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Tanja Cufer, MD, PhD University Clinic Golnik Medical Faculty Ljubljana, Slovenia 5th ESO-ESMO Masterclass in Medical Oncology Belgrade, 2018 Chemotherapy and Targeted Therapy for Lung Cancer

Chemotherapy and Targeted Therapy for Lung Cancer...Introduction of Targeted Therapy Lung Cancer Mutation Consortium Kris MG, et al. JAMA 2014. UCG registry data 2010 - 2013 Cufer

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Page 1: Chemotherapy and Targeted Therapy for Lung Cancer...Introduction of Targeted Therapy Lung Cancer Mutation Consortium Kris MG, et al. JAMA 2014. UCG registry data 2010 - 2013 Cufer

Tanja Cufer, MD, PhD

University Clinic Golnik

Medical Faculty Ljubljana, Slovenia

5th ESO-ESMO Masterclass in Medical Oncology

Belgrade, 2018

Chemotherapy and Targeted Therapy for Lung Cancer

Page 2: Chemotherapy and Targeted Therapy for Lung Cancer...Introduction of Targeted Therapy Lung Cancer Mutation Consortium Kris MG, et al. JAMA 2014. UCG registry data 2010 - 2013 Cufer

Disclosure

I have attended advisory boards and/or provided lectures for the following organizations:

AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Roche, MSD, and Pfizer.

I declare no conflict of interest.

Page 3: Chemotherapy and Targeted Therapy for Lung Cancer...Introduction of Targeted Therapy Lung Cancer Mutation Consortium Kris MG, et al. JAMA 2014. UCG registry data 2010 - 2013 Cufer

Lung Cancer: Evolution of Systemic Therapy

Alkylating/Anth-racycline -based Chemotherapy

• Platinum Based Chemotherapy

• Concurrent Cht-RT

Individualized ChtApproaches

Targeted Therapy and Sequencing

Immunotherapy and Combinations

1980s 1990s 2000-05 2005-10 2010s

Page 4: Chemotherapy and Targeted Therapy for Lung Cancer...Introduction of Targeted Therapy Lung Cancer Mutation Consortium Kris MG, et al. JAMA 2014. UCG registry data 2010 - 2013 Cufer

Chemotherapy and Targeted Therapy for SCLC

Page 5: Chemotherapy and Targeted Therapy for Lung Cancer...Introduction of Targeted Therapy Lung Cancer Mutation Consortium Kris MG, et al. JAMA 2014. UCG registry data 2010 - 2013 Cufer

Systemic Therapy for SCLC

Sorry - No important news since 2005.

Page 6: Chemotherapy and Targeted Therapy for Lung Cancer...Introduction of Targeted Therapy Lung Cancer Mutation Consortium Kris MG, et al. JAMA 2014. UCG registry data 2010 - 2013 Cufer

Current Treatment Algorithm for Advanced SCLC (ESMO Guidelines 2013)

Fruh M, et al. Ann Oncol 2013.

1L2(

&3)

L

- Cisplatin/Etoposide- CAV

SCLC

- CAV- Topotecan iv or oral

Page 7: Chemotherapy and Targeted Therapy for Lung Cancer...Introduction of Targeted Therapy Lung Cancer Mutation Consortium Kris MG, et al. JAMA 2014. UCG registry data 2010 - 2013 Cufer

Goto K, et al. Lancet Oncol 2016.

ED SCLC: Cisplatin, Etoposide and Irinotecan vs Topotecanin Patients with Sensitive Relapsed SCLC, Phase 3

First study to report significant improvement over topotecan in SL therapy.

Selected population (median age 64 years, good PS, sensitive relapse > 90 days) .

Concerns about toxicity , no QoL data.

Needs replication in Western population!

Page 8: Chemotherapy and Targeted Therapy for Lung Cancer...Introduction of Targeted Therapy Lung Cancer Mutation Consortium Kris MG, et al. JAMA 2014. UCG registry data 2010 - 2013 Cufer

Emerging Therapeutic Targets in SCLC

Adopted from Bunn PA, et al. J Thor Oncol 2016; Rudin CM, et al. Lancet 2017.

So far, all targeted therapies failed in SCLC. Some promising data with antibody-drug conjugate (rovalpituzumab) directed against NOTCH ligand DLL3, expressed in 80% of SCLC!

