Practice teaching course on head and neck cancer management

Transcription

1 28-29 October Saint-Priest en Jarez, France Practice teaching course on head and neck cancer management IMPROVING THE PATIENT S LIFE THROUGH MEDICAL EDUCATION

2 Nicolas Magné France Locally advanced squamous cell carcinoma (LA/HNSCC) General principles of systemic therapies IMPROVING THE PATIENT S LIFE THROUGH MEDICAL EDUCATION

3 Locally advanced squamous cell carcinoma (LA/HNSCC) General principles of systemic therapies Nicolas Magné France

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19 Meta-analysis: Locoregional treatment with/without chemotherapy (93 trials; 17,346 patients) Trial Category Risk reduction (%) p-value Absolute benefit at 5 years (%) Adjuvant -6 NS -1 Neoadjuvant 4 NS 2.4 Concomitant Total Absolute benefit with concomitant platinum alone (cis or carbo): 11% Pignon JP, et al. Radiother Oncol 2009;92:4 14

20 RT + high-dose cisplatin (100mg/m 2 q3w x 3) was established by pivotal Phase III cooperative group trials Nasopharynx 1 RT + 100mg/m 2 cisplatin + adjuvant cisplatin (80mg/m 2 ) vs RT alone (Int 0099) Larynx 3 RT + 100mg/m 2 cisplatin vs induction followed by RT vs RT (RTOG 91-11) Unresectable disease 2 RT mg/m 2 cisplatin vs RT alone (Int 0126) Postoperative setting 4-5 RT + 100mg/m 2 cisplatin vs RT alone (RTOG 9501) RT + 100mg/m 2 cisplatin vs RT alone (EORTC 22931) 1. Al-Sarraf M, et al. J Clin Oncol 1998;16: ; 2. Adelstein DJ, et al. J Clin Oncol 2003;21:92 98; 3. Forastiere AA, et al. N Engl J Med 2003;349: ; 4. Cooper JS, et al. N Engl J Med 2004;350: ; 5. Bernier J, et al. N Engl J Med 2004;350:

21 High-dose cisplatin is recognized as the gold standard treatment in LA SCCHN 1 but few studies have investigated this regimen Published study Cisplatin monotherapy (100mg/m 2 q3w) + RT Study Total patients in study Excludes adjuvant (post-surgery) CRT RT alone comparator arm Of the 17,346 patients included in the meta-analysis, 651 non-resected patients were treated with cisplatin + RT, and only: Studies including standard-dose (100mg/m 2 q3w) cisplatin monotherapy + RT: 2 Post-surgery? Published? patients with non-resected LA SCCHN were randomized to cisplatin 100mg/m 2 q3w EORTC Yes Yes 142 EORTC No No as recommended in the guidelines EORTC No No HeCOG No Yes Int No Yes RTOG No Yes RTOG Yes Yes 1. NCCN Guidelines: Head and Neck Cancers V1.2015; 2. Pignon JP, et al. Radiother Oncol 2009;92:4 14

22 Cisplatin + RT is associated with substantial acute and late toxicity Grade 3 toxicities with 100mg/m 2 q3w cisplatin + RT vs RT alone in LA SCCHN 1 RTOG analysis of three prospective studies of cisplatin + RT in LA SCCHN (N=230) 2 Toxicity, % Highdose cisplati n CRT (n=95) RT alone (n=98) Overall Mucositis/ dysphagia Nausea/vomit ing p-value < Leukopenia 40 1 <0.001 Thrombocyto penia 3 0 NS Anemia 17 0 <0.001 Concerns around acute/late toxicity may preclude patients from receiving the recommended dose of cisplatin 3 5 Renal Skin 7 13 NS *Late toxicity was defined as chronic Grade 3 4 pharyngeal/laryngeal toxicity; requirement 22 This for is a where feeding all tube footnotes 2 years and references after registration; go. and/or potential treatment-related death (e.g. pneumonia) within 3 years Any late toxicity* Pharyngeal dysfunction Laryngeal dysfunction Feeding tube dependence Other Death 2% 12% 13% 10% 27% 43% Patients (%) 1. Adelstein DJ, et al. J Clin Oncol 2003;21:92 98; 2. Machtay M, et al. J Clin Oncol 2008;26: ; 3. Espeli V, et al. Oral Oncology 2012;48: ; 4. Bernier J, et al. N Engl J Med 2004;350: ; 5. Argiris A, et al. Clin Cancer Res 2004;10:

