Enterprise Interest Lecture 9º Personalized Healthcare in Oncology sponsored by Roche, Lisbon 2017 Bladder Diagnostic Advisory Board Invitation sponsored by Astra-Zeneca, London 2017
SPEC-02 ESP/ESMO PD-L1 as predictive marker Novel challenges for PDL-1 IHC novel tests, novel entities Antonio Lopez-Beltran em1lobea@gmail.com
Overview mbc Patient Burden Predictive Biomarkers of Immune Checkpoint Inhibitors Immune Checkpoint Inhibitors in BC
Introduction In USA: 4th cancer in men and 8th in women 30 40% MIBC muscle-invasive disease (T2 T4a) at Diagnosis; Poor prognostic factor (? occult metastasis) Neoadjuvant ChemoRx cisplatin-based followed by Radical Cyst Patients presenting with metastatic bladder cancer (mbc) or developing visceral metastases after Rx INCURABLE WITH CURRENTLY AVAILABLE THERAPEUTICS
DFS Stein et al J Clin Oncol 2001-1054 pts -10.2 yrs median F/U OS
MIBC Neoadjuvant Chemotherapy (NAC) Urol Oncol 2015 NAC Regimens: GC MVAC DD-MVAC Can we predict Response/outcome? Pathologic non-responders fare worse than patients proceeding directly to RC alone do
Bladder Cancer Immune Checkpoint Breakthrough May 2016: anti-pd-l1 antibody atezolizumab approved by FDA for second line use in platinum-refractory muc on the basis of phase II trial (IMvigor 210) Atezolizumab missed the phase III (IMvigor211) trial s primary endpoint of improving OS in the second-line setting for patients with locally advanced or metastatic urothelial carcinoma, according to Genentech, the manufacturer of the PD-L1 inhibitor. (IMvigor130) accelerated approval in bladder cancer, this time as a frontline treatment for cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma (different cohort as in IMvigor 210) February 2017: FDA granted accelerated approval to nivolumab (anti- PD-1) for second-line use in platinum-refractory muc based on singlearm phase II study (CheckMate 275)
Predictive Biomarkers of Immune Checkpoint Inhibitors
Nature Reviews CANCER 2016
Pitfalls of PDL-1 IHC as Predictive Biomarker for Immune Checkpoint Inhibitors Focal (PDL1) expression may be missed in small biopsy PDL1 expression can vary over time and by anatomical site (ChemoRx, Radiation, Targeted Rx) PDL1 epitopes detected by some antibodies are potentially unstable with prolonged specimen fixation
Pitfalls of PDL-1 IHC as Predictive Biomarker for Immune Checkpoint Inhibitors Antibodies used for PDL1 detection have different affinities and specificities PDL1 expression can be membranous and/or cytoplasmic; only membranous PDL1 is functionally relevant, by contacting (PD1+) T cells PDL1 expressed by multiple cell types within TME: challenges for scoring and interpretation Cut-offs VARIABILITY: BLUE PRINT PROJECT
Blueprint PD-L1 IHC Assay Comparison Project (JTHO, 2017)
Blueprint PD-L1 IHC Assay Comparison Project (JTHO, 2017)
ROC curves of checkpoint inhibitor response in melanoma and NSCLC studies identified cutoff of 192 NsM In 7,757 samples of TCGA: 16.2% exceeded the 192 NsM threshold > 30% of BC, CoReCa, Gastric Ca. and Endometrial Ca. have NsM counts above 192
Mechanisms Driven Predictive Biomarker for Immune Checkpoint Inhibitors Immunologic Biomarkers IHC: PDL-1 CD8+ CD8+/Ki67 TIM3, LAG3 Mutational Load: NSCLC, Melanoma, BC Neoantigens MMR/MSI: CoReCa Viral Oncoproteins: HTLV-1, HPV, EBV, KSV, MCPyV, HBV, HCV
Multifactorial Predictive Biomarkers of Immune Checkpoint Inhibitors Response PDL1, TIM3, LAG3, B7H3 Mutational Load MSI Viral Oncoproteins CD8+/Ki67+ T Cell Density
