OTRAS TERAPIAS BIOLÓGICAS EN CPNM: Selección y Secuencia Óptima del Tratamiento

Transcription

1 OTRAS TERAPIAS BIOLÓGICAS EN CPNM: Selección y Secuencia Óptima del Tratamiento Dolores Isla Servicio de Oncología Médica HCU Lozano Besa de Zaragoza

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3 2008

4 Selection Factors in Advanced NSCLC ( 8y ago) Clinical characteristics: age, PS, comorbidities Histologic characteristics: Molecular characteristics:

5 Management of Advanced NSCLC x Docetaxel ± Nintedanib x x x x Docetaxel ± Nintedanib x Docetaxel ± Nintedanib x Docetaxel ± Nintedanib Docetaxel ± Nintedanib Docetaxel ± Nintedanib D Doroshow and R Herbst, JAMA Oncol 2018

6 Advanced NSCLC Therapies Current Algorithm Sq NSCLC Non-Sq NSCLC EGFR Mutation ALK Rearrangement ROS1 Rearrangement Others PLATINUM CT First-Line PLATINUM CT PEMBROLIZUMAB (PD-L1+ 1%) NIVOLUMAB/IPILIM UMAB (High TMB) GEFITINIB ERLOTINIB +/- BEVACIZUMAB AFATINIB ALECTINIB CRIZOTINIB PLATINUM/PEM/PE MBROLIZUMAB CARBO/PAC/BEV/AT EZOLIZUMAB PEMBROLIZUMAB (PD-L1+ 1%) NIVOLUMAB/IPILIMU MAB (High TMB) Maintenance PEM/BEV Second-Line DOCETAXEL ERLOTINIB PLATINUM CT NIVOLUMAB PEMBROLIZUMAB (PD-L1+ 1%) ATEZOLIZUMAB OSIMERTINIB (T790M+) PLATINUM CT ATEZOLIZUMAB CERITINIB BRIGATINIB LORLATINIB CRIZOTINIB PLATINUM CT ATEZOLIZUMAB PLATINUM CT DOCETAXEL +/- NINTEDANIB PEMETREXED ERLOTINIB PLATINUM CT NIVOLUMAB PEMBROLIZUMAB (PD-L1+ 1%) ATEZOLIZUMAB

7 Lung Cancer Mutation Consortium (LCMC 2.0): Precision medicine for advanced lung adenocarcinoma n = 187 Targetable Cohort with EGFR, ALK, ROS1, RET, MET, BRAF V600E, ERBB2 (HER2), and with clinical follow-up had median OS 2.8 vs. 1.5 years, p = Driver Mutation or Alteration? Targeted Therapy? Overall survival by driver and targeted therapy status 1 N Median Overall Survival Positive Yes years Negative No years Positive No years 7 Aisner et al., ASCO 2016

8 Advanced NSCLC Therapies Current Algorithm Sq NSCLC Non-Sq NSCLC EGFR Mutation ALK Rearrangement ROS1 Rearrangement Others 15% PLATINUM CT First-Line PLATINUM CT PEMBROLIZUMAB (PD-L1+ 1%) NIVOLUMAB/IPILIM UMAB (High TMB) GEFITINIB ERLOTINIB +/- BEVACIZUMAB AFATINIB ALECTINIB CRIZOTINIB LATINUM/PEM/PEM BROLIZUMAB CARBO/PAC/BEV/AT EZOLIZUMAB PEMBROLIZUMAB (PD-L1+ 1%) NIVOLUMAB/IPILIMU MAB (High TMB) Maintenance PEM/BEV Second-Line DOCETAXEL ERLOTINIB PLATINUM CT NIVOLUMAB PEMBROLIZUMAB (PD-L1+ 1%) ATEZOLIZUMAB OSIMERTINIB (T790M+) PLATINUM CT ATEZOLIZUMAB CERITINIB BRIGATINIB LORLATINIB CRIZOTINIB PLATINUM CT ATEZOLIZUMAB PLATINUM CT DOCETAXEL +/- NINTEDANIB PEMETREXED ERLOTINIB PLATINUM CT NIVOLUMAB PEMBROLIZUMAB (PD-L1+ 1%) ATEZOLIZUMAB