23 Percentage of patients Compliance with high-dose cisplatin is poor because of significant toxicities Completed cisplatin cycles Cisplatin cycles started on time 3-weekly 100mg/m 2 cisplatin concurrent with IMRT* 1 1 cycle 3-weekly 100mg/m 2 cisplatin concurrent with RT 2 No CT 1 cycle Post-operative 3-weekly 100mg/m 2 cisplatin concurrent with conventionally fractionated RT cycles 2 cycles cycles 3 cycles 20 0 Cycle 1 Cycle 2 Cycle 3 54% of patients completed the full 3 cycles of high-dose cisplatin 61% of patients completed the full 3 cycles of high-dose cisplatin 49% of patients started their third cycle on time *Retrospective data 1. Espeli V, et al. Oral Oncology 2012;48: ; 2. Cooper JS, et al. N Engl J Med 2004;350: ; 3. Bernier J, et al. N Engl J Med 2004;350:

24 Multiple factors may render a patient unsuitable for high-dose (100mg/m 2 ) cisplatin Cisplatin is contraindicated in patients with: >2 Poor performance status 1 Renal dysfunction (CrCl <50mL/min) 1,2 Neurologic disorders (>grade 1 neuropathy) 1 Otologic disorders (pre-existing hearing loss or tinnitus >grade 2) 1,2 Known hypersensitivity to platinum-based therapy 1,2 CrCl, creatinine clearance 1. Ahn MJ. Oral Oncol 2016;53:10 16; 2. Cisplatin SmPC, January 2016

25 Patients with certain characteristics are at high risk of cisplatinassociated complications 1 Patient factors, e.g. Age >70 1,2 Involuntary weight loss 20% 2 ECOG >1 2 Socioeconomic status/ social support 2 Comorbidities: Renal dysfunction (CrCl 50 60mL/min) 2,3 Cardiovascular disease 2 Treatment factors, e.g. Prior cisplatin treatment (e.g. TPF) 2 Borderline ear function (grade 1) 2 CrCl, creatinine clearance 1. Machtay M, et al. J Clin Oncol 2008;26: ; 2. Ahn MJ. Oral Oncol 2016;53:10 16; 3. Miller RP, et al. Toxins 2010;2:

26 Probability of survival Probability of survival Weekly cisplatin: Concerns for reduced efficacy in LA SCCHN CRT with 3-weekly (100mg/m 2 ) vs weekly (40mg/m 2 ) cisplatin in patients with LA SCCHN (retrospective analysis) 1 CRT with weekly (20mg/m 2 ) cisplatin vs RT alone in patients with LA SCCHN (Phase III ECOG) HR=0.50 (95% CI: ) p= No significant difference in OS p= Cisplatin 100mg/m 2 q3w (n=54) Cisplatin 40mg/m 2 qw (n=40) 0.8 Cisplatin 20mg/m 2 qw + RT (n=149) RT alone (n=159) Median OS, 4.3 years Median OS, 1.9 years Time (years) Time (years) Ongoing Japanese non-inferiority study (JCOG 1008) is comparing RT plus cisplatin 40mg/m 2 qw with RT plus high-dose cisplatin 100mg/m 2 q3w as postoperative CRT in patients with high-risk LA SCCHN 3 1. Espeli V, et al. Oral Oncol 2012;48: ; 2. Quon H, et al. Int J Radiat Oncol Biol Phys 2011;81: ; 3. Kunieda F, et al. Jpn J Clin Oncol 2014;44:

