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Role of Chemotherapy, Targeted therapy and Immunotherapy in NSCLC (Part II)

1) The document discusses targeted therapies for non-small cell lung cancer (NSCLC) with ALK translocations, including crizotinib, alectinib, brigatinib, ceritinib, and lorlatinib. 2) Alectinib is now considered the preferred first-line treatment for ALK-positive NSCLC based on Phase III trials showing it is more effective than crizotinib. 3) For patients who progress on a first-generation ALK inhibitor like crizotinib, later-generation ALK inhibitors such as ceritinib, brigatinib, and lorlatinib have demonstrated efficacy in clinical trials as subsequent therapies.

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Role of Chemotherapy, Targeted therapy and Immunotherapy in treatment of Non-Small Cell Lung cancer (NSCLC) (Part II) Mohammed Fathy Bayomy, MSc, MD Lecturer Clinical Oncology & Nuclear Medicine Faculty of Medicine Zagazig University
Treatment of ALK Translocation–Positive NSCLC
ALK Rearrangement: Context  Found in ~ 5% of NSCLC patients[1]  Occurs more frequently in younger patients, light or never-smokers, males, and those with the adenocarcinoma subtype[1,2]  Predominantly a fusion of ALK with partner oncogenes, particularly EML4[3]  Occurs in similar subgroups as patients with EGFR mutations, but EGFR mutations and ALK rearrangements are predominantly mutually exclusive[1-4] 1. American Cancer Society. Targeted therapy drugs for non-small cell lung cancer. 2. Shaw. J Clin Oncol. 2009;27:4247. 3. Hofman. Cancers (Basel). 2017;9:107. 4. Soda. Nature. 2007;448:561.
Alectinib: PD on or intolerant to crizotinib ALTA-1L: 1st-line brigatinib better than crizotinib J-ALEX: 1st-line alectinib better than crizotinib ASCEND-4: 1st-line ceritinib better than CT ALK rearrangements identified in NSCLC Evolution of Care: ALK Translocation–Positive Advanced NSCLC PROFILE 1001: crizotinib efficacy demonstrated 2007 2010 2011 2014 2015 2018 Herbst. Nature. 2018;553:446. Gandhi. Clin Cancer Res. 2012;18:3737. Kwak. NEJM. 2010;363:1693. Solomon. NEJM. 2014;371:2167. Soria. Lancet. 2017;389:917. Peters. NEJM. 2017;377:829. Camidge. NEJM. 2018;379:2027. Solomon. Lancet Oncol. 2018;19:1654. Hida. Lancet. 2017;390.29. Drug Approvals/ Other Landmarks Select Trials Ceritinib 1st line ALEX: 1st-line alectinib better than crizotinib 2017 PROFILE 1014: 1st-line crizotinib better than CT 2016 Crizotinib 1st-line Alectinib 1st line Brigatinib: PD on or intolerant to crizotinib Ceritinib: PD on or intolerant to crizotinib Phase II: later-line lorlatinib efficacy demonstrated ALK inhibitors enter clinical development 2005 Lorlatinib: 2nd or 3rd line
First-line Treatment With ALK Inhibitors in ALK- Rearranged NSCLC: Phase III Trials  Alectinib, crizotinib, and ceritinib are FDA approved for newly diagnosed ALK+, metastatic NSCLC[6-8] 1. Solomon. NEJM. 2014;371:2167. 2. Soria. Lancet. 2017;389: 917. 3. Hida. Lancet. 2017;390:29. 4. Peters. NEJM. 2017;377:829. 5. Camidge. NEJM. 2018;[Epub]. 6. Crizotinib PI. 7. Ceritinib PI. 7. Alectinib PI. Agent/Study N Study Design ORR, % Median PFS, Mos Crizotinib  PROFILE 1014[1] 343 Crizotinib vs pemetrexed + cis or carbo 74 vs 45 10.9 vs 7.0 Ceritinib  ASCEND-4[2] 376 Ceritinib vs pemetrexed + cis or carbo 72.5 vs 26.7 16.6 vs 8.1 Alectinib  J-ALEX[3]  ALEX[4] 207 303 Alectinib vs crizotinib Alectinib vs crizotinib 92 vs 79 82.9 vs 75.5 NR vs 10.2 NR vs 11.1 Brigatinib  ALTA-1L[5] 275 Brigatinib vs crizotinib 71 vs 60 NR vs 9.8
First-line ALK Translocation–Positive NSCLC  Alectinib is preferred treatment in this setting ‒ Effective in patients with CNS metastases and leptomeningeal disease  Biomarker testing for all patients with newly diagnosed nonsquamous NSCLC is essential
Alectinib: PD on or intolerant to crizotinib ALTA-1L: 1st-line brigatinib better than crizotinib J-ALEX: 1st-line alectinib better than crizotinib ASCEND-4: 1st-line ceritinib better than CT ALK rearrangements identified in NSCLC Evolution of Care: ALK Translocation–Positive Advanced NSCLC PROFILE 1001: crizotinib efficacy demonstrated 2007 2010 2011 2014 2015 2018 Herbst. Nature. 2018;553:446. Gandhi. Clin Cancer Res. 2012;18:3737. Kwak. NEJM. 2010;363:1693. Solomon. NEJM. 2014;371:2167. Soria. Lancet. 2017;389:917. Peters. NEJM. 2017;377:829. Camidge. NEJM. 2018;379:2027. Solomon. Lancet Oncol. 2018;19:1654. Hida. Lancet. 2017;390.29. Drug Approvals/ Other Landmarks Select Trials Ceritinib 1st line ALEX: 1st-line alectinib better than crizotinib 2017 PROFILE 1014: 1st-line crizotinib better than CT 2016 Crizotinib 1st-line Alectinib 1st line Brigatinib: PD on or intolerant to crizotinib Ceritinib: PD on or intolerant to crizotinib Phase II: later-line lorlatinib efficacy demonstrated ALK inhibitors enter clinical development 2005 Lorlatinib: 2nd or 3rd line
ALK Inhibitors for Progressive Disease After Previous ALK Inhibitors 1. Kim. Lancet Oncol. 2016;17:452. 2. Crinò. J Clin Oncol. 2016;34:2866. 3. Shaw. Lancet Oncol. 2016;17:234. 4. Ou. J Clin Oncol. 2016;34:661. 5. Kim. J Clin Oncol. 2017;35:2490. 6. Lin. J Thorac Oncol. 2018;[Epub]. 7. Shaw. Lancet Oncol. 2017;18:1590. 8. Horn. Clin Cancer Res. 2018;24:2771. 9. Alectinib PI. 10. Ceritinib PI. 11. Brigatinib PI. 12. Lorlatinib PI. N Phase Prior ALK TKI ORR, % Median PFS, Mos Ceritinib  ASCEND-1[1]  ASCEND-2[2] 163 140 I II Crizotinib Crizotinib 56 38.6 6.9 5.7 Alectinib  Shaw[3]  Ou[4] 87 138 II II Crizotinib Crizotinib 48 50 8.1 8.9 Brigatinib  ALTA[5]  Lin[6] 222 22 II Retrospective Crizotinib Alectinib 45 (90 mg QD) 54 (180 mg QD) 17 9.2 (90 mg QD) 12.9 (180 mg QD) 4.4 Lorlatinib[7] 54 I/II 1 (n = 14) 2-3 (n = 26) 57 42 13.5 9.2 Ensartinib[8] 31 I/II Crizotinib 69 9.0  FDA approvals in this setting: alectinib, ceritinib, and brigatinib for progression on/intolerance to crizotinib; lorlatinib for progression on crizotinib and ≥ 1 other ALK TKI or first-line alectinib or ceritinib[9-12]
Crizotinib in ALK-Positive NSCLC: Efficacy 1. Camidge DR, et al. Lancet Oncol. 2012;10:1011-1019. 2. Kim DW, et al. ASCO 2012. Abstract 7533. 3. Shaw AT, et al. N Engl J Med. 2013;368:2385-2394 *At Wk 8. †Range. Outcome PROFILE 1001[1] (N = 143) PROFILE 1005[2] (N = 259) PROFILE 1007[3] (N = 173) Best overall response, n (%) CR 3 (2) 4 (2) 1 (1) PR 84 (59) 151 (58) 112 (65) SD 31 (22)* 69 (27) 32 (18) PD NR 19 (7) 11 (6) Objective response rate, % (95% CI) 60.8 (52.3-68.9) 59.8 (53.6-65.9) 65 (58-72) Median duration of response, wks (95% CI) 49.1 (39.3-75.4) 45.6 (35.3-53.6) 32.1 (2.1-72.4)† Median duration of treatment, wks (range) 43.1 (0.1-138.6) N/A 15.9 (2.9-73.4) Median PFS, mos (95% CI) 9.7 (7.7-12.8) 8.1 (6.8-9.7) 7.7 (6.0-8.8)
PROFILE 1001: Study Design  Open-label, multicenter phase I trial  Tumor response assessed by RECIST v1.0, imaging at baseline and every 8 wks  Adverse events assessed by CTCAE v3.0 Advanced NSCLC with MET exon 14 alteration, no prior MET-directed targeted therapy (N = 21) Crizotinib 250 mg BID Drilon AE, et al. ASCO 2016. Abstract 108. 18 pts evaluable for response in current analysis
