Establishment of the first international large-scale, genomic screening platform to identify patients with rare oncogene drivers in non-small cell lung cancer (NSCLC) in East Asia.

9605 Background: A rapidly increasing number of oncogenic drivers have been identified in non-small cell lung cancer (NSCLC), and most of them occur in less than 5% of patients. Large-scale genomic screening to identify patients with rare driver alterations is thus necessary to enable precision medicine and to support the development of novel targeted therapies and companion diagnostics (CDx). Methods: A lung cancer genomic screening project (LC-SCRUM-Asia) capturing clinical outcome was established in 2013 with 206 institutions in Japan and 5 in Taiwan currently participating. A separate genomic screening project with similar structure was established in China (LC-IRICA-China) in collaboration with LC-SCRUM-Asia in 2019 (3 institutions enrolling, 17 about to open, 63 undergoing review). Samples are analyzed by a multi-gene PCR panel and targeted next-generation sequencing. The target is to enroll 70000 NSCLC patients (20000 from LC-SCRUM-Asia and 50000 from LC-IRICA-China) by 2022. Results: From March 2013, a total of 9383 lung cancer patients were enrolled in LC-SCRUM-Asia, and from October 2019, 1649 pts were included in LC-IRICA-China (January 2020). The rates of genomic alterations in LC-SCRUM-Asia: EGFR (17%) of which ex20ins (2%), KRAS (13%) of which G12C (4%), ALK fusions (2%), ROS1 fusions (2%), RET fusions (2%), HER 2 ex20ins (3%), MET ex14skip (2%), BRAF V600E (1%), NRG1 fusions (0.2%) and NTRK3 fusions (0.03%). Corresponding rates in the initial 243 pts in LC-IRICA China: EGFR (45%) of which ex20ins (2%), KRAS (8%), ALK (5%), ROS1 (2%), RET (1%), HER2 (2%), MET ex14skip (1%), BRAFV600E (1%). Through the screening, 266 patients from Japan and Taiwan were enrolled into genotype-matched clinical trials of unapproved targeted drugs. In Japan, ROS1-, BRAF- and TRK-targeted therapies were successfully approved based on these clinical trials, and a NGS-based multi-gene CDx for EGFR/ALK/ROS1/BRAF targeted-therapies was approved based a concordance study using archival samples from the project. Conclusions: An East Asian international genomic screening platform has been established to enable precision medicine for patients, accelerate drug and diagnostic development in patients with very rare alterations and to help provide a deeper understanding of the underlying biology of NSCLC in East Asian patients. The screening network will be further expanded to other countries in East Asia in the near future.

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Impact of large-scale nationwide genomic screening project for small cell lung cancer (LC-SCRUM-Japan).

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.8559 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 8559-8559

Author(s):

Naoki Furuya ◽

Shigeki Umemura ◽

Hibiki Udagawa ◽

Tadasuke Shimokawaji ◽

Takashi Seto ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Large Scale ◽

Genetic Alterations ◽

Small Cell ◽

Clinical Samples ◽

Small Cell Lung ◽

Platinum Based Chemotherapy ◽

Genomic Screening

8559 Background: A variety of genetic analyses have been performed in small cell lung cancer (SCLC), however the clinical relevance of them remains unclear. We prospectively analyzed clinical samples of small-cell lung cancer using a nationwide genomic screening project (LC-SCRUM-Japan). Methods: Submitted tumor samples were subjected to a next-generation sequencing (NGS) system, Oncomine™ Comprehensive Assay, enabling the simultaneous analysis of 143 (ver.1) or 161 (ver.3) cancer-related genes. Results: From July 2015 to January 2019, 707 SCLC patients had been enrolled. The median age was 68 years. 77% were male and 94% were smokers. Among 588 samples completed analysis, we identified high prevalence of inactivating TP53/RB1 mutations in 426 (72%) /194 (33%) of cases, respectively. MYC/MYCL1/MYCN amplifications were detected in 21 (4%) /30 (5%) /9 (2%) of cases, respectively. This NGS analysis also showed that 32 (5%) of cases had well-known genetic alterations in receptor tyrosine kinase genes: 9 EGFR mutations, 9 KRAS mutations and 14 FGFR1 copy number gains. Mutations in the PI3K pathway were detected in 44 (7%) of the tumors. Among them, 8 cases enrolled in the investigator-initiated phase II study of gedatolisib (UMIN 000020585). Survival data was available in 463 patients receiving platinum-based chemotherapy. Multivariate analysis revealed that the presence of PIK3CA mutation (HR; 2.56; 95% CI 1.19 – 5.52; p = 0.016) and MYCN amplification (HR; 4.36; 95% CI 1.91 – 9.97; p < 0.001) were significantly associated with unfavorable survival. The frequency of amplifications in MYC family genes was higher in the samples obtained ≥ 90 days after the first-line platinum-based chemotherapy (18.1%) than in those < 90 days (8.1%, p = 0.01), suggesting MYC family amplification as one of the resistance mechanisms. Conclusions: This large-scale nationwide screening system is helpful for identifying therapeutically relevant genetic alterations, prognostic prediction, and exploring resistance mechanism in SCLC. Updated screening results will be presented at the 2019 ASCO Annual Meeting. Clinical trial information: UMIN000018656.

