MALIGNANT PLEURAL MESOTHELIOMA

Transcription

1 MALIGNANT PLEURAL MESOTHELIOMA Giovanni Luca Ceresoli Thoracic & GU Oncology Unit Humanitas Gavazzeni, Bergamo

2 Unmet needs in MPM WCLC Role of surgery and radiotherapy (IMRT) 2. How to improve results of first-line treatments 3. Role of second-line treatments 4. Response radiological assessment 5. Better understanding of the biology of the disease WCLC SIDNEY Abstract presented during Plenary Session SURGERY & MULTIMODALITY TREATMENTS 1 Oral Abstract Session 2 Mini Oral Abstract SECOND-LINE Sessions THERAPY 3 Poster Sessions RESPONSE EVALUATION 2 Mini-Simposia 5 MTE Sessions

3 EPP in MPM: the MARS trial mos 14.4 mos (EPP group) 19.5 mos (no EPP group) Treasure T, Lancet Oncol 2011 Radical surgery in the form of EPP within trimodal therapy offers no benefit and possibly harms patients. 3

4 EPP versus Pleurectomy/Decortication 663 consecutive patients from 3 Institutions (MSKCC, NCI, Karmanos Cancer Institute). M 538, F125; median age 63 years P/D EPP n. Pts 278 (42%) 385 (58%) Progn. Variables Older, earlier stages More epithelial, more lk likely l to receive MMT Op. mortality 4% 7% Severe respiratory compl. 6.4% 10% msv 16 mos 12 mos Flores et al., JTCVS 2008

5 Role of surgery (P/D vs EPP) Non surgical group imbalanced: older than surgical pts, less epithelioid, less treated with chemotherapy Treatments not homogeneous (different centers, 30-yr span) 1227 evaluable pts, from 1982 to 2012 in 6 Institutions Bille et al., WCLC 2013

6 Role of surgery (P/D vs EPP) (age <70 yrs, epitheliod type, chemotherapy) 313 pts with favorable prognostic factors (25%) Bille et al., WCLC 2013

7 P/D in MPM: different techniques IMIG/IASLC consensus, JTO 2011; Cao et al., WCLC 2013

8 175 patients Primary endpoint: 1-yr OS; secondary endpoints: QoL, control of pleural effusion Rintoul et al., WCLC 2013

9 The mesovats trial: survival Rintoul et al., WCLC 2013

10 The mesovats trial: QoL & pleural effusion control 1. No difference in overall survival; 2. P/D has a modest advantage in QoL and effusion control; 3. P/D: more toxicities & lenght of stay in hospital, more expensive. Rintoul et al., WCLC 2013

11 Intensity modulated RT (IMRT) after EPP Can improve target volume coverage and normal tissue sparing in comparison to 3D-conformal RT (Krayenbuehl et al., 2007). Results in a relatively large proportion of the contralateral hemithorax receiving a small dose of radiation (V5, V20); risk of pulmonary toxicity (Allen et al., 2006; Rice et al., 2007; Miles et al., 2008).

12 Randomized trial: role of RT post-surgery

13 Hemithoracic pleural IMRT after P/D 20 pts have completed RT, 1 is on treatment. 5 pts with grade 2 RP, 1 grade 3; early intervention with steroids effective in controlling RP. Wu et al., WCLC 2013

14 Algorithm in pts progressing g during or after PBC progres ssed (%) ) Experimental trial Retreatment with PBC Prop portion 25 0 Single-agent ChT Time to progression (months)

15 CHEMOTHERAPY IN SECOND-LINE SETTING IN MPM Single Institution experience with VINORELBINE and GEMCITABINE Memorial Sloan-Kettering Cancer Center, New York, USA Review of 60 pts treated with VNR (33), GEM (15) or both (12) as second or third-line therapy for MPM between 2003 and % pretreated with pemetrexed/platinum, 10% with gemcitabine/platinum Imaging g studies reviewed with a radiologist according to modified RECIST criteria Drug PD SD PR Gemcitabine 59% 37% 4% Vinorelbine 47% 50% - mpfs 1.6 months, mos 5 months 9 Zauderer et al., WCLC 2013

