Successes and Challenges in Treating Squamous Cell Carcinoma of the Lung

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1 Successes and Challenges in Treating Squamous Cell Carcinoma of the Lung Noemi Reguart,MD, PhD Hospital Clinic de Barcelona Barcelona, Spain SC-CRP Conversations in Oncology 2018 is a standalone medical education meeting by Boehringer Ingelheim

2 Outline Introduction Key Differences Between ADC and SqCC of the Lung Evolving Treatment Landscape for Metastatic NSCLC First-Line Immunotherapy Trials in Patients With SqCC of the Lung Pembrolizumab: KEYNOTE-407 Atezolizumab: IMpower131 Nivolumab: CheckMate-227, Part 1 ErbB Receptor Family Is a Valid Therapeutic Target for SqCC of the Lung Afatinib: LUX-Lung 8 ADC = adenocarcinoma; SqCC = squamous cell carcinoma; NSCLC = non small cell lung cancer.. 2

3 Differences Between NSCLC Histologic Subsets: ADC vs SqCC of the Lung 1,2 SqCC [VALU E] [CATE GORY NAME] [VALU E] ADC 55% Age ADC Bimodal with younger subset SqCC ~Older Male/female Females Males Smoking Therapies contraindicated Never-smoker subset No ~Smokers Yes (pemetrexed, bevacizumab) Biomarker-driven targeted therapy as SOC Good candidate: PD-L1 therapy Yes Yes a No YES a a Advances in SOC = standard of care; PD-L1 = programmed death-ligand Gandara et al. Clin Cancer Res. 2015;21:2236; 2. Li et al. J Clin Oncol. 2013;31:

4 Genomic characterization of SqCC Mutations Amplifications MYCL MCL1 NFE2L2 REL SOX2 PDGFRA EGFR FGFR1 MDM2 CCND1 ERBB2 The Cancer Genome Atlas (TCGA) initiative The Cancer Genome Atlas Research Network. Nature. 2012;489: CRKL 4

5 Evolution of NSCLC Subtyping From Histologic to a Multitude of Genomically Defined Subsets NSCLC as 1 disease ADC ALK HER2 BRAF PIK3CA AKT1 MAP2K1 NRAS ROS1 RET EGFR KRAS Unknown SqCC [VALUE] [CATEG ORY NAME] [VALUE] ADC 55% SqCC EGFRvIII PI3KCA EGFR DDR2 FGFR1 Amp Unknown Li et al. J Clin Oncol. 2013;31:1039. Histology-Based Subtyping 5

6 PD-L1 expression in SqCC Pooled data from KEYNOTE-001, -010, and -024 PD-L1 TPS 1%_67% PD-L1 TPS 50%_ 28% Aggarwal et al. Ann Oncol. 2016;27(6):

7 ESMO IO Chemo Chemo-IO ESMO Guidelines Committee. Ann Oncol. 2018;29(suppl 4):iv193-iv237 Chemo Antiangiogenics EGFR inh 7

8 First-Line Immunotherapy Trials in Patients With SqCC of the Lung Are Rapidly Changing the Treatment Landscape Trial Name Histology Treatment Arms KEYNOTE KEYNOTE Mixed (N=305) Squamous (n=56) Mixed (N=1274) Squamous (n=492) Pembrolizumab vs chemotherapy (PD-L1 50%) Pembrolizumab vs chemotherapy (PD-L1 1%) KEYNOTE Squamous (N=559) Pembrolizumab + chemotherapy vs chemotherapy IMpower131 4 CheckMate 227, Part Squamous (N=1021) Mixed (N=1739) Squamous (n=487 a ) Arm A: atezolizumab + carboplatin + paclitaxel Arm B: atezolizumab + carboplatin + nab-paclitaxel Arm C: carboplatin + nab-paclitaxel Part 1a (PD-L1 1%): nivolumab + ipilimumab; chemotherapy; or nivolumab Part 1b (PD-L1 <1%): nivolumab + ipilimumab; chemotherapy; or nivolumab + chemotherapy a Squamous histology in 28% of all randomised patients Reck et al. N Engl J Med. 2016;375:1823; 2. Lopes et al. J Clin Oncol. 2018;36(suppl 18):LBA4; 3. Paz-Ares et al. J Clin Oncol. 2018;36(suppl):105; 4. Jotte et al. J Clin Oncol. 2018;36(suppl):LBA9000; 5. Hellmann et al. Cancer Res. 2018;78(suppl 13):CT077; 6. Borghaei et al. J Clin Oncol. 2018;36(suppl):9001; 7. Hellmann et al. N Engl J Med. 2018;378:2093.