27 Toxicity with weekly vs 3-weekly cisplatin Randomized trial: Postoperative CRT with 3-weekly cisplatin (100mg/m 2 )* vs weekly cisplatin (40mg/m 2 ) in patients with oral cavity SCCHN Neutropenia Leukopenia Anemia Nausea/vomitin g Dermatitis Laryngeal edema Stomatitis Pharyngitis Mucositis Patients, % Acute toxicity Cisplatin 100mg/m 2 q3w (n=26) Cisplatin 40mg/m 2 qw (n=24) p=0.012 Cisplatin 100mg/m 2 q3w (n=26) Cisplatin 40mg/m 2 qw (n=24) Grade Grade Grade Cisplatin 200mg/m p- value Patients with grade 3 acute toxicities, % Although OS and locoregional recurrence-free survival did not differ significantly between arms, the study was underpowered for the comparison of efficacy outcomes *Hydration with saline solution (500ml 2 hours before and after cisplatin infusion) was mandatory in the high-dose cisplatin arm only Tsan DL, et al. Radiat Oncol 2012;7:215

28 Proportion of patients, % Cetuximab has demonstrated significant efficacy in a well-designed, landmark Phase III study 1 4 Phase III Bonner study: 100 Overall survival 5 year follow up 1,2 Cetuximab + RT (n=211) RT alone (n=213) RT alone n=21 3 Cetuxima b + RT n=211 Median LRC* (months) 1 HR (95% CI) 0.68 ( ) p- value months HR=0.73 (95% CI: ) p= months 5-year OS 46% Median OS (months) ( ) % Median PFS (months) ( ) Time (months) *Primary endpoint; LRC, locoregional control 1. Bonner JA, et al. N Engl J Med 2006;354: ; 2. Bonner JA, et al. Lancet Oncol 2010;11:21 28; 3. Wirth LJ. J Clin Oncol 2016;34: ; 4. Griffin S, et al. Health Technol Assess 2009;13 Suppl 1:49 54

29 Baseline EORTC QLQ-C30 global health status (leastsquares mean) Cetuximab does not exacerbate the toxicity seen with RT* and does not impact on QoL Bonner study 1,2 Grades 3 5 adverse events 1 Quality of life 2 Mucositis Dysphagia RT (n=212) Cetuximab + RT (n=207) Radiation dermatitis Xerostomia p=0.103 Acne-like rash Infusion reactions* p=0.01 p<0.001 RT alone (n=212) Cetuximab + RT (n=208) Week 4 Month 4 Month 8 Month 12 Patients (%) The median 29 duration of mucositis and dysphagia in the overall population was similar in both treatment groups (p=0.17) 2 *Except for acne-like rash and infusion reactions 1. Bonner JA, et al. N Engl J Med 2006;354: ; 2. Curran D, et al. J Clin Oncol 2007;25:

30 1. NCCN Clinical Practice Guidelines in Oncology: Head and Neck Cancers V1.2015; 2. Pignon JP, et al. Radiother Oncol 2009;92:4 14; 3. Adelstein DJ, et al. J Clin Oncol 2003;21:92 98; 4. Machtay M, et al. J Clin Oncol 2008;26: ; 5. Espeli V, et al. Oral Oncology 2012;48: ; 6. Bonner JA, et al. N Engl J Med 2006;354: ; 7. Calais G, et al. J Natl Cancer Inst 1999;91: ; 8. Wirth LJ. J Clin Oncol 2016;34: ; 9. Griffin S, et al. Health Technol Assess 2009;13 Suppl 1:49 54; 10. Bonner JA, et al. Lancet Oncol 2010;11:21 28; 11. Curran D, et al. J Clin Oncol 2007;25: ; Cetuximab + RT is an evidence-based option with a good therapeutic index in patients not suitable for high-dose cisplatin + RT 1 Category 1 Regimen (+ RT) Cisplatin 100mg/m 2 Carboplatin + 5-FU Cetuximab Considerations Survival benefit vs RT alone 2 Can lead to severe acute and late toxicities 3,4 Associated with poor compliance 5,6 Improves OS vs RT alone 7 Associated with substantial acute toxicities 7 Efficacy and safety established in a well-designed, landmark Phase III trial 6,8,9 Does not exacerbate toxicity of RT 6,10,11

