Non-small Cell Lung Cancer: Multidisciplinary Role: Role of Medical Oncologist

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1 Non-small Cell Lung Cancer: Multidisciplinary Role: Role of Medical Oncologist Vichien Srimuninnimit, MD. Medical Oncology Division Faculty of Medicine, Siriraj Hospital

2 Outline Resectable NSCLC stage I IIIA Adjuvant chemotherapy Adjuvant targeted therapy (bevacizumab, gefitinib) Resectable NSCLC stage IIIA Surgery followed by adjuvant chemotherapy + radiotherapy Neoadjuvant chemotherapy followed by surgery Neoadjuvant concurrent chemoradiotherapy followed by surgery or observation Unresectable NSCLC stage III Sequential chemotherapy followed by radiotherapy Concurrent chemoradiotherapy (CCRT) CCRT followed by immunotherapy (Durvalumab)

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5 Multidisciplinary Team Resectable Unresectable Unresectable Unresectable

6 Adjuvant Chemotherapy in NSCLC:

7 Adjuvant Platinum-Based Chemotherapy Study Design Stage N Chemo ALPI RCT I-III 1209 Cis / Mito / Vindesine IALT RCT I-III 1867 Cis / Vinca or Etoposide BLT RCT I-IIIA 488* Cis regimen (1 of 4) JBR.10 RCT IB-II 482 Cis / Vinorelbine CALGB RCT IB 344* Carbo / Paclitaxel ANITA RCT I-IIIA 840 Cis / Vinorelbine Negative trial result Positive trial result Initial positive result, later follow-up negative *Failed to complete goal enrollment.

8 Adjuvant Chemotherapy for NSCLC Lung Adjuvant Cisplatin Evaluation (LACE) Meta-analysis of adjuvant cisplatin trials performed since 1995 BLT, ALPI, IALT, JBR.10, ANITA Pooled individual patient data 4584 resected patients, 5 randomized trials 7% Stage IA 30% Stage IB 36% Stage II 27% Stage III Pignon JP, et al. J Clin Oncol. 2008;26:

9 Adjuvant Chemotherapy for NSCLC LACE: Overall Survival Trial No Deaths Hazard Ratio / No Entered (Chemotherapy / Control) HR (95% [95% CI] CI) ALPI 569 / [0.81;1.12] ANITA 458 / [0.68;0.98] BLT 186 / [0.71;1.27] IALT 980 / [0.80;1.04] JBR / [0.54;0.94] Total 2390 / (0.82;0.96] [0.82;0.96] Chemotherapy better Control better Chemotherapy effect P = Pignon JP, et al. J Clin Oncol. 2008;26:

10 Adjuvant Chemotherapy for NSCLC LACE: Pooled Data Overall Survival Survival (%) Chemotherapy No chemotherapy % survival advantage at 5 years HR = % CI P = Time from Randomization (Years) Pignon JP, et al. J Clin Oncol. 2008;26:

11 Adjuvant Chemotherapy for NSCLC LACE Analysis by Stage Category No. Deaths / No. Entered Hazard Ratio (Chemotherapy / Control) HR [95% CI] Stage IA 104 / [0.96;2.09] Stage IB 515 / [0.78;1.10] Stage II 893 / [0.73;0.95] Stage III 878 / [0.73;0.95] Chemotherapy better Control better Adjuvant chemo has greatest benefit for stage II and III and may be detrimental for stage IA Test for trend: P = Pignon JP, et al. J Clin Oncol. 2008;26:

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14 Adjuvant Chemo for Stage IB III NSCLC Absolute Benefit in 5-Year Survival Die despite chemo Alive due to surgery Alive due to chemo Stage IB Stage II Stage III Based on HR from LACE meta-analysis and 5YS from ANITA trial Chemotherapy = 4 months of cisplatin + vinorelbine Pignon JP et al. J Clin Oncol. 2006;24(18S). Abstract 7008; Douillard JY et al. Lancet Oncol. 2006:7;

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16 Phase III E1505: Study Design Stratified by cisplatin doublet, stage, histology, sex Treatment naive pts with stage IB to IIIA, resected NSCLC, 6-12 wks post-op, with adequate nodal sampling, no planned post-op RT, acceptable organ function (N = 1501) ARM A: Cisplatin Doublet (Investigator s Choice)* x 4, 21-D cycles (n = 749) ARM B: Cisplatin Doublet (Investigator s Choice)* x 4, 21-D cycles Bevacizumab* Q3W, 1 yr (n = 752) Follow-up: every 3 mos for 2 yrs; every 6 mos through Yr 5; annually through Yr 10 Primary endpoint: OS Secondary endpoint: DFS * Chemotherapy regimens: Cisplatin partners: vinorelbine, docetaxel, gemcitabine, pemetrexed Study powered for primary endpoint only, [1] not for the subset analyses [2] 1. Wakelee HA, et al. WCLC Abstract Wakelee HA, et al. ASCO Abstract 8507.

