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Anna Nowak
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OA 02 - Mesothelioma: Challenges For New Treatment (ID 653)
- Event: WCLC 2017
- Type: Oral
- Track: Mesothelioma
- Presentations: 8
- Moderators:S. Hasegawa, Anna Nowak
- Coordinates: 10/16/2017, 11:00 - 12:30, F205 + F206 (Annex Hall)
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OA 02.01 - Randomized Phase II Study of Anetumab Ravtansine or Vinorelbine in Patients with Malignant Pleural Mesothelioma (ID 9377)
11:00 - 11:10 | Presenting Author(s): Hedy Lee Kindler | Author(s): Silvia Novello, Dean A Fennell, G. Blumenschein, A. Bearz, G.L. Ceresoli, J.G. Aerts, J. Spicer, P. Taylor, A. Greystoke, K. Nackaerts, Luana Calabro, S. Burgers, R. Jennens, A.F. Sporchia, A. Walter, J. Siegel, B.H. Childs, C. Elbi, R. Hassan
- Abstract
- Presentation
Background:
Anetumab ravtansine (BAY 94-9343) is a novel fully human anti-mesothelin IgG1 antibody conjugated to the maytansinoid tubulin inhibitor DM4. We report the results of a randomized phase II trial of anetumab ravtansine compared to vinorelbine in patients with advanced malignant pleural mesothelioma (MPM) who have high mesothelin expression and have progressed on platinum/pemetrexed-based first-line chemotherapy (NCT02610140).
Method:
Patients (≥18 years) with locally advanced or metastatic MPM with progressive disease following first-line treatment with pemetrexed-based chemotherapy, with or without bevacizumab, were eligible. Patients were pre-screened based on obligatory tumor staining for mesothelin as determined by the Ventana MSLN (SP74) immunohistochemistry assay. The primary efficacy endpoint was progression-free survival (PFS) per central radiologic review using modified RECIST criteria for MPM. Secondary objectives included overall survival, tumor response, and safety. Patients were randomized in a 2:1 ratio to anetumab ravtansine 6.5 mg/kg Q3W IV or vinorelbine 30 mg/m[2] QW IV.
Result:
A total of 166 patients were randomized to anetumab ravtansine and 82 to vinorelbine; 3 and 10 patients, respectively, not receiving treatment were included for efficacy but not safety assessments. The treatment arms were evenly balanced, with 73% male, 64% ECOG performance status 1, 96% epithelioid histology, and a mean 2.5 (±2.4) months since last progression. The median duration of treatment (anetumab vs vinorelbine) was 12.6 weeks (range 3-61) vs 13.0 weeks (range 1-43). Treatment-emergent grade (G) ≥3 adverse events (AEs) were seen in 85 (52.1%) and 53 (73.6%) of patients, respectively. G3/G4 neutropenia (22.2%/16.7%) occurred in the vinorelbine arm whereas corneal epitheliopathy (39.3% all grade, 1.8% G3) was distinct for the anetumab ravtansine arm. Serious AEs (any grade) were similar; 52 (31.9%) vs 25 (34.7%). Treatment-emergent AEs leading to dose modification were 42.9% in the anetumab ravtansine arm and 80.6% in the vinorelbine arm. There was one treatment-related G5 event in each arm. Median PFS was 4.3 months (95% CI:4.1, 5.2) for anetumab ravtansine vs 4.5 months (4.1, 5.8) for vinorelbine; hazard ratio 1.22 (0.85, 1.74), p=0.859. Fourteen (8.4%) patients in the anetumab ravtansine arm had an objective response vs 5 (6.1%) in the vinorelbine arm, with no complete responses. Interim median overall survival was 10.1 mo (7.6, -) vs 11.6 mo (7.7, 12.5), respectively, p-value 0.721.
Conclusion:
In relapsed MPM, anetumab ravtansine was not superior to vinorelbine with respect to PFS.
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OA 02.02 - Ipilimumab and Nivolumab in the Treatment of Recurrent Malignant Pleural Mesothelioma: A Phase II Study (ID 9389)
11:10 - 11:20 | Presenting Author(s): Paul Baas | Author(s): M. Disselhorst, E. Harms, H. Van Tinteren, J. Quispel-Janssen, K. Monkhorst, S. Burgers
- Abstract
- Presentation
Background:
There is an increasing interest in the use of IO therapy in Mesothelioma (MPM). We previously reported on the effect of nivolumab (s.a) in patients with recurrent MPM with a disease control rate of 50% at 12 weeks. We therefore decided to test the effect of the combination of nivolumab and ipilimumab in recurrent MPM.
