Aggiornamenti in oncologia tra ricerca e clinica: Carcinoma del polmone

Transcription

1 Convegno Interregionale AIOM Lombardia, Liguria, Piemonte e Valle D Aosta Coniugare innovazione, sostenibilità e continuità di cura in oncologia: il ruolo delle Reti regionali Milano, 19 Novembre 2016 Aggiornamenti in oncologia tra ricerca e clinica: Carcinoma del polmone Francesco Grossi UOS Tumori Polmonari Azienda Ospedaliera Universitaria San Martino IST Istituto Nazionale per la Ricerca sul Cancro Genova

2 Treatment strategies in advanced NSCLC in 2016 Chemotherapy Chemotherapy +Biological Patients w/o driver mutation Targeted therapy Patients with driver mutation Immunotherapy

3 Treatment strategies in advanced NSCLC in 2016 Chemotherapy Chemotherapy +Biological Patients w/o driver mutation Targeted therapy Patients with driver mutation Immunotherapy

4 : chemotherapy oriented research in NSCLC Grossi F, The Oncologist 2010

5 JMDB: OS in non-squamous & squamous patients Scagliotti G, JCO 2008

6 PARAMOUNT: PFS from randomization and from induction Paz-Ares L, Lancet Oncology 2013

7 E4599: pre-planned OS analysis in adenocarcinoma subgroup Sandler A, JTO 2010 & NEJM 2006

8 Squire: primary outcome OS Thatcher N, Lancet Oncol 2015

9 Garon EB, Lancet Oncology 2014 REVEL: Randomized phase III of doc +/- ramucirumab in 2 nd line NSCLC Primary endpoint: OS HR 0.86 (p=.023) Median OS 10.5 vs 9.1m PFS HR 0.76 (p<.001) Median PFS 4.5 vs 3.0m

10 Lume-Lung 1: significant OS benefit in pts with adenocarcinoma histology Reck M, Lancet Oncol 2014

11 NICE guidance on necitumumab, ramucirumab and nintedanib On Sept 28, 2016, the National Institute for Health and Care Excellence (NICE) published guidance not recommending necitumumab in combination with gemcitabine and cisplatin for untreated advanced or metastatic EGFR-expressing, squamous non-small-cell lung cancer (NSCLC). NICE technology appraisal guidance TA412. On Aug 24, 2016, the NICE published guidance not recommending ramucirumab in combination with docetaxel for the treatment of locally advanced or metastatic non-small-cell lung cancer (NSCLC) in adults whose disease has progressed after platinum-based chemotherapy. NICE Technology appraisal guidanceta403 On July 22, 2015, the National Institute for Health and Care Excellence (NICE) published guidance recommending nintedanib for previously treated locally advanced, metastatic, or locally recurrent non-small-cell lung cancer, providing the company (Boehringer Ingelheim, Bracknell, UK) offers nintedanib with the discount agreed in the patient access scheme. NICE Technology appraisal guidanceta347

12 Necitumumab in metastatic squamous cell Lung Cancer: Establishing a value-based cost Evaluation of the incremental cost-effectiveness ratios (ICERs) for the use of necitumumab across a range of values for its cost. Model robustness was assessed by probabilistic sensitivity analyses, based on Monte Carlo simulations, sampling values from the distributions of all model parameters. The probabilistic sensitivity analyses established that when necitumumab cost less than $563 and less than $1309 per cycle, there was 90% confidence that the ICER for adding necitumumab would be less than $ per QALY and less than $ per QALY, respectively. These findings provide a value-based range for the cost of necitumumab from $563 to $1309 per cycle. This study provides a framework for establishing value-based pricing for new oncology drugs entering the US marketplace. Goldstein DA, Jama Oncology 2015

13 Treatment strategies in advanced NSCLC in 2016 Chemotherapy Chemotherapy +Biological Patients w/o driver mutation Targeted therapy Patients with driver mutation Immunotherapy

14 NSCLC evolution: from single disease to many molecularly defined subsets NSCLC as 1 disease First-targeted tx ALK EGFR Adenocarcinoma ALK HER2 BRAF PIK3CA AKT1 MAP2K1 NRAS ROS1 RET EGFR KRAS Unknown Other 11% Squamous 34% Adenoca 55% EGFRvIII PI3KCA EGFR DDR2 FGFR1 Amp Unknown Histology-Based Subtyping Squamous Cell Cancer Li T, J Clin Oncol. 2013

