Paradigm Cancer Diagnostic (PCDx)

Transcription

1 Paradigm Cancer Diagnostic (PCDx) Date of Birth: PCDx Case#: Physician: Facility: PCDx-18-0XXXX Case/Specimen ID: Collection Site: Collection Date: Received for testing: Turnaround: 4 business days Tumor cells: 50% Specimen size: 72 mm² Requirement met: Optimal 1 actionable genomic finding 10 IHC results KRAS A146T Pertinent Negatives: ALK DNA, BRAF DNA, EGFR DNA, ERBB2 DNA, MET CNV, MYC CNV Immunotherapy tumor mutation burden: High (56 muts/mb) MMR: Proficient PD-L1: High 8 therapies with potential increased benefit 7 therapies with potential reduced benefit Atezolizumab* NCCN PDL1:TILs, PDL1:Tumor Docetaxel* NCCN EGFR Durvalumab NCCN PDL1:TILs, PDL1:Tumor Nivolumab* NCCN PDL1:Tumor Pembrolizumab* NCCN PDL1:Tumor Pembrolizumab NCCN PDL1:Tumor + Carboplatin + Pemetrexed* Nivolumab PDL1:Tumor + Ipilimumab* Avelumab PDL1:Tumor Afatinib Cetuximab Erlotinib Everolimus Gefitinib Gemcitabine Panitumumab EGFR, KRAS KRAS EGFR, KRAS KRAS EGFR, KRAS hent1 KRAS * Indicates associations supported by the highest level of evidence For additional information or to set up an interactive online account please contact your sales representative or call XXX

2 Specimen Tumor cells: 50 % Specimen size: 72mm² Residual tissue: Yes 10 IHC results ALK % Negative ROS % Negative PDL1:Tumor N/A 90% High PDL1:TILs 2+ 20% Low hent % Negative TRKpan % Negative MLH % Positive MSH % Positive MSH % Positive PMS % Positive Gross Description: Received from... is labeled as... (and PCDx-18-0XXXX) used to make one Paradigm H&E slide labeled as...(and PCDx-18-0XXXX) identified as belonging to the above named patient based on the accompanying surgical pathology report with specimen collection date of... Block... will be analyzed. 1 actionable genomic finding Gene Variant Gene Variant KRAS A146T Genes with indeterminate findings: AREG, PMS2 136 genomic findings of unknown significance Note: this table contains all non-reference alleles found in less than 1% of the population. These may be germline or somatic.

3 8 therapies with potential increased benefit Therapeutic On Indicating Option NCCN biomarkers Atezolizumab Yes PDL1:TILs Low I 17, 18 PDL1:Tumor High I 17, 18 Avelumab PDL1:Tumor High DTT 21 Docetaxel Yes EGFR Wild Type I 8 Durvalumab Yes PDL1:TILs Low DTT 19, 20 PDL1:Tumor High II-3 25 Nivolumab Yes PDL1:Tumor High II-2 16 Nivolumab PDL1:Tumor High II Ipilimumab Pembrolizumab Yes PDL1:Tumor High I 14, 15 Pembrolizumab Yes PDL1:Tumor High I 26 + Carboplatin + Pemetrexed Therapeutic Option 7 therapies with potential reduced benefit Contraindicating biomarkers Level of evidence References Afatinib EGFR Wild Type 6, 7 KRAS Mutated 27 Cetuximab KRAS Mutated 3, 4 Erlotinib EGFR Wild Type 1, 2 KRAS Mutated 9, 10 Everolimus KRAS Mutated 11, 12 Gefitinib EGFR Wild Type 1, 2 KRAS Mutated 27 Gemcitabine hent1 Negative 13 Panitumumab KRAS Mutated 4, 5 Reference

4 clinical notes Select Genomic Alteration: Activating KRAS mutations are detected in up to 30% of NSCLCs. Mutations in EGFR, KRAS and BRAF are considered mutually exclusive. Although rare, concomitant EGFR and KRAS mutations have been observed. Despite EGFR inhibition, KRAS mutations constitutively activate downstream MAPK signaling, thus presenting a potential mechanism that contributes to reduced efficacy if not primary resistance to TKIs. The NCCN Guidelines therefore regard KRAS mutations a negative predictor for EGFR-targeted therapies. PD-L1 (22C3) expression is determined by using a Tumor Proportion Score (TPS), which is the percentage of viable tumor cells showing partial or complete membrane staining at any intensity. The scoring system divides the results into three groups: those with 50% of tumor cells showing any level of positivity (high), those with <50% of tumor cells but 1% of tumor cells positive (low), and those with <1% positive (negative). A minimum of 100 viable tumor cells must be present in the PD-L1 stained slide for the specimen to be considered adequate for PD-L1 evaluation. Pembrolizumab (KEYTRUDA) is