Targeted Therapy In ALK Rearranged Advanced/Metastatic Non Small Cell Lung Cancer (NSCLC)

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1 Targeted Therapy In ALK Rearranged Advanced/Metastatic Non Small Cell Lung Cancer (NSCLC) NASR M. A. ALLAHLOUBI PROFESSOR OF MEDICAL ONCOLOGY NCI, CAIRO UNIVERSITY Bridging Gaps in Oncology, Thursday 28 th October 2015, Intercontinental Hotel Cairo Egypt

2 Advanced/Metastatic NSCLC: Evolution of Treatment NSCLC Treatment according to histology Targeting EGFR Targeting Oncogenic "drivers" EGFR mutation EGFR mutation NSCLC Squamous Nonsquamous Nonsquamous Squamous ALK rearrangement K-ras mutation B-raf, HER2 mutation ROS1, KIF5B-RET Other non-squamous MET Amplification Squamous Maintenance Therapy in NSCLC

3 Comorbidities Beva Eligibility PS, age Biomarqkers Histology Decision-Making Factors in Advanced NSCLC Non-squamous Cell Carcinoma Biomarkers Determination EGFR Mut+ ALK + EGFR wt and ALK - Squamous Cell Carcinoma PS 0-1 PS 2 or Age > 75 PS 0-1 PS 2 or Age > 75 Co-morbidities Eligibility to bevacizumab Co-morbidities

4 P-E C-E P-M-Vd C-M-Vd P-TPZ C-TPZ T-Z Nv-P P-T C-T T-P G-P D-P T-C Nv-P T-C G-P D-P D-C Nv-P G-P G-Nv-P G-Nv Ifo-Nv Median Overall Survival, months Advanced NSCLC: the 2000's Plateau NSCLC NSCLC NSCLC, non-small cell lung cancer. Courtesy of G. Scagliotti.

5 New Paradigms in the Treatment of Advanced NSCLC Targeting Oncogenic "drivers" EGFR mutation ALK rearrangement KRAS mutation Braf, HER2 mutation ROS1, KIF5B-RET Other non-squamous Squamous MET Amplification/Overexpression PD-L1 Expression NSCLC depending on an oncogene addiction EGFR activating mutations ALK rearrangement Emerging biomarkers: ROS1, BRAF, HER2, RET 'Non-oncogenic' NSCLC Induction treatment Maintenance therapy Treatment of PS2 and elderly patients Restoration or stimulation of host immune capacities Immunotherapy PS, performance status.

6 Agenda Lung Cancer Disease Burden Molecular biology & Detection Methods PROFILE 1007 (2nd line data) PROFILE 1014 (1st line data) Treatment beyond disease progression Activity in brain metastasis Guidelines

7 The most frequent cancers in Egypt estimated using the results of the National Population-Based Registry Program of Egypt

8 Incidence of Single Driver Mutations (LCMC) Kris MG, Johnson BE, Kwiatkowski DJ, et al. Identification of driver mutations in tumor specimens from 1000 patients with lung adenocarcinoma: the NCI's Lung Cancer Mutation Consortium (LCMC). J Clin Oncol 2011;29: (Suppl, abstract CRA 7506).

9 NSCLC (non-squamous) in 2013 Smokers Never smokers KRAS 35.2 EGFR 33.2 EGFR activ EGFR resist KRAS BRAF ALK ALK PI3K HER2 UNK * Including 2664 with full clinical data available at the time of this analysis. F.Barlesie et al. F.Barlesie et al. ASCO 2013

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11 Prevalence of ALK +ve NSCLC Although the frequency of the ALK gene rearrangement is relatively low (approximately 4% of NSCLC patients), this translates into 70,000 cases annually worldwide. Lung Cancer: Targets and Therapy 2014:

12 Schematic of ALK fusion oncogenes and important downstream signaling pathways Shaw AT, Solomon B. Clin Cancer Res 2011; 17: 2081

