Presentation on theme: "ONCO-INMUNOLOGÍA Cáncer de Pulmón"— Presentation transcript:
1 ONCO-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
2 Este 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.
3 Lung 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.
4 ONCO-INMUNOLOGÍA: cáncer de pulmón Outline Rationale for PD1 and PDL1 blockadePD1 and PDL1 inhibitors in advanced NSCLC
5 Rationale 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)
6 Rationale 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
7 Rationale 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
11 Phase 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
12 Safety 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)
13 PFS (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
14 MK-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
15 NSCLC 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
16 Responders 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
17 IRC 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
18 MPDL3280A 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
22 Challenges 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
23 PD-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)
24 PDL1 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
25 PD1 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?
26 Clinical 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
27 Clinical 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
28 Clinical 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
30 PD1 & 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