9 EGFR-TKI 1L Studies x

10 Recent EGFR-TKI Studies FLAURA Study, Planchard D, ELCC 2018 Ferrara R, JTO 2018

11 REVIEWS a Acquired resistance to TKIs in solid tumours: learning from lung cancer REVIEWS D. Ross Camidge, William Pao and Lecia V. Sequist Abstract The use of advanced molecular profiling to direct the use of targeted therapy, such as tyrosine kinase inhibitors (TKIs) for patients with advanced-stage non-small-cell lung cancer (NSCLC), has revolutionized the treatment of this disease. However, acquired resistance, defined as progression after initial benefit, to targeted therapies inevitably occurs. This Review explores breakthroughs in the understanding No identif cation and treatment of acquired resistance in NSCLC, focusing Re-Biopsy on EGFR mutant and ALK rearrangement-positive disease, which AR mechanism may be relevant across multiple different solid malignancies with oncogene-addicted subtypes. Mechanisms EMT ~1 2% of acquired resistance may be pharmacological (that is, failure of delivery of the drug ~15 20% to its target) or biological, resulting from evolutionary selection on molecularly diverse tumours. A number of clinical approaches can maintain HER2 control amplif of the disease cation in the acquired resistance setting, including the use of radiation to treat isolated areas of progression and adding or switching to cytotoxic chemotherapy. Furthermore, novel ~8 13% approaches that have already proven successful include the development of second-generation and thirdgeneration inhibitors and the combination of some of these inhibitors with antibodies directed against the same target. With our BRAF increased ~1% understanding of the spectrum of acquired resistance, major changes in how T790M we conduct clinical research in this setting are now underway. Bypass tracks ~20% Camidge, MET D. R. et amplif al. Nat. Rev. cation Clin. Oncol. ~5% Liquid Biopsy advance online publication 1 July 2014; doi: / nrclinonc Int roduct ion PIK3CA ~1 2% SCLC alone ~6% SCLC with PI3K ~4% RET BRAF P alone ~40 55% T790M with EGFR ROS1 amplif cation HER2 ~10% EGFR target MET alteration ~60% f Colorado sive Cancer stop F704, ncer m 5327, edical rora, USA b EGFR No identif cation AR mechanism EGFR Other EGFR point mutations 1 2% EGFR Nat Rev Clin Oncol 2014

12 Mechanisms of Resistance to 3 rd- generation EGFR-TKIs Ricordel C, Ann Oncol 2018

13 Sequential Treatment in EGFR + p. Ferrara R, JTO 2018

14 RELAY Study T790M-

15 BOOSTER Study ETOP

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17 ADAURA Study

18 Advanced NSCLC Therapies Current Algorithm Sq NSCLC Non-Sq NSCLC EGFR Mutation ALK Rearrangement ROS1 Rearrangement Others 5% PLATINUM CT First-Line PLATINUM CT PEMBROLIZUMAB (PD-L1+ 1%) NIVOLUMAB/IPILIM UMAB (High TMB) GEFITINIB ERLOTINIB +/- BEVACIZUMAB AFATINIB ALECTINIB CRIZOTINIB PLATINUM/PEM/PE MBROLIZUMAB CARBO/PAC/BEV/AT EZOLIZUMAB PEMBROLIZUMAB (PD-L1+ 1%) NIVOLUMAB/IPILIMU MAB (High TMB) Maintenance PEM/BEV Second-Line DOCETAXEL ERLOTINIB PLATINUM CT NIVOLUMAB PEMBROLIZUMAB (PD-L1+ 1%) ATEZOLIZUMAB OSIMERTINIB (T790M+) PLATINUM CT ATEZOLIZUMAB CERITINIB BRIGATINIB LORLATINIB CRIZOTINIB PLATINUM CT ATEZOLIZUMAB PLATINUM CT DOCETAXEL +/- NINTEDANIB PEMETREXED ERLOTINIB PLATINUM CT NIVOLUMAB PEMBROLIZUMAB (PD-L1+ 1%) ATEZOLIZUMAB

19 Strong Data Thai AA, Curr Opin Oncol 2018

20 Phase III Studies ongoing in 1 st -Line ALTA-1L NCT N=270 Primary NCT End Point: PFS EXALT3 Advanced NSCLC, ALK+. PS 0-2. Asymptomatic CNS allowed NCT Primary End Point: PFS R N=402 X mg QD Crizotinib 250 mg BID PD Toxicity Or death CROWN Advanced NSCLC, ALK+. PS0-2 Asymptomatic CNS allowed =NCT Primary End Point: PFS R N=280 Lorlatinib 100 mg QD Crizotinib 250 mg BID PD Toxicity Or death

21 Mechanisms of Resistance Gainor et al. Cancer Discov 2016

22 Mechanisms of Progression in ALK- Rearranged NSCLC and ALK inh. Activity What about Mechanisms of Resistance of Alectinib / Ceritinib in 1L???

23 Sequential Treatment in ALK+ p. Ferrara R, JTO 2018

24 1L Treatment Evolution In ALK+ NSCLC p.

25 Other Mutations Actionable mutations are relevant, no matter how rare they are Smokers can also have NSCLC with actionable mutations Patients with rare mutations should be enrolled in clinical trials Registries can provide complementary real world data

26 Crizotinib, Ceritinib, Brigatinib, Entrectinib, Lorlatinib Cabozantinib, Vandetanib??, BLU-667 (AACR 2018 ). TD-M1, Poziotinib (AACR 2018 )

27 Recent Non-EGFR or ALK + Studies Ferrara R, JTO 2018

28 x x Atezolizumab

29 IO Therapies in Combination with other Therapies

30 Nat Rev Cancer 2018

31 J Clin Oncol 2018

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37 Frampton G, et al. Nature Biotech, 2013, 31,

38 2017

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41 Clinical trials should be considered from the time of diagnosis and at each instance of disease progression We also strongly recommend the involvement of a palliative care team from diagnosis because this has been shown to improve: Patient outcomes and survival Can help facilitate transition to supportive care when appropriate The progress in the past 20 years has been enormous We look forward to the years ahead, as our growing understanding of the biology of NSCLC will enable us to better harness the potential of multimodality therapy for our patients with this challenging disease D Doroshow and R Herbst, JAMA Oncol 2018

42 X SIMPOSIUM!!!!!! GRACIAS POR LA CONFIANZA: 8/10!!!!