NSCLC 2 nd and further line therapies Egbert F. Smit MD PhD. Dept. Thoracic Oncology, Netherlands Cancer Institute e.smit@nki.nl
ESMO Guidelines 2016: Treatment of Stage IV nonsquamous NSCLC at progression Non-squamous Maintenance treatment: Pemetrexed (switch) (I, B) Pemetrexed (continuation) (I, A) Erlotinib (EGFR-activating mutation) (I, B) ± bevacizumab (if given before) Disease progression PS 3 4 BSC PS 0 2 Pemetrexed (I, B) Docetaxel (I, B) Nivolumab (I, B; MCBS 5) Pembrolizumab if PD-L1 > 1% (I, A; MCBS 3 if PD-L1 > 1%; MCBS 5 if PD-L1 > 50%) Ramucirumab docetaxel (I, B; MCBS 1) Nintedanib docetaxel (II, B) Erlotinib (II, C) Novello S, et al. Ann Oncol. 2016;27 Suppl 5:v1-v27.
3 The opportunities
1990 ~3.000 bp/day New technologies 2000 500.000 bp/day 2015 100 miljard bp/day Gene identification Reference genome Single genomes
Cost of whole genome sequencing
How GENIE Works GENIE: GENOMICS, EVIDENCE,NEOPLASIA,INFORMATION,EXCHANGE? Clinical question asked Aggregate tumor-only NGS data & limited clinical data set from project Participants into registry Necessary short & longterm clinical information linked to data within the registry Data made publicly available after defined periods. Separate, parallel data streams 6 www.aacr.org/genie 3
2017 by American Association for Cancer Research Landscape overview of GENIE dataset.
Implementing large scale genomics Netherlands Center for Personalized Cancer Treatment (CPCT) 87 hospitals 9 academic centers 21 teaching hospitals 57 general hospitals in the Netherlands 2010 2014 2015 2017 Initiated by NKI-AVL, UMC Utrecht, EMC Rotterdam Participation all academic medical centers Teaching hospitals All hospitals
Tumor sample logistics of CPCT-02 study Patient inclusion Biopsy (fresh frozen) (plus blood control) Clinical data collection network of Hospitals reimbursement for biopsy and data management Histology and DNA/RNA isolation WGS data analysis and databasing sequencing financed by philantropy
The Netherlands sequencing program n hospitals enrolling patients accrual in CPCT-02 study 40 35 30 25 20 15 10 11 11 12 12 13 13 14 14 16 20 24 24 26 29 33 35 36 37 200 Monthly accrual 175 150 127 125 100 101 100 78 66 67 75 57 59 40 45 49 50 139 149 139 178 132 186 189 5 25 0 0 2016 2017 2016 2017
Patients with advanced cancer Study flow chart Who have exhausted treatment options With tumor profiling performed: Via regular diagnostics or CPCT Revealing an actionable target For which targeted therapy is available But not for patients tumor type Start study treatment If so: Obtain informed consent Screen patient Obtain pre-treatment biopsy (target confirmation) Submit to DRUP study team: Actionable target present? Matching drug available? Evidence for potential efficacy? Study status Conclusion Acknowledgements
19 study drugs Available at start study September 2016 Amgen Panitumumab KRAS-BRAF-NRAS WT AstraZeneca Olaparib BRCA 1/2, ATM, RAD51 Bayer Regorafenib RET, VEGFR1, 2, 3, KIT, PDGFRB, RAF-1, BRAF, CSF1R BMS Nivolumab MSI or high mutational load Roche Erlotinib EGFR Trastuzumab + Pertuzumab Vemurafenib + Cobimetinib HER2 BRAF V600 Available from September 2017 Vismodegib PTCH1 Novartis Dabrafenib BRAF V600 Nilotinib KIT, ABL1, PDGFRA, PDGFRB Trametinib BRAF V600, NRAS BI Afatinib NRG1, ERBB4 (NSCLC only) Eisai Lenvatinib FGFR1, FGFR2, FGFR3, FGFR4 MSD Pembrolizumab High mutational load Pfizer Axitinib VEGFR1, 2, 3 Crizotinib ALK, MET, MST1R, ROS1 Sunitinib CSF1R, FGFR1,2,3, VEGFR1, 2, 3, KIT, PDGFRA, PDGFRB, RET,