indicated for the treatment of: (1) Patients with metastatic NSCLC whose tumors have high PD-L1 expression [TPS 50%] with no EGFR or ALK genomic tumor aberrations, and no prior systemic chemotherapy treatment for metastatic NSCLC. (2) Patients with metastatic NSCLC whose tumors express PD-L1 [TPS 1%], with disease progression on or after platinum-containing chemotherapy. The predictive value of the PD-L1 clone 22C3 for nivolumab, atezolizumab, avelumab or durvalumab is currently unclear. PD-L1 (22C3) expression on TILs is determined by evaluating the percentage of viable tumor cells showing partial or complete membrane staining at any intensity. The scoring system divides the results into three groups: those with 50% of tumor cells showing any level of positivity (high), those with <50% of tumor cells but 1% of tumor cells positive (low), and those with <1% positive (negative). Please note that for PD-L1 (22C3) TILs, the referenced studies utilize a prototype immunohistochemical assay with a proprietary antibody and cutoff. Tumors are classified as pmmr (proficient Mismatch Repair) if no loss in the MMR proteins is detected. Tumors without mutations in the mismatch repair genes generally do not show the elevated mutation rates or higher number of potential mutation-associated neoantigens that characterize the dmmr phenotype. Mutation-associated neoantigen recognition is an important component of the endogenous antitumor immune response and tumors with a high number of actual mutation-associated neoantigens are more likely to stimulate the immune system to react against the tumor (Le et al. 2015/PMID: ; Le et al. 2017/PMID: ). Tumor Mutation Burden (TMB) is defined as the total number of DNA mutations per megabase in a tumor sequence. TMB appears to have an evolving role as a predictive marker for immunotherapy treatment in the following cancers: melanoma, lung, and bladder cancer[1]. The threshold for TMB has not been clearly defined, and there is no consensus for the optimal quantitative or qualitative cutoff threshold by cancer type [2]. TMB may correlate with PFS but it is not prognostic for OS in lung cancer. OS and PFS must be evaluated in prospective, randomized trials [3]. Some tumors possess high TMB as a consequence of a defective mismatch repair of DNA [4] and tumors with high TMB are often mismatch repair deficient[5]. Additionally, there appears to be a correlation between smoking status and TMB. Paradigm will continue to evaluate/monitor the utility of including a standardized/consensus driven TMB [6] as a predictive and prognostic marker for immunotherapy treatment. [1] TMB is believed to be a surrogate marker for immunogenicity and the likelihood of clinical response or benefit from immunotherapy. [2] While no clear threshold or consensus has been identified (high vs low), there is broad agreement that more than 14 mutations/megabase should be considered high. Other studies have reported positive results for immunotherapy benefit at 10 mutations per megabase. (Including recent article from NEJM) [3] All patients with high TMB should be considered candidates for a trial of immunotherapy. Low/intermediate TMB does not rule out a response to immunotherapy, nor should it preclude the patient pursuing a clinical trial of immunotherapy. [4] While defective MMR is clearly associated with TMB, not all MMRD tumors have elevated TMB, probably reflecting that loss of MMR proficiency is a recent or branching event in the tumor rather than a truncal or founding event. [5] High TMB is also reported in some cancers with intact MMR, notably those with POLE mutations. These patients also appear to have robust responses to checkpoint immunotherapy. [6] TMB in context: the presence of other immune checkpoints, including TIM3, LAG3, PD-L2, IDO, and the composition of the tumor microenvironment (MDSC, FOX3P+ TIL), B2M loss, and aberrations within particular intracellular pathways (i.e. PTEN loss, IFN gamma defects) are also known to play key roles in the resistance/response to immunotherapy.

