The oncologist s point of view: the promise and challenges of increasing options for targeted therapies in NSCLC

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1 The oncologist s point of view: the promise and challenges of increasing options for targeted therapies in NSCLC Egbert F. Smit Department of Thoracic Oncology, Netherlands Cancer Institute, and Department of Pulmonary Diseases, VUMC, Amsterdam, Netherlands

2 Patient selection in lung cancer: evolution over time 199 Lung cancer 2 NSCLC SCLC ADC ADC and treatable oncogenic alterations Large cell carcinoma SCLC Squamous cell carcinoma ADC, adenocarcinoma; NSCLC, non-small-cell lung cancer; SCLC, small-cell lung cancer. Adapted from Reck M, et al. Lancet. 213;382:79-19.

3 Patient selection in NSCLC: evolution over time 28 Non-squamous cell carcinoma Squamous cell carcinoma 1. Non-squamous* (n = 1,) Squamous (n = 473) 1. Probability of survival Median OS (months) Pemetrexed + cisplatin 11.8 Gemcitabine + cisplatin 1.4 HR.81 (95% CI.7.94) p =.5 Probability of survival Median OS (months) Pemetrexed + cisplatin 9.4 Gemcitabine + cisplatin 1.8 HR 1.23 (95% CI ) p = Survival time (months) Survival time (months) *Non-squamous = adenocarcinoma and large cell carcinoma NSCLC histology. CI, confidence interval; HR, hazard ratio; OS overall survival. Scagliotti GV, et al. J Clin Oncol. 28;26:

4 Timeline for the discovery of relevant alterations in lung cancer NRAS mutations EGFR HER2 PIK3CA mutations ALK ROS1 fusions First lung cancer genomes Lung squamous ADC, SCLC exomes & genomes KRAS mutations PTEN mutations Lung ADC kinome 623 genes of lung ADC DDR2 mutations BRAF mutations Lung ADC copy numbers FGFR1 amplifications Before NGS NGS era Difficulty: picking the right gene finding the relevant genes ALK, anaplastic lymphoma kinase; BRAF, B-Raf proto-oncogene; DDR2, discoidin domain receptor 2; EGFR, epidermal growth factor receptor; FGFR1, fibroblast growth factor receptor 1; HER2, human epidermal growth factor receptor 2; KRAS, Kirsten rat sarcoma viral oncogene homologue; NGS, next-generation sequencing; NRAS, NRAS proto-oncogene; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha; PTEN, phosphatase and tensin homolog; ROS1, ROS1 proto-oncogene receptor tyrosine kinase. Adapted from Levy MA, et al. Genome Res. 212;22:211-8.

5 Frequencies in real life: French experience Overall Full WT 15% EGFR 11% ADC Full WT 15% EGFR 12% Unknown 35% ALK 5% KRAS 29% PIK3CA 2% HER2 1% BRAF 2% ALK 5% Unknown 32% KRAS 31% PIK3CA 2% HER2 1% BRAF 2% Women Full WT 12% EGFR 21% Never-smokers Unknown 13% Full WT 9% EGFR 44% ALK 6% PIK3CA 3% Unknown 28% KRAS 27% HER2 1% BRAF 2% PIK3CA 4% ALK 14% HER2 4% KRAS 9% BRAF 3% WT, wild type. Barlesi F, et al. Lancet. 216;387:

6 Oncogene-driven NSCLC: tailored treatment PFS probability Erlotinib vs chemotherapy in EGFR-driven advanced NSCLC 1 1. Erlotinib (n = 86) Chemotherapy (n = 87).8 Log-rank p < PFS, progression-free survival. HR (95% CI).342 ( ) Time (months) Patients at risk Erlotinib Chemotherapy Probability of survival without progression (%) Crizotinib vs chemotherapy in ALK+ NSCLC 2 Crizotinib (n = 173) Number at risk Erlotinib Chemotherapy Chemotheraphy (n = 174) Events, n (%) 1 (58) 127 (73) Median, mo HR (95% CI).49 (.37.64) p <.1 Time (months) 1. Adapted from: Rosell R, et al. Lancet Oncol. 212;13: Adapted from: Shaw AT, et al. N Engl J Med. 213;368:

7 Targeted therapy: improved survival, no cure Survival probability No targeted therapy Log-rank p <.1 Targeted therapy No driver Number at risk Patients with oncogenic driver Time (years) No targeted therapy Targeted therapy Patients with no driver Kris MG, et al. JAMA. 214;311:

8 Patient selection in lung cancer: evolution over time 199 Lung cancer 2 NSCLC SCLC 215 Established targets EGFR ALK ROS1 Mutation negative/unknown ADC Large cell carcinoma Squamous cell carcinoma ADC and treatable oncogenic alterations Small-cell lung cancer Adapted from Reck M, et al. Lancet. 213;382:79-19.

