2Checkpoint inhibitors for NSCLC An updateSolange Peters, MD-PhDOncology DepartmentCHUV Lausanne11
3“In any trial you get the odd patient who does very well, but this is an order of magnitude above that.”, Mick Peake, Glenfield Hospital
4Mutations in Cancer Cells Make Them Appear Different to the Immune System High mutational rates may contribute to increased immunogenicityLawrence MS, et al. Nature
5Melanomas and lung tumors display many more mutations than average, with~200 nonsynonymous mutations per tumor.These larger numbers reflect the involvement of potent mutagens. Accordingly, lung cancers from smokers have 10 times as many somatic mutations as those from nonsmokers.Vogelstein, Science 2013
6Lung cancer is the main cause of cancer death worldwide
7Rationale for immune therapy in NSCLC Liu H et al. Cancer Immunol Immunother 2012Presence of TILs associated with increased recurrence-free survival1Higher NSCLC-Infiltrating Tregs associated with worse recurrence-free survival2Recurrence-Free Survival (%)Survival Time (Months)24361248600.00.10.20.22.214.171.124.126.96.36.199FoxP3+ cell <3FoxP3+ cell ≥31020304050TIL–TIL+P=0.011Shimizu K, et al.J Thorac Oncol. 20102. Horne ZD, et al.J Surg Res. 2011
8NSCLC: An immune driven tumor? Tumour typePrognostica tumour infiltrating lymphocytesbImmune-related spontaneous tumour regressioncNSCLCYes1Yes13 (rare)CRCYes2Yes14BreastYes3,4NoMelanomaYes5,6Yes15RenalYes7,8Yes16,17ProstateYes9OvarianYes10Head and neckYes11CervicalYes12Evidence for cervical intraepithelial neoplasia 2/318,19aCovers correlation with improved overall or progression-free survival, disease stage, or therapy outcomebThe type of lymphocyte dictates where there is a correlation with improved or worsened outcomecBased on PubMed search conducted in October 2013 using the terms ‘spontaneous regression’ and the tumour type1. Hiraoka K, et al. Br J Cancer. 2006;94:275–280; 2. Galon J, et al. Science. 2006;29:1960–1964; 3. Mahmoud SM, et al. J Clin Oncol. 2011;29:1949–1955; 4. Loi S, et al. J Clin Oncol. 2013;31:860–867; 5. Piras F, et al. Cancer. 2005;104:1246–1254; 6. Azimi F, et al. J Clin Oncol. 2012;30:2678–2683; 7. Siddiqui SA, et al. Clin Cancer Res. 2007;13:2075–2081; 8. Donskov F, et al. Br J Cancer. 2002;87:194–201; 9. Flammiger A, et al. APMIS. 2012;120:901–908; 10. Zhang L, et al. N Engl J Med. 2003;348:203–213; 11. Badoual C, et al. Clin Cancer Res. 2006;12:465–472; 12. Piersma SJ, et al. Cancer Res. 2007;67:354–361; 13. Nakamura Y, et al. Lung Cancer. 2009;65:119–122; 14. Bir AS, et al. Anticancer Res. 2009;29:465–468; 15. Kalialis LV, et al. Melanoma Res. 2009;19:275–282; 16. Kawai K, et al. Int J Urol. 2004;11:1130–1132; 17. Kumar T, et al. Respir Med. 2010;104:1543–1550; 18. Øvestad IT, et al. Mod Pathol. 2010;23:1231–1240; 19. Castle PE, et al. Obstet Gynecol. 2009;113:18–25.
