NSCLC 2 nd and further line therapies. Egbert F. Smit MD PhD. Dept. Thoracic Oncology, Netherlands Cancer Institute

Transcription

1 NSCLC 2 nd and further line therapies Egbert F. Smit MD PhD. Dept. Thoracic Oncology, Netherlands Cancer Institute e.smit@nki.nl

2 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 3 The opportunities

4 1990 ~3.000 bp/day New technologies bp/day miljard bp/day Gene identification Reference genome Single genomes

5 Cost of whole genome sequencing

6 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 3

7 2017 by American Association for Cancer Research Landscape overview of GENIE dataset.

8 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 Initiated by NKI-AVL, UMC Utrecht, EMC Rotterdam Participation all academic medical centers Teaching hospitals All hospitals

9 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

10 The Netherlands sequencing program n hospitals enrolling patients accrual in CPCT-02 study Monthly accrual

11

12 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

13 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,

14 DRUP study Gene HGVS transcript Effect Mutation known Coverage Variant frequency BRCA2 c.2095c>t Stop gained Novel EGFR c.2235_2249delg Missense variant COSM6223 rs Before start olaparib After 8 weeks of olaparib

15 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

16 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

17 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

18 Ford. Nature May

19 How to proceed with targeted therapies in (lung) cancer?

20 MEKi in K-RAS mutated NSCLC RTK Ras MEKi B-Raf A-Raf MEK c-raf ERK 20 Cell Proliferation

21 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

22 MEK inhibition causes upregulation of HER-2 and HER-3 in KRASm tumor in vivo Sun et al. Cell Rep. 2014

23 MEKi plus pan-heri-based combination strategies for patients with KRASm tumors Pan-HERi + MEKi Clinicaltrials.gov dacomitinib PD NCT lapatinib trametinib NCT

24 Clinical phase I/II study Multi-center open-label proof of concept study consisting of two parts

25 Patient Preliminary results - Clinical activity CEA tumor marker & time on treatment CRC CRC Pancreatic ca CRC CRC Pancreatic ca NSCLC CRC CRC CRC Time on treatment (weeks) PR or SD on study PD off study

26 Immunotherapy <2015 >2015

27 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.

28 OS (%) Immunotherapy is not a magic bullet < 1% PD-L1 expression level Nivolumab Docetaxel HR (95% Cl) 0.87 ( ) Time (months) Borghaei H, et al. New Engl J Med. 2015;373:

29 PFS (%) OS (%) Immunotherapy is not a magic bullet < 1% PD-L1 expression level Patients, N (95% Cl) Nivolumab40 Docetaxel Nivolumab HR (95% Cl) 0.87 ( ) Docetaxel Time (months) Time (months) At risk, n PFS Deaths, n/ Median PFS Nivolumab Docetaxel year PFS (95% Cl) Nivolumab 234/ ( ) 19 (14 23) Docetaxel 245/ ( ) 8 (5 12) HR for disease progression or death, 0.92 (95% Cl, ) p = 0.39 Borghaei H, et al. New Engl J Med. 2015;373:

30 OS (%) OS (%) OS (%) Immunotherapy is not a magic bullet PFS < 1% PD-L1 expression level 100 OS, ITT (n = 850) Deaths, n/ Median PFS 1-year PFS Patients, N (95% Cl) (95% Cl) Nivolumab 234/ ( ) HR 0.73 a 19 (14 23) 80 Docetaxel 245/ ( ) (95% CI ) 8 (5 12) 70 HR for disease progression p or = death, (95% Cl, ) p = 0.39 Minimum follow-up = 19 months 50 Nivolumab40 60 Docetaxel Nivolumab HR (95% Cl) 0.87 ( ) Docetaxel Atezolizumab Time (months) Docetaxel Time (months) Median 9.6 mo Median 13.8 mo At risk, n (95%CI ) (95%CI ) Nivolumab Docetaxel Time (months) At risk, n Atezolizumab Docetaxel Barlesi F, et al. Ann Oncol. 2016;27 Suppl 6:abstract LBA44_PR.

31 Atezolizumab based on PD-L1 positivity

32 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

33 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

34 ESMO Guidelines nd 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.

35 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.