ESMO Updated Guidelines & Treatment Strategies in CML-CP: Maximizing Eligibility for TFR.

Transcription

1 ESMO Updated Guidelines & Treatment Strategies in CML-CP: Maximizing Eligibility for TFR. Pierre Laneuville, MD, FRCP(C) McGill University Health Center, Montreal. Korea, March 2018.

2 Disclosures Activity Research Support/P.I. Employee Consultant Stockholder Speakers Bureau Scientific Advisory Board Other Company/Agency Ariad, Astellas, Astrazeneca, BMS, ChemGenex, Gilead, Lundbeck, Novartis, Otsuka, Paladin N/A BMS, Celgene, Genzyme, Gilead, INESS, Lundbeck, Novartis, Paladin, Seagen N/A Abbvie, Amgen, BMS, Gilead, Janssen, Lundbeck, Novartis Abbvie, Amgen, Astrazeneca, BMS, Celgene, CSL Behring, Gilead, Janssen, Lundbeck, Novartis, Paladin, Pfizer, Roche, Servier N/A

3 Question 1 39F G 2 P 0 A 0 with CML CP with low risk Sokal/ELTS, no cardiovascular risk factors. What is your treatment goal and recommended first line TKI? 1) MMR, imatinib 2) TFR, imatinib 3) MMR, 2GTKI 4) TFR, 2GTKI 5) None of the above.

4 Three Main Goals of Treatment 1.Maximize overall survival (MMR) 2.Maximize potential for TFR (DMR) 3.Minimize TKI associated AEs (IM vs 2GTKIs)

5 STIM Trial: Treatment-Free Survival 1 st Line Imatinib UMRD4.5 BCR-ABL1 for > 2 years Retreated with loss of CMR Etienne G et al. JCO 35:298 (2017).

6 TFR in the Australian CML8 Trial of IM Withdrawal RNA DNA Negative Positive Negative Positive Median follow-up of 42 months (range months) Ross D et al. Leukemia 24:1719 (2010). Ross DM et al. Blood Jul 25;122(4):515-22

7 Percent Relapse-free (%) Discontinuation of TKIs: The A-STIM Study 100 Relapse-free Survival by Relapse Criteria MR4.5 x > 2 years, STOP IM Retreatment STIM loss CMR A-STIM - loss MMR Without loss of MMR: 63.7% STIM criteria: 38.1% 25 0 P < Months Rousselot P et al., Haematologica. 2012;97(s1): 77 [abstract 194]. Löffler, Roeder et al. CML Conference Weimar (2011).

8 After Discontinuation, Some Patients May Show Fluctuations in MRD CML patient in CP 31 years old Low risk Sokal score Rousselot P;2016 John Goldman Conference.

9 Summary of TKI Discontinuation Studies Total of 2844 Patients Study # Pts 1 st Line TKI 2 nd Line/ Consolidation TKI Median Duration TKI (years) Stable DMR at STOP Median Duration DMR (years) Retreatment Criteria Follow-up (years) Time TFR (years) Rate TFR (%) A-STIM[6] 80 I(100%) 6.58 UMRD 3.42 > MMR DADI[7] 63 I(100%) D(100%) % IS NR >0.0069% IS DASFREE[23] 84 I(85%),D D(100%) 5.91 MR4.5 NR >MMR NR 1 49 Destiny*[15, 38] 117 I(84%), D(8%), N(4%) 6.80 MR4.0* NR >MMR NR 2 77 D-STOP[19] 54 I(61%), D(39%) D(100%) 7.66 UMRD 4.25 >MR ENESTfreedom[22] 190 N(100%) N(100%) 3.58 MR >MMR NR ENESTop[16] 126 I(100%) N(100%) 7.3 MR > MR4 x 2, >MMR x Euro-Ski[21] 750 I(94%),N/D 15% D/N/I 7.58 MR >MMR Ginema[26] 293 I(72%), N(20%), D(8%) 6.42 MR Variable Hovon[12] 15 I(100%) 8.17 MR4.5 NR >1 log/>mmr ISAV[9] 112 I(100%) 8.59 UMRD 2.14 >UMRD x2, >MMR Japan[28] 43 I(100%) 3.77 UMRD 2.28 >MMR x Keio[20] 53 I(91%), N(8%), D(1%) 8.16 UMRD 3.17 >100 copies BCRABL NR KID[8] 90 I(100%) 6.73 UMRD 3.32 >MMR x Korea[27] 24 I(67%), D(21%), B(12%) 6.42 UMRD 4.16 >MMR LAST[14] 173 I(60%), N(23%), D(15%), B(2%) 6.58 MR4.0 NR >MMR MDA**[25] 27 I(77%), D(11%), N(6%), B(6%) 8.0 UMRD 5.25 >UMRD NILst[17] 87 I/N N(100%) 8.6 MR Y >MR4.5 x STAT2***[24] 73 I/N N(100%) 8.52 MR4.5 2 &, 2.58 && >MR4.5 x 2 NR STIM1[4] 100 I(100%) 4.9 UMRD 3.03 >UMRD x 2, >MMR STIM123[11] 68 I(100%) MR >MMR NR STIM-Pilot[5] 12 I(100%) 3.75 UMRD 2.67 >UMRD x STOP 2G-TKI[10] 60 D/N 1 st L 13.3%, 2 nd L 66.7%, 3 rd L 20% 6.3 UMRD 2.42 >MMR TRAD[18] 123 I(100%) 9.16 MR4.5 NR >MR4 x 2, >MMR NR Twister[13] 40 I(100%) 5.92 UMRD 2.5 >UMRD x 2, >MMR Laneuville P. Curr Treat Options Oncol 2018; doi: /s

