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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
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.
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
Chemotherapy and Targeted Therapy for SCLC
Systemic Therapy for SCLC
Sorry - No important news since 2005.
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
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!
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%)
Chemotherapy and Targeted Therapy for NSCLC
Adjuvant/Neoadjuvant Therapy
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%
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.
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
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
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!
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.
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.
Chemotherapy for Advanced NSCLC
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 !
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).
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.
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!
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
Targeted Therapy for NSCLC
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
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
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!!!
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).
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).
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
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
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.
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.
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
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
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
Should be Most Effective New Generation TKIs Used Upfront ?
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
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)
Gadgeel S, et al. ESMO 2017.
Consistent ~80% reduction in risk of CNS progression
ALEX : Time to CNS Progression
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.
What After Resistance to Osimertinib ?
Uchibori, et al. Nature Communications 2017.
Triple-mutant EGFR
Possible Future Treatment Algorithm in ALK+ NSCLC
Lin, et al. Cancer Discov 2017.
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%!
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
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!
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.
Current ESMO Guidelines for Advanced EGFR-positive or ALK-positive NSCLC (Year 2016)
Novello S, et al. Ann Oncol 2016
Current NCCN Guidelines for Advanced Oncogene-driven NSCLC (Version 3.2018)
Osimertinib not yet registered by EMA
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!
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.