Maintenance Treatment for Advanced NSCLC. Yvonne Summers PhD, FRCP ESMO Preceptorship Programme March 2017

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1 Maintenance Treatment for Advanced NSCLC Yvonne Summers PhD, FRCP ESMO Preceptorship Programme March 2017

2 Milestones in the Palliative Systemic Treatment of NSCLC Platinum based Chemotherapy (MIC, MVP) EGFR TKIs (unselected patients) Platinum +3 rd Generation Agents 1 st line EGFR TKIs (mutated patients) Pemetrexed in Non- Squamous NSCLC Crizotinib (ALK+patients) Maintenance therapies in NSCLC (Pemetrexed, Erlotinib, Docetaxel, Gemcitabine, Avastin) Crizotinib ROS 1 Immunotherapy (anti PD-1, PD-L1) Ongoing development - Molecular profiling & development of therapies targeting the biological drivers of cancer: Overcoming resistance to EGFR TKI s (T790M, rocelitinib), next generation ALK inhibitors (ceritinib, alectinib, brigatenib, lorlatinib) KRAS pathway (MEK, BRAF, MTOR), PI3K pathway, FGFR, ROS1, RET, HER2,etc

3 What is Maintenance Therapy? Patients receive 1 st line treatment for NSCLC (typically platinum doublet chemotherapy) Approximately 40% will progress whilst on treatment and may go on to receive 2 nd line treatment immediately Approximately 60% will not progress what happens next? Wait until Progression (Will patients be fit enough for treatment at this point?) Consider for Maintenance Therapy PD PD Consider for 2 nd line treatment Consider for 2 nd line treatment

4 The limitations of watch and wait Socinski, et al. JCO 2002 Belani, et al. JCO 2003 Brodowicz, et al. Lung Cancer 2006 von Plessen, et al. Br J Cancer 2006 Barata, et al. WCLC 2007 Park, et al. JCO 2007 Ciuleanu, et al. Lancet 2009 Pirker, et al. Lancet 2009 Scagliotti, et al. JCO 2008 Fidias, et al. JCO Percentage In studies of NSCLC, around 50% of patients did not receive any secondline therapy

5 What Maintenance Therapy Will We Consider? Continuation of a first line drug or switch to a new drug Immediately after initial 1 st line (chemo) therapy Providing response to initial therapy is stable disease or better and PS remains good (0-1) Pemetrexed, erlotinib, docetaxel, gemcitabine, bevacizumab Excluding: EGFR and ALK directed therapy Immunotherapy Continuing therapy after 2 nd line chemo eg nintedanib, ramicirumab

6 Immediate vs Delayed Docetaxel Stage IIIB/IV NSCLC PS 0-2 N=566 Gem Carbo x4 SD CR PR Immediate Docetaxel x6 N=153 Delayed Docetaxel X6 N=156 Fidias et al JCO 2009: 27;

7 Immediate versus Delayed Docetaxel 2-3% FN ~30% grade 3/4 neutropaenia PFS 5.7 vs 2.7 mo (p<0.0001) OS 12.3 vs 9.7 mo (p=0.085) Patients who actually received docetaxel in delayed arm had same OS 37% in delayed arm never received treatment OS for those who did not proceed to randomisation was 4.7 months Fidias et al JCO 2009: 27;

8 JMEN - Maintenance Pemetrexed Plus Best Supportive Care (BSC) Versus Placebo Plus BSC: A Phase III Study in Advanced NSCLC: Study Design Double-blind, Placebo-controlled, Multicenter, Phase III Trial Stage IIIB/IV NSCLC ECOG PS prior cycles of GEM, DOC, or PAC+CIS or CARB, with CR, PR, or SD Randomization factors: Sex Performance status Disease stage Best tumor response* Non-platinum drug* Brain metastases 2:1 Randomization Pemetrexed IV 500 mg/m 2 (d1, q21d)+ BSC (N=441) Primary Endpoint=PFS Placebo IV (d1, q21d)+bsc (N=222) *With regard to induction therapy. B 12, folate, and dexamethasone given in both arms. BSC=Best supportive care; CARB=carboplatin; CIS=cisplatin; CR=complete response; d1, q21d=day 1, dose once every 21 days; DOC=docetaxel; ECOG=Eastern Cooperative Oncology Group; GEM=gemcitabine; IV=intravenous; PAC=paclitaxel; PR=partial response; SD=stable disease. Ciuleanu et al. Lancet 2009: 374:

