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Sesión servicio NSCLC
 

Sesión servicio NSCLC

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  • NCI. Non-small-cell lung cancer treatment (PDQ®). http://www.cancer.gov/cancertopics/pdq/treatment/non-small-cell-lung/healthprofessional/page1. Accessed May 15, 2013. <br /> ACS. Cancer facts & figures: 2012. CDC. Lung cancer rates by race and ethnicity. Available at http://www.cancer.org/acs/groups/content/@epidemiologysurveilance/documents/document/acspc-031941.pdf. Accessed May 15, 2013. <br /> Howlader N, et al. SEER cancer statistics review. Available at: http://seer.cancer.gov/csr/1975_2009_pops09. Accessed May 15, 2013. <br />
  • BAC, bronchioloalveolar carcinoma; LPA, lepidic predominant adenocarcinoma; NOS; not otherwise specified; SCC, squamous cell carcinoma; SCLC, small cell lung cancer; <br />
  • CI, confidence interval; HR, hazard ratio; PFS, progression-free survival. <br /> Median OS: no significant difference between arms overall, and in patients with or without EGFR mutations <br />
  • ALK, anaplastic lymphoma kinase; EML4, echinoderm microtubule-associated protein-like 4; NSCLC, non-small-cell lung cancer; PFS, progression-free survival. <br />
  • ALK, anaplastic lymphoma kinase; EGFR, epidermal growth factor receptor; OS, overall survival; TTP, time to progression <br />
  • La viabilidad de la administración de la combinación de bevacizumab con quimioterapia fue probada por Johnson (JCO 2004); quien la probó en un fase II aleatorizado con carbo/paclitaxel y a dosis de 7,5 vs 15 vs placebo, y sin excluir subtipos histológicos. Las dosis altas de beva tuvieron una mejor SLP y lRR. <br />
  • In the E4599 trial (Sandler et al. 2006), 878 patients with recurrent or advanced NSCLC (stage IIIB or IV) were randomised to 15mg/kg bevacizumab with carboplatin/paclitaxel (CP) (n=434) or CP alone (n=444) every 3 weeks for six cycles until disease progression or unacceptable toxicity. The 15mg/kg dose was chosen based on its activity in an earlier phase II trial (Johnson et al. 2004). The primary endpoint for E4599 was OS. <br /> In the bevacizumab in Lung cancer (AVAiL [BO17704]) trial (Manegold et al. 2007), 1,043 patients with advanced or recurrent non-squamous NSCLC were randomised to cisplatin/gemcitabine (CG) for up to six cycles plus 7.5 mg/kg bevacizumab (n=345), 15 mg/kg bevacizumab (n=351) or placebo (n=347) every 3 weeks until disease progression or unacceptable toxicity. Following the positive survival results of the E4599 trial for bevacizumab-based therapy versus chemotherapy alone, the primary endpoint of AVAiL was amended from OS to PFS. <br />
  • Both E4599 and AVAIL excluded predominantly squamous cell disease. <br />
  • The primary objective for the pivotal phase III 1st line ALIMTA trial was noninferior overall survival. This Kaplan-Meier curve clearly shows that the primary objective of this study was met: ALIMTA/cisplatin was demonstrated to be noninferior to GEMZAR/cisplatin for median OS. <br /> As illustrated by the Kaplan-Meier curve here, median OS was 10.3 months in each treatment group (adjusted HR, 0.94; 95% CI, 0.84 to 1.05; noninferiority p&lt;0.001). The confidence intervals for the HR were well below the 1.176 margin set for noninferiority, meaning that superiority studies based on histology could be conducted. <br /> The 1-year survival rate for ALIMTA/cisplatin was 43.5% vs 41.9% for GEMZAR/cisplatin. <br /> Complete Reference for Citation: <br /> 1.Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin/gemcitabine with cisplatin/ALIMTA in chemonaïve patients with advanced-stage non-small cell lung cancer. J Clin Oncol. 2008;26:3543-3551. <br />
  • OS was significantly longer with ALIMTA/cisplatin vs GEMZAR/cisplatin when limiting the analysis to patientswith nonsquamous histologies (11.0 vs 10.1 months; HR, 0.84; 95% CI, 0.74, 0.96; superiority p=0.011). <br /> Complete Reference for Citation: <br /> 1.Scagliotti GV, et al. Oncologist. 2009;14:253-263. <br />
  • AE, adverse event; Bev, bevacizumab; Carbo, carboplatin; CNS, central nervous system; Pac, paclitaxel; PD, progressive disease; Pem, pemetrexed; PFS, progression-free survival; PS, performance status; q21d, every 21 days. <br /> David R. Gandara, MD: <br /> PRONOUNCE was designed as a phase III superiority trial evaluating a regimen of pemetrexed/carboplatin followed by maintenance pemetrexed vs the ECOG regimen of paclitaxel/carboplatin plus bevacizumab followed by maintenance bevacizumab. The study was performed in patients with advanced-stage NSCLC of the nonsquamous type and represents an attempt to sort out the histology-related benefit of pemetrexed. <br />   <br /> The primary study endpoint was PFS in those patients who did not have grade 4 toxicity. This composite endpoint is a bit unconventional and, to my knowledge, has never been used in another clinical trial in lung cancer. I think this endpoint was used in an attempt to find a less toxic therapy that could also prolong PFS. <br />
  • Pem, pemetrexed; Cb, carboplatin; Bev, bevacizumab; G4PFS, progression-free survival without grade 4 adverse events. <br /> David R. Gandara, MD: <br /> Unfortunately, similar to the POINTBREAK trial[1] last year, PRONOUNCE did not meet its primary endpoint. <br />   <br /> Reference <br /> Patel JD, Socinski M, Garon EB, et al. A randomized, open-label, phase III, superiority study of pemetrexed (Pem) + carboplatin (Cb) + bevacizumab (Bev) followed by maintenance Pem + Bev versus paclitaxel (Pac)+ Cb + Bev followed by maintenance Bev in patients with stage IIIB or IV non-squamous non-small cell lung cancer (NS-NSCLC). Program and abstracts of the 2012 Multidisciplinary Symposium in Thoracic Oncology; September 6-8, 2012; Chicago, Illinois. Abstract LBA8003; Abstract LBPL1. <br />
  • Pac, paclitaxel; Pem, pemetrexed; Cb, carboplatin; Bev, bevacizumab. <br /> David R. Gandara, MD: <br /> Secondary endpoints also did not differ markedly between the 2 arms. In fact, OS favored the paclitaxel arm numerically. <br />
  • Bev, bevacizumab; Cb, carboplatin; CTCAE, Common Terminology Criteria for Adverse Events; Pac, paclitaxel; Pem, pemetrexed. <br /> David R. Gandara, MD: <br /> The investigators did not present the grade 4 toxicity data, only grade 3/4 data. The toxicity profile was consistent with what has been seen with these regimens in other trials. <br />