31 Progression-free-survival Overall survival GORTEC : RT/cetuximab vs RT/cetuximab/carboplatin/5-FU PFS: HR* 0.73 ( ) 2-sided log-rank p=0.015 OS: HR* 0.80 ( ) 2-sided log-rank p= CT /cetuximab/rt Cetuximab/RT CT /cetuximab/rt Cetuximab/RT 0.00 No. at risk: CT /cetux/rt 204 Cetux/RT Years since randomization No. at risk: CT /cetux/rt Cetux/RT Years since randomization PFS at 3 years (95% CI): CT /cetuximab/rt 52.3% (45 59) Cetuximab/RT 40.5% (34 48) OS at 3 years (95% CI): CT /cetuximab/rt 60.8% (54 67) Cetuximab/RT 54.9% (48 62) Toxicity was increased in the intensified regimen *HR adjusted for N (0 vs 1 2), T (0 2 vs 3 4) and center in Cox model CT consisted of carboplatin + 5-FU 1. Bourhis J, et al. ASCO 2016 (Abstract No. 6003)

32 Cetuximab + RT is a category 1 evidence-based option for all patients with LA SCCHN 1 * NCCN category 1 evidence-based options for treatment of LA SCCHN 1 Cisplatin 100mg/m 2 q3w + RT? Cetuximab + RT? 2,3 Carboplatin/5-FU + RT* 32 *Outcome of the advisory board Determining unsuitability for cisplatin + RT 11/02/2016 Unsuitable High-risk patients Suitable Suitability for cisplatin 100mg/m 2 q3w + RT 1. NCCN Clinical Practice Guidelines in Oncology: Head and Neck Cancers V1.2015; 2. Hitt R, et al. ASCO 2016 (Abstract No. 6001); 3. Geoffrois L, et al. ASCO 2016 (Abstract No. 6000)

33 New elements in the continuum of care in recurrent and/or metastatic SCCHN? 1st line 2nd and later lines Cetuximab + platinumbased CT cetuximab until PD? Taxane +/- platin Cetuximab* +/- taxane Cetuximab* Methotrexate Checkpoint inhibitors *Cetuximab monotherapy or in combination with taxane is not approved for the treatment of SCCHN in the EU 2 Checkpoint inhibitors are not currently approved for the treatment of SCCHN CT, chemotherapy; PD, progressive disease 1. NCCN Clinical Practice Guidelines in Oncology. Head and Neck Cancers. V ; 2. Erbitux SmPC, June 2014.

34 EXTREME regimen improves response and symptom control in 1st line 1,2 Response rates in EXTREME: 1,3 Real-life importance of tumor shrinkage with cetuximab % 6.8% Cetuximab + CT* CR PR 20% 0.9% CT* alone *CT consisted of cisplatin/carboplatin + 5- FU 1. Vermorken JB, et al. N Engl J Med 2008;359: ; 2. Mesia et al. EMA assessment report, Erbitux, Available at _Variation/human/000558/WC pdf (Accessed 19 February 2016); 3. Mesía R, et al. Ann Oncol 2010;21:

35 OS (%) Cetuximab + platinum-based CT followed by cetuximab maintenance: efficacy outcomes Cetuximab + CT* (n=222) 100 CT* alone (n=220) HR=0.80, p= months 10.1 months 81% disease control in the cetuximab arm Months *CT consisted of cisplatin/carboplatin + 5-FU Vermorken JB, et al. N Engl J Med 2008;359:

36 OS (probability) High response rates and promising mos with TPEx TPEx Phase II study 1 : Cis/doceT+cet OS TPEx real-world study 2 : OS Median OS: 14.0 months (95% CI: ) % 57.4% Median OS: 13.6 months (95% CI: NR) % 19.0% Time (months) Time (months) No. at risk ORR: 44% 80% disease stabilization ORR: 86% 97% disease stabilization *taxanes are not approved for R/M SCCHNin the EU 3 Cetuximab administered every 2 weeks at 500mg/m 2 in the maintenance phase (Note: off-label use 3 ) 1. Guigay J, et al. Ann Oncol 2015;26: ; 2. Even C, et al. ESMO 2014 (Abstract No. 997P); 3. Erbitux SmPC, June 2014.

