INMUNOTERAPIA EN CÁNCER DE CABEZA Y CUELLO. JULIO LAMBEA SORROSAL Servicio de Oncología Médica CLÍNICO LOZANO BLESA ZARAGOZA

Transcripción

1 INMUNOTERAPIA EN CÁNCER DE CABEZA Y CUELLO JULIO LAMBEA SORROSAL Servicio de Oncología Médica CLÍNICO LOZANO BLESA ZARAGOZA

2 HISTORIA DEL TRATAMIENTO DE LOS TUMORES DE CABEZA Y CUELLO 2

3 HISTORIA DEL TRATAMIENTO DE LOS TUMORES DE CABEZA Y CUELLO AÑO 2000: 1º SIMPOSIUM INTERNACIONAL DE TUMORES DE CABEZA Y CUELLO AÑO 2001: NACE EL TTCC 3

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5 En 1884 se había observado cierta relación entre la infección por erisipela y la remisión de ciertos tumores y se dice que Anton Chekhov recogió datos sobre esa relación. 5

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7 INMUNOTERAPIA FDA Grants Nivolumab Breakthrough Designation for Head and Neck Cancer Published Online: Monday, Apr 25, Apr 2016 The FDA has granted a breakthrough therapy designation to nivolumab (Opdivo) as a treatment for patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) following a platinum-based therapy, according to the developer of the PD-1 inhibitor Bristol-Myers Squibb The FDA is expected to act on the review by Nov. 11, 2016, according to a written statement from Bristol-Myers Squib, makers of nivolumab.

8 8 INMUNOTERAPIA The FDA granted accelerated approval based on early data from 174 patients with HNSCC enrolled in the nonrandomized KEYNOTE-012 trial. These patients had HNSCC that continued to grow and spread despite treatment with a platinum-containing chemotherapy; the majority of patients in the trial previously had received at least two different courses of treatment. According to the FDA approval summary, 28 patients (16%) experienced a tumor response following treatment with pembrolizumab. In 23 (82%) of those patients, the tumor response lasted for 6 months or longer, and several have lasted for more than 2 years. Several patients in the trial had a complete response, according to data from the trial presented in JuneExit Disclaimer at the American Society of Clinical Oncology annual meeting by trial investigator Ranee Mehra, M.D.

9 Por qué nos hemos vuelto locos con la inmunoterapia? 9

10 Por qué nos hemos vuelto locos con la inmunoterapia? 10

11 Por qué nos hemos vuelto locos con la inmunoterapia?

12 Por qué nos hemos vuelto locos con la inmunoterapia? 12

13 RETOS Y PROBLEMAS DE LA INMUNOTERAPIA -Cuando parar, cómo valorar la respuesta? 13

14 PROBLEMAS -Cuando parar, cómo valorar la respuesta? -Qué diana seleccionar para diseñar tratamiento? Upadhyay R et al. Lymphoma: Immune Evasion Strategies. Cancers 2015, 7,

15 PROBLEMAS -Cuando parar, cómo valorar la respuesta? -Qué diana seleccionar para diseñar tratamiento? -Sostenibilidad? Combinaciones? De momento en cabeza y cuello solo en ensayo. DESDE EL PUNTO DE VISTA DEL ONCÓLOGO Y DEL PACIENTE MERECE LA PENA 15

16 PROBLEMAS -Cuando parar, cómo valorar la respuesta? -Qué diana seleccionar para diseñar tratamiento? -Sostenibilidad? Combinaciones? De momento en cabeza y cuello solo en ensayo. -Selección de pacientes PD-L1? 16

17 PROBLEMAS -Cuando parar, cómo valorar la respuesta? -Qué diana seleccionar para diseñar tratamiento? -Sostenibilidad? Combinaciones? De momento en cabeza y cuello solo en ensayo. -Selección de pacientes PD-L1? PD-L2? HPV? VEB? 17

