Treatment of ALK- and ROS-1 translocated NSCLC Massimo Di Maio, MD Department of Oncology, University of Torino massimo.dimaio@unito.it

Treatment of ALK- and ROS-1 translocated NSCLC Massimo Di Maio, MD Department of Oncology, University of Torino massimo.dimaio@unito.it

Rapid success in a short time: ALK drug development timeline Chromosomal translocation is the most common ALK abnormality in cancer EML4-ALK discovered in NSCLC Crizotinib resistance mechanism reported Crizotinib US FDA approved for ALK+ NSCLC Ceritinib US FDA approved for ALK+, crizotinib-resistant NSCLC NPM-ALK discovered in ALCL 1994 2007 2010 2011 2014

Characteristics of ALK translocation in advanced NSCLC Patients: younger, non smokers, with adenocarcinoma (or adenosquamous carcinoma; rarely SCC) Incidence: ~4% in all patients, up to 33% in EGFR-negative never smokers Biology: >15 EML4-ALK variants have been identified in NSCLC. Clinical significance of each variant is unknown. Shaw AT, ASCO; 2010; Kris MG. ASCO 2011; abstract CRA7506. Rodig SJ, Clin Cancer Res; 2009;15 Soda M, et al. Nature; 2007;448

Testing for ALK translocation: a rule for clinical practice All non-squamous tumors in patients with advanced / recurrent NSCLC should be tested for EGFR mutation and ALK rearrangement. Also selected squamous tumours (from patients with minimal or remote smoking history) should strongly be considered for testing. Kerr KM et al. Second ESMO consensus conference on lung cancer: pathology and molecular biomarkers for NSCLC. Ann Oncol 2014 Sep;25(9):1681-90

Activity of crizotinib in patients with ALK+ NSCLC Camidge DR et al. Lancet Oncol. 2012 Oct;13(10):1011-9.

Randomized trial: crizotinib vs chemotherapy as second-line Shaw AT et al. N Engl J Med 2013;368:2385-2394.

Crizotinib vs chemotherapy: impact on QoL Shaw NEJM; June 2013 Shaw AT et al. N Engl J Med.2013 Jun 20;368(25):2385-94. Blackhall F et al. J Thorac Oncol. 2014 Nov;9(11):1625-33.

Solomon BJ et al. N Engl J Med 2014;371:2167-2177. Randomized trial: crizotinib vs chemotherapy as first-line Solomon BJ et al. N Engl J Med 2014;371:2167-2177.

Adverse events with crizotinib Shaw AT et al. N Engl J Med.2013 Jun 20;368(25):2385-94.

Patient-reported impact on activities of daily living of visual disturbances with crizotinib Besse B et al. ESMO 2012 [abstract 1268P] Cappuzzo E et al. Lung Cancer 2015; 87: 89-95

All patients will eventually experience disease progression Sharma SV, Settleman J. Genes Dev. 2007;21:3214-3231 ©2007 by Cold Spring Harbor Laboratory Press

Summary of crizotinib resistance mechanisms in ALK+ NSCLC Shaw A T , and Engelman J A JCO 2013;31:1105-1111

Potential strategies at the time of clinical progression for ALK-translocated NSCLC Switch to chemotherapy Add chemotherapy Continue crizotinib beyond progression Local therapies Different targeted therapy

Potential strategies at the time of clinical progression for ALK-translocated NSCLC Switch to chemotherapy Add chemotherapy Continue crizotinib beyond progression Local therapies Different targeted therapy

Crizotinib superior to standard chemotherapy 1st Line therapy 2nd Line therapy PROFILE 1014: Crizotinib vs. Platinum/Pemetrexed PROFILE 1007: Crizotinib vs. Doc / Pem ORR: Crizotinib 74% vs. Chemo 45% ORR: Crizotinib 65% vs. Chemo 20% …but, of course, this does not mean that patients should never receive chemotherapy Solomon BJ et al, N Engl J Med 2014;371(23):2167-77. Shaw A et al., N Engl J Med 2013; 368(25):2385-94

Potential strategies at the time of clinical progression for ALK-translocated NSCLC Switch to chemotherapy Add chemotherapy Continue crizotinib beyond progression Local therapies Different targeted therapy

