PMID- 37507657
OWN - NLM
STAT- MEDLINE
DCOM- 20230731
LR  - 20230731
IS  - 1471-2407 (Electronic)
IS  - 1471-2407 (Linking)
VI  - 23
IP  - 1
DP  - 2023 Jul 28
TI  - A phase Ib/II study of galunisertib in combination with nivolumab in solid tumors 
      and non-small cell lung cancer.
PG  - 708
LID - 10.1186/s12885-023-11153-1 [doi]
LID - 708
AB  - BACKGROUND: In this phase Ib/II open-label study, tumor immune suppression was 
      targeted in patients with advanced refractory solid tumors and patients with 
      recurrent/refractory non-small cell lung cancer (NSCLC) using galunisertib with 
      nivolumab. METHODS: Eligible patients were >/= 18 years old, had an Eastern 
      Cooperative Oncology Group performance status </= 1, and were treatment-naive for 
      anti-programmed cell death-1, its ligand, or transforming growth factor beta 
      receptor 1 kinase inhibitors. Phase Ib was an open-label, dose-escalation 
      assessment of the safety and tolerability of galunisertib with nivolumab in 
      patients with advanced refractory solid tumors. Phase II evaluated the safety of 
      galunisertib with nivolumab in NSCLC patients who had received prior 
      platinum-based treatment but were immuno-oncology agent-naive. RESULTS: This 
      trial was conducted between October 2015 and August 2020. No dose-limiting 
      toxicities were observed in phase I. In the phase II NSCLC cohort (n = 25), 
      patients received 150 mg twice daily galunisertib (14 days on/14 days off dosing 
      schedule for all phases) plus nivolumab at 3 mg/kg (intravenously every 2 weeks). 
      In this phase, the most frequent treatment-related adverse events (AEs) were 
      pruritus (n = 9, 36%), fatigue (n = 8, 32%), and decreased appetite (n = 7, 28%). 
      No grade 4 or 5 treatment-related AEs were observed. Six (24%) patients had 
      confirmed partial response (PR) and 4 (16%) had stable disease; 1 additional 
      patient had confirmed PR after initial pseudo-progression. The median duration of 
      response was 7.43 months (95% confidence interval [CI]: 3.75, NR). Among the 7 
      responders, including the delayed responder, 1 had high PD-L1 expression (>/= 50%). 
      The median progression-free survival was 5.26 months (95% CI: 1.77, 9.20) and the 
      median overall survival was 11.99 months (95% CI: 8.15, NR). Interferon gamma 
      response genes were induced post-treatment and cell adhesion genes were 
      repressed, although the association of these observations with tumor response and 
      clinical outcomes was not statistically powered due to limited samples available. 
      CONCLUSIONS: The study met its primary endpoint as galunisertib combined with 
      nivolumab was well tolerated. Preliminary efficacy was observed in a subset of 
      patients in the Phase 2 NSCLC cohort. TRIAL REGISTRATION: Trial registered with 
      ClinicalTrials.gov (NCT02423343; 22.04.2015).
CI  - (c) 2023. The Author(s).
FAU - Nadal, Ernest
AU  - Nadal E
AD  - Department of Medical Oncology, Catalan Institute of Oncology, IDIBELL, 
      L'Hospitalet, Barcelona, Spain. esnadal@iconcologia.net.
FAU - Saleh, Mansoor
AU  - Saleh M
AD  - University of Alabama, Birmingham, AL, USA.
FAU - Aix, Santiago Ponce
AU  - Aix SP
AD  - Hospital 12 de Octubre - Oncology, Madrid, Spain.
FAU - Ochoa-de-Olza, Maria
AU  - Ochoa-de-Olza M
AD  - Hospital Universitario Vall d'Hebron, Barcelona, Spain.
FAU - Patel, Sandip Pravin
AU  - Patel SP
AD  - University of California, San Diego, CA, USA.
FAU - Antonia, Scott
AU  - Antonia S
AD  - H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
FAU - Zhao, Yumin
AU  - Zhao Y
AD  - Eli Lilly and Company, Indianapolis, IN, USA.
FAU - Gueorguieva, Ivelina
AU  - Gueorguieva I
AD  - Eli Lilly and Company, Indianapolis, IN, USA.
FAU - Man, Michael
AU  - Man M
AD  - Eli Lilly and Company, Indianapolis, IN, USA.
FAU - Estrem, Shawn T
AU  - Estrem ST
AD  - Eli Lilly and Company, Indianapolis, IN, USA.
FAU - Liu, Jiangang
AU  - Liu J
AD  - Eli Lilly and Company, Indianapolis, IN, USA.
FAU - Avsar, Emin
AU  - Avsar E
AD  - Eli Lilly and Company, Indianapolis, IN, USA.
AD  - Bristol Myers Squibb, Princeton, NJ, USA.
FAU - Lin, Wen Hong
AU  - Lin WH
AD  - Bristol Myers Squibb, Princeton, NJ, USA.
AD  - Immune-Onc Therapeutics, Palo Alto, CA, USA.
FAU - Benhadji, Karim A
AU  - Benhadji KA
AD  - Eli Lilly and Company, Indianapolis, IN, USA.
FAU - Gandhi, Leena
AU  - Gandhi L
AD  - Eli Lilly and Company, Indianapolis, IN, USA.
