pts which opportunities with biologic agents Silvia Novello s ilvianovellounitoit Life was so simple back in 2008 Di Maio M EJC 2010 In 2014 second line therapy is ID: 1043672
Download Presentation The PPT/PDF document "Second line treatments in WT" is the property of its rightful owner. Permission is granted to download and print the materials on this web site for personal, non-commercial use only, and to display it on your personal computer provided you do not modify the materials and that you retain all copyright notices contained in the materials. By downloading content from our website, you accept the terms of this agreement.
1.
2. Second line treatments in WT pts: which opportunities with biologic agents?Silvia Novellosilvia.novello@unito.it
3. Life was so simple back in 2008
4. Di Maio M, EJC 2010
5. In 2014, “second line therapy” is no longer as simpleWe must now take into consideration:Tumor histologyMolecular phenotype (EGFR, ALK, ROS1, etc)Frontline chemo components Maintenance therapy (continuation, switch)Bevacizumab useOthers (adequacy of tumor tissue, third party reimbursement, guidelines, “pathways”, etc)
6. INDUCTIONMAINTENANCE2 nd LINE3 rd LINE
7. Which is the influence of Maintenance on 2nd linePARAMOUNT discontinuation treatment
8. Di Maio M, JCO 2009
9. Clinical Lung Cancer 2014
10. Second line therapy Outside Clinical Trials (N=464)De Marinis F et al, Clinical Lung Cancer 2014
11. Timing of Biomarker Analyses (excluded those with no computable timing)De Marinis F et al, Clinical Lung Cancer 2014EGFR=37; KRAS=13; Alk=18
12.
13. [TITLE]Presented By Yoshio Okano, MD. PhD at 2013 ASCO Annual Meeting
14.
15. [TITLE]Okano ASCO 2013
16. [TITLE]Presented By Yoshio Okano, MD. PhD at 2013 ASCO Annual Meeting
17. [TITLE]Okano ASCO 2013
18. Kawaguchi JCO 2014EGFR Unselected
19. Kawaguchi JCO 2014EGFR Wild-Type
20. If the selection is (more or less) real from the beginning
21. Garasssino M, LO 2013OSPFS
22. Zhou et al, WCLC 2013
23. Zhou et al, WCLC 2013
24.
25. Guidelines [ESMO-AIOM]
26. Zer, JCO 2014
27. Zer, JCO 2014
28. How we can select?
29. 01.07 PROSE Secondary Endpoint Analysis Vanesa Gregorc, MD*PCR amplification/Sanger sequencing of common mutationsVS-G96 (72%)VS-P38 (28%)Chemotherapy (129)Erlotinib (134)VS-G88 (68%)VS-P41 (32%)3 major protocol violations19 never received therapy285 patients randomized 263 included for primary analysis PROSE Patient FlowThe patient population was 72% male, 63% adenocarcinoma, 14% never smokers, 52% ECOG PS 0, and 41% ECOG PS 1, and was well balanced between arms.Third-line treatment at progression: CT arm: 41% overall (48% VS-G and 27% VS-P)ERL arm: 52% overall (56% VS-G and 39% VS-P)
30.
