The evolving treatment of NSCLC

Transcription

1 The evolving treatment of NSCLC Maya Gottfried Head of Oncology Institute Meir Medical Center Dr.Natalie.M.R.

2 Lung cancer: most common malignancy and leading cause of cancer-related mortality GLOBOCAN 2012 (worldwide, both sexes) million 1 estimated new cases worldwide 1.59 million 1 (1 in 5) estimated deaths worldwide More people die from lung cancer than breast, colorectal and prostate cancers combined 1 Within Europe, ~1,000 people die from lung cancer every day 1,2 1. Ferlay J, et al. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11[Internet]. Lyon, France: International Agency for Research on Cancer; Available from: Accessed March 2014; 2. Ferlay J, et al. Eur J Cancer. 2013;49: Dr.Natalie.M.R. I

3 Lung cancer in 2000: an easy-to-treat disease Tumor biology irrelevant Tumor histology irrelevant Amount of tissue not an issue Cytology enough for any decision Any NSCLC Early stages: Surgery +/- Radiotherapy Metastatic disease: Platinum-based chemotherapy Limited role for pathologist Limited role for chest physician No role for molecular biology Lung cancer team: medical oncologist-surgeon-radiation oncologist Dr.Natalie.M.R. Istituto Toscano Tumori Livorno, Italy

4 NSCLC, the Most Common Type of Lung Cancer, Is Genomically Diverse Types of Lung Cancer Types of NSCLC Driver Mutations in Adenocarcinoma Other 11% SCLC 15% NSCLC 85% Squamous 34% Adenocarcinoma 55% Driver Mutations in Squamous Cell Carcinoma Li et al. J Clin Oncol. 2013;31:1039. Dr.Natalie.M.R.

5 Incidence of Mutations in Lung Cancer Mutation found in 54% (280/516) of tumors completely tested (95% CI 50-59%) Dr.Natalie.M.R. Kris MG, J Clin Oncol 2011; 29: Abstr CRA 7506

6 Lung cancer in 2014: a hard-to-treat disease Tumor histology relevant Tumor biology high relevant Tissue is an issue Cytology not enough Relevant role for Pathologist Relevant role for Chest Physician Relevant role for Molecular Biologist Lung cancer team: medical oncologist-surgeon-radiation oncologistchest physician-molecular biologist-radiologist Dr.Natalie.M.R. Istituto Toscano Tumori Livorno, Italy

7 Dr.Natalie.M.R.

8 Case 1 55 year old female non-smoker Presented with progressive increase in shortness of breath ECOG-1 PET-CT showed a mass 6 cm in the LUL and bilateral lung lesions, enlarge lymph nodes in the mediastinum Biopsy from Lt Lung- Adenocarcinoma Dr.Natalie.M.R.

9 Dr.Natalie.M.R. Bx from left Lung lesion confirmed- EGFR exon 19 mutation

10 EGFR Mutations Overall incidence in population ~10% in Western countries ~30% in Asian countries

11 Molecular alterations in lung cancer Europe All histology US Adenocarcinoma East Asia Adenocarcinoma, never smokers (n=9,911) (n=733) (n=52) Johnson, et al. ASCO 2013 Sun, et al. J Clin Oncol 2010; Barlesi, et al. ASCO 2013 Dr.Natalie.M.R.

12 Studies of EGFR TKIs versus chemotherapy as first-line therapy in EGFR Act Mut+ NSCLC Study EGFR TKI n Median PFS in TKI arm (months) P value HR OPTIMAL Erlotinib < First Signal Gefitinib IPASS Gefitinib < WJTOG 3405 Gefitinib < NEJSG 002 Gefitinib < EURTAC Erlotinib < LUX-3 Afatinib < LUX-6 Afatinib <

13 Most Frequent AEs Related to Afatinib LUX-Lung 3 1,2 Afatinib (n=229), % LUX-Lung 6 3 Afatinib (n=239), % All Grade 3 Grade 4 All Grade 3 Grade 4 Diarrhoea Rash/acne a Stomatitis/mucositis a Paronychia ALT increase AST increase Epistaxis Pruritus Decreased appetite Fatigue a Ocular a Dry skin Cheilitis a Grouped term for closely related AEs. AST = aspartate. 1. Sequist et al. J Clin Oncol. 2013;31: Data on file. Boehringer Ingelheim. 3. Wu et al. ASCO Abstract Dr.Natalie.M.R.