PROFILE 1001: Efficacy  Median duration of treatment: 5.3 mos (range: 0.2-12.2)  Median duration of follow-up: 5.7 mos (range: 0.2-12.2) ‒ Tumor shrinkage in 14/16 pts with measurable disease at BL ‒ Response typically seen within first 2 mos of treatment Drilon AE, et al. ASCO 2016. Abstract 108. *Pt discontinued therapy in cycle 1; response imaging could not be performed but response-evaluable per protocol. Response Response-Evaluable Pts (n = 18) ORR, % (95% CI) 44 (22-69) Best overall response, %  CR  PR  SD • Unconfirmed CR/PR  PD  Indeterminate* 0 44 50 28 0 6 Median PFS, mos NE
Tumor Responses to Crizotinib for Patients With ALK-Positive NSCLC Camidge DR. Lancet Oncol. 2012;1011-1019. Crizotinib in ALK-Positive NSCLC (N = 143)100 80 60 40 20 0 -20 -40 -60 -80 -100 ChangeFromBaseline(%) PD SD PR CR
ALK Inhibitor Alectinib in Pts With ALK-Positive NSCLC  2-yr update of phase II study of ALK inhibitor alectinib in crizotinib-naive pts with ALK-rearranged NSCLC Tamura T, et al. Chicago Multidisciplinary Symposium in Thoracic Oncology 2014. Abstract 10.  ALK inhibitor–naive Japanese patients 20 yrs of age or older with ≥ 1 prior lines of chemotherapy  ALK+ stage IIIB/IV or relapsed NSCLC  ECOG performance status 0/1 (n = 46) Alectinib 300 mg PO BID Continued until no further clinical benefit, as assessed by investigator Primary endpoint: objective response rate by IRC Secondary endpoints: PFS by IRC, OS, safety
Alectinib in Pts With ALK-Positive NSCLC: Results  ORR: 93.5% (95% CI: 82.1-98.6); CR: 19.6%; PR: 73.9%; SD: 2.2% Tamura T, et al. Chicago Multidisciplinary Symposium in Thoracic Oncology 2014. Abstract 10. 1.0 0.8 0.6 0.4 0.2 0 0 5 10 15 20 25 30 35 Mos PFS Median PFS: 27.7 mos (95% CI: 26.9-NR) 1.0 0.8 0.6 0.4 0.2 0 0 5 10 15 20 25 30 35 Mos OS 2-yr OS rate: 79% (95% CI: 63-89)
Alectinib in Pts With ALK-Positive NSCLC: Adverse Events in ≥ 20% of Pts  No treatment-related grade 4/5 adverse events Tamura T, et al. Chicago Multidisciplinary Symposium in Thoracic Oncology 2014. Abstract 10. Adverse Event, n (%) All Grades Grade 3 Increased blood bilirubin 21 (36.2) 2 (3.4) Dysgeusia 20 (34.5) 0 Increased AST 19 (32.8) 0 Increased blood creatinine 18 (31.0) 0 Constipation 17 (29.3) 0 Rash 17 (29.3) 0 Neutropenia 15 (25.9) 4 (6.9) Increased ALT 15 (25.9) 2 (3.4) Increased blood creatine phosphokinase 12 (20.7) 2 (3.4) Leukopenia 12 (20.7) 1 (1.7)
Alectinib in Pts With ALK-Positive NSCLC: Conclusions  Alectinib effective and safe in progressive ALK inhibitor–naive ALK+ NSCLC – ORR: 93.5% – Median PFS: 27.7 mos (95% CI: 26.9-NR) – PFS unaffected by baseline brain metastases – No treatment-related grade 4/5 AEs; 3.4% had grade 3 AST/ALT elevation – 31/46 patients progression free and remain on treatment  Alectinib may offer a new therapeutic option for ALK+ NSCLC pts – Ongoing phase III J-ALEX study aims to confirm phase II results – Other phase II and III studies are evaluating alectinib in a wider population Tamura T, et al. Chicago Multidisciplinary Symposium in Thoracic Oncology 2014. Abstract 10.
J-ALEX: Study Design Alectinib 300 mg BID PO 28-day cycle (n = 103) Crizotinib 250 mg BID PO 28-day cycle (n = 104) Stage IIIB/IV or recurrent ALK+ NSCLC (by IHC/FISH or RT-PCR), ECOG PS ≤ 2, ≥ 1 measurable lesion (investigator assessed), ≤ 1 previous chemotherapy, treated/asymptomatic brain metastasis permitted (N = 207) Stratified by clinical stage (IIIB/IV vs recurrent), previous chemotherapy, ECOG PS (≤ 1 vs 2) 1:1 Nokihara H, et al. ASCO 2016. Abstract 9008. 3 preplanned interim analyses for efficacy: 33%, 50%, 75% of final events (current report: second interim analysis)  Primary endpoint: PFS by independent review facility.  Secondary endpoint: OS, ORR, PK, QoL, CNS PFS, safety.
J-ALEX: Response Rate Nokihara H, et al. ASCO 2016. Abstract 9008. Reproduced with permission. ORR* assessed by IRF ORR assessed by investigator in ITT population *In pts with measurable lesion assessed by IRF at baseline. 0 -20 -40 -60 -80 -100 0 -20 -40 -60 -80 -100 Water fall plot* assessed by IRF %ChangeFromBaseline%ChangeFromBaseline 0 -20 -40 -60 -80 -100 0 -20 -40 -60 -80 -100 Crizotinib (n = 90) Alectinib (n = 83) Water fall plot* assessed by IRF %ChangeFromBaseline%ChangeFromBaseline CR or PR SD, PD, or NE ORR* assessed by IRF ORR assessed by investigator in ITT population *In pts with measurable lesion assessed by IRF at baseline. Alectinib (n = 103) Crizotinib (n = 104) ORR (95% CI) 85.4% (78.6-92.3) 70.2% (61.4-79.0) CR or PR 88 73 Alectinib (n = 83) Crizotinib (n = 90) ORR (95% CI) 91.6 (85.6-97.5) 78.9% (70.5-87.3) CR or PR 76 71
J-ALEX: PFS  Alectinib showed consistent favorable treatment effect vs crizotinib for multiple prognostic factors – Brain metastases: HR: 0.08 (95% CI: 0.01-0.61) Nokihara H, et al. ASCO 2016. Abstract 9008. Reproduced with permission. 6 60 100 80 40 20 0 272421181512930 1 Mos 76 65 19 4 27 14 36 21 49 40 93 86 103 104 103 102 10.2 mos PFS(%) Pts at Risk, n Alectinib Crizotinib Events, n (%) Median, mos (95% CI) P value HR (99.6826% CI) 25 (24.3%) NR (20.3-NR) 58 (55.8%) 10.2 (8.2-12.0) < .0001 0.34 (0.17-0.71) Alectinib (n = 103) Crizotinib (n = 104) NR
J-ALEX: Safety  8.7% alectinib discontinuations due to AE vs 20.2% for crizotinib  29.1% alectinib dose interruptions due to AE vs 74.0% for crizotinib Nokihara H, et al. ASCO 2016. Abstract 9008. AEs (≥ 20%, Either Arm) Alectinib (n = 103) Crizotinib (n = 104) All Grade Grade 3/4 All Grade Grade 3/4 Constipation 36 (35) 1 (1.0) 46 (44.2) 1 (1.0) Nausea 11 (10.7) 0 (0) 77 (74.0) 2 (1.9) Diarrhea 9 (8.7) 0 (0) 76 (73.1) 2 (1.9) Vomiting 6 (5.8) 0 (0) 60 (57.7) 2 (1.9) AST increase 11 (10.7) 1 (1.0) 32 (30.8) 5 (4.8) ALT increase 9 (8.7) 1 (1.0) 33 (31.7) 13 (12.5) Visual disturbance 1 (1.0) 0 (0) 57 (54.8) 0 (0) Nasopharyngitis 21 (20.4) 0 (0) 24 (23.1) 0 (0) Dysgeusia 19 (18.4) 0 (0) 54 (51.9) 0 (0) Pyrexia 10 (9.7) 1 (1.0) 21 (20.2) 0 (0) Decreased appetite 1 (1.0) 1 (1.0) 21 (20.2) 1 (1.0)
ALEX: Alectinib vs Crizotinib in Untreated ALK-Positive NSCLC  Randomized, open-label phase III trial Peters. NEJM. 2017;377:829.  Primary endpoint: investigator-assessed PFS  Secondary and other endpoints: IRC-assessed PFS, time to CNS progression, response, OS, safety Patients with advanced ALK-positive NSCLC, ECOG PS 0-2, no prior systemic tx for advanced NSCLC, measurable disease, asymptomatic brain or leptomeningeal mets permitted, CNS RT permitted if ≥ 14 days before enrollment (N = 303) Until PD, unacceptable toxicity, or withdrawal; no crossover permitted* Alectinib 600 mg BID PO (n = 152) Crizotinib 250 mg BID PO (n = 151) Stratified by ECOG PS (0/1 vs 2), race (Asian vs non-Asian), CNS mets (yes vs no) *Patients in crizotinib arm may have received alectinib after PD in countries where alectinib available.
