1783 - Clinical development of molecular-targeted therapies for non-small cell lung cancer through nationwide genome screening in Japan (LC-SCRUM-Japan)

Background

A nationwide genome screening project in Japan (LC-SCRUM-Japan) has been established for the development of molecular-targeted therapies for lung cancers.

Methods

Since 2013, ALK/ROS1/RET fusions have been analyzed by RT-PCR and FISH, and since 2015, multi-gene alterations have been also analyzed by a next-generation sequencing (NGS) system, Oncomine™ Comprehensive Assay. A large-scale clinico-genomic database has been developed based on the molecular screening and the monitoring of therapeutic efficacy and patient survival.

Results

As of December, 2018, 263 institutions were participating and 5360 non-squamous non-small cell lung cancer patients had been enrolled. The success rates of RT-PCR and NGS were 94% and 91%, respectively. Of 4874 available samples, a total of 2135 targetable gene alterations (521 KRAS mut, 157 ROS1 fus, 136 MET ex14skip/amp, 131 BRAF mut, 128 ERBB2 ex20ins, 126 RET fus, 118 ALK fus, 73 EGFR ex20ins, 10 AKT1 mut, 9 NRG1 fus, 6 FGFR2/3 fus, 2 NTRK3 fus and others) were detected. Through this screening, 963 genotype-matched patients to molecular-targeted clinical trials were identified, and 172 of them (18%) were enrolled into the trials, resulting in the approval of ROS1- and BRAF-targeted therapies in Japan. Based on our database, in patients with EGFR/ERBB2 ex20ins, MET ex14skip and RET fusions, the median overall survivals were 18.5 (95%CI, 15.4-28.1), 38.0 (8.8-NR) and 51.3 (33.4-73.4) months, respectively. In these 3 subtypes, the objective response rate of 1^st-line platinum-containing chemotherapies were 33%, 23% and 30%, respectively, and the progression-free survivals were 6.0 (95%CI, 5.0-7.0), 6.8 (4.4-8.4) and 10.5 (8.1-15.2) months, respectively. These historical data are valuable for evaluating efficacy of novel targeted drugs.

Conclusions

Our large-scale screening and clinico-genomic database contribute to the development of novel targeted therapies, especially for ROS1-, BRAF-, EGFR/ERBB2 ex20ins-, MET- and RET-positive lung cancers. In addition to the tissue-based NGS assay, NGS with liquid biopsy and multi-target qPCR assay will be started for further development of targeted drugs and companion diagnostics from 2019 in LC-SCRUM-Japan.

Clinical trial identification

UMIN000010234.

Editorial acknowledgement

Legal entity responsible for the study

National Cancer Center Japan.

Funding

Astellas Pharma, AstraZeneca, Amgen, Eisai, Ono Pharmaceutical, Kyowa Hakko Kirin, MSD, Merck Serono, Daiichi Sankyo, Taiho Pharmaceutical, Takeda Pharmaceutical, Pfizer, Novartis Pharma, Eily Lilly.

