ESMO 2017 Press Release: Combination Immunotherapy in Second/third Line Extends Mesothelioma Survival to 15 Months

LUGANO-MADRID – Combination immunotherapy as second or third line treatment extends overall survival to at least 15 months in patients with pleural malignant mesothelioma, according to late-breaking results from the MAPS2 trial presented today at the ESMO 2017 Congress in Madrid. (1)

Malignant pleural mesothelioma (MPM) is a rare disease usually caused by occupational exposure to asbestos. First line therapy is pemetrexed and platinum chemotherapy, with or without bevacizumab. There is no approved second line treatment and drugs that have been tested in this setting had low efficacy, with a disease control rate under 30%. Phase II studies have shown promising activity of checkpoint inhibitors as second line treatment.

MAPS2 was an academic, Intergroupe Francophone de Cancérologie Thoracique (IFCT)-sponsored, non-comparative randomised phase II trial of two checkpoint inhibitors in patients with MPM who had relapsed after one or two lines of pemetrexed and platinum chemotherapy. Patients were randomly allocated to receive the PD-L1 inhibitor nivolumab or nivolumab plus the CTLA-4 inhibitor ipilimumab until progression or unacceptable toxicity.

As previously reported (2), the primary endpoint of disease control rate (the proportion of patients in whom the cancer shrank or did not grow) at 12 weeks was 50% in the combination arm and 44% with nivolumab monotherapy.

Today the investigators report the overall survival results in 125 patients. At one year the rate of overall survival was 51% in the nivolumab arm and 58% in the combination therapy arm. After a median follow-up of 15 months, the median overall survival was 13.6 months with nivolumab monotherapy and was not reached in the combination arm. There were no unexpected toxicities.

Lead author Professor Gérard Zalcman, Head of Thoracic Oncology Department, IFCT past-president, Hôpital Bichat-Claude Bernard, Université Paris-Diderot, Paris, France, said: “These overall survival results for second or third line treatment of mesothelioma are impressive and comparable with the results of standard chemotherapy in the first line setting. The fact that the median overall survival has not been reached in the combination arm suggests that it would be more than 15 months.”

At a median follow-up of 15 months the progression-free survival was 4.0 months with nivolumab and 5.6 months for the combination therapy.

Zalcman said: “These overall survival and progression-free survival results support a recent decision by the US Food and Drug Administration to grant orphan drug status to the combination therapy for mesothelioma.”

Immunohistochemistry performed in 99 patients revealed that just 41% expressed PD-L1 and only three patients expressed PD-L1 in more than 50% of tumour cells. There was no correlation between PD-L1 expression and overall survival or progression-free survival. “The findings are disappointing and could be related to the assay used to measure PD-L1 or the use of a tumour specimen from the time of diagnosis rather than on inclusion into the study,” said Zalcman.

New data on quality of life and duration of response will also be presented at the ESMO 2017 Congress.

Commenting on the research on behalf of ESMO, Professor Rolf Stahel, Chair, Cancer Centre Zürich, Switzerland, said: “In lung cancer a high mutation burden and a strong PD-L1 expression have been associated with a better response to immune checkpoint inhibition. In mesothelioma the tumour mutation burden is low and the expression of PD-L1 is less prominent; however, there is often an immune cell infiltrate and an inflamed state which suggests it may respond to treatment.”

“This trial found an objective response rate of 18–27% with a PD-1 inhibitor alone or a PD-1 inhibitor and CTLA-4 inhibitor combined,” he continued. “This is a similar range to that found in several other solid tumours with a higher mutation burden, which is good news. However, it appears to be promising in just a fraction of these patients.”

Regarding the implications of the results and next steps in this research, Stahel said: “The role of immunotherapy in mesothelioma needs to be further explored. Comparative trials are needed to further define the place of immunotherapy in the second or third line setting.”

