Novedades en cáncer de pulmón microcítico y mesotelioma Bartomeu Massutí [email protected] @bmassutis Indice Situación epidemiológica y resultados terapéuticos Carcinoma microcítico: estrategia terapéutica inicial Carcinoma microcítico e inmunoterapia Carcinoma microcitico pretratado Carcinoma microcítico: líneas de investigación Mesotelioma: líneas de investigación Epidemiology Worldwide age standardized mesothelioma incidence rates (per 100,000) for males in 1998–2002 SCLC 200.000 new cases/year 2/3 Stage IV Median Survival / Overall Survival 5 years (SEER) The WHO estimated that ≈ 107.000/y people in the world die from asbestos-related disease 1983-1992 1993-2003 2003-2012 EUROCARE-5 (2000-07): European mean pleural Cancers: 34.146 (Spain 226). 5y RS: 7.2% 7 months / 7 months / 7 months / 4.9% 5.9% 6.4% 2003: MPM CDDP/Pemetrexed Nothing new. No 2nd line EMPHACIS Current therapeutic strategy and outcomes for SCLC • 1L treatment for unresectable SCLC generally consists of Pt-doublet chemotherapy (±RT in LD) – Most patients relapse within 1 year of diagnosis, even when responsive to therapy – Treatment decisions in SCLC must often account for comorbidities due to smoking history • Outcomes improvement have relied on Radiotherapy • Five-year survival rates for patients with SCLC are poor – LS-SCLC: 10–13% – ES-SCLC: 1–2% • Historical lack of consensus for SOC treatment in 2L+ SCLC – Topotecan has limited efficacy in 2L setting (7% ORR) – Nivolumab monotherapy approved for 3L+ SCLC (USA, FDA) Genomic instability characteristic of SCLC Sabari et al., Nat Rev Clin Oncol. 2017 Immunotherapy DLL3 inhibitors Roval T Nocht inhibitors PARP inhibitors Aurora Kinase Veliparib Alisertib Methylation Sabari et al., Nat Rev Clin Oncol. 2017 0.5%-3.0% of patients with SCLC develop Lambert- Eaton syndrome, which involves an immune response to tumor antigens and nerve cells, and have a better prognosis, presumably due to the antitumor immune response Phase III CA184-156 trial randomized trial of platinum/ etoposide plus ipilimumab or placebo in 1L for ED-SCLC patients • No signal of efficacy was observed with the addition of ipilimumab • Toxicity was significantly higher (mainly diarrhea and rash) in the ipilimumab arm • Discontinuation rate was higher in the ipilimumab arm (18% vs 2%) Phase I/II CheckMate 032 trial: evaluation of nivolumab +/- ipilimumab in pretreated ED- SCLC population unselected for PD-L1 expression Key patient inclusion criteria Nivolumab 3 mg/kg IV q2w (n=40) •SCLC •Progressive disease Nivolumab 1 mg/kg + •≥1 prior therapy including ipilimumab 1 mg/kg IV first-line platinum-based q3w for 4 cycles (n=3) Nivolumab 3 mg/kg IV therapy Nivolumab 1 mg/kg + q2w •Unselected by PD-L1 ipilimumab 3 mg/kg IV expression q3w for 4 cycles (n=47) (n=128) Nivolumab 3 mg/kg + ipilimumab 1 mg/kg IV q3w for 4 cycles (n=38) Primary endpoint • ORR per RECIST v1.1 Long-term sustained benefit is observed in some unselected ED- SCLC patients 100 Events / No. Median OS, Minimum follow-up, at risk months (95%CI) months Nivolumab 82/98 4.1 (3.0, 6.8) 19.6 80 