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14 Two CE-marked ALK testing kits are currently available and recommended by ESMO/CAP & Approved by FDA FISH IHC ALK Intra-chromosome inversion? AL EML4 K EML4 Vysis ALK break-apart FISH probe VENTANA anti-alk (D5F3) primary antibody Wild type ALK rearranged FISH, fluorescence, in-situ hybridisation

15 Tucson, AZ, June 15, 2015 The VENTANA ALK Assay was approved as a CE-IVD in Europe in 2012 and was approved by the Chinese Food and Drug Administration (CFDA) in With this US FDA Class III approval, ALK IHC testing is now widely accessible on VENTANA BenchMark1 immunohistochemistry (IHC) instruments globally, can be easily integrated into standard lab workflow and offers fast test results with a binary, straightforward scoring method.

16 ALK Signaling & Crizotinib Mechanism of Action Normal ALK signaling Pathologic ALK signalling Crizotinib mode of action EXTRACELLULAR EXTRACELLULAR EXTRACELLULAR EXTRACELLULAR ALK receptor Ligand: Pleiotrophin? Midkine? ALK kinase domain abnormally activated due to fusion with EML4 INTRACELLULAR Proliferation & survival upon ligand binding to ALK Constitutive proliferation & inhibition of apotosis EML4-ALK fusion protein silenced by Crizotinib

17 Presented By Leena Gandhi at 2014 ASCO Annual Meeting

18 Presented By Leena Gandhi at 2014 ASCO Annual Meeting

19 Crizotinib Studies in ALK+ NSCLC: Efficacy PROFILE (N=143) PROFILE (N=765) PROFILE (N=172) Phase Line of therapy Any line 2 nd line and beyond 2 nd line ORR 61% 48% 65% Duration of response, median (wks) Duration of treatment, median (wks) PFS, median (mos) 9.7 NA 7.7 Survival probability at 12 mos 75% NA 70% 1 Camidge et al., Lancet Onc 13(10): , United States Package Insert, November Shaw et al., NEJM 368(25): , 2013

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21 Profile 1007: PFS of crizotinib versus pemetrexed or docetaxel

22 Profile 1007: PFS of crizotinib versus pemetrexed or docetaxel by independent central review (ITT)

23 Profile 1007: ORR by independent radiologic review

24 Profile 1007: Interim analysis of OS

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26 Profile 1007: Adverse events

27 Case 1 A 53-year-old female, PS 2, never smoker presented with persistent cough in June 2012, and imaging studies revealed a right hilar mass. An endobronchial biopsy of the tumor revealed a moderately differentiated mucinous adenocarcinoma, TTF-1, positive, and mucicarmine positive. Initial molecular analysis revealed the tumor to be EGFR wild type. Her staging workup revealed metastasis to the liver Patient started platinum/pemetrexed combination chemotherapy followed with a partial response to treatment. In November 2012, she decided to undertake a treatment holiday. By February 2013, however, her disease had progressed, and she commenced single-agent erlotinib treatment but had documented disease progression after 6 weeks.

28 She had a persistent cough, daily low-grade fevers, anorexia, and right neck pain due to tumor invasion of the right subscapalaris muscle Because her clinical profile would fit with ALK +ve: female, adenocarcinoma histology, neversmoking status, and her tumor is EGFR wild type, FISH test for ALK was asked The results showed her tumor to be positive for an ALK gene rearrangement using a FISH probe (15% of cells harboring isolated 3 ALK FISH signals) Further molecular testing confirmed that the tumor harbored the EML4-ALK variant 1 transcript (E13; A20), which is the most common EML4-ALK variant

29 The patient started on crizotinib 250 mg twice a day orally in June 2013 and 13 days later reported that the daily low-grade fevers had disappeared, her right neck pain had resolved, and her cough had significantly decreased. By week 3, she had gained 1.5 kg of weight, and her cough had also completely resolved. PET-CT performed after 6 weeks, showed a 70.5% decrease in maximum standard uptake value activity with a corresponding 36.4% decrease in the total tumor measurement by RECIST.

