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Jan P Van Meerbeeck
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MS13 - Immunotherapy for Mesothelioma (ID 76)
- Event: WCLC 2019
- Type: Mini Symposium
- Track: Mesothelioma
- Presentations: 1
- Now Available
- Moderators:Arnaud Scherpereel, Roberto Ferrara
- Coordinates: 9/10/2019, 11:30 - 13:00, Seoul (2007)
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MS13.01 - Immunotherapy and Mesothelioma: Rationale and Strategies (Now Available) (ID 3514)
11:30 - 13:00 | Presenting Author(s): Jan P Van Meerbeeck
- Abstract
- Presentation
Abstract
Unresectable malignant pleural mesothelioma (MPM) is a uniformly fatal rare cancer with increasing incidence worldwide. Combination chemotherapy with platinum/antifolate –either pemetrexed or raltitrexed- is the only standard of care 1st line treatment with proven improvement of survival, which varies according to series and patient selection between 12-16 months median overall survival (mOS), with corresponding 1 year survival rate of 50-60%. After a median progression-free survival of ~ 3 months, patients relapse and few if any drugs have any proven efficacy at this stage. Survival after progression varies from 3-18 months according to tumors’ biological behavior and patient’s prognostic factors. Therefore, innovative drugs are urgently needed.
Although called ‘immunologically cold tumours’ and presenting with a low mutational burden, MPM express distinct targetable antigens (WT1, mesothelin), contain tumour-infiltrating lymphocytes (TILs) and PDL-1 expression is variably present, mostly on the sarcomatoid subtype. Experimental models have demonstrated chronic inflammation and local tumor suppression as crucial to MPM pathogenesis. This led to the investigation of immunotherapy in MPM.
Monoclonal antibodies against immune check point inhibition (ICI-) molecules have been evaluated as salvage therapy after first-line chemotherapy in several phase 2 trials, either as single agent or in combination. The randomized DETERMINE trial evaluated in 564 patients the anti–CTLA-4 antibody tremelimumab versus placebo in second or third line and found no benefit in outcome (hazard ratio 0.92; p = 0.408). Results from the anti–PD-1 or anti–PD-L1 trials with nivolumab, pembrolizumab and durvalumab are fairly consistent with a response rate of 19-30%, a median PFS of 3.5 – 6.0 months and mOS of 12-18 m, all uncontrolled in selected patients with good prognostic features. Addition of CTLA-4 inhibitors to PD(L)-1 seem to increase efficacy and prolong the time-to-event endpoints. Preliminary results suggest that PD-L1 tumour proportional score (TPS) is both a predictive and prognostic biomarker.
Several trials are underway investigating ICI alone or in combination with SOC-chemotherapy as frontline treatment. The DREAM trial, a single-arm, open-label phase II trial of durvalumab with cisplatin/pemetrexed, followed by durvalumab maintenance therapy for 1 year. The primary endpoint was PFS at 6months. Interim results in the first 54 patients show a mPFS of 6.2 months, with 48% achieved a partial response based on immune-modified RECIST. The -immature- 1-year OS estimate is 65% at a median follow-up of 14.4 months.
Other randomized studies of triplet combinations are ongoing, including SOC-chemotherapy w/wo pembrolizumab (NCT02784171) or durvalumab (NCT02899195). The phase III CheckMate743 (NCT02899299) trial randomly selected 600 patients with treatment-naïve MPM to nivolumab plus ipilimumab -until progression or unacceptable toxicity- versus up to six cycles of SOC-chemotherapy.
Surgical management in resectable MPM represents an excellent opportunity for window-of-opportunity trials when treating patients with neo-adjuvant immunotherapies to improve resectability, fight residual disease and improve patient outcome. Several studies are ongoing with anti–PD(L)-1 with or without CTLA-4 inhibitors or chemotherapy in the neo-adjuvant setting, but results have not yet been published.
Immunotherapy beyond ICI have been also tested in MPM but with discordant results. Several randomized phase II trials have targeted mesothelin, including amatuximab, an antimesothelin chimeric monoclonal antibody, anetumab-ravtansine, an antibody drug conjugate, and CRS-207, a vaccine targeting mesothelin: these have not yet shown any efficacy in MPM (unpublished data). Cell therapies in phase I trials are being investigated in MPM, including chimeric antigen receptor (CAR) T cells targeting surface antigens such as mesothelin, given both intravenously (NCT02159716) and intrapleuraly (NCT02414269).