ALEX: Investigator-Assessed PFS (Primary Analysis) Peters. NEJM. 2017;377:829. Mos Median follow up: alectinib, 18.6 mos; crizotinib, 17.6 mos. Alectinib (n = 152) Crizotinib (n = 151) Events, n (%) 62 (41) 102 (68) Median PFS, mos (95% CI) NR (17.7-NR) 11.1 (9.1-13.1) HR: 0.47 (95% CI: 0.34-0.65; P < .0001) PFS PFS(%) 0 20 40 60 80 100 0 3 6 9 12 15 18 21 24 27 30 11.1 mos Alectinib NR Crizotinib
ALEX: Investigator-Assessed PFS (Updated Analysis) Camidge. ASCO 2018. Abstr 9043. HR: 0.43 (95% CI: 0.32-0.58) Alectinib 34.8 (17.7-NE) Crizotinib: 10.9 (9.1-12.9) Median PFS, Mos (95% CI) Alectinib (n = 152) Crizotinib (n = 151) HR (95% CI) Overall 34.8 (17.7-NE) 10.9 (9.1-12.9) 0.43 (0.32-0.58) CNS mets+ (n = 64) 27.7 (9.2-NE) 7.4 (6.6-9.6) 0.35 (0.22-0.56) CNS mets- (n = 88) 34.8 (22.4-NE) 14.7 (10.8-20.3) 0.47 (0.32-0.71) PFS Updated median follow up: alectinib, 27.8 mos; crizotinib, 22.8 mos. PFS(%) Mos 100 80 60 40 20 0 Day 1 12 18 24 36306
ALEX: OS (Updated Analysis) OS(%) Mos Camidge DR, et al. ASCO 2018. Abstr 9043. Alectinib (n = 152) Crizotinib (n = 151) Events, n (%) 43 (28) 48 (32) Median OS, mos (95% CI) NE (NE-NE) NE (31.2-NE) HR: 0.76 (95% CI: 0.50-1.15) Updated median follow-up: alectinib, 27.8 mos; crizotinib, 22.8 mos. Day 1 6 12 8 24 30 36 100 80 60 40 20 0
ALEX: Time to CNS Progression by CNS Metastases at Baseline  Alectinib delayed time to CNS progression in patients with and without CNS metastases at BL compared with crizotinib Patients With CNS Metastases at BL Patients Without CNS Metastases at BL Gadgeel. Ann Oncol. 2018;29:2214. CumulativeIncidence(%) Mos Alectinib (n = 64) Crizotinib (n = 58) 12-mo CIR, % (95% CI) 16.0 (8.2-26.2) 58.3 (43.4-70.5) Alectinib (n = 64) Crizotinib (n = 58) 12-mo CIR, % (95% CI) 4.6 (1.5-10.6) 31.5 (22.1-41.3) HR: 0.18 (95% CI: 0.09-0.36; P < .0001) HR: 0.14 (95% CI: 0.06-0.33; P < .0001) In a competing risk analysis of CNS progression, non-CNS progression, and death, the first event of CNS progression, non-CNS progression, or death was counted for each patient 6 12 18 24 100 80 60 40 20 0 0 CumulativeIncidence(%) Mos 6 12 18 24 100 80 60 40 20 0 0
Alectinib in Patients With NSCLC and Symptomatic or Large Brain Metastases  Retrospective review of 19 patients with advanced ALK-positive NSCLC and CNS metastases ≥ 1 cm in size or symptomatic ‒ 2 first line ‒ 8 symptomatic ‒ 4 with leptomeningeal disease ‒ 6 with metastases > 2 cm  CNS DCR: 100%  Median time to SRS (n = 6): 15.8 mos Lin. J Thorac Oncol. 2019; 14:683. Patient 1 Patient 6
Pre-Alectinib 6 Wks on Alectinib Pre-Alectinib CSF Cytology Leptomeningeal Carcinomatosis Responded to Alectinib Ou. Oncologist. 2015;20:224.
ALEX: Adverse Events With ≥ 10% Difference in Incidence AE (Any Grade), % Alectinib (n = 152) Crizotinib (n = 151) Nausea 16 50 Diarrhea 13 46 Vomiting 9 41 Elevated ALT 17 33 Peripheral edema 18 32 Elevated AST 16 27 Dysgeusia 3 20 Visual impairment 2 12 Anemia 22 7 Myalgia 16 2 Elevated blood bilirubin 19 1 Camidge. ASCO 2018. Abstr 9043.
ALTA: Study Design  Randomized, multicenter, open-label, international phase II trial  Primary endpoint: confirmed ORR per RECIST v1.1 by investigator  Secondary endpoints: confirmed ORR by IRC, intracranial ORR/PR by IRC in pts with active brain mets,* PFS, OS, DoR, safety/tolerability  Study not designed for statistical comparison between arms, but dose selection supported by post hoc comparisons of PFS and OS Locally advanced or metastatic ALK+ NSCLC, ECOG PS ≤ 2, PD on crizotinib, no other ALK- targeted therapy (N = 222) PD requiring change of therapy, intolerable toxicity, or other reason for discontinuation Brigatinib 90 mg QD (n = 112) Brigatinib 180 mg QD* (n = 110) Kim D-W, et al. ASCO 2016. Abstract 9007. *After 7-day lead-in at 90 mg. Stratified by baseline brain metastases and best response to prior crizotinib *Lesions with no previous RT or investigator-assessed PD after prior RT.
ALTA: ORR  1 confirmed PR at 180-mg brigatinib in pt with baseline G1202R  Confirmed ORR after prior CT: 42% (90 mg) and 54% (180 mg) Kim D-W, et al. ASCO 2016. Abstract 9007. Reproduced with permission. *Unconfirmed response. †After 7-day lead in at 90 mg. ORR: 45% ORR: 54% 90 mg QD 180 mg QD† 20 0 -20 -40 -60 -80 -100 BestChangeFromBaseline inTargetLesions(%) * * 20 0 -20 -40 -60 -80 -100 * * PD SD PR CR BestChangeFromBaseline inTargetLesions(%) 40 40
ALTA: PFS Kim D-W, et al. ASCO 2016. Abstract 9007. Reproduced with permission. *After 7-day lead in at 90 mg. †Post hoc analysis, not designed to compare arms statistically. Mos 240 6 12 18 PFS(%) 100 90 80 70 60 50 40 30 20 10 0 90 mg QD 180 mg QD* Median PFS, Mos (95% CI) HR (95% CI)† 9.2 (7.4-15.6) 12.9 (11.1-NR) 0.55 (0.35-0.86)
ALTA: Adverse Events Kim D-W, et al. ASCO 2016. Abstract 9007. *Median time on treatment: 7.5 mos. †With 7-day lead in at 90 mg; median time on treatment: 7.8 mos.  Select AEs seem dose related with increased rates mostly in grade 1/2 events TEAE Occurring in ≥ 10% of All Pts, % Brigatinib 90 mg QD* (n = 109) Brigatinib 180 mg QD† (n = 110) Any Grade Grade ≥ 3 Any Grade Grade ≥ 3 Nausea 33 1 40 1 Diarrhea 19 0 38 0 Headache 28 0 27 1 Cough 18 0 34 0 Fatigue 20 1 27 0 Vomiting 24 2 23 0 Dyspnea 21 3 21 2 Increased blood CPK 11 3 30 9 Hypertension 11 6 21 6 Rash 7 1 16 3 Increased amylase 8 1 15 1 Increased AST 8 0 15 0
Brigatinib vs Crizotinib in ALKi-Naive Patients With Advanced ALK-Positive NSCLC (ALTA-1L): Background  In patients with ALK-positive NSCLC, phase III PROFILE 1014 trial demonstrated significantly superior median PFS with first-line crizotinib vs platinum–pemetrexed doublet CT (10.9 vs 7.0 mos; P < .001)[1]  Brigatinib: next-generation ALK/ROS1 inhibitor ‒ Activity reported against ALK inhibitor–resistance mutations and EGFR mutations in in vitro and mouse models[2,3]  Phase I/II trials evaluating brigatinib after crizotinib treatment have reported high rates of response systemically and in the CNS with a prolonged median PFS of ~ 16 mos[4,5]  Current prespecified first interim analysis compares efficacy and safety of brigatinib vs crizotinib in ALK inhibitor–naive patients with advanced ALK-positive NSCLC[6] 1. Solomon BJ, et al. N Engl J Med. 2014;371:216 7-2177. 2. Uchibori K, et al. Nat Commun. 2017;8:14768. 3. Huang WS, et al. J Med Chem. 2016;59:4948-4964. 4. Huber RM, et al. ASCO 2018. Abstract 9061. 5. Camidge DR, et al. J Clin Oncol. 2018;36:2693-2701. 6. Camidge DR, et al. WCLC 2018. Abstract PL02.03.