30 Case 2 A 66-year-old woman, PS 3, known to have stage IV pulmonary adenocarcinoma (TTF-1 +) & EGFR wild, presented to me in December 2012, 3 months after ending 6 cycles of pemetrexed and carboplatin. She was admitted to the ICU due to severe dyspnea. During the workup, recurrent lung mass, progressively accumulating pleural effusion was newly developed. The analysis of pleural effusion indicated malignant hemothorax, and more than 2.8 liters of bloody pleural effusion was drained through a chest tube. In the biomarker analysis, IHC for ALK protein showed moderately positive staining,

31 After ICT-underwater seal drainage of the effusion, CT on day 17 th, showed an unresolved primary lung mass and a mediastinal lymph node compressing the right main bronchus (Figure A). In view of IHC + ALK, We prescribed crizotinib (250 mg twice a day), starting February 16, The pleural effusion decreased rapidly, and the chest tube was removed 6 days after the initiation of crizotinib therapy. At day 32 (Figure B), chest images showed a great decrease in the lung lesions and At day 83, the lesions decreased further; this partial response was confirmed with chest images (Figure C)

32 First-line Crizotinib Versus Pemetrexed Cisplatin or Pemetrexed Carboplatin in Patients With Advanced ALK-positive Non-Squamous Non-Small Cell Lung Cancer: Results of a Phase III Study (PROFILE 1014) T MOK, 1 D-W KIM, 2 Y-L WU, 3 BJ SOLOMON, 4 K NAKAGAWA, 5 T MEKHAIL, 6 E FELIP, 7 F CAPPUZZO, 8 J PAOLINI, 9 T USARI, 9 J TURSI, 9 F BLACKHALL 10 1 THE CHINESE UNIVERSITY OF HONG KONG, SHATIN, CHINA; 2 SEOUL NATIONAL UNIVERSITY HOSPITAL, SEOUL, SOUTH KOREA; 3 GUANGDONG LUNG CANCER INSTITUTE, GUANGZHOU, CHINA; 4 PETER MACCALLUM CANCER CENTRE, MELBOURNE, AUSTRALIA; 5 KINKI UNIVERSITY, OSAKA, JAPAN; 6 FLORIDA HOSPITAL CANCER INSTITUTE, ORLANDO, FL, USA; 7 VALL D HEBRON UNIVERSITY HOSPITAL, BARCELONA, SPAIN; 8 OSPEDALE RIUNITI, LIVORNO, ITALY; 9 PFIZER ONCOLOGY, MILAN, ITALY; 10 THE CHRISTIE HOSPITAL, MANCHESTER, UK Solomon BJ et al. First-Line Crizotinib versus Chemotherapy in ALK-Positive Lung Cancer. N Engl J Med 2014;371: DOI: /NEJMoa

33 Solomon BJ et al. First-Line Crizotinib versus Chemotherapy in ALK-Positive Lung Cancer. N Engl J Med 2014;371: DOI: /NEJMoa PROFILE 1014 Study Design Key entry criteria ALK-positive by central FISH testing a Locally advanced, recurrent, or metastatic non-squamous NSCLC No prior systemic treatment for advanced disease ECOG PS 0 2 Measurable disease Stable treated brain metastases allowed R A N D O M I Z E b N=343 Crizotinib 250 mg BID PO, continuous dosing (n=172) Pemetrexed 500 mg/m 2 + cisplatin 75 mg/m 2 or carboplatin AUC 5 6 q3w for 6 cycles (n=171) Endpoints Primary PFS (RECIST 1.1, independent radiologic review [IRR]) Secondary ORR OS Safety Patient-reported outcomes (EORTC QLQ- C30, LC13) CROSSOVER TO CRIZOTINIB PERMITTED AFTER Progression