31. PROSE in NCCN Guidelines in second line NSCLCGregorc V, Novello S, Lazzari C, Lancet Oncology 2014; 15.713-21
32. Lung Cancer is caused by cumulative epigenetic and genetic damage to the bronchial epitheliumHYPERPLASIA DYSPLASIACARCINOMAINVASIVE CARCINOMAGene Methylation Mutations TranslocationsPromotion of survival signals and evasion of apoptosisTissue invasion and metastasisLimitless potential for replicationVascular recruitment and endothelial cell growthCellular proliferation through independent growth signalingAdapted from Weinberg RA. Sci Am. 1996;275:62-70. Bronchial EpitheliumAir Space…..but the vasculature plays a RELEVANT role
33. Ramucirumab (RAM) is a human IgG1 monoclonal antibody, specifically binding to the extra-cellular domain of VEGFR-2.Two phase III studies in second-line gastric cancer demonstrated that RAM monotherapy or in combination with chemotherapy prolongs OS. Ramucirumab (CYRAMZATM) monotherapy is approved by the FDA as second-line treatment of advanced gastric cancer (April 2014).Nintedanib is an oral angiokinase inhibitor targeting VEGFR 1–3, FGFR 1–3, and PDGFR α/β as well as RET
34. REVEL: Study DesignAbbreviations: Bev=bevacizumab; ECOG PS=Eastern Cooperative Oncology Group performance status; ORR=objective response rate; PFS=progression-free survival; ROW=rest of the world; q3wks=every 3 weeks. Stage IV NSCLC after one platinum- based chemo +/- maintenancePrior Bev allowedAll histologies PS 0 or 1Treatment until disease progression or unacceptable toxicityRamucirumab 10 mg/kg +Docetaxel 75 mg/m2 q3wksN=628Placebo +Docetaxel 75 mg/m2 q3wksN=625RANDOMIZE1:1Stratification factors:ECOG PS 0 vs 1Gender Prior maintenanceEast-Asia vs. ROW Primary endpoint: Overall SurvivalSecondary endpoints:PFS, ORR, safety, patient-reported outcomes
35. LUME-Lung 1 Study DesignNintedanib 200mg BID p.o., D2–21,+ Docetaxel 75mg/m2 IV, D1,21-day cycles (n=655)Placebo BID p.o., D2–21,+ Docetaxel 75mg/m2 IV, D1,21-day cycles (n=659)N=1314RANDOMIZEStratification: ECOG PS (0 vs 1) Prior bevacizumab (yes vs no) Histology (squamous vs non- squamous) Brain metastases (yes vs no)Stage IIIB/IVor recurrentNSCLC patients after 1st line chemotherapy(all histologies) 1:1PDPDNumber of docetaxel cycles not restricted Monotherapy allowed after ≥4 cycles of combination therapyPrimary end point: PFSNext analysis step only allowed if PFS confirmed with all PFS events at time point of OS analysis RECK LBA8011, ASCO 2013
36. Randomized (ITT) Population N=1253PL+DOC (N=625)Excluded (n=572) Screened (N=1825) RAM+DOC (N=627)*Patients not receiving treatment (n=4)Reasons for discontinuation (N=613)PD 341Adverse event 94Subject decision 90Investigator decision 37Death due to adverse events 30Death from study disease 12Other 9On treatment at data cutoff N=11RAM+DOC (N=628)PL+DOC (N=618)*Patients not receiving treatment (n=4)Reasons for discontinuation (N=611)PD 429Adverse event 55Subject decision 53Investigator decision 19Death due to adverse events 31Death from study disease 14Other 10On 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.Safety Population N=1245REVEL: Patient Disposition31%wt 33%mutant 2.4%unknown 64%wt 31.5%mutant 2.9%unknown 65%
37. REVEL:Tumor Response by RECIST v1.1ITT Population, Investigator AssessmentRAM+DOC N=628PL+DOC N=625P-valueResponse, n (%)CR 3 (0.5) 2 (0.3)PR141 (22.5) 83 (13.3)SD258 (41.1)244 (39.0)PD128 (20.4)206 (33.0)Unknown/not assessed 98 (15.6) 90 (14.4) ORR (CR+PR), % (95% CI)22.9 (19.7-26.4)13.6 (11.0-16.5)<.001 DCR (CR+PR+SD), % (95% CI)64.0 (60.1-67.8)52.6 (48.6-56.6 )<.001Abbreviations: CI=confidence interval; CR=complete response; DCR=disease control rate; ITT=intention-to-treat; ORR=objective response rate; PD=progressive disease; PR=partial response; RECIST=Response Evaluation Criteria in Solid Tumors; SD=stable disease.