10 Relationship Between Rate of TFR and Median TKI Duration TFR Rate (%) TFR above/below cut-off median TKI duration STIM Pilot ENESTfreedom Japan STIM1 Cut-off 4.5 years DASfree Twister Korea Destiny Ginema STOP 2G N = 2844 KID DADI A-STIM Median TKI Duration Prior to TFR (Years) Last ENESTop Imatinib Nilotinib Cut-off 5.8 years D-STOP EURO-Ski STIM123 MDA Keio Imatinib followed by nilotinib Imatinib followed by dasatinib STAT2 ISAV NILst HOVON TRAD Cut-off 8.5 years Imatinib or 2GTKI 1 st & 2 nd Line Laneuville P. Curr Treat Options Oncol 2018; doi: /s

11 EURO-SKI Study Design Relapse defined as BCR-ABL > 0.1% (loss of MMR) at one time point EURO-SKI presented by FX Mahon at ASH 2016 Courtesy of ELN

12 EURO-SKI Study: Molecular Recurrence-Free Survival (n=755) Months MRFS (95% CI) 6 months 61% (58% - 65%) 12 months 55% (51% - 58%) 18 months 52% (49% - 56%) 24 months 50% (47% - 54%) 36 months 47 % (43% - 51%) EURO-SKI presented by FX Mahon at ASH 2016

13 EURO-SKI Study: Treatment Duration Cut-Off for Loss of MMR at 6M It means that we tested for several cutoff candidates. We chose the one with the minimal p-value. That is, the one which separates 2 groups with most significant differences with regard to the MMR status at 6 months. EURO-SKI presented by FX Mahon at ASH 2016 Identified with the minimal p-value approach*.

14 EURO-SKI Study: Probability of MMR at 6M Depends on MR4 Duration (n=405) Using the minimal p-value approach a 3.1 years cut-off was significant and chosen with respect to patient safety* *20% of the patients in the smallest group EURO-SKI presented by FX Mahon at ASH 2016

15 EURO-SKI Study: Probability of MMR at 6M Depends on MR4 Duration (n=405) With the 43 patients with >1.5 years IFN pretreatment excluded, the influence of MR4 duration before TKI was still present MR4 duration: Odds ratio: 1.13 (95%-CI ) One additional year of imatinib therapy increases the odds to stay in MMR at 6 months by 13%. EURO-SKI presented by FX Mahon at ASH 2016

16 EURO-Ski Total Duration TKI Versus Duration of DMR DMR DMR Duration TKI is a surrogate for duration DMR EURO-SKI: Duration DMR more important 1 For Equal Duration of TKI Speed of Response is a surrogate for Duration of DMR Speed of Response is a Marker of TKI Sensitivity (1) Sauselle S et al. Blood 130:A313 (2017).