5 clinical trials in tumor type KRAS NCT AZD MK-2206 Lapatinib Erlotinib sunitinib Molecular Profiling and Targeted Therapy for Advanced, Small Cell Lung Cancer, and Thymic Malignancies KRAS NCT MEK162 Erlotinib A Phase I/IB Trial of MEK162 in Combination With Erlotinib in NSCLC Harboring KRAS or EGFR Mutation KRAS NCT Antroquinonol Efficacy, Safety and Pharmacokinetics Study of Antroquinonol to Treat NSCLC PDL1:Tumor NCT MEDI4736 Placebo Double Blind Placebo Controlled Controlled Study of Adjuvant MEDI4736 In Completely Resected NSCLC EGFR NCT INC280 (capmatinib) Clinical Study of Oral cmet Inhibitor INC280 in Adult Patients With Advanced Non-small Cell Lung Cancer Who Have Received One or Two Prior Lines of Therapy PDL1:Tumor NCT Avelumab Platinum Doublet Avelumab in First-line (JAVELIN Lung 100) PDL1:Tumor NCT Nivolumab Nivolumab After Surgery and Chemotherapy in Treating Patients With Stage IB-IIIA Non-small Cell Lung Cancer PDL1:Tumor NCT CPI-444 CPI Atezolizumab Phase 1/1b Study to Evaluate the Safety and Tolerability of CPI-444 Alone and in Combination With Atezolizumab in Advanced Cancers PDL1:Tumor NCT MPDL3280A Carboplatin Nab-Paclitaxel Neoadjuvant MPDL3280A, Nab-paclitaxel and Carboplatin (MAC) in NSCLC PDL1:Tumor NCT Ipilimumab Nivolumab Lung-MAP: Nivolumab With or Without Ipilimumab as Second-Line Therapy in Treating Patients With Recurrent Stage IV Squamous Cell Lung Cancer and No Matching Biomarkers KRAS NCT LY Midazolam Abemaciclib Nab-paclitaxel Gemcitabine A Study of LY Administered Alone or in Combination With Other Agents in Participants With Advanced/Metastatic Cancer PDL1:Tumor NCT Durvalumab Radiation Tremelimumab Durvalumab and Tremelimumab With or Without High or Low-Dose Radiation Therapy in Treating Patients With Metastatic Colorectal or Non-small Cell Lung Cancer EGFR NCT CB-1158 Nivolumab A Phase 1 Study of Arginase Inhibitor CB-1158 in Combination With Immune Checkpoint Therapy in Solid Tumors PDL1:Tumor NCT Durvalumab Tremelimumab Chemotherapy Study of Durvalumab + Tremelimumab With Chemotherapy or Durvalumab With Chemotherapy or Chemotherapy Alone for Patients With Lung Cancer (POSEIDON). KRAS NCT Binimetinib Palbociclib Study of the CDK4/6 Inhibitor Palbociclib (PD ) in Combination With the MEK Inhibitor Binimetinib (MEK162) for Patients With Advanced KRAS Mutant KRAS NCT Pembrolizumab Trametinib Pembrolizumab and Trametinib in Treating Patients With Stage IV and KRAS Gene Mutations PDL1:Tumor NCT Avelumab Talazoparib Avelumab Talazoparib Javelin Parp Medley: Avelumab Plus Talazoparib In Locally Advanced Or Metastatic Solid Tumors KRAS NCT ASN007 A Study of ASN007 in Patients With