Second/third-line nivolumab vs nivo plus ipilimumab in malignant pleural mesothelioma: Long-term results of IFCT-1501 MAPS2 phase IIR trial with a focus on hyperprogression (HPD)

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      Abstract

      Background

      The phase IIR trial IFCT-1501 (MAPS2) tested nivo or nivo+ipi in pts with relapsed MPM as second/third-line. This trial reached its primary endpoint with 40% or more of pts with disease control in both arms. We now focus on long-term survivals and specific patterns of progression.

      Methods

      125 pts were randomized to receive Nivo 3 mg/kg q2w or Nivo 3 mg/kg q2w+Ipi 1mg/kg q6w, until progr or unacceptable toxicity. Median follow-up for OS is 32.5 months (Mar. 1st2019). HPD was defined by calculating the tumor growth rate before and during i.o. with determining the variation per month (ΔTGR) (Ferrara, JAMA Oncol 2018) or by measuring the tumor growth kinetics (TGK)on i.o. and on last treatment before, with TGK ratio (TGKr) calculation (Saâda-Bouzid, Ann. Oncol. 2017). HPD was defined as disease progression (assessed by BICR) with ΔTGR exceeding 50% or with a TGKr>2.

      Results

      Median OS was 11·9 mo. (6·7–17·4) in the nivo arm and 15·9 mo. (10·7–22.2) in the nivo+ipilimumab arm. 52 (82%) /63 pts in the nivo group and 49 (79%)/62 patients in the combo group had died by data cutoff. 1 & 2-year survivals were 49·2% (36·4–60·8) & 25·4% (15·5–36·6) in the nivo arm, and 58·1% (44·8–69·2) & 31·7% (20·5–43·4) in the Nivo +Ipi arm. With ΔTGR method, 4 and 2 patients in Nivo and combo group had HPD respectively, while 7 and 4 patients had HPD by using TGKr. HPD pts with TGKr had a poorer OS than pts with standard progression only in the nivolumab arm (median OS = 1.6 mo [0.8-7.7] vs. 4.4 mo [2.4-10.8], (p = 0.02 in Cox model), while no difference was seen with ΔTGR definition.When both arms were analyzed together, only HPD pts defined with the TGKr had significantly worse survival: HR (progressive pts vs HPD): 0.37 [0.19-0.75], p = 0.006, with HR (pts with DCR vs. HPD)= 0.12 [0.06-0.25], p < 0.0001 and 2.6, 5.5 and 23.1 mos of median OS for HPD, progressive and pts with DCR respectively. All HPD patients with available IHC data (n = 8/11) had PDL1-neg expression at 1% cut-off (p = 0.001).

      Conclusions

      The durable efficacy of Nivo & Nivo+Ipi in MPM in confirmed, with 1/4 and 1/3 of pts alive at 2 yrs respectively. HPD pattern of progression did exist in both arms, associated with significantly worse survival when the TGKr definition of HPD is used.

      Clinical trial identification

      NCT02716272.

      Legal entity responsible for the study

      IFCT: French Cooperative Thoracic Intergroup.

      Funding

      BMS.

      Disclosure

      G. Zalcman: Honoraria (self), Honoraria (institution), Advisory / Consultancy, Research grant / Funding (self): BMS; Honoraria (self), Honoraria (institution), Research grant / Funding (self), Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy: Inventiva; Honoraria (self), Advisory / Consultancy: Merck (MSD); Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche-France; Travel / Accommodation / Expenses: AbbVie. J. Mazieres: Honoraria (institution), Research grant / Funding (self): Roche-France; Honoraria (institution): BMS; Honoraria (institution), Research grant / Funding (self): Merck; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca. L. Greillier: Honoraria (self), Non-remunerated activity/ies: Roche; Honoraria (self), Non-remunerated activity/ies: Novartis; Honoraria (self), Non-remunerated activity/ies: Lilly; Honoraria (self), Non-remunerated activity/ies: Pfizer; Honoraria (self), Non-remunerated activity/ies: BMS; Honoraria (self), Non-remunerated activity/ies: Boerhinger-Ingelheim; Honoraria (self), Non-remunerated activity/ies: AstraZeneca; Honoraria (self), Non-remunerated activity/ies: AbbVie; Honoraria (self), Non-remunerated activity/ies: MSD. S. Lantuejoul: Honoraria (self), Non-remunerated activity/ies: MSD; Honoraria (self), Non-remunerated activity/ies: Roche-Diagnostics; Honoraria (self), Travel / Accommodation / Expenses, Non-remunerated activity/ies: AstraZeneca; Honoraria (self), Non-remunerated activity/ies: BMS. O. Bylicki: Honoraria (self), Non-remunerated activity/ies: MSD; Non-remunerated activity/ies: Roche. I. Monnet: Travel / Accommodation / Expenses: BMS. R. Corre: Advisory / Consultancy: Roche; Advisory / Consultancy: BMS. C. Audigier-Valette: Honoraria (self): Roche; Honoraria (self): Pfizer; Honoraria (self): Boerhinger-Ingelheim; Honoraria (self): Novartis; Honoraria (self): AstraZeneca; Honoraria (self): Lilly; Honoraria (self): Amgen; Honoraria (self): BMS; Honoraria (self): Sysmex; Honoraria (self): MSD; Honoraria (self): Clovis Oncology; Honoraria (self): AbbVie. O. Molinier: Honoraria (self): BMS. F. Guisier: Honoraria (self), Non-remunerated activity/ies: 3MS; Honoraria (self): MSD US; Honoraria (self): AstraZeneca; Honoraria (self): Roche; Honoraria (self), Research grant / Funding (self): Boerhinger-Ingeheim; Non-remunerated activity/ies: Chugai. D. Planchard: Honoraria (self): AstraZeneca; Honoraria (self): Boerhinger Ingelheim; Honoraria (self): BMS; Honoraria (self): Celgene; Honoraria (self): Novartis; Honoraria (self): MSD; Honoraria (self): Pfizer; Honoraria (self): Roche. E. Amour: Full / Part-time employment: IFCT. F. Morin: Full / Part-time employment: IFCT. D. Moro-Sibilot: Honoraria (self), Non-remunerated activity/ies: BMS; Honoraria (self): Roche; Honoraria (self): MSD; Honoraria (self): Lilly; Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self): AstraZeneca; Honoraria (self): Boerhinger Ingelheim; Honoraria (self): Takeda; Honoraria (self): Leurquin Mediolanum. A. Scherpereel: Honoraria (self): BMS; Honoraria (self): Roche; Honoraria (self): MSD; Honoraria (self): Boerhinger Ingelheim. All other authors have declared no conflicts of interest.