17 TRAD (Treatment-Free Remission Accomplished with Dasatinib): TFR 1 (Discontinuation After 1 st Line Imatinib) Rate TFR 12M 57.5% (loss MR4.0) 74.1% (loss MMR) Kim D et al. Blood 130:A1622 (2017).

18 Can More Potent 2 nd Generation TKIs Improve the Rate of TFR?

19 ENESTfreedom Study Design: Discontinuation after First Line Nilotinib Enroll Adults with CML-CP b2a2 and/or b3a2 transcripts 2 years of frontline nilotinib MR4.5 at screening (central laboratory) RQ-PCR (standardized to the IS) every 12 weeks Nilotinib consolidation phase (52 weeks) RQ-PCR (standardized to the IS) every 4 weeks for the first 48 weeks, every 6 weeks for the second 48 weeks, and then every 12 weeks TFR phase (up to 264 weeks after last patient enters TFR phase) Loss of MMR Nilotinib treatment reinitiation phase Primary end point: Proportion of patients in MMR at 48 weeks after treatment discontinuation a Sustained deep molecular response defined as the following (in the last 4 quarterly PCR assessments): MR4.5 in the last assessment, no assessment worse than MR4, and 2 assessments between MR4 and MR4.5. References: 1. Hochhaus A ASH [abstract 3066]. 2. Hochhaus A et al. Leukemia Mar 17. doi: /leu [Epub ahead of print]. 3. Habucky K et al. TASIGNA (nilotinib) 50 mg, 150 mg and 200 mg hard capsules core data sheet, version 1.8. West Sussex, United Kingdom: Novartis Europharm Limited; 2016:1-56.

20 ENESTfreedom: Discontinuation after First Line Nilotinib Median Duration NIL = 3.6 years Median Duration MR4.5 = 2.5 year Ross D et al. Haematologica 102(s2):P601 (2017).

21 Cumulative Incidence of MR 4.5, % Throughout 6 Years of Follow-up, Nilotinib Resulted in Higher Rates of MR 4.5 vs Imatinib More than half of Tasigna-treated patients achieved MR 4.5, a key eligibility criterion for potential inclusion in TFR studies Tasigna 300 mg BID (n = 282) Tasigna 400 mg BID (n = 281) Imatinib 400 mg QD (n = 283) By 1 Year 11%; P <.0001 a 7%; P <.0001 a Δ 6% to 10% 1% Months Since Randomization MR 4.5, BCR-ABL IS %; TFR, treatment-free remission. a P values are nominal. Larson RA, et al. Blood. 2014;124 [abstract 4541]. By 5 Years 54%; P <.0001 a 52%; P <.0001 a 31% Δ 21% to 23% By 6 Years 56%; P <.0001 a 55%; P <.0001 a Δ 22% to 23% 33% X

22 Patients With MR 4.5, % Patients With MR 4.5, % Patients With MMR, % Patients With MMR, % ENESTnd: MR4.5 by BCR-ABL1 Levels at 3 Months Nilotinib 300 mg BID Imatinib 400 mg QD % MMR by 2 Years* MMR by 1 Year* 4% P < % 67% P =.0001 P = % 29% P =.0008 BCR-ABL IS 1%: 56% of pts Time Since Randomization, Calendar Years BCR-ABL Level 1% > 1% - 10% > 10% Pts % MMR by 1 Year* 31% P < % MMR by 2 Years* 78% P = % P < % BCR-ABL IS 1%: 16% of pts P < Time Since Randomization, Calendar Years BCR-ABL Level 1% > 1% - 10% > 10% Pts Saglio G, et al. Blood. 2013:[abstract 92] BCR-ABL Level 1% > 1% - 10% > 10% Pts P = % 28% P = % MR 4.5 by 4 Years* 70% MR 4.5 by 5 Years* 52% 8% P =.0046 P = Time Since Randomization, Calendar Years BCR-ABL Level 1% > 1% - 10% > 10% Pts P <.0001 MR 4.5 by 4 Years* 67% 65% 24% 5% P =.0001 MR 4.5 by 5 Years* 34% 15% P =.0001 P = Time Since Randomization, Calendar Years * Cumulative response rates reported consider each year to consist of 12, 28-day cycles.

