Immune Checkpoint Therapy Toxicities: Lessons learned and new strategies to improve outcomes

Transcription

1 Immune Checkpoint Therapy Toxicities: Lessons learned and new strategies to improve outcomes Geoffrey T. Gibney, MD Associate Professor Co-leader, Melanoma Disease Group Lombardi Comprehensive Cancer Center Medstar Georgetown University Hospital

2 Disclosures Consultant for Novartis and Genentech Speakers Bureau for Merck and Genentech

3 Outline Establish a general knowledge base of immune checkpoint therapy toxicities - the immune related adverse events (iraes) and their management. Review current data on novel immunotherapy combinations that enhance efficacy but minimize patient toxicity risks Explore evolving concepts on biomarker development for patient selection and optimized management of iraes

4 Immune Checkpoints Accelerator (co-stimulator) versus Brake (co-inhibitory) Ott P, et al, Clin Cancer Res, 2013

5 Roles of the immune checkpoints Tolerance Tissue recovery from acute injury Immune responses against bacterial and viral infections Autoimmune/inflammatory disorders PD-L1 IHC on First Trimester Placenta Petroff MG, et al, Placenta, 2002

6 Polymorphisms in CTLA-4, PD-1, and PD-L1 linked to autoimmune disorders Michot JM, et al, Eur J Cancer, 2016

7 Thymus lacks corticomedullary compartmentalization Splenic red pulp largely replaced by white pulp Myocardium infiltrated by immune cells and fibroblasts Lung with sheets of plasma cells surrounded by lymphocytes Lethal by week 3-4 Thymus Heart Science 270, 1995 Spleen Lung

8 Glomerulonephritis PD-1 +/+ PD-1 -/- Arthritis PD-1 +/+ PD-1 -/- Nishimura H, et al, Science, 2001 Nishimura H, Immunity, 1999

9 Spectrum of toxicities of immune checkpoint blockade agents Champiat S, et al, Ann Oncol, 2016

10 Toxicity Grade Kinetics of Appearance of iraes with Ipilimumab Rash, pruritus Liver toxicity Diarrhea, colitis Hypophysitis Wks Weber J, et al, J Clin Oncol, 2012

11 Checkmate 067: Study Design Randomized, double-blind, phase III study to compare NIVO+IPI or NIVO alone to IPI alone N=314 NIVO 1 mg/kg + IPI 3 mg/kg Q3W for 4 doses then NIVO 3 mg/kg Q2W Unresectable or Metatastic Melanoma Previously untreated 945 patients Randomize 1:1:1 Stratify by: Tumor PD-L1 expression* BRAF mutation status AJCC M stage N=316 NIVO 3 mg/kg Q2W + IPI-matched placebo Treat until progression* * or unacceptable toxicity Larkin J, et al, N Engl J Med, 2015 Wolchock J, et al, ASCO, 2016 N=315 IPI 3 mg/kg Q3W for 4 doses + NIVO-matched placebo 11

12 Checkmate 067: TRAEs by Organ System Updated from Wolchock J, et al, ASCO,2016 Any Grade NIVO+IPI (N=313) Grade 3-4 Any Grade NIVO (N=313) Grade 3-4 Any Grade IPI (N=311) Grade 3-4 All AEs % Skin AEs, % Rash Pruritus Gastrointestinal AEs, % Diarrhea Colitis Endocrine AEs, % Hypothyroidism Hyperthyroidism Hepatic AEs, % Elevated ALT Elevated AST Pulmonary AEs, % Pneumonitis Renal AEs, % Elevated creatinine Death from irae 0 0.3% 0.3% Database lock Nov 2015

13 Managing iraes Principles of Managing iraes: Hold immunotherapy for grade > 2 Initiate corticosteroids (e.g.,1 2 mg/kg of prednisone) Consider infliximab (if gastrointestinal toxicity) or mycophenolate (if hepatotoxicity) if no improvement with corticosteroids CTCAE = Common Terminology Criteria for Adverse Events Champiat S, et al, Ann Oncol, 2016

14 Pneumonitis is more common with anti-pd1/ctla-4 combination therapy Important to address respiratory symptoms and check oxygen saturations at each visit On any patients where pneumonitis is suspected based on H&P or clinical exam, hold treatment and order a CT scan of the chest. Specific management is necessary for grade 2 or greater pneumonitis. Grade 2 pneumonitis Hold treatment and administer steroids; Taper steroids over 4-5 weeks Resume if: Improved to grade 0 or 1 Discontinue if: Not improved to < grade 2 Chow LQM, ASCO Educational Book, 2013.