Rovalpituzumab in recurrent SCLC, phase1 trial

Response Rate All pts 11/60 (18%)High DLL3 10/26 (38%)

Page 9: Chemotherapy and Targeted Therapy for Lung Cancer...Introduction of Targeted Therapy Lung Cancer Mutation Consortium Kris MG, et al. JAMA 2014. UCG registry data 2010 - 2013 Cufer

Chemotherapy and Targeted Therapy for NSCLC

Page 10: Chemotherapy and Targeted Therapy for Lung Cancer...Introduction of Targeted Therapy Lung Cancer Mutation Consortium Kris MG, et al. JAMA 2014. UCG registry data 2010 - 2013 Cufer

Adjuvant/Neoadjuvant Therapy

Page 11: Chemotherapy and Targeted Therapy for Lung Cancer...Introduction of Targeted Therapy Lung Cancer Mutation Consortium Kris MG, et al. JAMA 2014. UCG registry data 2010 - 2013 Cufer

Adjuvant Chemotherapy NSCLC: Lung Adjuvant CisplatinEvaluation (LACE) Meta-analysis

HR 0.89; p=0.004 Adjuvant Cht is associated with 11% risk

reduction of death and 5.5 % absolute survivalbenefit in pts with PS 0-1, regardless of age (up to

75 years) and histology.Pignon JP, et al. J Clin Oncol 2008.

5.5%

Page 12: Chemotherapy and Targeted Therapy for Lung Cancer...Introduction of Targeted Therapy Lung Cancer Mutation Consortium Kris MG, et al. JAMA 2014. UCG registry data 2010 - 2013 Cufer

LACE: OS by Stage and by Combined Drugs

Pignon JP, et al. J Clin Oncol 2008.

N+

Relative risk reductions mainly seen in N-positive disease! Tri-modality Cht is not beneficial. Significant benefit achieved by most frequently used platinum-vinorelbine schedule.

Page 13: Chemotherapy and Targeted Therapy for Lung Cancer...Introduction of Targeted Therapy Lung Cancer Mutation Consortium Kris MG, et al. JAMA 2014. UCG registry data 2010 - 2013 Cufer

Strauss G M, et al. JCO 2008.

Benefit of Adjuvant Chemotherapy in N0 NSCLC CALGB Trial

OS, all DFS, all

OS, ≥ 4 cm

OS, < 4 cm

Page 14: Chemotherapy and Targeted Therapy for Lung Cancer...Introduction of Targeted Therapy Lung Cancer Mutation Consortium Kris MG, et al. JAMA 2014. UCG registry data 2010 - 2013 Cufer

Benefit of Different Adjuvant Chemotherapy Regimens E1505 trial: Chemotherapy +/- Bevacizumab

P = .18 P = .991.0

0.8

0.6

0.4

0.2

00 12 24 36 48 60 72 84 96

1.0

0.8

0.6

0.4

0.2

00 12 24 36 48 60 72 84 96Mos

Pro

babi

lity

of O

S

Nonsquamous

Mos

Pro

babi

lity

of O

S

Squamous

Cis/Docetaxel (85 events/201 cases)Cis/Gemcitabine (52 events/131 cases)Cis/Pemetrexed (126 events/497 cases)Cis/Vinorelbine (78 events/249 cases)

Cis/Docetaxel (50 events/142 cases)Cis/Gemcitabine (45 events/152 cases)Cis/Vinorelbine (39 events/128 cases)

Wakelee, et al. ASCO 2016. Abstract 8507.

E1505 trial: No benefit of adjuvant bevacizumab; In addition, no significant OS difference between chemotherapy regimens was observed!

TREAT phase 2: Cis/Pem vs Cis/Vino, favorable toxicity of Cis/Pem. Efficacy comparison not supported by trial design and sample size (Kreuter, Ann Oncol 2013).

JIPANG Ongoing phase 3: Carbo/Pem vs Carbo/Vinorelbine

Page 15: Chemotherapy and Targeted Therapy for Lung Cancer...Introduction of Targeted Therapy Lung Cancer Mutation Consortium Kris MG, et al. JAMA 2014. UCG registry data 2010 - 2013 Cufer

Meta-analysis of Neoadjuvant Chemotherapy in Operable NSCLC (n = 2358)

NSCLC Meta-analysis Coll. Group, Lancet 2014.

15 RCT, 2385 pts Stage IB-IIIA

13% relative relative survival benefit with the addition of neoadjuvant chemotherapy (HR = 0.87; 95% CI 0.78 – 0.96; p= 0.007)

5% absolute survival improvement at 5 years.

5%

Concerns regarding neo-adjuvant Cht: disease progression during Cht, higher postoperative morbidity/mortality.