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18 E1505 Chemotherapy Subset Analysis: Overall Survival by Histology OS not significantly different between chemotherapy groups 1.0 Nonsquamous 1.0 Squamous P =.18 P =.99 Probability of OS Cis/Docetaxel (85 events/201 cases) Cis/Gemcitabine (52 events/131 cases) Cis/Pemetrexed (126 events/497 cases) Cis/Vinorelbine (78 events/249 cases) Probability of OS Cis/Docetaxel (50 events/142 cases) Cis/Gemcitabine (45 events/152 cases) Cis/Vinorelbine (39 events/128 cases) Mos From Registration Mos From Registration Wakelee HA, et al. ASCO Abstract Reproduced with permission.

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20 ADJUVANT study design (NCT ) Presented By Yi-Long Wu at 2017 ASCO Annual Meeting Zhong WZ, et al. Lancet Oncol. 2018;19:

21 Primary endpoint: DFS (ITT population) Presented By Yi-Long Wu at 2017 ASCO Annual Meeting Zhong WZ, et al. Lancet Oncol. 2018;19:

22 Resectable Stage III NSCLC

23 Stage IIIA (N2) Non-Small Cell Lung Cancer Heterogeneity Microscopic mediastinal disease prognosis compared to macroscopic disease. Single station mediastinal node involvement compared to multiple station involvement Minimal clinical nodal involvement vs. Bulky mediastinal node involvement

24 Resectable Locally Advanced NSCLC Resectable in this situation usually refers to the following situations: Single station N2 disease T4N0 tumours when a R0 resection is considered to be feasible After induction therapy, when there has been nodal downstaging and a pneumonectomy can be avoided If, despite adequate mediastinal staging procedures, N2 disease is only documented intraoperatively, surgery should be followed by adjuvant ChT All such cases should be evaluated within an experienced multidisciplinary team

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37 INTERGROUP 0139/RTOG 9309 PROGRESSION-FREE SURVIVAL BY TREATMENT ARMS 100 % Alive without Progression / Logrank p = Hazard ratio = 0.77 (0.62, 0.96) CT/RT/S 159/202 CT/RT 172/194 / /// / // / / /// // // / / / / / / / / Months from Randomization Failed/Total

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41 Resectable Stage III NSCLC: Recommendation If, despite adequate mediastinal staging procedures, N2 disease is only documented intraoperatively, surgery should be followed by adjuvant chemotherapy If single station N2 disease can be demonstrated by preoperative pathological nodal analysis: Resection followed by adjuvant chemotherapy Induction chemotherapy followed by surgery or Induction CCRT followed by surgery In multistation N2, concurrent definitive CCRT is preferred In potentially resectable superior sulcus tumours, concurrent CRT induction followed by definitive surgery is the treatment of choice

42 Unresectable Stage III NSCLC

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45 Vokes E, et al. J Clin Oncol 2007;25:

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48 Durvalumab vs Placebo After Concurrent CRT in Unresectable Stage III NSCLC (PACIFIC) Stratified by age (< 65 vs 65 yrs), sex, and smoking history (current/former vs never) Pts with locally advanced, unresectable, stage III NSCLC with 2 cycles platinum-based chemotherapy with radiation therapy and no progression, WHO PS 0/1 (n = 713) Durvalumab 10 mg/kg IV Q2W for up to 12 mos (n = 473) Placebo IV Q2W for up to 12 mos (n = 236) Until disease progression or unacceptable toxicity Primary endpoints: PFS, OS Secondary endpoints including: ORR, DoR, OS at 24 mos Antonia SJ, et al. N Engl J Med. 2017;[Epub ahead of print].

49 PACIFIC: PFS and Secondary Efficacy Endpoints PFS (%) Pts at Risk, n Durvalumab Placebo Mos Durvalumab Placebo HR: 0.52 (95% CI: ; P <.001) Median PFS, Mos (95% CI) 16.8 ( ) 5.6 ( ) Mo PFS, % (95% CI) 55.9 ( ) 35.3 ( ) Mo PFS, % (95% CI) 44.2 ( ) 27.0 ( ) Durvalumab Placebo Event, % Durvalumab (n = 443) Placebo (n = 213) ORR* Ongoing response 12 mos 18 mos New lesions Brain *P < Antonia SJ, et al. N Engl J Med. 2017;[Epub ahead of print].

50 Conclusions Multimodality therapy is a key factor to improve the overall survival in early stage and locally advanced NSCLC Adjuvant chemotherapy with cisplatin-based regimen for 4 cycles is the standard of care for stage II-IIIA NSCLC and may be considered in stage IB with tumor size > 4 cm Adjuvant EGFR TKIs (gefitinib) improved PFS in EGFRmutated early stage NSCLC, but no data on OS For resectable stage IIIA, many options can be considered: Surgery followed by adjuvant chemotherapy + RT, Neoadjuvant chemotherapy followed by surgery or RT, Neoadjuvant CCRT followed by surgery or CCRT alone For unresectable stage III, CCRT is preferred Maintenance with immunotherapy (durvalumab) after CCRT in unresectable locally advanced NSCLC improved PFS, but no data on OS