ALTA-1L: Brigatinib vs Crizotinib in Untreated ALK- Positive NSCLC  First interim analysis of multicenter, randomized, open-label phase III trial (data cutoff 2/19/18) Camidge. NEJM. 2018;[Epub].  Primary endpoint: BIRC-assessed PFS (RECIST v1.1) ‒ First interim analysis includes 99 PFS events with significance threshold prespecified as 2-sided P = .0031  Secondary endpoints: confirmed ORR, confirmed intracranial ORR, intracranial PFS, OS, safety Patients with stage IIIB/IV ALK-positive NSCLC, no previous ALK inhibitor, ≤ 1 previous systemic tx for locally advanced or metastatic NSCLC (N = 275) Until PD,* unacceptable toxicity, or other reasons for d/c Brigatinib 180 mg QD after 7-day lead-in at 90 mg (n = 137) Crizotinib 250 mg BID (n = 138) Stratified by BL brain mets (yes/no), prior CT for locally advanced or metastatic disease (yes/no) *Crossover permitted to brigatinib arm on PD.
ALTA-1L: Baseline Characteristics  Continuing on study treatment: brigatinib, n = 95 (69%); crizotinib, n = 59 (43%) ‒ Median follow-up: brigatinib, 11.0 mos; crizotinib, 9.25 mos ‒ 35 patients crossed over to brigatinib after d/c crizotinib due to PD Camidge DR, et al. WCLC 2018. Abstract PL02.03. Characteristic, % Brigatinib (n = 137) Crizotinib (n = 138) All Patients (N = 275) Median age, yrs (range) 58 (27–86) 60 (29–89) 59 (27–89) Female sex 50 59 55 Race  White  Asian  Other 55 43 1 62 36 2 59 39 2 ECOG PS  0  1  2 42 53 4 43 52 4 43 53 4 Disease stage at study entry  IIIB  IV 6 94 9 91 7 93 Characteristic, % Brigatinib (n = 137) Crizotinib (n = 138) All Patients (N = 275) Locally assessed ALK status per FDA-approved test 90 81 86 Brain mets 29 30 29 Prior RT to brain 13 14 13 Prior CT in locally advanced or metastatic setting 26 27 27
ALTA-1L: BIRC-Assessed PFS (Primary Endpoint) Camidge. WCLC 2018. Abstr PL02.03. Camidge. NEJM. 2018;379:2027. 0 20 40 60 80 100 0 3 6 9 12 15 18 21 Mos PFS(%) Events, n (%) Median PFS, Mos (95% CI) 1-Yr PFS, % (95% CI) ORR, % (95% CI) ICR,* % (95% CI) Brigatinib (n = 137) 36 (26) NR (NR-NR) 67 (56-75) 71 (62-78) 78 (52-94) Crizotinib (n = 138) 63 (46) 9.8 (9.0-12.9) 43 (32-53) 60 (51-68) 29 (11-52) Median follow-up: 11 mos (range: 0-20) Median follow-up: 9.3 mos (range: 0-21) HR: 0.49 (95% CI: 0.33-0.74); P < .001 *Among patients with measurable CNS lesions. HR: 0.49 (95% CI: 0.33-0.74); P < .001
Patients With Brain Metastases at BL: 30% ALTA-1L: PFS by CNS Metastases at BL Popat. ESM0 2018. Abstr LBA58. Median follow-up: 9-11 mos. Whole Body BIRC-Assessed Intracranial Patients Without Brain Metastases at BL: 70% HR: 0.27 (95% CI: 0.13-0.54; P < .0001) HR: 0.96 (95% CI: 0.42-2.22; P = .9274) Brigatinib (n = 40) Crizotinib (n = 41) Median PFS, Mos (95% CI) NR (NR-NR) 5.6 (3.8-11.1) Brigatinib n = 97) Crizotinib (n = 97) Median PFS, Mos (95% CI) NR (NR-NR) 11.1 (9.2-NR) Brigatinib Crizotinib Median iPFS, Mos (95% CI) NR (11.0-NR) 5.6 (4.1-9.2) Brigatinib Crizotinib Median iPFS, Mos (95% CI) NR (NR-NR) NR (NR-NR) Mos Mos 183 6 9 12 150 PFS(%) 100 80 60 40 20 0 183 6 9 12 150 PFS(%) 100 80 60 40 20 0 183 6 9 12 150 PFS(%) 100 80 60 40 20 0 183 6 9 12 150 PFS(%) 100 80 60 40 20 0 HR: 0.20 (95% CI: 0.09-0.46; P < .0001) HR: 0.72 (95% CI: 0.44-1.18; P < .20)
ALTA-1L: BIRC-Assessed PFS by Prespecified Subgroup Camidge DR, et al. WCLC 2018. Abstract PL02.03. Camidge DR, et al. N Engl J Med. 2018;[Epub ahead of print]. Subgroup Overall Age 18-64 yrs ≥ 65 yrs Sex Female Male Race Non-Asian Asian History of tobacco use Never smoked Former smoker ECOG PS 0 1 Brain metastases at baseline Yes No Previous chemotherapy Yes No Brigatinib 137 93 44 69 68 78 59 84 49 58 73 40 97 36 101 Crizotinib 138 95 43 81 57 89 49 75 56 60 72 41 97 37 101 No. of Patients HR for Disease Progression or Death (95% CI) 0.49 (0.33-0.74) 0.44 (0.26-0.74) 0.59 (0.30-1.18) 0.44 (0.24-0.84) 0.49 (0.28-0.85) 0.54 (0.33-0.90) 0.41 (0.20-0.86) 0.47 (0.27-0.84) 0.51 (0.27-0.97) 0.19 (0.06-0.55) 0.60 (0.37-0.98) 0.20 (0.09-0.46) 0.72 (0.44-1.18) 0.35 (0.14-0.85) 0.55 (0.34-0.88) 0 0.5 1.0 1.5 2.0 Brigatinib Better Crizotinib Better
ALTA-1L: Systemic and Intracranial Response Camidge DR, et al. WCLC 2018. Abstract PL02.03. Systemic Objective Response in ITT Population Brigatinib (n = 137) Crizotinib (n = 138) OR (95% CI) Confirmed ORR, %  CR  PR 71 4 67 60 5 55 1.59 (0.96-2.62); P = .0678 Median DoR, mos NR 11.1 -- 12-mo probability of maintaining response, % 75 41 -- Intracranial Objective Response in Patients With BL Brain Mets Brigatinib Crizotinib OR (95% CI) Measurable* BL brain mets n = 18 n = 21 Confirmed ORR, %  CR  PR 78 11 67 29 0 29 10.42 (1.90-57.05); P = .0028 Any BL brain mets n = 43 n = 47 Confirmed ORR, %  CR  PR 67 37 30 17 4 13 16.30 (5.32-49.92); P < .0001 *≥ 10 mm in diameter.
ALTA-1L: Safety  ILD/pneumonitis: brigatinib, 4%; crizotinib, 2% ‒ In brigatinib arm, 3% observed within 14 days of starting treatment  AE-related dose modifications with brigatinib vs crizotinib ‒ Reductions: 29% vs 21% ‒ D/c: 12% vs 9% Camidge. WCLC 2018. Abstr PL02.03. TEAEs in Either > 20% of Patients or With > 5% Difference Between Arms,* % Brigatinib (n = 136) Crizotinib (n = 137) Any Grade Grade ≥ 3 Any Grade Grade ≥ 3 Diarrhea 49 1 55 2 Increased blood CPK 39 16 15 1 Nausea 26 1 56 3 Cough 25 0 16 0 Increased AST 23 1 25 6 Hypertension 23 10 7 3 Increased ALT 19 1 32 9 Increased lipase 19 13 12 5 Vomiting 18 1 39 2 Constipation 15 0 42 1 Increased amylase 14 5 7 1 Pruritus 13 1 4 1 *Also includes rash, decreased appetite, dermatitis acneiform, dyspepsia, epistaxis, bradycardia, peripheral edema (4%/1% brigatinib vs 39%/1% crizotinib), dysgeusia, upper abdominal pain, pain in extremity, increased blood creatinine, neutropenia, pleural effusion, photopsia (1%/0% vs 20%/1%), GERD, hypoalbuminemia, visual impairment (0%/0% vs 16%/0%), and deep vein thrombosis.
