Presentation on theme: "ONCO-INMUNOLOGÍA Cáncer de Pulmón"— Presentation transcript:
1ONCO-INMUNOLOGÍA Cáncer de Pulmón Enriqueta Felip, Hospital Vall d’Hebron, BarcelonaXVII Simposio “Revisiones en Cáncer”Tratamiento Médico del Cáncer en el Año 2015Madrid, 11, 12 y 13 de Febrero 2015
2Este ponente ha dispuesto de total libertad para la elaboración de esta ponencia en la recogida y presentación de datos e información científica actualizada y de interés; sin embargo los principios activos y terapias mencionadas en esta ponencia podrían no estar autorizados en todos los países para las indicaciones comentadas. Pembrolizumab no está aún autorizado en la UE.
3Lung cancer: most common malignancy and leading cause of cancer-related mortality GLOBOCAN 2012 (worldwide, both sexes)11.82 million1estimated new cases worldwide1.59 million1(1 in 5) estimated deaths worldwideMore people die from lung cancer than breast, colorectal and prostate cancers combined1Within Europe, ~1,000 people die from lung cancer every day1,21. Ferlay J, et al. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11[Internet]. Lyon, France: International Agency for Research on Cancer; Available from: Accessed September 2014; 2. Ferlay J, et al. Eur J Cancer. 2013;49:1374–1403.
4ONCO-INMUNOLOGÍA: cáncer de pulmón Outline Rationale for PD1 and PDL1 blockadePD1 and PDL1 inhibitors in advanced NSCLC
5Rationale for PD1 and PDL1 blockade How cancer cells evade immune destruction Immune system recognizes and eliminates cancer cells from the bodyT cells, crucial in anti-tumor immune responseT cells require a co-stimulatory signal to become fully activatedActivated T cells recognize tumor antigensT cells kill tumor cellsEvading immune control, a hallmark of cancer (Hanahan & Weinberg Cell 11)
6Rationale for PD1 and PDL1 blockade PD1/PDL1 pathway Limits activity T cells and plays a role in the tumor immune escapePDL1 expression prevalent human tumors and associated with prognosisPDL1/PD1 inhibitors promising resultsChen D, Clin Cancer Res 2012
7Rationale for PD1/PDL1 blockade in lung cancer Target immune system rather than tumorActivity in different tumor types including NSCLC, melanoma, renal cancer, bladder carcinoma and head & neckMay well have greater activity in tumors with a large number of mutationsManageable toxicity profileSuspected impact on long-term survival
11Phase I study of MK-3475 in pre-treated NSCLC p RECIST v1.1Immune-related response criteriaPDL1+PDL1-n = 159n= 35n = 177n = 40ORR, %2391912Disease control rate, %42315153Response duration, weeks, medianNRRizvi ASCO 14, abstract 8007
12Safety and activity of MK-3475 as initial therapy in advanced NSCLC p and PDL1 expressing tumors RECIST v1.1 per independent central reviewImmune-related response criteria per investigator assessmentORR, %2647Interim median PFS (95% CI), weeks27.0 (13.6, 45.0)37.0 (27.0, NR)Responses ongoing, n/N (%)11/11 (100)19/21 (90)Responders remaining on treatment, n/N (%)7/11 (64)18/21 (86)Treatment-related AEs (any grade) occurring in >5% of p: fatigue (22%), pruritus (13%), hypothyroidism (9%), dermatitis acneiform (7%), diarrhoea (7%), dyspnoea (7%) and rash (7%)Rizvi J Clin Oncol 2014; 32 (suppl 5; abstr 8007)
13PFS (RECIST v1.1, Central Review) Activity of MK-3475 and correlation with PDL1 expression in a pooled analysis of advanced NSCLC pStrong PDL1 positivity defined as staining in ≥50% of tumour cells, and weak PDL1 positivity as staining in 1–49% of tumour cells. Negative staining is no PDL1 staining in tumour cellsMK-3475 effective, in particular, p with strong PDL1 tumour expressionPFS (RECIST v1.1, Central Review)OSStrong Weak Negative81624324048100806020Progression-free survival, %Time, weeksn at riskStrong WeakNegative4453492843301817151279 616324681010080604020Time, months445349435142342927221421181151279302632313848Overall survival, %Garon et al. Ann Oncol 2014; 25 (suppl 4): abstr LBA43
14MK-3475 phase I in pre-treated p, activity across NSCLC sub-populations SubgroupORR,* % (n/N) [95% CI]HistologyNon-squamous16 (4/26) [4, 35]Squamous33 (2/6) [4, 78]Patients with measurable disease on baseline imaging and an evaluable tumour specimen for PD-L1Score ≥ potential cut point57 (4/7) [18, 90]Score < potential cut point9 (2/22) [1, 29]SmokingCurrent/former smokers26 (NR/129) [19, 35]Never smokers8 (NR/60) [3, 18]Garon et al. Ann Oncol 2014
15NSCLC responders by histology BMS in advanced NSCLC p: OS and clinical activity by subgroup analysis (n=129)NSCLC responders by histologyOS by BMS dose in NSCLCOS by histology in NSCLCOS 1 year 56%OS 2 year 45%ORR 17% (24% in 3mg/kg)SquamousDuration of response up to discontinuation of therapyOngoing responseTime to responseResponse duration following discontinuation of therapyNon-squamous81624324048566472808896104112120128136144152160Time (Week)Similar RR in SCC vs non-SCC (16.7 vs 17.6%)Responses in PDL1-Similar OS by PDL1 or molecular (EGFR/KRAS) status (only 53% tissue disposition)Brahmer ASCO 14, poster, abstr 8112