Adjuvant Cht remains a standard in operable disease!

Page 16: Chemotherapy and Targeted Therapy for Lung Cancer...Introduction of Targeted Therapy Lung Cancer Mutation Consortium Kris MG, et al. JAMA 2014. UCG registry data 2010 - 2013 Cufer

Any Advances in Adjuvant Targeted Therapy of Operable NSCLC? Targeted therapies not yet introduced into adjuvant therapy. RADIANT Ph3 and CTONG 1104 Ph3 not convincing: flaws in methodology, lack of

OS data); ALCHEMIST trial is ongoing,

Kelly K, et al. J Clin Oncol 2015. Wu Y-L, et al. ASCO 2017, Abstr 8500.

Page 17: Chemotherapy and Targeted Therapy for Lung Cancer...Introduction of Targeted Therapy Lung Cancer Mutation Consortium Kris MG, et al. JAMA 2014. UCG registry data 2010 - 2013 Cufer

Take Home Messages:Adjuvant/Neoadjuvant Therapy of NSCLC Adjuvant Cht with platinum-doublet is recommended in pts with Stage II, III A

disease and should be considered in Stage IB (≥ 4 cm); regardless of age, PS (up to 2) and histology.

Neoadjuvant Cht seems to be equally effective as adjuvant Cht (approx. 5% absolute benefit); however, it is preferred only in Stage III disease.

Due to approx. 30% increased risk of non-lung cancer related mortality(Petrelli F, et al. Med Oncol 2013.) the risks and benefits of adjuvant Cht have to be carefully weighed in each individual patient!

Adjuvant EGFR TKIs may improve DFS in EGFR+ early NSCLC; confirmatory trials are ongoing.

Adjuvant trials with ALK TKIs are ongoing.

Page 18: Chemotherapy and Targeted Therapy for Lung Cancer...Introduction of Targeted Therapy Lung Cancer Mutation Consortium Kris MG, et al. JAMA 2014. UCG registry data 2010 - 2013 Cufer

Chemotherapy for Advanced NSCLC

Page 19: Chemotherapy and Targeted Therapy for Lung Cancer...Introduction of Targeted Therapy Lung Cancer Mutation Consortium Kris MG, et al. JAMA 2014. UCG registry data 2010 - 2013 Cufer

Chemotherapy for Advanced NSCLC: “One size fits all” Strategy

NSCLC Meta-Analyses Collaborative Group, BMJ 1995 and J Clin Oncol 2008; Schiller JH, et al. N Engl J Med 2002.

4-6 cycles of platinum-based Cht for all patients, with PS up to 2. RR from 20% to 30%, mTTP 3.5–5 months, mOS of 8–10 months, no cure. Lack of QoL data !

Surv

ival

Dis

trib

utio

nFu

nctio

n

1.0

0.8

0.6

0.4

0.2

0

0 5 10 15 20 25 30

Months

Cisplatin/paclitaxelCisplatin/gemcitabineCisplatin/docetaxelCarboplatin/paclitaxel

3 months gain in mOS !

Page 20: Chemotherapy and Targeted Therapy for Lung Cancer...Introduction of Targeted Therapy Lung Cancer Mutation Consortium Kris MG, et al. JAMA 2014. UCG registry data 2010 - 2013 Cufer

Advanced NSCLC: Tailoring Chemotherapy by Histology Cisplatin/Pemetrexed vs Cisplatin/Gemcitabine

Scagliotti GV, et al. J Clin Oncol 2008.

Cisplatin/Pemetrexed is slightly superior and thus recommended in non-squamous-cell (NSCC), but not in squamous-cell carcinoma (SCC).

Page 21: Chemotherapy and Targeted Therapy for Lung Cancer...Introduction of Targeted Therapy Lung Cancer Mutation Consortium Kris MG, et al. JAMA 2014. UCG registry data 2010 - 2013 Cufer

Advanced NSCLC: Continuation Maintenance Chemotherapy (Randomized Phase 3 Trials)

STUDY (Ref) Induction therapy Maintenance therapy and control

arm

Median PFS (months)

Median OS(months)

North American StudyBelani et al, 2003

Carboplatin / Paclitaxel

Paclitaxel vs Observation

38 wk29 wkp = NR

75 wk60 wkp = NR

CECOGBrodowicz et al, 2006

Cisplatin / Gemcitabine 4 cycles

Gemcitabine vs BSC

6.6 5.0 p< 0,001

13.011.0 p = 0.172

POI-01-003Belani et al, 2010

Carboplatin / Gemcitabine4 cycles

Gemcitabine vs BSC

7.47.7p = 0,575

8.09.3p = 0,838

IFCT-GFPC Perol et al, 2010

Cisplatin / Gemcitabine 4 cycles

Gemcitabine vs BSC

3.8 1.9 p< 0,0001

NR

PARAMOUNT Paz-Ares et al, 2012

Cisplatin / Pemetrexed4 cycles

Pemetrexedvs BSC

4.1 2.8 p< 0,0001

13.911.0p = 0.0195

In patients achieving CB (CR, PR or S) maintenance Cthwith pemetrexedis recommended.