34 Solomon BJ et al. First-Line Crizotinib versus Chemotherapy in ALK-Positive Lung Cancer. N Engl J Med 2014;371: DOI: /NEJMoa Baseline Clinical Characteristics Characteristic Crizotinib (N=172) Chemotherapy (N=171) Age, years Median (range) 52 (22 76) 54 (19 78) Sex, n (%) Male 68 (40) 63 (37) Race, n (%) White Asian Other 91 (53) 77 (45) 4 (2) 85 (50) 80 (47) 6 (4) Smoking, n (%) Never smoked Former smoker Current smoker 106 (62) 56 (33) 10 (6) 112 (65) 54 (32) 5 (3) Histology, n (%) ECOG PS, n (%) 0/1 2 Extent of disease, n (%) Adenocarcinoma Non-adenocarcinoma Locally advanced Metastatic 161 (94) 11 (6) 161 (94) 10 (6) 4 (2) 168 (98) 161 (94) 10 (6) 163 (95) 8 (5) 3 (2) 168 (98) Time since first diagnosis, months Median (range) 1.2 ( ) 1.2 ( ) Brain metastases, n (%) Present 45 (26) 47 (27)

35 Primary Endpoint Met: Crizotinib Superior to Pemetrexedbased Chemotherapy in Prolonging PFS Solomon BJ et al. First-Line Crizotinib versus Chemotherapy in ALK-Positive Lung Cancer. N Engl J Med 2014;371: DOI: /NEJMoa

36 Solomon BJ et al. First-Line Crizotinib versus Chemotherapy in ALK-Positive Lung Cancer. N Engl J Med 2014;371: DOI: /NEJMoa PFS in patient subgroups Subgroup n HR (95% CI) All patients ( ) Age 65 years ( ) Age <65 years ( ) Male ( ) Female ( ) Non-Asian ( ) Asian ( ) Smoker or ex-smoker ( ) Non-smoker ( ) >1 year since diagnosis ( ) 1 year since diagnosis ( ) ECOG PS ( ) ECOG PS 0/1 a ( ) Adenocarcinoma ( ) Non-adenocarcinoma ( ) Metastatic disease ( ) Locally advanced disease ( ) Brain metastases present b ( ) Brain metastases absent b ( ) a Data missing for ECOG PS (n=1) b By investigator assessment Favors crizotinib 0 1 Favors chemotherapy 2 HR

37 Solomon BJ et al. First-Line Crizotinib versus Chemotherapy in ALK-Positive Lung Cancer. N Engl J Med 2014;371: DOI: /NEJMoa

38 Waterfall Plot: Best Percent Change from Baseline in Target Lesion Size

39 ORR (95% exact CI; %) Solomon BJ et al. First-Line Crizotinib versus Chemotherapy in ALK-Positive Lung Cancer. N Engl J Med 2014;371: DOI: /NEJMoa ORR by independent review 80 Crizotinib (N=172) Chemo (N=171) ORR, % (n) 74 (128) 45 (77) 95% exact CI of ORR P b < Median time to response, c weeks Range Median duration of response, c,d weeks % CI e Crizotinib Chemotherapy b Pearson χ 2 test d Kaplan Meier method c I n patients with an objective response e Brookmeyer Crowley method

40 OS (ITT Population) With only 26% of all-cause deaths at data cutoff, median OS was not reached in either group Analysis was not adjusted for the potentially confounding effects of crossover 120/171 chemotherapy patients (70%) received crizotinib after progression 21/172 crizotinib patients (12%) subsequently received platinum-based chemotherapy

41 Solomon BJ et al. First-Line Crizotinib versus Chemotherapy in ALK-Positive Lung Cancer. N Engl J Med 2014;371: DOI: /NEJMoa Safety Overview Duration of treatment was longer with crizotinib than with chemotherapy (median 10.9 vs. 4.1 months) Most AEs in both treatment groups were grade 1 or 2 Rates of treatment-related AEs associated with permanent discontinuation were 5% with crizotinib and 8% with chemotherapy (before crossover) Safety profile of crizotinib was consistent with that reported in patients with previously treated advanced ALK-positive NSCLC 1