-END-

Notes to Editors

Please make sure to use the official name of the meeting in your reports: ESMO 2017 Congress

References

  1. Abstract LBA58_PR ‘Second or 3rd line Nivolumab (Nivo) versus Nivo plus Ipilimumab (Ipi) in Malignant Pleural Mesothelioma (MPM) patients: up-dated results of the IFCT-1501 MAPS2 randomized phase 2 trial’ will be presented by Professor Gérard Zalcman during Proffered Paper session ‘Mesothelioma and SCLC’ on Sunday, 10 September 2017, 09:15 to 10:45 (CEST) in Barcelona Auditorium.
  2. ASCO: http://meetinglibrary.asco.org/record/145342/abstract

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Abstract LBA58_PR

Second or 3rd line nivolumab (Nivo) versus nivo plus ipilimumab (Ipi) in malignant pleural mesothelioma (MPM) patients: Updated results of the IFCT-1501 MAPS2 randomized phase 2 trial

G. Zalcman1, J. Mazieres2, L. Greillier3, S. Lantuejoul4, P. Dô5, O. Bylicki6, I. Monnet7, R. Corre8, C. Audigier-Valette9, M. Locatelli-Sanchez10, O. Molinier11, L. Thiberville12, T. Urban13, D. Planchard14, C. Ligeza-Poisson15, E. Amour16, F. Morin16, D. Moro-Sibilot17, A. Scherpereel18 

1Thoracic Oncology, Hôpital Bichat-Claude Bernard, Université Paris-Diderot, Paris, France, 2Pulmonology and Thoracic Oncology, Hôpital Larrey, CHU Toulouse, Toulouse, France, 3Thoracic Oncology, Hôpital Nord, APHM, Marseille, France, 4Pathology, MESOPATH, CRLCC Léon Berard, Lyon, France, 5Oncology, CRLCC François Baclesse, Caen, France, 6Pneumologie et Oncologie Thoracique, HIA Percy, Clamart, France, 7Pneumologie, CHI Créteil, Créteil, France, 8Pneumologie, CHU Pontchaillou, Rennes, France, 9Pneumologie, CH Toulon, Toulon, France, 10Pneumologie et Oncologie Thoracique, HCL Lyon-Sud, Pierre-Bénite, France, 11Pneumologie, CHR du Mans, Le Mans, France, 12Pneumologie, CHU Charles Nicolle, Rouen, France, 13Pneumologie, CHU Angers, Angers, France, 14Oncologie Médicale, Institut Gustave Roussy, Villejuif, France, 15Oncologie Médicale, Clinique de l'Estuaire, Saint-Nazaire, France, 16Clinical Research Unit, Intergroupe Francophone de Cancérologie Thoracique (IFCT), Paris, France, 17Pulmonology and Thoracic Oncology, CHU de Grenoble, La Tronche, France, 18Pulmonology and Thoracic Oncology, CHRU de Lille, Lille, France

Background: No treatment is currently recommended in MPM pts progressing after 1st-line pemetrexed platinum doublet. Disease control rate (DCR) is <30% with all drugs tested in this setting. Anti-PD1 or anti-PD-1 plus anti-CTLA-4 combo efficacy deserves confirmation in MPM.

Methods: Multicenter randomized non-comparative phase 2 trial. Eligible pts: age>18, PS 0-1, histologically proved MPM relapsing after 1 or 2 prior lines including pemetrexed/platinum doublet, measurable disease. Randomized pts (1:1) received Nivo 3 mg/kg q2w, or Nivo 3 mg/kg q2w plus Ipi 1 mg/kg q6w, until progression or unacceptable toxicity. Primary endpoint was DCR at 12 weeks.