9 JMEN: Patient Characteristics Pemetrexed n=441 % Placebo n=222 Median Age (years) Males/Females 73/27 73/27 White/Asian/Other* 63/32/4 67/30/3 Disease Stage IIIB/IV 18/82 21/79 Smoker/Neversmoker % 73/26 71/28 ECOG PS 0/1 40/60 38/62 Histology Nonsquamous Adenocarcinoma Large cell carcinoma Other or indeterminate Squamous *Other includes Hispanic, African, Aboriginal. ECOG=Eastern Cooperative Oncology Group; PS=performance status. Ciuleanu et al. Lancet 2009: 374:

10 JMEN: Initial Therapy Pemetrexed n=441 % Placebo n=222 % Docetaxel-carboplatin 5 3 Docetaxel-cisplatin 2 2 Paclitaxel-carboplatin Paclitaxel-cisplatin 6 9 Gemcitabine-carboplatin Gemcitabine-cisplatin Best response to induction treatment CR+PR/SD 47/52* 52/48 *Three patients had progressive disease following induction (protocol violation); one patient was unknown. CR=complete response; PR=partial response; SD=stable disease. Ciuleanu et al. Lancet 2009: 374:

11 Ciuleanu et al. Lancet 2009: 374: Study Treatment Pemetrexed n=441 Placebo n=222 Number of patients treated Median number of cycles (range) 5.0 (1-55) 3.5 (1-46) Dose reductions (%) 5 1 Discontinuations due to drug-related toxicities (%) 5 1 Patients completing 6 cycles (%) Patients completing 10 cycles (%) 23 9 Mean weekly dose intensity (%) Median follow-up time (months)

12 Ciuleanu et al. Lancet 2009: 374: Drug-related Non-laboratory Toxicities* Pemetrexed (n=441) Placebo (n=222) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Fatigue <1 Anorexia Infection Diarrhea 5 <1 3 0 Nausea 19 <1 5 <1 Vomiting 9 <1 1 0 Sensory neuropathy 9 <1 4 0 Mucositis/Stomatitis 7 <1 2 0 Rash 2 <1 <1 0 *Updated safety analysis performed 6 months after initial progression-free survival (PFS) analysis. For the purpose of this table, a cut-off of 5% was used for inclusion of all events where the investigator considered a possible relationship to pemetrexed. p<0.05 for grade 3 or 4 rate of fatigue between study arms.

13 Progression-free Probability Survival Probability Ciuleanu et al. Lancet 2009: 374: JMEN: PFS AND OS Progression-free Survival - Nonsquamous (Intent-to-treat Population)* PLA 2.6 months HR=0.44 (95% CI: ) p< PEM 4.5 months *Based on the ITT population, assessed by investigators (N=663). CI=confidence interval; HR=hazard ratio; PEM=pemetrexed; PLA=placebo. Time (months) Overall Survival - Nonsquamous (Intent-to-treat Population)* PLA 10.3 months HR=0.70 (95% CI: ) p=0.002 PEM 15.5 months *Based on the ITT population, assessed by investigators (N=663). CI=confidence interval; HR=hazard ratio; PEM=pemetrexed; PLA=placebo. Time (months)

14 JMEN: Efficacy by Histology Histology Groups PEM Median OS (months) PLA Overall population Nonsquamous * (n=481) Adenocarcinoma (n=328) Large cell (n=20) Other (n=133) Squamous (n=182) p-value (HR) (0.79) (0.70) (0.73) (0.98) (0.61) (1.07) There was a statistically significant treatment-by-histology interaction with OS (p=0 033). * Nonsquamous histology included patients with adenocarcinoma, large cell carcinoma, and other/unknown histology (that is, all patients without a diagnosis of predominantly squamous cell carcinoma). HR=hazard ratio; OS=overall survival; PEM=pemetrexed; PFS=progression-free survival; PLA=placebo. Ciuleanu et al. Lancet 2009: 374:

15 JMEN Conclusions Pemetrexed is well-tolerated and offers significantly superior PFS and OS over placebo in patients with advanced NSCLC 50% reduction in the risk of progression and a 21% reduction in the risk of death in the intent-to-treat population This benefit is primarily limited to those with nonsquamous histology

16 PARAMOUNT: Study Design Randomized, placebo-controlled, double-blind phase III study Pemetrexed 500 mg/m 2 ; Cisplatin 75 mg/m 2 Folic acid and vitamin B 12 administered to both arms Induction Therapy 4 cycles, q21d Continuation Maintenance Therapy q21d until PD Previously untreated PS 0/1 Stage IIIB-IV NS-NSCLC Pemetrexed + Cisplatin CR/PR/SD per RECIST R 2:1 Stratified for: PS (0 vs 1) Disease stage (IIIB vs IV) prior to induction Response to induction (CR/PR vs SD) Pemetrexed + BSC Placebo + BSC Pas-Ares et al. Lancet 2012: 13:247-55

17 PARAMOUNT: Initial Patient Disposition 1022 Patients (Pts) Screened 83 Pts Failed Screening 400 Pts Not Randomized 217 Progressive Disease 62 Adverse Event (AE) 56 Death 29 Study Disease 15 AE 11 Drug-related AE 1 Procedure-related AE 65 Other Reasons 939 Pts Enrolled 539 Pts Randomized (2:1 Randomization) Induction Phase Maintenance Phase 548 Patients Eligible for Maint 8 Discontinued Pt Decision 1 Discontinued Phys Decision Pemetrexed Arm N=359 Placebo Arm N=180 Pas-Ares et al. Lancet 2012: 13:247-55

18 PARAMOUNT: Patient Characteristics Age Pemetrexed (N=359) Placebo (N=180) Median Age, yrs < 65 yrs, % Male, % Caucasian, % Smoker, % Ever Smoker Never Smoker ECOG PS, % /3* *Protocol violations. Pas-Ares et al. Lancet 2012: 13:247-55

19 PARAMOUNT: Disease Characteristics Pemetrexed (N=359) % Placebo (N=180) % Disease stage IV* Histology Adenocarcinoma Large cell 7 7 Other Nonsquamous 7 4 Induction Response CR/PR SD PD/Unknown 3 6 * TNM Staging System for Lung Cancer, 5 th edition. Protocol violations.

20 Survival Probability PARAMOUNT PFS from randomisation PFS: Reassessed at Time of Final OS Patients at Risk Pemetrexed Placebo Unadjusted HR: 0.60 ( ) mpfs 4.4 vs 2.8 months Time (Months) Pem +BSC Plac + BSC

21 Survival probability PARAMOUNT final OS from Log-rank P= Unadjusted HR: 0.78 (95% CI: ) randomisation Pemetrexed Placebo Time from randomisation (Months) Pemetrexed Placebo Median OS (mo) (95% CI) ( ) ( ) Censoring (%) Survival rate (%, 95% CI) 1-year 58 (53 63) 45 (38 53) 2-year 32 (27 37) 21 (15 28) Patients at risk Pem + BSC Placebo + BSC Pas-Ares et al. Lancet 2012: 13:247-55

22 PARAMOUNT: Subgroup OS Hazard Ratios Hazard Ratio All Randomized Patients (N=539) Stage IV (n=490) Stage IIIB (n=49) Induction Response CR/PR (n=234) Induction Response SD (n=285) Pre-randomization ECOG PS 1 (n=363) Pre-randomization ECOG PS 0 (n=173) Non-smoker (n=117) Smoker (n=418) Male (n=313) Female (n=226) Age < 70 (n=447) Age 70 (n=92) Age < 65 (n=350) Age 65 (n=189) Other Histologic Diagnosis (n=32) Large Cell Carcinoma (n=36) Adenocarcinoma (n=471) Treatment Hazard Ratio (95% CI) Favors Pemetrexed Favors Placebo The survival results were internally consistent; benefit was seen across all subgroups

23 PARAMOUNT: Post-discontinuation Therapy Pemetrexed (N=359) %* Placebo (N=180) %* Patients Receiving Post Discontinuation Therapy Erlotinib Docetaxel Gemcitabine 10 8 Vinorelbine 8 6 Investigational drug 6 4 Carboplatin 5 4 Paclitaxel 3 3 Pemetrexed 2 4 Cisplatin 1 2 *Data expressed as % of randomized patients. Systemic therapies used in 2% of patients in either arm are shown. Only docetaxel usage differed significantly between arms (P=0.013).