  • AE, adverse event; Bev, bevacizumab; Cb, carboplatin; Pac, paclitaxel; Pem, pemetrexed; PFS, progression-free survival; ORR, overall response rate; OS, overall survival. <br /> David R. Gandara, MD: <br /> This study leaves the field with many questions about the role of pemetrexed in nonsquamous NSCLC compared to other agents. A few years ago, Dr. Scagliotti and I published the results of a phase III trial comparing pemetrexed/cisplatin to gemcitabine/cisplatin,[1] which suggested that pemetrexed is the best drug for nonsquamous histology. However, this has not been the case in many studies. For example, a large Norwegian phase III trial of over 430 patients comparing pemetrexed-carboplatin to gemcitabine-carboplatin showed equivalent results regardless of histology, with no specificity for pemetrexed.[2] ECOG just published their analysis of various chemotherapy regimens that included pemetrexed and showed that there was no difference in efficacy based on histologic subtype. I think the cumulative data suggest that pemetrexed is a more efficacious drug in nonsquamous NSCLC, but it is not necessarily in comparison with other agents such as taxanes, as we saw in PRONOUNCE and POINTBREAK. <br /> . <br /> Heather Wakelee, MD: <br /> I have a slightly different interpretation of this study. I take issue with the primary endpoint of PFS without grade 4 adverse events (AEs). The trial did not meet the endpoint. However, even if it did, I would question the meaning of the result. It is not an endpoint that will likely be used in other trials; OS and PFS are still the preferred clinical endpoints of interest. Quality of life measures can play a role, but I do not think that was captured by only analyzing grade 4 toxicity as part of the primary endpoint. <br />   <br /> I think the findings showed that the carboplatin/pemetrexed regimen is active, but it is not more active than carboplatin/paclitaxel plus bevacizumab. Carboplatin/pemetrexed yields different toxicities compared with carboplatin/paclitaxel plus bevacizumab, including more anemia and thrombocytopenia but less neutropenia. Carboplatin/pemetrexed also showed a better toxicity profile with a lower incidence of grade 1/2 alopecia and sensory neuropathy, which are very relevant toxicities for patients. As clinicians try to determine the optimal regimen for their patients, those types of lower-grade AEs need to be included in the discussion. <br />   <br /> It is also confusing to interpret the results of this trial in light of the POINTBREAK trial,[3] considering that both studies included a carboplatin/paclitaxel/bevacizumab arm with bevacizumab maintenance. Overall survival in the 2 trials was actually a little different. Median OS with carboplatin/paclitaxel/bevacizumab in POINTBREAK was 13.4 months, whereas in PRONOUNCE, it was 11.7 months. Although it is not appropriate to make cross-study comparisons, these differences make it difficult to ascertain the benefit of adding bevacizumab to carboplatin/pemetrexed. Median OS reached 10.5 months with carboplatin/pemetrexed in PRONOUNCE and 12.6 months with carboplatin/pemetrexed/bevacizumab in POINTBREAK. These 2 trials leave us with a lot of questions. Should we be using pemetrexed instead of paclitaxel? Should we be adding bevacizumab to chemotherapy? <br />   <br /> In sum, PRONOUNCE does not lead to any practice changes for me. I still think that pemetrexed is a reasonable first-line choice. PRONOUNCE did not really answer the question as to whether bevacizumab should be added to chemotherapy, and the POINTBREAK data leave this question unanswered as well. My take-home from this is that carboplatin/paclitaxel/bevacizumab is still a good first-line option. Carboplatin/pemetrexed is no better than the triple-therapy regimen, but it is a viable choice with a different toxicity profile. Whether bevacizumab should be added to carboplatin/pemetrexed is something that can be considered, but it may not offer a substantial clinical benefit based on the POINTBREAK data. <br />   <br /> David R. Gandara, MD: <br /> POINTBREAK and PRONOUNCE reflect the fact that sometimes performing additional clinical trials does not clarify the issue; instead, it sometimes makes the issue less clear and makes clinical decisions more complex. I think the key message to take away from these studies is that clinicians have multiple options for first-line therapy, including carboplatin/pemetrexed and carboplatin/paclitaxel/bevacizumab. <br />   <br /> References <br /> 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;26:3543-3551. <br /> Grønberg BH, Bremnes RM, Fløtten O, et al. Phase III study by the Norwegian lung cancer study group: pemetrexed plus carboplatin compared with gemcitabine plus carboplatin as first-line chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol. 2009;27:3217-3224. <br /> Patel JD, Socinski M, Garon EB, et al. A randomized, open-label, phase III, superiority study of pemetrexed (Pem) + carboplatin (Cb) + bevacizumab (Bev) followed by maintenance Pem + Bev versus paclitaxel (Pac)+ Cb + Bev followed by maintenance Bev in patients with stage IIIB or IV non-squamous non-small cell lung cancer (NS-NSCLC). Program and abstracts of the 2012 Multidisciplinary Symposium in Thoracic Oncology; September 6-8, 2012; Chicago, Illinois. Abstract LBA8003; Abstract LBPL1. <br />
  • OS, overall survival; PFS, progression-free survival <br />

Sesión servicio NSCLC Sesión servicio NSCLC Presentation Transcript

  • Oncología Médica Revisión  Introducción  Caso 1: Tratº según perfil molecular  Caso 2: Tratº según histología I  Caso 3: Tratamiento según histología II XXI Vigo
  • Introducción: NSCLC avanzado
  • Oncología Médica XXI Vigo Lung Cancer: Incidence and Mortality  New cases in 2013: 228,190  40% with stage IV disease at presentation (~ 90,000)  ~ 160,000 deaths in 2012, comparable to prostate, pancreas, breast, and colon cancer combined  5-yr relative survival rate: 15.7 % overall; 3.7% for patients with distant-stage disease 180,000 Estimated Cancer Deaths by Site, 2012 160,000 140,000 120,000 100,000 80,000 60,000 Prostate Pancreas Breast Lung cancer 40,000 20,000 Colon 0 Other Cancers Lung Cancer NCI. Non-small-cell lung cancer treatment (PDQ ®). ACS. Cancer facts & figures: 2012. CDC. Lung cancer rates by race and ethnicity. Howlader N, et al. SEER cancer statistics review.