Method:
Patients with previously treated MPM and a PS of 0-1 are consented in this single arm prospective study. Pleural lesions must be available for biopsy before and after 6 weeks of treatment.Nivolumab is administered at a fixed dose of 240 mg (q2w) until progression and combined with ipilimumab (1mg/kg) on week 1, 7, 13 and 19. CT scans are performed every 6 weeks for analysis and duration of response. The primary endpoint is disease controle rate at 12 weeks. Translational research is performed on paired biopsies. A Simon’s minimax two-stage design is used to identify a DCR of >50%. Therefore 33 patients will be included.
Result:
From October 2016 until August 2017 38 patients gave informed consent. Three patients did not start due to progression or impossibility to biopsy. Two stopped after 1 cycle (due to progression or withdrawn consent). At time of analysis (August 29) 25 patients could be evaluated for response. At 12 weeks a DCR of 72% (18/25) and ORR of 28% (7/25) is observed. Two patients continued treatment after progression at 6 weeks; 1 achieved a PR after 4 months , and the other one is stable. Of the first 11 patients that have been in study for 6 months, 5 have PR, 1 SD and 4 PD. Toxicity is mild. SAE’s reported in the 38 patients occurred in 11 patients with grade 3 or 4 toxicity. No grade 5 toxicity was observed.
Conclusion:
In this interim analysis nivolumab plus ipilimumab meets the primary endpoint for patients with recurrent malignant mesothelioma. Toxicity is mild. The full data set will be presented at the WCLC.
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OA 02.03 - Prophylactic Irradiation of Tracts (PIT) in Patients with Pleural Mesothelioma: Results of a Multicentre Phase III Trial (ID 7980)
11:20 - 11:30 | Presenting Author(s): Corinne Faivre-Finn | Author(s): Neil Bayman, W. Appel, L. Ashcroft, David Raymond Baldwin, A. Bates, Liz Darlison, J.G. Edwards, V. Ezhil, D. Gilligan, M. Hatton, T. Mansy, M.D. Peake, L. Pemberton, Robert Campbell Rintoul, D.J. Ryder, P. Taylor
- Abstract
- Presentation
Background:
It has been widespread practice across Europe to irradiate diagnostic or therapeutic chest wall (CW) intervention sites in patients with malignant pleural mesothelioma (MPM) post-procedure - a practice known as prophylactic irradiation of tracts (PIT). This study aims to determine the efficacy of PIT in reducing the incidence of CW metastases following a chest wall procedure in MPM.
Method:
In this multicentre phase III randomised controlled trial, MPM patients following a chest wall procedure were randomised 1: 1 to receive PIT (within 42-days of procedure) or no PIT. Large thoracotomies, needle biopsy sites and indwelling pleural catheters were excluded. PIT was delivered at a dose of 21Gy in 3 fractions over 3 consecutive weekdays using a single electron field adapted to maximise coverage of the tract from skin surface to pleura. The primary outcome was the incidence of CW metastases within 6 months from randomisation, assessed in the intention-to-treat population. Stratification factors included epitheloid histology and intention to give chemotherapy. Trial registration number NCT01604005.
Result:
375 patients (186 PIT and 189 no PIT) were randomised between 06/2012-12/2015 from 54 UK centres. Comparing PIT vs no PIT, %male patients was 89.8/88.4%, median age 72.8/74.6 years, %ECOG PS (0,1,2) 32.2,56.5,11.3/23.8,56.1,20.1%, %confirmed epithelioid histology 79.6/74.1%, and %with intention to give chemotherapy 71.5/71.4%. The chest wall procedures were VATS (58.1/51.3%), open surgical biopsy (2.7/5.3%), local-anaesthetic-thoracoscopy (26.9/27.0%), chest drain (5.9/8.5%) and others (6.5/7.9%) for the PIT vs no PIT arm respectively. Radiotherapy was received as intended by 181/186 patients in the PIT arm. The proportion of CW metastases by 6 months was 6/186 (3.2%) vs 10/189 (5.3%) for the PIT vs no PIT arm respectively (odds ratio 0.60 [95% CI 0.17-1.86]; p=0.44) and by 12 months 15/186 (8.1%) versus 19/189 (10.1%) respectively (OR=0.79 [95% CI 0.36-1.69];p=0.59). Cumulative incidence of CW metastases at 6months/12 months/24 months was 3.3/8.5/10.0% in the PIT arm vs 5.6/10.9/18.7% in the no PIT arm. Evaluable patients who developed CW metastases reported a mean increase in visual analogue scale pain score of 13.3 (p<0.01) compared to baseline. Skin toxicity was the most common radiotherapy-related adverse event in the PIT arm with 96(51.6%) grade 1, 19(10.2%) grade 2, and 1(0.5%) grade 3 radiation dermatitis (CTCAE V4.0). There were no other grade 3 or higher radiotherapy-related adverse events.
