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First Line Therapy in EGFR Mutant Advanced/Metastatic NSCLC

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Selecting First-line Therapy in the EGFR Mutant Advanced/Metastatic NSCLCEmad Shash MBBCh., MSc., MD.Medical Oncology DepartmentNational Cancer Institute, Cairo University

How to Hit a Target? The art of Precision Medicine

NSCLC Pathology: From Traditional View to more sub-molecular categorization

Evolution Of Knowledge

The EGFR Signal Transduction PathwaySalomon, et al. Crit Rev Oncol Hematol 1995

Tyrosine kinase

Evolution Of Knowledge

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EGFR Sub-Mutations in NSCLC

9%exon 20variants3%codon 719variants2%othervariants40%L858Rsubstitution46%exon 19deletions

Herbst RS, et al. N Engl J Med. 2008.Sequist LV, et al. J Clin Oncol. 2007.

Evolution Of Knowledge

Locations and types of the 134 epidermal growth factor receptor (EGFR) gene mutations detected in lung cancers. The structure of the EGFR gene is shown at left, and the locations and types of the mutations in the tyrosine kinase (TK) domain are shown at right. All mutations were located within exons 1821, which encode the N lobe and part of the C lobe of EGFR (shaded area of the gene on the left, which is presented in magnified form on the right). Three major types of mutations (shown in bold) formed 94% of the 134 mutations detected and consisted of deletions in exon 19 immediately 5 of the C-helix (11 types, labeled 111), duplications and/or insertions in exon 20 immediately 3 of the C-helix (eight types labeled D1D8), and a single-point mutation, L858R (labeled M1), in the A-loop. The remaining 6% of mutations consisted of missense mutations in the P-loop in exon 18 (six types labeled M2M7), in the C-helix in exon 20 (a single type labeled M8), or in the A-loop in exon 21 (a single type labeled M9).

Advanced NSCLC: Evolution of Treatment2000 - 20062006 - 200920102011 2017..EGFR mutationALK rearrangementK-ras mutationB-raf, HER2 mutationROS1, RETImmunotherapyNon-SquamousSquamousTargeting an Oncogenic DriverEGFR mutationNon-SquamousSquamousNon-SquamousSquamousNSCLCTargeting EGFRTreating according histologyNSCLC

AdenoLCC-NOSSCCSCLC

EGFR mutantsALKROS/RETHER2BRAFKRASKRAS

Changes in the Therapeutic Landscape of Stage IV Lung Cancer: 2017

More individualization of therapy?

Adeno, adenocarcinoma; ALK, anaplastic lymphoma kinase; EGFR, epidermal growth factor receptor; LCC/NOS, large-cell carcinoma, not otherwise specified; SCC, squamous cell carcinoma; SCLC, small-cell lung cancer.

But how many of our patients who are diagnosed with a molecular abnormality are druggable or not druggable today? Let me help you with this cartoon. You can see here in the slide 100 newly diagnosed patients all with stage IV. Excluding 10% of them with a diagnosis of small-cell lung cancer (as you can see in the blue men at the bottom of the slide), all the others are categorized as non small-cell lung cancer. Of these, 20% to 25% have a diagnosis of squamous cell carcinoma, 10% of undifferentiated large cell carcinoma, and the other 50% are adenocarcinomas.

The most common druggable genomic alterations are almost invariably observed in adenocarcinoma and, overall, only 8% of all lung cancers have an EGFR mutation. That translates in 10% to 15% of the adenocarcinomas, and the lower proportion of adenocarcinomas, which is estimated to be between 4% to 7%, have an ALK rearranged tumor. In addition, 2% of the patients have either a ROS1 or RET translocation, 1%at the best accountfor HER2 and BRAF mutation, and 10 patients on the average have a KRAS mutation. For this last group of patients, there is no specific targeted therapy with consolidated data, and consequently, in the best case scenario, only 10-12 of the original 100 cases may benefit from targeted therapies. For all the others, the main determinants remain histologic.

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Hows The Story Began?Can we get rid of chemotherapy administration?

