Second-line treatment for advanced NSCLC

Transcription

1 Second-line treatment for advanced NSCLC Silvia Novello UNIVERSITY OF TORINO DEPARTMENT OF ONCOLOGY

2 DISCLOSURE OF INTEREST Speaker Bureau: Eli Lilly, MSD, BI, BMS, Roche, AZ UNIVERSITY OF TORINO DEPARTMENT OF ONCOLOGY

3 Life was so boring simple and back disappointing in 2008 back in 2008 UNIVERSITY OF TORINO DEPARTMENT OF ONCOLOGY

4 Di Maio M, EJC 2010

5 UNIVERSITY OF TORINO DEPARTMENT OF ONCOLOGY In 2018, second line therapy is no longer as simple We must now take into consideration: 1.Tumor histology 2.Molecular phenotype (EGFR, ALK, ROS1, etc), 3.Frontline chemo components (i.e. bevacizumab) 4. IO in First Line 5. Maintenance therapy (continuation, switch) 6. Others (adequacy of tumor tissue, third party reimbursement, guidelines, pathways, etc)

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7 .even worse than this Country First Author (yr) Patients With Second-Line Treatment Brazil # Younes % Canada # Sacher % Europe Bischoff % France Carpentier % Germany Zietemann % Japan Asahina % US * Davis % # Only consisted of patients with stage IV NSCLC; Countries included France, Germany, Portugal, Finland, Denmark, the United Kingdom, Sweden, the Netherlands, Israel, Romania, and Peru.; * only squamous ca Davis Jet al, PlosONE 2017

8 BUT this will change in the future

9 .not only an increase in N

10 Di Maio M, JCO 2009

11 UNIVERSITY OF TORINO DEPARTMENT OF ONCOLOGY Clinical Lung Cancer 2014

12 UNIVERSITY OF TORINO DEPARTMENT OF ONCOLOGY Median Age: Second Line Candidates: Larger proportion of Male pt characteristics Adenocarcinoma was the most common NSCLC (33% in Brazil to 77% in Japan) Never Smoker#: highest proportion in Japanese cohort (range from 7.5% Germany, to 34%) PS*: most patients having a Karnofsky Performance Status of 70 or better or an ECOG score of 0 or 1 *only in 5 trials; # in 8 trials Davis Jet al, PlosONE 2017

13 UNIVERSITY OF TORINO DEPARTMENT OF ONCOLOGY Second line therapy Outside Clinical Trials (N=464, 86% of pts progressing after first line) Gridelli C et al, JCancerRes ClinOncol De Marinis Fet al, ClinicalLungCancer2014

14 Distribution of Second line treatment in advanced NSCLC Davis Jet al, PlosONE 2017 UNIVERSITY OF TORINO DEPARTMENT OF ONCOLOGY

15 Guidelines [ESMO-AIOM] UNIVERSITY OF TORINO DEPARTMENT OF ONCOLOGY

16 UNIVERSITY OF TORINO DEPARTMENT OF ONCOLOGY Treatment Options Post-platinum Progression: Docetaxel Docetaxel was the first treatment to be approved for NSCLC patients with disease progression following first-line chemotherapy Patients receiving docetaxel 75 mg/m 2 had OS of 7.5 months, compared with 4.6 months for those receiving BSC 2 Docetaxel-treated patients had a significantly higher 1-year survival rate compared with patients receiving vinorelbine or ifosfamide (32% vs. 19%; p=.025) 3 Cumulative probability Docetaxel 75 mg/m 2 (n=55) BSC (n=49) Survival (months) 1. Sanofi Aventis. Taxotere (docetaxel) prescribing information. Nov Shepherd FA et al. J Clin Oncol 2000;18: Fossella FV et al. J Clin Oncol 2000;18:

17 UNIVERSITY OF TORINO DEPARTMENT OF ONCOLOGY Treatment Options Post-platinum Progression: Pemetrexed in nonsquamous NSCLC Pemetrexed was approved for patients progressing after chemotherapy after it demonstrated non-inferiority vs. docetaxel, but with a better toxicity profile 1-3 In patients with nonsquamous histology, pemetrexed treatment resulted in a median OS of 9.3 months, compared with 8.0 months for docetaxel 4 Pemetrexed is only suitable for patients with nonsquamous histology 1 Survival distribution function Survival (months) The increased use of pemetrexed in first-line treatment means docetaxel remains an option as subsequent therapy for patients of all histologies Pemetrexed Docetaxel Adjusted HR 0.78 (95% CI ) 1. Eli Lilly and Company. Alimta (pemetrexed) prescribing information. Sep Hanna N et al. J Clin Oncol 2004;22: Weiss GJ et al. J Clin Oncol 2006;24: Scagliotti G et al. Oncologist 2009;14:253-63

18 Tanaka F. et al. Ann. Oncol p< P<0.001 UNIVERSITY OF TORINO DEPARTMENT OF ONCOLOGY Relative expre. levels Relative expre. levels P<0.001 Ceppi et al. Cancer 2006 TS (N=965) 649 AC, 316 SCCA 5 Monica V. et al. Clin. Cancer Res TS relative mrna levels 1 0 Gandara D. et al. Proc. ASCO 2010 ADC SCC non-ne LCC LCNEC SCLC

19 UNIVERSITY OF TORINO DEPARTMENT OF ONCOLOGY Treatment Options Post-platinum Progression: Erlotinib The EGFR TKI erlotinib is approved for use in unselected patients with disease progression after first-line chemotherapy 1 However, erlotinib was inferior to docetaxel for OS and PFS in patients without an EGFR mutation; other options may be preferred in this setting 2,3 Erlotinib is not recommended for patients with a poor classification following proteomic testing in patients with WT or unknown EGFR status 3,4 Overall survival (%) Cox model adjusted HR 0.73 (95% CI ) Erlotinib Docetaxel Survival (months) 1. Astellas Pharma and Genentech. Tarceva (erlotinib) prescribing information. June Garassino MC et al. Lancet Oncol 2013;14: NCCN Clinical Practice Guidelines for Non-Small Cell Lung Cancer, V Gregorc V et al. Lancet Oncol 2014;15:713-21

20 UNIVERSITY OF TORINO DEPARTMENT OF ONCOLOGY Revisiting ancient history: Phase III trials in 2 nd line NSCLC Erlotinib 1,2 Docetaxel 3,4 Pemetrexed 5 Outcome 150mg/day 75mg/m 2 500mg/m 2 Response rate (%) Median duration of response (months) 1-year survival rate (%) Median survival in PS 0/1 patients with 1 prior regimen (months) Median survival (months) *Results cannot be compared directly because of different patient populations Shepherd F, et al. N Engl J Med 2005;353:123 32; 2 OSI and Roche data on file; 3 Shepherd F, et al. J Clin Oncol 2000;18: ; 4 Fossella F, et al. J Clin Oncol 2000;18: ; 5 Hanna N, et al. J Clin Oncol 2004;22:

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22 SQUAMOUS and NON-SQUAMOUS Carcinoma: rooms for improvements SQUAMOUS and NON-SQUAMOUS UNIVERSITY OF TORINO DEPARTMENT OF ONCOLOGY

23 UNIVERSITY OF TORINO DEPARTMENT OF ONCOLOGY HYPERPLASIA DYSPLASIA CARCINOMA Air Space Cellular proliferation through independent growth signaling Gene Methylation Mutations Translocations Bronchial Epithelium Promotion of survival signals and evasion of apoptosis Limitless potential for replication Vascular recruitment and endothelial cell growth INVASIVE CARCINOMA Tissue invasion and metastasis Adapted from Weinberg RA. SciAm. 1996;275:62-70.