14 Dr.Natalie.M.R.

15 Mechanism of Acquired Resistance to EGFR TKIs Unknown mechanism (30%) With EGFR amp HER2 amplification (12%)+ BRAF mutation (1%)+ T790M (49%) PIK3CA (5%) SCLC transformation Met (14%) amp (5%) Sequist LV, et al. Sci Trans Med. 2011;3:75ra26. Oxnard GR, et al. Clin Cancer Res. 2011;17: Ohashi K, et al. Proc Nat Acad Sci USA. 2012;109:E2127-E2133. Takezawa K, et al. Cancer Discov. 2012;2: Dr.Natalie.M.R.

16 A Phase I study of AZD9291 in patients with EGFR-TKI-resistant advanced NSCLC updated progression-free survival and duration of response data Pasi A. Jänne 1, Myung-Ju Ahn 2, Dong-Wan Kim 3, Sang-We Kim 4, David Planchard 5, Suresh S. Ramalingam 6, Paul Frewer 7, Mireille Cantarini 7, Serban Ghiorghiu 7, James Chih-Hsin Yang 8 1 Dana-Farber Cancer Institute, Boston, MA, USA; 2 Samsung Medical Center, Seoul, Republic of Korea; 3 Seoul National University Hospital, Seoul, Republic of Korea; 4 Asan Medical Center, Seoul, Republic of Korea; 5 Gustave Roussy, Villejuif, France; 6 Emory University, Winship Cancer Institute, Atlanta, GA, USA; 7 AstraZeneca, Alderley Park, Macclesfield, UK; 8 National Taiwan University Hospital, Taipei, Taiwan Presented by Pasi A Jänne at the 2015 European Lung Cancer Conference. Ann Oncol 2015; 26(Suppl1): i60, LBA April 2015, Geneva, Switzerland Organisers Partners

17 Response rate in T790M positive cohorts (central test) D D* D* D D D D D D D D D D D 20 mg 40 mg 80 mg 160 mg 240 mg D D D D D D Best percentage change from baseline in target lesion D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D DCR (CR+PR+SD) in patients with centrally tested T790M positive tumours was 90% (141 / 157; 95% CI 84, 94) 20 mg 40 mg 80 mg 160 mg 240 mg Total N (157) ORR (95% CI) 50% (19, 81) 59% (41, 76) 66% (52, 77) 51% (35, 67) 54% (25, 81) 59% (51, 66) *Imputed values for patients who died within 14 weeks (98 days) of start of treatment and had no evaluable target lesion assessments Nine patients (seven in the 160 mg cohort) currently have a best overall response of not evaluable, as they have not yet had a 6-week follow-up RECIST assessment Patients are evaluable for response if they were dosed and had a baseline RECIST assessment. Data cut-off 2 Dec 2014 CI, confidence interval; CR, complete response; D, discontinued; DCR, disease control rate; PR, partial response; RECIST, Response Evaluation Criteria In Solid Tumors; SD, stable disease Presented by Pasi A Jänne at the 2015 European Lung Cancer Conference. Ann Oncol 2015; 26(Suppl1): i60, LBA3.

18 Probability of progression-free survival Probability of progression-free survival T790M positive (central test) 80 mg cohort progression-free survival Investigator assessed Independent review # Month Number of patients at risk: Median progression-free survival, 10.9 months (95% CI 8.3, not calculable; 40% maturity, 25/63 events) Month Number of patients at risk: Median progression-free survival, 13.5 months (95% CI 8.3, not calculable; 38% maturity, 24/63 events) Dots indicate censored observations, shaded area represents 95% CIs. Progression based on RECIST 1.1; progression events that do not occur within 14 weeks of the last evaluable assessment (or first dose) are censored Population: 80 mg centrally confirmed T790M positive patients (n=63) # One patient did not have measurable disease; one patient s scan was not sent for independent review Data cut-off 2 Dec 2014 Presented by Pasi A Jänne at the 2015 European Lung Cancer Conference. Ann Oncol 2015; 26(Suppl1): i60, LBA3.