  • Oncología Médica Lung Cancer: Evaluación  Diagnóstico: biopsia!  Información sobre histología y alteraciones moleculares, útiles para la selección de tratamiento XXI Vigo
  • Oncología Médica XXI Vigo Complexities of Lung Cancer Pathogenesis Result in Diverse Histologic Subtypes SCLC (~ 15%) Adenocarcinoma (~ 45%) Sun S, et al. Nat Rev Cancer. 2007; 7:778-790. Travis WD, et al. J Clin Oncol. 2013;[Epub ahead of print]. SCC (~ 25%) LPA (formerly BAC) (~ 5% to 10%) Large Cell (~ 5% to 10%) NOS (~ 10% to 30%)
  • Oncología Médica XXI Vigo Lung Cancer: Histology Small-cell carcinoma Adenocarcinoma 10% to 15% Large-cell carcinoma 10% to 15% 40% 25% to 30% Squamous cell carcinoma American Cancer Society. Lung cancer (non-small-cell). 2013.
  • Oncología Médica Potential Oncogenic Drivers in NSCLC XXI Vigo Squamous Cell Carcinoma Adenocarcinoma FGFR2 Mutation 5 Mutation 9 Mutation deletion 18 Amplification 8 Deletion/mutati on 45 PDGFRA Amplification mutation 9 Amplification 10 MCL1 Amplification 10 BRAF Mutation 3 Mutation 4 ERBB2 Reprinted by permission from Macmillan Publishers Ltd: Pao W, et al. Nat Med. 2012;18:349-351. 20-25 DDR2 KRAS Amplification EGFR EGFR FGFR1 CCND1 Unknown Frequency, % PTEN KIF5B-RET Event Type PIK3CA NRAS ROS1 fusions Gene CDKN2A MAP2K1 AKT1 PIK3CA BRAF HER2 ALK fusions Amplification 2 Hammerman P, et al. IASLC WCLC 2011. Abstract PRS.1
  • Oncología Médica XXI Vigo NSCLC: AJCC Staging Lung Cancer Staging: Differences Between the AJCC Cancer Staging Manual 6th and 7th Editions AJCC 6th Edition AJCC 7th Edition T1 ≤ 3 cm T1a: ≤ 2 cm T1b: > 2 cm but ≤ 3 cm T2 3 cm or Invades visceral pleura Atelectasis of less than entire lung Proximal extent at least 2 cm from carina T2a: > 3 cm but ≤ 5 cm T2b: > 5 cm but ≤ 7 cm Or tumors ≤ 7 cm with invasion of visceral pleura, atelectasis of less than entire lung, proximal extent at least 2 cm from carina T3 Tumors with invasion of chest wall, diaphragm, mediastinal pleura Tumors > 7 cm or with: Direct invasion of chest wall, diaphragm, phrenic nerve, mediastinal pleura, parietal pericardium, main bronchus < 2 cm from carina (without involvement of carina) Tumor nodules in the same lobe as the primary tumor T4 Tumor of any size with: Invasion of mediastinum, heart, great vessels, trachea, esophagus Malignant pleural or pericardial effusions Tumor nodules in the same lobe as the primary Tumor of any size with: Invasion of mediastinum, heart, great vessels, trachea, esophagus Metastatic tumor nodules in different lobe from the primary tumor T descriptor N descriptor No changes M descriptor M1 Distant metastasis: metastatic tumor nodules in a different lobe from the primary tumor Subdivided into: M1a: Malignant pleural or pericardial effusion pleural nodules, nodules in contralateral lung M1b: Distant metastasis Edge SB, et al. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2010. pp. 253-270.
  • Oncología Médica NSCLC avanzado: Factores pronóstico XXI Vigo  En pacientes inoperables, el pronóstico se ve afectado de forma adversa por:  Mal PS  Pérdida de peso > 10%  Sexo masculino  Edad avanzada: no afecta a pronóstico por sí misma NCI. Non-small-cell lung cancer treatment (PDQ ®).
  • Oncología Médica XXI Vigo First-line Therapy: 2005 Platinum agent (select one)  Cisplatin  Carboplatin “1990s agent” (select one)  Vinorelbine  Paclitaxel  Docetaxel  Gemcitabine
  • Oncología Médica XXI Vigo First-line Therapy: 2013 Column A Cisplatin Carboplatin Column B Vinorelbine Gemcitabine Paclitaxel Docetaxel Pemetrexed Nab-paclitaxel Irinotecan Column C Bevacizumab Cetuximab? Column D Erlotinib Crizotinib Option 1: choose 1 from column A and 1 from column B Option 2: choose 2 from column B Option 3: option 1 + column C (for certain patients) Option 4: choose 1 from column D (for selected patients) National Comprehensive Cancer Network clinical practice guidelines in oncology: Non-small-cell lung cancer (v2.2013). www.nccn.org
  • Oncología Médica Consideraciones para la primera línea  PS  Edad: comorbilidad  Hemoptisis  Histología  Alteraciones moleculares  Otras  Metástasis SNC  Tratº previo en la adyuvancia XXI Vigo
  • Caso 1
  • Oncología Médica Caso 1 XXI Vigo  Mujer de 68; antecedentes:  Alergia a tetraciclinas.  Nunca fumadora. Bebedora: poco       importante. HTA a tratº con Micardis Plus. Mastopatía fibroquística. Artrosis de hombro derecho y rotura del tendón del supra e infraespinoso de hombro derecho, con atrofia muscular asociada. Presbiacusia. Apendicectomía. Neumonía mayo 2011
  • Oncología Médica Caso 1  Debut en octubre de 2011: bulto supraclavicular izquierdo, no otros síntomas  TAC t/a Nódulo que 8 mm en LSI ; 2 lesiones sólidas de en LII 34.51 mm y 29 . Conglomerado de adenopatías abrazando a la carina en su margen inferior. En D11 en el margen derecho se evidencia una lesión blástica que sugiere un islote óseo  Biopsia: adenocarcinoma de origen pulmonar; mutación EGFR positiva (exón 19) XXI Vigo
  • Oncología Médica PET-TAC XXI Vigo  Masa hipermetabólica de 4,8 cms en LII, en contacto posterior con pleura visceral, con compromiso lobar inferior izdo.  Adenopatías de localización cervical, supraclavicular y mediastínicas  Múltiples lesiones hipermetabólicas en hígado y bazo. Lesión focal hipermetabólica en glándula suprarrenal derecha.  Estadio IV