9 ADC: targets and therapy EGFR sensitizing Gefitinib 4 Erlotinib 4 Afatinib 4 Osimertinib 4 Necitumumab 4 Rociletinib 3 Key 1 - Phase Phase Phase Approved ALK Crizotinib 4 Alectinib 4 Ceritinib 4 Lorlatinib 2 Brigatinib 2 EGFR sensitizing 17% KRAS 25% ALK 7% MET Crizotinib 2 Cabozantinib 2 EGFR other 4% MET 3% > 1 mutation 3% Unknown oncogenic driver detected 31% HER2 2% ROS1 2% BRAF 2% RET 2% NTRK1 1% PIK3CA 1% MEK1 1% HER2 Trastuzumab emtansine 2 Afatinib 2 Dacomitinib 2 ROS1 Crizotinib 4 Cabozantinib 2 Ceritinib 2 Lorlatinib 2 DS-651b 1 BRAF Vemurafenib 2 Dabrafenib 2 Only three of these targets have agents through approval by the FDA MEK1 Trametinib 2 Selumetinib 3 Cobimetinib 1 PIK3CA LY PQR 39 1 NTRK1 Entrectinib 2 LOXO-11 2 Cabozantinib 2 DS-651b 1 RET Cabozatinib 2 Alectinib 2 Apatinib 2 Vandetanib 2 Ponatinib 2 Lenvatinib 2 FDA, US Food and Drug Administration; MEK1, mitogen-activated protein kinase 1; MET, mesenchymal-epidermal transition; NTRK1, neurotrophic tyrosine kinase receptor 1; RET, rearranged during transfection. Tsao AS, et al. J Thorac Oncol. 216;11:

10 Maximum reduction from baseline measurement (%) Dabrafenib trametinib in previously treated BRAF V6E patients Maximum change in target lesion by best investigator-assessed confirmed response 4 ORR: 63% (95% CI 49 76) Best confirmed response CR PR 8 SD PD 1 NE Patients NE patients did not have a follow-up scan required for confirmation One-half of responses (18/36) were ongoing at the time of data cutoff CR, complete respose; NE, not evaluable; PD; progressive disease; PR, partial response; SD, stable disease. Patients Duration of response Investigator assessment n = 36 DOR, median (95% CI), months 9. ( ) Number of previous systemic anticancer therapy regimens for metastatic disease DOR (months)

11 cmet alterations in LUAC Polysomy not sensitive to cmeti Amplification sensitive to cmeti when highly amplified Mutation exon 14 skipping mutations are highly sensitive to cmeti cmeti, cmet inhibitor; LUAC, lung adenocarcinoma.

12 Tumour shrinkage seen with capmatinib treatment in intermediate and high MET cohorts Best response n (%) GCN < 4 (n = 17) GCN 4 and < 6 (n = 12) GCN 6 (n = 15) CR PR 2 (17) 7 (47) SD 8 (47) 3 (25) 5 (33) PD 5 (29) 3 (25) 2 (13) Unknown 4 (24) 4 (33) 1 (7) ORR 2 (17) 7 (47) 95% CI DCR 95% CI 8 (47) (42) (8) Best % change from baseline cmet GCN < 4 n/n (%) = 11/17 (64.7%) Best % change from baseline cmet GCN 4 and < 6 n/n (%) = 7/12 (58.3%) Best % change from baseline 8 cmet GCN 6 n/n (%) = 12/15 (8.%) DCR, disease control rate; GCN, gene copy number. Schuler M, et al. Presented at ASCO 216. Abstract 967.

13 cmet exon 14 skipping mutations are sensitive to cmet inhibitors Never received a MET TKI N = 34 Received a MET TKI N = 27 OS from date of stage IV diagnosis OS probability OS probability Median OS (95% CI) 8.1 months (5.3 NR) Time (months) Median OS (95% CI) 24.6 months (12.1 NR) Time (months) TKI, tyrosine kinase inhibitor. Awad MM, et al. Presented at ASCO 217. Abstract 8511.

14 ROS1 rearrangement Cytologic analysis of a pleural effusion FISH Sequence of the CD74-ROS1 fusion transcript cd74, cluster of differentiation antigen 74; FISH, fluorescent in-situ hybridization. Awad MM, et al. N Engl J Med 213;368:

15 Change from baseline (%) Crizotinib in ROS1-rearranged LUAC: results from a phase 1 extension cohort (n = 5) * 3 patients (6%) CR 33 patients (66%) PR 9 patients (18%) SD M PD SD PR CR ORR: 72% A DoR Time (months) DoR, duration of response. Shaw AT, et al. N Engl J Med. 214;371:

16 Ceritinib has activity in crizotinibresistant ROS1-rearranged LUAC Change from baseline in sum of longest tumour diameters (%) PD SD PR CR PFS (proportion) PFS 9.3 months (95% CI 22) 19.3 months (95% CI 1 37) Duration (months) All Crizotinib-naive Lim SM, et al. J Clin Oncol. 217;35:

17 Lorlatinib in ROS1 + NSCLC ROS + patients Best change from baseline (%) prior TKI No prior TKI Ongoing treatments Solomon BJ, et al. Presented at Proc ASCO 216. Abstract 99.