9Lung cancer immunotherapy Landscape Cancer immunotherapy: any interaction with the immune system to treat cancerActive: priming of the immune systemPassive: delivery of compounds that may use immune systemAntigen- specificNon-antigen-specificMonoclonal antibodiesAdoptive cell transfer-> AG-specific antibodies & cytotoxic T cellsBCG impressive for non-invasive bladder cancer. Modest IFNalpha and IL2 in melanoma and renal cancer.Step to specific is more recent for lung cancer.Onder nonASCI zitten de immune checkpoint inhibitors (immuunsuppressie opheffen) én de adoptieve T-cel therapie (tolerantie overkomen).-> enhancement of immune systemcytokinescheckpoint inhibitorscetuximabtrastuzumabT cells engineeringCARsDendritic cellsCancer vaccination therapyCancer immunomodulation therapyTargeted antibodies immunotherapyCellularimmunotherapy9
14Ipilimumab: NSCLC phase III trial Squamous Cell NSCLC, stage IV. Primary EP: OSN=920, accrual completed
15Clinical Development of Inhibitors of PD-1 Immune Checkpoint Nivolumab-BMSFully human IgG4 mAbBristol-Myers SquibbPhase IIIPidilizumabCT-011Humanized IgG1 mAbCureTechPhase IIPembrolizumabMK-3475Humanized IgG4 mAbMerckAMP-224Recombinant PD-L2-Fc fusion proteinGlaxoSmithKlinePhase IPD-L1BMSMedI-4736Engineered human IgG1 mAbMedImmuneMPDL-3280AGenentechMSB CEMD SeronoNivo ph2 incl combinations; prolonged responses
16Anti-PD1/Anti PDL1: What do we know at the end of 2014? Monotherapy treatment with various drugs accross histologies and molecular subtypesIn >2 line of NSCLC treatment (incl. maintenance)In first line NSCLC treatment2) The challenge of the biomarker
17Gettinger et al, ASCO 2014 and CMSTO 2014 Nivolumab>2 nd line, phase 1 DATAGettinger et al, ASCO 2014 and CMSTO 2014
18OS by Dose (data lock )Pts at RiskGroupDied/TreatedMedian OS, mo (95% CI)1-year2-year3-year9.2 (5.3, 11.1)14.9 (7.3, 30.3)9.2 (5.2, 12.4)Months Since Initiation of Treatment1009080706050403020103691215183327242136394245485154666357Censored3-year OS = 27%2-year OS = 42%Nivolumab 1 mg/kgNivolumab 3 mg/kgNivolumab 10 mg/kgOS (%)33 (17, 49)56 (38, 71)38 (26, 50)15 (5, 30)42 (24, 58)20 (11, 31)27 (12, 43)14 (7, 25)26/3323/3750/591 mg/kg3 mg/kg10 mg/kg37592634351629172271413411152OS rate, % (95% CI)Pts were heavily pretreated; 54% had 3–5 prior therapies50% of responders (11/22) demonstrated response at first assessment (8 wks)Responses were ongoing in 41% of pts (9/22) at the time of analysis
19Characteristics of Responses Time to and duration of response while on tttOngoing responseTime to responseResponse duration following discontinuation of tttTime (Months)NSCLC Responders246810121416182022242628303234363840425% unconvientional “immune-related” responses, with persistent reduction in target lesions in the presence of new lesions or regression following initial progressionManageable safety profile with no new safety signals emerging with all pts having >1 year of follow-up
20Best Change in Target Lesion Tumor Burden by Tumor PD-L1 Expression PtsPositiveNegativePD-L1 Status (5% cut-off)15010050-77%33%Change in Baseline Target Lesions (%)There was no clear association between PD-L1 expression and RR, PFS or OS (archival samples)
231st line, phase 1 DATA monotherapy & combinations Nivolumab1st line, phase 1 DATA monotherapy & combinationsRizvi et al; Antonia et al, CMSTO 2014
24PFS and OS With Nivolumab Monotherapy frontline PFS at rateWks24 = 40%PFS rate atwks24= 31%108642Time Since First Dose (Weeks)B/L1379OSSqNon-sq5All treated pts524842301514122718Non-sq (mPFS 15.6 wks) Sq (mPFS 15.4 wks)All treated pts (mPFS 15.6 wks)Number of Pts at RiskNon-sq (mOS NR)Sq (mOS 73.1 wks)All treated pts (mOS 98.3 wks)