Disclosure

S. Matsumoto: Honoraria (self), Research grant / Funding (institution): Novartis; Honoraria (self), Research grant / Funding (institution): Chugai Pharma; Honoraria (self): Pfizer; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Merck Serono; Research grant / Funding (institution): MSD. K. Yoh: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Lilly Japan; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Chugai Pharma; Honoraria (self): Boehringer Ingelheim; Honoraria (self), Research grant / Funding (institution): Novartis; Honoraria (self), Research grant / Funding (institution): MSD; Honoraria (self), Research grant / Funding (institution): Daiichi Sankyo; Honoraria (self): Kirin Pharmaceuticals ; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Taiho Pharmaceutical; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Ono Pharmaceutical. T. Kato: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Lilly; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Chugai Pharma; Advisory / Consultancy: Nitto Denko; Advisory / Consultancy, Research grant / Funding (institution): AbbVie; Advisory / Consultancy: Merck Serono; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Honoraria (self): Roche; Honoraria (self): Boehringer Ingelheim; Honoraria (self), Research grant / Funding (institution): Ono Pharmaceutical ; Honoraria (self), Research grant / Funding (institution): Taiho Pharmaceutical; Honoraria (self): Bristol-Myers Squibb Japan; Honoraria (self), Research grant / Funding (institution): Merck Sharp & Dohme; Honoraria (self): Novartis; Honoraria (self): Sumitomo Dainippon Pharma; Honoraria (self): Quintiles; Honoraria (self): Takeda; Research grant / Funding (institution): Kyowa Hakko Kirin; Research grant / Funding (institution): Astellas Pharma . K. Nishino: Honoraria (self): Chugai Pharma. S. Sugawara: Honoraria (self): AstraZeneca; Honoraria (self): Chugai Pharma ; Honoraria (self): Nippon Boehringer Ingelheim; Honoraria (self): Taiho Pharmaceutical ; Honoraria (self): Pfizer ; Honoraria (self): Lilly; Honoraria (self): Novartis; Honoraria (self): Kyowa Hakko Kirin; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Ono Pharmaceutical; Honoraria (self): MSD K.K . Y. Ohe: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Chugai Pharma; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Lilly Japan; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Ono Pharmaceutical; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Kyorin ; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Takeda; Honoraria (self), Advisory / Consultancy: Celltrion; Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Research grant / Funding (institution): Bristol-Myers Squibb Japan; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Bayer; Honoraria (self), Research grant / Funding (institution): Pfizer; Honoraria (self): MSD ; Honoraria (self), Research grant / Funding (institution): Taiho Pharmaceutical; Honoraria (self): Kyowa Hakko Kirin; Research grant / Funding (institution): Sumitomo Dainippon Pharma; Research grant / Funding (institution): Ignyta. T. Seto: Honoraria (self): Astellas Pharma; Honoraria (self), Research grant / Funding (institution): AstraZeneca ; Honoraria (self): Bristol-Myers Squibb; Honoraria (self), Research grant / Funding (institution): Chugai Pharma; Honoraria (self), Research grant / Funding (institution): Lilly; Honoraria (self), Research grant / Funding (institution): MSD; Honoraria (self), Research grant / Funding (institution): Nippon Boehringer Ingelheim; Honoraria (self), Research grant / Funding (institution): Novartis; Honoraria (self): Ono Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Pfizer; Honoraria (self): Taiho Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Takeda; Honoraria (self): Thermo Fisher Scientific; Research grant / Funding (institution): Bayer Yakuhin; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Kissei Pharmaceutical; Research grant / Funding (institution): Loxo; Research grant / Funding (institution): Merck Serono. N. Furuya: Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim; Honoraria (self): Bristol-Myers Squibb Japan; Honoraria (self): Lilly; Honoraria (self): Chugai Pharma; Honoraria (self): AstraZeneca; Honoraria (self): Pfizer; Honoraria (self): Taiho Pharmaceutical; Honoraria (self): Ono Pharmaceutical . K. Goto: Advisory / Consultancy: Otsuka; Honoraria (self), Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self), Research grant / Funding (institution): Pfizer; Honoraria (self), Research grant / Funding (institution): Chugai Pharma; Honoraria (self), Research grant / Funding (institution): Taiho Pharmaceutical ; Honoraria (self), Research grant / Funding (institution): Ono Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Novartis; Honoraria (self), Research grant / Funding (institution): Lilly; Honoraria (self), Research grant / Funding (institution): Boehringer Ingelheim; Honoraria (self): Quintiles; Honoraria (self), Research grant / Funding (institution): Merck Serono; Honoraria (self), Research grant / Funding (institution): Life Technologies; Honoraria (self), Research grant / Funding (institution): MSD; Honoraria (self): AbbVie; Honoraria (self), Research grant / Funding (institution): Riken Genesis; Honoraria (self): Nippon Kayaku; Honoraria (self), Research grant / Funding (institution): Takeda; Honoraria (self): Otsuka; Honoraria (self): SRL Diagnostics. All other authors have declared no conflicts of interest.