Setting up the ground in Unselected population: Previously TreatedStudyEGFR TKI UsedPhasePopulationOSRemarkISELGefitinib VS PlaceboIIIPreviously Treated5.6 vs 5.1 months (p value = 0.087)Negative TrialBR 21Eroltinib VS PlaceboIIIPreviously Treated6.7 vs 4.7 months (p value < 0.001)Positive Trial

Adapted from Shash E et al. J Thorac Dis 2011.Lessons Learnt & Identification of Subgroups that might benefit moreStudySubgroup analysisResultsISELNever Smokers8.9 vs 6.1 months (p value = 0.012)ISELAsian Ethnicity9.5 vs 5.5 months (p value = 0.01)BR 21Females, non-smokers & AdenocarcinomaConfirmed ISEL Subgroup analysis

More gaining evidence that those patients with EGFR Mutations yielded better RR, PFS & OS

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Moving Forward with Selected population Trial Designs!Optimizing therapy for EGFR Mutant patients

Mok TS, et al. N Engl J Med. 2009.IPASS: First-line Gefitinib vs Paclitaxel/ Carboplatin in Stage IIIB/IV NSCLCOpen-label phase III trial

Primary endpoint: PFSSecondary endpoints: OS, ORR, quality of life, symptom reduction, safetyStudy conducted in Asian countriesPreviously untreated pts with stage IIIB/IV NSCLC, adenocarcinoma, never or ex-light smokers, WHO PS 0-2(N = 1217)Up to six 3-wk cyclesGefitinib 250 mg/day PO(n = 609)Paclitaxel 200 mg/m2 IV on Day 1 +Carboplatin AUC 5-6 mg/mL/min IV on Day 1(n = 608)

AUC, area under the curve; NSCLC, non-small-cell lung cancer; PS, performance status; WHO, World Health Organization.11

Gefitinib vs Paclitaxel/Carboplatin in Advanced NSCLC: PFS by EGFR StatusPFS: gefitinib superior to carboplatin/paclitaxel in ITT populationHR for progression/death: 0.74 (95% CI: 0.65-0.85; P < .001)EGFR mutations strongly predicted PFS (and tumor response) to first-line gefitinib vs carboplatin/paclitaxelMok TS, et al. N Engl J Med. 2009.

EGFR Mutation PositiveHR: 0.48 (95% CI: 0.36-0.64; P < .001)Probability of PFSMos Since Randomization1.00.80.60.40.2004812162024

EGFR Mutation NegativeHR: 2.85 (95% CI: 2.05-3.98; P < .001)Probability of PFSMos Since Randomization1.00.80.60.40.2004812162024GefitinibPac/carboGefitinibPac/carbo

Carbo, carboplatin; ITT, intent to treat; NSCLC, non-small-cell lung cancer; Pac, paclitaxel.

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EURTAC: Erlotinib vs Chemo in EGFR MutationPositive, Stage IIIB/IV NSCLCPrimary endpoint: PFS (interim analysis planned at 88 events)Secondary endpoints: ORR, OS, location of progression, safety, EGFR-mutation analysis, QoLPts with no prior chemotherapy, stage IIIB/IV NSCLC, mutated EGFR,* ECOG PS 0-2(N = 174)PDPDErlotinib 150 mg/day(n = 86)Platinum DoubletQ3W x 4 cycles(n = 87)

Stratified by mutation type,* ECOG PS (0 vs 1 vs 2)*Exon 19 deletion or exon 21 L858R mutation. 1227 pts screened; 174 pts with mutated EGFR enrolled; 1 pt withdrawn. Cisplatin 75 mg/m2 Day 1/docetaxel 75 mg/m2 Day 1; cisplatin 75 mg/m2 Day 1/ gemcitabine 1250 mg/m2 Days 1, 8; carboplatin AUC = 6 Day 1/docetaxel 75 mg/m2 Day 1; carboplatin AUC = 5 Day 1/gemcitabine 1000 mg/m2 Days 1, 8.Rosell R, et al. Lancet Oncol. 2012.Randomized, open-label phase III trial

AUC, area under the curve; ECOG, Easter Cooperative Oncology Group; NSCLC, non-small-cell lung cancer; PD, progressive disease; PS, performance status; QoL, quality of life.