Conclusion:
There is no role for the routine use of PIT following diagnostic or therapeutic CW procedures in patients with MPM.
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OA 02.04 - Discussant - OA 02.01, OA 02.02, OA 02.03 (ID 10827)
11:30 - 11:45 | Presenting Author(s): Daniel H. Sterman
- Abstract
- Presentation
Abstract not provided
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OA 02.05 - RESPECT-MESO: An International Randomised Controlled Trial to Assess Early Specialist Palliative Care in Malignant Pleural Mesothelioma (ID 8880)
11:45 - 11:55 | Presenting Author(s): Fraser Brims | Author(s): S. Gunatilake, I. Lawrie, L. Marshall, C. Fogg, N. Maskell, K. Forbes, N. Rahman, S. Morris, S. Gerry, A. Chauhan
- Abstract
- Presentation
Background:
Malignant pleural mesothelioma (MPM) has a high symptom burden and early specialist palliative care (SPC) may have a beneficial role for these patients. We examined the effect of early SPC in patients with MPM.
Method:
Participants with newly diagnosed MPM (within the last 6 weeks) were randomised to early SPC integrated with standard care, or standard care alone, in a 1:1 ratio. SPC visits were 4 weekly throughout the study period. Quality of life (QoL) and mood were assessed at baseline and every 4 weeks for up to 24 weeks with the EORTC QLQ–C30 questionnaire for QoL and General Health Questionnaire (GHQ-12) for anxiety/depression. The primary outcome was the change in EORTC C30 Global Health Status (GHS) QoL 12 weeks after randomisation.
Result:
174 participants underwent randomisation with 148 (85.1%) completing the primary outcome. The two groups were well matched after randomisation. Median (IQR) age was 72.6 (68.5-78.3) years and 139 (79.9%) were male. Epithelioid was the most common MPM subtype in 136 (78.2%) cases, ECOG PS was 0 in 66 (37.9%) and 1 in 108 (62.1%) participants. At randomisation, 134 (77.0%) participants reported dyspnoea and 100 (57.4%) had chest pain. At least 1 cycle of chemotherapy was completed in 103 (59.2%) participants. At 24 weeks 30 (17.2%) participants had died. Table 1 presents the primary and secondary outcome data. 68 (78.2%) participants in the intervention arm completed all scheduled monthly SPC visits at 12 weeks, and 46 (52.9%) at 24 weeks. 15 (17.2%) participants in the control arm were referred to SPC within 12 weeks, and 30 (34.5%) by 24 weeks.Table 1. Primary and secondary outcomes
Control SPC Mean difference* p= Mean (SD) GHS QoL 12 weeks 59.5 (SD 21.2) 60.2 (23.6) 1.8 (95% CI -4.0 to 8.5) 0.60 Mean (SD) GHS QoL 24 weeks 63.7 (SD 19.8) 61.3 (20.8) -2.0 (-8.8 to 4.6) 0.55 Mean (SD) GHQ-12 anxiety / depression scores 12 weeks 2.6 (3.2) 2.2 (3.0) -0.6 (-1.5 to 0.4) 0.24 Mean (SD) GHQ-12 anxiety / depression scores 24 weeks 2.1 (2.55) 1.75 (2.5) -0.4 (-1.2 to 0.4) 0.28 Median (95% CI) survival (months) 12.6 (10.7-19.7) 11.5 (9.8-15.9) - 0.51 Mean (SD) GHS QoL alive after 6 months of randomisation 60.9 (20.9) (n=66) 64.3 (19.9) (n=63) - - Mean (SD) GHS QoL in those who died within 6 months of randomisation 46.4 (21.4) (n=7) 38.9 (30.6) (n=12) 3.9 (-2.8 to 10.7)** 0.25 * adjusted for baseline score; ** post hoc analysis SPC = specialist palliative care; SD = standard deviation; CI = confidence interval; GHS = Global Health Status (from EORTC QLQ–C30; higher score – better QoL); GHQ = General Health Questionnaire (higher score - higher depression/anxiety)
Conclusion:
Provision of early palliative care for all patients with recently diagnosed MPM is not associated with beneficial changes in quality of life as compared to palliative care review based on symptom burden.