19 CO1686

20 Case 2 Male 53 years old Never smoker Pleural effusion cytology: NSCLC, adenocarcinoma poorly diffrentiated Molecular report: EGFR wild-type ALK positive

21 Clinical characteristics associated with ALK-positive NSCLC Higher prevalence of the EML4-ALK fusion is suggested in patients who have the following characteristics 1-3 Adenocarcinoma histology Never/light smoking history Younger age compared to ALK-negative NSCLC Example: Lung Cancer Mutation Consortium Analysis of Adenocarcinomas 3 N=643 ALK-positive ALK-negative p Mean age 52.3 yr 59.9 yr < Smoking history Current Former 3% 33% 8% 61% Never 64% 31% 1. Rodig et al., Clin Cancer Res. 2009; 15: Shaw et al., J Clin Oncol. 2009; 27: Varella Garcia et al., IASLC 2011; Abs #O05.01

22 PROFILE 1014: first-line study Eligibility criteria: ALK-positive locally advanced/metastatic non-squamous NSCLC No prior treatment for advanced disease Primary endpoint PFS* R A N D O M I S E Crizotinib 250mg b.i.d. continuous dosing schedule (n=167) Crossover on PD Pemetrexed/cisplatin OR pemetrexed/carboplatin d1, q3w (n=167) Secondary endpoints OS, ORR*, DR, safety, QoL, lung cancer-specific symptoms *Based on RECIST v 1.1 and confirmed by independent radiology review NCT

23 PROFILE 1014: Crizotinib versus chemotherapy as 1L in advanced ALK-positive NSCLC Mok, ASCO 2014

24 Crizotinib: acquired resistance and brain metastases Acquired resistance 1 2 Kinase domain?? Target gene alteration (29%) * 30% Secondary resistance mutations EGFR L747S D761Y T790M T854A 1151Tins S1206Y L1152R C1156Y L1196M G1202R G1269A * Bypass track activation (45% ALK amplification ALK mutation EGFR activation CKIT amplification ALK Secondary resistance mutations Unknown 5 fusion partner Kinase domain Brain metastases 3 5 CNS was the first site of progression in 46% of ALK+ crizotinib treated patients 1. Shaw & Engelman. J Clin Oncol 2013; 2. Gainor & Shaw. J Clin Oncol Chun, et al. Cancer Biol Ther 2012; 4. Weickhardt, et al. ASCO 2012; 5. Otterson, et al. ASCO 2012

25 Ceritinib in advanced ALK-rearranged NSCLC: Results of the ASCEND-1 trial Key results 246patients had ALK-rearranged NSCLC, with a median follow-up of 7.0 months; of these, 43% had received at least 3 prior treatment regimens Overall response rate : 58.5%all patients ; 54.6% ALK inhibitor pretreated 66.3% ALK inhibitor naïve PFS at 12 months : 39.1%all patients 28.4% ALK inhibitor pretreated 61.3% ALK inhibitor naïve Kim, ASCO 2014 (abs 8003)

26 Duration of Response in ALK+ NSCLC Patients with Confirmed CR or PR NSCLC ALK inhibitor with prior treated ALKi (N=89) NSCLC ALK inhibitor ALKi naïve (N=55) All NSCLC (N=144) () Median: non-estimable (95% CI 9.59, non-estimable) DOR rate at 12 months: 65.2% Median: 9.69 months (95% CI 7.00, 11.40) DOR rate at 12 months: 33.0% Median: 7.39 months (95% CI 5.42, 10.12) DOR rate at 12 months: 17.9%. Kim DW et al. Oral presentation ASCO 2014

27 Marked responses to Ceritinib Baseline After 6 weeks

28 Alectinib and ceritinib: first-line phase III studies Alectinib Eligibility criteria: ALK-positive locally advanced/metastatic non-squamous NSCLC No prior treatment for advanced disease Primary endpoint PFS* R A N D O M I S E Ceritinib Alectinib 600mg b.i.d (n=143) Crizotinib 250mg (n=143) Eligibility criteria: ALK-positive locally advanced/metastatic non-squamous NSCLC No prior treatment for advanced disease Primary endpoint PFS R A N D O M I S E *Determined by investigators, based on RECIST v1.1 Ceritinib 750mg (n=174) Pemetrexed/cisplatin OR pemetrexed/carboplatin q3w (n=174) Pemetrexed q3w 1. NCT NCT

