Faculty Mark A. Socinski, MD Professor of Medicine and Thoracic Surgery Director, Lung Cancer Section, Division of Hematology/Oncology Co-Director, UPMC Lung Cancer Center of Excellence Co-Director, Lung and Thoracic Malignancies Program University of Pittsburgh Pittsburgh, PA Activity Planners Shari J. Dermer, PhD Manager, Educational Strategy and Content Med-IQ Baltimore, MD Lisa R. Rinehart, MS, ELS Director, Editorial Services Med-IQ Baltimore, MD Lung Cancer Facts and Figures • Most common cause of cancer-related mortality in US • Accounts for more deaths than breast, prostate, and colorectal cancers combined • Histologically and molecularly a very heterogeneous disease • Unfavorable stage distribution at the time of diagnosis (screening not routinely practiced) • 25,000 to 30,000 never-smoking Americans will develop lung cancer this year (more common than esophageal, gastric, ovarian, testicular, Hodgkin, myeloma, CML) • Historically shrouded by therapeutic nihilism American Cancer Society. Facts & Figures. 2010. First-Line Considerations • How well established is the histologic diagnosis? • Is tissue available for “special” studies? – EGFR mutation, EML4-ALK, others • Optimal chemotherapy • Role of targeted therapies – Antiangiogenic – Anti-EGFR • Genotypically driven therapy • Treatment-related side effects and toxicities M. Socinski, MD. Molecular Profiling and Therapeutic Decision Making for Advanced NSCLC • NCCN1 – Test for EGFR mutations and ALK in lung adenocarcinoma, large-cell lung cancer, NSCLC NOS as determinants for treatment selection • ASCO2 – Test for EGFR mutations in patients with advanced NSCLC who are being considered for first-line treatment with an EGFR TKI • CAP/IASLC/AMP3 – Test for EGFR mutation and ALK fusion (+ others?) in NSCLC adenocarcinoma patients at the time of diagnosis and after a targeted therapy intervention (to assess for tumor evolution in the molecular profile) 1. NCCN. Clinical Practice Guidelines in Oncology. NSCLC V1.2014; 2. Keedy VL, et al. J Clin Oncol. 2011;29:2121-7; 3. Lindeman NI, et al. J Thorac Oncol. 2013;8:823-59. Mutations in NSCLC Distribution of Mutations in 733 Genotyped • Association between EGFR mutations and sensitivity to TKIs – Exon 19 deletion – Exon 21 (L858R) – Exon 18 (G719X) • Exon 20 insertion may predict resistance to TKIs • EGFR and KRAS mutations are mutually exclusive in NSCLC • 10% of Western and 50% of Asian NSCLC patients have mutation of EGFR • KRAS mutation associated with primary resistance to TKIs Presented by: Bruce E. Johnson, MD. NCCN. Clinical Practice Guidelines in Oncology. NSCLC V1.2014. ALK Translocations in NSCLC • ALK: anaplastic lymphoma kinase • Gene rearrangements: – Chromosome 2 inversion – Fusion with EML4 gene • Abnormal expression and activation • Rearrangement occurs in 2% to 5% of NSCLC • Occurs independently of EGFR or KRAS mutations • Predominantly in: – Young patients (50 years or younger) – Never- or former-smokers with adenocarcinoma Gridelli C, et al. Cancer Treat Rev.2013;39:466-72 ORRa by Independent Radiologic Review ORR ratio: 3.4 (95% CI: 2.5-4.7); P < 0.0001 ORR, % 60- 65.3 _ | _ _| Crizotinib (n = 172C) Pemetrexed (n = 99C) Docetaxel (n = 72C) 65.7 _ | _| 60- 40 19.5 _ | | _ 20 80 Crizotinib (n = 173b) Chemotherapy (n = 174b) ORR, % 80 40 29.3 _ | _| 20 6.9 _ | _| 0 0 Treatment Treatment Treatment-related AEs (≥ grade 3): elevated liver aminotransferase (16%) and neutropenia (13%); there was 1 patient with febrile neutropenia. Other common treatment-related AEs were visual impairment and GI disturbances. aRECIST v1.1 population cas-treated population bITT Shaw AT, et al. N Engl J Med. 2013;368:2385-94. Cisplatin/Pemetrexed vs. Cisplatin/ Gemcitabine in Advanced NSCLC: Results Squamous Median Survival 11.8 mos 10.4 mos Adjusted HR CP vs. CG 0.81;0.70, 0.94 0.81 Survival Time (months) in Patients With Nonsquamous Histology Survival Probability Survival Probability Nonsquamous Median Survival 9.4;8.4, 10.2 9.4 mos 10.8;9.5, 12.1 10.8 mos CP vs. CG Adjusted HR 1.23;1.00,1.23 1.51 Survival Time (months) in Patients With Squamous-Cell Carcinoma Reprinted with permission from Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 2008;26(21):3543-3551. Efficacy Outcomes in Trials of Sequential vs. Delayed Second-Line Therapy Fidias1 JMEN2 SATURN3 ATLAS4 562/307 (55%) ?/663 (?) 