  • Mutación de EGFR: factor predictivo de respuesta a EGFR-TKI EGF • Receptor L domain 90% de las mutaciones son en los exones 18–24 – Delecciones exon 19 – Mutación exon 21 (L858R) • Consecuencias: - Activación constitutiva del receptor - Dimerización con HER3 → activación vía AKT/STAT Furin-like domain Receptor L domain Extracellular domain Transmembrane region Intracellular domain G719C del E746–A750 del L747–T751insS del L747–P753insS L858R Catalytic kinase domain L861Q Y1068 STAT3 MAPK AKT Sordella et al. Science 2004
  • Oncología Médica IPASS: PFS by EGFR Mutation Status XXI Vigo  Randomized phase III trial; previously untreated pts with advanced NSCLC (N = 1217)  PFS: gefitinib superior to carboplatin/paclitaxel in ITT population  EGFR mutations strongly predicted PFS (and tumor response) to first-line gefitinib vs carboplatin/paclitaxel 1.0 EGFR Mutation Negative Gefitinib Pac/carbo 0.8 HR: 0.48 (95% CI: 0.36-0.64; P < .001) 0.6 0.4 0.2 0 0 4 8 12 16 20 24 Mos Since Randomization Mok TS, et al. N Engl J Med. 2009;361:947-957. Probability of PFS Probability of PFS EGFR Mutation Positive 1.0 Gefitinib Pac/carbo 0.8 HR: 2.85 (95% CI: 2.05-3.98; P < .001) 0.6 0.4 0.2 0 0 4 8 12 16 20 24 Mos Since Randomization
  • TKI en CNMP con mutación EGFR Study EGFR TKI Sample size Response rate (%) Median PFS (months) HR IPASS1 Gefitinib 261 71 vs 47 9.8 vs 6.4 0.48 First-SIGNAL2 Gefitinib NR 85 vs 37 8.4 vs 6.7 NR WJTOC34053 Gefitinib 177 62 vs 31 9.2 vs 6.3 0.49 NEJ0024 Gefitinib 198 74 vs 31 10.8 vs 5.4 0.30 OPTIMAL5 Erlotinib 154 83 vs 36 13.7 vs 4.6 0.16 EURTAC6 Erlotinib 174 58 vs 15 9.7 vs 5.2 0.37 Afatinib (vs cis-pem) 345 56 vs 22 11,1 vs 6.9 0,001 LUX-Lung 3[7] Mok et al NEJM 2009, 2Lee et al WCLC 2009, 3Mitsudomi et al Lancet Oncol 2010, 4Maemondo NEJM 2010, 5Zhou et al ESMO 2010, 6Rosell et al ASCO 2011; 7-Sequist LV, et al. J Clin Oncol. 2013 1
  • Oncología Médica XXI Vigo EURTAC Erlotinib 150 mg/día  Sin quimioterapia previa  CPNM en estadio IIIB/IV  Deleción de exón 19 EGFR o mutación exón 21 L858R  ECOG PS 0–2 R Quimioterapia con doblete de platino cada 3 semanas x 4 ciclos* (n=174) Objetivo principal  Supervivencia libre de progresión (SLP) − análisis intermedio planeado a los 88 eventos 1227 pts screened  224 mut + (17.6%) Estratificación  Tipo de mutación  ECOG PS (0 vs. a 1 vs. 2) Objetivos secundarios  Tasa de repuesta objetiva (%)  Supervivencia global (SG)  Localización de la progresión  Seguridad  Análisis de la mutación del EGFR en suero  Calidad de vida *Cisplatino 75 mg/m2 d1 / docetaxel 75 mg/m2 d1; cisplatino 75 mg/m2 d1 / gemcitabina 1250 mg/m2 d1,8; carboplatino AUC6 d1 / docetaxel 75 mg/m2 d1; carboplatino AUC5 d1 / gemcitabina 1000 mg/m2 d1,8 Rosell, et al. Lancet Oncol. 2012
  • Oncología Médica Erlotinib en1ª línea duplicó la SLP en comparación con la quimioterapia XXI Vigo Erlotinib (n=86) Chemotherapy (n=87) 10· 4 5·1 Patients at risk Rosell et al. ESMO 2012
  • Oncología Médica XXI Vigo La tasa de respuesta con erlotinib fue más de tres veces mayor que la de la quimioterapia 100 Erlotinib (n=69) Deleción en el exón 19 Mutación en el exón 21 80 60 40 20 0 -20 -40 -60 -80 -100 Mejor cambio desde valores iniciales (%) Mejor cambio en comparación con la medida basal (%) 100 Quimioterapia (n=64) Deleción en el exón 19 Mutación en el exón 21 80 60 40 20 0 -20 -40 -60 -80 -100 0 10 20 30 40 50 60 70 0 10 20 30 40 50 60 70 Tasa de repuesta global: 58% Erlotinib frente a 15% quimioterapia de Marinis, et al. EMCC 2011
  • Subgroup analyses of PFS in ITT population (updated analysis 26 Jan 2011) HR (95% CI) 0.37 (0.25–0.54) All n 173 0.44 (0.25–0.75) 0.28 (0.16–0.51) 85 Male 0.38 (0.17–0.84) 47 Female 0.35 (0.22–0.55) 126 PS 0 0.26 (0.12–0.59) 57 PS 1 0.37 (0.22–0.62) 92 PS 2 0.48 (0.15–1.48) 24 Current smoker 0.56 (0.15–2.15) 19 Former smoker 1.05 (0.40–2.74) 34 Never smoker 0.24 (0.15–0.39) 120 Exon 19 deletion 0.30 (0.18–0.50) 115 L858R mutation 0.55 (0.29–1.02) 58 <65 yrs ≥65 yrs 0.1 0.2 0.4 0.6 0.8 1.0 Favors erlotinib HR 1.5 2.0 4.0 Favors chemotherapy 88
  • Protocolo 049/11 Gefitinib 250 mg/24 h 46 pacientes mut + (36 m, 10 h) 20 exon 19 4 exon 20 20 exón 21 Mediana edad: 67 años 93%: PS 0-1 RR SLP SG 57% 6 meses 17 meses
  • Protocolo 049/11
  • Oncología Médica Nuestra paciente… Noviembre 2011: inicia erlotinib Primera reevaluación: febrero de 2012 Agosto 2013: progresión. Actualmente con pemetrexed. XXI Vigo
  • Oncología Médica Timeline: ALK-Fusion in NSCLC EML4-ALK chromosomal rearrangements reported in NSCLC[1] Crizotinib antitumor activity in advanced cancers with EML4-ALK rearrangement[4] FDA approves crizotinib for treatment of ALK+ NSCLC[6] 2007 2009 XXI Vigo 2011 2008 2010 Preclinical studies document Crizotinib produces a antitumor activity of ALK inhibitors response in 47/82 ALK+ in lung cancer cell lines and patients and a 6-mo PFS [2,3] xenografts of 72%[5] 1. Soda M, et al. Nature. 2007;448:561-566. 2. McDermott U, et al. Cancer Res. 2008;68:3389-3395. 3. Koivunen JP, et al. Clin Cancer Res. 2008;14:4275-4283. 4. Kwak EL, et al. ASCO 2009. Abstract 3509. 5. Kwak EL, et al. N Engl J Med. 2010;363:1693-1703. 6. US Food and Drug Administration.