Page 22: Chemotherapy and Targeted Therapy for Lung Cancer...Introduction of Targeted Therapy Lung Cancer Mutation Consortium Kris MG, et al. JAMA 2014. UCG registry data 2010 - 2013 Cufer

Add-on (Targeted) Therapy in Molecularly Unselected NSCLC: EGFR MAb First-line

Study Design Response rate

Median PFS (months)

Median OS (months)

FLEX1

(EGFR IHC+ NSCLC) CV + CetuximabCV

3528

4.84.8

11.3*10.1

BMS 009 2

(all NSCLC) CT + CetuximabCT

2617

4.44.2

9.68.3

SQUIRE 3

(SCC)CG + NecitumumabCG

3129

5.7*5.5

11.5*9.9

1. Pirker R, et al. Lancet 2009; 2. Lynch TJ, et al. J Clin Oncol 2010; 3. Thatcher N, et al. Lancet Oncol 2015.

* = significant

Addition of cetuximab to Cht is NOT recommended by any guidelines. Addition of necitumumab to Cht is NOT recommended by ASCO 2017 neither by NCCN V3. 2018!

Page 23: Chemotherapy and Targeted Therapy for Lung Cancer...Introduction of Targeted Therapy Lung Cancer Mutation Consortium Kris MG, et al. JAMA 2014. UCG registry data 2010 - 2013 Cufer

Add-on (Targeted) Therapy in Molecularly Unselected NSCLC: Anti-angiogenic AgentsStudy Design Response

RateMedian PFS

(months)Median OS (months)

First-line SettingECOG 1

(NSCC)CarboP + BevaCarboP

35*15

6.2*4.5

12.3*10.3

AVAIL 2,3

(NSCC)CG + Beva (7.5 mg)CG + Beva (15 mg)CG + Placebo

34.130.420.1

6.8*6.6*6.2

13.613.413.1

BEYOND4

(NSCC)CarboP+ BevaCarboP

54*26

9.2*6.5

24.3*17.7

Second-line SettingREVEL 5

(all NSCLC)Doce + RamucirumabDoce

22.913.6

4.5*3.0

10.5*9.1

Lume-Lung1 6

(Adenoca)Doce + NintedanibDoce

4.73.6

3.4*2.7

12.6*10.3

1. Sandler, et al. N Engl J Med 2006; 2. Manegold, et al. ESMO 2008; 3. Reck, et al. J Clin Oncol 2009; 4. Zhou, et al. J Clin Oncol 2015; 5. Perol M, et al. ASCO 2014, LBA 8006; 6. Reck M, et al. Lancet Oncol 2014.

*=significant

Page 24: Chemotherapy and Targeted Therapy for Lung Cancer...Introduction of Targeted Therapy Lung Cancer Mutation Consortium Kris MG, et al. JAMA 2014. UCG registry data 2010 - 2013 Cufer

Targeted Therapy for NSCLC

Page 25: Chemotherapy and Targeted Therapy for Lung Cancer...Introduction of Targeted Therapy Lung Cancer Mutation Consortium Kris MG, et al. JAMA 2014. UCG registry data 2010 - 2013 Cufer

21th Century: Recognition of Oncogene Drivers and Introduction of Targeted Therapy

Lung Cancer Mutation Consortium Kris MG, et al. JAMA 2014.

UCG registry data 2010 - 2013 Cufer T, et al. CELLC Abstract 2014. Gandara D, et al. JCO 2013.

EGFR

ALK

Page 26: Chemotherapy and Targeted Therapy for Lung Cancer...Introduction of Targeted Therapy Lung Cancer Mutation Consortium Kris MG, et al. JAMA 2014. UCG registry data 2010 - 2013 Cufer

EGFR Mutations and ALK Rearrangements: The Essence of Targeted Therapy in Advanced NSCLC EGFR mutations and ALK re-arrangements are driving

molecular alterations, present in approx.15% and 4% of NSCLC in Western population, respectively.