9 KEYNOTE-024 Study Design Brahmer et al. WCLC Abstract OA

10 KEYNOTE-024: updated OS Brahmer et al. WCLC Abstract OA

11 KEYNOTE-024: OS in subgroups Brahmer et al. WCLC Abstract OA

12 First Line, Stage IV Sq-NSCLC, PDL-1 50%, smoker > 2 years on IO Aug 2017 Oct 2017 Sept 2018 ToT 13 mo CR Case report by N.Reguart, C.Cabrera 12

13 KEYNOTE-407 Study Design a Percentage of tumor cells with membrabous PD-L1 staining assessed using the PD-L1 IHC 22C3 pharmdx assay. b Patients could crossover during combination therapy or monotherapy. To be eligible for crossover, PD must have been verified by BICR and all safety criteria had to be met. TPS = tumour proportion score; AUC = area under the concentration/time curve; Q3W = every 3 weeks; Q1W = every week; PFS = progression-free survival; RECIST = Response Evaluation Criteria in Solid Tumors; BICR = blinded independent central review; OS = overall survival; ORR = objective response rate; DOR = duration of response; IHC = immunohistochemistry Paz-Ares et al. ASCO Abstract

14 KEYNOTE-407: PFS at Interim Analysis, ITT 14 Paz-Ares L, et al. ASCO Presented June 3, 2018.

15 KEYNOTE-407: OS at Interim Analysis ITT population. HR = hazard ratio; CI = confidence interval; NE = not evaluable; ITT = intention to treat. Paz-Ares et al. ASCO Abstract

16 KEYNOTE-407: OS at Interim Analysis by PD-L1 TPS Paz-Ares et al. ASCO Abstract

17 IMpower131 Study Design Jotte et al. ASCO Abstract LBA

18 IMpower 131: PFS in ITT Population (Arm B vs Arm C, Investigator-Assessed) Data cutoff: January 22, 2018 a Stratified HR CnP = carboplatin + nab-paclitaxel. Jotte et al. ASCO Abstract LBA

19 IMpower131: Interim OS (Arm B vs Arm C) Data cutoff: January 22, 2018 a Stratified HR Jotte et al. ASCO Abstract LBA

20 Impower 131: Second OS Interim Analysis 43% cross-over to IO (other than atezolizumab) Socinsky et al. ESMO Poster LBA65. 20

21 IMpower131: Interim OS by PD-L1 Subgroups (Arm B vs Arm C) Impower 110 Data cutoff: January 22, 2018 a Unstratified HR TC = tumour cell; IC = tumour-infiltrating immune cell. Jotte et al. ASCO Abstract LBA

22 CheckMate-227, Part 1 Study Design Borghaei et al. ASCO Abstract

23 CheckMate-227, Part 1 PFS in Patients With <1% Tumor PD-L1 Expression All Randomised Patients (Squamous and Nonsquamous) Borghaei et al. ASCO Abstract

24 CheckMate-227 Part 1 PFS Subgroup Analyses in Patients With <1% Tumour PD-L1 Expression TMB = tumour mutational burden. Borghaei et al. ASCO Abstract

25 PFS: Nivolumab + Chemotherapy vs Chemotherapy By TMB TMB 10 mut/mb: ORR was 60.5% with nivo + chemo and 20.8% with chemo TMB <10 mut/mb: ORR was 27.8% with nivo + chemo and 22.0% with chemo 25