23 Relationship Between Rate of TFR and Median TKI Duration Studies of TKI Discontinuation After Second Line Therapy TFR Rate (%) N = 534 STAT2 D-STOP NILst DASfree DADI ENESTop STOP 2G Imatinib followed by nilotinib Imatinib followed by dasatinib Median TKI Duration Prior to TFR (Years) Laneuville P. Curr Treat Options Oncol 2018; doi: /s

24 ENESTPath Study Design Rate MR4 in first 300 patients to complete 24M NIL Rea D et al. ASH 2016, Abst #3094.

25 ENESTGoal 18 (31%) D/C 41 (69%) 17 (29%) 7/17 (41%) 102 days Ritchie EK et al. ASH 2017, Abst #2875.

26 STOP-2G TKI Study Rea D et al. Blood 129:846 (2017). * Resistant/suboptimal response as per ELN 2009 criteria.

27 ENESTop Study Second Line Nilotinib Mahon F-X et al. Ann Intern Med (2018); doi: /m

28 ENESTop Study Second Line Nilotinib TFR = 58% at 48 weeks 93% Regained MR4.0 or MR4.5 by 96 weeks Time Since TFR, wk Time Since TFR, wk Mahon F-X et al. Ann Intern Med (2018); doi: /m

29 ENESTop TFR Rate at 48 Weeks by Reasons for Switch 100 Patients in TFR at 48 Weeks, % a % (73/126) 58.8% (30/51) 53.3% (16/30) 61.4% (27/44) 10 0 Total TFR Population Intolerance Resistance Physician Preference Hughes TP et al. JCO 2016;34 (suppl) [Abstract 7054].

30 ENESTop Study Second Line Nilotinib Resistance and Suboptimal Response Not Clearly Defined Resistant Resistance/treatment failure Cytogenetic Suboptimal Response Loss of Cytogenetic Response Intolerant Resistant MD Preference 40% 24% 36% Physician Preference Loss of Hematological Response Loss of MMR Adapted from Mahon F-X et al. Ann Intern Med (2018); doi: /m Clinical Trial Molecular Suboptimal Response New Therapy Available Unknown

31 Somatic Mutation Dynamics in CML Following TKI Therapy: Five Distinct Patterns Ph-ve clone ABL1 mut Ph+ve epigenetic Kim T et al. Blood 129:38 (2017). VAF = variant allele frequency

32 Second TKI Discontinuation in CML Patients N=67 IM 100% 1 st 16% switch to NIL or DAS for int CMR=35m STOP 1 IM 73% NIL 16% TFR 1 DAS 11% 2.5m TFR 2 TKI 1 =63m TKI 2 =31m UMRD4.5 = 85% STOP m TFR 1 TFR 2 Pagliardini T ASH 2016 [Abst 788]

33 Recommendations and Guidelines for TFR Criteria CML past history Hughes*[1] Green Yellow Red CP only Resistance or KD mutation NCCN**[2] ESMO**[3] Quebec & Nilotinib On Label [4] AP/BP CP only CP only CP Only CP only Sokal Non-high High NA Non-high Non High ELTS Response to TKI Rx Optimal Warning Failure Not resistant Optimal Not resistant Int/Res BCR-ABL1 transcript Typical (e13a2, e14a2) Quantifiable atypical Not quantifiable Measurable Measurable Duration TKI > 8 years 3-8 years < 3 years > 3 years > 5 years Measurable not e1a2 > 5Y IM, >3Y 2GTKI Typical > 3 years DMR < MR4.5 < MR4.0 > MR4.0 < MR4.0 < MR4.5 < MR4.5 < MR4.5 Duration DMR > 2 years 1-2 years < 1 year > 2 years < MR4 > 2 years > 2 years > 1 year Retreatment Loss MMR Loss MMR Loss MMR PCR sensitivity < MR4.5 < MR4.5 < MR4.5 Frequency of Monitoring Q1M first 6 months, Q2-3 months Q1M x 6, Q6W x 6M, Q3M Q1M x 6, Q6W x 6, Q3M Q1M x 12, Q2M x 12, Q3M Q1M x 12, Q6W x 8, Q3M PCR turn around < 4 weeks < 2 weeks < 2 weeks < 4 weeks # * Expert recommendations, ** Guidelines, & Proposed, # reinitiate treatment within 4 weeks loss of MMR [1] Hughes TP et al. Blood 128:17 (2016), [2] NCCN CML Guidelinews 2018, [3] Hochhaus A et al. Ann Oncol 28 (suppl 4):iv41-51 (2017). [4] Tasigna product monograph (FDA approved Dec 22,2017)