15 Outline Establish a general knowledge base of immune checkpoint therapy toxicities - the immune related adverse events (iraes) and their management. Review current data on novel immunotherapy combinations that enhance efficacy but minimize patient toxicity risks Explore evolving concepts on biomarker development for patient selection and optimized management of iraes

16 Can we give anti-pd-1 and anti-ctla-4 therapies sequentially or on different dose schedules to reduce toxicity risks?

17 Randomize CheckMate 064: Study Design Randomized, open-label, phase II study evaluating the safety and efficacy of two immune checkpoint inhibitors given sequentially with planned switch Induction Period 1 Induction Period 2 Continuation Period Cohort A N= ~70 NIVO 3 mg/kg Q2W x 6 2W IPI 3 mg/kg Q3W x 4 NIVO 3 mg/kg Q2W Week # Cohort B N= ~70 1 IPI 3 mg/kg Q3W x 4 3W 13 NIVO 3 mg/kg Q2W x 6 25 Until PD, unacceptable toxicity, or withdrawal of consent TA TA TA TA = Tumor Assessment; = Biopsy Timepoint; PD = Progressive Disease; Q2W = every 2 weeks Database lock; Nov 13, 2015 Weber J, et al, ASCO, 2016 Weber J, et al, Lancet Oncol,

18 Safety Summary During Overall Study Period Overall Study Period NIVO IPI (N=68) IPI NIVO (N=70) Patients with treatment-related Grade 3-4 AEs (%) Patients with treatment-related AEs leading to discontinuation (%) Treatment-related deaths (%)

19 KEYNOTE-029: Study Design Dose Run-In (Part 1A) Patients Advanced MEL, 0 prior therapies OR Advanced RCC, 1 prior therapy Pembro 2 mg/kg Q3W up to 24 months + Ipi 1 mg/kg Q3W x 4 doses Tolerable based on DLT rate? Yes Dose Expansion (Part 1B) Patients Advanced MEL 0 prior therapies No prior anti CTLA- 4, PD-1, or PD-L1 ECOG PS 0 or 1 No Stop development Combination tolerable based on DLT rate and AE profile 1,2 Primary end point: Safety Secondary end points: ORR, DOR, PFS, OS ClinicalTrials.gov, NCT Presenter: GV Long 1. Atkins MA et al. Presented at 2015 ASCO Annual Meeting; May 29-Jun 2, 2015; Chicago, IL. Abstr Atkins MA et al. Presented at 2016 ASCO Annual Meeting; Jun 3-Jun 7, 2016; Chicago, IL. Abstr 3009.

20 AE Summary Category Treatment Related N = 153 Immune Mediated a N = 153 Any grade 145 (95%) 89 (58%) Grade (42%) 38 (25%) Led to death 0 0 Led to ipilimumab discontinuation only 16 (10%) 12 (8%) Led to pembrolizumab 11 (7%) 6 (4%) discontinuation b Led to ipilimumab and pembrolizumab discontinuation c Presenter: GV Long 16 (10%) 11 (7%) a Regardless of attribution by the investigator. b After completion or discontinuation of ipilimumab. c Includes 1 patient who discontinued ipilimumab for colitis and later discontinued pembrolizumab for increased lipase. Data cutoff date: Mar 17, 2016.