Advanced Solid Tumors PDL1:Tumor NCT Anetumab Ravtansine Atezolizumab Anetumab Ravtansine and Atezolizumab in Treating Participants With Advanced Non-small Cell Lung Cancer PDL1:Tumor NCT REGN2810/ipi REGN2810/chemo/ipi Pembrolizumab REGN2810 (Anti-PD-1 Antibody), Platinum-based Doublet Chemotherapy, and Ipilimumab (Anti-CTLA-4 Antibody) Versus Pembrolizumab Monotherapy in Patients With Lung Cancer TMB NCT Pembrolizumab MK-1308 MK-4280 Lenvatinib A Study of Biomarker-Directed, Pembrolizumab (MK-3475) Based Combination Therapy for Advanced (MK ) PDL1:Tumor NCT ALT Pembrolizumab Pembrolizumab QUILT-2.023: A Study of ALT-803, a Fusion Protein Activator of Natural Killer and T-Cells, in Combination With Pembrolizumab vs Pembrolizumab Alone as First-Line Treatment for Patients With Metastatic NSCLC. KRAS NCT Methotrexate Regorafenib Regorafenib and Methotrexate in Treating Participants With Recurrent or Metastatic KRAS Mutated PDL1:Tumor NCT PembroRT ChemoRT The Selective Personalized Radio-Immunotherapy for Locally Advanced NSCLC Trial. PDL1:Tumor NCT Atezolizumab MTIG7192A Placebo A Study of MTIG7192A in Combination With Atezolizumab in Chemotherapy-Naïve Patients With Locally Advanced or Metastatic

6 clinical trials - continued multi-indication trials PDL1:Tumor NCT MEDI0680 MEDI4736 A Phase 1/2, Open-label Study to Evaluate the Safety and Antitumor Activity of MEDI0680 (AMP-514) in Combination With MEDI4736 and MEDI0680 Monotherapy in Subjects With Select Advanced Malignancies PDL1:Tumor NCT LAG525 PDR001 Safety and Efficacy of LAG525 Single Agent and in Combination With PDR001 in Patients With Advanced Malignancies KRAS NCT AZD2281 AZD5363 AZD1775 AZD2014 OLAParib COmbinations PDL1:Tumor NCT MBG453 PDR001 Safety and Efficacy of MBG453 as Single Agent and in Combination With PDR001 in Patients With Advanced Malignancies PDL1:Tumor NCT Interferon-gamma and Nivolumab Combination of Interferon-gamma and Nivolumab for Advanced Solid Tumors PDL1:Tumor NCT TAB001, Recombinant Humanized anti-pd-1 Monoclonal Antibody Safety, Tolerability and Pharmacokinetics of an Anti-PD-1 Monoclonal Antibody in Subjects With Advanced Malignancies TMB NCT IBI308 IBI308 in Subjects With Advanced/Metastatic Solid Malignancies genes negative for small variants ABL1 BAP1 CDK6 EPHA5 FCGR2A IDH2 MET PBRM1 RICTOR TSC1 ADAMTS1 BCOR CDK12 EPHA7 FGF4 IKZF1 MGMT PDCD1LG2 RRM1 TSC2 ADAMTS16 BNIP3 CDKN2A ERBB2 FGFR2 JAK3 MLH1 PDGFRB SDHB TSHR ADAMTS9 BRCA1 CHKA ERBB3 FGFR3 KDM5C MSH6 PIK3CB SDHC VEGFA AKT1 BTK CIC ERCC1 FLT3 KDR MTOR PIK3CD SF3B1 VHL AKT3 BUB1B CTLA4 ERCC2 FOXL2 KEAP1 MUTYH PIK3CG SMAD2 WT1 APLNR CBL CYP1A1 ERCC3 FUBP1 MAP2K1 MYC PLCG1 