1,949/889 (46%) 1,145/743 (66%) RR (%) Rx vs. control 11 vs. 11* 3 vs. 1 12 vs. 5 NR DCR (%) Rx vs. control 67 vs. 56* 49 vs. 29 61 vs. 51 NR PFS HR (P value) NR (< 0.0001) 0.60 (< 0.00001) 0.71 (< 0.0001) 0.71 (0.001) ∆ in Med PFS 3.7 months 2 months 1 week 1.1 months OS HR (P value) NR (0.085) 0.79 (0.012) 0.81 (0.008) NS ∆ in MST 2.6 months 2.8 months 1 month 1.1 months No. of patients (entered/ randomized after 4 cycles) * Compares patients treated on the immediate vs. delayed docetaxel arms 1. Fidias PM, et al. J Clin Oncol. 2009;27:591-8; 2. Belani CP, et al. Lancet Oncol. 2012;13:292-9; 3. Cappuzzo F, et al. Lancet Oncol. 2010;11:521-9; 4. Johnson B, et al. J Clin Oncol. 2013;31:3926-34. Maintenance Therapy: Strategies • Continuation – Continuing one of the same agents from the original combination – Continuing a targeted agent • Switch – Initiating a new agent NCCN. Clinical Practice Guidelines in Oncology. NSCLC V1.2014. AVAPERL: Trial Design First-line induction 4 cycles, q3w Previously untreated stage IIIB-IV nsNSCLC N = 376 Bevacizumabb + pemetrexedb + cisplatinb PD Follow-Up Stratification factors: • Gender • Smoking status • Response at randomization Continuation maintenance q3w until PD CR/PR/SD Per RECISTC R N = 253 67% Arm A: Bevacizumab N = 125 Arm B: Bevacizumab + pemetrexed* N = 128 Primary objective: PFS Secondary objectives: OS, response rate, DCR, duration of response, duration disease control, safety, QOL aRandomized open-label phase 3 study of bevacizumab = 7.5 mg/kg; dose of pemetrexed = 500 mg/m 2; dose of cisplatin = 75 mg/m2. RECIST-related end points measured from the preinduction phase bDose *Investigational Barlesi F, et al. ESMO 2011.[Abstract 34LBA]. Slide courtesy of F Barlesi. PFS From Date of Randomization, % AVAPERL: PFS 100 – Bev+pem 7.4 months (81 events) Bev 3.7 months (104 events) HR, 0.48 (0.35-0.66); P < 0.001 75 – Cont. maintenance bev+pem (n = 128) Cont. maintenance bev (n = 125) 50 – 25 – 0 –| 0 Patients at risk Bev+pem 128 Bev 125 | 3 | 6 104 73 67 36 | 9 Time, months 25 13 | 12 | 15 4 2 0 0 Median follow-up time in ITT population (excluding induction): 8.28 months (bev+pem arm), 7.95 months (bev arm) Barlesi F, et al. ESMO 2011.[Abstract 34LBA]. Slide courtesy of F Barlesi. PointBreak: Pemetrexed/Carboplatin/Bevacizumab* vs. Paclitaxel/Carboplatin/Bevacizumab Inclusion Criteria: Stage IIIB/IV NSCLC ECOG PS 0-1 No prior systemic Rx for lung cancer Exclusion Criteria: Peripheral neuropathy ≥ grade 1 Uncontrolled pleural effusions *Investigational R A N D O M I Z E Arm A 450 patients Arm B 450 patients Pemetrexed 500 mg/m2 IV q21d Carboplatin AUC of 6 IV q21d Bevacizumab‡ 15 mg/kg IV q21d Pemetrexed* 500 mg/m2 IV q21d Bevacizumab‡ 15 mg/kg IV q21d Paclitaxel 200 mg/m2 IV q21d Carboplatin AUC of 6 IV q21d Bevacizumab‡ 15 mg/kg IV q21d Bevacizumab‡ 15 mg/kg IV q21d Induction Therapy: Up to four 21-day cycles Patients with CR, PR, or SD after 4 cycles of induction therapy continue on to maintenance therapy Maintenance Therapy: Until PD or treatment discontinuation Reprinted with permission from Patel JD, Bonomi P, Socinski MA, et al. Treatment rationale and study design for the pointbreak study: a randomized, open-label phase III study of pemetrexed/carboplatin/bevacizumab followed by maintenance pemetrexed/bevacizumab versus paclitaxel/carboplatin/bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer. Clin Lung Cancer. 2009;10(4):252-256. PointBreak: OS and PFS for the Maintenance Population Survival Probability OS 1.0 — 0.9 — 0.8 — 0.7 — 0.6 — 0.5 — 0.4 — 0.3 — 0.2 — 0.1 — 0.0 — | 0 Pem+Cb+Bev Pac+Cb+Bev (n = 292) (n = 298) OS median (mos) 17.7 15.7 Censoring (%) 36.0 30.2 Bev | 3 | 6 | 9 | 12 | | 15 18 Pem-Bev | | | 21 24 27 | | 30 33 PFS | | 36 39 Prespecified exploratory non-comparative subgroup analyses Survival Probability Time From Induction, months 1.0 — 0.9 — 0.8 — 0.7 — 0.6 — 0.5 — 0.4 — 0.3 — 0.2 — 0.1 — 0.0 —| 0 Pem+Cb+Bev Pac+Cb+Bev (n = 292) (n = 298) PFS median (mos) 8.6 6.9 Censoring (%) 24.7 14.1 Pem-Bev Bev | 3 | 6 | 9 | 12 | 15 | | | 18 21 24 | | 27 30 Time From Induction, months | | 36 33 Reprinted with permission from Patel JD, Socinski MA, Garon EB, et al. PointBreak: a randomized phase III study of pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer. J Clin Oncol. 2013;31(34):4349-4357. Supportive Care Issues in NSCLC • • • • • • Smoking cessation Pain/discomfort management Nutrition Psychosocial issues Palliative care Patient preferences – Treatment – Palliative care Acknowledgement of Commercial Support This activity is supported by educational grants from Bayer HealthCare Pharmaceuticals, Onyx Pharmaceuticals, Celgene Corporation, Daiichi Sankyo, Inc., and Lilly. For further information concerning Lilly grant funding visit www.lillygrantoffice.com Copyright © 2014 Med-IQ®. All rights reserved.