Mainly in adenocarcinomas, non-smokers, females and young patients.

Predictors of response to targeted therapies. Rapid and remarkable responses to TKIs are seen in a majority of patients!

del19 L858M

Lynch, et al. NEJM 2004; Paez, et al. Science 2004.

EGFR mutations

ALK rearrangements

Page 27: Chemotherapy and Targeted Therapy for Lung Cancer...Introduction of Targeted Therapy Lung Cancer Mutation Consortium Kris MG, et al. JAMA 2014. UCG registry data 2010 - 2013 Cufer

Study (n) Comparison ORR (%) PFS (Mos) HR OS (Mos)IPASS***(n=261)

Geftinib vs Carbo/Pac

*71 vs 47 9.5 vs 6.3 *0.48 (0.36-0.64) 21.6 vs 21.9

WJOTG(n=172)

Geftinib vs Cis/Doce

*62 vs 32 9.2 vs 6.3 *0.49 (0.34-0.71) 35.5 vs 38.8

NEJ002(n=230)

Geftinib vs Carbo/Pac

*74 vs 31 10.8 vs 5.4 *0.30 (0.22-0.41) 27.7 vs 26.6

EURTAC(n=174)

Erlotinib vs Chemotherapy

*58 vs 15 9.7 vs 5.2 *0.37 (0.25-0.54) 19.3 vs 19.5

OPTIMAL(n=165)

Erlotinib vs Carbo/Gem

*83 vs 36 13.1 vs 4.6 *0.16 (0.10- 0.26) 22.7 vs 28.9

LUX-lung 3(n=345)

Afatinib vs Cis/Pem

#*61 vs 22*56 vs 23

13.6 vs 6.911.1 vs 6.9

*0.47 (0.34-0.65)*0.58 (0.34-0.65)

30.3 vs 26.228.1 vs 28.2

LUX-Lung 6 (n=364)

Afatinib vs Cis/Gem

*67 vs 23 11.0 vs 5.6 *0.28 (0.20-0.39) 22.11 vs22.24

LUX-Lung 3 +6 (n=631)

Afatinib vs Cis/Gem

NR NR NR #*27.3 vs 24.3

* Significant differences , #Del 19, L858 mu, *** Post-hoc analysis of EGFR mutant patients,

EGFR TKIs vs Cht in First-line Therapy of EGFR+ Advanced NSCLC

Remarkable survival rates, we have never

seen before!!!

Page 28: Chemotherapy and Targeted Therapy for Lung Cancer...Introduction of Targeted Therapy Lung Cancer Mutation Consortium Kris MG, et al. JAMA 2014. UCG registry data 2010 - 2013 Cufer

How to Further Improve on First-generation EGFR TKIs Efficacy?

JO25567 phase 2 trial: Bevacizumab + erlotinib significantly extendedPFS by 6.3 months with increase in G3/4 toxicity (91% vs53%), no diff. SAE.

ETOP 2-11 Belief trial: The addition of beva to erlotinib sign. improves RR and PFS, especially in pts with de novo T790M (Stahel R, et al. ECC 2015.) Seto T, et al. Lancet Oncol 2014.

1.0

0.0

0.2

0.4

0.6

0.8

PFS

estim

ate

9.7 16.0300

Time (months)126 18 24

bevacizumab + erlotiniberlotinibHR=0.54 (0.36–0.79)Log-rank p=0.0015

A confirmatory phase 3 trial is currently ongoing (NCT02633189).

Page 29: Chemotherapy and Targeted Therapy for Lung Cancer...Introduction of Targeted Therapy Lung Cancer Mutation Consortium Kris MG, et al. JAMA 2014. UCG registry data 2010 - 2013 Cufer

ALK TKIs vs Cht in First-line Therapy of ALK+ Advanced NSCLC

PROFILE 1014crizotinib

ASCEND – 4ceritinib

Solomon, et al. NEJM 2014; De Castro, et al. WCLC 2016.

Median PFS rates 10.9 -16.6 months, with 2-year OS up to 70%!

ASCEND-8 phase 1 trial showed the same efficacy with lower toxicity for ceritinib450 mg with low-fat meal compared to 750 mg/ day ( Cho BC, et al. JTO 2017) .

Update OS analysis of PROFILE 1014 revealed an impressive 4-year OS of 56% (Mok T, et al. ESMO 2017).

