The therapeutic i mplications of eml4 alk ros 1 and other n ew biomarkers
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The Therapeutic I mplications of EML4/ALK, ROS-1 and Other N ew Biomarkers . Lyudmila Bazhenova , MD Associate Clinical Professor Lung Cancer Unit Leader UC San Diego Moores Cancer Center. Objectives. Review current state of targetable lung cancer biomarkers

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The Therapeutic I mplications of EML4/ALK, ROS-1 and Other N ew Biomarkers

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The therapeutic i mplications of eml4 alk ros 1 and other n ew biomarkers

The Therapeutic Implications of EML4/ALK, ROS-1 and Other New Biomarkers

Lyudmila Bazhenova, MD

Associate Clinical Professor

Lung Cancer Unit Leader

UC San Diego Moores Cancer Center


Objectives

Objectives

  • Review current state of targetable lung cancer biomarkers

  • Review and contrast clinical characteristics of patients with EML4-ALK, ROS 1, and KIFB5-RET fusion protein, testing strategies and agents with clinical activity.


Genomic evolution of lung c ancer

Genomic Evolution of Lung Cancer


Mechanism of action of alk ros1 and ret fusion o ncogenes

Mechanism of Action of ALK, ROS1 and RET Fusion Oncogenes

  • All three are receptor tyrosine kinases (RTK)

  • ALK and RET are capable of homodimerization and self (ligantindependend) activation

  • Mechanism of self activation of ROS1 is being debated

  • Downstream signaling via RAS/ERK (proliferation), and PI3K/AKT and JAK/STAT( resistance to apoptosis)


Testing for fusion oncogenes

Testing for Fusion Oncogenes

F

IHC expression

Break apart FISH

Amount of protein on the surface

of the cell

RT-PCR


Alk fusion gene

ALK Fusion Gene


Alk fusion g ene

ALK Fusion Gene

Echinoderm microtubule

associated protein-like 4

N

C

?

anaplastic lymphoma kinase

Adapted from Soda et al. Nature; 2007.


Alk fusion v ariants

ALK Fusion Variants

Sasaki, European Journal of Cancer; 2010.


Methods of alk detection

Methods of ALK Detection

  • FISH break apart

    • Pros: independent of FPE

    • Cons: if inversion involves a small locus of 2p it could be false negative; can not distinguish variants; cut of is 15% of nuclei with split signal; low throughput

  • RT-PCR

    • Pros: Rapid detection and identification of each unique variant

    • Cons: False negatives; Loss of RNA during de parafinization; has to be multiplexed, i.e probes to all known variants. Unknown variants will not be detected.

  • IHC

    • Pros: easy

    • Cons: several antibodies have been developed which look promising as a screening tool. No commercially available IHC in the US.

      • VENTANA just received an approval in China with 93% concordance with FISH, sensitivity 100%, specificity 98%


Eml4 alk fusion

EML4-ALK Fusion

  • Patients:younger, non smokers, with adenocarcinoma, adenosquamous carcinoma and rarely SCC

  • Frequency:4% in all, 33% in EGFR negative never smokers

  • Biology: 16 EML4-ALK variants have been identified in NSCLC. Clinical significance of each variant is unknown.

  • Testing:Visys break apart FISH (>15% cells with split signal in 50 nuclei scored).

    • ALK PCR, IHC

  • Therapy: crizotinib

1Shaw AT, ASCO; 2010;

2Kris MG. ASCO 2011; abstract CRA7506.

3Rodig SJ, Clin CancerRes; 2009;15

Soda M, et al. Nature; 2007;448


The therapeutic i mplications of eml4 alk ros 1 and other n ew biomarkers

Clinical Efficacy of Crizotinib

Some degree of tumor shrinkage 90%

ORR - 60.8%

DCR - 82.5% at week 8

Median time to response 7.9 weeks (2.1 - 39.6 weeks)

Median response duration 49.1 weeks

Median PFS 9.7 months (95% CI 7∙7–12∙8)

N=149

  • Unknown…

  • How crizotinib compares to chemotherapy 1st line

  • QOL

  • OS

  • TTP

Camidge, Lancet oncology 13, 2012


1 st line or second l ine

1stLine or Second Line

  • No studies examining the best placement of the drug.

  • FDA approved the drug without mentioning the line of therapy.

  • One can make a leap of faith from EGFR inhibitors and use it in the first line.