Results: From April to August 2016, 125 pts were accrued in 20 centers. Males: 80%, median age: 71.8 years (range 32.5-88.1), PS 1: 62.4%, epithelioïd 83.2%, 1 previous line: 69.6%.70%of pts received at least 3 cycles of either treatment. 12 weeks-DCR assessed by BICR in the first 108 pts was 44.4% [CI95%: 31.2-57.7%] with Nivo (n=54), and 50.0% [36.7-63.3%] with Nivo+Ipi (n=54). ORR was 18.5% [8.2-28.9%] with Nivo, and 27.8% [15.8-39.7%] with Nivo+Ipi. Grade 3/4 toxicities were slightly increased in the combo arm (Nivo: 12.7%/0% vs. Nivo+Ipi: 22.9%/3.3%) with 3 treatment-related deaths in the combo arm. Median follow-up was15 months (July, 31th 2017), median PFS was 4.0 months, 95%CI[2.8-5.7] and 5.6 months 95%CI[3.2-8.4] in Nivo and Nivo+Ipi arms, respectively. Median OS was 13.6 months, 95%CI[6.7-NR] and not reached in Nivo and Nivo+Ipi arms, respectively. 12-months OS were 51% and 58% in Nivo and Nivo+Ipi arms respectively. PD-L1 IHC (mAb 28.8) available in 99/125 patients, was positive (>1% PDL1+ tumor cells) in 41.4%. Positive PD-L1 IHC did not predict longer PFS or OS, either in the whole population or in each treatment group separately.

Conclusions: Both Nivo or Nivo+Ipi reached their endpoint in 2nd/3rd line MPM pts without any unexpected toxicity, leading to meaningful progression-free and overall survivals. These updated results support the efficacy of checkpoints inhibitors in MPM patients, deserving future phase 3 trials.

Clinical trial identification: NCT02716272

Legal entity responsible for the study: Intergroupe Francophone de Cancérologie Thoracique (IFCT)

Funding: BMS

Disclosure:G. Zalcman: Advisory board for MSD, Boehringer-Ingelheim, BMS Grants and personal fees from BMS, Roche, Astra-Zeneca, Novartis Compensation for meeting attendance and accommodation: Roche, Astra-Zeneca, BMS, Pfizer.
J. Mazieres: Research funding from BMS & Roche.
L. Greillier: Honoraria from Boehringer-Ingelheim , BMS, Lilly, Pfizer, Astra-Zeneca, Novartis, Roche. Avisory role for Borhingher-Ingelheim, BMS, Roche. Research funding for my institution from Roche. Travel and accomodation from Lilly, Pfizer, Boehringer-Ingelheim.
I. Monnet: Research funding from MSD, Astellas oncology, Astra-Zeneca. Travel & accomodation from MSD, Novartis.
R. Corre: Advisory role for Roche, Lilly, BMS, Astra-Zeneca. Travel & accomodations from Boerhinger-Ingelheim, Amgen, Roche. Honoraria from Boerhinger-Ingelheim.
C. Audigier-Valette: Advisory role: Roche, Pfizer, Boerhinger, Novartis, Astra-Zeneca, Lilly, Amgen, BMS, Sysmex, MSD, Clovis Oncology, Medimmune. Travel/accomodations from Roche, Pfizer, Lilly, Amgen, Novartis, BMS, MSD, Medimmune. 
M. Locatelli-Sanchez: Travel & accomodation from Pierre Fabre and Boerhinger-Ingelheim.
O. Molinier: Advisory role for BMS, Boerhinger-Ingelheim, Astra-Zeneca, Novartis, Roche.
D. Planchard: Avisory Role for Lilly, BMS, Pfizer, Clovis oncology, MSD, Sanofi, Astra-Zeneca, Novartis, Roche. Research funding from Novartis.
D. Moro-Sibilot: Honoraria from La Lettre du Cancérologue, Roche, BMS, Pfizer, Borhinger, Lilly, Astra-Zeneca. Travel and accomodation from Roche.
A. Scherpereel: Invitations at international meetings (ASCO, iMig, CPLF, AACR): Roche, MSD, BMS, France Oxygene Honoraria for participation to scientific or advisory Boards, organized by Astra-Zeneca, BMS, Boehringer-Ingelheim, MSD, Roche. 
All other authors have declared no conflicts of interest.

Keywords: ipilimumab-nivolumab combo, malignant pleural mesothelioma, immunotherapy, checkpoint inhibitors