Vaccines targeting the Wilms tumor-1 (WT-1) antigen have also been tested in MPM with variable results. Dendritic cell vaccination was found to be efficacious in small trials of MPM, providing the rationale for ongoing trials, such as the large randomized phase II trial (DENIM) with dendritic cell therapy as maintenance after P/P frontline chemotherapy or a phase I/II trial testing autologous dendritic cells loaded with WT-1 tumor antigen following standard first-line chemotherapy. Autologous tumor infiltrating lymphocytes and interleukin-2 (IL-2) infusion after lympho-depletion are also currently under investigation in a phase I/II trial in MPM. Immune-gene therapy using intrapleural delivery of adenovirus-expressing interferon-α combined with celecoxib and chemotherapy was well tolerated and provided a remarkable mOS of 21.5 months as second-line treatment. Finally, oncoviral therapy is being assessed in a phase I trial with intrapleural injection of measles virus (NCT01503177), or with an oncolytic adenovirus coding for GM-CSF combined with chemotherapy and cyclophosphamide versus chemotherapy alone in a randomized phase II trial (NCT02879669).
In conclusion, immunotherapies are being investigated in different settings of MPM. Regulatory approval is anticipated soon for ICI (anti–PD-1 with or without anti–CTLA-4) as salvage treatment in MPM. However, state of the art phase III trials comparing ICI with SOC-chemotherapy are needed to firmly establish immunotherapy, either alone or in combination with standard treatment, and to validate biomarkers for patient selection.
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P1.06 - Mesothelioma (ID 169)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Mesothelioma
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.06-06 - EORTC 1205: Randomized Study of Pleurectomy/Decortication (P/D) Preceded or Followed by Chemotherapy in Malignant Pleural Mesothelioma (ID 2511)
09:45 - 18:00 | Presenting Author(s): Jan P Van Meerbeeck
- Abstract
Background
P/D is considered a valid surgical approach in selected pts with resectable MPM with less morbidity than extrapleural pneumonectomy. The procedure is however, poorly standardized and never radical, and is hence preferably preceded or followed by systemic chemotherapy.
EORTC 1205 aims at comparing the optimal sequencing of chemotherapy with P/D with regard to overall treatment time and feasibility.
Method
Functionally operable treatment-naïve pts with T1-3 N0-2 epithelial or biphasic mesothelioma and PS 0-1 are randomized between adjuvant (arm A) and neo-adjuvant chemotherapy (arm B). Chemotherapy in both arms consists of 3 cycles of cisplatin and pemetrexed at standard dosage and with premedication. P/D is performed by experienced thoracic surgeons in credentialed centers. Strict timelines between both procedures apply and surgical quality is audited with intra-operative mapping and imaging and comprehensive registration of complications. Primary endpoint in the intention-to-treat population is successful completion of the multimodality treatment within 20 weeks of randomisation and being alive with no signs of PD and/or persistent grade III-IV toxicity.
Result
As of April 10, 2019, 30 pts of the required sample size of 64 have been randomized and 17 operated. Baseline patient and tumor characteristics appear well balanced sofar (table).
Characteristics and treatment results as per 1/04/2019 Table
Arm A
Arm B
All
N
16
14
30
Male gender (%)
56
71
63
Median age (y)
62
66
64
WHO PS 0/1
10/6
7/7
17/13
TNM Stage 1/2/3 at presentation
6/6/4
9/2/3
15/8/7
% administered 3 cycles of chemotherapy
88
100
94
N operated
9
8
17
Median time between randomization and 1st treatment modality (weeks)
2.9
1.6
2.0
Median time between 1st and 2nd treatment modality
5.7
11.0
10.1
N completed treatment
9
8
17
Median overall treatment time in those completing treatment
23.7
18.7
21.3
Conclusion
Trial accrual proceeds on schedule and last patient will be included in 2020. A protocol amendment will allow carboplatin/pemetrexed as induction regimen. An updated analysis on all included patients as per 1/08/2019 will be presented at the meeting.
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P2.04 - Immuno-oncology (ID 167)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Immuno-oncology
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.04-44 - Combined Immune Checkpoint Blockade in Mesothelioma: In Vivo Investigation of in Vitro Data (ID 908)
10:15 - 18:15 | Presenting Author(s): Jan P Van Meerbeeck
- Abstract
Background
Malignant pleural mesothelioma (MPM) is an aggressive cancer that is causally associated with asbestos exposure. Due to its aggressive nature and despite the effectiveness of conventional anti-cancer treatment, the prognosis of patients diagnosed with MPM remains dismal, highlighting the urgent need for new therapeutic strategies. Our group and others have recently demonstrated PD-1 and PD-L1 expression in MPM patients, providing rationale to evaluate their suitability as immunotherapeutic targets in MPM.