ALTA-1L: Conclusions  In ALK inhibitor–naive patients with ALK-positive NSCLC, first interim analysis showed significantly improved PFS with brigatinib vs crizotinib ‒ Median PFS: NR vs 9.8 mos (HR: 0.49; log-rank P = 0.0007) ‒ PFS benefit observed across most subgroups except those aged 65 yrs or older or with brain mets at BL ‒ Short median follow-up may account for CNS progression driving PFS events in those with BL CNS disease  Brigatinib was well tolerated with most trial-mandated dose reductions due to asymptomatic laboratory abnormalities  Early-onset ILD/pneumonitis observed in 3% of brigatinib-treated patients  Investigators concluded that brigatinib a promising first-line treatment option for patients with ALK-positive NSCLC. Camidge DR, et al. WCLC 2018. Abstract PL02.03.
Lorlatinib in ALK+ NSCLC: Phase I Results  Single-arm, first-in-human phase I dose-escalation trial of lorlatinib, a brain- penetrant ALK/ROS1-targeted TKI, in ALK+ NSCLC (n = 41), ROS1+ NSCLC (n = 12) Shaw. Lancet Oncol. 2017;18:1590. n/N ORR, % Overall ALK+  1 prior ALK TKI  ≥ 2 prior ALK TKIs 19/41 8/14 11/26 46 57 42 Best Confirmed Tumor Response to Lorlatinib in ALK+ NSCLC CR PR SD PD Off treatment or PD occurred ChangeFromBL(%) 100 80 60 40 20 0 -20 -40 -60 -80 -100 2 2 2 1+ 2 0 2 2 2 3 2 1 1 2 1+ 2 2 2 1 2 2 2 1 1 3 2 1 2 1+ 1 2 2 1 2 1 2 1 3 Number of ALK TKIs received by each patient prior to lorlatinib indicated. 30% PR Threshold
 Primary endpoints: objective (CR or PR) and intracranial (RECIST v1.1) tumor response assessed in pooled subgroups of ALK+ patients  Secondary endpoints: DoR, intracranial DoR, time to first tumor response, PFS, safety/tolerability Lorlatinib in ALK+ NSCLC: Phase II Study Design  Open-label, single-arm phase II study ALK+ or ROS1+ advanced NSCLC; treatment-naive or PD after ≥ 1 prior ALK/ROS1 TKI; CNS metastases allowed (N = 276) Lorlatinib 100 mg QD Q3W Tx until PD,* unacceptable toxicity, withdrawal of consent, or death Solomon. Lancet Oncol. 2018;19:1654. ALK+ Expansion Cohorts (n = 228) ROS1+ Cohort (n = 47) EXP1 EXP2 EXP3 EXP4 EXP5 EXP6 Tx naive (n = 30) Prior crizotinib only (n = 27) Prior crizotinib and CT (3A; n = 32) or prior ALK TKI ± CT (3B; n = 28) 2 prior ALK TKIs ± CT (n = 65) 3 prior ALK TKIs ± CT (n = 46) Any prior tx (n = 47) *Tx beyond PD allowed if evidence of clinical benefit.
** ** Phase II Lorlatinib: Efficacy in Patients With ≥ 2 Prior ALK TKIs (± CT)  Pooled data from EXP4 (2 ALK TKIs ± CT), EXP5 (3 ALK TKIs ± CT) ‒ 83 patients (75%) had brain metastases at baseline CI, confidence interval; CT, chemotherapy; DOR, duration of response; mo, months; NR, not reache Solomon. Lancet Oncol. 2018;19:1654. Solomon. WCLC 2017. Abstr OA 05.06. Intracranial Tumor Response† Overall Tumor Response† Outcome n = 111 ORR, n (%; 95% CI)  Intracranial ORR, n/N (%) 43 (39; 30-49) 26/49 (53) Median DoR, mos (95% CI)  DoR ≥ 6 mos, n/N (%) NR (5.5-NR) 20/43 (47) Median PFS, mos (95% CI) 6.9 (5.4-9.5) †Patients with ≥ 1 on-study target lesion assessment as per ICR were included in overall and intracranial tumor response analysis. 70 60 10 0 30 20 50 40 -10 -20 -30 -40 -50 -60 -70 -80 -90 -100 ChangeinTumorSizeFromBL(%) 80 CR PR SD/no response PD Indeterminate Off treatment or PD occurred * * * * *** ** * ** **** * * *** * *** ****** *** ****** * *********** * * * *** ****** 70 60 10 0 30 20 50 40 -10 -20 -30 -40 -50 -60 -70 -80 -90 -100 ChangeinTumorSizeFromBL(%) 80 * * * * ** * * * * * * * * * * * * * * * * * ** * * * **
Lorlatinib Activity Against ALK Resistance Mutations Including G1202R  12 ALK+ patients who were previously treated with 2 or more ALK TKIs Shaw. Lancet Oncol. 2017;18:1590. Best Tumor Response Duration of Treatment20 0 -20 -40 -60 -80 -100 BestChangeFromBL(%) G1202R ALKMutation G1202R G1202R F1174C L1196M D1203N/ F1174C Gly1202del Wild Type Wild Type G1202R Wild Type Days 10000 100 200 300 400 500 600 700 800 900 Wild Type
Lorlatinib Toxicities Bauer. Oncologist. 2019;[Epub]. Adverse Event, n (%) Lorlatinib 100 mg QD (N = 295*) All Grades Grade 3 Grade 4 Hypercholesterolemia 243 (82.4) 41 (13.9) 5 (1.7) Hypertriglyceridemia 179 (60.7) 39 (13.2) 7 (2.4) Edema 151 (51.2) 7 (2.4) 0 Peripheral neuropathy 129 (43.7) 7 (2.4) 0 Cognitive effects 68 (23.1) 5 (1.7) 0 Fatigue 68 (23.1) 1 (0.3) 0 Mood effects 62 (21.0) 4 (1.4) 0 Weight increase 61 (20.7) 7 (2.4) 0 Arthralgia 58 (19.7) 0 0 Diarrhea 52 (17.6) 2 (0.7) 0 Constipation 42 (14.2) 0 0 Vision disorder 39 (13.2) 1 (0.3) 0 Speech effects 28 (9.5) 1 (0.3) 0 *Pooled phase I data.
Lorlatinib Toxicity Management  Hyperlipidemia ‒ Early initiation of lipid-lowering therapy for cholesterol > ULN ‒ Recommended agents include pravastatin or rosuvastatin ‒ Fenofibrates or fish oils can be added ‒ Hold lorlatinib and dose reduce for severe (grade 3) hyperlipidemia not effectively managed with maximal lipid-lowering therapy  Mood/cognitive effects ‒ Irritability, anxiety, depression, agitation ‒ Memory impairment, amnesia ‒ Typically occur within 2 mos of treatment initiation ‒ Patients should be counseled about these adverse events ‒ Treatment break and dose- reduction can be effective Bauer. Oncologist. 2019;[Epub].
Lorlatinib in Advanced ALK+ or ROS1+ NSCLC: Study Design  Open-label phase I/II trial  Primary objective: safety/tolerability at increasing dose levels to establish RP2D  Secondary objectives: antitumor activity, PK, pt-reported outcomes, correlative studies ALK+ or ROS1+ NSCLC; treatment-naive or PD after ≥ 1 prior ALK/ROS1 TKI; ≥ 1 measurable extracranial lesion (N = 54) Lorlatinib 10, 25, 50, 75, 100,* 150, or 200† mg QD Q3W 35, 75, or 100 mg BID Q3W Solomon BJ, et al. ASCO 2016. Abstract 9009. *Chosen as RP2D, n = 17. †1 DLT observed. Dose Escalation Tx until PD or unacceptable toxicity
Lorlatinib in Advanced ALK+ or ROS1+ NSCLC: ORR Solomon BJ, et al. ASCO 2016. Abstract 9009. Response 1 Prior ALK TKI (n = 14) ≥ 2 Prior ALK TKIs (n = 26) Total ALK+ (n = 41) ORR, % (95% CI) 57 (29-82) 42 (23-63) 46 (31-63) Best overall response, %  CR  PR  Unconfirmed PR  SD  PD  Indeterminate 7 50 0 21 14 7 8 35 4 19 27 8 7 39 2 20 24 7
Lorlatinib in Advanced ALK+ or ROS1+ NSCLC: PFS Solomon BJ, et al. ASCO 2016. Abstract 9009. Reproduced with permission. 2120191817161514131211109876543210 Mos 0 0 1 0 1 1 1 1 1 1 2 1 3 1 3 2 5 2 6 2 7 3 8 4 8 7 8 8 8 8 8 11 10 13 10 14 11 16 11 17 14 24 14 26 1 prior ALK TKI ≥ 2 prior ALK TKIs 100 80 60 40 20 0 SurvivalProbability(%) 1 prior ALK TKI 13.5 (1.6-NR) ≥ 2 prior ALK TKI 9.2 (1.5-NR)Median PFS, mos (95% CI)
Lorlatinib in Advanced ALK+ or ROS1+ NSCLC: Safety Solomon BJ, et al. ASCO 2016. Abstract 9009. *Most frequently because of hypercholesterolemia. Treatment-Related AE, % All LOR Doses (N = 54) LOR 100 mg QD (n = 17) Any Grade 3/4 Any Grade 3/4 Any 93 30 94 29 Causing dose delay 33 20 24* 18* Causing dose reduction 24 9 0 0 Hypercholesterolemia 69 11 82 12 Peripheral edema 37 0 53 0 Hypertriglyceridemia 33 6 41 12 Peripheral neuropathy 22 0 NR NR Fatigue 15 0 NR NR Slow speech NR NR 18 0
Limited Role of Other Second-Generation ALK TKIs After PD on First-line Alectinib  Ceritinib[1] ‒ Retrospective analysis of 35 patients with ALK+ NSCLC treated with ceritinib ‒ ORR: 44% (all patients) ‒ 16% in 9 patients who received ceritinib immediately after alectinib  Brigatinib[2] ‒ Retrospective analysis of 22 patients with alectinib-refractory ALK+ NSCLC treated with brigatinib ‒ ORR: 17%; median PFS: 4.4 mos 1. Yoshida. In Vivo. 2018;32:1587. 2. Lin. J Thorac Oncol. 2018;13:1530. Best Tumor Response PD SD PR 60 40 20 0 -20 -40 -60 -80 -100ChangeFromBL(%) * *Patient with 0% change from BL.
