Phase III CONVERT: Twice-Daily vs Once-Daily Concurrent CRT in Limited-Stage SCLC CCO Independent Conference Coverage* of the 2016 ASCO Annual Meeting, June 3-7, 2016 *CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs. CRT, chemoradiotherapy; SCLC, small-cell lung cancer. This activity is supported by educational grants from Amgen, Ariad, Bayer Healthcare Pharmaceuticals, Celgene Corporation, Genentech, Incyte, Merck, and Taiho Pharmaceuticals.

Once- vs Twice-Daily Concurrent CRT in LS-SCLC (CONVERT): Background SCLC: 10% to 15% of all lung cancers; ~ 30% present with limited stage or stage I-III disease[1] Concurrent CRT standard of care for pts with SCLC and good PS Median OS advantage with twice-daily concurrent CRT vs once-daily CRT (23 vs 19 mos; P = .004)[2] Grade 3/4 esophagitis: 32% with twice daily vs 16% with once daily Due to toxicity and logistics, twice-daily RT not widely adopted In the US, only 21% of patients given twice-daily RT in 2006-2007[3] Consensus lacking on standard RT regimen for LS-SCLC Phase III randomized, multinational study compared concurrent twice- daily CRT with once-daily CRT in pts with LS-SCLC and good PS[4] CRT, chemoradiotherapy; LS, limited-scope; PS, performance status; RT, radiotherapy; SCLC, small-cell lung cancer. 1. Shepherd FA, et al. J Thorac Oncol. 2007;2:1067-1077. 2. Turrisi AT, et al. N Engl J Med. 199928;340:265-271. 3. Komaki R, et al. Int J Radiat Oncol Biol Phys. 2012;83:e531-536. 4. Faivre-Finn C, et al. ASCO 2016. Abstract 8504. Slide credit: clinicaloptions.com

Twice-daily thoracic RT Once-daily thoracic RT Once- vs Twice-Daily Concurrent CRT in LS-SCLC (CONVERT): Phase III Design Stratified by center, chemotherapy cycles (4 vs 6), and PS (0-1 vs 2) Twice-daily thoracic RT 45 Gy/30F/19D* plus chemotherapy† (n = 274) LS-SCLC, ECOG PS 0-1 (or PS 2 if due to disease), FEV1 > 1L or 40% predicted, KCO > 40% predicted (N = 547) SD, PR, or CR PCI Once-daily thoracic RT 66 Gy/33F/45D* plus chemotherapy† (n = 273) No PCI < SD Primary endpoint: OS Secondary endpoints: treatment compliance, local PFS, metastatic PFS, toxicity (CTCAE v3.0), exploratory translational objectives including archival tissue, blood samples, germline DNA, and CTCs 3DCRT, 3 dimensional conformal radiotherapy; CTCs, circulating tumor cells; D, days; ECOG PS, Eastern Cooperative Oncology Group performance status; ENI, elective nodal irradiation; F, fractions; FEV1, forced expiratory volume in 1 sec; IMRT, intensity-modulated radiotherapy; KCO, carbon monoxide transfer coefficient; L, liter; LS-SCLC, limited-scope small-cell lung cancer; PCI, prophylactic cranial irradiation; PI, principle investigator; SD, stable disease. *RT started on Day 22 of chemotherapy Cycle 1 (3DCRT mandatory, IMRT allowed, ENI not allowed) †4 or 6 cycles of chemotherapy, (prespecified by PI based on their routine practice) Days 1-3, 22-24, 43-45, 64-66 consisting of cisplatin 25 mg/m2 Days 1-3 or cisplatin 75 mg/m2 Day 1 and etoposide 100 mg/m2 Days 1-3 Slide credit: clinicaloptions.com Faivre-Finn C, et al. ASCO 2016. Abstract 8504.

Once- vs Twice-Daily Concurrent CRT in LS-SCLC (CONVERT): Pt Characteristics Twice-Daily RT + Chemotherapy (n = 274) Once-Daily RT + Chemotherapy (n = 273) Median age, yrs (range) 62 (29-84) 63 (34-81) Male, % 53.7 55.0 ECOG PS, % 1 2 45.6 50.0 3.3 45.1 52.0 2.9 PET-CT staging, % Yes No 57.3 41.3 57.0 43.0 UICC/AJCC stage, % I II III 0.4 12.4 79.9 1.1 17.5 75.9 Smoking history Never Exsmoker Current smoker 63.5 34.3 1.5 59.7 38.8 Median gross tumor volume, cc (range) 81.6 (1.6-635.1) 85.6 (0.5-593.0) AJCC, American Joint Committee on Cancer; CRT, chemoradiotherapy; ECOG PS, Eastern Cooperative Oncology Group performance status; LS-SCLC, limited-scope small-cell lung cancer; RT, radiotherapy; UICC, Union for International Cancer Control. Slide credit: clinicaloptions.com Faivre-Finn C, et al. ASCO 2016. Abstract 8504.