18 PROBLEMAS -Cuando parar, cómo valorar la respuesta? -Qué diana seleccionar para diseñar tratamiento? -Sostenibilidad? Combinaciones? De momento en cabeza y cuello solo en ensayo. -Selección de pacientes PD-L1? PD-L2? HPV? VEB? - Qué dar a la progresión? 18

19 Study First Author SCCHN Presentatio n Type Slide Range CheckMate 141 Ferris Further Evaluations of Nivolumab Versus Investigator s Choice Chemotherapy for Recurrent or Metastatic (R/M) Squamous Cell Carcinoma of the Head and Neck (SCCHN): CheckMate 141 Oral

20 Phase 3 CheckMate 141 Study Design Nivolumab in R/M SCCHN After Platinum Therapy Randomized, global, phase 3 trial of the efficacy and safety of nivolumab vs investigator s choice in patients with R/M SCCHN Key Eligibility Criteria R/M SCCHN of the oral cavity, pharynx, or larynx Progression on or within 6 months of last dose of platinum-based therapy Irrespective of no. of prior lines of therapy Documentation of p16 to determine HPV status (oropharyngeal) Regardless of PD-L1 status a Stratification factor Prior cetuximab treatment a Tissue required for testing. R 2:1 Nivolumab 3 mg/kg IV Q2W Investigator s Choice Methotrexate 40 mg/m² IV weekly Docetaxel 30 mg/m² IV weekly Cetuximab 400 mg/m² IV once, then 250 mg/m² weekly Primary endpoint OS Other endpoints PFS ORR Safety DOR Biomarkers Quality of life DOR = duration of response; IV = intravenous; ORR = objective response rate; PFS = progression-free survival; Q2W = once every 2 weeks; R = randomized. Clinicaltrials.gov NCT

21 Demographics Nivolumab in R/M SCCHN After Platinum Therapy Nivolumab (n = 240) Investigator s Choice (n = 121) Total (N = 361) Median age, years <65, n (%) 172 (71.7) 76 (62.8) 248 (68.7) Smoking/tobacco use, n (%) Current/former 191 (79.6) 85 (70.2) 276 (76.5) Never 39 (16.3) 31 (25.6) 70 (19.4) ECOG performance status, n (%) 0 49 (20.4) 23 (19.0) 72 (19.9) (78.8) 94 (77.7) 283 (78.4) 2 1 (0.4) 3 (2.5) 4 (1.1) Not reported 1 (0.4) 1 (0.8) 2 (0.6) Number of prior lines of systemic cancer therapy, n (%) (44.2) 58 (47.9) 164 (45.4) 2 80 (33.3) 45 (37.2) 125 (34.6) 3 54 (22.5) 18 (14.9) 72 (19.9) p16 status a,b, n (%) Positive 63 (26.3) 29 (24.0) 92 (25.5) Negative 50 (20.8) 36 (29.8) 86 (23.8) Not tested 127 (52.9) 56 (46.3) 183 (50.7) a Required from patients with oropharyngeal cancer only. b Determined via p16 immunohistochemistry ECOG = Eastern Cooperative Oncology Group. 21

22 Overall Survival (% of patients) Investigator s Choice Overall Survival Nivolumab in R/M SCCHN After Platinum Therapy Median OS, mo (95% CI) HR (97.73% CI) P-value Nivolumab (n = 240) 7.5 (5.5, 9.1) (0.51, 0.96) Investigator s Choice (n = 121) 5.1 (4.0, 6.0) % (8.6, 26.8) No. at Risk Months Nivolumab year OS rate (95% CI) 36.0% (28.5, 43.4) 22