Conclusions  Lorlatinib is the preferred treatment for an ALK+ patient who progresses on first-line alectinib ‒ ORR 43%, median PFS 6.9 mos among patients with > 2 prior ALK TKIs ‒ Excellent CNS activity: intracranial ORR 53% in a pre-treated population ‒ Broad-spectrum activity to most known ALK resistance mutations  Common lorlatinib side effects include hypercholesterolemia, hypertriglyceridemia, cognitive side effects, peripheral neuropathy, and edema
What Is the Role of Chemotherapy in Treating ALK-Positive NSCLC?  PROFILE 1014: first-line crizotinib vs platinum/pemetrexed (N = 343)[1]  ASCEND-4: first-line ceritinib vs platinum/pemetrexed (N = 376)[2] 1. Solomon. NEJM. 2014;371:2167. 2. Soria. Lancet. 2017;389:917. Ceritinib CT Median PFS, mos 16.6 8.1 ORR, % 72.5 26.7 HR for PFS: 0.55 (95% CI: 5.8-11.1; P < .00001) Crizotinib CT Median PFS, mos 10.9 7.0 ORR, % 74 45 HR for PFS: 0.45 (95% CI: 0.35-0.60; P < .001) Mos Platinum/Pemetrexed CT Median PFS: 7.0 mos (95% CI: 6.8-8.2) ORR: 45% (95% CI: 37-53) Platinum/Pemetrexed CT Median PFS: 8.1 mos (95% CI: 5.8-11.1) ORR: 26.7% (95% CI: 20.5-33.7) 100 80 60 40 20 0 PFS(%) 0 355 10 15 20 25 30 Mos Censored Ceritinib CT 100 80 60 40 20 0 0 342 PFS(%) 4 6 8 101214161820222426283032 Crizotinib CT
Treatment of ROS1 Rearrangement, BRAF V600E and other Mutation–Positive NSCLC
Targeted Agents for ROS1 Rearrangements and BRAF V600E Mutation *Other methodologies commonly employed include FISH, IHC, and RT-PCR.[1,3] †Non-V600E mutations have variable kinase activity and response to these agents.[11] ‡Previously treated patients. §Previously untreated patients. 1. Bergethon. J Clin Oncol. 2012;30:863. 2. Gainor. Oncologist. 2013;18:865. 3. FDA. List of cleared or approved companion diagnostic devices. 4. Crizotinib PI. 5. Shaw. NEJM. 2014;371:1963. 6. Chen. PLoS One. 2014;9:e101354. 7. Paik. J Clin Oncol. 2011;29:2046. 8. Dabrafenib PI. 9. Planchard. Lancet Oncol. 2016;17:984. 10. Planchard. Lancet Oncol. 2017;18:1307. 11. Litvak. J Thorac Oncol. 2014;9:1669. Genetic Alteration Incidence FDA-Approved Testing Method FDA-Approved Targeted Agents ORR, % Median PFS, Mos (95% CI) ROS1 rearrangements 1% to 2%; more common in younger patients, never- smokers, adenocarcinoma, high-grade histology[1,2] NGS*[3] Crizotinib[4] 72[5] 19.2 (14.4-NR)[5] BRAF V600E mutation† 1% to 2%; more common in adenocarcinoma; occurs in both smokers and never- smokers[6,7] NGS[3] Dabrafenib + trametinib[8] 63.2‡[9] 64§[10] 9.7 (6.9-19.6)‡[9] 10.9 (7.0-16.6)§[10]  Dabrafenib + trametinib[8]: any-grade AEs, pyrexia (46%), nausea (40%), vomiting (35%), and diarrhea (33%); most frequent grade ≥ 3 AE, neutropenia (9%)
 Larotrectinib was recently approved by the FDA for adult and pediatric patients with solid tumors that have a neurotrophic receptor tyrosine kinase (NTRK) gene fusion without a known acquired resistance mutation, that are either metastatic or where surgical resection is likely to result in severe morbidity, and who have no satisfactory alternative treatments or whose cancer has progressed following treatment[6] Emerging Molecular Targets in Advanced NSCLC 1. Gallant. J Pathol. 2018;244:565. 2. Yap. J Thorac Oncol. 2017;12:12. 3. Farago. Transl Lung Cancer Res. 2017;6:550. 4. Kim. PLoS One. 2017;12:e0171280. 5. Pillai. Cancer. 2017;123:4099. 6. Larotrectinib PI. Genetic Alteration Incidence Targeted Agents With Early Evidence of Activity MET exon 14 alterations/MET amplification[1,2] 3% to 5% (exon 14 skipping; more common in adenocarcinoma) Crizotinib RET rearrangements[3] 1% to 2%; more common in adenocarcinoma; occurs in both smokers and never-smokers Cabozantinib Vandetanib LOXO-292 NTRK rearrangements[3] ≤ 1%; clinical and pathologic features not well characterized Larotrectinib Entrectinib HER2 mutations[4,5] 2% to 4% Ado-trastuzumab emtansine
TRK Inhibitors  Larotrectinib: FDA approved for adult and pediatric patients with solid tumors with a NTRK gene fusion without a known acquired resistance mutation, who are either metastatic or not candidates for surgical resection due to likely severe morbidity, and who have no satisfactory alternative treatments or whose cancer has progressed following standard treatment[1]  Entrectinib: granted FDA priority review for select adult and pediatric patients with locally advanced or metastatic NTRK fusion–positive solid tumors and for patients with metastatic ROS1+ NSCLC[2]  LOXO-195: second-generation TKI with activity against multiple TRK kinase domain mutations in patients with solid tumors with a TRK gene fusion[3] 1. Larotrectinib PI. 2018. 2. Demetri. ESMO 2018. Abstr LBA17. 3. Hyman. AACR 2019. Abstr CT127.