21 Checkmate 012: Safety and efficacy of firstline nivolumab and ipilimumab in NSCLC Nivo3 Q2W (n=52) Nivo3 Q2W + Ipi1 Q12W (n=38) Nivo3 Q2W + Ipi1 Q6W (n=39) Treatment- related Grade 3 4 AEs 19% 37% 33% Skin 4% 3% 5% Gastrointestinal 2% 5% 5% Endocrine 0% 3% 5% Hepatic 2% 0% 5% Pulmonary 2% 5% 3% Renal 0% 5% 0% TRAEs (all grades) leading to DC, % 10% 11% 13% ORR 23% 47% 39% Median duration of response NR (5.7, NR) N (11.3, NR) NR (8.4, NR) 1-yr OS rate NC 69% 73% Hellman MD, et al, ASCO 2016 (abstract 3001)

22 Roadmap for Immunotherapy Development 4 Trafficking of T cells to tumors Priming and activation Anti-CTLA4 Anti-CD137 (agonist) Anti-OX40 (agonist) Anti-CD27 (agonist) IL-2 IL BB 3 5 Infiltration of T cells into tumors Anti-VEGF Anti-CXCR4 Cancer antigen presentation 2 Vaccines IFN-α GM-CSF / TVEC Anti-CD40 (agonist) TLR agonists Release of cancer cell antigens 1 Chemotherapy Radiation therapy Targeted therapy 7 6 Recognition of cancer cells by T cells CAR T-cell therapy HDAC inhibitors Targeted therapy Killing of cancer cells and tolerance Anti-PD-1/PD-L1 IDO inhibitors Anti-LAG-3 Adapted from Chen DS, et al. Immunity. 2013;39:1-10.

23 Phase 1/2 Study of Epacadostat plus Pembro Study Design Phase 1b Phase 2 Patients Age 18 Advanced or recurrent cancers Life expectancy >12 weeks ECOG PS 1 No previous treatment with checkpoint inhibitors Dose Escalation Epacadostat 25 mg BID + Pembrolizumab 2 mg/kg Q3W Epacadostat 50 mg BID + Pembrolizumab 2 mg/kg Q3W Epacadostat 100 mg BID + Pembrolizumab 2 mg/kg Q3W Epacadostat 300 mg BID + Pembrolizumab 200 mg Q3W Dose Expansion Epacadostat 50 mg BID + Pembrolizumab 200 mg Q3W Epacadostat 100 mg BID + Pembrolizumab 200 mg Q3W Epacadostat 300 mg BID + Pembrolizumab 200 mg Q3W Epacadostat RP2D + Pembrolizum ab200 mg Q3W Melanoma NSCLC TCC SCCHN TNBC Ovarian Cancer DLBCL Response assessment every 9 weeks per RECIST 1.1 Clinicaltrials.gov: NCT Gangadhar TC, et al, SITC, 2015

24 Treatment-Related AEs Gangadhar TC, et al, ESMO, patients (8%) TRAEs that led to discontinuation No treatment-related deaths Epacadostat up to 300mg bid with pembrolizumab tolerated

25 Other New PD-1/PD-L1 Combination Strategies ASCO 2016 Phase 1B trial of pembrolizumab plus PF (41BB agonist) Phase 1B trial of atezolizumab plus MOXR0916 (OX40 agonist) Phase 1 trial of pembrolizumab plus peg-ifn Phase 1 trial of pembrolizumab plus dabrafenib/trametinib Phase 1 trial of durvalumab plus olaparib (PARP inhibitor) or cediranib (VEGFR inhibitor) Phase 1 trial of pembrolizumab plus AM0010 (peg-il10) Phase 1 trial of pembrolizumab plus ramucirumab (VEGFR-2 antagonist) Phase 1B/2 trial of pembrolizumab or nivolumab plus indoximod (IDO inhibitor)

26 Outline Establish a general knowledge base of immune checkpoint therapy toxicities - the immune related adverse events (iraes) and their management. Review current data on novel immunotherapy combinations that enhance efficacy but minimize patient toxicity risks Explore evolving concepts on biomarker development for patient selection and optimized management of iraes

27 Key Questions Can we predict which patients will have severe iraes with checkpoint immunotherapies? Can we prevent or lower the risk of iraes with checkpoint immunotherapies?