SMAD4 YES1 AR CCND1 CYP2D6 ERRFI1 GATA3 MAP2K2 NF1 PPP2R1A SMARCB1 ARAF CCND2 CYP3A4 ESR1 GLI1 MAP3K1 NF2 PTCH1 SOCS1 ARID1A CCND3 CYP19A1 ESR2 GNA11 MAPKAPK5 NFE2L2 PTEN STAT3 ATRX CCNE1 CYSLTR2 FAM175A GNAS MAPK1 NOTCH1 RAD51D TERT AURKA CD274 DNMT3A FANCE GSTT1 MAPK3 NPM1 RAF1 TNFAIP3 AURKB CDA EGFR FANCF HDAC2 MDM4 NRAS RBM10 TOP2A AXIN1 CDC73 EMSY FANCG HGF MED12 NTRK1 RET TP53 B2M CDK4 EPCAM FBXW7 HRAS MEN1 PALB2 RHEB TYMS

7 genes negative for copy number variants (amplifications) ABL1 ATR CDC73 EGFR FANCM HNF1A MDM4 NTRK1 RAD51D STAG2 ADAMTS1 ATRX CDH1 EMSY FAT1 HRAS MED12 NTRK2 RAF1 STAT3 ADAMTS16 AURKA CDK4 EP300 FBXW7 HSD3B1 MEN1 NTRK3 RB1 STK11 ADAMTS9 AURKB CDK6 EPCAM FCGR2A IDH1 MET PALB2 RBM10 SUFU AKT1 AXIN1 CDK12 EPHA5 FGD4 IDH2 MGMT PBRM1 RECQL1 TERT AKT3 AXL CDKN2A EPHA7 FGF3 IGF1R MLH1 PDCD1LG2 RET TGFBR2 APLNR B2M CHEK1 ERBB2 FGF4 IKZF1 MRE11A PDGFRA RHEB TNFAIP3 AR BAP1 CHEK2 ERBB3 FGFR1 JAK1 MSH2 PDGFRB RICTOR TOP2A ARAF BARD1 CHFR ERBB4 FGFR2 JAK2 MSH6 PIK3CA RIT1 TP53 ARID1A BCOR CHKA ERCC1 FGFR3 JAK3 MTHFR PIK3CB RNF43 TYMS ATRX BNIP3 CIC ERCC2 FGFR4 KDM5C MTOR PIK3CD ROS1 TSC1 AURKA BRAF CREBBP ERCC3 FLT3 KDM6A MUTYH PIK3CG RPTOR TSC2 AURKB BRCA1 CSF1R ERRFI1 FLT4 KDR MYC PIK3R1 RRM1 TSHR AXIN1 BRCA2 CTLA4 ESR1 FOXL2 KEAP1 MYCN PLCB4 SDHB VEGFA B2M BRIP1 CTNNB1 ESR2 FUBP1 KIT MYOD1 PLCG1 SDHC VHL BAP1 BTK CYP1A1 EWSR1 GATA3 KRAS NBN PMS2 SETD2 WT1 BCOR BUB1B CYP2D6 EZH2 GLI1 MAF NF1 POLD1 SF3B1 YES1 BNIP3 CBL CYP3A4 FAM175A GNA11 MAP2K1 NF2 POLE SMAD2 XRCC1 BRCA1 CCND1 CYP19A1 FANCA GNAQ MAP2K2 NFE2L2 PPP2R1A SMAD4 BTK CCND2 CYSLTR2 FANCC GNAS MAP3K1 NOTCH1 PTCH1 SMARCA4 BUB1B CCND3 dck FANCD2 GSTP1 MAPKAPK5 NOTCH2 PTEN SMARCB1 CBL CCNE1 DDR2 FANCE GSTT1 MAPK1 NOTCH3 PTPN11 SMO CCND1 CD274 DICER1 FANCF HDAC2 MAPK3 NPM1 RAD50 SOCS1 CCND2 CDA DNMT3A FANCG HGF MDM2 NRAS RAD51C SPOP references 1. Travis, W. D., Brambilla, E., Noguchi, M., Nicholson, A. G., Geisinger, K. R., Yatabe, Y., Beer, D. G., et al. (2011). International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, 6(2), Gao, G., Ren, S., Li, A., Xu, J., Xu, Q., Su, C., Guo, J., et al. (2012). Epidermal growth factor receptor-tyrosine kinase inhibitor therapy is effective as first-line treatment of advanced nonsmall-cell lung cancer with mutated EGFR: A meta-analysis from six phase III randomized controlled trials. International journal of cancer. Journal international du cancer, 131(5), E ERBITUX (cetuximab) - HIGHLIGHTS OF PRESCRIBING INFORMATION; Revised: 10/ De Roock, W., De Vriendt, V., Normanno, N., Ciardiello, F., & Tejpar, S. (2011). KRAS, BRAF, PIK3CA, and PTEN mutations: implications for targeted therapies in metastatic colorectal cancer. The lancet oncology, 12(6), VECTIBIX (panitumumab) - HIGHLIGHTS OF PRESCRIBING INFORMATION; Revised: 03/ Park, K., Tan, E.