Immune Checkpoint Inhibitors in Bladder Cancer
Powels et al Nature 2014
Powels et al Nature 2014
Rosenberg J et al Lancet 2016 315 patients; 70 centers; anti PDL-1 agent Netto GJ. Lancet 2016 Lancet 2017
SP142 assay (Ventana) IC: 0,1,2,3 Rosenberg J et al Lancet 2016
Rosenberg J et al Lancet 2016
Molecular Taxonomy UB-MIBC (TCGA) Luminal MIBCs Cluster I (luminal, differentiated) with FGFR3 aberrations and CDKN2A deletions Cluster II (luminal, less differentiated, p53like) (Cluster II,p53like, luminal>>chemo-resistant) Basal MIBCs Cluster III (squamous) Cluster IV (EMT and immune infiltrated) Cancer Cell 25, 152 165, February 10, 2014
Cancer Cell 25, 152 165, February 10, 2014
Scoring for atezolizumab in UC clinical trials VENTANA PD-L1 (SP142) Assay detects PD-L1 expression in both tumor cells (TC) and tumor-infiltrating immune cells (IC) In UC, prevalence of PD-L1 on TC is low, 1,2 and patients who express PD-L1 on TC are captured within IC cutoffs >2/3 UC tumors express PDL1 on IC 2 70% 22% IC > 1% TC > 1% 22% 1% no overlap 3 68% PD-L1 Prevalence in UC 4 IC Level (N = 205) IC score IC Scored as PD-L1+, n (%) IC3 10% 18 (9%) IC2 5% but < 10% 37 (18%) IC1 1% but < 5% 89 (43%) IC0 <1% 61 (30%) References: 1. Bellmunt et al. ESMO, 2014. 2. Petrylak et al. ASCO 2015. 3. Boyd Z et al. AACR 2015 4. Powles et al. Nature. 2014. 26
VENTANA PD-L1 (SP142) Assay shows robust staining in tumor infiltrating immune cells (IC) and tumor cells (TC) Urothelial Cancer tissues are evaluated only for IC staining 10x TC staining 20x IC staining 27
Scoring method tumor area IC are scored as the proportion of tumor area occupied with IC showing staining PD- L1 staining of any intensity Tumor area is defined as tumor cells with their associated intratumoral and contiguous peritumoral desmoplastic stroma 4x Tumor area Intratumoral stroma Lymphoid aggregate Tumor cell mass Contiguous peri-tumoral stroma 28
Tumor area in different tissue types Resection TURBT* Biopsy *TURBT: Transurethral Resection of Bladder Tumor; all images at 1x magnifcation 29
2x Review the H&E-stained slide for the presence of tumor, necrosis, adequacy (at least 50 viable tumor cells with associated stroma), and assessment of tumor area. Only IC staining observed 10x Scoring of Review the PD-L1 (SP142) stained slide and confirm overall staining pattern as IC, TC or both. IC aggregates Visually encircle IC aggregates as closely as possible. Tumor area R 2 2x 1 IC aggregates Combine the aggregate staining and estimate the proportion of tumor area occupied by IC aggregates. The IC score for this case is 5% (IC2/3). Reference images should be used as an aid in scoring. F 2x 30
IC scoring single cell spread Density of spread determines the score Reference images to be used as a guide Single cell spread is most often homogeneous; if heterogeneous average it to the total tumor area Cell density for single cell spread IC is <5% (IC0/1 - Negative) Cell density for single cell spread IC is 5% (IC2/3 - Positive) All images at 10x magnification 31
Drugs Today (Barc). 2017 Apr;53(4):217-237. doi: 10.1358/dot.2017.53.4.2589163. Atezolizumab: A novel PD-L1 inhibitor in cancer therapy with a focus in bladder and non-small cell lung cancers. Krishnamurthy A 1, Jimeno A 2. Abstract: There are 117 ongoing clinical trials of atezolizumab currently. Given its efficacy in NSCLC and urothelial carcinoma, atezolizumab holds much potential in the future of cancer therapeutics.