  • Oncología Médica XXI Vigo  Los reordenamientos del oncogén ALK están presentes en el 4-5% de pacientes con CNMP.  El oncogén ALK se activa por una ruptura (separación) y posterior refusión de los 2 genes en la dirección opuesta.  La traslocación ALK se determina mediante FISH.
  • Oncología Médica XXI Vigo EML4/ALK Translocations  Typical phenotype  Young, male or female, never/scant smokers  Adenocarcinoma ± signet ring morphology  Poor response to EGFR TKI; conventional response to standard chemotherapy  No overlap with EGFR mutation genotype Change From Baseline (%) 100 PD SD PR CR 80 60 40 20 Crizotinib in ALK-Positive NSCLC (N = 143) 0 -20 -40 -60 -80 -100 Camidge DR, et al. Lancet Oncol. 2012;13:1011-1019.
  • Overall survival 2nd/3rd line Crizotinib ALK ALK Control Crizotinib (n=23) (n=30) 100% Median Survival, mo 6 1-yr Survival, % 70 44 2-yr Survival, % 80% NR 55 12 HR=0.36, p=0.004 60% From 2nd/3rd line crizotinib 40% 20% From 2nd line therapy 0% 0 1 2 Years 3 4
  • Caso 2
  • Oncología Médica Caso 2  Paciente varón de 56 años  Tabaquismo desde los 16 años; enolismo moderado  EPOC  Cólico nefrítico 2009 (litotricia)  Marzo-2012: Bulto en axila derecha de 1 mes de evolución. No sde general  TAC t/a: masa mediastínica de 5 cm; adenopatías axilares derechas; adenopatías subcarinal e hiliares derechas  Biopsia ganglio linfático: adenocarcinoma, TTF1 +, wtEGFR XXI Vigo
  • Oncología Médica XXI Vigo
  • Trial N Schema Results Johnson et al phase II; random JCO 2004 99 Carboplatin/paclitaxel Carbo/paclitaxel/beva 15/7.5 PFS: 7.4 m (15 arm) PFS: 4.2 m Niho et al phase II; random Lung ca. 2012 180 Carbo/paclitaxel PFS : 5.9 m OS: 22.8 m PFS: 6.9 m OS: 23.4 m ECOG 4599 878 Carbo/pacl/beva 15 AVAiL phase III, randomized JCO 2009 1043 PFS: 4.5 m OS: 10.3 m Carbo/paclitaxel/beva 15 mg/kg phase III; randomized NEJM 2006 Carboplatin/paclitaxel PFS: 6.2 m OS: 12.3 m Cisplatin/gemcitabine PFS: 6 m OS: 13 m Cisplatin/gemc/bevacizumab 7.5 PFS: 6.7 m OS: 13.6 m Cisplatin/gemc/bevacizumab 15 PFS: 6.5 m OS: 13.4 m
  • Bevacizumab: E4599 y AVAIL Diseño E45991 Previously untreated stage IIIB/IV non-squamous NSCLC (n=878) Squamous excluded as higher risk (20%) severe hemoptysis AVAiL2 Previously untreated, stage IIIB, IV or recurrent non-squamous NSCLC (n=1,043) *No crossover permitted CP x 6 (n=444) Bevacizumab (15mg/kg) every 3 weeks + CP x 6 (n=434) PD* Bev PD Placebo + CG x 6 (n=347) Bevacizumab (15mg/kg) every 3 weeks + CG x 6 (n=351) Bevacizumab (7.5mg/kg) every 3 weeks + CG x 6 (n=345) PD* Bev PD Bev PD 1 Sandler, et al. NEJM 2006 2 Reck, et al. JCO 2009
  • Bevacizumab: PFS No-escamosos PFS in E45991 PFS in AVAiL2 Probability of PFS 1.0 Placebo + CG bevacizumab 7.5mg/kg + CG bevacizumab 15mg/kg + CG 0.8 0.6 0.4 0.2 0 0 6 12 18 24 Duration of PFS (months) PFS bevacizumab 15mg/kg PFS bevacizumab 7.5mg/kg PFS bevacizumab 15mg/kg 6.2 months 6.8 months 6.6 months HR=0.66 p<0.001 HR=0.75 p=0.0003 HR=0.85 p=0.0456 1 Sandler, et al. NEJM 2006; 2Reck et al JCO 2009 30
  • Bevacizumab: OS No-escamosos OS in E45991 OS in AVAiL2 CP + bevacizumab CP Probability of OS 1.0 Placebo + CG bevacizumab 7.5mg/kg + CG bevacizumab 15mg/kg + CG 0.8 0.6 0.4 0.2 0 0 6 12 18 24 30 36 Duration of OS (months) OS bevacizumab 15mg/kg OS bevacizumab 7.5mg/kg OS bevacizumab 15mg/kg 12.3 months 13.6 months 13.4 months HR=0.93 p=NS p=0.4203 HR=1.03 p=NS p=0.7613 HR=0.79 p=0.003 1 Sandler, et al. NEJM 2006; 2Reck, et al. JCO 2009; 3Reck, et al. Ann Oncol 2010
  • Oncología Médica XXI Vigo Bevacizumab in Nonsquamous NSCLC: Key Results E4599[1] (N = 878) AVAiL[2,3] (N = 1043) JO19907[4] (N = 180) Outcome PCB PC CGB (7.5 mg/kg) CGB (15 mg/kg) Placebo PCB Placebo ORR, % 35 15 37.8 34.6 21.6 60.7 31.0 P < .001 P < .0001 P = .0002 P = .001 0.66 (P < .001) 0.75 (P = . 0003) 0.85 (P = . 046) 0.61 (P = .009) 6.7 6.5 0.93 (P = NS) 1.03 (P = NS) 13.6 13.4 HR for PFS Median PFS, months 6.2 HR for OS 0.79 (P = . 003) Median OS, months 12.3 4.5 10.3 6.1 6.9 5.9 0.99 (P = .95) 13.1 22.8 23.4 1. Sandler A, et al. N Engl J Med. 2006;355:2542-2550. 2. Reck M, et al. J Clin Oncol. 2009;27:1227-1234. 3. Reck M, et al. Ann Oncol. 2010;21:1804-1809. 4. Niho S, et al. Lung Cancer. 2012;362-367.