42 Common AEs of Any Cause in 25% of Patients With 5% Difference Between Groups Higher frequency ( 5% absolute difference) in crizotinib arm Crizotinib (n=171), n (%) Chemotherapy (n=169), n (%) b Any grade Grade 3/4 Any grade Grade 3/4 Vision disorder c 122 (71) 1 (1) 24 (14) 0 Diarrhea 105 (61) 4 (2) 29 (17) 1 (1) Edema c 83 (49) 1 (1) 22 (13) 1 (1) Vomiting 78 (46) 3 (2) 68 (40) 6 (4) Constipation 74 (43) 3 (2) 53 (31) 0 Elevated transaminases c 61 (36) 24 (14) 22 (13) 4 (2) Upper respiratory infection 55 (32) 0 21 (12) 1 (1) Abdominal pain c 45 (26) 0 20 (12) 0 Dysgeusia 45 (26) 0 11 (7) 0 Higher frequency ( 5% absolute difference) in chemotherapy arm Nausea 95 (56) 2 (1) 103 (61) 3 (2) Decreased appetite 51 (30) 4 (2) 59 (35) 1 (1) Fatigue 49 (29) 5 (3) 65 (38) 4 (2) Neutropenia c 36 (21) 19 (11) 51 (30) 26 (15) Asthenia 22 (13) 0 42 (25) 2 (1) Anemia c 15 (9) 0 54 (32) 15 (9) Permanent treatment discontinuations due to treatment-related AEs: 5% in crizotinib arm; 8% in chemotherapy arm b No grade 5 AEs reported to be related to treatment; 1 patient in chemotherapy arm had grade 5 pneumonitis after crossover to crizotinib, considered to be treatment-related Solomon BJ et al. First-Line Crizotinib versus Chemotherapy in ALK-Positive Lung Cancer. N Engl J Med 2014;371: DOI: /NEJMoa

43 Profile 1014: Conclusions PROFILE 1014 met its primary objective, demonstrating prolonged PFS with first-line crizotinib versus pemetrexed-based chemotherapy in patients with ALK-positive NSCLC First-line crizotinib treatment resulted in a statistically significant increase in tumor response rate compared with standard chemotherapy Overall survival data were immature First-line crizotinib was associated with an acceptable safety profile that was consistent with previous reports These findings establish crizotinib as the standard of care for patients with previously untreated advanced ALK-positive non-squamous NSCLC 1-Solomon BJ et al. First-Line Crizotinib versus Chemotherapy in ALK-Positive Lung Cancer. N Engl J Med 2014;371: DOI: /NEJMoa

44 Summary of XALKORI Phase III studies Two phase III studies have established XALKORI as standard of care ALK-inhibitor in TKI-naïve ALK-positive NSCLC PROFILE st Line mpfs: 10.9 vs 7.0 mo HR: p-value <0.001 ORR 74% vs 45% PROFILE nd Line mpfs : 7.7 vs 3.0 mo HR: p-value <0.001 ORR 65% vs 20% 1-Solomon BJ et al. First-Line Crizotinib versus Chemotherapy in ALK-Positive Lung Cancer. N Engl J Med 2014;371: DOI: /NEJMoa ; 2- Shaw et al., Crizotinib versus Chemotherapy in Advanced ALK-Positive Lung Cancer. NEJM 368(25): , 2013

45 Disease progression on crizotinib: Three clinical scenarios RECIST-defined progression does not always reflect treatment failure symptomatic and rapid progression GENERAL PROGRESSION treatment with XALKORI lesions start growing slowly again SMOLDERING DISEASE response single new or newly growing lesions (LN, brain, liver, etc.) OLIGOPROGRESSION

46 Management of oligometastatic disease pre treatment 2 months on crizotinib 9 months on crizotinib 12 months on crizotinib 14 months on crizotinib 17 months on crizotinib local radiotherapy local radiotherapy local radiotherapy 9 months PFS until first progression 17 months disease control until discontinuation of crizotinib Gan et al., Int J Rad Oncol 2013