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Comparative Efficacy of Targeted Therapies in Patients with Non-Small Cell Lung Cancer: A Network Meta-Analysis of Clinical Trials

Journal of Clinical Medicine ◽

10.3390/jcm9041063 ◽

2020 ◽

Vol 9 (4) ◽

pp. 1063 ◽

Cited By ~ 1

Author(s):

Tung Hoang ◽

Seung-Kwon Myung ◽

Thu Thi Pham ◽

Jeongseon Kim ◽

Woong Ju

Keyword(s):

Lung Cancer ◽

Clinical Trials ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Targeted Therapies ◽

Meta Analysis ◽

Small Cell ◽

Cochrane Library ◽

Comparative Efficacy ◽

Small Cell Lung

This study aims to investigate the efficacy of targeted therapies in the treatment of non-small cell lung cancer (NSCLC) by using a network meta-analysis of clinical trials. PubMed, EMBASE, Cochrane Library, and Clinicaltrials.gov were searched by using keywords related to the topic on 19 September 2018. Two investigators independently selected relevant trials by pre-determined criteria. A pooled response ratio (RR) for overall response rate (ORR) and a hazard ratio (HR) for progression-free survival (PFS) were calculated based on both the Bayesian and frequentist approaches. A total of 128 clinical trials with 39,501 participants were included in the final analysis of 14 therapeutic groups. Compared with chemotherapy, both ORR and PFS were significantly improved for afatinib, alectinib, and crizotinib, while only PFS was significantly improved for cabozantinib, ceritinib, gefitinib, and osimertinib. Consistency was observed between the direct and indirect comparisons based on the Bayesian approach statistically and the frequentist approach visually. Cabozantinib and alectinib showed the highest probability for the first-line treatment ranking in ORR (62.5%) and PFS (87.5%), respectively. The current network meta-analysis showed the comprehensive evidence-based comparative efficacy of different types of targeted therapies, which would help clinicians use targeted therapies in clinical practice.

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Nationwide genomic screening network for the development of novel targeted therapies in advanced non-small cell lung cancer (LC-SCRUM-Japan).

Journal of Clinical Oncology ◽

10.1200/jco.2015.33.15_suppl.8093 ◽

2015 ◽

Vol 33 (15_suppl) ◽

pp. 8093-8093 ◽

Cited By ~ 2

Author(s):

Shingo Matsumoto ◽

Kiyotaka Yoh ◽

Takashi Seto ◽

Takuma Yokoyama ◽

Haruyasu Murakami ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Targeted Therapies ◽

Small Cell ◽

Small Cell Lung ◽

Genomic Screening

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Large-scale nationwide genomic screening system for small cell lung cancer in Japan (LC-SCRUM-Japan)

Annals of Oncology ◽

10.1093/annonc/mdy374.013 ◽

2018 ◽

Vol 29 ◽

pp. vii54

Author(s):

Norio Okamoto ◽

Shigeki Umemura ◽

Taku Nakagawa ◽

Shingo Miyamoto ◽

Kenichiro Kudo ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Large Scale ◽

Small Cell ◽

Screening System ◽

Small Cell Lung ◽

Genomic Screening

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A nationwide genomic screening project for small cell lung cancer in Japan (LC-SCRUM-Japan).