23 No. of patients Overall Survival Subgroups a Nivolumab IC Unstratified Hazard Ratio (95% CI) Overall (0.53, 0.91) Age category, years < (0.45, 0.89) 65 to < (0.56, 1.54) ECOG performance status (0.30, 1.23) (0.53, 0.96) Tobacco use Current/Former (0.52, 0.99) Never (0.32, 1.06) Prior lines of systemic therapy, n (0.48, 1.07) (0.40, 1.00) (0.38, 1.57) Intended IC therapy Methotrexate (0.43, 0.96) Docetaxel (0.53, 1.28) Cetuximab (0.22, 1.01) a Hazard ratios were not calculated for subgroups with fewer than 20 patients across both arms Favors Nivolumab Favors IC 23

24 Progression-Free Survival (% of patients) Investigator s Choice Progression-Free Survival Nivolumab in R/M SCCHN After Platinum Therapy Median OS, mo (95% CI) HR (97.73% CI) P-value Nivolumab (n = 240) 2.0 (1.9, 2.1) (0.70, 1.1) Investigator s Choice (n = 121) 2.3 (1.9, 3.1) month PFS rate (95% CI) % (14.6, 25.4) % (5.0, 16.9) No. at Risk Months Nivolumab

25 Objective Response Rate Nivolumab in R/M SCCHN After Platinum Therapy Nivolumab (n = 240) Investigator s Choice (n = 121) Objective response rate, n (%) 32 (13.3) 7 (5.8) 95% CI 9.3, , 11.6 Best overall response, n (%) Complete response 6 (2.5) 1 (0.8) Partial response 26 (10.8) 6 (5.0) Stable disease 55 (22.9) 43 (35.5) Progressive disease 100 (41.7) 42 (34.7) Not determined 53 (22.1) 29 (24.0) Time to response, mo Median (range) 2.1 ( ) 2.0 ( ) 25

26 Overall Survival (% of patients) Overall Survival (% of patients) Overall Survival by p16 Status Nivolumab in R/M SCCHN After Platinum Therapy p16-positive p16-negative HR (95% CI) 0.56 (0.32, 0.99) Nivolumab (n = 63) 10 Investigator s Choice 0 (n = 29) Months No. at Risk Nivolumab Investigator s Choice HR (95% CI) 0.73 (0.42, 1.25) Nivolumab (n = 50) Investigator s Choice 0 3 (n = 36) Months

27 Overall Survival (% of patients) Overall Survival (% of patients) Overall Survival by Tumor PD-L1 Expression at 1% Nivolumab in R/M SCCHN After Platinum Therapy PD-L1 1% PD-L1 < 1% Investigator s Choice HR (95% CI) 0.55 (0.36, 0.83) Nivolumab (n = 88) 10 Investigator s Choice (n = 61) Months o. at Risk Nivolumab HR (95% CI) 0.89 (0.54, 1.45) 50 Nivolumab (n = 73) Investigator s Choice (n = 38) Months

28 Overall Survival by Tumor PD-L1 Expression Level Nivolumab in R/M SCCHN After Platinum Therapy Nivolumab n = 240 Investigator s Choice n = 121 PD-L1 Expression n Median OS, mo n Median OS, mo Unstratified Hazard Ratio (95% CI) 1% (0.36, 0.83) 5% (0.30, 0.83) 10% (0.31, 1.01) < 1% (0.54, 1.45) < 5% (0.55, 1.21) < 10% (0.50, 1.06) Favors Nivolumab Favors Investigator s Choice 28

29 Overall Survival by Tumor p16 Status and PD-L1 Expression at 1% Nivolumab Investigator s Choice n Median OS, mo n Median OS, mo Hazard ratio (95% CI) PD-L1 1%/p16-positive (0.21, 1.19) PD-L1 1%/p16-negative (0.18, 1.10) PD-L1 < 1%/p16-positive (0.22, 1.39) PD-L1 < 1%/p16-negative (0.31, 2.19) The hazard ratios for OS favored nivolumab vs investigator s choice for all subgroups 29

30 Objective Response Rate by PD-L1 Expression Nivolumab in R/M SCCHN After Platinum Therapy PD-L1 Expression Level Nivolumab Objective Response Rate Investigator s Choice n/n % n/n % 1% 15/ / % 12/ / % 12/ / < 1% 9/ / < 5% 12/ / < 10% 12/ /