25Percent Changes in Target Lesion Tumor Burden by PD-L1 in first line B. Best percent change in target lesiontumor burden from baselinePositiveNegativePts10080604020-20-40-60-80-100PD-L1 Status (5% cut-off)Change in Baseline Target Lesion (%)aA. Percent change in target lesions from baselineTime Since First Dose (Weeks)12243648728496Change From Baseline (%)
26PFS and OS in NSCLC pts Treated With Nivolumab Plus Ipilimumab 2422211915112252017141210Nivolumab 1 mg/kg+ ipilimumab 3 mg/kg8631Nivolumab 3 mg/kg+ ipilimumab 1 mg/kgNumber of Pts at Risk4PFS1008040B/L36486072PFS rate at 24 wks = 44%PFS rate at24 wks = 33%Nivolumab 1 mg/kg +ipilimumab 3 mg/kg(mPFS 16.1 wks)Nivolumab 3 mg/kg +ipilimumab 1 mg/kg(mPFS 14.4 wks)OS1-year OS rate = 44%841-year OS rate = 65%Nivolumab 1 mg/kg + ipilimumab 3 mg/kg(mOS NR)Nivolumab 3 mg/kg + ipilimumab 1 mg/kg (mOS 47.9 wks)PFS (%)OS (%)Time Since First Dose (Weeks)
27Safety : Nivo + Ipi in NSCLC Treatment-related AEs led to discontinuation of any study drug in 37%, and included pneumonitis, increased ALT or AST, colitis or diarrhea, and allergic nephritis, ulcerative colitis, impaired gastric emptying, Miller Fisher syndrome, and pulmonary hemorrhageMost treatment-related AEs leading to discontinuation occurred during induction (15 pts, 31%)
281st line combination with chemotherapy PatientsChange in Baseline Target Lesions (%)10080604020-20-40-60-80-100Nivolumab mg/kg + Gem/CisNivolumab 10 mg/kg + Pem/CisNivolumab 10 mg/kg +Pac/CarbNivolumab 5 mg/kg + Pac/CarbORR for nivolumab plus chemotherapy in 1st-line treatment are similar to those previously reported for chemotherapy alone
2920 refractory after TKI failure , 1 naïve EGFR M+ patients PFS and OS in EGFR + NSCLC Treated With Nivolumab Plus Erlotinib20 refractory after TKI failure , 1 naïve EGFR M+ patientsPFS108642Time Since First Dose (Weeks)B/L1379OSNumber of Pts at Risk5Nivolumab +erlotinibNivolumab 3 mg/kg + erlotinib(mPFS 29.4 wks)(mOS NR)18-month OS rate = 64%PFS rate at 24 weeks = 50%PFS (%)OS (%)
30Squamous >2 ND line, phase 2 monotherapy DATA NivolumabSquamous >2 ND line, phase 2 monotherapy DATA
31Response to Nivolumab in SQ NSCLC Brain Metastasis Pre-treatmentWeek 14Week 6873 year-old male, stage IIIB, former smokerPrior radiotherapy (mediastinal), 3 prior systemic regimens (cisplatin/gemcitabine, docetaxel, vinorelbine)No prior CNS-directed radiotherapy
32Overall Survival : All Treated Patients 100908070605040302010Median OS, months (95% CI)8.2 (6, 11)1-year OS rate, % (95% CI)41 (32, 50)Number of events72/117Median OS = 8.2 monthsOverall Survival (%)1-year OS = 41%369121815Overall Survival (Months)Number of Patients at Risk117936851285Nivolumab 3mg/kgMedian follow-up for survival: 8 months (range, 0–17 months)
33NSCLC pooled analysis 1st and susequent lines, monotherapy PembrozilumabNSCLC pooled analysis 1st and susequent lines, monotherapyGaron et al, ESMO 2014
34Pembrolizumab (MK-3475)PDL1 +: RR 23%, PFS 11 wksPDL1 -: RR 9%, PFS 10 wksIn all evaluable patients, regardless of dose or PD-L1 statusORR (confirmed and unconfirmed): 20% by RECIST v1.1, 18% by irRCDCR (confirmed and unconfirmed): 40% by RECIST v1.1, 52% by irRCHerbst, ASCO 2014
36Immunosuppressive properties of previous cytotoxic agents through lymphocytes depletion? Impact of steroids as antiemetic co-medication on the immune system?Progressive T cell exhaustion during tumor progression?Increase in expression of PD-L1 in the course of the disease?