15 Targeted therapy for adenocarcinoma EGFR Sensitizing Gefitinib 4 Erlotinib 4 Afatinib 4 Osimertinib 4 Necitumumab 4 Rociletinib 3 1. Phase I 2. Phase II Key 3. Phase III 4. Approved ALK Crizotinib 4 Alectinib 4 Ceritinib 4 Lorlatinib 2 Brigatinib 2 EGFR Sensitizing 17% KRAS 25% Tsao AS, J Thorac Oncol ALK 7% MET Crizotinib 2 Cabozantinib 2 EGFR Other 4% Unknown Oncogenic Driver 31% HER2 Trastuzumab emtansine 2 Afatinib 2 Dacomitinib 2 MET 3% > 1 Mutation 3% HER2 2% ROS1 2% BRAF 2% RET 2% NTRK1 1% PIK3CA 1% MEK1 < 1% PIK3CA LY PQR MEK1 Trametinib 2 Selumetinib 3 Cobimetinib 1 ROS1 Crizotinib 4 Cabozantinib 2 Ceritinib 2 Lorlatinib 2 DS-6051b 1 BRAF Vemurafenib 2 Dabrafenib 2 RET Cabozantinib 2 Alectinib 2 Apatinib 2 Vandetanib 2 Ponatinib 2 Lenvatinib 2 NTRK1 Entrectinib 2 LOXO Cabozantinib 2 DS-6051b 1

16 Benefit of first-line EGFR TKIs: 9 randomized phase III studies

17 PFS and OS in EGFR mutated pts treated with EGFR TKIs inhibitors Lin JJ, JTO 2016

18 Resistance to EGFR TKI Regardless of extent of initial response, resistance to TKI develops invariably due to T790 mutation (~ 50% to 60%) HER 2 mutation (8%-12%) MET amplification (~ 5% to 20%) Conversion to SCLC (< 5%) EGFR mutated tumors might progress rapidly upon withdrawal of TKI Role of continuation of TKI beyond progression is under evaluation Afatinib, AZ9291, CO1686, HM targets T790 mutation EGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor. Sequist LV, et al. Sci Transl Med. 2011;3(75):75ra Pao W, et al. PLoS Med. 2005;2(3):e73.

19 AURA (AZD9291): best % change in target-lesion size and PFS Janne PA, NEJM 2015

20 Crizotinib superior to standard chemotherapy 1 st Line therapy 2nd Line therapy Pfizer 1014: Crizotinib vs. Platinum/Pemetrexed Pfizer 1007: Crizotinib vs. Chemotherapy ORR: Crizotinib 74% vs. Chemo 45% ORR: Crizotinib 65% vs. Chemo 20% Mok T, ASCO 2014; Shaw AT, NEJM 2013

21 Excellent tumor response seen with multiple next generation ALK inhibitors ceritinib alectinib brigatinib 56% 55% 61%

22 Crizotinib in ROS-1 positive NSCLC: best response and PFS RR=72% PFS= 19.2 mos Shaw AT, NEJM 2014

23 BRF113928: Responses With Dabrafenib +Trametinib Planchard D, Lancet Oncology 2016

24 Elenco Centri validati al Controllo di Qualità Nazionale per l'espressione di ALK in IHC nel carcinoma polmonare Lombardia= 9 (Milano 6, Pavia, Lecco, Varese) Piemonte e Valle d Aosta= 4 (Torino 3, Aosta) Liguria= 1 (Genova) Fonte: AIOM-SIAPEC

25 Treatment strategies in advanced NSCLC in 2016 Chemotherapy Chemotherapy +Biological Patients w/o driver mutation Targeted therapy Patients with driver mutation Immunotherapy

26 CheckMate 017 and 057 in secondline in unselected patients: design Brahmer J, NEJM 2015; Borghaei H, NEJM 2015

27 CheckMate 017 and 057 in secondline in unselected patients: OS Borghaei H, ASCO 2016

28 CheckMate 017 and 057: OS by PD-L1 expression Spigel DR, ASCO 2015; Horn L, ECCO/ESMO 2015

29 Landmark OS in PD-L1 non-expressors (<1%) Randomized Subjects with PD-L1 Expression <1% Randomized Subjects with PD-L1 Expression <1% Alive at Month Probability of Survival Probability of Survival Nivolumab Docetaxel Overall Survival (Months) The majority of patients with no PD-L1 expression are alive at month 3 OS HR and separation of curves favoring nivolumab are observed in the landmark analysis Overall Survival (Months) Borghaei H, NEJM 2015; Assessment report EMA/246304/2016