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OA 02.06 - Radioimmunotherapy Combining CTLA-4 Blockade or Low-Dose Cyclophosphamide with Local Radiation in Murine Malignant Mesothelioma (ID 8843)
11:55 - 12:05 | Presenting Author(s): Mikihiro Kohno | Author(s): L. Wu, L. De La Maza, Z. Yun, M. Chan, Y. Yao, Y. Zhao, Marc De Perrot
- Abstract
- Presentation
Background:
Our group has developed a new approach focusing on Surgery for Mesothelioma After Radiation Therapy (SMART), with encouraging results in a phase I/II clinical trial. The impact on the immune system of high-dose hypofractionated radiation therapy is expected to open the door for new combination therapy of immunotherapy and radiation to optimize their synergism on the immune system. The aim of this study is to investigate the antitumor effect of non-ablative hypofractionated radiation combined with anti-CTLA-4 antibody (a-CTLA-4) or low-dose cyclophosphamide (LD-CTX) in murine malignant mesothelioma model.
Method:
Balb/c mice were subcutaneously injected with murine mesothelioma AB12 cells into the left flank on day 0 (primary tumor) and into the right flank on day 7 (secondary tumor). Local radiotherapy (LRT) 5 Gy was delivered to primary tumor once daily for 3 consecutive days (total dose: 15 Gy). Mice were randomized into six groups: (1) No treatment, (2) LRT, (3) a-CTLA-4, (4) LRT+a-CTLA-4, (5) LD-CTX, (6) LRT+LD-CTX. We assessed local and abscopal effects by measuring primary and secondary tumor growth. Furthermore, CD4+ and CD8+ T cell proportion in tumor, spleen and peripheral blood were determined by flow cytometry.
Result:
Mice treated with LRT+a-CTLA-4 and LRT+LD-CTX showed the most significant deceleration in primary tumor growth compared to the other 4 groups. Both combination groups showed similar antitumor effects on the primary tumor. The secondary tumor growth tested the abscopal effect tended to be decreased in mice treated with LRT and LRT+a-CTLA-4 or LRT+LD-CTX compared to untreated mice, but the difference was not significant. Quantification of tumor-infiltrating T cells by flow cytometry showed that the percentages of total T cells, and CD4+ and CD8+ T cells in the primary tumor were increased in the combination groups.
Conclusion:
Combination of LRT and immunotherapy showed synergistic antitumor effects in controlling irradiated-tumor growth. CTLA-4 blockade and LD-CTX might be good candidates in combination with radiotherapy.
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OA 02.07 - Surgical Selection in Pleurectomy Decortication for Mesothelioma – an Overview from Screening and Selection from MARS 2 Pilot (ID 10185)
12:05 - 12:15 | Presenting Author(s): Eric Lim | Author(s): M. Trialists
- Abstract
- Presentation
Background:
Encouraging survival has been reported with pleurectomy decortication (PD) for malignant pleural mesothelioma (MPM) in several surgical case series. However, doubts remain over the degree of selection bias that constitutes the final composition of these series which therefore lead to questions surrounding the validity of the reported outcomes. We have reviewed our initial experience in the MARS 2 study to analyse this surgical selection process in more detail.
Method:
The MARS 2 pilot is randomised trial of RCT of 14 UK centres recruiting into a cisplatin/pemetrexed with or without the addition of PD for meseothelioma in those who remain suitable after an induction two cycle regime. We completed the pilot to analyse screening, eligibility, consent and randomisation data to estimate the eventual pool of patients considered suitable for surgery.
Result:
From 19 Jun 2015 to 5 Dec 2016, 331 patients were screened from the participating centres. In total, 254 patients were excluded, 176 for failed screening and 78 who declined participation. Of the 176, who failed screening the reasons were non resectable disease (74), poor performance status (24), not fit for surgery (4), not mesothelioma (6), death (5) and other (63). From the 331 screened participants, 77 were enrolled to and received the initial two cycles of chemotherapy and a further 21 withdrew. The reasons for withdrawal were declining randomisation (5), progressive disease (10) and other reasons (6), leaving 56 participants randomised into the trial.