  • Profile 1007 compared crizotinib to 2nd line chemotherapy

    • PFS 7.7 m vs. 3 m in favor of crizotinib (HR 0.49; 95% CI, 0.37 to 0.64; P<0.001)

    • RR 65% vs. 20 % in favor of crizotinib ( p<0.001)

    • OS not different, 64% of patients in chemotherapy arm received crizotinib

    • QOL: greater reduction of symptoms and delay in new symptoms on crizotinib arm.

  • Profile 1014 will compare crizotinib to 1st line chemotherapy.

Shaw NEJM ;June 2013


The therapeutic i mplications of eml4 alk ros 1 and other n ew biomarkers

PFS

Shaw NEJM; June 2013.


Patient related o utcomes

Patient Related Outcomes

Shaw NEJM; June 2013


Characteristics of progression

Characteristics of Progression

  • Patients were allowed to stay on the study post progression if they continued to derive clinical benefi

  • Median duration of treatment 43.1 m (Range 0.1-136.8)

  • 69/149 patients had disease progression at the data cut off.

    • 39 continued to receive crizotinib for at least 2 weeks post progression

      • 12 of them did that for 6 months

      • Range of post progression treatment is 21 to 591 days.

    • Most common new sites of progression were brain ( N=10), lung (n=5), liver ( N=3)

Camidge, Lancet oncology 13, 2012.


Duration of initial r esponse a nd post p rogression t herapy

Duration of Initial Response and Post Progression Therapy


Crizotinib resistance

CrizotinibResistance

  • L1196M

  • L1152R

  • C1156Y

  • F1174L

Sasaki Clinical Cancer Research. Epub2011.


Management of crizotinib r esistance

Management of CrizotinibResistance

  • Local treatment with radiation for locally progressing disease

    • Clonal evolution

  • Platinum based doublet or triplet

  • Second generation ALK inhibitors

    • AP26114

    • LDK378

    • CH5424802 (RG7853)

  • HSP 90 inhibitors


Responses to second g eneration i nhibitors in crizotinib r esistant tumors

Responses to Second Generation Inhibitors in crizotinibResistant Tumors

  • LDK378( phase I)

    58% ORR1

    • CNS penetration

  • CH5424802 ( phase I/II)

    • 48% ORR2

    • CNS penetration

  • AP26113 ( phase I/II)

    • 76% ORR3

    • CNS penetration

1Shaw. ASCO 2013 abstr 8010.

2Gadgeel, World Lung 2013, O16.06.

3Camidge. World Lung, MO0706


Ros1 fusion

ROS1 Fusion


Oncogenic ros1

Oncogenic ROS1

  • First described fusion gene FIG-ROS1 was found in glioblastoma

    • 240kb deletion on 6p21q resulting in a fusion gene coding for oncogenic fusion protein.

    • Short and long isoforms

    • Induce tumorigenesis in xenograft mouse models

  • Also expressed in cholangiocarcinoma in 8.7% and ovarian cancer in 0.5%, gastric and colon, myofibroblastic tumors and angiosarcoma

  • EZR–ROS1 fusion gene has been shown to promote lung adenocarcinoma when ectopically expressed in lung epithelium

Gu TL, PLoS One; 2011.

Birch AH, PLoS One; 2011;

Lee, Cancer; May 2013

Bergethon et al. JCO; 2012 (30)8.


Ros 1 f usion gene

ROS 1 Fusion Gene

Arai, PLOS ONE; February 2013.


Ros 1 f usion g ene variants

ROS 1 Fusion Gene Variants


Ros1 fusion1

ROS1 Fusion

  • Patients:Younger, never smokers, adenocarcinoma, high grade histology

  • Frequency: 1.2 -1.7% in all

  • Biology: 9 variants have been identified in NSCLC so far

    • Clinical significance is unknown. Mechanism of activation is different.

    • FIG-, CD74-, SCL34A2-, TPM3-, SDC4-, EZR-, LRIG3, KDELR2–, and CCDC6–

  • Testing:Visys break apart FISH (>15% cells with split signal in 50 nuclei scored)

    • ROS PCR, IHC

  • Therapy: crizotinib

Shaw AT, JCO 2012;30:(suppl; abstr 7508)

Ou, Exprevi. of anticancer therapy 2012,;12

GuTL, PLoSOne. 2011; 6:e15640.

