMONARY TEAM FOR
FOLLOW UP AS ” POST COVID-19 CASE”: NOTES
1.POST COVID-19
2. DYSPNEA ON ORDINARY EFFORT
3.INTERMITTENT DRY COUGHING
4.O2SAT 95%
5. DULL PERCUSSION LEFT LOWER LUNG FIELD

15. FOLLOW:
.LABS:
HB:11.9 WBC:8.9 PLT.:21,000
CHESISTRY:NORMAL
.CXR:MODERATED LEFT SIDED
PLEURAL EFFUSION AND PLEURAL
THICKENING
.PET SCAN: HYPERMETABOLIC LEFT
PLEURAL THICKENING, BILATERAL
LUNGS , SUPRACLAV AND INTRA
ABDOMINAL LN

18. PET SCAN REPORT

19. -CT GUIDED PLERURAL BIOPSY WAS THEN
DONE:

22. -DIAGNOSIS WAS MADE:
NSCLC-ADENOCARCINOMA STAGE
IV-B

23. “MUTATION ANALYSIS WAS SENT
PRIOR TO TREATMENT AS PER
GUIDELINES”

26. -OUR PATIENT WAS TESTED FOR :
1. EGFR: WILD TYPE
2. PDL-1:NEGATIVE
+
3. ALK –EML FUSION:POSITIVE

28. .The ALK gene is located at chromosome 2
.ALK GENE CODES FOR ALK-TYROSIN KINASE RECEPTOR
.There is great similarity to insulin receptors and togeather with it
belongs to the insulin receptor subfamily of the whole tki-receptors
superfamily
. ALK-TK RECEPTOR consists of 3 domains:
an extracellular domain , transmembrane and intracellular domain
. Pleiotrophin and midkine display neurotrophic functions on receptor
binding, so this binding results in proliferation of nerve cells during
embryogenesis
.SO, The receptor ALK plays a pivotal role in cellular
communication and in the normal development and function of the
nervous system.

29. Different mutations occurs in Alk gene This results in ligand-independent
dimerization and, thus, continuous activation of the ALK-tyrosin kinase receptor:
A. POINT MUTATION :
.Point mutations have been found in 6 to 8% of primary neuroblastomas
B. GENE RE-ARRANGEMENT:
Several types of ALK gene rearrangements (ALK fusion genes) have been found
in many types of cancers:
. ALK was first identified as the fusion gene nucleophosmin (NPM)1-ALK in
ALCL in 1994:
.2;5 chromosomal translocation is associated with approximately 60% ALCL
. In 2007, a novel ALK fusion gene, EML4-ALK, was discovered in lung cancers
as a strong driver oncogene
+. EML-4 gene : is a member of the echinoderm microtubule family. encode
protein that is involved in microtubule formation AND stabilization

30. Tumor type ALK alteration Incidence
Lung cancer EML4-ALK 3–7%
Breast cancer EML4-ALK
0–2.4% FUSION GENE
Colorectal cancer EML4-ALK 0–2.4%
ALCL NPM-ALK 60–80%
Neuroblastoma Point mutations 6–8%, 4.4%
point

32. -IHC:
A laboratory method that uses antibodies to check for
certain antigens (markers) in a sample of tissue. The
antibodies are usually linked to an enzyme or a fluorescent
dye.
After BINDING OF antibodies to the antigen in the tissue
sample, the enzyme or dye is activated, and the antigen can
then be seen under a microscope.
.
-IHC analysis using anti-ALK antibodies (such as clone 5A4),
which recognize the tyrosine kinase domain of ALK.

35. -Fluorescence in situ hybridization (FISH) :
.is a laboratory technique for detecting and locating a
complementary DNA sequence on a chromosome.
.The technique relies on exposing chromosomes to a
small DNA sequence called a probe that has a
fluorescent molecule attached to it.
.(This probe) sequence binds to its corresponding
sequence (ALK-EML FUSION GENE)
SEQUENCE.

37. Alk gene
Eml gene
Eml gene
Alk gene
Alk-eml

39. .ROS1 is a receptor tyrosine kinase (encoded by the gene ROS1). This proto-
oncogene is located on chrmosome 6.
.mutation in this gene results in over activation of ROS1-TKR..ROS-1 FUSION is
the most common mutation that occured with many other different genes .
. ROS1-TKR :has structural similarity to the anaplastic lymphoma kinase (ALK)
protein and it is mutually exclusive to ALK rearrangement
. in 2007 a ROS1 fusion was 1stly identified in a cell line derived from a lung
adenocarcinoma patient.
. Accounts for about 2% of NSCLC , 7patients tend to be younger, with a median
age of 49.8 years, never-smokers , Asian ethnicity and patients with Stage IV
disease ,
. The ROS1ders : is a worldwide collaboration of ROS1+ cancer patients and
caregivers with a goal of improving patient outcomes and accelerating research for
any type of ROS1+ cancer. It is the first such collaboration focused on cancers
driven by a single oncogene.