Page 30: Chemotherapy and Targeted Therapy for Lung Cancer...Introduction of Targeted Therapy Lung Cancer Mutation Consortium Kris MG, et al. JAMA 2014. UCG registry data 2010 - 2013 Cufer

Sooner or Later Resistance to TKIs Develop Primary (de novo) resistance is rare. Aquired resistance to TKIs in metastatic setting is inevitable, it usually occurs

after approx. 12 months of therapy!

Unknown

Bypass tracks

EGFRCKIT

SRCIGF1R

Other

~1% BRAF mutations

~5% small-cell cancer transformations

~5% PIK3CA mutations

5–10% MET amplification

~60% second-site EGFRmutations

(mostly T790M)

~30–40%

Mechanisms of EGFR and ALK TKIs resistence

Page 31: Chemotherapy and Targeted Therapy for Lung Cancer...Introduction of Targeted Therapy Lung Cancer Mutation Consortium Kris MG, et al. JAMA 2014. UCG registry data 2010 - 2013 Cufer

Different Patterns of Disease Progression

Adopted from Gandara D, ASCO 2013.

Oligo-PD

CNS-PD(Sanctuary)

“Local Ablative Therapy”for Oligo-PD

&Continue Same Targeted

Therapy

Systemic-PDSwitch to another TKI

orChemotherapy

Page 32: Chemotherapy and Targeted Therapy for Lung Cancer...Introduction of Targeted Therapy Lung Cancer Mutation Consortium Kris MG, et al. JAMA 2014. UCG registry data 2010 - 2013 Cufer

Local Therapy and Continuation of Targeted Therapy is Recommended Option for Oligo Progressive Disease

Local therapy plus EGFR/ALK TKI beyond progression in CNS oligo progressive disease

Median OS 29.6 and 10.8 months HR=0.30 (0.19−0.46)p<0.0001

Weickhardt AJ, J Thorac. Oncol. 2012.

Continuation of crizotinib beyond progression, PROFILE 1005 & PROFILE 1007

Ou S-HI, et al. Ann Oncol 2014.

Page 33: Chemotherapy and Targeted Therapy for Lung Cancer...Introduction of Targeted Therapy Lung Cancer Mutation Consortium Kris MG, et al. JAMA 2014. UCG registry data 2010 - 2013 Cufer

Overcoming EGFR TKIs Resistance with Mutant –Selective EGFR TKI

1 Janne PA, et al. NEJM 2015.

Osimeritinib (by T790M) :RR: 61% vs 21%mPFS: 9.6 vs 2.8 ms

AURA 3: Osimeritinib vs Cht in T790M-positive advanced NSCLC

Mok T, et al. NEJM 2016.

Page 34: Chemotherapy and Targeted Therapy for Lung Cancer...Introduction of Targeted Therapy Lung Cancer Mutation Consortium Kris MG, et al. JAMA 2014. UCG registry data 2010 - 2013 Cufer

Proposed T790M Testing in Patients with Acquired EGFR TKI Resistance

Acquired resistance to EGFR TKI

FDA-approved plasma assay for T790M and sensitizing mutations

T790M+

Biopsy, FDA approved FFPE assay for T790M

T790M+

Mutant specific EGFR TKI

T790M-

Chemotherapy

T790M-

Mutant specific EGFR TKI

UCG data (Mohorcic K, et al. WCLC 2016)23 pts progressing while on FL EGFR TKIT790M positivity rate: ctDNA : 9/23 (39%) ctDNA plus re-biopsy:14/23 (61%) Re-biopsy feasibility rate: 6/14 (42%)

Liquid biopsy

Page 35: Chemotherapy and Targeted Therapy for Lung Cancer...Introduction of Targeted Therapy Lung Cancer Mutation Consortium Kris MG, et al. JAMA 2014. UCG registry data 2010 - 2013 Cufer

Efficacy of 2nd Generation ALK TKIs vs Cht in Crizotinib Pre-treated Patients, Phase 3 Trials

Novello S, et al. ESMO 2017.

Shaw, et al. Lancet Oncol 2017.

ASCEND 5 trial

ALUR 5 trial

9.6

Page 36: Chemotherapy and Targeted Therapy for Lung Cancer...Introduction of Targeted Therapy Lung Cancer Mutation Consortium Kris MG, et al. JAMA 2014. UCG registry data 2010 - 2013 Cufer

Sequential Use of ALK TKIs is Associated with Prolonged Survival in ALK+ Advanced NSCLC

Median OS: 49.4 months

Median OS: 51.1 months

Gainor, et al. Clin Cancer Res 2015; Watanabe, et al. Clin Lung Cancer 2016; Duruisseaux, et al. Oncotarget 2017.