  • Oncología Médica XXI Vigo Bevacizumab Safety Profile: 5000+ NSCLC Patients Treated in Clinical Trials Patients (%) 30 Grade ≥ 3 Adverse Events of Special Interest E4599[1] (15 mg/kg) AVAiL[2] (7.5 mg/kg) AVAiL[2] (15 mg/kg) SAiL[3] ARIES[4,5] 20 10 7.0 4.4 4.0 4.0 4.0 3.6 9.0 6.0 6.0 < 5.0 3.0 1.9 1.5 0.9 1.0 0.9 0 Bleeding (All Types) Pulmonary Hemorrhage/ Hemoptysis 3.0 < 1.0 Hypertension 1.0 NR Proteinuria 1. Sandler A, et al. N Engl J Med. 2006;355:2542-2550. 2. Reck M, et al. J Clin Oncol. 2009;27:1227-1234. 3. Crinò L, et al. Lancet Oncol. 2010;11:733-740. 4. Jahanzeb M, et al. ECCO-ESMO 2009. Abstract O-9006. 5. Wozniak AJ, et al. ASCO 2010. Abstract 7618.
  • Oncología Médica XXI Vigo 18-75 años CNMP no-escamoso Estadios IIIB-IV PS=0-1 1ª línea Cisplatino 80 mg/m2 d 1 Vinorelbina 25 mg/m2 d 1+8 Bevacizumab 15 mg/kg d 1 Cada 21 d hasta 6 ciclos Si no PD: mant con beva León L, et al. Expert Opin Pharmacother. 2012 Jul;13(10):1389–96. N= 50 OP: PFS
  • Oncología Médica Eficacia Outcome Objective response rate Complete response, n (%) PR, n (%) SD, n (%) Progressive disease, n (%) XXI Vigo N=45 % 0 13 20 12 0 29 44 27 Median PFS, months (95% CI) 6.0 (4.5-7.5) Median OS, months (95% CI) 14.7 m (8.4-21) Median duration of response, months (95% CI) 1-year survival León L, et al. Expert Opin Pharmacother. 2012 Jul;13(10):1389–96. 4.6 (2.9-6.4) 57%
  • Oncología Médica Eficacia León L, et al. Expert Opin Pharmacother. 2012 Jul;13(10):1389–96. XXI Vigo
  • Oncología Médica XXI Vigo Bevacizumab en combinación con cisplatino y docetaxel quincenal en primera línea en CNMP no epidermoide avanzado (047/10) Edad > 18 años CNMP no-escamoso Estadios IIIB-IV PS=0-1 1ª línea Cisplatino 50 mg/m2 d 1+15 Docetaxel 50 mg/m2 d 1+15 Bevacizumab 5 mg/kg d 1+15 Cada 28 d hasta 4 ciclos Si no PD: mant con beva Lázaro M, et al. ECCO 2013, WCLC 2013 N= 22 (50) pac analizados OP: PFS
  • Oncología Médica Características de los pacientes XXI Vigo Characteristics N=24 Median age, years > 65 years 60 28% Gender, n (%) Female Male 6 (19) 26 (81) ECOG PS, n (%) 0 1 2 9 (28%) 20 (62%) 3 (9) Histological type, n (%) adenocarcinoma large cell 27 (84%) 4 (12.5%)
  • Oncología Médica XXI Vigo Eficacia Outcome Objective response rate Complete response, n (%) PR, n (%) SD, n (%) Progressive disease, n (%) Median PFS, months (95% CI) En pacientes con mantenimiento En pacientes sin mantenimiento N=22 % 0 14 7 1 0 63 32 4.6 6.4 (4.1-8.6) 9.5 (5.9-13) 4.6 (2.6-6.5)
  • Oncología Médica Eficacia XXI Vigo
  • Oncología Médica XXI Vigo Toxicidad Toxicity Grade 1-2 n (%) Grade 3-4 n (%) Anemia 10 (31) 2 (6) Neutropenia 12 (37) 13 (40) Thrombocytopenia 3 (9) 2 (6) Vomiting 3 (9) - Asthenia 18 (56) 4 (12) Mucositis 7 (22) 2 (6)
  • Comparativa SG y SLP (meses)
  • Comparativa SG y SLP (meses)
  • Oncología Médica XXI Vigo Cis-doc-beva : inicio en abril 2012 HTA grado 1 Marzo 2012 Pendiente valoración de tratº con RDT Julio 2013
  • Caso 3
  • Oncología Médica Caso 3  Paciente mujer de 68 años  Fumadora < 5 cig/d  TBP 2000 HISTORIA  Diciembre de 2012: Febrícula de 20 días de evolución  Hemoptisis leve Rx tórax aumento de densidad paramediastínico derecho con pérdida de volumen XXI Vigo
  • Oncología Médica XXI Vigo TAC t/a (12/2/12): masa en LSD; adenopatías mediastínicas y axilares. Nódulos pulmonares PET-TAC (12/2/12) Biopsia (FBC): adenocarcinoma pulmonar; no mutaciones T4N3M1
  • 1 Pemetrexed: JMDB Diseño Randomization factors • ECOG PS • Stage • History of brain metastases • Gender • Pathological Dx (histological vs cytological) R R A A N N D D O O M M II Z Z E E ALIMTA (N=862) 500 mg/m2 IV q21d + Cisplatin 75 mg/m2 Day 1 GEMCITABINA (N=863) 1250 mg/m2 on D1 and D8 + Cisplatin 75 mg/m2 Day 1 Patients in both arms received folic acid, vitamin B 12, and dexamethasone 1. Scagliotti GV, et al. J Clin Oncol. 2008;26:3543-3551.