40. Cancer Type ROS1 Fusion Gene
NSCLC
FIG - ROS1*; SLC34A2 - ROS1*; CD74 -
ROS1*; SDC - ROS1*; EZR - ROS1; LRIG3 -
ROS1; TPM3 - ROS1
Gastric SLC34A2 - ROS1*
Colorectal SLC34A2 - ROS1*
Spitzoid melanoma TPM3 - ROS1
Cholangiosarcoma FIG - ROS1*
Glioblastoma FIG - ROS1*
Ovarian FIG - ROS1*
Angiosarcoma CEP85L-ROS1

42. -ALK INHIBITORS:
1st GENERATION : PFIZER :investigated Crizotinib as MEK -inhibitors
,But then Pfizer shifted its investigations to focus on ALK-positive + ROS-posstive
NSCLC ,it was approved in Aug 2011 by the US FDA for this indication./
PROFILE 1007 TRIAL
-2nd GENERATION
AFTER this significant crizotinib success, there was a need to conceive new drugs
with better brain penetrance and can overcome the newly developed resistance
mutation, thus:
.Novartis: ceritinib was approved by the FDA in 2014 for treatment of NSCLC/
ASCEND-4 trial.
.Roche : alectinib was FDA approved in 2017 FOR treatment for ALK-positive
NSCLC./alex trial
. Ariad's and Takeda: brigatinib which was the latest second-generation
inhibitor and was approved in April 2017 by the US FDA for ALK-positive
NSCLC
-3rd GENERATION:

43. -Profile 1004 was published on June 1,2013
From February 2010
through February
2012

45. 4M
8 M

48. -CONCLUSION OF PROFILE 1007:
. This study showed that crizotinib, as compared
with chemotherapy, prolonged progression-free
survival, increased response rates, and improved
the quality of life in patients with advanced,
previously treated ALK-positive non–small-cell
lung cancer.

49. 2016

55. “OUR PATIENT WAS STARTED ON
XALKORI-CRIZOTINIB”

57. -DOSAGE:
.The recommended dosage of XALKORI for patients with NSCLC is 250 mg
orally twice daily, with or without food, until disease progression or TOXICTY
-STRENGTHS: Capsules: 250 mg, 200 mg.
-THE Recommended Dosage Reductions: ALK- or ROS1-positive metastatic
NSCLC ARE:
First dose reduction: XALKORI 200 mg taken orally twice daily
Second dose reduction: XALKORI 250 mg taken orally once daily
Permanently discontinue if unable to tolerate XALKORI 250 mg taken orally once
daily.
-MONITORING:
. Baseline: CBC, creatinine, alkaline phosphatase, ALT, total bilirubin, LDH,
calcium, magnesium, sodium, potassium, ECG
.should be checked every two weeks during cycle 1 and cycle 2 and at each
subsequent visit thereafter
. PREMEDICATIONS: no premedications needed

58. - ADVERSE REACTIONS:
The most common adverse reactions (≥25%) in
patients with NSCLC are :
1.GIT :
nausea, diarrhea, vomiting, edema, constipation,
elevated transaminases, fatigue, decreased appetite,
2. VISIUAL DISORDERES
3. Embryo-Fetal Toxicity: Can cause fetal harm.
Advise females of reproductive potential of the
potential risk to a fetus and use of effective
contraception

59. ANC (x109 /L)+- Platelets (x109 /L) Dose
greater than or
equal to 1.0
and greater than or equal to 50 250 mg twice daily
0.5 to less than 1.0 or 25 to less than 50 Withhold until
recovery, then
resume at same dose
schedule
less than 0.5 or less than 25 Withhold until
recovery, then
resume at 200 mg
twice daily
-a In case of recurrence , withhold until recovery, then resume at 250 mg once daily
-Permanently discontinue in patients who are unable to tolerate XALKORI after 2 dose
reductions.
1. Hematological:
- WARNINGS ,PRECAUTIONS AND DOSE MODIFICATIO
Severity of Adverse Reaction DOSE MIDIFICATION
Grade 3
Withhold until recovery to Grade 2 or less,
then resume at the same dosage.
Grade 4
Withhold until recovery to Grade 2 or less,
then resume at next lower dosage.