AD  - Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
FAU - Guba, Susan C
AU  - Guba SC
AD  - Eli Lilly and Company, Indianapolis, IN, USA.
FAU - Diaz, Inmaculada Ales
AU  - Diaz IA
AD  - UGCI Oncologia Medica, Hospitales Universitarios Regional Y Virgen de La 
      Victoria, IBIMA, Malaga, Spain.
LA  - eng
SI  - ClinicalTrials.gov/NCT02423343
PT  - Clinical Trial, Phase I
PT  - Clinical Trial, Phase II
PT  - Journal Article
DEP - 20230728
PL  - England
TA  - BMC Cancer
JT  - BMC cancer
JID - 100967800
RN  - 0 (Antineoplastic Agents, Immunological)
RN  - 700874-72-2 (LY-2157299)
RN  - 31YO63LBSN (Nivolumab)
SB  - IM
MH  - Adolescent
MH  - Humans
MH  - *Antineoplastic Agents, Immunological/therapeutic use
MH  - Antineoplastic Combined Chemotherapy Protocols/adverse effects
MH  - *Carcinoma, Non-Small-Cell Lung/drug therapy/etiology
MH  - *Lung Neoplasms/pathology
MH  - Neoplasm Recurrence, Local/drug therapy
MH  - Nivolumab/therapeutic use
PMC - PMC10386782
OTO - NOTNLM
OT  - Galunisertib
OT  - Immune checkpoint inhibitor
OT  - NSCLC
OT  - Nivolumab
OT  - TGF-beta
COIS- This work was supported by Eli Lilly and Company. S. Estrem, I. Gueorguieva, M. 
      Man, and J. Liu are full time employees and minor stockholders of Eli Lilly and 
      Company. L. Ghandi was a full time employee of Eli Lilly and Company at the time 
      of this work and is minor stockholder of Eli Lilly and Company, has received 
      consultancy fees from Pilant Therapeutics, 28-7 Therapeutics, Riva Therapeutics, 
      and Eli Lilly and company, has received speaker's bureau honoraria from Tempus, 
      is on the advisory board for Beigene, Bristol-Myers Squibb, Mersana, Eisai, 
      Xilio, and Tentarix, and is on the board of directors for Bright Peak 
      Therapeutics an Neximmune. Y. Zhao, and S. Guba were full time employees and 
      minor stockholders of Eli Lilly and Company at the time of this work. S. Guba has 
      also received medical writing support from Eli Lilly and Company. K.A. Benhadji 
      owns a patent with and is a minor stockholder of Eli Lilly and Company. E. Avsar 
      is a full time employee of Eli Lilly and Company and a minor stockholder in Eli 
      Lilly and Company and BMS, and was a full time employee of BMS at the time of 
      this work. W. H Lin was an employee of BMS when this work was performed. E. Nadal 
      has received grants or research funding from Bristol-Myers Squibb, Eli Lilly and 
      Company, Pfizer, Roche, and Merck Serono, and has received speaker's bureau 
      honoraria from Roche, Bristol Myers Squibb, Merck Sharp Dohme, Merck-Serono, 
      Sanofi, Pfizer, Eli Lilly, Amgen, Boehringer-Ingelheim, AstraZeneca, Takeda, 
      Sanofi, Janssen, Qiagen and Bayer. S. Patel is an advisory board member for 
      Amgen, AstraZeneca, Bristol-Myers Squibb, Certis, Eli Lilly and Company, Jazz, 
      Genentech, Illumina, Merck, Pfizer, Rakuten, and Tempus. S. Patel's university 
      receives research funding from Amgen, AstraZeneca/MedImmune, Bristol-Myers 
      Squibb, Eli Lilly and Company, Fate Therapeutics, Iovance, Merck, Pfizer, 
      Roche/Genentech, and SQZ Biotechnologies. M. Saleh received medical writing 
      support from Eli Lilly and Company. S. Antonia has been a consultant or advisory 
      board member for Achilles Therapeutics, Amgen, Bristol-Myers Squibb, Celsius 
      Therapeutics, G1 Therapeutics, Glimpse, Guardian Bio, GSK, Immutep, Memgen, 
      Merck, RAPT Therapeutics, Shoreline, Taurus, Xilis, has been on the data safety 
      monitoring board for EMD Serano, is a stockowner of Guardian, Shoreline, and RAPT 
      Therapeutics, and has received travel reimbursement from RAPT Therapeutics. I. 
      Ales Diaz, M. Ochoa-de-Olza, and S. Ponce Aix have nothing to declare.
EDAT- 2023/07/29 06:42
MHDA- 2023/07/31 06:42
PMCR- 2023/07/28
CRDT- 2023/07/28 23:33
PHST- 2022/10/26 00:00 [received]
PHST- 2023/07/05 00:00 [accepted]
PHST- 2023/07/31 06:42 [medline]
PHST- 2023/07/29 06:42 [pubmed]
PHST- 2023/07/28 23:33 [entrez]
PHST- 2023/07/28 00:00 [pmc-release]
AID - 10.1186/s12885-023-11153-1 [pii]
AID - 11153 [pii]
AID - 10.1186/s12885-023-11153-1 [doi]
PST - epublish
SO  - BMC Cancer. 2023 Jul 28;23(1):708. doi: 10.1186/s12885-023-11153-1.