26 The ErbB Receptor Family Is a Valid Therapeutic Target for SqCC of the Lung Dysregulation of the ErbB pathway is frequently observed in SqCC of the lung EGFR overexpression and gene amplification aberrations of other ErbB receptors and dysregulation of the downstream pathways have been implicated in the pathobiology of SqCC 1,2 These findings likely account for the benefits these patients derive from erlotinib and other EGFR-directed therapies in different treatment settings, despite the low frequency of EGFR-activating mutations 17 ErbB Receptor Frequency (%) EGFR overexpression EGFR amplification 2, EGFRvIII mutation 6 5 EGFR kinase domain mutation 7 <5% ERBB2 mutation/amplification 2 5 ERBB3 mutation 8 1 ERBB3 overexpression 9 10 ERBB Frequency of known genetic drivers in SqCC 17 EGFRvIII PI3KCA EGFR DDR2 FGFR1 Amp Unknown 5% 1. Hirsch FR et al. J Clin Oncol. 2003;21:3798; 2. Lopez-Malpartida et al. Lung Cancer. 2009;65:25; 3. Lee et al. Lung Cancer. 2010;68:375; 4. Gately et al. Clin Lung Cancer. 2014;15:58; 5. Dacic et al. Am J Clin Pathol. 2006;125:860; 6. Ji et al. Proc Natl Acad Sci U S A. 2006;103:7817; 7. Dearden et al. Ann Oncol. 2013;24:2371; 8. Jaiswal et al. Cancer Cell. 2013;23:603; 9. Gorgoulis et al. Pathol Res Pract. 1995;191:973; 10. Kan et al. Nature. 2010;466:869; 11. Shepherd et al. N Engl J Med. 2005;353:123; 12. Clark et al. Clin Lung Cancer. 2006;7:389; 13. Leon et al. ESMO Abstract 1277; 14. Pirker et al. Lancet. 2009;373:1525; 15. Pirker et al. Lancet Oncol. 2012;13:33; 16. Thatcher et al. ASCO Abstract 8008; 17. Li et al. J Clin Oncol. 2013;31:

27 Therapeutic targets in SqCC, defined by TCGA PI3K/RTK/RAS signaling 69% altered EGFR STK11 2% AMPK PTEN 15% Alteration pattern RTK RAS 26% 24% PI3K 47% MTOR AKT1 <1% TSC1 3% PIK3CA 16% AKT2 4% TSC2 3% AKT3 16% 9% ERBB2 4% Proliferation, cell survival, translation The Cancer Genome Atlas Research Network. Nature. 2012;489: KRAS 3% ERBB3 2% HRAS 3% BRAF 4% FGFR1 7% NRAS <1% FGFR2 3% percent of cases (%) inactivated activated activation FGFR3 2% RASA1 4% NF1 11% inhibition Possible therapeutic target in over 60% of SqCC Targets will need to be validated in pre-clinical models 27

28 Afatinib Is the First Irreversible ErbB Family Blocker Afatinib covalently binds and irreversibly blocks EGFR, HER2, and ErbB4 1-3 Targeting the whole ErbB Family enhances the effect on important signalling pathways 2 1. Hirsh. BioDrugs. 2015;29:167; 2. Li et al. Oncogene. 2008;27:4702; 3. Solca et al. J Pharmacol Exp Ther. 2012;343:

29 Advanced SqCC in a non-smoker female H-E: squamous cells p40 positive Progression On Nivolumab Response On Afatinib Case report, Noemi Reguart Hospital Clínic Barcelona 29

30 LUX-Lung 8 Study Design: Afatinib vs Erlotinib in SqCC of the Lung Advanced SqCC NSCLC (stage IIIB/IV) PD after 4 cycles of a first-line platinum doublet ECOG PS 0 or 1 No prior anti-egfr therapy No active brain metastases Randomisation 1:1 (N=795) Afatinib (n=398) 40 mg QD Erlotinib (n=397) 150 mg QD Treatment until disease progression or unacceptable AEs Stratification: East Asian vs non East Asian Tumour tissue collected for correlative science Radiographic tumour assessment at baseline; weeks 8, 12, 16; every 8 weeks thereafter Primary endpoint: PFS; key secondary endpoint: OS PD = progressive disease; AE = adverse event; QD = once daily. Soria et al. Lancet Oncol. 2015;16:

31 Probability of PFS LUX-Lung 8: Significant Improvement in PFS and OS With Afatinib Compared With Erlotinib Updated PFS Analysis by Independent Review (n=795) Afatinib 0.8 Erlotinib Updated OS [Data Cutoff: March 2018] (n=795) 2 Afatinib (n=398) Erlotinib (n=397) No. at risk Time (mo) Afatinib 40 mg QD (n=398) Erlotinib 150 mg QD (n=397) Afatinib 40 mg QD (n=398) Erlotinib 150 mg QD (n=397) Patients progressed or died, n (%) 299 (75.1) 306 (77.1) Median PFS (mo) Patients died, n (%) (77.1) 325 (81.9) Median OS (mo) HR 0.81; 95% CI: ; HR 0.84; 95% CI: ; P= P=0.019 Erlotinib Soria et al. Lancet Oncol. 2015;16:897; 2. Goss et al. ESMO Poster 1442P; 3. Boehringer Ingelheim Data on File. 31