DRUP study Gene HGVS transcript Effect Mutation known Coverage Variant frequency BRCA2 c.2095c>t Stop gained Novel 116 13.79 EGFR c.2235_2249delg Missense variant COSM6223 rs121913421 160 11.25 Before start olaparib After 8 weeks of olaparib
Results (as of Aug 1 st, 2017) 220 patients have been submitted for review 65 patients have received treatment 136 patients were excluded for treatment 19 patients are pending 250 200 150 100 50 0
Results 65 patients have started study treatment in 22 cohorts; 6 cohorts graduated to stage II Nilotinib KIT mut GIST PDGFRα mut GIST Nivolumab HML tumors MSI tumors Olaparib ATM mut tumors BRCA mut tumors Panitumumab BRAF-KRAS-NRAS wt HNSCC BRAF-KRAS-NRAS wt sarcoma EGFR mut NSCLC Regorafenib RET mut NSCLC RET mut neuroblastoma Trametinib MEK1 mut NSCLC NRAS mut NSCLC Trastuzumab + Pertuzumab Vemurafenib + Cobimetinib NRAS mut ovarian HER2 ampl CRC HER2 mut NSCLC BRAF mut ACUP BRAF mut ovarian HER2 ampl cholangio HER2 ampl salivary duct BRAF mut salivary duct BRAF mut thyroid
Results Clinical benefit is observed in 38% of patients n patients with 1 response evaluation 45 Complete response (CR) 2 (4%) Currently ongoing 2 Mean duration exceeding 4.5 months Partial response (PR) 8 (18%) Currently ongoing 6 Mean duration exceeding 5 months Stable disease (SD) 16 wks 7 (16%) Currently ongoing 6 Mean duration exceeding 7 months
Ford. Nature May 24 1974
How to proceed with targeted therapies in (lung) cancer?
MEKi in K-RAS mutated NSCLC RTK Ras MEKi B-Raf A-Raf MEK c-raf ERK 20 Cell Proliferation
MEK inhibition causes upregulation of HER-2 and HER-3 in KRASm tumors Pan-HER inhibitor Upregulation expression and activity of HER-2 en HER-3 C-MYC MEK-inhibitor Proliferation Cell survival (anti-apoptosis) Angiogenesis Cell death Sun et al. Cell Reports 7; 1-10; 2014
MEK inhibition causes upregulation of HER-2 and HER-3 in KRASm tumor in vivo Sun et al. Cell Rep. 2014
MEKi plus pan-heri-based combination strategies for patients with KRASm tumors Pan-HERi + MEKi Clinicaltrials.gov dacomitinib PD-0325901 NCT02039336 lapatinib trametinib NCT02230553
Clinical phase I/II study Multi-center open-label proof of concept study consisting of two parts
Patient Preliminary results - Clinical activity CEA tumor marker & time on treatment CRC CRC Pancreatic ca CRC CRC Pancreatic ca NSCLC CRC CRC CRC 0 5 10 15 20 25 30 Time on treatment (weeks) PR or SD on study PD off study
Immunotherapy <2015 >2015
PD-(L)1, What are the data, second line? Key patient-inclusion criteria Previously treated with a first-line platinum-based regimen Differences between studies PD-L1 status PD-L1 cut-off Histology R Docetaxel PD-(L)1 checkpoint inhibitor PD or toxicity PD or toxicity Primary endpoint: OS Secondary endpoint: PFS, response rate, QoL QoL, quality of life.
OS (%) Immunotherapy is not a magic bullet 100 90 80 70 60 50 40 30 20 10 0 < 1% PD-L1 expression level Nivolumab Docetaxel HR (95% Cl) 0.87 (0.63 1.19) 0 3 6 9 12 15 18 21 24 27 30 Time (months) Borghaei H, et al. New Engl J Med. 2015;373:1627-39.
PFS (%) OS (%) Immunotherapy is not a magic bullet 100 90 80 70 60 50 40 30 20 10 0 < 1% PD-L1 expression level 100 90 Patients, N (95% Cl) 80 70 60 50 Nivolumab40 Docetaxel 30 19 20 Nivolumab HR (95% Cl) 0.87 (0.63 1.19) 10 0 3 6 9 12 0 8 Docetaxel 15 18 21 24 27 30 Time (months) 0 3 6 9 12 15 18 21 24 27 Time (months) At risk, n PFS Deaths, n/ Median PFS Nivolumab 292 128 82 58 46 35 17 7 2 0 Docetaxel 290 156 87 38 18 6 2 1 1 0 1-year PFS (95% Cl) Nivolumab 234/292 2.3 (2.2 3.3) 19 (14 23) Docetaxel 245/290 4.2 (3.5 4.9) 8 (5 12) HR for disease progression or death, 0.92 (95% Cl, 0.77 1.11) p = 0.39 Borghaei H, et al. New Engl J Med. 2015;373:1627-39.