Conclusion:
Screening data of a prospective randomised trial (MARS 2) has provided a unique insight into the detailed selection process for PD for MPM. Exclusions occurred at multiple points in the pathway but these have identified potential points for intervention in patient education, staging and fitness assessment and the proportion of tumour progression which will inform the forthcoming phase III study. The clear extent of possible selection bias underscores the importance of evaluating the efficacy of surgery within the context of this randomised trial to be able derive robust estimates of treatment effect.
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OA 02.08 - Discussant - OA 02.05, OA 02.06, OA 02.07 (ID 10828)
12:15 - 12:30 | Presenting Author(s): Prasad S. Adusumilli
- Abstract
- Presentation
Abstract not provided
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Author of
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MA 19 - Mesothelioma: Bench to Bedside (ID 680)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Mesothelioma
- Presentations: 1
- Moderators:Dean A Fennell, Hedy Lee Kindler
- Coordinates: 10/18/2017, 11:00 - 12:30, Room 315
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MA 19.03 - Nintedanib + Pemetrexed/Cisplatin in Malignant Pleural Mesothelioma (MPM): Phase II Biomarker Data from the LUME‑Meso Study (ID 8111)
11:10 - 11:15 | Presenting Author(s): Anna Nowak
- Abstract
- Presentation
Background:
Nintedanib is a triple angiokinase inhibitor. LUME-Meso (NCT01907100) is a randomised, Phase II/III study of ≤6 cycles of nintedanib+pemetrexed/cisplatin versus placebo+pemetrexed/cisplatin, followed by nintedanib or placebo maintenance, in chemo-naïve patients with MPM. In Phase II results, nintedanib+pemetrexed/cisplatin improved progression-free survival (PFS) versus control (hazard ratio [HR]=0.54; p=0.010), with a trend for prolonged overall survival (OS; HR=0.77; p=0.319). Benefit was most pronounced in patients with epithelioid tumours. Since no pharmacodynamic/predictive biomarkers are validated for anti-angiogenic therapies, exploratory analyses were conducted to investigate potential associations of plasma-derived angiogenic factors and genomic markers with treatment outcome in the LUME-Meso Phase II epithelioid population.
Method:
Blood samples were collected at baseline and, for patients receiving maintenance, at monotherapy Cycle 3 (C3mono) and end of monotherapy (EoTmono). Analyses focused on 58 angiogenic factors (Human AngiogenesisMAP[®] panel, Myriad RBM) and single-nucleotide polymorphisms (SNPs) in genes implicated in mesothelioma and/or associated with response to anti-angiogenic therapies in other tumour types (VEGFR1, VEGFR3 and mesothelin). Associations of biomarkers with treatment effect were evaluated by Cox regression and tested for interaction with false discovery rate (FDR) adjustment. Adjusted mean changes in angiogenic factor levels were compared between arms by ANCOVA. Analyses were exploratory, limited by small sample size, and considered hypothesis generating.
Result:
Of 77 patients with epithelioid tumours, angiogenic factor and genomic data were available for 71 and 67 patients, respectively. PFS/OS benefit of nintedanib appeared potentially more pronounced in patients with baseline plasma endoglin level below the median. There were possible weak associations between major homozygous genotypes for two VEGFR3 SNPs (rs307821 G/G and rs307826 A/A), and OS benefit and between VEGFR1 SNP rs9582036 A/A genotype and PFS benefit. Biomarker treatment associations were limited by small subgroup size, especially for low-frequency SNPs, and interaction tests were not significant after FDR adjustment. Regarding pharmacodynamic effects, adjusted mean change in interleukin-8 levels with nintedanib was greater from baseline to C3mono and lower from C3mono until EoTmono, compared with placebo. Nintedanib showed lower adjusted mean changes versus placebo for VEGFR2 from baseline to C3mono, and for VEGFR2 and VEGFR3 from baseline to EoTmono.
Conclusion:
These analyses represent the first biomarker results for nintedanib-treated MPM. While there seemed to be signals for greater PFS and OS improvement in patients with low plasma endoglin and major homozygous VEGFR1/3 genotypes, no biomarkers showed clear significant association with treatment benefit. These findings warrant further evaluation in the Phase III study.