28 Ipilimumab in melanoma patients with pre-existing autoimmune disorders Retrospective multicenter study of 30 patients with pre-existing autoimmune disorders and advanced melanoma who were treated with ipilimumab Outcome Objective Response 6 (20%) Flare of autoimmune d/o requiring steroids New irae requiring steroids or other 8 (27%) 10 (33%) Johnson DB, et al, JAMA Oncol, 2016

29 Johnson DB, et al, JAMA Oncol, 2016

30 Anti-PD-1 therapy in melanoma patients with pre-existing autoimmune disorders Retrospective multicenter study of 52 patients with pre-existing autoimmune disorders and melanoma treated with anti-pd-1 therapy AD Class Types No (%) N=52 Rheumatologic RA, sarcoidosis, PMR, SLE, scleroderma, psoriatic arthritis, sjogrens 27 (52%) Dermatologic psoriasis, eczema, erythema nodosum 8 (15%) Gastrointestinal CD, UC with colectomy, celiac disease 6 (12%) Neurologic GBS, CIPD, myasthenia, bells palsy 5 (10%) Endocrine graves disease 4 (8%) Respiratory asthma 2 (4%) Hematologic ITP 2 (4%) Clinically active 15 (29%) On immunosuppression at time of anti-pd-1 20 (38%) Outcome Objective Response 17 (33%) Flare of autoimmune d/o requiring steroids or other New irae requiring steroids or other 20 (38%) 7 (13%) No treatment related deaths Menzies AM, et al, ASCO 2016

31 Are immune checkpoint therapies safe in elderly patients? Friedman CF, et al, ASCO 2016 (Abstract 10009) Systemic steroids were required in 28% of pts with Ipi, 28% of pts with anti-pd-1, and 75% of pts with Nivo/Ipi

32 Circulating cytokines may be associated with checkpoint toxicity Phase 2 study of neoadjuvant ipilimumab 10mg/kg given to predominantly stage IIIB/C melanoma patients (n=35) Blood samples were analyzed using a multiplex assay for 36 cytokines 20 patients (57%) developed diarrhea/colitis, 5 patients (14%) were grade 3 Tarhini AA, et al, J Immunother Cancer, 2015

33 Clin Cancer Res 2009;15(17):5591 8)

34 Studies to improve immune-colitis management Agent Mechanism Title clinicaltrials.gov Infliximab Vedolizumab Blocks TNFalpha Blocks a4ß7 integrin interaction with MAdCAM-1; inhibits T-cell migration in mucosa Infliximab With Prednisone or Methylprednisolone With Prednisone Combination Treatment in Immune Related or Severe Diarrhea Patients Treated With Yervoy and/or Opdivo An Open-Label, Phase 1b, Multi- Arm Study to Evaluate the Safety, Tolerability, and Pharmacodynamics of Investigational Treatments in Combination With Standard of Care Immune Checkpoint Inhibitors in Patients With Advanced Melanoma NCT Sponsored by BMS NCT Sponsored by Millennium Pharmaceuticals

35 Can immunotherapy combination strategies reduce serious toxicities? JAMA. 2014;312(17): Randomized phase II study Primary endpoint = overall survival Arms: (1) ipilimumab 10mg/kg IV + GM-CSF 250ug SC days 1-14 every 21 days (2) ipilimumab 10mg/kg IV alone

36 Toxicities 45% Gr3-5 toxicities for ipi+gm-csf vs 58% for ipilimumab only (P=0.04) 2 treatment-related deaths in ipi+gm-csf vs 7 for ipilimumab only

37 ECOG 6141 Nivo/Ipi plus GM-CSF Melanoma Unresectable stage III or IV ECOG 0-1 Adjuvant therapy allowed including ipilimumab (if >1yr) Ineligible if received prior anti-pd-1/pd-l1 therapy No untreated, active brain metastases 1:1 randomization Stratification by BRAF and Stage Nivo 1/Ipi 3 followed by Nivo 3 maintenance concurrent with GM-CSF 250ug daily 2weeks on/1week off x 2 years Nivo 1/Ipi 3 followed by Nivo 3 maintenance Primary Endpoint OS Secondary Endpoints RFS Tolerability ORR by irrc and RECIST

38 Conclusions Immune checkpoint toxicities are managed with dose hold/discontinuation and corticosteroids. Combination anti-pd-1/ctla-4 immunotherapy significantly increases the grade 3-4 AE rate. New immunotherapy combinations require thorough safety evaluation. Improved strategies for management of iraes and biomarkers to predict toxicity risks are needed.