34 Question 2 What rate of successful TFR do you consider worthwhile for treatment discontinuation? 1) 20% 2) 30% 3) 40% 4) 50% 5) 60% 6) None of the above

35 Question 3 62M CML-CP, intermediate Sokal/ELTS, no DMII, non-smoker, SBP 134, total cholesterol 5.23 mmol/l, HDL 1.20 mmol/l. Rx imatinib 400 mg/d with 3M EMR 2.36% IS and 0.033% IS by 19 months when switched to nilotinib 300 mg bid for intolerance. Reaches MR4.5 by 24 months and has UMRD5.0 by 36 months. What would you advise? 1) Continue nilotinib 300 mg bid. 2) Decrease nilotinib to 300 mg qd. 3) Switch to dasatinib 100 mg/day 4) Switch to bosutinib 400 mg/day 5) Stop nilotinib attempt TFR. 6) None of the above.

36 Life Expectancy of CML Patients Approaching Normal 2040 Bower H et al. JCO 34:2857 (2016).

37 Age (Years) Impact of Population Demographics on the Potential of TFR Canada Population: 36,626,083 Life Expectancy: 82.2 years Median Age CML: 67 years Malaysia Population: 31,164,177 Life Expectancy: 74.0 years Median Age CML: 40 years Percent Percent

38 Molecular Monitoring in TFR Assay Requirements qrt-pcr standardized to the International Scale (IS) qrt-pcr sensitivity of > MR4.5 Sensitivity of individual test should be in the report! (ie. BCR-ABL1 was undetectable with sensitivity MR5.21) Frequency of Monitoring Q1M first year, Q2M second year, Q3M indefinitely afterwards Turnaround time for reporting test results Less than 1 month, less than 2 weeks ideal (especially with MMR retreatment threshold). If any of the above cannot be done, then don t try TFR!...Patient safety cannot be assured!

39 Atypical and Rare BCR-ABL1 Transcripts (1 2%) Multiplex PCR Analysis International Scale applies only to e13a2/b2a2 and e14a2/b3a2 transcripts M e19a2 SD1 e1a2 K562 b3a2 Healthy Donor Negative control M e19a2 BCR e1a2 b3a2 Cross NC et al. Leukemia 8:186 (1994).

40 Ideal Laboratory Report Trends, treatment response and sensitivity clearly indicated Approximate sample sensitivity is indicated by the number of control gene transcripts (ie. 10,000 ABL1 = sensitivity of 0.01%) Sample sensitivity is critical to identify potential false negative results (ie. as at 6/5/12) Cross NC, CML GOLS 2015.

41 Question 4 55M CML-CP, e19a2 transcript, low Sokal/ELTS. On imatinib 400 mg/d for 12 years with UMDR4.5 for 8 years. Chronic grade 2 musculoskeletal symptoms and fatigue. Patients asks if he can stop TKI therapy. What is your recommendation? 1) No. Atypical transcript. 2) No. Pre-existing musculoskeletal symptoms increases risk TKI withdrawal syndrome. 3) No. PCR not standardized and cannot establish reliable re-treatment threshold. 4) Yes. Measurable atypical transcript with normally good prognosis. 5) Yes. But would use re-treat with confirmed loss of molecular response. 6) None of the above.

42 Advantages and Disadvantages of TFR Safety: Risk AP/BC Fear of loosing Molecular Response 4 Risk TKI Associated Toxicity Cost of Medication Monitoring None None No Discontinuation May represent significant cumulative risk in some patients (ie. CVS events on 2G TKIs, DMII on nilotinib, etc ) Significant: Major motivation in many countries. Q6M for patients with deep MR TFR < 1/3000 so far 1, risk longer term especially if monitoring infrequent? ~ 50% will loose their molecular response 5 None, BUT TKI withdrawal syndrome in up to 30% after stopping IM 2, also reported after stopping 2GTKIs 3 None. Cost monitoring << cost TKI. Q1M 1 st year, Q2M 2 nd year, Q3M later Monitoring may be required indefinitely 1. Hughes TP et al Blood 128:17 (2016), 2. Richter J et al. JCO 32:2821 (2014), 3. ENESTfreedom - Hochhaus ASCO 2016, Campiotti et al. Eur J Cancer 77:48 (2017).