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MS 08 - Novel Treatment for Mesothelioma (ID 530)
- Event: WCLC 2017
- Type: Mini Symposium
- Track: Mesothelioma
- Presentations: 1
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MS 08.04 - Immunotherapy in MPM (ID 7678)
16:30 - 16:45 | Presenting Author(s): Anna Nowak
- Abstract
- Presentation
Abstract:
The recent success of checkpoint blockade in other malignancies has led a resurgence of interest in this modality for mesothelioma. Historically, occasional responses were seen with cytokine therapy, immunomodulatory gene therapy, and vaccination incorporating suicide genes or immunological adjuvants. However, the availability of checkpoint blockade and identification of mesothelioma tumour antigens has opened the field to a plethora of multicentre clinical trials and to interest in developing immunotherapy for this indication. The cytotoxic T-lymphocyte Antigen 4 (CTLA-4) blocking antibody tremelimumab was the first checkpoint blockade treatment trialled in mesothelioma, with two single arm phase II clinical trials reporting modest objective responses and encouraging stable disease(1, 2). Unfortunately, the subsequent randomised phase IIb study of tremelimumab versus placebo as second-line treatment for pleural mesothelioma, the DETERMINE trial, did not reach its primary endpoint (Kindler et al. in press). The next reported trials examined the efficacy of PD pathway blockade. Results from the phase I KEYNOTE 028 study mesothelioma cohort of 25 pre-treated patients were recently published. Using single agent pembrolizumab, the partial response (PR) rate of 20% was lower than originally reported, although a 72% disease control rate (DCR) was observed(3). All patients were selected for >1% tumour PD-L1 expression. The median duration of response was 12.0 months, with no new safety concerns. Three other trials of single-agent PD-pathway inhibition have been reported subsequently. Preliminary results have been reported from a second study of pembrolizumab as second line therapy, with PR of 21%, DCR of 80%, and median progression free survival (PFS) of 6.2 months(4). The NivoMes study of second-line single agent nivolumab reported a PR rate of 15%, with stable disease rates of 35% and a median PFS of 3.6 months(5). Neither of these studies selected for PD-L1 expression. Finally, the JAVELIN study of Avelumab, a PD-L1 inhibitor, in patients with prior therapy reported a PR rate of 9.4% and DCR of 57%(6). There is no clarity on the importance of PD-L1 expression as a predictor of response. As with other cancers, pseudoprogression and subsequent response can be seen in some patients with the use of checkpoint blockade in mesothelioma. Whilst the results of single-agent therapies have been hailed as promising, only a minority of patients derive durable benefit, and as yet there is no clear predictive biomarker. The current generation of clinical trials are focusing on a. evaluating single agent checkpoint blockade in randomised trials; b. combining immunotherapies; and c. combining checkpoint blockade with existing therapies. The MAPS-2 study recently reported on combination ipilimumab and nivolumab as second or third line treatment(7). 125 participants were rapidly recruited to this phase IIb clinical trial, and were randomised to receive either nivolumab alone, or nivolumab with ipilimumab. In the intention to treat population, the disease control rate was 51.6% for the combination and 39.7% for nivolumab alone, with PR rates of 24.2% and 17.5% respectively. PFS was 5.6 months in the combination arm vs. 4.0 months in the nivolumab arm, and there was a promising survival signal in the combination arm. Nevertheless, as with this combination in other settings, toxicity was substantial (although manageable) and three treatment-related deaths were reported. Further maturity of these data is awaited. Ongoing clinical trials of single agent checkpoint blockade included the randomised phase III CONFIRM trial, comparing nivolumab with placebo in 336 previously treated patients (NCT03063450), and the randomised phase III PROMISE-Meso study, comparing pembrolizumab with chemotherapy in the second line (plus) setting in 142 patients (NCT02991482). These studies should be sufficient to confirm results of the previous single agent/single arm trials, with further single agent studies of PD1 blockade in the second/third line setting unlikely to move the field forward substantially unless they are focussed on biomarker questions. The