Nivolumab + ipilimumab 47/61 7.8 (3.6, 14.2) 20.2 60 1-yr OS = 40% OS, % 40 2-yr OS = 26% 1-yr OS = 27% 20 2-yr OS = 14% 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 No. at risk Time,months Nivolumab 98 56 39 35 26 21 17 12 7 7 5 4 4 0 Nivolumab + 61 43 33 26 24 21 19 16 14 7 3 1 1 0 ipilimumab 11.9% ORR Pooled analysis of activity of pembrolizumab as 3/+ line in advanced SCLC: Results from the KEYNOTE-028 and KEYNOTE-158 studies CPI in >Second Line SCLC N ORR(%) mPFS (months) mOS 1 -Year OS (%) Atezolizumab 49 2 1.4 9.5 NR (IFCT-1603)¹ Nivolumab (CM- 98 10 1.4 4.1 33 032)² Pembrolizumab 24 1.9 9.7 38 (KN-028)³ 33 (PD-L1+) Pembrolizumab 107 19 2 9.1 40 (KN-028)⁴ Atezolizumab 17 6 NA NA NA (PCD4989)⁵ Durvalumab⁶ 21 10 1.5 4.8 28 Nivolumab (CM- 284 14 1.4 7.8 37 331)⁷ ¹Pujol JTO 2019; ²Hellman ASCO 2017 abstr 8503; ³ Ott J Clin Oncol 2017; ⁴ Chung ASCO 2018 abstr 8506; ⁵ Goldaman Asco 2018 abstr 8518; ⁶Sequist ESMO 2017 abstr 1425; ⁷ Reck ESMO IO 2018 20 IMpower133: Global Phase 1/3, double-blind, randomized, placebo-controlled trial evaluated atezolizumab + carboplatin + etoposide in 1L ES-SCLC Patients (N = Induction (4 x 21-day cycles) Maintenance 403): • Measurable ES- Atezolizumab (1200 mg IV, Day 1) SCLC + carboplatin Atezolizumab (RECIST v1.1) + etoposide up - • ECOG PS 0 or 1 Treat until • No prior systemic R PD or loss 1:1 of clinical treatment for ES- benefit SCLC Placebo • Patients with treated + carboplatin Placebo follow Survival asymptomatic brain + etoposide metastases were eligible Carboplatin: AUC 5 mg/mL/min IV, Day 1 Etoposide: 100 mg/m2 IV, Days 1–3 PCI per local standard of care Stratification: • Sex (male vs. female) Co-primary end points: Key secondary end points: • ECOG PS (0 vs. 1) • Overall survival • Objective response rate • Investigator-assessed PFS • Duration of response • Brain metastases • Safety (yes vs. no)a a Only patients with treated brain metastases were eligible. ECOG PS, Eastern Cooperative Oncology Group Performance Status; IV, intravenous; PCI, prophylactic cranial irradiation; PD, progressive disease; PFS, progression-free survival; R, randomized; RECIST, Response Evaluation Criteria In Solid Tumors. Baseline characteristics Atezolizumab + CP/ET Placebo + CP/ET Characteristic (N = 201) (N = 202) Median age (range) — years 64 (28−90) 64 (26−87) Age group — no. (%) < 65 years 111 (55) 106 (52) ≥ 65 years 90 (45) 96 (48) Male sex — no. (%)a 129 (64) 132 (65) Smoking statusb Current smoker 74 (36.8) 75 (37.1) Former smoker 118 (58.7) 124 (61.4) Race — no. (%) White 163 (81) 159 (79) Asian 33 (16) 36 (18) Other 5 (2) 7 (3) ECOG PS — no. (%)a 0 73 (36) 67 (33) 1 128 (64) 135 (67) Brain metastases — no. (%)a Yes 17 (8) 18 (9) Liver metastases — no. (%) Yes 77 (38) 72 (36) Clinical data cutoff date: April 24, 2018. a Data reported per electronic case report form. b Nine patients in the atezolizumab group and three patients in the placebo group have never smoked. CP/ET, carboplatin + etoposide. Overall survival Atezolizumab Placebo + CP/ET + CP/ET 100 (N = 201) (N = 202) OS events, n (%) 104 (51.7) 134 (66.3) 90 Median OS, 12.3 10.3 80 months (95% CI) (10.8, 15.9) (9.3, 11.3) 12-month OS 0.70 (0.54, 0.91) 70 HR (95% CI) p = 0.0069 60 51.7% Median follow-up, 13.9 monthsa 50 40 Atezolizumab 30 + CP/ET Overall survival (%) survival Overall 38.2% Placebo 20 + CP/ET 10 + Censored 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 No. at risk Months Atezolizumab 201 191 187 182 180 174 159 142 130 121 108 92 74 58 46 33 21 11 5 3 2 1 Placebo 202 194 189 186 183 171 160 146 131 114 96 81 59 36 27 21 13 8 3 3 2 2 a Clinical data cutoff date: April 24, 2018, 11 months after the last patient was enrolled. CI, confidence interval; HR, hazard ratio; CP/ET, carboplatin + etoposide. Investigator-assessed progression-free survival Atezolizumab Placebo 100 + CP/ET + CP/ET (N = 201) (N = 202) 90 PFS events, n (%) 171 (85.1) 189 (93.6) 80 Median PFS, 5.2 4.3 70 months (95% CI) (4.4, 5.6) (4.2, 4.5) 0.77 (0.62, 0.96) 60 HR (95% CI) 6-month PFS p = 0.017 50 Median follow-up, a 13.9 free survival (%) survival free months - 40 30.9% 12-month PFS Atezolizumab 30 + CP/ET Placebo 20 12.6% + CP/ET Progression 10 22.4% + Censored 5.4% 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 No. at risk Months Atezolizumab 201 190 178 158 147 98 58 48 41 32 29 26 21 15 12 11 3 3 2 2 1 1 Placebo 202 193 184 167 147 80 44 30 25 23 16 15 9 9 6 5 3 3 a Clinical data cutoff date: April 24, 2018, 11 months after the last patient was enrolled. CI, confidence interval; HR, hazard ratio; CP/ET, carboplatin + etoposide. Confirmed objective response and duration of response 70 Atezolizumab + CP/ET 60 Placebo + CP/ET Atezolizumab Placebo 50 + CP/ET + CP/ET Duration of response (N = 121) (N = 130) 40 Median duration, months 4.2 3.9 (range) (1.4a to 19.5) (2.0 to 16.1a) 30 HR (95% CI) 0.70 (0.53, 0.92) Response (%) Response 6-month event-free rate 32.2 17.1 20 — % 12-month event-free rate 14.9 6.2 10 — % Patients with ongoing 18 (14.9) 7 (5.4) 0 response — no. (%)b CR CR/PR SD PD a Censored. b At clinical cutoff date: April 24, 2018. CR, complete response; EFS, event-free survival; PD, progressive disease; PR, partial response; SD, stable disease. Overall survival in subgroups Median overall survival (months) OS hazard ratioa Population Atezolizumab + CP/ET Placebo + CP/ET (95% CI) Male (n = 261) 12.3 10.9 0.74 (0.54, 1.02) Female (n = 142) 12.5 9.5 0.65 (0.42, 1.00) < 65 years (n = 217) 12.1 11.5 0.92 (0.64, 1.32) ≥ 65 years (n = 186) 12.5 9.6 0.53 (0.36, 0.77) ECOG PS 0 (n = 140) 16.6 12.4 0.79 (0.49, 1.27) ECOG PS 1 (n = 263) 11.4 9.3 0.68 (0.50, 0.93) Brain metastases (n = 35) 8.5 9.7 1.07 (0.47, 2.43) No brain metastases (n = 368) 12.6 10.4 0.68 (0.52, 0.89) Liver metastases (n = 149) 9.3 7.8 0.81 (0.55, 1.20) No liver metastases (n = 254) 16.8 11.2 0.64 (0.45, 0.90) bTMB < 10 mut/mb (n = 139) 11.8 9.2 0.70 (0.45, 1.07) bTMB ≥ 10 mut/mb (n = 212) 14.6 11.2 0.68 (0.47, 0.97) bTMB < 16 mut/mb (n = 271) 12.5 9.9 0.71 (0.52, 0.98) bTMB ≥ 16 mut/mb (n = 80) 17.8 11.9 0.63 (0.35, 1.15) ITT (N = 403) 12.3 10.3 0.70 (0.54, 0.91) 0.1 1.0 2.5 Clinical data cutoff date: April 24, 2018.