OS (%) OS (%) OS (%) Immunotherapy is not a magic bullet 100 90 80 70 60 50 40 30 20 10 0 PFS < 1% PD-L1 expression level 100 OS, ITT (n = 850) Deaths, n/ Median PFS 1-year PFS Patients, N (95% Cl) (95% Cl) 90 100 Nivolumab 234/292 2.3 (2.2 3.3) HR 0.73 a 19 (14 23) 80 Docetaxel 245/290 4.2 (3.5 4.9) (95% CI 0.62 0.87) 8 (5 12) 70 HR for disease progression p or = death, 0.0003 60 80 0.92 (95% Cl, 0.77 1.11) p = 0.39 Minimum follow-up = 19 months 50 Nivolumab40 60 Docetaxel 30 19 20 Nivolumab HR (95% Cl) 0.87 (0.63 1.19) 10 40 0 3 6 9 12 0 8 Docetaxel 15 18 21 24Atezolizumab 27 30 Time (months) 0 3 6 Docetaxel 9 12 15 18 21 24 27 20 Time (months) Median 9.6 mo Median 13.8 mo At risk, n (95%CI 8.6 11.2) (95%CI 11.8 15.7) Nivolumab 292 1280 82 58 46 35 17 7 2 0 Docetaxel 290 156 0 87 38 3 18 6 2 9 1 1 12 0 15 18 21 24 Time (months) At risk, n Atezolizumab Docetaxel 425 407 382 363 342 326 305 279 260 248 234 223 218 205 198 188 175 163 157 141 116 74 54 41 28 15 4 1 425 390 365 336 311 286 263 236 219 195 179 168 151 140 132 123 116 104 98 90 70 51 37 28 16 6 3 27 Barlesi F, et al. Ann Oncol. 2016;27 Suppl 6:abstract LBA44_PR.
Atezolizumab based on PD-L1 positivity
Cancer immunogram Tumor foreignness Mutational load Tumor sensitivity to immune effectors MHC expression IFN-γ sensitivity General immune status Lymphocyte count Absence of inhibitory anti-tumor mechanisms LDH, glucose utilization Immune cell infiltration Intra-tumoral T cells Absence of soluble inhibitors IL-6 CRP/ESR Absence of checkpoints PD-L1 Blank et al., Science 2016
Patients with a high IFN/T-cell/BATF3 signature have a good clinical outcome Adjuvant Neo-adjuvant Batf3 DC signature 1 T cell signature 2 IFN-γ signature 3, 1 Spranger et al., Cancer Cell 2017; 2 Spranger et al., Nature 2015; 3 Ayers et al., JCI 2017
ESMO Guidelines 2016 2nd and 3rd-line treatment of stage IV non-squamous NSCLC Non-squamous Maintenance treatment: Pemetrexed (switch) (I, B) Pemetrexed (continuation) (I, A) Erlotinib (EGFR-activating mutation) (I, B) ± bevacizumab (if given before) Disease progression PS 3 4 BSC PS 0 2 Pemetrexed (I, B) Docetaxel (I, B) Nivolumab (I, B; MCBS 5) Pembrolizumab if PD-L1 > 1% (I, A; MCBS 3 if PD-L1 > 1%; MCBS 5 if PD-L1 > 50%) Ramucirumab docetaxel (I, B; MCBS 1) Nintedanib docetaxel (II, B) Erlotinib (II, C) Novello S, et al. Ann Oncol. 2016;27 Suppl 5:v1-v27.
ESMO Guidelines 201? 2nd and 3rd-line treatment of stage IV non-squamous NSCLC Non-squamous Maintenance treatment: Pemetrexed (switch) (I, B) Pemetrexed (continuation) (I, A) Erlotinib (EGFR-activating mutation) (I, B) ± bevacizumab (if given before) Disease progression PS 3 4 BSC PS 0 2 Pemetrexed (I, B) Docetaxel (I, B) Nivolumab (I, B; MCBS 5) PD-1/PD-L1 Pembrolizumab based on if PD-L1 sophisticated > 1% (I, A; MCBS 3 if PD-L1 biomarkers > 1%; MCBS 5 if PD-L1 > 50%) Ramucirumab docetaxel (I, B; MCBS 1) Nintedanib docetaxel (II, B) Erlotinib (II, C) Modified from: Novello S, et al. Ann Oncol. 2016;27 Suppl 5:v1-v27.