38. REVEL: Progression-Free SurvivalITT Population, Investigator AssessmentMedian (95% CI)Censoring RateRAM+DOC vs PL+DOC:4.5 (4.2-5.4)11.1%3.0 (2.8-3.9) 6.7%Stratified HR (95% CI) = 0.762 (0.677-0.859)Stratified log-rank P < .0001RAM+DOCPL+DOCProgression-Free Survival (%)RAM+DOCPL+DOCNumber at riskRAM+DOCPL+DOCCensored036912151821242730333833012041721209559373817119743332000036Survival Time (months)62862500020406080100
39. REVEL: Overall SurvivalITT PopulationMedian (95% CI)Censoring RateRAM+DOCRAM+DOC vs PL+DOC:10.5 (9.5-11.2)31.8%PL+DOC 9.1 (8.4-10.0)27.0%Stratified HR (95% CI) = 0.857 (0.751-0.979)Stratified log-rank P = .0235020406080100Overall Survival (%)RAM+DOCPL+DOCNumber at risk03691215182124273033527501415386329306231197156129103867056453623231192036Survival Time (months)62862500RAM+DOCPL+DOCCensored
40. Selected Treatment-Emergent Adverse Events Occurring in ≥20% of Patients or ≥5% Higher in the RAM+DOC Arm Presented By Maurice Perol at 2014 ASCO Annual Meeting
41. Reck M et al, Lancet Oncol 2014LUME1: PFSTOTAL populationADENOCARCINOMASQUAMOUS CARCINOMA
42. Reck M et al, Lancet Oncol 2014LUME1: OSAdenocarcinoma <9moADENOCARCINOMATotal population
43. Reck M et al, Lancet Oncol 2014LUME1: Safety
44.
45.
46. 46New Educational Tracks:Community practices, ,Nurses, Patient Advocacy,Palliative care
47.
48.
49.
50. LBA42_PR: Cisplatin plus pemetrexed (CP) versus cisplatin plus gemcitabine (CG) according to thymidylate synthase expression in non-squamous NSCLC: A biomarker-stratified randomized phase II trial – Ahn M et alStudy objectiveTo investigate whether thymidylate synthase (TS) expression is a predictive factor for pemetrexed + cisplatin compared with gemcitabine + cisplatin in patients with non-squamous NSCLCAhn et al. Ann Oncol 2014; 25 (suppl 4): abstr LBA42_PRPrimary endpointResponse rateSecondary endpointsPFS, OSSafetyR1:1PDKey patient inclusion criteriaNon-squamous NSCLC Stage IIIB or IVECOG PS 0 or 1Adequate organ function(n=321)Gemcitabine + cisplatin x6(n=77)Pemetrexed + cisplatin x6(n=83)TS-negative(n=160)Pemetrexed 500 mg/m2 + cisplatin 70 mg/m2 D1 q3w orgemcitabine 1000 mg/m2 D1–D8 + cisplatin 70 mg/m2 D1 q3wPDR1:1PDGemcitabine + cisplatin x6(n=82)Pemetrexed + cisplatin x6(n=79)TS-positive(n=161)PD
51. LBA42_PR: Cisplatin plus pemetrexed (CP) versus cisplatin plus gemcitabine (CG) according to thymidylate synthase expression in non-squamous NSCLC: A biomarker-stratified randomized phase II trial – Ahn M et alKey resultsIn the TS-negative group, pemetrexed + cisplatin was more efficacious than gemcitabine + cisplatin, while in the TS-positive group efficacy was similar between treatmentsAhn et al. Ann Oncol 2014; 25 (suppl 4): abstr LBA42_PRInvestigator assessmentInteraction p=0.0084p=0.0008p=1.0Independent assessmentInteraction p=0.0077p=0.02p=0.3447%21%40%39%39%21%40%48%
52. LBA42_PR: Cisplatin plus pemetrexed (CP) versus cisplatin plus gemcitabine (CG) according to thymidylate synthase expression in non-squamous NSCLC: A biomarker-stratified randomized phase II trial – Ahn M et alKey results (cont.)Low expression of TS was asssociated with prolonged OS irrespective of treatment regimenConclusionTS is a predictive and prognostic biomarkerAhn et al. Ann Oncol 2014; 25 (suppl 4): abstr LBA42_PRNumber at riskTS (-) 159 116 52 18TS (+) 156 90 31 8HR 0.64, 95% CI 0.45, 0.901.00.90.80.70.60.50.40.30.20.10Probability of overall survival0 10 20 30MonthsMedian OS (months)95% CIp valueTS-negative30.326.4, not reached<0.0001TS-positive15.211.5, 21.0