Birch AH, PLoSOne. 2011; 6:e28250

Lee, Cancer May 2013

Davis ClinCancer Res . Sep 2012

Bergeron, JCO, 30, 2012


Methods of ros1 detection

Methods of ROS1 Detection

  • RT-PCR

    • Cons: False negatives; 9 variants have been described in a matter of 12 months. Has to be multiplexed, i.e., probes to all known variants. Unknown variants will not be detected.

  • FISH break apart

    • Cons: if inversion involves a small locus it could be false negative; can not distinguish variants; cut of is 15% of nuclei with split signal; low throughput

  • IHC

    • Cons: not commercially available, several antibodies appear promising


Response of a ros1 positive p atient to c rizotinib

Response of a ROS1 Positive Patient to Crizotinib

  • 49% homology in the TK domain and ATP binding site

  • Crizotinib is active in ROS1 fused cell cultures

12 weeks

Baseline

Bergeron, JCO, 30, 2012.


Clinical validation of ros1 as a therapeutic t arget

Clinical Validation of ROS1 as a Therapeutic Target

  • 14 patients enrolled in phase I study

  • Safety/efficacy of crizotinib 250mg bid

  • ROS1 rearrangement by FISH

  • Negative for ALK rearrangement

  • Average 54 yo, 13/14 never smokers

  • 80% received prior therapy

  • 8/14 responded (57%)

Shaw et al. JCO. 2012, 30 (suppl; abstr7508.)


Ret fusion

RET FUSION


Methods of ret detection

Methods of RET Detection

  • RT-PCR

    • Cons: False negatives; 3 variants have been described in a matter of 12 months. Has to be multiplexed, i.e probes to all known variants. Unknown variants will not be detected.

  • FISH break apart

    • Cons: if inversion involves a small locus it could be false negative; can not distinguish variants; cut of is 15% of nuclei with split signal; not widely available; low throughput

  • IHC

    • Current IHC antibodies do not correlate with RET fusion


Ret fusion g ene

RET Fusion Gene


Ret fusion1

RET Fusion

  • Patients:AdenoCAand adenoSCC carcinoma, never or former smokers, poor differentiation ?, earlier LN metastases

  • Frequency:

    • 1.4% in all,

    • 5.6 % in “triple negative”( EGFR, ALK, KRAS)

    • 6.3% in non smokers negative for EGFR, KRAS, ALK, HER2, BRAF, and ROS1

    • 16% in non smokers negative for EGFR, KRAS, ALK, ROS1, NRAS, BRAF, HER2, PIK3CA, MEK1, and AKT

  • Biology:4variants have been identified in NSCLC so far

    • Clinical significance is unknown.

    • KIF5B-, CCDC6-, NCOA4-. TRIM33

Ju YS, Genome Res, 2012 Drilon, CancerDiscoverMarch 2013

Wang R, J ClinOncol 30: 2012 Kohno, Cancer Science Aug 2013


Ret f usion g ene

RET Fusion Gene

  • Testing:Visys break apart FISH (> 15% cells with split signal in 50 nuclei scored)

    • RET PCR

  • Therapy: Unknown

    • Sunitinib, Sorafenib, Vandetanib, Carbozatinib, Ponatinib, and Lenvatinib all have potential for activity

    • All active in KIF5B-RET–transformed cell lines

    • Last 4 are in formal clinical trials


Clinical activity of c arbozatinib in ret fused patients

Clinical Activity of Carbozatinibin RET Fused Patients

4 weeks

4 weeks

4 weeks

Drilon, Cancer Discover March 2013.


Summary

Summary


Her 2 insertions

HER 2 Insertions

  • Patients:Adenocarcinomas, never smokers

  • Frequency:Incidence 2.8-4.2%

  • Biology:

    • In-frame insertions into exon 20. Transgenic mouse models confirm oncogenicity

  • Therapy:

    • Drugs of interest: neratinib, afatinib, dacomitinib

      • Preclinical models show synergy with mTORinhibitors.

      • Clinical trial of neratinib + temsirolimusongoing, several PR are reported

      • Both afatinib and dacomitinib have case reports of responses


Braf mutations

BRAF Mutations

  • Patients: smokers and non smokers

  • Frequency: 1.6-3%

  • Biology: majority of the mutations are non V600E (more likely in smokers), V600E ( more likely in never smokers)

  • Therapy:

    • One case report or a NSCLC patient with V600E patient responding to vemurafenib

    • Dabrafenib is being tested in patients with V600E NSCLC

    • MEK inhibitors are being considered for non V600E patients


The therapeutic i mplications of eml4 alk ros 1 and other n ew biomarkers

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