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Home , Nimotuzumab

Innovación en Ca Gástrico 2ª línea de tratamiento

Ramon Salazar Instituto Catalán de Oncología mOS in second-line setting

Salati M, et al. ESMO Open 2017 Nutritional score and suport

Quiu M, et al. Support Care Cancer 2015, 23:1933-9

ICO+centre. Servei/Unitat 2nd Line: Positive Studies

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Salati M, et al. ESMO Open 2017 Kim, et al. Second-line versus supportive cancer treatment in advanced gastric cancer: a meta-analysis. Ann Oncol 2013 2nd Line recent trials

Fármaco / Estudio Tratamiento Objetivo ppal

Inhibidores HER2 (rama experimental vs rama estándar)

Lapatinib, TyTAN Taxol +/- SG (11 vs 8.9, HR 0.84, p no sign) (HER2 – EGFR1) T-DM1 Taxol/TXT vs T-DM1 SG ----- (ongoing)

Inhibidores EGFR1

Nimotuzumab CPT11 +/- Nimotuzumab SG ----- (ongoing)

Inhibidores Angiogénesis

Ramucirumab, REGARD vs Placebo SG (3.8 vs 5.2, HR 0.77, p sign) VEGFR2 Ramucirumab, RAINBOW Taxol +/- Ramucirumab SG (9.6 vs 7.3, HR 0.80, p sign) VEGFR2 Inhibidores mTOR

Everolimus, GRANITE-1 BSC +/- Everolimus SG (5.4 vs 4.3mo, HR 0.90, p no sign) 2aL o 3aL

TyTAN; Satoh, et al. J Clin Oncol 2014; T-DM1; NCT01641939; NIMO; NCT01813253; APATINIB; Shukui Q, et al. J Clin Oncol 32:5s, 2014 (suppl; abstr 4003); REGARD; Fuchs CS et al. Lancet Oncol 2014; RAINBOW; Wilke H et al. Lancet Oncol 2014; GRANITE-1; Ohstu, et al. J Clin Oncol 2013

Ramucirumab in GC

• A fully human immunoglobulin (Ig) G1 targeting VEGFR-2

• Has demonstrated improved survival both as monotherapy (REGARD study 1) and in combination with paclitaxel (RAINBOW study 2) in the second-line setting

• FDA and EMA *

1. Fuchs CS et al. Lancet Oncol 2014 2. Wilke H et al. Lancet Oncol 2014 REGARD study

Stratified by: geographic region (asia only 7-8%), weight loss (> vs < 10% over 3 mos), location of primary tumor (gastric vs GEJ)

Metastatic gastric or GEJ adenocarcinoma Ramucirumab 8 mg/kg IV q2w + BSC progressing on first-line 2 (n = 238) platinum-and/or Treatment until fluoropyrimidine-containing PD, unacceptable combination therapy, toxicity, or death ECOG PS 0-1 BSC + Placebo (N = 355) * 1 (n = 117) (NO crossover)

• Primary endpoint: OS. Secondary endpoints: PFS, 12-wk PFS, ORR, DOR, QoL, safety and ramucirumab immunogenicity • Inclusion and exclusion criteria: 4m 1stL or 6m adj. Anti-angiogenic therapy Fuchs CS et al. Lancet Oncol 2014 Resultados SG

Fuchs CS et al. Lancet Oncol 2014 REGARD study

Good toxic-effect profile HR 0.77 – Δ mOS = 1.4m AE special interest Ramu Placebo All G3o+ All G3o+ Hypertension 16% 8% 8% 3% Tumor Response Ramucirumab Placebo Bleeding or haemorrh. 13% 3% 11% 3% <1% 0 CR Arterial thromboemb. 2% 1% 0 0 3% 3% PR Venous thromboemb. 4% 1% 7% 4%

SD 45% 21% Proteinuria 3% <1% 3% 0

Progressive disease 33% 54% GI perforation <1% <1% <1% <1%

Not evaluable 18% 23% Fistula formation <1% <1% <1% <1%

Infusion-related reaction <1% 0 2% 0

DCR (CR+PR+SD) 49% 23% Cardiac failure <1% 0 0 0 P<0.0001

Fuchs CS et al. Lancet Oncol 2014 RAINBOW study

Stratified by: geographic region, measurable vs nonmeasurable disease; TTP on first-line treatment (< 6 4-wk cycle mos vs ≥ 6 mos)

Ramucirumab 8 mg/kg D 1, 15 Metastatic or locally 1 Paclitaxel 80 mg/m2 D 1, 8, 15 advanced gastric cancer (n = 330) or GEJ cancer and Progression or progression on first-line intolerable toxicity chemotherapy Placebo D 1, 15 2 ECOG PS 0-1 1 Paclitaxel 80 mg/m D 1, 8, 15 (N = 665) (n = 335) (NO crossover)

• Primary endpoint: OS. Secondary endpoints: PFS, ORR, TTP, QoL (EORTC-QLQ-C30 y EQ-5D), safety and ramucirumab immunogenicity • Inclusion and exclusion criteria: (= REGARD study).

