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• 25162

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  Immunotherapy and next-generation TKIs: From second to frontline treatment (ID 55)

  • Event: ELCC 2018
  • Type: Poster Discussion session
  • Track:
  • Presentations: 1
  • Moderators:P. Garrido Lopez, S. Ekman, S. Ortiz-Cuaran, E. Wauters
  • Coordinates: 4/12/2018, 07:45 - 09:00, Room A

  • 25163

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    134PD - Primary PFS and safety analyses of a randomized phase III study of carboplatin + paclitaxel +/− bevacizumab, with or without atezolizumab in 1L non-squamous metastatic NSCLC (IMpower150) (ID 469)

    07:45 - 09:00  |  Author(s): D. Rodríguez-Abreu
    • Abstract
    • Slides

    Background:
    Atezolizumab (atezo; anti–PD-L1) inhibits PD-L1 binding to PD-1 and B7.1, restoring anti-cancer immunity. Bevacizumab (bev) may further enhance atezo efficacy by inhibiting VEGF immunosuppression and promoting T-cell tumour infiltration. IMpower150 evaluates the addition of atezo to carboplatin (C) + paclitaxel (P) ± bev in chemo-naive patients (pts) with non-squamous (NSQ) mNSCLC.
    
    Methods:
    1202 pts received atezo 1200 mg + C AUC 6 + P 200 mg/m[2] (Arm A) or atezo + bev 15 mg/kg + C + P (Arm B) vs bev + C + P (Arm C) IV q3w for 4 or 6 cycles per investigator (INV) discretion, then maintenance atezo, atezo + bev or bev, respectively. Co-primary endpoints assessed at this data cutoff (15 Sep 2017; minimum follow up, 9.5 mo) were INV-assessed PFS in the ITT-WT (EGFR or ALK negative) population and in WT pts with expression of a tumour T-effector gene signature (Teff-WT; centrally assessed), and OS in the ITT-WT population, for the Arm B vs Arm C comparison. Due to pre-specified statistical testing hierarchy, Arm A vs Arm C has not been formally tested yet.
    
    Results:
    356 pts in Arm B and 336 pts in Arm C were enrolled in the ITT-WT. Median age was 63 y; 60% were previous smokers (both arms). 61% and 62% were male, and 39% and 43% had ECOG PS 0 in Arms B and C, respectively. The HRs for INV-assessed PFS in Arm B vs C were 0.62 (95% CI: 0.52, 0.74; P < 0.0001) in the ITT-WT and 0.51 (0.38, 0.68; P < 0.0001) in the Teff-WT populations. Median PFS in Arm B vs C was 8.3 mo vs 6.8 mo and 11.3 mo vs 6.8 mo in the ITT-WT and Teff-WT populations, respectively. PFS benefit was seen regardless of PD-L1 IHC status, including PD-L1–negative pts (TC0/IC0; HR, 0.77 [95% CI: 0.61, 0.99]). Landmark PFS and ORR are shown (Table). Arm B had a comparable safety profile to Arm C; treatment-related serious AEs were 25% vs 19%, respectively.Table:IMpower150 Primary PFS Analysis, Landmark PFS and ORR

    	Arm C (bev + C + P; N = 400)	Arm B (atezo + bev + C + P; N = 400)
    ITT-WT population[a]	n = 336	n = 356
    Median PFS (95% CI), mo	6.8 (6.0, 7.1)	8.3 (7.7, 9.8)
    HR (95% CI; P value)	0.62 (0.52, 0.74; P < 0.0001)
    ITT-WT landmark PFS (95% CI), %
    6-month	56% (51, 62)	67% (62, 72)
    12-month	18% (13, 23)	37% (31, 42)
    ORR[b,c] (95% CI), %	48% (43, 54)	64% (58, 68)
    Teff-WT population[a]	n = 129	n = 155
    Median PFS (95% CI), mo	6.8 (5.9, 7.4)	11.3 (9.1, 13.0)
    HR (95% CI; P value)	0.51 (0.38, 0.68; P < 0.0001)
    Teff-WT landmark PFS (95% CI), %
    6-month	57% (48, 66)	72% (65, 79)
    12-month	18% (10, 25)	46% (38, 54)
    ORR[b,d] (95% CI), %	54% (44, 62)	69% (61, 76)

    HR, hazard ratio; ORR, objective response rate; PFS, progression-free survival; Teff, T-effector; WT, wild-type.aWT populations exclude patients with EGFR or ALK driver mutations.bUnconfirmed ORR.cn = 353 in Arm B and n = 331 in Arm C.dn = 153 in Arm B and n = 127 in Arm C.
    
    Conclusions:
    IMpower150 is the first Phase III study to show a statistically significant and clinically meaningful PFS benefit with atezo + bev + chemo vs bev + chemo in pts with 1L NSQ mNSCLC. Acknowledgement of contribution: G. Finley (Allegheny Cancer Center, Pittsburgh, PA, USA), R. Jotte (Rocky Mountain Cancer Centers, Denver, CO, USA), C. Kelsch, A. Lee, S. Coleman, Y. Shen, M. Kowanetz, A. Lopez-Chavez, A. Sandler (Genentech, Inc., South San Francisco, CA, USA).
    