37Focus on pembrozilumab first line data 10 mg/kg Q3W10 mg/kg Q2W2 mg/kg Q3W*Still on treatment*********************Interim median PFSc:27.0 weeks (95% CI, ) by RECIST v1.1 per central review37.0 weeks (95% CI, 27.0-NR) by irRC per investigator review
39Soria et al , WCLC 2013 and Brahmer et al, 2014 MPLD3280A>2 nd line, phase 1 DATASoria et al , WCLC 2013 and Brahmer et al, 2014
40MPDL3280A Phase Ia: Best Response by PD-L1 IHC Status - NSCLC Diagnostic Populationa(n = 53)ORRb% (n/n)PD RateIHC 383% (5/6)17% (1/6)IHC 2 and 346% (6/13)23% (3/13)IHC 1/2/331% (8/26)38% (10/26)All Patientsc23% (12/53)40% (21/53)Overall response rate: 21% (n=175)Soria, ESMO 2013
41MPDL3290A: Specific predictors Horne et al., WLCC 2013 #MO18.1
42Histology is not predictive through all available data Squamous CarcinomaNon-squamousNivolumab (PD-1)17%(9/54)18%(13/74)MPDL3280A (PD-L1)27%(3/11)21%(9/42)Pembrolizumab(irRECIST)25%(66/262)23%(60/262)
43THE CHALLENGE OF THE BIOMARKER PD-L1 as a predictive biomarker / inclusion criteriaTHE CHALLENGE OF THE BIOMARKER
44Intricate role of PD-1 signalling with different cell types Image from J. Allison
45PD-L1 analysis: differences in evaluation and interpretation AgentAssayAnalysisDefinition of positivityPD-L1 expressionNivolumab (anti-PD-1) 14Dako automated IHC assay(28-8 rabbit Ab)Analytically validatedArchival FFPE1% and 5% cut-off among >100 evaluable tumour cells56%: 1% cut-off49%: 5% cut-offPembrolizumab (anti-PD-1)5,6(22C3 mouse Ab)Tumour dependent:- Melanoma > 1%- NSCLCPD-L1 (+): Strong (≥50%) and weak staining (1–49%)PD-L1 (–): no staining~25%: ≥50% staining~45–70%: ≥1% stainingMPDL3280A (anti-PD-L1)7,8Ventana automated clinical research IHC assayPD-L1 (+):IHC 3 (≥10%), IHC 2,3 (≥5%), IHC 1,2,3 (≥1%)PD-L1 (–):IHC 1, 0 or unknown11%: IHC 375%: IHC 1, 0MEDI-4736 (anti-PD-L1)9First-generation or Ventana IHC Automated Assay (in dev.)Not reportedNivolumabAntonia SJ, et al. Poster presented at WCLC 2013 (Abstract P );Brahmer JR, et al. Poster 293 presented at ASCO 2014 (Abstract 8112);Gettinger SN, et al. Poster presented at ASCO 2014 (Abstract 8024);Topalian SL, et al. N Engl J Med 2012;366:2443–2454.PembrolizumabGaron EB, et al. Poster presented at ASCO 2014 (Abstract 8020);Gandhi L, et al. Oral presentation at AACR 2014 (Abstract CT105).MPDL3280A Soria ECC 2013 and Horn oral 2013;Rizvi NA et al. Poster presented at ASCO 2014 (Abstract TPS 8123).MEDI-4736Brahmer JR, et al. Poster presented at ASCO 2014 (Abstract 8021).
47MPDL3280A Phase Ia: Duration of Treatment in Responders - NSCLC Duration of Treatment and ResponseHistology IHCNonsquamous IHC 0PD-L1 expression is dynamicPD-L1 is heterogeneous within tissuePD-L1 “threshold” is to be defined (tumour material, mAB, technique, sampling, criteria)Importance of co-localization with TILsSquamous IHC 3Nonsquamous IHC 0Nonsquamous IHC 1Nonsquamous IHC 0Squamous IHC 2Nonsquamous IHC 3Squamous IHC 3Nonsquamous IHC 3aNonsquamous IHC 0Nonsquamous IHC 3Nonsquamous IHC 1Time (Weeks)a Patient experiencing ongoing benefit per investigator. Patients first dosed at 1-20 mg/kg by Oct 1, 2012; data cutoff Apr 30, 2013.
49Tumor Infiltrating Lymphocytes as a biomarker? The HNSCC example Diffuse infiltration with CD8+ TILs in HNSCC Absence of TILs in HNSCCPresented by: Tanguy Seiwert
50PD1/PDL1 summary Clear evidence of anti PD1/PD-L1 activity Optimal dose?Treatment sequence?Combination strategyChemotherapyOther checkpoint inhibitorTargeted therapy (TKI)Pharmacodynamic biomarkers of activity? (circulating CD8+Ki-67+ T cells and/or plasma proteins (eg, IL-18))
51PD1/PDL1 summary Predictors of activity: PD-L1 as the biomarker? Selection by PD-L1 expression likely enhances response rateActivity seen in PD-L1 negHow do we define PD-L1 positivity?How does PD-L1 evolve over time ?Is PD-L1 more strongly expressed in defined patients subgroups (smokers?)Randomized trials with PD-L1 stratification awaited!
52PD1/PDL1 summary Phase III trials: Ongoing in first line vs platinum-based chemotherapy in PD-L1+, with/out crossoverCompleted in second line vs docetaxel in squamous and non-squamous subtypesOngoing in second line vs docetaxel in PD-L1+Starting in radically resected stage IB-III adjuvant setting (PDL1+ and all)Starting in consolidation after radical chemoradiotherapy in stage III