18 RET rearrangements Modifying variants G691 Y791 G533 C69 C611 C618 C62 C63 C634 E768 L79 Y791 V84 A883 S891 M918 FMTC MEN2A FMTC FMTC MEN2B Papillary thyroid carcinoma CCDC RET-PTC1 NCOA RET-PTC3 Lung adenocarcinoma KIF5B KIF5B-RET Chronic myelomonocytic leukaemia BCR BCR-RET Real frequency unknown 1 2% of LUAC Responses observed vandetanib sorafenib regorafenib alectinib cabozantinib FGFR1P FGFR1OP-RET Mulligan LM. Nat Rev Cancer. 214;14:

19 Cabozantinib phase 2 in RET-rearranged LUAC Maximum reduction from baseline measurement (%) Best confirmed response PR SD OS (%) Time from start of treatment (months) Number at risk (number censored) 25 () 15 (5) 7 (5) 6 (5) 6 (5) 6 (5) 4 (7) 1 (8) (9) Drillon A, et al. Lancet Oncol. 216;17:

20 HER2 mutation and amplification are distinct molecular targets HER2 amplification Testing FISH (HER2/CEP17 2) N = 175 5/175 = 3% (95% CI 1 7) HER2 mutation Testing Fragment analysis and mass spectrometry genotyping (insertions, deletions, indels, recurrent point mutations L755S, D769H, V777L, V777M) N = 145 4/145 = 3% (95% CI 1 7) Overlap testing HER2 mutation and HER2 amplifications N = 145 /175 = % (95% CI 3) CEP17, chromosome enumeration probe 17. Li BT, et al. Presented at ASCO Annual meeting 217. Abstract 851. Li BT, et al. J Thorac Oncol. 216;11:414-9.

21 TDM-1 in LUAC with HER2 ins mutations 2% of lung cancers Most common HER2 mutation is insyvma Li BT, et al. Presented at ASCO Annual meeting 217. J Thorac Oncol. 216;11: Adapted from: Arcila ME, et al. Clin Cancer Res. 212;18: Kris MG, et al. JAMA. 214;311: Stephens P, et al. Nature. 24;431:525-6.

22 TDM-1 in LUAC with HER2 ins mutations ORR by RECIST v1.1 PFS % Best response per RECIST v HER2 mutant lung cancer responses Patients Confirmed PR SD/PD Probability of PFS Time since treatment start (months) HER2 mutant patients receiving ado-trastuzumab emtansine Time on treatment (months) 8 Treatment ongoing Response Response and treatment ongoing 9 11 ORR 44% (8/18; 95% CI 22 69), study met primary endpoint Median PFS: 4 months (95% CI 3. to NR, n = 18 with 13 events) Median DoR: 5 months (95% CI 3. to NR, n = 8 with 6 events) RECIST, Response evaluation criteria in solid tumours. Li BT, et al. Presented at ASCO Annual meeting 217. J Thorac Oncol. 216;11:414-9.

23 How about squamous cell lung cancer? Oncogene addiction ~ 25% of ADC almost no squamous cell carcinoma Oncogene expedience most ADC vast majority of squamous cell carcinomas

24 Potential therapeutic targets in squamous NSCLC FGFR1 amplification 22% DDR2 mutation 4% PIK3CA amplification 33% MET amplification 5% MET mutation 1% BRAF mutation 2% Others Unknown Perez-Moreno P, et al. Clin Cancer Res. 212;18:

25 FGFR1 amplifications in SCC of the lung: from discovery to clinical evaluation n = 153 Genomic discovery 1 Pre-clinical validation 1 FISH diagnostics 2 Chromosome 8p geography Clinical evaluation Understanding response on the molecular level 3 FIM trial BGJ398 in FGFR1-ampl. SQLC SCC, squamous cell carcinoma; SQLC, squamous lung cancer. 1. Weiss J, et al. Sci Transl Med. 21;2:62ra Heucamp LC, et al. Sci Transl Med. 212;4:141ra Malchers F, et al. Cancer Discov. 214;4: Nogova L, et al. Presented at ASCO 214. Abstract 834.

26 BGJ398 has clinical activity at doses 1 mg/day Best % change from baseline (sum of longest diameters of target lesions) RR FGFR1 amplified lung: 16% (RR FGFR-altered bladder: 4%) Bladder Breast Lung Cholangiocarcinoma HNSCC Other HNSCC, head and neck squamous cell carcinoma. Sequist L, et al. Presented at AACR 214. Abstract CT326.

27 Conclusion Targeted therapies extend survival over conventional chemotherapy (with improved QoL) in NSCLC Identification of patients for targeted therapies is key This can only be done by proper sequencing techniques no clinical factor predicts reliably Calls for close cooperation between pathologists and treating physicians

28 Thank you for your attention!

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