30 Keynote-010 and OAK in second-line selected/unselected patients: design Herbst RS, Lancet 2015; Barlesi F, ESMO 2016

31 Keynote-010 and OAK in second-line selected or unselected patients Herbst RS, Lancet 2015; Barlesi F, ESMO 2016

32 Relationship between PD-L1 expression and outcome in the Keynote 010 and OAK Bass P, ASCO 2016; Barlesi F, ESMO 2016

33 KEYNOTE 024 and CheckMate 026: study design Reck M, ESMO 2016 Socinski MA, ESMO 2016

34 KEYNOTE 024 and CheckMate 026: Progression-free survival Reck M, NEJM 2016 Socinski MA, ESMO 2016

35 KEYNOTE 024 and CheckMate 026: Overall survival Reck M, NEJM 2016 Socinski MA, ESMO 2016

36 Rimm DL, WCLC 2015 Candidate predictive PD-L1antibodies PD-L1 Drug and Vendor Nivolumab BMS Pembrolizumab Merck Atezolizumab Roche Durvalumab AstraZeneca Clone and Source IVD Class III partner Scoring Method 28-8 Abcam 22c3 Dako SP142 Spring Bio SP263 Spring Bio Dako Dako Ventana Ventana % cells with membrane staining at any intensity Thresholds 1%, 5%, or 10% >1% 1-49% >50% Method Pathologist/ Subjective % cells with membrane staining at any intensity Pathologist/ Subjective TC =Tumor cell IC= Immune cell Combine both percentage and subjective intensity TC3 =TC>50% IC3 = IC>10% TC2/IC2 = TC or IC >5% TC1/IC1 = TC or IC >1% Pathologist/ Subjective % cells with membrane staining at any intensity >25% Pathologist/ Subjective

37 MPDL3280A Phase Ia: Response by smoking and mutational status Former / Current Smokers Smoking Status (NSCLC; n = 53) Never Smokers EGFR Status (NSCLC; n = 53) Unknown EGFR Mutant Pts With PR, % Pts With PR, % Response by Smoking Status (ORR a ) 11/43 1/10 Response by EGFR Status (ORR a ) 9/40 1/6 KRAS Status (NSCLC; n = 53) Response by KRAS Status (ORR a ) Unknown KRAS Mutant Pts With PR, % 8/27 1/10 a ORR includes investigator-assessed u/c PR by RECIST 1.1. Patients first dosed at 1-20 mg/kg by Oct 1, Data cutoff: Apr 30, 2013.

38 High versus low TMB according to molecular alterations Slide 3 Spigel DR, ASCO 2016

39 Potential characteristics of immunogenic and nonimmunogenic tumors Evaluation of tumor tissues may reveal an immunogenic tumor microenvironment consisting of many immunologic markers, including CD8 T cells, CD4 T cells, PD-L1, granzyme B, and CD45 RO, which may be effectively treated with immune checkpoint therapy to elicit clinical benefit. Tumor tissues that lack expression of many immunologic markers may indicate a nonimmunogenic tumor microenvironment, which may require combination therapies consisting of an agent to create an immunogenic tumor microenvironment plus an immune checkpoint agent to further enhance the immune response for clinical benefit Sharma P, Science

40 Potential mechanisms of action to mediate synergistic effects of combined therapies Melero I, Nat Rev Cancer 2015

41 Challenges Which combination and sequence? Scientific rationale is lacking With or without chemotherapy Which combination of checkpoint inhibitor Sequencing duration of treatment Patient selection biomarker Differences per tumor location Differences within a tumor location Pardoll DM, Nature Rev Cancer 2012

42 Examples of phase III anti-pd1/pd-l1 combination trials in 1 st -line advanced NSCLC

43 Anti CTLA-4+anti PD-1/L1 or CT+ PD-1/L1 Hellmann MD, ASCO 2016; Antonia S, Lancet Oncol 2016 Langer CJ, Lancet Oncol 2016

44 Timeline of key therapeutic advances for advanced-stage disease in predominant histological subgroups of lung cancer Tan WL, Lancet Oncol 2016

45 Immunotherapy vs Targeted therapy vs Chemotherapy Sharma P, Cell 2015

46 Grazie per l attenzione! francesco.grossi@hsanmartino.it