24 Pemetrexed Maintenance: Audit of practice Median PFS 4.2 months N=18 Median OS 14.9 months N=32 Retrospective audit from April April N = 32, PS 0-1, 80%/20% PR/SD to Cisplatin Pemetrexed Patients received a median of 6 cycles of Pemetrexed (range 1 to 25 cycles), with 14 patients (43.8%) still on treatment at the time of data analysis. Majority of patients (n=15/18, 83.3%) discontinued treatment due to progression, and 3 patients stopped due to Grade 3/4 toxicities Most did not require dose reduction (n=28/32, 87.5%), and 7 patients (21.9%) required 1 to 2 dose delays. Of the 18 patients who progressed, 44.4% proceeded to have second line systemic therapies Lim et al. Lung Cancer 2016:S (17)

25 SATURN a double-blind, randomised, phase III study of maintenance erlotinib versus placebo following nonprogression with 1st-line platinum-based chemotherapy in patients with advanced NSCLC Chemonaïve advanced NSCLC n=1,949 4 cycles of 1st-line platinumbased doublet* Non-PD n=889 Erlotinib 150mg/day 1:1 PD Mandatory tumour sampling Placebo PD Stratification factors: EGFR IHC (positive vs negative vs indeterminate) Stage (IIIB vs IV) ECOG PS (0 vs 1) CT regimen (cis/gem vs carbo/doc vs others) Smoking history (current vs former vs never) Region *Cisplatin/paclitaxel; cisplatin/gemcitabine; cisplatin/docetaxel cisplatin/vinorelbine; carboplatin/gemcitabine; carboplatin/docetaxel carboplatin/paclitaxel EGFR = epidermal growth factor receptor; IHC = immunohistochemistry Co-primary endpoints: PFS in all patients PFS in patients with EGFR IHC+ tumours Secondary endpoints: Overall survival (OS) in all patients and those with EGFR IHC+ tumours, OS and PFS in EGFR IHC tumours; biomarker analyses; safety; time to symptom progression; quality of life (QoL) Cappuzzo et al. Lancet Oncol Jun;11(6):521-9

26 OS probability SATURN: PFS and OS all patients PFS*: All patients (ITT) OS*: All Patients (ITT) PFS probability HR=0.71 ( ) Log-rank p< Erlotinib Placebo PFS at 12 wks (%) PFS at 24 wks (%) Erlotinib (n=437) HR=0.81 ( ) Log-rank p= Erlotinib (n=438) Placebo (n=451) 0.2 Placebo (n=447) Time (weeks) *PFS is measured from time of randomisation into the maintenance phase; assessments were every 6 weeks; ITT = intent-to-treat population Time (months) Cappuzzo F et al Lancet Oncology June 2010;11(6): TARC00589 July 2010 Cappuzzo F et al Lancet Oncology June 2010;11(6): TARC00589 July *OS is measured from time of randomisation into the maintenance phase; ITT = intent-to-treat population Cappuzzo et al. Lancet Oncol Jun;11(6):521-9

27 SATURN: Summary of Safety Data Erlotinib (n=433) Placebo (n=445) Withdrawal due to any AE, % 5 2 Dose modification/interruption due to any AE, % 16 3 AEs occurring in 10% of patients Rash, % grade 3/4 Diarrhoea, % grade 3/ Erlotinib has a well-characterised safety profile; no unexpected safety signals were seen in this study No deterioration in QoL was seen in the erlotinib and placebo arms (FACT-L questionnaire) Cappuzzo F et al Lancet Oncology. 2010;11(6):