Wilke H et al. Lancet Oncol 2014 Resultados Supervivencia Global

Wilke H et al. Lancet Oncol 2014 RAINBOW study

Ramucirumab Placebo + Paclitaxel + Pacliatxel AE (> 10%) All G3o+ All G3o+ Fatigue 57% 12% 44% 6%

Neutropenia* 54% 41% 31% 19% Tumor response Ramucirumab Placebo + + Neuropathy 46% 8% 36% 5% Paclitaxel Pacliatxel Bleed./hemorrhage (incl. epistaxis) 42% 4% 18% 2% Response Rate 28% 16% P=0.0001 Decreased appetite 40% 3% 32% 4% Disease Control Rate 80% 64% Abdominal pain 36% 6% 30% 3% (CR+PR+SD) p<0.0001 Anaemia 35% 9% 36% 10%

Diarrhea 32% 4% 23% 2% Post-progression Ramucirumab Placebo treatment + + Epistaxis 31% 0% 7% 0% Paclitaxel Pacliatxel Vomiting 27% 3% 21% 4% QT 48% 45% Hypertension 25% 15% 6% 3%

Peripheral edema 25% 2% 14% 1%

Proteinuria 17% 1% 6% 0%

Thrombocytopenia 14% 2% 6% 2% *Febrile neutropenia (G3o+): 3% vs 2% AE leading to death: 6 pac (2%) vs 5 pac (2%) GI hemorrhage 10% 4% 6% 2%

3ª linea

• Apatinib, a novel VEGFR-2 selective TK inhibitor (Asian)

Apatinib Apatinib vs Placebo SG (195 vs 140 days, HR 0.71, p sign) TKI VEGFR2 / 3aL • (GRANITE) ongoing

• PD1 inhibitors – –

ICO+centre. Servei/Unitat

KEYNOTE-061 Nivolumab en Cáncer Gástrico o de la Unión Gastroesofágica Avanzado

ATTRACTION-2 Phase 3 Study11,a CheckMate-032 Phase 1/2 Study12,b (Asian) (Western)

Patients with advanced/metastatic G/GEJ/E cancer with progression on ≥ 1 prior chemotherapy Nivolumab (N = 160) 3 mg/kg IV Q2W (n = 330) • Unresectable

Primary endpoint: advanced or • OS G/GEJ/E cancer recurrent G/GEJ nivolumab monotherapy cancer 2:1 Other endpoints: 3 mg/kg IV Q2W cohort Primary endpoint: • Refractory • Safety (n = 59) • ORR to/intolerant of • ORR, PFS, ≥ 2 standard Randomization • DOR Other endpoints: therapy regimens • Safety Placebo • OS, PFS, Subset of patients with G/GEJ cancer (n = 163) DOR and ≥ 2 prior regimens (n = 42) aData cutoff for ATTRACTION-2 was August 2016; bData cutoff for CheckMate-032 was March 2016, except for OS analyses (November 2016) DOR = duration of response; E = esophageal; G = gastric; GEJ = gastroesophageal junction ATTRACTION-02: 2L+ Nivolumab monotherapy Overall Survival 100 Nivolumab Median follow-up*: 15.7 months (range, 12.1–27.2) 90 Median OS, months 80 (95% CI)

70 Nivolumab 5.3 (4.6–6.4) Placebo 60 Placebo 4.1 (3.4–4.9)

50 Hazard ratio, 0.62 (95% CI: 0.50–0.76)

40 12-month OS rate P < 0.0001

30 27% Overall Survival (%) Survival Overall 24-month OS rate 20 12% 12% 10 5% 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 Months No. at Risk Nivolumab 330 275 192 143 123 97 84 54 34 22 12 7 6 1 0 Placebo 163 121 82 54 37 24 18 8 6 5 4 3 3 2 0

• Compared to placebo, treatment with nivolumab resulted in a 38% reduction in risk of death

*Time from first dose to data cut-off for surviving patients. CI, confidence interval; OS, overall survival. Boku N et al. Oral presentation at ESMO 2017. Abstract 617O. CHANGING CLINICAL PRACTICE

Kang YK et al. Lancet 2017. Published online October 6, 2017 https://news.bms.com/press-release/corporatefinancial-news/japan-ministry-health-labor-and-welfare-approves-opdivo-nivolu Results

Table 2. Clinical benefit in Asian and Western patientsa ATTRACTION-211 CheckMate-032 G/GEJ cancer12,b

Placebo Nivolumab Nivolumab n = 163 n = 330 n = 42 4.1 5.3 8.5 (3.4, 4.9) (4.6, 6.4) (3.3, 15.0) Median OS (95% CI), mo P < 0.0001 NA HR: 0.63 (0.51, 0.78) 12-mo OS rate (95% CI), % 11 (6, 17) 26 (21, 32) 44 (28, 59) 1.45 (1.45, 1.5) 1.6 (1.5, 2.3) 1.4 (1.3, 2.3) Median PFS (95% CI), mo P < 0.0001 NA HR: 0.60 (0.49, 0.75)

aNivolumab data shown are from different clinical trials and should not be directly compared; median follow-up (in surviving patients) was 8.9 months (IQR: 6.6–12.4) in the nivolumab group and 8.6 months (IQR: 5.65–11.4) in the placebo group in ATTRACTION-211; median follow-up (from first dose to data cutoff) was 27.9 months (range: 17.0–35.2) for OS and 19.75 months (range: 9.5–27.7) for PFS in CheckMate-03212; bPatients with ≥ 2 prior regimens IQR = interquartile range • ORR (by investigator assessment) with nivolumab was 11% (95% CI: 8, 16) in Asian patients11 and 17% (95% CI: 7, 31) in Western patients12 Summary

Nutritional SCORE¡¡¡ & SUPPORT

/ PD-1 inh

Salati M, et al. ESMO Open 2017 Biomarkers

Gulley P. ASCO GI 2018 MUCHAS GRACIAS [email protected] @RamonSalazarS www.tertuliasoncologicas.com @TOncologicas

ICO+centre. Servei/Unitat New Trials

Takahari D, et al. Gastric Cancer (2017) 20:395–406