47 Clinical Experience With Crizotinib in Patients With Advanced ALK-Rearranged Non Small-Cell Lung Cancer and Brain Metastases Costa DB, Shaw AT, Sai-Hong I, et al. Clinical Experience With Crizotinib in Patients With Advanced ALK-Rearranged Non Small-Cell Lung Cancer and Brain Metastases. JOURNAL OF CLINICAL ONCOLOGY. Published Ahead of Print on January 26, 2015 as /JCO

48 12% 19% 69%

49 Disease Control Rate (DCR) at week 12 Pts. With Untreated BM* Pts. With treated BM Pts. With No BM Systematic DCR 63% 65% 71% Intracranial DCR 56% 62% NA Systematic ORR** 53% 46% 55% Intracranial ORR 18% 33% NA When systemic DCR at 12 weeks was evaluated in conjunction with intracranial DCR at 12 weeks, a positive and statistically significant relationship was found (P.001) In the pooled group of patients with previously treated or untreated brain metastases, suggesting that patients with systemic DCR at 12 weeks were also likely to experience intracranial DCR at 12 weeks and vice versa. *BM: Brain Metastasis **ORR: Objective Response Rate Daniel B. Costa, Alice T. Shaw, Sai-Hong I. Ou et al. Clinical Experience With Crizotinib in Patients With Advanced ALK-Rearranged Non Small-Cell Lung Cancer and Brain Metastases. Published online ahead of print at on January 26, 2015 DOI: /JCO

50 Intra-cranial Outcome Pts. With Untreated BM Pts. With treated BM Pts. With No BM Intracranial (IC) ORR 18% 33% NA IC mttr, weeks NA IC mdor, weeks 26.4 NR NA IC mttp, months NA mttr: median Time to Tumor Response mdor: median Duration of Response mttp: median Time to Tumor Progression

51 Intracranial target lesions for patients with one intracranial target lesion at baseline with previously untreated Brain Mets

52 Intracranial target lesions for patients with one intracranial target lesion at baseline with previously treated brain Mets

53 Progression during Crizotinib TTT Pts. with untreated brain mets Occurred in 43% of patients (47 of 109) in this group at the time of data cutoff. Of the patients with non-target or new lesions as PD, the CNS was the most common site of progression, occurring in 70% of patients. Pts. with treated brain mets Occurred in 37% of patients (62 of 166) at the time of data cutoff. Of the patients with nontarget or new lesions as PD, the CNS was the most common site of progression, occurring in 72% of patients (39 of 54). Pts. With no brain mets The development of brain metastases (by investigator review of imaging scans) occurred in 20% of patients (51 of 253) with PD at the time of data cutoff. The median time to detection of brain metastases in these 51 patients was 29.9 weeks (range, 2.6 to 79 weeks).

54 Study Conclusion Crizotinib was associated with systemic and intracranial disease control in patients with ALK rearranged NSCLC who were ALK inhibitor naive and had brain metastases. However, progression of preexisting or development of new intracranial lesions while receiving therapy was a common manifestation of acquired resistance to Crizotinib. Daniel B. Costa, Alice T. Shaw, Sai-Hong I. Ou et al. Clinical Experience With Crizotinib in Patients With Advanced ALK-Rearranged Non Small-Cell Lung Cancer and Brain Metastases. Published online ahead of print at on January 26, 2015 DOI: /JCO

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57 ESMO guidelines 2014 First-line: Patients with NSCLC harboring an ALK rearrangement should be considered for crizotinib, a dual ALK and mesenchymal epithelial transition factor (MET) TKI, during the course of their disease [I, A]. Upfront comparisons with chemotherapy are not available to date. Second-line: In the presence of an ALK rearrangement, second-line treatment with crizotinib should be considered, as a large phase III trial comparing crizotinib with docetaxel or pemetrexed (based on investigator s preference) has demonstrated significant ORR and PFS advantages for crizotinib [I, A].

58 Nasr Allahloubi