Method
Tree human cell lines representative for the epithelioid and sarcomatoid subtypes of MPM were placed in allogeneic co-cultures with healthy donor peripheral blood mononuclear cells. The co-cultures were treated with the following immune checkpoint blocking antibodies: anti PD-1 (Nivolumab®, BMS) or anti PD-L1 (Durvalumab®, AstraZeneca) in combination with anti TIM-3 or anti LAG-3. Supernatant was collected and enzyme-linked immunosorbent assays and multiplex electrochemo-luminescence were used to look at the secretion of 7 cytokines, being IFNγ, IL-2/5/6/10, IL-1band TNF-α, as well as the enzyme granzyme B.
Result
Significant differences were found for the secretion of IFNγ, granzyme B, IL-2, IL-5 and IL-10. Though the differences were not always significant for the 3 MPM cell lines, the same trends were observed among them. Interestingly, highest concentrations of the aforementioned cytokines were all noticed for monotherapy treatment with anti PD-1, anti PD-L1 or or their combination with anti TIM-3. In vivo investigation of PD-1, PD-L1 and TIM-3 blockade, alone or in combination is required for validation of our in vitro results and is currently ongoing.
Conclusion
Our data show that treatment with anti PD-1, anti PD-L1 or their respective combination with anti TIM-3 resulted in the highest secretion of cytokines and granzyme B, suggesting that these treatments stimulate the antitumor response the most. Results of our in vivo validation are awaited in order to confirm our in vitro findings.
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P2.06 - Mesothelioma (ID 170)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Mesothelioma
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.06-01 - STELLAR Trial: Radiological Response Patterns of TTFields Plus Chemotherapy in First-Line Treatment of Malignant Pleural Mesothelioma (ID 2533)
10:15 - 18:15 | Author(s): Jan P Van Meerbeeck
- Abstract
Background
Tumor Treating Fields (TTFields) are an anti-mitotic, regional treatment modality, utilizing low intensity alternating electric fields delivered non-invasively to the tumor using a portable, medical device. TTFields have significantly extended survival of glioblastoma patients. In-vitro, human malignant pleural mesothelioma (MPM) cells were highly susceptible to TTFields. In the STELLAR trial [NCT02397928], patients with unresectable MPM treated with first-line chemotherapy in combination with TTFields had a significantly higher median overall survival compared to historical controls (18.2 Vs. 12.1 months). We analyzed radiological data from STELLAR patients whose tumors responded while receiving the combined therapy.
Method
The trial accrued 80 patients with unresectable, previously untreated mesothelioma who were treated with continuous 150 kHz TTFields (>18h/day) in combination with pemetrexed and cisplatin or carboplatin (at standard dosing). Inclusion criteria: ECOG PS of 0-1, pathologically proven mesothelioma and at least one measurable lesion according to modified RECIST criteria. Patients were followed q3w (CT scan q6w) until disease progression. Radiological assessments were done at each study site. EOCG status and cancer-related pain were assessed until disease progression using a visual analog scale.
Result
Partial responses (PRs) were seen in 40.3% of evaluable patients and clinical benefit (PR+SD) was seen in 97.2% of patients. The median time between treatment start and PR was 1.8 (1.4-4.4) months). All patients presenting with PR during the STELLAR study had continuous reduction in the total sum of lesion diameters, suggesting no initial/pseudo-progression. 83% of the patients who responded to the combined therapy finally had disease progression within median response duration of 5.7 (1.4-13) months, per Kaplan-Meier Estimator. One patient did not progress for more than 27 months. Median time to deterioration in performance status was 13.1 months. Average pain score was lower compared to baseline during the first 7 months of treatment and higher later with a median time to a clinical significant 33% increase in pain of 8.4 months. Compliance with TTFields was 68% (16.3 hours/day) during the first 3 months of therapy. No TTFields-related other than expected dermatitis below the arrays were reported.
Conclusion
The STELLAR study showed significant survival extension in previously untreated MPM patients. Response rates were similar to that of current SOC treatment, but lasted longer with the addition of TTFields. TTFields was not associated with a decrease in performance status or an increase in pain. TTFields in combination with chemotherapy are efficacious in MPM vs chemotherapy alone reported in historical data.