24 1:1 - Stage IV NSCLC after one platinum- based chemo +/- maintenance - Prior Bev allowed - All histologies - PS 0 or 1 R A N D O M I Z E Ramucirumab 10 mg/kg + Docetaxel 75 mg/m 2 q3wks N=628 Placebo + Docetaxel 75 mg/m 2 q3wks N=625 Treatment until disease progression or unacceptable toxicity Stratification factors: ECOG PS 0 vs 1 Gender Prior maintenance East-Asia vs. ROW Primary endpoint: Overall Survival Secondary endpoints: PFS, ORR, safety, patient-reported outcomes

25 Overall Survival (%) ITT population RAM+DOC PL+DOC Censored Median (95% CI) Censoring Rate RAM+DOC 10.5 ( ) 31.8% PL+DOC 9.1 ( ) 27.0% RAM+DOC vs PL+DOC: Stratified HR (95% CI) = ( ) Stratified log-rank P =.023 Number at risk RAM+DOC PL+DOC Survival Time (months)

26 Progression-Free Survival (%) ITT population, Investigator Assessment RAM+DOC PL+DOC Censored Median (95% CI) Censoring Rate RAM+DOC 4.5 ( ) 11.1% PL+DOC 3.0 ( ) 6.7% RAM+DOC vs PL+DOC: Stratified HR (95% CI) = 0.76 ( ) Stratified log-rank P = Number at risk RAM+DOC PL+DOC Survival Time (months)

27 Response a, n (%) Ramucirumab + Docetaxel (n=628) Placebo + Docetaxel (n=625) CR 3 (0.5) 2 (0.3) p value Ramucirumab improved ORR and DCR in nonsquamous and squamous histologies PR 141 (22.5) 83 (13.3) SD 258 (41.1) 244 (39.0) PD 128 (20.4) 206 (33.0) Unknown 98 (15.6) 90 (14.4) ORR (95% CI) 144 (22.9) ( ) 85 (13.6) ( ) <.001 DCR (95% CI) 402 (64.0) ( ) 329 (52.6) ( ) <.001

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29 QoL was measured using LCSS and ASBI A similar increase in symptom burden was observed in both treatment arms Addition of ramucirumab had no detrimental effect on QoL Mean ASBI Total Score Mean LCSS Total Score n = n = * * * * * * * * * Ramucirumab * Placebo * * * * * * * * * * * * * * Sum 30-day vis follow-up * * * * * * * * * * * * * * * * * * Cycle * * * * * * Sum 30-day vis follow-up

30 REVEL: Patient Disposition Screened (N=1825) Randomized (ITT) Population N=1253 Excluded (n=572) Patients not receiving treatment (n=4) RAM+DOC (N=628) RAM+DOC (N=627) * wt 33% mutant 2.4% unknown 64% PL+DOC (N=625) PL+DOC (N=618) * wt 31.5% mutant 2.9% unknown 65% Patients not receiving treatment (n=4) Reasons for discontinuation (N=613) PD 341 Adverse event 94 Subject decision 90 Investigator decision 37 Death due to adverse events 30 Death from study disease 12 Other 9 On treatment at data cutoff N=11 Safety Population N=1245 Reasons for discontinuation (N=611) PD 429 Adverse event 55 Subject decision 53 Investigator decision 19 Death due to adverse events 31 Death from study disease 14 Other 10 On treatment at data cutoff N=10 *Three PL+DOC arm patients were inadvertently treated with RAM and are therefore considered part of the RAM+DOC arm for the safety analyses, but the PL+DOC arm for the ITT efficacy analysis.

31 Forest plot PFS UNIVERSITY OF TORINO DEPARTMENT OF ONCOLOGY

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33 SQUAMOUS Carcinoma: rooms for improvements

34 New treatment opportunities

35 When number of new strategies make the difference

36 Previous ESMO Guidelines

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39 Is there a room for targeted therapies (WITHOUT target) in SQUAMOUS carcinoma SC10.04: Second-Line Therapy and Beyond in Squamous Cell NSCLC - Silvia Novello