Once- vs Twice-Daily Concurrent CRT in LS-SCLC (CONVERT): Treatment Delivery Radiotherapy Twice-Daily RT + Chemo (n = 274) Once-Daily RT + Chemo (n = 273) No thoracic RT given, % 7.3 9.5 Concurrent CRT, % Sequential CRT, % Not known 90.9 1.8 -- 87.9 2.2 0.4 IMRT,† % 15.7 17.4 PCI, % 88.0 86.0 Assessed for toxicity,† n 254 246 †Analysis in pts receiving concurrent or sequential CTRT. Chemotherapy Twice-Daily RT + Chemo (n = 274) Once-Daily RT + Chemo (n = 273) Cycles planned, % 4 6 68.6 31.4 67.0 33.0 Cycles delivered, % 58.8 20.4 57.1 19.4 Optimal treatment time achieved, % 64 48 Assessed for toxicity,* n 266 263 *5 pts died before toxicity assessment. CRT, chemoradiotherapy; IMRT, intensity modulated radiation therapy; LS-SCLC, limited-scope small-cell lung cancer; PCI, prophylactic cranial irradiation; RT, radiotherapy. RT Treatment Delivery, % Twice Daily (n = 249) Once Daily (n = 240) Full dose delivered 98 83 Optimal number of fractions delivered 86 80 Optimal treatment time achieved 64 48 Slide credit: clinicaloptions.com Faivre-Finn C, et al. ASCO 2016. Abstract 8504.

Once- vs Twice-Daily Concurrent CRT in LS-SCLC (CONVERT): OS Twice-Daily RT (n = 273) Once-Daily RT (n = 270) HR (95% CI; P Value) Median OS, mos (95% CI) 30 (24-34) 25 (21-31) 1.17 (0.95-1.45; P = .15) 1 yr, % (95% CI) 83 (78-87) 76 (71-81) 2 yr, % (95% CI) 56* (50-61) 51 (45-57) 3 yr, % (95% CI) 43 (37-49) 39 (33-45) CRT, chemoradiotherapy; LS-SCLC, limited-scope small-cell lung cancer; RT, radiotherapy. Median follow-up: 45 mos Slide credit: clinicaloptions.com Faivre-Finn C, et al. ASCO 2016. Abstract 8504.

Once- vs Twice-Daily Concurrent CRT in LS-SCLC (CONVERT): PFS Time to Progression (N = 543) Twice-Daily Concurrent CRT Once-Daily Concurrent CRT P Value Overall progression, n Median TTP, mos (95% CI) 182 15 (13-19) 190 14 (12-17) .26 Local progression, n 175 21 (16-28) 186 18 (16-22) .21 Metastatic progression, n 176 20 (16-25) 17 (14-22) .24 CRT, chemoradiotherapy; LS-SCLC, limited-scope small-cell lung cancer; TTP, time to progression. Slide credit: clinicaloptions.com Faivre-Finn C, et al. ASCO 2016. Abstract 8504.

Once- vs Twice-Daily Concurrent CRT in LS-SCLC (CONVERT): Toxicity Comparable toxicities in twice-daily and once-daily arms except for significantly more grade 3-5 neutropenia in twice-daily RT arm Similar rates of severe esophagitis, severe pneumonitis between treatment arms Late toxicities mostly grades 0-2 More grade 1/2 esophagitis with once-daily vs twice-daily RT: 16.7% vs 11.7% No myelitis grade > 1 1 pt with grade 4 pneumonitis in each arm AE, % Twice Daily Once Daily P Value (0-2 vs 3-5) Treatment-related neutropenia Grade 1/2 Grade 3-5 13.7 74.1 18.1 65.4 .03 Grade 3-5 esophagitis 18.5 19.2 .85 Grade 3-5 pneumonitis Deaths (from radiation pneumonitis), n 2.0 1 2.4 2 .70 AE, adverse event; CRT, chemoradiotherapy; LS-SCLC, limited-scope small-cell lung cancer; RT, radiotherapy. Slide credit: clinicaloptions.com Faivre-Finn C, et al. ASCO 2016. Abstract 8504.

Once- vs Twice-Daily Concurrent CRT in LS-SCLC (CONVERT): Conclusions Similar OS with both once-daily and twice-daily concurrent RT 2-yr OS: 56% with twice daily vs 51% with once daily Median OS: 30 mos with twice daily vs 25 mos with once daily Better survival than previously reported for both regimens More RT delivery in twice-daily arm Similar toxicities, with the exception of significantly more grade 3/4 neutropenia in twice daily arm No difference in grade 3/4 esophagitis (19% in both arms) Grade 3/4 radiation pneumonitis rare (2.5% vs 2.2%) Results support the use of either once-daily or twice-daily RT as SoC for pts with LS-SCLC and good PS CRT, chemoradiotherapy; LS-SCLC, limited-scope small-cell lung cancer; PS, performance status; RT, radiotherapy; SoC, standard of care. Slide credit: clinicaloptions.com Faivre-Finn C, et al. ASCO 2016. Abstract 8504.

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