The role of adding crizotinib to chemotherapy: SWOG 1300 Eligibility Non-SCC NSCLC patients with ALK+ tumors (FISH) Systemic progression on crizotinib after clinical benefit (either ORR or SD ≥ 3 mo.) Start treatment within 3-30d post-criz Absent/asymptomatic brain metastases pemetrexed-naïve R A N D O M I Z E 1:1 crizotinib 250 mg PO BID daily + pemetrexed 500 mg/m2 IV d1 re-challenge crizotinib 250 PO BID Disease Progression N = 108 BIOPSY Resistance mechanisms and association with benefit Trial PI: Camidge Translational Medicine PI: Doebele Robert Doebele, 2014

Potential strategies at the time of clinical progression for ALK-translocated NSCLC Switch to chemotherapy Add chemotherapy Continue crizotinib beyond progression Local therapies Different targeted therapy

Duration of initial response in patients who continued crizotinib after progression 69/149 patients had PD at the data cut off. 39 continued crizotinib for at least 2 weeks post PD. 12 of them did that for 6 months. Range of post-PD treatment is 21-591 days. Camidge DR et al. Lancet Oncol. 2012 Oct;13(10):1011-9.

Crizotinib beyond progression Although solid evidence supporting the continuation of crizotinib beyond progression is lacking, in some cases (minimal, asymptomatic progression, or oligoprogression manageable by local therapy), treatment continuation beyond progression could be justified. Weickhardt AJ et al, J Thorac Oncol. 2012 December ; 7(12): 1807–1814. Gan GN et al, Int J Radiat Oncol Biol Phys. 2014 March 15; 88(4): 892–898.

Stereotactic Radiotherapy for Extra-CNS Oligoprogressive Disease in ALK+ Lung Cancer Patients on Crizotinib Gan GN et al, Int J Radiat Oncol Biol Phys. 2014 March 15; 88(4): 892–898.

Stereotactic Radiotherapy for Extra-CNS Oligoprogressive Disease in ALK+ Lung Cancer Patients on Crizotinib Gan GN et al, Int J Radiat Oncol Biol Phys. 2014 March 15; 88(4): 892–898.

In the absence of randomized trials… Feasibility ? Efficacy Selection bias

Potential strategies at the time of clinical progression for oncogene addicted NSCLC Switch to chemotherapy Add chemotherapy Continue EGFR or ALK TKIs beyond progression Local therapies Different targeted therapy

ALK Inhibitors in clinical development Awad MM, Shaw AT. Clin Adv Hematol Oncol. 2014 Jul;12(7):429-39.

Response to ceritinib in ALK-translocated advanced NSCLC Shaw AT et al. N Engl J Med. 2014 Mar 27;370(13):1189-97.

Ceritinib activity in a crizotinib-resistant patient Shaw AT et al. N Engl J Med. 2014 Mar 27;370(13):1189-97.

Progression-free survival for ALK+ NSCLC treated with ceritinib 750 mg/day Felip E, et al. ECCO/ESMO Madrid 27 September, 2014

Future scenario: Ceritinib as first-line option? Di Maio M et al. Int J Oncol 2014 Aug;45(2):509-15.

Responses to second generation inhibitors in crizotinib-resistant tumors Ceritinib (LDK378); phase I 56% ORR1 CNS penetration Alectinib (CH5424802); phase I/II 55% ORR2 AP26113; phase I/II 76% ORR3 1Shaw AT et al. N Engl J Med 2014 Mar 27;370(13):1189-97. 2Gadgeel SM et al, Lancet Oncol 2014 Sep;15(10):1119-28. 3Camidge R. WCLC 2013. MO0706

Gadgeel SM et al. Lancet Oncology 2014; 15(10):1119-1128 Activity of alectinib against systemic disease and brain metastases in patients with crizotinib-resistant ALK-rearranged NSCLC Gadgeel SM et al. Lancet Oncology 2014; 15(10):1119-1128

Alectinib in CNS relapses of ALK+ patients previously treated with crizotinib and ceritinib Gainor JF, et al. J Thorac Oncol. 2015 Feb;10(2):232-6.