28 Survival rate (%) Survival rate (%) SATURN: PFS and OS in EGFR mutation group with SD on 1 st line chemotherapy PFS and OS* in EGFR mutation group with SD on first-line chemotherapy PFS OS Erlotinib (n=15) Placebo (n=15) HR=0.03 ( ) Log-rank p< Erlotinib (n=15) Placebo (n=15) Time (months) *OS is measured from time of randomisation into the maintenance phase Roche Data on File TAR035 HR=0.48 ( ) Log-rank p= Time (months) Data are not mature; 67% of patients with EGFR mutation+ disease in the placebo arm received a second line EGFR TKI TARC00589 July 2010 Cappuzzo F et al Lancet Oncology. 2010;11(6):

29 IUNO: randomised double-blind placebo controlled trial of maintenance erlotinib compared to erlotinib on progression (in patients without EGFR mutations) Chemonaïve advanced NSCLC 4 cycles of 1st-line platinumbased doublet* Non-PD N=643 Erlotinib 1:1 Chemo/ BSC EGFR-activating mutation in exon 19 or L858R NOT present *Cisplatin/paclitaxel; cisplatin/gemcitabine; cisplatin/docetaxel cisplatin/vinorelbine; carboplatin/gemcitabine; carboplatin/docetaxel, carboplatin/paclitaxe, cisplatin /pemetrexed, carboplatin/pemetrexed EGFR = epidermal growth factor receptor Placebo Primary endpoint: Overall Survival (OS) Secondary endpoints: PFS RR DCR Erlotinib Cicenas et al J.Lungcan

30 IUNO study results Maintenance erlotinib did not improve OS or PFS in patients without an EGFR activating mutation mos 9.7 vs 9.5 months HR=1.02, 95% CI , p=0.82 PFS HR 0.94, 95% CI , p=0.48 Erlotinib is not recommended for 1 st line maintenance treatment in patients without an EGFR activating mutation Cicenas et al J.Lungcan

31 Maintenance with either gemcitabine or erlotinib versus observation with predefined second-line treatment after cisplatin-gemcitabine induction chemotherapy in advanced NSCLC: IFCT-GFPC 0502 phase III study Study aim Two primary objectives to determine whether maintenance gemcitabine (Gem) is better than observation and whether sequential erlotinib is better than observation. Primary endpoint: PFS from randomisation by independent panel review. Secondary endpoints: OS, safety of maintenance treatment, symptom control. Perol et al. JCO 30: , 2012

32 IFCT-GFPC 0502 phase III study Pemetrexed administered as 2 nd line treatment in all 3 arms Study population Stage IIIB/IV NSCLC PS 0-1, years, brain metastases allowed No evidence of disease progression after 4 cycles of Gem-Cis induction CT Stratification based on gender, histology (adenocarcinoma vs other), smoking status, centre and response vs stabilisation to induction CT Perol et al. JCO 30: , 2012

33 Patient characteristics Observation (n=155) Gemcitabine (n=154) Erlotinib (n=155) Median age, years Male/Female, % 73/27 73/27 73/27 ECOG PS 0/1 at inclusion, % 50/50 47/53 52/48 ECOG PS 0/1/2 at randomisation, % 44/53/3 40/54/6 38/56/6 Stage IIIB/IV, % 9/91 9/91 7/93 Brain metastases, % Ever/never smoker, % 62/38 62/38 62/38 Adenocarcinoma/ squamous/other, % 67/19/14 66/22/12 63/17/20 Response to induction CT: OR/SD, % 53/47 53/47 53/47 Perol et al. JCO 30: , 2012

34 Drug-related adverse events Observation (n=155) Gemcitabine (n=154) Erlotinib (n=155) 1 drug-related grade 3/4 AE, % Grade 3/4 AE. Anaemia, % Neutropenia, % Thrombopenia, % Rash, % Diarrhoea, % Anorexia, % Asthenia, % Drug-related deaths 0 2* 0 *1 death due to bacterial pneumonia, 1 death caused by pneumonia and renal failure. Perol et al. JCO 30: , 2012

35 Probability Results: PFS by independent review Gemcitabine vs Observation 1.0 Obs (n=152) Gem (n=149) HR=0.56 ( ) Log-rank test, p<0.001 Median PFS, months PFS at 3 months, % PFS at 6 months, % Observation Gemcitabine Time (months) Perol et al. JCO 30: , 2012