    Clinical trial identification:
    NCT02366143
    
    Legal entity responsible for the study:
    F. Hoffmann-La Roche Ltd/Genentech, Inc
    
    Funding:
    F. Hoffmann-La Roche Ltd/Genentech, Inc
    
    Disclosure:
    M. Reck: Consulting or Advisory Role: Lilly, F.Hoffmann‐La Roche, BI, BMS, MSD, AstraZeneca, Merck, Novartis, Pfizer, Celgene. Speakers’ Bureau: F. Hoffmann‐La Roche, Lilly, Pfizer, BI, AstraZeneca, MSD, BMS, Merck, Novartis, Pfizer, Celgene. M. A. Socinski: Honoraria: Genentech, Speakers Bureau: Genentech, Research Funding: Genentech. F. Cappuzzo: Participation in advisory boards for Roche, AZ, BMS, Takeda, MSD, Lilly, Pfizer. F. Orlandi: Research grants from Astrazeneca, MSD, Genetech-Roche, Advisory tasks for AstraZeneca, Roche, Boehringer Ingelheim, Pfizer. N. Nogami: Honoraria: Meiji Seika Pharma Co., Ltd., AstraZeneca, Pfizer Inc., Bristol‐Myers Squibb, ONO Pharmaceutical CO., LTD., Kyowa Hakko Kirin, Taiho Phamaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd, Eli Lilly Japan, Boehringer Ingelheim. D. Rodríguez-Abreu: Honoraria for lectures and Advisory Board from Bristol-Myers-Squibb, Merck Sharp & Dohme and Hoffmann-La Roche. D. Moro-Sibilot: Advisory boards for Roche, MSD, Pfizer, Novartis, BMS, Astra Zeneca, Lilly. F. Barlesi: Honarium from Genentech & Roche. G. Finley: Promotional speaking on behalf of Bristol Meyers, Boehringer Ingleheim, and Astellas Medivation, and Merck. C. Kelsch: Genentech Employee with Roche Stock. A. Lee: Genentech Employee with Roche Stock. S. Coleman: Genentech Employee with Roche Stock. Y. Shen: Genentech Employee with Roche Stock. M. Kowanetz: Genentech Employee with Roche Stock. A. Lopez-Chavez: Genentech Employee with Roche Stock. A. Sandler: Genentech Employee with Roche Stock. All other authors have declared no conflicts of interest.
    
    

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• 25520

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  Poster Display session (Friday) (ID 65)

  • Event: ELCC 2018
  • Type: Poster Display session
  • Track:
  • Presentations: 2
  • Moderators:
  • Coordinates: 4/13/2018, 12:30 - 13:00, Hall 1

  • 25389

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    188P - Treatment switching–adjusted overall survival (OS) in KEYNOTE-024: First-line pembrolizumab versus chemotherapy in patients with advanced non-small cell lung cancer (NSCLC) (ID 622)

    12:30 - 13:00  |  Author(s): D. Rodríguez-Abreu
    • Abstract

    Background:
    In KEYNOTE-024, pembrolizumab was superior to chemotherapy for advanced untreated NSCLC with PD-L1 tumor proportion score (TPS) ≥50% and no sensitizing EGFR mutations/ALK translocations. We present OS adjusted for the potential bias introduced by switching treatment from chemotherapy to pembrolizumab after a median of 25.2 months of follow-up.
    
    Methods:
    Patients were randomized to pembrolizumab 200 mg every 3 weeks or investigator-choice platinum-doublet chemotherapy with optional pemetrexed maintenance for patients with nonsquamous histology. Patients in the chemotherapy arm could switch to pembrolizumab (prior to the second interim analysis that revealed superiority, only patients with progressive disease confirmed by blinded, independent central radiology review were eligible). Three statistical methods were applied to adjust for treatment switching: the simplified 2-stage method, the rank preserving structural failure time (RPSFT) method, and the inverse probability of censoring weighting (IPCW) method.
    
    Results:
    305 patients were randomized; all but 1 patient in the chemotherapy arm received protocol-specified treatment. 82 (54%) patients had switched from chemotherapy to pembrolizumab per protocol. OS results per the intent-to-treat (ITT) analysis and the 3 adjustment methods are listed in the Table. The 3 methods adjusting for treatment switching in the chemotherapy arm provided larger treatment estimates (lower HRs) than the ITT estimate. As there was some evidence towards a deviation from the common treatment effect assumed in the RPSFT method, and the IPCW method is more prone to bias in the presence of relatively small sample sizes, the simplified 2-stage method was the favored method in this study. Results obtained with the RPSFT and IPCW methods were consistent with those from the 2-stage analyses.Table: (Abstract: 188P)Treatment switching–adjusted OS in KEYNOTE-024 after median follow-up of 25.2 months