16Responders by histology 1st-line BMS monotherapy (3mg/kg q 2 wks): Safety, efficacy, and correlation with PDL1 status (n=52)Responders by histologyResponders by PDL1RR 21%: 15% SCC, 23% Non-SCCKey resultsPDL1 expression status correlate with RR (31% in PDL1+; 10% PDL1-)Grade 3–4 treatment-related AEs 20%Rizvi, Chicago 2014
17IRC Assessed (per RECIST v1.1)a Phase II study of BMS in p with advanced, refractory squamous NSCLC (N=117)IRC Assessed (per RECIST v1.1)aORR, % (n) [95% CI]15 (17) [9, 22]Disease control rate, % (n)40 (47)Median DOR, months (range)NR (2+, 12+)Ongoing responders, % (n)76 (13)Median time to response, months (range)3 (2, 9)PFS rate at 1-year, % (95% CI)20 (13, 29)Median PFS, months (95% CI)2 (2, 3)Ramalingam, Chicago 14
18MPDL3280A phase I: efficacy Single Agent RECIST 1.1 Response Rate (ORRa)SD of 24 Weeks or Longer24-Week PFS RateOverall population (N = 175)21%19%42%NSCLC(n = 53)23%17%45%Nonsquamous(n = 42)44%Squamous(n = 11)27%18%46%Herbst RS Nature 2014
22Challenges with PDL1 assessment Tumor heterogeneitySmall tumor sampleFresh tumor vs archival samplesPD-L1 expression may change over timeDifferent IHC mAB, different cut-off for PDL1 positivity
23PD-L1 analysis: differences in evaluation and interpretation AgentAssayAnalysisDefinition of positivityBMSDako automated IHC assay(28-8 rabbit Ab)Analytically validatedArchival FFPE1% and 5% cut-off among >100 evaluable tumour cellsMK-3475(22C3 mouse Ab)New tumour biopsy within 60 days prior to first dose of pembrolizumabTumour dependent:- Melanoma > 1%- NSCLCPD-L1 (+): Strong (≥50%) and weak staining (1–49%)PD-L1 (–): no stainingMPDL3280AVentana automated clinical research IHC assayPD-L1 (+):IHC 3 (≥10%), IHC 2,3 (≥5%), IHC 1,2,3 (≥1%)PD-L1 (–):IHC 0 (<1%)MEDI-4736First-generation or Ventana IHC Automated Assay (in development)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).Gettinger S, et al, ASCO 2014 (Abstract 8024); Topalian S, et al. NEJM. 2012; Garon E, et al. ASCO 2014 (Abstract 8020); Gandhi L, et al. AACR 2014 (Abstract CT105); Soria J, et al. at ELCC 2013 (Abstract 3408); 8. Rizvi N, et al, ASCO 2014 (Abstract TPS 8123) Brahmer J, et al. ASCO 2014 (Abstract 8021)
24PDL1 expression and EGFR mutation Activation of PD1 pathway contributes to immune-escape in EGFR-driven tumors (Akbay Cancer Discov 13)PDL1 expression by IHC associated with ADC histology and the presence of EGFR-mutation (D’Incecco Br J Cancer 14)PDL1 expression by IHC in 164 resected NSCLC p (Azuma Ann Oncol 14)Higher for women, for never smokers, for p with ADCPresence of EGFR-mut and ADC significantly associated with increased PDL1 expression, in multivariate analysis
25PD1 and PDL1 inhibitors: questions to answer Best predictive marker for response: PD-L1, smoking history, mutations?Optimal cut-off for PDL1 positivity and the best IHC mAB?Optimal dose and treatment sequence?Best surrogate of efficacy (RECIST vs irRC)?Activity in CNS?Any role in the adjuvant setting?
26Clinical case A 77-yr-old man Smoker, 50 packs/year November 2013: history of 2-month dry cough, no other symptomsChest-X-ray: mass in right hilusPhysical examination: normal, ECOG PS 1CT-thorax: 8 cm mass in upper right lobe, bilateral mediastinal lymph nodes, contralateral lung metastasesBlood tests: normal except LDH 467
27Clinical caseBronchoscopy: tumor in anterior branch of right upper lobeHistology: squamous cell-cell carcinomaPET-CT: primary tumor, bilateral mediastinal nodes, right supraclavicular lymph node, contralateral lung metastasesBrain MRI: no brain metastasesNo EGFR mutation or ALK rearrangementP was enrolled in an anti-PD1 clinical trialCentral determination of PD-L1, positive
28Clinical caseIn summary, a 77-yr-old man diagnosed with stage IVa squamous cell carcinomas included an anti-PD-1 clinical trial, with a central determination of PDL-1 positivityDecember 31, 2013 he started anti-PD-1 (10 mg/kg every 3 wks)After 9 wks of treatment a CT-scan revealed PRFebruary 3, 2015, still on treatment, maintaining PRToxicity: G1 pruritusLong PR > 12 months, no toxicity, good general health
30PD1 & PDL1 inhibitors in advanced NSCLC Responses in all histologic typesToxicity profiles differ from that of CT; generally much better toleratedIdentification of biomarkers is complex; PDL1 the most analyzed but some PDL1 negative p also benefitPD1 and PDL1 inhibitors, promising results in NSCLC, suspected impact on long-term survivalTargeting PD1/PDL1 means new hope for NSCLC p