Median OS: 89.6months

Page 37: Chemotherapy and Targeted Therapy for Lung Cancer...Introduction of Targeted Therapy Lung Cancer Mutation Consortium Kris MG, et al. JAMA 2014. UCG registry data 2010 - 2013 Cufer

Should be Most Effective New Generation TKIs Used Upfront ?

Page 38: Chemotherapy and Targeted Therapy for Lung Cancer...Introduction of Targeted Therapy Lung Cancer Mutation Consortium Kris MG, et al. JAMA 2014. UCG registry data 2010 - 2013 Cufer

Systemic PFS (not CNS)

Ramalingam SS, et al. ESMO 2017.

Osimertinib vs Standard-of-care EGFR-TKI as First-line Treatment in EGFR+ Advanced NSCLC: FLAURA, Phase 3

Page 39: Chemotherapy and Targeted Therapy for Lung Cancer...Introduction of Targeted Therapy Lung Cancer Mutation Consortium Kris MG, et al. JAMA 2014. UCG registry data 2010 - 2013 Cufer

Alectinib vs Crizotinib in First-line Treatment of Advanced ALK+ NSCLC: ALEX , Phase 3 trial

39

Systemic PFS (not CNS)

Shaw, et al. ASCO 2017, LBA900.

Peters S, et al. NEJM 2017.

Systemic PFS (not CNS)

Page 40: Chemotherapy and Targeted Therapy for Lung Cancer...Introduction of Targeted Therapy Lung Cancer Mutation Consortium Kris MG, et al. JAMA 2014. UCG registry data 2010 - 2013 Cufer

Gadgeel S, et al. ESMO 2017.

Consistent ~80% reduction in risk of CNS progression

ALEX : Time to CNS Progression

Page 41: Chemotherapy and Targeted Therapy for Lung Cancer...Introduction of Targeted Therapy Lung Cancer Mutation Consortium Kris MG, et al. JAMA 2014. UCG registry data 2010 - 2013 Cufer

How to Maximize Treatment Benefit of TKIs? Upfront use of new-generation inhibitors Longer PFS Better CNS efficacy Improved safety profile? No OS data? Unknown resistance mechanisms

Adopted from Ferrara R, et a.l TJO 2018.

Page 42: Chemotherapy and Targeted Therapy for Lung Cancer...Introduction of Targeted Therapy Lung Cancer Mutation Consortium Kris MG, et al. JAMA 2014. UCG registry data 2010 - 2013 Cufer

What After Resistance to Osimertinib ?

Uchibori, et al. Nature Communications 2017.

Triple-mutant EGFR

Page 43: Chemotherapy and Targeted Therapy for Lung Cancer...Introduction of Targeted Therapy Lung Cancer Mutation Consortium Kris MG, et al. JAMA 2014. UCG registry data 2010 - 2013 Cufer

Possible Future Treatment Algorithm in ALK+ NSCLC

Lin, et al. Cancer Discov 2017.

Page 44: Chemotherapy and Targeted Therapy for Lung Cancer...Introduction of Targeted Therapy Lung Cancer Mutation Consortium Kris MG, et al. JAMA 2014. UCG registry data 2010 - 2013 Cufer

Efficacy of Crizotinib in ROS1+ Advanced NSCLC

PROFILE 10011

(n=53)EUROS12

(n=31)AcSé3

(n=37)OxOnc4

(n=127)Trial Phase 1 expansion Retrospective Phase 2 Phase 2Ethnicity Global

(42% Asian)Europe Europe Asia

Diagnostic Local FISH Local FISH FISH RT-PCRResponse rate 70% 80% 71% 72%PFS, median (MOS) 19.3 9.1 10.0 15.9

1. Shaw, et al. ESMO 2016; 2. Mazieres, et al. JCO 2015; 3. Moro-Sibilot, et al. ASCO 2015; 4. Goto, et al. ESMO 2017.

ROS1 rearrangements: 1-2% of NSCLC, characteristics similar to ALK+ pts Incidence in EGFR-/KRAS-/ALK-: 7-12%!