successful rapid recruitment of MAPS-2 augurs well for rapid completion of other combination immunotherapy studies. The CA-209-743 (CheckMATE 743) trial is comparing platinum based chemotherapy to combination nivolumab and ipilimumab in 600 patients (NCT02899299). The INITIATE trial (NCT03048474) is testing nivolumab and ipilimumab in just 33 patients, but with a biomarker focus. The completed NIBIT-Meso 1 trial is a phase II study of tremelimumab and durvalumab for which results are likely to be available soon (NCT02588131), with a further phase II trial of the same agents and similar design open in the USA (NCT03075527). Finally, in combinations of checkpoint inhibitors with conventional therapies, the most mature concepts are combinations with chemotherapy in the first line setting. Two single arm phase II clinical trials of identical design are combining cisplatin and pemetrexed first line chemotherapy with durvalumab, one Australian (ACTRN 12616001170415) and one in the USA (NCT02899195). A randomised phase II study in Canada is comparing first line cisplatin/pemetrexed with either pembrolizumab or chemotherapy plus pembrolizumab (NCT02784171). The Australian ‘DREAM’ study has completed recruitment. All trials are incorporating biomarker studies, which may prove particularly challenging in the context of concurrent chemotherapy. No discussion on immunotherapy in mesothelioma would be complete without comment on anti-mesothelin strategies. The anti-mesothelin immunotoxin SS1P has undergone phase I testing, however neutralising antibody development mandated combination with immunosuppressive pre-treatment moving forward. Durable responses have been seen in small numbers of patients(8). The chimeric monoclonal mesothelin antagonist MORAb-009 (Amatuximab) has completed early phase testing and is now in phase III combined with cisplatin and pemetrexed (NCT02357147). Mesothelin is also being used as the target antigen in Chimeric Antigen Receptor (CAR) T cell therapy in pilot testing. Finally, anetumab ravtansine is an antibody drug conjugate linking a human anti-mesothelin monoclonal antibody to the spindle poison DM4(9). Results have recently been released suggesting no benefit over single agent vinorelbine in a second-line phase IIb study (NCT02610140). This abstract is not exhaustive, with other immunotherapies under investigation including dendritic cell therapy, CAR-T cell therapy, and allogeneic tumour cell vaccine therapies amongst others. It remains unclear which immunotherapies, in which combinations, and at which point in the disease trajectory will be permanently integrated into management. Biomarker studies to predict both toxicities and outcomes are likely to be critical to guide patient selection. REFERENCES 1. Calabro L, et al. (2013) Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial. Lancet Oncol 14(11):1104-1111. 2. Calabro L, et al. (2015) Efficacy and safety of an intensified schedule of tremelimumab for chemotherapy-resistant malignant mesothelioma: an open-label, single-arm, phase 2 study. Lancet Respir Med 3(4):301-309. 3. Alley EW, et al. (2017) Clinical safety and activity of pembrolizumab in patients with malignant pleural mesothelioma (KEYNOTE-028): preliminary results from a non-randomised, open-label, phase 1b trial. Lancet Oncol 18(5):623-630. 4. Kindler H, et al. (2016) OA13.02 Phase II Trial of Pembrolizumab in Patients with Malignant Mesothelioma (MM): Interim Analysis. J Thorac Oncol 12(1):S293-294. 5. Quispel-Janssen J, et al. (2016) OA13.01 - A Phase II Study of Nivolumab in Malignant Pleural Mesothelioma (NivoMes): With Translational Research (TR) Biopies. J Thorac Oncol 12(1):S292-293. 6. Hassan R, et al. (2016) Avelumab (MSB0010718C; anti-PD-L1) in patients with advanced unresectable mesothelioma from the JAVELIN solid tumor phase Ib trial: Safety, clinical activity, and PD-L1 expression. J Clin Oncol 34:abstr 8503. 7. Scherpereel A, et al. (2017) Second- or third-line nivolumab (Nivo) versus nivo plus ipilimumab (Ipi) in malignant pleural mesothelioma (MPM) patients: Results of the IFCT-1501 MAPS2 randomized phase II trial. J Clin Oncol, p LBA8507. 8. Hassan R, et al. (2013) Major cancer regressions in mesothelioma after treatment with an anti-mesothelin immunotoxin and immune suppression. Sci Transl Med 5(208):208ra147. 9. Golfier S, et al. (2014) Anetumab ravtansine: a novel mesothelin-targeting antibody-drug conjugate cures tumors with heterogeneous target expression favored by bystander effect. Mol Cancer Ther 13(6):1537-1548.