16 VINORELBINE AS SECOND-THIRD LINE TX Author Design Regimen N. Pts Line RR % DCR % mpfs mos Single agent Stebbing 2009* Prospective VNB % 2L 16% 84% NR 9.6 mos Zucali Retrospective VNB 59 58% 2L 2013** 42% 3L 15% 49% 2.3 mos 6.2 mos Sorensen 2010 Prospective VNB OS % 2L 7% NR 2.3 mos 77+ days Zauderer 2012 Retrospective VNB 45 53% 2L 47% 3L 0% 52% 2.5 mos 5.0 mos Combination regimens Zucali 2008* Prospective GEMVIN % 2L 10% 43% 2.8 mos 10.9 mos * Published as full papers; ** Submitted

17 Vorinostat as 2nd-line therapy in MPM: Vantage 014 Study 660 patients with advanced MPM (up to two lines of previous systemic chemotherapy including PEM) Vorinostat 300 mg orally twice per day 3 of 7 days; 3-week cycle Vorinostat (median OS: 31 wks) Placebo (median OS: 27 wks) HR (vorinostat vs placebo): 0.98 (P =.858) OS (%) Days Pts at Risk, n Placebo Vorinostat t Krug LM, et al. ECCO-ESMO 2011

18 Second-line targeted therapy: inhibition of angiogenesis Author (year) Agent No. RR DCR mttp msv (mos) (mos) Dubey et al. (2010) Sorafenib 30 3% 60%* 3.6* 13.2 Irshad et al. (2010) Sorafenib 19 6% 87% NR NR Laurie et al. (2011) Sunitinib 17 0% 65% Nowak et al. (2012) Sunitinib 53 12% 77% Garland et al. (2011) Cediranib 47 9% 43% Jackman et al. (2008) Bevacizumab % 50% Erlotinib Gregorc et al. (2010) NGR-hTNF 43 0% 44% 2.8 NR Nowak et al. (2013) BNC105P 30 3% 43% * On a total of 50 pts (20 chemo-naïve); Patients pretreated with cisplatin-based chemotherapy Modified from Ceresoli et al., Expert Opin Investig Drugs 2012

19 NGR015: Phase III trial in second-line MPM NCT

20 PI3K/mTOR INHIBITORS IN SECOND-LINE SETTING IN MPM GDC 0980, 30 mg orally daily Phase I + MPM expanded cohort at P2RD Overall 33 pts; 4 PR, RR 12% PI3K mutationsti and pten loss uncommon n Dolly et al., WCLC 2013

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22 Mossoba et al. Clin Cancer Res 2011; Weldon et al., Mol Cancer Ther 2013; Hassan et al. Sci Transl Med 2013; Hassan et al., WCLC 2013.

23 Hassan et al., WCLC 2013

24 SS1P plus PC in MPM Hassan et al., WCLC 2013

25 SS1P plus PC in MPM Hassan et al., WCLC 2013

26 VINORELBINE and BRCA1 in MPM Sensitivity to vinorelbine correlates with BRCA1 expression in 6 mesothelioma cell lines % 61.1 % 9 Busacca et al., J Pathol 2012

27 VINORELBINE and BRCA1 in MPM Randomised phase II trial of oral vinorelbine as second-line therapy for patients with MPM expressing BRCA1 VIM trial Relapsed MPM R 2:1 Weekly oral VINORELBINE + ASC ASC (active symptom control) BRCA1 expression IHC will be evaluated as a stratification factor. Primary endpoint: overall survival. 114 participants required (76 VNR, 38 ASC) 9 Fennell et al., WCLC 2013, Poster Session 2 Mesothelioma, P

28 Tremelimumab: an anti-ctla-4 mab T-cell costimulatory receptors Tremelimumab (CP675,206) Pfizer/MedImmune IgG2 isotype antibody half-life time: 22 days T-cell potentiation T cell TCR MHC APC B7 CTLA-4 CTLA-4 mab