36 Probability Results: PFS by independent review Erlotinib vs Observation Obs (n=152) Erl (n=153) Median PFS, months PFS at 3 months, % HR=0.69 ( ) Log-rank test, p=0.003 PFS at 6 months, % Observation Erlotinib Time (months) Perol et al. JCO 30: , 2012

37 Probability Results: Overall Survival Observation median 10.8 mo Gemcitabine median 12.1 mo Erlotinib median 11.4 mo Gemcitabine vs observation HR=0.89 ( ) p=0.39 Erlotinib vs observation HR=0.87 ( ) p= Time (months) Perol et al. JCO 30: , 2012

38 Gemcitabine vs observation: Subgroup analysis of PFS Obsv. Gem Factor N N HR 95% CI All Stable disease Objective response Adenocarcinoma No adenocarcinoma Smoker Non-smoker Male Female Pemetrexed No pemetrexed PS PS PS Perol et al. JCO 30: ,

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40 AVAPERL RESULTS Bevacizumab + Pemetrexed N=125 Bevacizumab N=128 p-value PFS (median, months) OS (median, months) p< HR 0.57 P=0.29 HR 0.87 Maintenance pemetrexed in combination with bevacizumab is associated with improvement in PFS for patients who have had first line treatment with Cisplatin+Pemetrexed and Bevacizumab Should the control arm been pemetrexed alone as there is more single agent activity associated with this agent? Berlesi et al. JCO 31: , 2013, Ann Oncol 2014; 5;

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42 Patel et al. JCO 31: , 2013

43 PointBreak: PFS and OS in patients who went onto receive maintenance Patel et al. JCO 31: , 2013

44 Summary of Maintenance Trials Trial PFS (months) OS (months) Fidias (Docetaxel) 5.7 vs 2.7 p< vs 9.7 p= JMEN (Pemetrexed) 4.5 vs 2.6 HR vs 10.3 HR 0.70 PARAMOUNT (Pemetrexed) 4.4 vs 2.8 HR vs 11.0 HR 0.78 SATURN (Erlotinib) 3.0 vs 2.8 HR vs 11 HR 0.81 IUNO (Erlotinib, EGFR wt) 3.0 vs 2.8 HR vs 9.5 HR1.02 Perol (Gemcitabine) 3.8 vs 1.9 HR vs 10.8 HR 0.89 AVAPERL (Beva+Pem vs Beva) POINTBREAK (Pem CBeva vs PacCBeva) 7.4 vs 3.7 HR vs 13.2 HR vs 5.6 HR 0.83 (8.6 vs 6.9 in those who got to maintenance) 12.6 vs 13.4 HR1.00 (17.7 vs 15.7 in those who got to maintenance)

45 Guidelines for Maintenance Treatment Guideline ESMO 2016 ASCO 2015 NCCN 2017 Recommendation PS 0-1, after 4 cycles platinum doublet Pemetrexed for NS-NSCLC with SD/PR, switch or continuation Erlotinib (EGFR activating mutation)+/- bevacizumab if given before Pemetrexed for NS-NSCLC with SD/PR, switch or continuation Erlotinib switch for all histologies Docetaxel switch for all histologies NS-NSCLC: Pemetrexed switch Pemetrexed, gemcitabine, bevacizumab +/- pemetrexed continuation Sq-NSCLC: gemcitabine continuation docetaxel switch

46 Summary Maintenance treatment is an option for patients of good PS (0-1) after 4 cycles of platinum doublet chemotherapy with stable disease or better Needs discussion with patient: o some patients want a break from treatment o Increased toxicity burden, increased frequency of follow up visits Clinically meaningful improvements in PFS and OS Options include: o Pemetrexed switch or continuation for NS NSCLC most robust data ( ) o Less robust evidence for gemcitabine ( ) o Evidence for docetaxel but toxicity is a barrier ( ) o Erlotinib no longer an option for patients without EGFR activating mutations o Continuation bevacizumab +/- pemetrexed ( ) Rapidly changing therapeutic environment with PD-L1 expression now changing first line therapy (patients with PD-L1>/= 50% now receiving Pembrolizumab for up to 2 years)

47 Questions?