40 Lux Lung 8: Study design Stratified by East Asian vs. Non-East Asian SCC of the lung (Stage IIIB/IV) 1 Progressed after 4 cycles of a first-line platinum doublet ECOG PS 0 1 Adequate organ function 1:1 Afatinib 40 mg QD Erlotinib 150 mg QD Primary Endpoint: PFS by Independent Review Key secondary Endpoint: Overall Survival Other secondary Endpoints: ORR, DCR, tumor shrinkage, PRO, safety Dose escalaoon to 50 mg and dose reducoon to 30 or 20 mg permiped Dose reduction to 100 or 50 mg permitted Tumor assessment at baseline, Weeks 8, 12, 16; every 8 weeks thereafter. 1. American Joint Committee on Cancer staging manual 7th edition SoriaJC et al, ASCO 2015

41 UNIVERSITY OF TORINO DEPARTMENT OF ONCOLOGY Events, % LUX LUNG 8: Safety Afatinib (N=392) Afatinib (n=392) Erlotinib (n=395) Any AE Drug-related AEs AEs leading to dose reduction AEs leading to discontinuations CTCAE grade 3 or higher Serious AEs Drug-related fatal AEs Erlotinib (N=395) AE category, % All Grade 3 Grade 4 All Grade 3 Grade 4 Total with related AEs Diarrhea <1 Rash/acne* Stomatitis* Fatigue* Nausea Decreased appetite Paronychia* <1 0 Dry skin Pruritus 8 < Vomiting Dehydration GossGD IASLC Geneva 2015; SoriaJC et al, ASCO 2015

42 LUX LUNG 8: Efficacy OS Forest plot PFS PFS SC10.04: Second-Line Therapy and Beyond in Squamous Cell NSCLC - Silvia Novello SoriaJC et al, Lancet Oncol2015

43 For Patients and Caregivers -A 60-page booklet in English, designed as an information guide for patients with SqCLC -The most frequent key questions from a patient with SqCLC

44 ADENOCarcinoma ( non-squamous ): rooms for improvements UNIVERSITY OF TORINO DEPARTMENT OF ONCOLOGY

45 LUME-Lung 1 Study Design Stage IIIB/IV or recurrent NSCLC patients after 1 st line chemotherapy (all histologies) R A N D O M I Z E 1:1 Nintedanib 200mg BID p.o., D2 21, + Docetaxel 75mg/m 2 IV, D1, 21-day cycles (n=655) Placebo BID p.o., D2 21, + Docetaxel 75mg/m 2 IV, D1, 21-day cycles (n=659) PD PD N=1314 Number of docetaxel cycles not restricted Monotherapy allowed after 4 cycles of combination therapy Stratification: ECOG PS (0 vs 1) Prior bevacizumab (yes vs no) Histology (squamous vs nonsquamous) Brain metastases (yes vs no) Primary end point: PFS Next analysis step only allowed if PFS confirmed with all PFS events at time point of OS analysis RECK LBA8011, ASCO 2013

46 LUME1: PFS TOTAL population ADENOCARCINOMA SQUAMOUS CARCINOMA ReckM et al, Lancet Oncol2014 UNIVERSITY OF TORINO DEPARTMENT OF ONCOLOGY

47 LUME1: OS Adenocarcinoma <9mo ADENOCARCINOMA Total population ReckM et al, Lancet Oncol2014 UNIVERSITY OF TORINO DEPARTMENT OF ONCOLOGY

48 LUME1: Safety ReckM et al, Lancet Oncol2014 UNIVERSITY OF TORINO DEPARTMENT OF ONCOLOGY

49 Forest plot PFS UNIVERSITY OF TORINO DEPARTMENT OF ONCOLOGY

50 Take Home Messages UNIVERSITY OF TORINO DEPARTMENT OF ONCOLOGY Chemotherapy is still present in second line NSCLC advanced patients Antiangiogenic compound found a second youth in second line Immunotherapy plays a relevant role in this setting.at least when it has no role in first line Today, even more than yesterday, is crucial to design a treatment algorithm for patients with advanced NSCLC not to waste therapeutic opportunities

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