Page 45: Chemotherapy and Targeted Therapy for Lung Cancer...Introduction of Targeted Therapy Lung Cancer Mutation Consortium Kris MG, et al. JAMA 2014. UCG registry data 2010 - 2013 Cufer

Dabrafenib plus Trametinib for Untreated Advanced BRAFV600E+ NSCLC: Phase 2

Planchard, et al. Lancet Oncol 2017.

mPFS: 10.9 months(95% CI 7.0-16.6)

mOS: 24.6 months(95% CI 12.3-NR)

RR: 64%

BRAF mutations: ~4.9% of NSCC and 0.3% of SCC ≈ 56% V600E mutations, most frequent in current or former smokers

Page 46: Chemotherapy and Targeted Therapy for Lung Cancer...Introduction of Targeted Therapy Lung Cancer Mutation Consortium Kris MG, et al. JAMA 2014. UCG registry data 2010 - 2013 Cufer

Targetable Molecular Aberrations in Lung Adenocarcinoma

Tsao, et al. JTO 2016; Kalemkerian GP, et al. JCO 2018.

For EGFR/ALK/ROS1/BRAFtargeted drugs are already available.

EGFR/ALK/ROS1/BRAF testing is recommended for all advanced NSCC and in selected pts with SCC (CAP/ASCO JCO 2018)

For multiple other genomic alterations targeted drugs are under development!

Page 47: Chemotherapy and Targeted Therapy for Lung Cancer...Introduction of Targeted Therapy Lung Cancer Mutation Consortium Kris MG, et al. JAMA 2014. UCG registry data 2010 - 2013 Cufer

Targeted Therapy for Elderly and/or Poor PS Advanced NSCLC treated by Gefitinib, n= 30 PS 3-4 or 70-79 years with PS 2-4 or ≥ 80 years with PS 1

mPFS 6.5 mos

mOS 17.8 mos

Inoue A, et al. J Clin Oncol 2009.

Change of PS

Targeted therapy is equally effective in elderly and poor PS compared to whole population.

Targeted therapy leads to rapid improvements in PS.

Page 48: Chemotherapy and Targeted Therapy for Lung Cancer...Introduction of Targeted Therapy Lung Cancer Mutation Consortium Kris MG, et al. JAMA 2014. UCG registry data 2010 - 2013 Cufer

Current ESMO Guidelines for Advanced EGFR-positive or ALK-positive NSCLC (Year 2016)

Novello S, et al. Ann Oncol 2016

Page 49: Chemotherapy and Targeted Therapy for Lung Cancer...Introduction of Targeted Therapy Lung Cancer Mutation Consortium Kris MG, et al. JAMA 2014. UCG registry data 2010 - 2013 Cufer

Current NCCN Guidelines for Advanced Oncogene-driven NSCLC (Version 3.2018)

Osimertinib not yet registered by EMA

Page 50: Chemotherapy and Targeted Therapy for Lung Cancer...Introduction of Targeted Therapy Lung Cancer Mutation Consortium Kris MG, et al. JAMA 2014. UCG registry data 2010 - 2013 Cufer

Take Home Messages:Chemotherapy Advanced NSCLC Patients with advanced NSCLC without EGFR mutations , ALK rearrangements or

any other druggable targets should be considered for first-line platinum-based chemotherapy, when immunotherapy is not indicated/accessible.

In NSCC platinum-based doublet chemotherapy with pemetrexed or with bevacizumab, upfront and maintenance is a preferred option.

In fit elderly patients and in selected PS2 patients carboplatin-doublets should be considered, while mono-chemotherapy represents a standard for others.

Second-line therapy:• All NSCLC patients should be considered for immunotherapy with nivolumab or

with pembrolizumab, if PD-L1 positive.• Adenocarcinoma patients might be considered for docetaxel plus nintedanib. • NSCLC patients might be considered for docetaxel alone or docetaxel plus

ramucirumab. Palliative care and proactive symptoms control added to systemic therapy

represents a vital part of advanced NSCLC care!

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Take Home Messages:Targeted Therapy of Advanced NSCLC

EGFR mutations, ALK and ROS1 rearrangements should be determined in all NSCC and in selected SCC patients! Determination of BRAF is highly recommended, when targeted drugs are accessible.

Patients with EGFR-positive, ALK–positive, ROS1-positive disease should receive first-line EGFR , ALK or ROS TKI, respectively.

In BRAF-positive patients targeted therapy is highly recommended, if accessible.

In patients with oligoprogressive EGFR- or ALK-positive disease local ablative therapy and continuation of EGFR/ALK TKI is recommended.

After progression on first-line EGFR TKI search for T790M in ctDNA or re-biopsy is recommended, osimeritinib is preferred option in T790M + patients.

ALK TKI patients with acquired resistance should be considered for treatment with second-line ALK TKIs.