    Median OS, months (95% CI)	Pembrolizumab(n = 154)	Chemotherapy(n = 151)	HR (95% CI)
    ITT analysis	30.0 (18.3–not reached)	14.2 (9.8–19.0)	0.63 (0.47–0.86) 2-sided log-rank P = 0.003
    2-stage method	N/A	8.7 (7.3–11.5)	0.49 (0.34–0.69)
    RPSFT method	N/A	11.8 (8.7–not reached)	0.52 (0.33–0.75)
    IPCW method	N/A	11.8 (8.7–21.3)	0.52 (0.33–0.80)

    
    
    Conclusions:
    In this study, pembrolizumab demonstrated an OS advantage compared to chemotherapy as first-line therapy, which becomes more pronounced when utilizing treatment switching analyses that adjust for bias introduced when switching from chemotherapy to pembrolizumab. Pembrolizumab remains a standard-of-care first-line therapy for patients with advanced NSCLC expressing PD-L1 TPS ≥50%.
    
    Clinical trial identification:
    NCT02142738
    
    Legal entity responsible for the study:
    Merck & Co., Inc., Kenilworth, NJ, USA
    
    Funding:
    This study and medical writing assistance were funded by Merck & Co., Inc., Kenilworth, NJ, USA.
    
    Disclosure:
    M. Reck: Advisory board member for Roche, Lilly, AstraZeneca, BMS, MSD, Merck, Boehringer-Ingelheim, Celgene, Pfizer, and Novartis; Speakers’ bureaus for Roche, Lilly, AstraZeneca, BMS, MSD, Merck, Boehringer-Ingelheim, Celgene, Pfizer, and Novartis; Research funding from Boehringer-Ingelheim. A.G. Robinson: Honoraria from Merck & Co., Inc., Kenilworth, NJ; his institution has received research funding from AstraZeneca, Merck & Co., Inc. (Kenilworth, NJ USA), Bristol-Myers Squibb, and Roche Canada. R. Hui: Honoraria from MSD, BMS, AstraZeneca, Boehringer-Ingelheim, and Pfizer; Consulting or Advisory role for MSD, AstraZeneca, Pfizer, and Novartis. K. Vandormael: Employee of MSD Europe. W. Malbecq: Employee of and owns stock in MSD Europe. M.C. Pietanza: Employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ USA. J. Brahmer: Advisory board member for BMS (uncompensated), Celgene, Eli Lilly, Merck; Research funding from BMS, MedImmune/AstraZeneca, Merck. All other authors have declared no conflicts of interest.
    
    

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    198TiP - Afatinib plus EGF pathway targeting immunization (EGF-PTI) as first line therapy for EGFR mutant NSCLC: The EPICAL study (ID 332)

    12:30 - 13:00  |  Author(s): D. Rodríguez-Abreu
    • Abstract
    • Slides

    Background:
    EGF-PTI elicits an antibody response against EGF and suppresses EGFR signaling. It is a vaccine with autologous humanized recombinant EGF conjugated with recombinant P64K protein of Neisseria meningitides. We previously showed signal transducer and activator of transcription 3 (STAT3) activation as a mechanism of innate resistance to EGFR tyrosine kinase inhibitors (TKIs) in EGFR mutant (EGFR+) NSCLC1,2. Anti-EGF antibodies block STAT3 activation in EGFR+ cells alone and in combination with EGFR TKIs. They also delay the emergence of resistance to afatinib in vitro3. Sera from patients immunized with EGF-PTI block the EGF-induced EGFR and ERK phosphorylation in serum starved cells. Based on the above data we designed the first phase Ib study to evaluate the safety and efficacy of afatinib plus EGF-PTI as 1st line therapy for metastatic EGFR+ NSCLC patients (NTC….).
    
    Trial design:
    This is a multicenter open-label exploratory phase Ib clinical study in Spain and Colombia. Thirty metastatic EGFR+ NSCLC patients will receive treatment with afatinib 40 mg daily plus EGF PTI. EGF PTI will be administered (4 injections, 4.8 mL) on day 1, 14, 28, 43 and 92 (immunization phase) and every 3 months (2 injections, 2.4 mL) (maintenance phase). Treatment will continue until disease progression, intolerable adverse events, consent withdrawal or noncompliance with the study protocol. The primary objective of the study is to evaluate the safety and tolerability of the combination. Secondary objectives include overall response rate, progression free survival, overall survival, time to treatment failure, duration of response and disease control rate. A pre-specified secondary objective of the study is to unravel the molecular mechanisms underlying the potential efficacy of afatinib plus EGF-PTI. To this end, EGFR, ERK, AKT and STAT3 phosphorylation levels will be longitudinally evaluated in EGF-stimulated serum starved cells treated with sera from the patients. Longitudinal blood analyses of EGFR mutations and the expression of a panel of possible predictive biomarkers in the baseline tissue will be also performed.
    
    Clinical trial identification:
    EudraCT number: 2017-003237-28
    
    Legal entity responsible for the study:
    Pangaea Oncology.
    
    Funding:
    Bioven
    
    Disclosure:
    All authors have declared no conflicts of interest.
    
    

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