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P1.09 - Mesothelioma (ID 695)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Mesothelioma
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.09-011 - LUME-Meso Phase II/III Study: Nintedanib + Pemetrexed/Cisplatin in Chemo-Naïve Patients with Malignant Pleural Mesothelioma (ID 7937)
09:30 - 09:30 | Author(s): Anna Nowak
- Abstract
Background:
Pemetrexed/cisplatin is the standard first-line treatment for unresectable malignant pleural mesothelioma (MPM), with median overall survival (OS) of ~1 year. Nintedanib is a triple angiokinase inhibitor of vascular endothelial growth factor (VEGF) receptors 1–3, platelet-derived growth factor (PDGF) receptors α/β and fibroblast growth factor receptors 1–3. VEGF and PDGF overexpression are associated with poor prognosis in MPM, and nintedanib has demonstrated efficacy in preclinical MPM models. Nintedanib also targets the Src and Abl kinases, which are involved in MPM cell migration. A randomised Phase II trial of nintedanib or placebo + pemetrexed/cisplatin in MPM followed by maintenance nintedanib or placebo, with progression-free survival (PFS) as the primary endpoint, was performed. With regulatory authority guidance, the Phase II data were unblinded. At the primary analysis, PFS benefit was observed with nintedanib, and confirmed at the updated analysis (hazard ratio [HR]=0.54, 95% confidence interval [CI]: 0.33–0.87; p=0.010; median PFS: nintedanib 9.4 months vs placebo 5.7 months). A strong signal towards improved OS also favoured nintedanib (HR=0.77, 95% CI: 0.46–1.29; p=0.319; median OS: 18.3 vs 14.2 months). The study was expanded to include a confirmatory Phase III part based on the primary PFS results, and the Phase II data assisted in planning of the Phase III part, including sample size estimation. Nintedanib was granted US Food and Drug Administration orphan drug designation for the treatment of MPM in December 2016.
Method:
The Phase III part of the study (NCT01907100) is currently recruiting participants. Four hundred and fifty chemotherapy-naïve patients worldwide (~140 sites in 27 countries), aged ≥18 years with unresectable MPM of epithelioid histology and Eastern Cooperative Oncology Group performance score 0–1 will be randomised 1:1 to receive up to six 21-day cycles of pemetrexed (500 mg/m[2])/cisplatin (75 mg/m[2]) on Day 1 + nintedanib or placebo (200 mg twice daily, Days 2–21), followed by nintedanib or placebo monotherapy until disease progression or undue toxicity. The primary endpoint is PFS with the key secondary endpoint being OS. An adaptive design will be used at the time of the primary PFS analysis to reassess the number of OS events for sufficient OS power. Other secondary endpoints are objective response and disease control (using modified Response Evaluation Criteria in Solid Tumors). The frequency and severity of adverse events, as well as health-related quality of life, will also be assessed. An exploratory analysis of predictive/prognostic biomarkers is planned.
Result:
Section not applicable
Conclusion:
Section not applicable
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P3.09 - Mesothelioma (ID 725)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Mesothelioma
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.09-004 - Routine Clinical Parameters Can Stratify Survival Characteristics in Mesothelioma Patients Undergoing Surgery (ID 8318)
09:30 - 09:30 | Author(s): Anna Nowak
- Abstract
Background:
Malignant pleural mesothelioma (MPM) is a rare cancer with a heterogeneous prognosis. We have previously described and validated a prognostic model using a classification and regression tree (CART) model to analyse the interaction of multiple variables with survival in a broad MPM population.(1) We aimed to test the performance of our model on a population with MPM who had surgical intervention.
Method:
Cases from Australia and Japan with confirmed MPM who underwent surgery were analysed with clinical variables available at the time of referral recorded. The model uses combinations of different variables (Table 1) to stratify participants into different risk groups (1-4) and the survival characteristics were compared using the Log Rank test. Figure 1
Result:
A total of 289 cases were included (205 from Australia and 84 from Japan) who had surgery between 1991-2016. Overall median survival was 34.6 (IQR 17.5-56.1) months; median age 63.0 (IQR 57.0-67.8) years, 240/289 (83.0%) were male. Epithelioid MPM was the most common subtype (80.9%), weight loss was present in 36.6%, dyspnoea in 54.4%, chest pain in 29.0% and 91.8% had an ECOG performance status of 0. EPP was the most common operation performed (56.7%), followed by pleurectomy/decortication in 30.4%. There were no clinically meaningful differences between the cohorts; 40 patients were alive at censure. Survival across the risk groups was significantly different (Log Rank test p<0.0001). The group with the longest survival (median 78.1, IQR 28.1-152.4 months) had no weight loss, Hb >153g/L and serum albumin >43g/L at the time of referral to specialist surgical centre.
Conclusion:
The combination and interaction of simple, clinical variables available early after diagnosis of MPM is able to stratify survival and discriminate higher and lower risk of death in high performance status patients