32 Estimated Probability of OS Retrospective Analysis of LUX-Lung 8 Patients Deriving Long-Term Benefit OS: Primary Analysis (ITT population) 1 OS and PFS in Patients Deriving Long-Term Benefit Afatinib (n=398) Erlotinib (n=397) 21 patients received 12 months of afatinib treatment Median treatment duration was 19.0 months (range: months) % 22.0% 28.2% 14.4% Time (months) Afatinib ITT (n=398) Median OS, mo 7.9 Median PFS, mo 2.6 Afatinib LTB (n=21) 27.5 (range: ) 12.9 (range: ) LTB = long-term benefit. 1. Yang et al. ELCC Poster 102P; 2. Soria et al. Lancet Oncol. 2015;16:897; 3. Goss et al. ESMO Poster 1442P. 32

33 LUX-Lung 8 Long-Term Benefiters: Treatment Response Median treatment duration, mo (range) Median OS, mo (range) Median PFS, mo (range) Complete response, n (%) Partial response, n (%) Stable disease, n (%) 19.0 ( ) 27.5 ( ) 12.9 ( ) 1 (5) 6 (29) 13 (62) Patients were ordered and numbered by treatment duration (at data cut-off), with patient 1 being on treatment longest; Patient transferred to commercial drug on discontinuation from study drug; Patient also had rearrangements in two genes; First observed response at time of tumour measurement; ** 1 SV present in at least 3/10 patients with long-term disease control, or part of the ErbB family (EGFR, ErbB2, ErbB3, ErbB4); One patient was not evaluable. VS = VeriStrat; VS-G = VeriStrat-Good; VS-P = VeriStrat-Poor. Goss et al. ESMO Poster 1442P. 33

34 ErbB Family Mutations in SqCC of the Lung in the LUX-Lung 8 Trial (Afatinib-treated Patients) All Afatinib-Treated Patients (n=132 a ) Afatinib-Treated LTBs (n=10 a ) EGFR, 6.8% ErbB2, 6.8% ErbB3, 4.6% ErbB4, 2.3% ErbB2, 20.0% ErbB3, 0% ErbB4, 10.0% ErbB WT, 81.1% EGFR, 20.0% ErbB WT, 50.0% 34 a Next-generation sequencing was undertaken in 10/21 LTRs and 132/398 afatinib-treated patients overall. ErbB family mutations were more frequent in LTBs than in the overall afatinib-treated population. WT = wild type. Yang et al. ELCC Poster 102P.

35 Recent Additional Trial on Activity of Afatinib in HER2 Exon 20 Mutated NSCLC All HER2 Mutation Positive Patients Patients With p.a775_g776insyvma in Exon 20 Patients With M774dup in Exon 20 n (%) 28 (100) 10 (36) 2 (7) TTF Median TTF, mo TTF >1 y 8 (29) 4 (40) 0 (0) Tumour response Patients with response data available 16 (57) 6 (60) 0 (0) ORR 3 (19) 2 (33) ND DCR 11 (69) 6 (100) ND PR 3 (19) 2 (33) ND SD 8 (50) 4 (67) ND TTF = time to treatment failure; DCR = disease control rate; PR = partial response; SD = stable disease; ND = not determined as no assessments were available. Peters et al. J Thorac Oncol. doi: /j.jtho

36 Summary and Conclusions Major differences exist between SqCC of the lung and ADC, including identification of treatable oncogene subsets Immune checkpoint inhibitors have emerged as promising novel treatment options for advanced SqCC ErbB receptor family is a valid therapeutic target for SqCC of the lung In LUX-Lung 8, patients with ErbB mutation positive tumours showed a more pronounced PFS and OS benefit with afatinib over erlotinib In the treatment of advanced SqCC, afatinib should be considered: As a treatment option in patients who have failed previous treatment with chemotherapy and immunotherapy In the second-line setting in patients who are not eligible for immune checkpoint inhibitors 36