Phase I/II: 61 advanced BC with prior Rx (40 PD-L1 positive, 21 PD-L1 negative)
Ventana SP263 ; 25% TC or 25% IC
Lancet Oncology 2016 NO RELATION TO PDL-1 EXPRESSION Dako 28-8 Any Tumor Cell
Lancet Oncology 2016
Lancet Oncology 2016 2 TREATMENT-RELATED DEATHS: 1 thrombocytopenia /1 pneumonitis
Lancet Oncol. 2017 Mar;18(3):312-322. doi: 10.1016/S1470-2045(17)30065-7. Epub 2017 Jan 26. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Sharma P 1, Retz M 2, Siefker-Radtke A 3, Baron A 4, Necchi A 5, Bedke J 6, Plimack ER 7, Vaena D 8, Grimm MO 9, Bracarda S 10, Arranz JÁ 11, Pal S 12, Ohyama C 13, Saci A 14, Qu X 15, Lambert A 16, Krishnan S 17, Azrilevich A 17, Galsky MD 18. Abstract: Nivolumab monotherapy provided meaningful clinical benefit, irrespective of PD-L1 expression, and was associated with an acceptable safety profile in previously treated patients with metastatic or surgically unresectable urothelial carcinoma. Expert Opin Biol Ther. 2017 Jul 24:1-7. doi: 10.1080/14712598.2017.1353076. [Epub ahead of print] Nivolumab for the treatment of bladder cancer. Hakenberg OW 1. Abstract:. It is unclear which patients will respond and PD- 1/PD-L1 expression alone is not a sufficiently reliable response marker. Treatment costs are extreme and further trials will have to clarify which subset of patients in which context of management will have a substantial benefit.
Bellmunt t al NEJM2017 PD-L1 IHC 22C3 pharmdx assay (Dako) % of Tumor cell AND IC positivity
Immunotherapy in BC Completed Clinical Trials Curr Opin Oncol 2017, 29:184 195
Immunotherapy in BC Ongoing Clinical Trials Curr Opin Oncol 2017, 29:184 195
PD-L1 assay (antobod y) Cell-types scored for UC PD-L1 cut offs: High/posi tive Low/nega tive Durvalumab Atezolizumab Nivolumab Pembrolizumab Avelumab Ventana SP263 Ventana SP142 Dako 28.8 Dako 22C3 Dako 73-10 IC and TC IC TC TC and IC TC 25% TC or IC <25% TC and IC Study (Phase) Study 1108 - UC cohort (phase 1/2) 5% IC <1% IC IMvigor 210 (phase 2) BLADDER CANCER IMMUNOTHERAPY 5% IC <1% IC IMvigor 210 (phase 2) 1% TC <1% TC CM-032 UC cohort (phase 1/2) 1%, 5% TC <1% TC CM-275 (phase 2) 10% CPS NA KN-045 (phase 3) 10% CPS <10% CPS KN-052 (phase 2) 5% TC No visible staining JAVELIN - UC cohort (phase 1b) Line of therapy 1L 2L 1L 2L 2L 2L 1L 2L Lopez-Beltran A, Vau N, et al 2017
TAKE-HOME MESSAGES Over 60 clinical trials: monotherapy or in combination with chemorx/ targeted Rx/ ImmunoRx Mechanistic based predictive Biomarkers of Immune Checkpoint Inhibitors are emerging IHC assessment of PD1-PDL1 axis needs further investigation External quality assessment may have a role in standardizing PDL 1 assessment. Tumor and/ or tumor immune-infiltrating cell (IC) PD- L1 IHC seem not to be the optimal biomarkers to predict treatment response, but may be a good start to guide and inform patients and physicians on the prognosis. Mutational load promising predictive marker of response: neoantigen expression/neoantigen clonality/ immunogenicity could provide basis for personalized adaptive cell therapy
THANKS Acknowledgement: Special Thanks To Prof. George Netto