In the next future : Head to head comparison The ALEX study Alectinib 600mg BID (n≈143) Eligible patients: Advanced or metastatic ALK+ NSCLC Treatment naïve ECOG PS 0–2 N≈286 Until PD*, toxicity, withdrawal or death Subsequent therapy and survival follow up R 1:1 Crizotinib 250mg BID (n≈143) *RECIST v1.1 Primary endpoint: PFS Recruitment Status Recruiting Estimated Enrollment  286 Study start date August 2014 Estimated Completion Date December 2017 Estimated Primary Completion Date December 2017 ClinicalTrials.gov Identifier NCT02075840 (accessed February 7, 2015)

ALK+ Treatment Algorithm* Crizotinib Oligoprogressive disease? Study available? No Y Y N Yes Alectinib or AP26113 S1300 ceritinib Local ablative therapy Y Oligoprogression? N Study available? Continue current therapy Y Y N HSP90 Immunotherapy Chemo *Subject to change (rapidly) Robert Doebele, 2014

Treatment of ALK- and ROS-1 translocated NSCLC

ROS1 ROS1 is activated by chromosomal rearrangement in several human cancers, including NSCLC, cholangio-carcinoma, gastric cancer, ovarian cancer, and glioblastoma multiforme.1-5 Rearrangement leads to fusion of a ROS1 portion (including the tyrosine kinase domain) with 1 of 12 different partner proteins.6 ROS1 rearrangements occur in approximately 1% of NSCLC patients.7 Similarly to ALK, ROS1 rearrangements are more common in patients who have never smoked or have a history of light smoking and in adenocarcinoma.7,8 Charest A. Genes Chromosomes Cancer 2003;37:58-71. Rikova K. Cell 2007;131:1190-203. Gu TL. PLoS One 2011;6(1):e15640. Lee J. Cancer 2013;119:1627-35. Birch AH. PLoS One 2011;6(12): e28250. Davies KD. Clin Cancer Res 2013;19:4040-5. Gainor JF. Oncologist 2013;18:865-75. Bergethon K. J Clin Oncol 2012;30:863-70.

ALK and ROS1 Encode Related Receptor Tyrosine Kinases Ron ROS1 ALK LTK PTK7 Brock TG, Receptors and Tyrosine Kinases http://www.caymanchem.com/app/template/Article.vm/article/2187

Response of ROS1 Positive Patients to Crizotinib Baseline 12 weeks Bergeron, JCO, 30, 2012.

Female 56%, never smokers 78%, adenocarcinoma 98% 50 patients Median age 53 (range 25-77) Female 56%, never smokers 78%, adenocarcinoma 98% Shaw AT et al, N Engl J Med 2014;371:1963-71.

Tumor responses to crizotinib in ROS1-rearranged NSCLC Overall response rate 72% (6% CR, 66% PR). Median time to response 7.9 weeks (range, 4.3 - 32.0) Shaw AT et al, N Engl J Med 2014;371:1963-71.

Tumor responses to crizotinib in ROS1-rearranged NSCLC Median duration of response: 17.6 months (95%CI 14.5 – not reached) Median progression-free survival: 19.2 months (95%CI 14.4 – not reached) Shaw AT et al, N Engl J Med 2014;371:1963-71.

[…] The study by Shaw et al. proves that it is possible to conduct trials in small subgroups of patients with NSCLC and demonstrate big results.

Crizotinib in ROS1-rearranged NSCLC: European retrospective study 32 patients, mostly pre-treated Overall response rate: 80% Disease control rate: 86.7%. Median PFS: 9.1 months. Mazieres J et al. J Clin Oncol 2015 Feb 9. [Epub ahead of print]

Conclusions In the majority of patients with ALK and ROS1 rearrangements, durable clinical responses can be obtained with recently developed targeted agents. The availability of these drugs highlights the importance of screening for these genetic alterations in patients with advanced NSCLC. Improvement in the management of resistance remains the major challenge in the treatment of these patients.

Thanks for your attention! Massimo Di Maio Department of Oncology, University of Torino massimo.dimaio@unito.it