  • JMDB : Resultados OS No-escamosos1* ALIMTA/Cisplatin GEMZAR/Cisplatin (n=618) (n=634) Median OS (95% CI) Adjusted HR (95% CI) p-value 11.0 mo (10-12.5) 10.1 mo (9.3-10.9) 0.84 (0.74-0.96) 0.011* † * Nonsquamous=adenocarcinoma, large cell carcinoma, and other/indeterminate NSCLC histology † Superiority p-value. 1. Scagliotti GV, et al. Oncologist. 2009;14:253-263.
  • JMDB: Tasas de Respuesta Median OS, months Cis/ Cis/ Pem Gem Median PFS, months Adj. p-value HR (95%CI) Cis/ Pem Cis/ Gem Adj. p-value HR (95%CI) RR, % Cis/ Cis/ Pem Gem Adj. p-value Adenocarcin. n=847 12.6 10.9 p=0.033 0.84 (0.71, 0.99) 5.5 5.0 p=0.125 0.90 (0.78, 1.03) 31.9 24.5 p=0.024 Large Cell n=153 10.4 6.7 p=0.027 0.67 (0.48, 0.96) 4.5 4.2 p=0.499 0.89 (0.65, 1.24) 31.3 30.9 p=0.954 Other* n=252 8.6 9.2 p=0.586 1.08 (0.81, 1.45) 4.5 5.6 p=0.064 1.28 (0.99, 1.67) 33.0 24.2 p=0.156 Squamous n=473 9.4 10.8 p=0.050 1.23 (1.00, 1.51) 4.4 5.5 p=0.002 1.36 (1.12, 1.65) 26.9 36.7 p=0.033 * Patients whose histologic diagnosis did not clearly qualify as adenocarcinoma, large or squamous cell carcinoma Cis/Pem, cisplatin/pemetrexed; Cis/Gem, cisplatin/gemcitabine; OS, overall survival; PFS, progression free survival; RR, response rate Manegold et al. 14th European Congress of Clinical Oncology: Sept 27, 2007; Barcelona, Spain.
  • JMDB: conclusiones  Se cumplió el objetivo primario del estudio: Cisplatino/Pemetrexed no es inferior a Cisplatino/Gemcitabina (HR=0.94)  Ambos regímenes fueron generalmente bien tolerados pero las toxicidades hematológicas y no-hematológicas, a excepción de la náusea, fueron significativamente favorables a Cisplatino/Pemetrexed  Un análisis pre-planificado mostró: • En los histotipos no escamosos la combinación de cis/pemetrexed se asoció con una OS estadísticamente superior (p=0.03) • En histología escamosa, Cisplatino/Gemcitabina mostró una SG marginalmente mayor (P=0.05)
  • Oncología Médica XXI Vigo PARAMOUNT  Estudio de fase III doble ciego, aleatorizado, controlado con placebo  Pemetrexed 500 mg/m2; cisplatino 75 mg/m2  Ácido fólico y vitamina B12 administrados en ambos brazos Tratamiento de inducción Tratamiento de mantenimiento de continuación 4 ciclos, cada 21 días cada 21 días hasta progresión • No tratados previamente • PS 0/1 • CPNM-NS estadio IIIB-IV Pemetrexed + Cisplatino CR/PR/SD según RECIST Pemetrexed ++BSC Pemetrexed BSC R 2:1 Placebo ++ Placebo BSC BSC Estratificados según: •PS (0 vs 1) •Estadio de la enfermedad (IIIB vs IV) previo a la inducción •Respuesta a la inducción (CR/PR vs SD) 1. Paz-Ares et al. Lancet Oncol 2012;13:247. 2. Paz-Ares et al. J Clin Oncol 2012;30 (suppl; abstr LBA7507).
  • Oncología Médica XXI Vigo Pemetrexed en mantenimiento de continuación demostró un beneficio significativo en la SLP SLP: revaluada en el momento del análisis de la SG Probabilidad de Supervivencia 1.0 Pemetrexed + BSC (n=359) Placebo + BSC (n=180) 0.8 HR no ajustada: 0.60 (0.50–0.73); p<0.0001 0.6 HR=0.6 HR=0.6 0.4 0.2 0.0 0 3 6 9 12 359 215 139 180 75 33 18 21 24 27 30 33 16 2 5 0 0 0 Tiempo (meses) Patients at risk Pem + BSC Plac + BSC 15 97 16 67 9 47 7 32 6 22 4 10 0 1. Paz-Ares et al. J Clin Oncol 2012;30 (suppl; abstr LBA7507).
  • Oncología Médica XXI Vigo Pemetrexed/cisplatino seguido de Pemetrexed demostró un beneficio significativo en la SG Pemetrexed + BSC (n=359) Placebo + BSC (n=180) SG desde la aleatorización 1.0 Log-rank P=0.0195 HR no ajustada: 0.78 (95% CI: 0.64–0.96) 0.9 Probabilidad de Supervivencia 0.8 HR=0.78 0.7 13.9 0.6 0.5 11.0 0.4 0.3 0.2 0.1 0.0 0 Patients at risk Pem + BSC 359 43 Placebo + BSC 180 12 3 6 9 12 15 18 21 24 27 30 33 36 Tiempo desde la aleatorización (meses) 333 15 169 8 272 2 131 3 235 0 103 0 200 166 138 105 79 78 65 49 35 23 1. Paz-Ares et al. J Clin Oncol 30, 2012 (suppl; abstr LBA7507).
  • Tasa de Supervivencia a 2 años1 Placebo + BSC 21% 32% Pemetrexed + BSC Tras 2 años desde el fin de la inducción, 1 de cada 3 pacientes permanecía vivo en el brazo de pemetrexed mientras que sólo 1 de cada 5 sobrevivía en el brazo de placebo 1. Paz-Ares et al. J Clin Oncol 30, 2012 (suppl; abstr LBA7507)
  • Oncología Médica XXI Vigo Paramount: SG desde el inicio de la inducción1 Los pacientes en tratamiento de mantenimiento con Pemetrexed se beneficiaron de aprox. mediana de SG comparado con placebo SG desde inicio de la inducción: en la Pemetrexed Mediana SG=16.9 meses (95% CI: 15.8–19.0) Placebo Mediana SG=14.0 meses (95% CI: 12.9–15.5) Log-rank P=0.0191 HR=0.78 (95% CI: 0.64–0.96) 1.0 0.9 0.8 Probabilidad de Supervivencia 3 meses 0.7 16.9 0.6 0.5 0.4 14.0 0.3 0.2 0.1 0.0 0 3 6 9 12 15 18 21 24 27 30 33 36 Tiempo desde la inducción (meses) 1. Paz-Ares et al. J Clin Oncol 30, 2012 (suppl; abstr LBA7507).