37 OS (percentage) CSPOR-HN02 study: Carbo/pacliT+ cet OS Median OS: 14.7 months (95% CI: 12.1 NR) 60 ORR: 40% 60% disease stabilization Time from registration (months) No. at risk Chemotherapy for R/M SCCHN. Chemotherapy consisted of paclitaxel 100mg/m 2 on day 1, 8; carboplatin AUC 2.5 on day 1, 8, repeated every 3 weeks for up to 6 cycles; and cetuximab at an initial dose of 400mg/m 2, followed by 250mg/m 2 weekly until disease progression or unacceptable 37 Tahara M, et al. ASCO 2016 (Abstract No. 6026);

38 The ability of cetuximab to induce ADCC may contribute to its clinical efficacy 1,2 1. Trivedi S, et al. Ann Oncol 2015;26:40 47; 2. Belluci R, et al. OncoImmunol 2015;4:6,e ; 3. Lo Nigro C, et al. Cancer Res 2015;75:1327. NK cell activation 1 EGFR Lysis 1 Tumor cell Cetuximab NK cell FC Receptor Dendritic cell activation and T cell recruitment 2 Tumor cell FC region of antibody

39 and could contribute to synergy with checkpoint inhibition NK cell activation 1 IFNγ 2 EGFR Tumor cell Cetuximab PD-L1 2 Cetuximab also attenuates the decrease in T and NKT cells seen with platinum + 5-FU 3 1. Trivedi S, et al. Ann Oncol 2015;26:40 47; 2. Belluci R, et al. OncoImmunol 2015;4:6,e ; 3. Lo Nigro C, et al. Cancer Res 2015;75:1327.

40 New elements in the continuum of care in recurrent and/or metastatic SCCHN? 1st line 2nd and later lines Cetuximab + platinumbased CT cetuximab until PD? Taxane +/- platin Cetuximab* +/- taxane Cetuximab* Methotrexate Checkpoint inhibitors *Cetuximab monotherapy or in combination with taxane is not approved for the treatment of SCCHN in the EU 2 Checkpoint inhibitors are not currently approved for the treatment of SCCHN CT, chemotherapy; PD, progressive disease 1. NCCN Clinical Practice Guidelines in Oncology. Head and Neck Cancers. V ; 2. Erbitux SmPC, June 2014.

41 CheckMate 141, KEYNOTE-55 & KEYNOTE-012 Study designs CheckMate KEYNOTE-055 2,3 N=361 N=172 KEYNOTE N=192 *ITT population (Note: 13 patients actually received cetuximab); ASCO 2016 data cover analysis of the first 50 patients 1. Ferris RL, et al. ASCO 2016 (Abstract No. 6009); 2. Bauml J, et al. ASCO 2016 (Abstract No. 6011); 3. (Accessed May 29, 2016); 4. Chow LQ, et al. ASCO 2016 (Abstract No. 6010)

42 CheckMate 141 and KEYNOTE-055: Inclusion criteria CheckMate KEYNOTE-055 2,3 Age 18 years PS 1 R/M SCCHN not amenable to curative local therapy Tumor progression or recurrence within 6 months of last dose of platinum therapy in the adjuvant, recurrent or metastatic setting Measurable disease by CT or MRI Age 18 years PS 1 R/M SCCHN not amenable to curative local therapy Tumor progression or recurrence within 6 months of any number of platinum-bases and cetuximab therapy lines in the adjuvant, recurrent or metastatic setting Must be resistant (not responding) to both platinum and cetuximab Measurable disease by CT or MRI 1. Ferris RL, et al. ASCO 2016 (Abstract No. 6009); 2. Bauml J, et al. ASCO 2016 (Abstract No. 6011); 3. (Accessed May 29, 2016).