29 Immuno-Oncology Immunotherapy represents a new hope for NSCLC patients, Cancer patient In any trial you get the odd patient who does very well, but this is an order of magnitude above that., Mick Peake, Glenfield Hospital The high level of excitement around this space is that immune checkpoint inhibitors may apply to a very broad range of cancer types, as both monotherapies and combination therapies. The data we are seeing so far, including recently released at ASCO, also indicates the mechanism works in patients who have failed previous cancer therapies., Stephen Dunn, LifeTech Capital We look forward to the potential for the combination of checkpoint inhibitors, like nivolumab, with small molecule inhibitors in patients with EGFR mutated lung cancer, Naiyer Rizvi, Memorial Sloan Kettering Cancer Center The PD-1 antibodies stop lung cancer cells from blocking the body's natural immune response to cancer. A drug that can inhibit PD-1 may be able to treat a variety of cancers, which is very exciting, Myron Bednar, Hunterdon Regional Cancer Center The field of immunotherapy has exploded in the last decade, and more and more patients are benefiting, Steven O'Day, USC

30

31

32

33 PD-1 Receptor Blocking Ab IFNγ IFNγR MHC T-cell receptor T-cell receptor MHC Tumor cell PD-L1 PD-L2 PD-1 Shp-2 PI3K NFκB Other T cell Shp-2 CD28 PD-1 B7 PD-L1 Dendritic cell PD-1 PD-1 PD-L2 Role of PD-1 Pathway in Suppressing Anti-tumor Immunity

34

35

36 Docetaxel RECIST v1.1 Responders Nivolumab Response Characteristics of Confirmed Responders 63% (17/27) of patients had ongoing response Time to first response On treatment (nivolumab) On treatment (docetaxel) Off treatment Ongoing response 33% (4/12) of patients had ongoing response Time (Weeks)

37

38

39

40

41

42

43

44 Common immune-related adverse events experienced with I-O therapies Pneumonitis (anti-pd-1) Rash (anti-ctla-4) 1 Reticular erythematous rash Perivascular lymphocyte infiltrate extending into epidermis Colonoscopy Gastrointestinal adverse events (anti-ctla-4) 2 Histopathology Bowel oedema and ulceration in the descending colon Focal active colitis (left) with crypt destruction, loss of goblet cells, and neutrophilic infiltrates in the crypt epithelium (right) Dr.Natalie.M.R.. 1Hodi F, et al. Proc Natl Acad Sci USA. 2003;100: ; 2. Maker A, et al. Ann Surg Oncol. 2005;12:

45

46 Immune-checkpoint inhibitors: clinical questions to answer Which is the optimal dose and treatment sequence? Which is the best predictive marker for response: PDL1, smoking history, mutations? Which is the optimal cut-off for PDL1 positivity and the best IHQ mab? Which is the best surrogate of efficacy (RECIST vs irrc)? Is there activity in CNS? How to convert T-Cell poor tumours into T-Cell inflamed tumours (chemo, targeted therapies, vaccines)? Is there a role of immune-checkpoint inhibitors in molecular driven tumours? Dr.Natalie.M.R.

47

48 Median Survival months IMPROVEMENT IN SURVIVAL IN ADVANCED NSCLC EGFR +ve directed TKI therapy Single agent platinum 8-10 Platinum-based doublets 12+ Histology directed therapy Platinum- triplet therapy One Bite BSC s 1980 s Non-small cell Lung Cancer Collaborative Group. BMJ 1995;311: , Schiller JH, et al. N. Engl J Med. 2002;346:92-98, Sandler A, et al N Engl J Med. 2006;355: ; Scagliotti G et al Oncologist 2009; 14: ; Fukuoka et al J Clin Oncol 2011; Dr.Natalie.M.R. Shaw et al NEJM 2013;

49 So is cancer mostly 'bad luck' or not? Dr.Natalie.M.R. Thank You!