  • Oncología Médica XXI Vigo Inició cis/pem: respuesta parcial; sigue tratº hasta le fecha 12/2012 2/2013
  • Oncología Médica PRONOUNCE: Phase III Superiority Trial of Pem/Carbo → Pem vs Pac/Carbo → Bev XXI Vigo Induction (q21d, 4 cycles) Pemetrexed (folic acid & vitamin B12) + Carboplatin Bev-Eligible Population Inclusion: Chemo-naive patients PS 0/1 Stage IV, nonsquamous Stable treated CNS mets Exclusion: Uncontrolled effusions R 1:1 Maintenance (q21d until PD) Pemetrexed (folic acid & vitamin B12) 180 patients each Paclitaxel + Carboplatin + Bevacizumab  Primary objective: PFS without grade 4 AE  Bevacizumab Composite endpoint considers the first occurrence of either: – Grade 4 AE (lower grade AEs are not considered) or disease progression or death (PFS) Zinner R, et al. ASCO 2013. Abstract LBA8003. Used with permission.
  • Oncología Médica XXI Vigo PRONOUNCE: Primary Endpoint (G4PFS) 100 Pts (%) 80 Pem + Cb, median G4PFS: 3.9 mos Pac + Cb + Bev, median G4PFS: 2.9 mos 60 Log-rank P = 0.176 HR: 0.85 (95% CI: 0.70-1.04) 40 20 0 0 3 6 9 12 15 18 21 24 27 5 0 3 0 1 0 0 0 Mos Pts at Risk, n Pem + Cb 182 87 44 26 14 7 Pac + Cb + 179 75 33 17 9 3 Bev Zinner R, et al. ASCO 2013. Abstract LBA8003. Used with permission.
  • Oncología Médica XXI Vigo PRONOUNCE: OS (ITT) 100 Pem + Cb, median OS: 10.5 mos Pac + Cb + Bev, median OS: 11.7 mos HR: 1.07 (95% CI: 0.83-1.36; log-rank P = .615) Patients, % 80 Pem + Cb, % (n = 182) Pac + Cb + Bev, % (n = 179) 1 yr 43.7 48.8 2 yrs 18.0 17.6 60 40 20 0 0 3 6 9 12 15 18 21 Mos 24 27 Pts at Risk, n Pem + Cb 182 156 125 102 72 48 33 20 11 11 Pac + Cb + 179 151 121 96 73 59 38 28 10 3 Bev Zinner R, et al. ASCO 2013. Abstract LBA8003. Used with permission. 30 33 36 39 42 5 1 5 1 5 0 5 0 5 0
  • Oncología Médica XXI Vigo Possibly Drug-Related Grade 3/4 CTCAE Event Pem + Cb, % (n = 171) Pac + Cb + Bev, % (n = 166) P Value Anemia 19 5 < .001 Thrombocytopenia 24 10 < .001 Neutropenia 25 49 < .001 Febrile neutropenia 0 2 .118 Hypertension 0 2 .058 Thrombosis/embolism 0 2 .058 Any hemorrhagic events 1 0 .499 Zinner R, et al. ASCO 2013. Abstract LBA8003. Used with permission.
  • Oncología Médica Conclusiones  Falló en demostrar que pemetrexed/carboplatin fuese superior a la combinación paclitaxel/carboplatino/bevacizumab para PFS  PFS, OS, y ORR fueron similares  Diferentes perfiles de toxicidad, aunque manejables:  Pem + Cb: más anemia/trombocitopenia  Pac + Cb + Bev: más neutropenia Zinner R, et al. ASCO 2013. Abstract LBA8003. XXI Vigo
  • Oncología Médica XXI Vigo Switch vs Continuation Maintenance Therapy Switch Register 4 courses of platinum + Drug A SD, or R PS 0-1 Drug B Randomize Observation PD Off study Continuation Register Drug A 4 courses of platinum + Drug A SD, or R PS 0-1 Randomize Observation PD Off study
  • Oncología Médica XXI Vigo Switch Maintenance Trials Study Switch Agent Median PFS, Mos Median OS, Mos Immediate docetaxel Delayed docetaxel 5.7 2.7 12.3 9.7 Pemetrexed Placebo 4.3 2.6 13.4 10.6 SATURN[3] Erlotinib Placebo 2.8 2.6 12.0 11.0 ATLAS[4,5] Erlotinib + bevacizumab Placebo + bevacizumab 4.8 3.8 15.9 13.9 INFORM[6] Gefitinib Placebo 4.8 2.6 18.7 16.9 Fidias et al[1] JMEN[2] 1. Fidias PM, et al. J Clin Oncol. 2009;27:591-598. 2. Ciuleanu T, et al. Lancet. 2009;374:1432-1440. 3. Cappuzzo F, et al. Lancet Oncol. 2010;11:521-529. 4. Miller VA , et al. 2009 ASCO. Abstract LBA8002. 5. Kabbinavar J, et al. 2010 ASCO. Abstract 7526. 6. Zhang L, et al. 2011 ASCO. Abstract LBA7511.
  • Oncología Médica XXI Vigo Continuation Maintenance Trials Study Continuation Agent Median PFS, Mos Median OS, Mos Belani et al[1] Gemcitabine Best supportive care 7.4 7.7 8.0 9.3 IFCT[2] Gemcitabine Erlotinib Best supportive care 3.8 2.9 1.9 12.1 11.4 10.8 Pemetrexed Placebo 4.1 2.8 13.9 11.0 PARAMOUNT[3] 1. Belani CP, et al. 2010 ASCO. Abstract 7506. 2. Perol M, et al. 2010 ASCO. Abstract 7507. 3. Paz-Ares L, et al. Lancet Oncol. 2012;13:247-255.
  • 2013: First-line Treatment of Advanced/ Metastatic NSCLC 75% 25% Non-SCCa Other mutations 5% to 10% Mutational analysis EGFR mutation +15% KRAS or no other “actionable” mutation: 80% SCCa EGFR-TKI 10% EML4/ALK ROS1 Crizotinib RET 90% Any hemoptysis No hemoptysis Platinum + pemetrexed Carboplatin + paclitaxel + bevacizumab or platinum + pemetrexed ? Vandetanib Platinum + paclitaxel, docetaxel gemcitabine or vinorelbine nab-paclitaxel (? cetuximab)