43 New potential options in 2nd line R/M SCCHN Nivolumab 1 Pembrolizumab 2 Nivolumab CheckMate vs IC n=240 ORR, % 13.3 vs 5.8 (NS) CR, % 2.5 vs 0.8 PR, % 10.8 vs 5.0 SD, % 22.9 vs 35.5 PD, % 41.7 vs 34.7 Not determined mpfs (mo) 22.1 vs vs 2.3 (NS) KEYNOTE n=92 ORR, % 17 PR, % 17 SD, % 19 PD, % 55 Not applicable 9 Patients with 6 months followup ORR, overall response rate; CR complete response; PD, progressive disease; PR, partial response; SD, stable disease. 1. Ferris RL, et al. ASCO 2016 (Abstract No. 6009); 2. Bauml J, et al. ASCO 2016 (Abstract No. 6011).

44 Overall survival (ITT population) CheckMate 141 KEYNOTE Ferris RL, et al. ASCO 2016 (Abstract No. 6009); 2. Bauml J, et al. ASCO 2016 (Abstract No. 6011).

45 Progression-free survival (ITT population) CheckMate 141 KEYNOTE This is where all footnotes and references go. 1. Ferris RL, et al. ASCO 2016 (Abstract No. 6009); 2. Bauml J, et al. ASCO 2016 (Abstract No. 6011).

46 Relevance of biomarkers: PD-L1 expression 1. Ferris RL, et al. ASCO 2016 (Abstract No. 6009)

47 Relevance of biomarkers: PD-L1 expression 1. Ferris RL, et al. ASCO 2016 (Abstract No. 6009)

48 Relevance of biomarkers: PD-L1 expression 1. Ferris RL, et al. ASCO 2016 (Abstract No. 6009)

49 ORR and OS by PD-L1 expression CheckMate (nivolumab arm only) n=240 1 % KEYNOTE ,3 n=92 KEYNOTE * PD-L1 PD-L1 PD-L1 5% 10% + + ORR, % Median OS, months Median PFS, months NR NR *Data for tumor and inflammatory cells Estimated from data provided in days (303 and 151, respectively) 49 This is where all footnotes and references go. 1. Ferris RL, et al. ASCO 2016 (Abstract No. 6009); 2. Bauml J, et al. ASCO 2016 (Abstract No. 6011); 3. (Accessed May 29, 2016); 4. Chow LQ, et al. ASCO 2016 (Abstract No. 6010)

50 Other biomarkers (KEYNOTE-012) ORR by PD-L2 status Nonresponders n Responder s n ORR, % (95% CI) p- value 50 CPS (tumor and inflammatory cells) This is where all footnotes and references go. PD- L2+ PD- L (15 31) (4 20) Chow LQ, et al. ASCO 2016 (Abstract No. 6010)

51 Best of both worlds in future treatment concepts? ADCC and T cell receptor regulation NK cell Tumor cell FC Receptor FC region of antibody Regulation of T-cell activation This is where all footnotes and references go. 1. Janeway CA Jr, et al. Immunobiology; The immune system in health and disease; 5 th Ed. 2001; 2. Pardoil DM. Nat Rev Cancer 2012; 12:

52 First line R/M ongoing development strategies: Answering all the questions? Questions being answered in the ongoing Phase 3 studies Study KESTREL 1 (N=628) Phase III KEYNOTE (N=780) Phase III CHECKMAT E (N=490) Phase III NCT (N=104) Phase I Others? Comparator arm(s) MEDI4736 MEDI tremelimumab Cetuximab + platinum + 5-FU Pembrolizumab Pembrolizumab + platinum + 5-FU Cetuximab + platinum + 5-FU Mono checkpoi nt? Chemo +ionc? ionc combi? EXTREM E combi? Maintena nce ionc switch? Nivolumab + ipilimumab Cetuximab + platinum + 5-FU Urelumab + cetuximab