43 Treatment Goal Life Expectancy My Personal Approach for Choice 1 st Line Therapy Aiming for Deep MR and TFR is Best Decided at Diagnosis MR4.5 High ELTS Sokal Score Low 2GTKIs High FRS Uncontrolled DM GOLD st III COPD Imatinib 10 YEARS? CCI > 4 OS MMR Co-morbidity

44 ENESTcmr Study Design Eligibility: Ph+ CML-CP 2 years prior imatinib CCyR Detectable BCR-ABL a 2 years imatinib mg QD R A N D O M I Z E b Nilotinib 400 mg BID (n = 104) Nilotinib 400 mg BID (n = 46) Crossover c Continue same dose of imatinib (n = 103) Study treatment duration: 4 years CCyR, complete cytogenetic response; Ph+, Philadelphia chromosome positive; QD, once daily. a By real-time quantitative polymerase chain reaction (RQ-PCR) with sensitivity of 4.5 logs. b Randomization was stratified by duration of prior imatinib ( 36 months or > 36 months) and prior interferon (none, 12 months, or > 12 months). c Crossover from nilotinib to imatinib was not permitted per the study protocol. Hughes TP et al. Leukemia 31:2529 (2017).

45 ENESTcmr Hughes TP et al. Leukemia 31:2529 (2017).

46 STOP TFR Attempt Clinical Case 1 24 months 100 IM NIL Baseline Diagnosis 2006/12/21* Age/Sex* 76/F Transcript e13a2 Sokal Low risk EMR 3M 1.44% EMR 6M CMR Reason Switch Intolerance % BCR-ABL1 (IS) MR MMR Reason STOP CVS Risk Years Case from Pierre Laneuville. Updated Oct 30, EMR (early molecular response), 3M (3 months), 6M (6 months), MMR (major molecular response), IS (international scale), IM (imatinib), NIL (nilotinib).

47 STOP TFR Attempt Clinical Case 2 23 months Baseline 1 IM DAS Diagnosis 2003/02/16* Age/Sex* 57/F Transcript e13a2 Sokal Int risk EMR 3M? EMR 6M? Reason Switch Intolerance % BCR-ABL1 (IS) MR ? MMR Reason STOP No drugs Years Case from Pierre Laneuville. Updated Jan 25, EMR (early molecular response), 3M (3 months), 6M (6 months), MMR (major molecular response), IS (international scale), IM (imatinib), DAS (dasatinib).

48 STOP STOP TFR Attempt Clinical Case IM NIL Baseline Diagnosis 2005/05/13* Age/Sex* 22/F Transcript b2a2 Sokal Low risk EMR 3M 14.5% EMR 6M 2.54% Reason STOP Pregnancy % BCR-ABL1 (IS) M EMR 14.5% M 4M MMR Years Case from Pierre Laneuville. Updated Nov 16, 2017.

49 Summary Achieving deep sustained molecular responses is the key to TFR Nearly twice as many patients can be eligible for TFR on 2GTKIs and achieve same rate TFR in ~ half the time as with imatinib Duration of TKI > 5 years or > 3 years on IM or 2GTKI respectively, and duration DMR > 2 years are reasonable minimal criteria. Difficult to establish firm guidelines need to balance with patient considerations. Discontinuation in suboptimal/resistant patients controversial To safely attempt TFR requires the following Standardized laboratory with PCR sensitivity > MR4.5 Rapid turnaround of lab results (< 4 weeks, ideal < 2 weeks) Reliable patient, monitoring Q1M x 12, Q2M x 12, Q3M

50 Thank you for your attention! McGill University Health Centre (MUHC-Glen) Division of Hematology Geoff Blake Denis Cournoyer Kelly Davison Jonathan How Pierre Laneuville Veronique Naessens Patricia Pelletier Gizelle Popradi Rayan Kaedbey Jean Pierre Routy Michael Sebag Chantal Seguin Chaim Shustik Suzan Solymoss John Storring Margaret Warner