-H., O Byrne, K., Zhang, L., Boyer, M., Mok, T., Paz-Ares, L. (2016). Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial. The Lancet Oncology, 15(5), e Sequist, L. V., Yang, J. C.-H., Yamamoto, N., O Byrne, K., Hirsh, V., Mok, T., Schuler, M. (2013). Phase III Study of Afatinib or Cisplatin Plus Pemetrexed in Patients With Metastatic Lung Adenocarcinoma With EGFR Mutations. Journal of Clinical Oncology, Garassino, M. C., Martelli, O., Broggini, M., Farina, G., Veronese, S., Rulli, E., Marsoni, S. (2013). Erlotinib versus docetaxel as second-line treatment of patients with advanced nonsmall-cell lung cancer and wild-type EGFR tumours (TAILOR): a randomised controlled trial. The lancet oncology, 14(10), Karampeazis, A., Voutsina, A., Souglakos, J., Kentepozidis, N., Giassas, S., Christofillakis, C., Georgoulias, V. (2013). Pemetrexed versus erlotinib in pretreated patients with advanced nonsmall cell lung cancer: A Hellenic Oncology Research Group (HORG) randomized phase 3 study. Cancer, Qi, W.-X., Wang, Q., Jiang, Y.-L., Sun, Y.-J., Tang, L.-N., He, A.-N., Yao, Y. (2013). Overall survival benefits for combining targeted therapy as second-line treatment for advanced nonsmall-cell-lung cancer: a meta-analysis of published data. PloS one, 8(2), e Ng, K., Tabernero, J., Hwang, J., Bajetta, E., Sharma, S., Del Prete, S. a., Fuchs, C. S. (2013). Phase II Study of Everolimus in Patients with Metastatic Colorectal Adenocarcinoma Previously Treated with Bevacizumab-, Fluoropyrimidine-, Oxaliplatin-, and Irinotecan-Based Regimens. Clinical cancer research : an official journal of the American Association for Cancer Research, 19 (14),

8 12. Di Nicolantonio, F., Arena, S., Tabernero, J., Grosso, S., Molinari, F., Macarulla, T., Bardelli, A. (2010). Deregulation of the PI3K and KRAS signaling pathways in human cancer cells determines their response to everolimus. The Journal of clinical investigation, 120(8), Oguri, T., Achiwa, H., Muramatsu, H., Ozasa, H., Sato, S., Shimizu, S., Ueda, R. (2007). The absence of human equilibrative nucleoside transporter 1 expression predicts nonresponse to gemcitabine-containing chemotherapy in non-small cell lung cancer. Cancer letters, 256(1), Reck, M., Rodríguez-Abreu, D., Robinson, A. G., Hui, R., Csőszi, T., Fülöp, A., Brahmer, J. R. (2016). Pembrolizumab versus Chemotherapy for PD-L1 Positive Non Small-Cell Lung Cancer. New England Journal of Medicine, 375(19), Antonia, S. J., Villegas, A., Daniel, D., Vicente, D., Murakami, S., Hui, R., Özgüroğlu, M.