Neurotrophins and Tropomyosin Receptor Kinases: A Novel Oncogenic Target  Sympathetic nervous system development is orchestrated by neurotrophins (NT) and respective neurotrophin receptors  3 neurotrophin receptors encoded by 3 distinct genes – NTRK1  TRKA – NTRK2  TRKB – NTRK3  TRKC  Normal function of TRK in adults – TRKA  pain, thermoregulation – TRKB  movement, memory, mood, appetite, body weight – TRKC  proprioception  Receptors and ligands commonly dysregulated in multiple tumor types Amatu. ESMO Open. 2016;1:e000023. NGF NTF-3 TRKA TRKB TRKC P P P P P P P P P P P P ERK AKT BDGF
TRK Fusions Observed Across Diverse Cancer Types in Both Adults and Children Hyman. ASCO 2017. Abstr LBA2501. Brain cancers (glioma, GBM, astrocytoma) Thyroid cancer Salivary (MASC) Lung cancer Secretory breast cancer Pancreatic Cholangiocarcinoma GIST Colon Melanoma Sarcoma (multiple) Gliomas Infantile fibrosarcoma Thyroid cancer Congenital nephroma Spitz nevi Sarcoma (multiple) Common cancer with low TRK fusion frequency Rare cancer with high TRK fusion frequency Estimated 1500-5000 patients with NTRK fusion–positive cancers in the US annually
Larotrectinib: Antitumor Activity Across Tumor Types Lassen. ESMO 2018. Abstr 279. MaximumChangeinTumorSize(%) 40 20 0 -20 -40 -60 -80 -100 50 30 10 -10 -30 -50 -70 -90 Infantile fibrosarcoma Soft tissue sarcoma Thyroid Salivary gland Melanoma Breast Appendix Lung Gastrointestinal stomal tumor Colon Pancreas Cholangiocarcinoma Congenital mesoblastic nephroma Unknown primary Bone sarcoma ORR, % (95% CI)† Best response, %† PR CR Integrated‡ (n = 109) 81 (72-88) 63 17 93.2 * ##
Larotrectinib: Duration of Treatment Lassen. ESMO 2018. Abstr 279. 0 10 2015 25 30 4035 455 84% of responding patients and 73% of all patients remain on treatment or underwent surgery with curative intent Overall Treatment Duration (Mos) Treatment after progression Treatment after surgery Treatment ongoing Surgical CR n = 122 patients Median time to response: 1.8 mos
Integrated Efficacy and Safety Analysis of Entrectinib: NTRK Fusion–Positive Solid Tumors Integrated analysis Efficacy population§ 54 adult patients with NTRK fusion–positive, TRK inhibitor–naive solid tumours Safety population 355 patients overall have received entrectinib (all tumor types and gene rearrangements) Primary endpoints* ORR and DoR Secondary endpoints* PFS and OS Intracranial ORR and DoR† Safety and tolerability STARTRK-12 Phase I dose escalation N = 2 NTRK+ patients ALKA-372-0012 Phase I dose escalation N = 1 NTRK+ patient STARTRK-21 Phase II, multicenter, global basket study 600 mg QD, 28-day cycle N = 51 NTRK+ patients Data cutoff: May 31, 2018 §Patients with at least 6 mos of follow-up *Per blinded independent central review measured by RECIST v1.1 †Patients with measurable and non-measurable CNS lesions at baseline Demetri. ESMO 2018. Abstr LBA17.
Entrectinib in NTRK Fusion–Positive Solid Tumors: Individual Patient Responses by Tumor Type Demetri. ESMO 2018. Abstr LBA17. 0 -30 -50 -90 Best%ChangeFromBaseline 15 -80 -70 -60 -40 -20 -10 20 30 40 -100 50 CRC NSCLCSarcoma Neuroendocrine tumors PancreaticThyroid MASC Breast CholangiocarcinomaGynecological NTRK+ Patients (n = 54) ORR, % (95% CI) 57.4 (43.2-70.8) SD 9 (16.7) PD 4 (7.4) Non-CR/PD, missing or unevaluable 10 (18.5) Results per blinded independent central review (BICR) Cutoff date: May 31, 2018. Note: Patients (n = 6) without matched pre/post therapy scans were excluded from the plot
Entrectinib Activity in NTRK Fusion–Positive Solid Tumors: Duration of Response, PFS and OS Median duration of survival follow-up (PFS, OS): 12.9 mos Median duration of response follow-up (DoR): 13.1 mos DoR PFS OS Patients included in analysis, n 31 54 54 Patients with event, n (%) 16 (51.6) 29 (53.7) 16 (29.6) PD, n Death, n 13 3 20 9 -- 16 Median , mos 10.4 11.2 20.9 95% CI for median 7.1-NE 8.0-14.9 14.9-NE 0 5 10 15 20 Time (mos) DoR Continuing Rx (censored) First PD Death Demetri. ESMO 2018. Abstr LBA17.
Entrectinib Activity in NTRK Fusion–Positive Solid Tumors: Intracranial ORR in Patients With CNS Mets at Baseline Patients With CNS Mets at Baseline (n = 11) per BICR Intracranial ORR, n (%) (95% CI) CR PR SD PD Non CR/PD, Missing or unevaluable 6 (54.5) (23.4-83.3) 3 (27.3) 3 (27.3) 1 (9.1) 1 (9.1) 3 (27.3) Intracranial median DoR, mos (95% CI) NE (5.0-NE) Intracranial median PFS, mos (95% CI) 14.3 (5.1-NE) Demetri. ESMO 2018. Abstr LBA17.
LOXO-195: Rationale Drilon. Cancer Discov. 2017;7:963.  Potent, second-generation TKI that inhibits all 3 TRKs (IC50 < 5 nM)  > 1000 x more selective for TRK than 98% of 226 non-TRK kinases  Preclinical activity against acquired solvent front, xDFG, gatekeeper, and TRK mutations (in vitro, in vivo)  Oral administration with high drug exposure
LOXO-195: ORR by Resistance Mechanism Hyman. AACR 2019. Abstr CT127. Characteristic, n N CR/PR SD PD Nonevaluable ORR, n/N (%) TRK mutation 20 9 6 2 4 9/20 (45)  Solvent front 14 7 4 2 1 7/14 (50)  Gatekeeper 4 1 1 0 2 1/4 (25)  xDFG 2 1 1 0 0 1/2 (50) Identified bypass 3 0 0 3 0 0/3 (0) Other/unknown 6 1 3 0 2 1/6 (17) Total 29 10 9 5 5 10/29 (34)
LOXO-195: Best Tumor Change by Resistance Mechanism Hyman. AACR 2019. Abstr CT127. MaximumChangeinTumorsize(%) 40 20 0 -20 -40 -60 -80 -100 80 60 100 7 patients were non-evaluable. *Patients with responses at or close to 0%. # SPP population. 1 SPP patient with an SF kinase mutation had PD is not included Resistance mechanism SF GK xDFG Bypass None * * * # # # # # # # # #
ROS1 Inhibitors  Entrectinib: granted FDA priority review for select adult and pediatric patients with locally advanced or metastatic NTRK fusion–positive solid tumors and for patients with metastatic ROS1+ NSCLC[1]  Crizotinib: Approved for patients with metastatic ROS1 rearrangement–positive or ALK fusion–positive NSCLC[2]  Lorlatinib: granted FDA accelerated approval for patients with metastatic ALK fusion–positive NSCLC who have progressed on crizotinib and at least one other ALK inhibitor, alectinib, or ceritinib[3] ‒ MOA: highly potent, selective, and brain-penetrant TKI that inhibits ALK and ROS1 proto-oncogene 1. Demetri. ESMO 2018. Abstr LBA17. 2. Crizotinib PI. 2018. 3. Lorlatinib PI. 2018.
ROS1 Rearrangements in NSCLC  ROS1 rearrangements are identified in approximately 1% to 2% of NSCLC cases[1-3]  ROS1 rearrangements lead to fusion of a portion of ROS1, including its tyrosine kinase domain, to a variety of different partner proteins[3,4]  ROS1 fusion kinases are constitutively activated and function as potent oncogenic drivers[3,4] 1. Bergethon. JCO. 2012;30:863. 2. Dugay. Oncotarget. 2017;8:53336. 3. Davies. Clin Cancer Res. 2013;19:4040. 4. Lin. J Thorac Oncol. 2017;12:1611. 5. Lin. J Thorac Oncol. 2017;12:1611.
Entrectinib: Early Data in Patients With Solid Tumors  2 phase I trials (N = 119) ‒ Age: 18-80 yrs ‒ Female: 54%  ORR ‒ 100% for NTRK fusions ‒ 86% for ROS1 fusions ‒ 57% in ALK fusions  Median DoR ‒ 2.6-15.1 mos for NTRK fusions ‒ 17.4 mos for ROS1 fusions ‒ 7.4 mos for ALK fusions  Median PFS ‒ NR for NTRK fusions ‒ 19.0 mos for ROS1 fusions ‒ 8.3 mos for ALK fusions Drilon. Cancer Discov. 2017;7:400. Tumor Type, n (%) ALKA- 372-001 STARTRK-1 Total NSCLC 35 (65) 36 (56) 71 (60) GI tract 9 (17) 9 (14) 18 (15) CNS 4 (7) 1 (2) 5 (4) Head and neck 1 (2) 4 (6) 5 (4) Other 5 (9) 15 (23) 20 (17)
Entrectinib: Tumor Response by Gene Alteration Drilon. Cancer Discov. 2017;7:400. Maximum%CHANGEFROMBASELINE inSumofLongestDiameters 20 0 -20 -40 -60 -80 -100 NTRK ROS1 ALK * 0% Change LMNA-NTRK1 SQSTM1-NTRK1 ETV6-NTRK3 a EZR-ROS1 ROS1+(FISH) ROS1+(FISH) ROS1+(FISH) GOPC-ROS1 ROS1+(FISH) ROS1+(FISH) ROS1+(FISH) ROS1+(FISH) ROS1+(FISH) ROS1+(FISH) CD74-ROS1 ALK+(FISH) D5F3-ALK ALK+(FISH) CAD-ALK VCL-ALK ALK+(FISH) ALK+(FISH) *b aSDC4-ROS1 bROS1+ (FISH)
Entrectinib: Duration of Treatment Drilon. Cancer Discov. 2017;7:400. SQSTM1-NTRK1 NSCLC BCAN-NTRK1 glioneuronal ETV6-NTRK3 MASC LMNA-NTRK1 mCRC ROS1+ (FISH) NSCLC ROS1+ (FISH) NSCLC CD74-ROS1 NSCLC ROS1+ (FISH) NSCLC ROS1+ (FISH) NSCLC EZR-ROS1 NSCLC GOPC-ROS1 melanoma ROS1+ (FISH) NSCLC ROS1+ (FISH) NSCLC ROS1+ (FISH) NSCLC ROS1+ (FISH) NSCLC ROS1+ (FISH) NSCLC ROS1+ (FISH) NSCLC SDC4-ROS1 NSCLC ALK+ (FISH) NSCLC ALK+ (FISH) NSLCLC VCL-ALK RCC ALK+ (FISH) NSCLC CAD-ALK mCRC ALK+ (FISH) NSCLC D5F3-ALK unknown primary NTRK ROS1 ALK 0 3 6 9 12 15 18 21 24 27 30 33 36 Mos
Crizotinib in ROS1 Rearrangement–Positive NSCLC Best % Change From Baseline in Target Lesion Size (N = 51) Best overall response: CR PR Stable disease Progressive disease 20 ChangeFromBaseline(%) 40 60 80 100 0 -20 -40 -60 -80 -100 * * * *Indicates tumor assessment by RECIST v1.1. aExcludes 2 patients: one with early death and one with indeterminate response. ROS1-Rearranged NSCLC (N = 53) Shaw et al 2014 (N = 50) BOR, n (%) CR PR SD PD NEa 6 (11.3) 32 (60.4) 10 (18.9) 3 (5.7) 2 (3.8) 3 (6) 33 (66) 9 (18) 3 (6) 2 (4) ORR, % 95% CI 71.7 57.7-83.2 72.0 58-84 Median TTR, wks (range) 7.9 4.3-103.6 7.9 4.3-32.0 Responses could not be evaluated in 2 patients because of early death or indeterminate response. Shaw. NEJM. 2014;371:1963.