31 Treatment-Related Adverse Events Nivolumab in R/M SCCHN After Platinum Therapy Nivolumab (n = 236) Investigator s Choice (n = 111) Any grade Grade 3 4 Any grade Grade 3 4 Event n (%) n (%) n (%) n (%) Any treatment-related AE in 10% of patients a 139 (58.9) 31 (13.1) 86 (77.5) 39 (35.1) Fatigue 33 (14.0) 5 (2.1) 19 (17.1) 3 (2.7) Nausea 20 (8.5) 0 23 (20.7) 1 (0.9) Diarrhea 16 (6.8) 0 15 (13.5) 2 (1.8) Anemia 12 (5.1) 3 (1.3) 18 (16.2) 5 (4.5) Asthenia 10 (4.2) 1 (0.4) 16 (14.4) 2 (1.8) Mucosal inflammation 3 (1.3) 0 14 (12.6) 2 (1.8) Alopecia (12.6) 3 (2.7) Treatment-related select AEs Skin 37 (15.7) 0 14 (12.6) 2 (1.8) Endocrine 18 (7.6) 1 (0.4) 1 (0.9) 0 Gastrointestinal 16 (6.8) 0 16 (14.4) 2 (1.8) Hepatic 5 (2.1) 2 (0.8) 4 (3.6) 1 (0.9) Pulmonary 5 (2.1) 2 (0.8) 1 (0.9) 0 Hypersensitivity/infusion reaction 3 (1.3) 0 2 (1.8) 1 (0.9) Renal 1 (0.4) 0 2 (1.8) 1 (0.9) a One Grade 5 event (hypercalcemia) in the nivolumab arm and one Grade 5 event (lung infection) in the investigator s choice arm were reported. A second death occurred in the nivolumab arm subsequent to pneumonitis. 31

32 Quality of Life and Symptom Burden Actualización ESMO 2016 y NEJM

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34 Journal of Clinical Oncology - published online before print September 30,

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42 ASCO % 59%

43 Dose escalation Dose expansion Study design FASE I DURVALUMAB. ESMO 2016 Safety and Efficacy of Durvalumab, an Anti-PD-L1 Antibody, in Patients from a Squamous Cell Carcinoma of the Head and Neck (SCCHN) Expansion Cohort Durvalumab mg/kg q2w 15 mg/kg q3w x 1 year 10 mg/kg q2w x 1 year SCCHN (PD-L1 + and PD-L1 ) NSCLC (squamous + nonsquamous) Pancreatic adenocarcinoma Melanoma (uveal + cutaneous) Gastroesophageal cancer Triple-negative breast cancer Hepatocellular carcinoma (hepatitis C and B virus-positive) Eight additional tumour types After one year of treatment, patients enter follow-up Treatment beyond progressive disease was permitted in the absence of clinical deterioration and if the investigator considered that the patient continued to receive benefit Upon progressive disease during the followup period, retreatment was offered for up to an additional 12 months Key inclusion criteria Confirmed recurrent/metastatic SCCHN incurable with local therapy ECOG PS 0 1 Adequate organ function Key exclusion criteria Active autoimmune disease Prior severe or persistent irae Prior anti-pd-1 or anti-pd-l1 therapy Prior anti-ctla-4 therapy permitted PD-L1 + and PD-L1 patients Segal NH, et al. Poster presented at ASCO Poster

44 Segal NH, et al. Presented at ESMO

45 DEBEMOS SEGUIR INVESTIGANDO 45

46 CONCLUSIONES La inmunoterapia ofrece una oportunidad a pacientes que no tenían posibilidades, con sólida evidencia científica. Existen multitud de ensayos en marcha que posicionaran el uso de estos fármacos. El beneficio en SG de estos pacientes hoy por hoy se produce en respondedores. A priori no sabemos seleccionarlos adecuadamente. 46

47 GRACIAS