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.8518 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 8518-8518 ◽

Cited By ~ 1

Author(s):

Haruyasu Murakami ◽

Shigeki Umemura ◽

Masahiro Shinoda ◽

Masato Shingyoji ◽

Yukari Ogawa ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Targeted Therapies ◽

Small Cell ◽

Small Cell Lung ◽

Genomic Alterations ◽

Activating Mutations ◽

Genomic Screening ◽

Inactivating Mutations

8518 Background: Recent genomic studies of small-cell lung cancer (SCLC) have identified promising therapeutic strategies for this highly lethal form of cancer. Thus, we established a nationwide lung cancer genomic screening project in Japan (LC-SCRUM-Japan) to identify SCLC patients harboring targetable genomic alterations for the development of novel targeted therapies. Methods: The samples were subjected to a next-generation sequencing (NGS) system, Oncomine™ Comprehensive Assay, enabling the simultaneous analysis of 143 cancer-related genes. Results: As of December 2016, 133 institutions were participating and 295 patients had been enrolled. The median age was 69 years (range, 14-90 years). Two hundred seventeen (74%) were male and most patients (93%) were smokers. Among 268 samples completed analysis, we identified high prevalence of inactivating TP53/RB1 mutations in 198 (74%) /82 (31) of cases, respectively. MYC/MYCL1/MYCN amplifications were detected in 10 (4%) /13 (5) /4 (1) of cases, respectively. The NGS analysis also showed that 62 (23%) of cases had at least one targetable genomic alterations, including 7 EGFR activating mutations (3%), 6 KRAS activating mutations (2%), and 8 FGFR1 copy number gains (3%). No case was positive for ALK or ROS1 fusions. Never-smokers (71% vs. 5%, p<0.001) were significantly frequent in the EGFR type compared to the others. The KRAS type showed significantly poor progression free survival (PFS) of the first-line chemotherapy compared to the others (median PFS 1.2 vs. 6.1 months, respectively; p<0.001). Mutations in the PI3K/AKT/mTOR pathway were detected in 22 (8%) of the tumors: 10 PIK3CA mutations (4%), 9 PTEN inactivating mutations (3%) and 3 TSC2 inactivating mutations (1%). Among them, a case with PTEN mutation was enrolled in the investigator initiated phase II study of gedatolisib named “EAGLE-PAT” (UMIN 000020585). Conclusions: We identified a series of targetable genomic alterations in SCLC. This nationwide screening system is helpful for identifying targetable genomic alterations and their clinical features, contributing to the development of novel targeted therapies for this disease. Updated screening results will be presented at the 2017 ASCO Annual Meeting.

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Trastuzumab Deruxtecan: Changing the Destiny of HER2 Expressing Solid Tumors

International Journal of Molecular Sciences ◽

10.3390/ijms22094774 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4774

Author(s):

Alice Indini ◽

Erika Rijavec ◽

Francesco Grossi

Keyword(s):

Colorectal Cancer ◽

Gastric Cancer ◽

Lung Cancer ◽

Clinical Trials ◽

Small Cell Lung Cancer ◽

Solid Tumors ◽

Targeted Therapies ◽

Small Cell ◽

Small Cell Lung ◽

Her2 Positive

HER2 targeted therapies have significantly improved prognosis of HER2-positive breast and gastric cancer. HER2 overexpression and mutation is the pathogenic driver in non-small cell lung cancer (NSCLC) and colorectal cancer, however, to date, there are no approved HER2-targeted therapies with these indications. Trastuzumab deruxtecan (T-DXd) is a novel HER2-directed antibody drug conjugate showing significant anti-tumor activity in heavily pre-treated HER2-positive breast and gastric cancer patients. Preliminary data have shown promising objective response rates in patients with HER2-positive NSCLC and colorectal cancer. T-DXd has an acceptable safety profile, however with concerns regarding potentially serious treatment-emergent adverse events. In this review we focus on the pharmacologic characteristics and toxicity profile of T-Dxd, and provide an update on the most recent results of clinical trials of T-DXd in solid tumors. The referenced papers were selected through a PubMed search performed on 16 March 2021 with the following searching terms: T-DXd and breast cancer, or gastric cancer, or non-small cell lung cancer (NSCLC), or colorectal cancer. Oral presentation, abstracts, and posters presented at the American Society of Clinical Oncology (ASCO, Alexandria, VA, USA) 2020 and the European Society for Medical Oncology (ESMO, Lugano, Switzerland) 2020 annual meetings were retrieved for data on T-DXd. We also overview ongoing research and data of combination therapies currently under investigation, which will impact on future therapeutic strategies. Clinicaltrials.gov was searched to identify ongoing clinical trials of T-DXd alone or in combination in solid tumors.

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