Crizotinib in ROS1 Rearrangement–Positive NSCLC  Median follow-up for OS: 62.6 mos  14 patients (26%) remain in follow-up ROS1-Rearranged NSCLC (N = 53) Deaths, n (%) 26 (49.1) Median OS, mos (95% CI) 51.4 (29.3-NR) 40 OS(%) Mos 60 80 100 20 0 0 4020 60 80 53Pts at Risk, n 48 42 37 31 27 23 20 18 17 9 5 4 02033 13 3 1-yr OS rate: 79% 4-yr OS rate: 51% Censored Shaw. Ann Oncol. 2019. [Epub]
Crizotinib in ROS1 Rearrangement–Positive NSCLC ROS1-Rearranged NSCLC (N = 53) Shaw et al 2014 (N = 50) Events, n (%) 36 (67.9) 23 (46) Median PFS, mos (95% CI) 19.3 (15.2-39.1) 19.2 (14.4-NR) PFS(%) 53 41 35 31 19 17 16 11 10 9 4 2 2 01422 7 2 Patients at Risk, n 40 60 80 100 20 0 0 4020 60 80 Mos Shaw. Ann Oncol. 2019. [Epub]
Lorlatinib: Active Against ALK and ROS1 Resistance Mutations (in vitro Data) Zhou. AACR 2013. Abstr A277. EML4-ALK Mutation Cell Line Cellular ALK Phosphorylation Mean IC50 (nM) Lorlatinib Crizotinib Ceritinib Alectinib v1 NIH3T3 BaF3 1.3 3.6 80 90 NA 41 62 24 L1196M NIH3T3 BaF3 21 43 843 1154 NA 70 250 113 G1269A NIH3T3 BaF3 15 80 605 689 NA 134 NA 112 G1202R NIH3T3 BaF3 77 113 1003 562 > 1000 549 > 10,000 362 I1151Tins NIH3T3 BaF3 38 50 1268 902 1066 296 1770 126 S1206Y NIH3T3 BaF3 4.2 3.2 626 152 NA 60 NA 29 C1156Y NIH3T3 BaF3 1.6 1.5 478 406 NA 177 NA 21 F1174L NIH3T3 BaF3 0.2 4.0 165 150 NA 161 NA 26 CD74-ROS1(s) Mutation Cellular ROS1 Phosphorylation Mean IC50 (nM) Lorlatinib Crizotinib Ceritinib NIH3T3 BaF3 0.23 0.11 11 3.9 51 G2032R BaF3 186 2033 2666 IC50 < 100 nM IC50 ≥ 100 < 200 nM IC50 ≥ 200 nM
Lorlatinib: Tumor Reduction in ROS1-Positive NSCLC Solomon. ASCO 2016. Abstr 9009. BestChangeFromBaseline(%) 20 0 -20 -40 -60 -80 -100 Ongoing treatment No prior TKI 1 prior TKI
Lorlatinib: Overall Efficacy in Crizotinib-Pretreated ROS1-Positive NSCLC Patients Shaw. Lancet Oncol. 2017;18:1590. Crizotinib Pretreated (n = 34) BOR, n (%) CR PR SD PD IND 2 (5.9) 7 (20.6) 16 (47.1) 3 (8.8) 6 (17.6) ORR, n (%) 95% CI 9 (26.5) 12.9-44.4 Median TTR, mos Range 2.5 1.4-4.2 Median DoR, mos 95% CI NR 7.1-NR DoR ≥ 12 mos, n⁰/N (%) 5/9 (55.6) Median PFS, mos 95% CI 8.5 4.4-18.0Patients with at least 1 on-study target lesion assessment as per independent central review were included. If any procedure was different and not interchangeable from the procedure at screening, the percent change from baseline could not be calculated and is not displayed. 70 60 10 0 30 20 50 40 -10 -20 -30 -40 -50 -60 -70 -80 -90 -100 BestChangeFromBaseline(%) Indeterminate (IND) CR PR Stable disease (SD) Progressive disease (PD) Off treatment or PD occurred
Lorlatinib: Intracranial Efficacy in Crizotinib-Pretreated ROS1-Positive NSCLC Crizotinib Pretreated (n = 19)* IC-BOR, n (%) CR PR SD PD IND 8 (42.1) 2 (10.5) 5 (26.3) 0 4 (21.1) IC-ORR, n (%) 95% CI 10 (52.6) 28.9-75.6 Median IC-DoR, mos 95% CI NR 5.0-NR IC-DoR ≥ 6 mos, n⁰/N (%) 6/10 (60) *Based on all intracranial lesions. 70 60 10 0 30 20 50 40 -10 -20 -30 -40 -50 -60 -70 -80 -90 -100 BestChangeFromBaseline(%) Off treatment or PD occurred CR PR Stable disease (SD) Shaw. Lancet Oncol. 2017;18:1590. Patients with at least 1 on-study target lesion assessment as per independent central review were included. If any procedure was different and not interchangeable from the procedure at screening, the percent change from baseline could not be calculated and is not displayed.
Lorlatinib: Safety Summary (ROS1-Positive Patients) TRAEs in ≥ 10% of Patients, n (%) Total (N = 47) Grade 3 Grade 4 Hypercholesterolemia* 39 (83.0) 4 (8.5) 0 Hypertriglyceridemia* 28 (59.6) 9 (19.1) 0 Edema* 21 (44.7) 1 (2.1) 0 Peripheral neuropathy* 16 (34.0) 1 (2.1) 0 Cognitive effects* 11 (23.4) 0 0 Weight increased 10 (21.3) 3 (6.4) 0 Dizziness 7 (14.9) 2 (4.3) 0 Mood effects* 6 (12.8) 0 0 Lipase increased 6 (12.8) 3 (6.4) 0 Fatigue* 5 (10.6) 1 (2.1) 0 ALT increased 5 (10.6) 0 0 Arthralgia 5 (10.6) 0 0 Thrombocytopenia 5 (10.6) 0 1 (2.1) Safety Summary, n (%) Total (N = 47) TRAEs 45 (95.7) Grade 3/4 TRAEs 23 (48.9) TRAEs leading to dose delay 17 (36.2) TRAEs leading to dose reduction 11 (23.4) TRAEs leading to discontinuation 0 TRAEs leading to death 0 Shaw. Lancet Oncol. 2017;18:1590.
Dabrafenib + Trametinib in Previously Treated NSCLC With a BRAF Mutation  BRF113928: Single-arm, multicenter, open-label phase II trial  Interim analysis with N = 33 (safety population) ‒ 24 pts evaluated for efficacy  Primary endpoint: ORR (by investigator); secondary endpoints: PFS, OS, DoR, safety, tolerability, PK Dabrafenib 150 mg BID + Trametinib 2 mg QD (n = 20) Pts with progressing stage IV BRAF V600E–mutant NSCLC after 1-3 prior regimens (≥ 1 platinum- based) ECOG PS 0-2 (N = 40) Planchard D, et al. ASCO 2015. Abstract 8006. Dabrafenib 150 mg BID + Trametinib 2 mg QD (n = 20) If ≥ 6 responses Stage 1 Stage 2