60. Baseline bilirubin > 1.5 x ULN
and ≤ 3 x ULN (with any ALT or
AST)
Reduce starting dose to dose level
-1 (200 mg twice daily)
Baseline bilirubin > 3 x ULN (with
any ALT or AST)
Reduce starting dose to dose level -
2 (250 mg once daily)
ALT elevation to > 5.0 x ULN with
bilirubin ≤1.5 x ULN
Withhold until recovery of ALT to
≤ 3.0 x ULN or baseline, then
resume at the next lower dosea
ALT elevation to > 3.0 x ULN and
concurrent bilirubin elevation to >
1.5 x ULN
Permanently discontinue
2. Hepatic Dysfunction: : Crizotinib is extensively metabolized in the liver and
hepatic impairment may result in higher plasma concentrations.
3-RENAL IMPAIRMENT: The recommended dosage of XALKORI in patients
with severe renal impairment ( (CLcr) less than 30 mL/min, not requiring dialysis)
is : 250 mg orally once daily

61. 4.CARDIOTOXOCITY:
-QT interval prolongation and symptomatic bradycardia have been observed in
patients treated with crizotinib. SO IT should be administered with caution in
patients with pre-existing LONG QT or symptomatic bradycardia . And , in
those who are taking medications that are known to prolong the QT interval or
bradycardia
-treatment interruption and subsequent dose reduction is required UNTIL QTc ≥
500 msec AND HEART RATE > 60.
-PERMANENT D/C IF PERSISTANT QTc ≥ 500 msec AND
HEART RATE > 60 DESPITE 2nd dose reduction or if torse de
point , polymorphic v.tach
-5.RESPIRATORY:
-Crizotinib has been associated with severe, life-threatening pneumonitis. occurred within
3m
-3 % of XALKORI-treated patients had ILD of any grade, 1% had Grade 3 or 4 ILD, and
0.5% had fatal ILD

62. 7.Ocular Toxicity, including Visual Loss
Visual Symptoms, Grade 1 (mild symptoms)
or Grade 2 (moderate symptoms affecting
ability to perform age-appropriate activities
of daily living)
Monitor symptoms and report any symptoms
to an eye specialist. Consider dose reduction
for Grade 2 visual disorders.
Visual Loss (Grade 3 or 4 Ocular Disorder,
marked decrease in vision) the incidence of
Grade 4 visual field defect with visual loss was
0.2%
Permanently discontinue XALKORI for
Grade 3 or 4 ocular disorders, if no other
cause found on evaluation
8.Gastrointestinal Toxicity: Grade 3 and more occurred in 27% of patients
Vomiting (Grade 3: more than 6 episodes in 24
hours for more than 3 days, , Grade 4: life-
threatening consequences, urgent intervention
indicated)
Grade 3 or 4 (despite maximum medical therapy):
Withhold until resolved, and then resume at the next
lower dose level.§
Diarrhea (Grade 3: increase of 7 or more stools
per day Grade 4: life-threatening
consequences, urgent intervention indicated)
Grade 3 or 4 (despite maximum medical therapy):
Withhold until resolved, and then resume at the next
lower dose level.

63. -Drug interactions: Crizotinib is a substrate of CYP3A. The concurrent use of
strong CYP3A inhibitors may increase crizotinib plasma concentration and
should be avoided. The concurrent use of strong CYP3A inducers may decrease
crizotinib plasma concentration and should be avoided:

67. -FOLLOW-UP PET SCAN SHOWED:
1.DIS-APPEARANCE OF INTRA
ABDOMINAL LNS
2.ONLY MILD LEFT SIDED PLEURAL
EFFUSION
3.DECREASE IN SIZE AND
METABOLIC ACTIVITY OF LEFT
PLEURAL THICKENING

68. Decreased in size of
metastatic brain
lesions

69. -CONCLUSION:
.CRIZOTINIB WAS WELL-TOLERATED
.DRAMATIC REPSONSE WAS SEEN
AFTER 4 MONTHS ONLY OF XALKORI
.THE RESPONSE WAS OBSERVED IN BOTH
SYSTEMIC AND BRAIN METASTATIC
LESIONS
.WE AND THE PATIENT ARE SATISFIFED
WITH THIS CURRENT STATUS.

70. THANK YOU