53. LBA40_PR: TARGET: A randomized, phase II trial comparing vintafolide versus vintafolide plus docetaxel, versus docetaxel alone in second-line treatment of folate-receptor-positive non-small cell lung cancer (NSCLC) patients – Hanna N et alStudy objectiveTo compare vintafolide with vintafolide + docetaxel and docetaxel alone as second-line treatment in patients with folate-receptor-positive NSCLCHanna et al. Ann Oncol 2014; 25 (suppl 4): abstr LBA40_PRPrimary endpointPFSSecondary endpointsORR, DCR, OSR1:1:1PDPDKey patient inclusion criteriaAdeno and squamous NSCLC One prior chemotherapyArm C: docetaxel 75 mg/m2 IV day 1 q3w(n=68)Arm A: vintafolide 2.5 mg IVdays 1, 4, 8, 11, q3w(n=63)PDArm B: vintafolide + docetaxelAs per Arm A and Arm C schedules (n=68)99mTc-etarfolatide scanAll target lesions are FR positiveStratificationTime since last chemotherapy (<3 vs. ≥3 months); best response to chemotherapy; stage IIIB vs. IV; prior EGFR inhibitor treatment (yes vs. no)
54. LBA40_PR: TARGET: A randomized, phase II trial comparing vintafolide versus vintafolide plus docetaxel, versus docetaxel alone in second-line treatment of folate-receptor-positive non-small cell lung cancer (NSCLC) patients – Hanna N et alHanna et al. Ann Oncol 2014; 25 (suppl 4): abstr LBA40_PRVintafolide (n=63)Vintafolide + docetaxel (n=68)Docetaxel (n=68)All patientsMedian (95% CI) PFS, months 1.6 (1.4, 3.2)4.2 (2.8, 5.4)3.3 (1.7, 4.2)PFS HR (95% CI; vs. docetaxel)*; p value†1.35 (0.92, 1.96); 0.94210.75 (0.52, 1.09); 0.0696Median (95% CI) OS, months8.4 (5.6, 12.3)11.5 (7.3, 13.4)8.8 (5.4, 12.6)OS HR (95% CI; vs. docetaxel)*; p value†1.05 (0.68, 1.61); 0.58180.88 (0.58, 1.36); 0.2874Stratified analysisAll patientsn=63n=68PFS HR (95% CI; vs. docetaxel); p value†1.35 (0.89, 2.04); 0.92660.78 (0.52, 1.17); 0.1175OS HR (95% CI; vs. docetaxel); p value†0.96 (0.62, 1.50); 0.43960.75 (0.48, 1.18); 0.1066Adenocarcinoman=41n=43PFS HR (95% CI; vs. docetaxel); p value†1.32 (0.79, 2.21); 0.85900.68 (0.41, 1.14); 0.0732OS HR (95% CI; vs. docetaxel); p value†0.88 (0.51, 1.52); 0.32740.51 (0.28, 0.94); 0.0147*Unstratified log-rank; †1-sidedKey results
55. Key results (cont.)OSConclusionsCompared with docetaxel alone, vintafolide + docetaxel provided a non-significant trend in PFS and OS outcomesOutcomes were better in patients with adenocarcinomaLBA40_PR: TARGET: A randomized, phase II trial comparing vintafolide versus vintafolide plus docetaxel, versus docetaxel alone in second-line treatment of folate-receptor-positive non-small cell lung cancer (NSCLC) patients – Hanna N et alHanna et al. Ann Oncol 2014; 25 (suppl 4): abstr LBA40_PR1.00.80.60.40.20Probability of overall survival0 3 6 9 12 15 18 21MonthsPatientsEventsTreatment6340Vintafolide only6841Vintafolide + docetaxel6843Docetaxel only1.00.80.60.40.20Probability of overall survival0 3 6 9 12 15 18 21MonthsPatientsEventsTreatment4125Vintafolide only4321Vintafolide + docetaxel4930Docetaxel onlyAll patientsAdenocarcinoma
56.