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PFS in ITT PopulationProbability of PSErl (n = 86)Chemotherapy (n = 87)HR: 0.37 (95% CI: 0.25-0.54;log-rank P < .0001)Mos03691215182124273033

Pts at Risk, nErl866354322117974220 Chemo 8749208543100001.00.80.60.40.20

9.75.2Rosell R, et al. Lancet Oncol. 2012;13:239-246.

Erl, erlotinib; ITT, intent to treat. 14

First-line Treatment With EGFR TKIs vs Chemotherapy in EGFR-Mutated NSCLCStudyTreatmentNMedian PFS, MosMedian OS, MosMaemondo[1]Gefitinib vs carboplatin/paclitaxel23010.8 vs 5.4(P < .001)30.5 vs 23.6(P = .31)Mitsudomi[2,3]Gefitinib vscisplatin/docetaxel1729.2 vs 6.3(P < .0001)35.5 vs 38.8(HR: 1.19)OPTIMAL[4,5]Erlotinib vscarboplatin/gemcitabine16513.1 vs 4.6(P < .0001)22.8 vs 27.2(HR: 1.19)EURTAC[6]Erlotinib vsplatinum-based chemotherapy1749.7 vs 5.2(P < .0001)19.3 vs 19.5(P = .87)LUX-Lung 3[7,8]Afatanib vscisplatin/pemetrexed34511.1 vs 6.9(P = .001)28.2 vs 28.2(P = .39)LUX-Lung 6[8,9]Afatinib vs cisplatin/gemcitabine36411.0 vs 5.6(P < .0001)23.1 vs 23.5 (P = .61)

1 Maemondo M, et al. N Engl J Med. 2010. 2Mitsudomi T, et al. Lancet Oncol. 2010. 3Mitsudomi T, et al. ASCO 2012.4 Zhou C, et al. Lancet Oncol. 2011. 5Zhou C, et al. Ann Oncol. 2015. 6Rosell R, et al. Lancet Oncol. 2012. 7Sequist LV, et al. J Clin Oncol. 2013. 8Yang JC, et al. Lancet Oncol. 2015. 9Wu YL, et al. Lancet Oncol. 2014.

NSCLC, non-small-cell lung cancer; TKI, tyrosine kinase inhibitor.15

Lee CK, et al. J Natl Cancer Inst. 2013.Favors EGFR TKIFavors ChemoMeta-analysis of Randomized First-line EGFR TKI Studies: Improved PFSStudyHR(95% CI)HR(95% CI)EGFRmut (first-line therapy)EURTACFirst-SIGNALGTOWGINTACT1-2IPASSLUX LUNG3NEJ002OPTIMALTALENTTOPICALTRIBUTEWJTOG3405Subtotal

0.37 (0.25-0.54)0.54 (0.27-1.10)1.08 (0.24-4.90)0.55 (0.19-1.60)0.48 (0.36-0.64)0.58 (0.43-0.78)0.32 (0.24-0.44)0.16 (0.11-0.26)0.59 (0.21-1.67)0.90 (0.39-2.06)0.49 (0.20-1.20)0.52 (0.38-0.72)0.43 (0.38-0.49)

EGFR, epidermal growth factor receptor; PFS, progression-free survival; TKI, tyrosine kinase inhibitor.

The clinical trial findings previously mentioned have been confirmed by several metaanalyses, and this one represented in the slide from 2013, similarly to others, confirmed the significant advantage in terms of improvement to PFS. 16

Lee CK, et al. J Natl Cancer Inst. 2013.Favors EGFR TKIFavors ChemoFirst-line EGFR TKI Studies: Improved QoLStudyHR(95% CI)HR(95% CI)EGFRmut (first-line therapy)EURTACFirst-SIGNALGTOWGINTACT1-2IPASSLUX LUNG3NEJ002OPTIMALTALENTTOPICALTRIBUTEWJTOG3405Subtotal

0.37 (0.25-0.54)0.54 (0.27-1.

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