29 Immunotherapy in MPM: tremelimumab Calabrò et al., Lancet Oncol 2013

30 Phase II Multicenter, International, Randomized Trial of Tremelimumab in Patients With Unresectable Mesothelioma (Trial D4880C00003 Sponsored by MedImmune) Relapsed/Refractory Malignant Mesothelioma (2 nd /3 rd line) 2:1 Treme 10mg/kg Q4Wk x 6 doses Treme 10mg/kg g Q12Wk (Non Dosing visits: V9, 11, 13) Total recruitment = 180 patients (OS events) Placebo Q4Wk x 6 doses Placebo Q12Wk (Non Dosing visits: V9, 11, 13) Primary endpoint: OS NCT Randomized TREMELIMUMAB: PLACEBO 2:1 (120/60) Stratification Factors European Organization for Research and Treatment of Cancer (EORTC) status (lowrisk vs high-risk) Line of therapy (second vs third) Anatomical site (pleural vs peritoneal) Kindler et al., WCLC 2013, Poster Session 2 Mesothelioma, P

31 Focal adhesion kinases (FAK) inhibitors in MPM Pemetrexed and cisplatin increase cancer stem cells (CSCs). FAK inhibitors decrease CSCs in mesothelioma models. NF2 tumor suppressor gene is inactivated in 40-50% of MPM pts, resulting in lack of expression of functional Merlin protein. Mesothelioma cells that lack NF2/Merlin are especially sensitive to FAK inhibitors. Poulikakos et al., Oncogene 2006

32 Focal adhesion kinases (FAK) inhibitors in MPM: VS-6063 (or Carbo/Cis) 1:1 Primary Endpoint: PFS Approx. 370 pts included Keegan et al., WCLC 2013, Poster Session 2 Mesothelioma, P

33 NVALT Thalidomide maintenance study mttp 3.6 mos (Th) vs 3.5 mos Buikhuisen et al., Lancet Oncol 2013 REALITY OR DREAM? Monza 22 NOV 2013

34 CALGB 30901: pemetrexed maintenance Randomized Phase II Study of Maintenance Pemetrexed Versus Observation for Patients With MPM without Progression After First-Line Chemotherapy 96 patients PEMETREXED + CIS/CARBOPLATIN X 4 cycles PEMETREXED UNTIL PROGRESSION Stratification: R - Cisplatin vs carboplatin - Epithelioid vs other SD PR CR OBSERVATION UNTIL PROGRESSION Pi Primary endpoint: Progression-free survival REALITY OR DREAM? Monza 22 NOV 2013 PI: A. Dudek

35 Modified RECIST criteria for MPM Modified RECIST response criteria Complete response (CR) Disappearance of all target lesions with no evidence of tumor elsewhere Partial response (PR) Reduction of at least 30% in the total tumor measurement (sum of six unidimensional measurements, acquired in two positions at three separate levels on transverse cuts of CT scan) Disease progression (PD) Increase of at least 20% in the total tumor measurement (as defined above) over the nadir measurement, or appearance of new lesions Stable disease (SD) Disease meeting the criteria of neither PR nor PD Byrne & Nowak, Ann Oncol 2004

36 Volumetric CT tumor response in MPM Armato et al., WCLC 2013

37 Volumetric CT tumor response in MPM Semi-automated method to determine MPM volume from CT scans retrospectively collected from 70 patients undergoing standard of care chemotherapy. Armato et al., WCLC 2013

38 Volumetric CT tumor response in MPM 41 consecutive radical P/D CONCLUSIONS 1. OS and PFS were correlated with tumor volume (TV). 2. All radiographic techniques underestimated actual TV. 3. Estimates closer to actual TV as they became less automated and more manual. Friedberg et al., WCLC 2013

39 Conclusions 1. The debate on surgery in MPM continues: expanding role of P/D, mesovats. 2. IMRT after P/D or no surgery. 3. l treatment: poor results of 2-nd line chemo in unselected pts; SS1P plus PC promising; new options/studies: BRCA1/vinorelbine, tremelimumab, FAK-inhibitors. 4. Volumetric CT response evaluation: pitfalls and challenges.

40 Grazie per l attenzione giovanni_luca.ceresoli@gavazzeni.it