OA03.07 Safety and Efficacy of D-1553 in Patients with KRAS G12C Mutated Non-Small Cell Lung Cancer: A Phase 1 Trial

Lu, S.; Jian, H.; Zhang, Y.; Song, Z.; Zhao, Y.; Wang, P.; Jiang, L.; Gong, Y.; Zhou, J.; Dong, X.; Yang, N.; Fang, J.; Zhuang, Wuwei; Cang, S.; Ma, R.; Shi, J.; Wu, Peipei; Lu, J.; Xiang , Zhiwei; Shi, Z.; Zhang, L.; Wang, Y.

doi:10.1016/j.jtho.2022.07.026

Cited by 5 publications

(4 citation statements)

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“…In a phase I dose escalation and expansion trial, 79 NSCLC patients carrying KRAS G12C who failed at least one prior line of systemic therapy were given D-1553. The ORR was 37.8% and the median PFS was 7.6 months [69]. The data were encouraging and still immature given the high censor rate (68%).…”

Section: Krasmentioning

confidence: 87%

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Emerging Targeted Therapies in Advanced Non-Small-Cell Lung Cancer

Correia

Wang

et al. 2023

Cancers

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Lung cancer remains the leading cause of cancer-related mortality worldwide. Non-small-cell lung cancer (NSCLC) is the most common type and is still incurable for most patients at the advanced stage. Targeted therapy is an effective treatment that has significantly improved survival in NSCLC patients with actionable mutations. However, therapy resistance occurs widely among patients leading to disease progression. In addition, many oncogenic driver mutations in NSCLC still lack targeted agents. New drugs are being developed and tested in clinical trials to overcome these challenges. This review aims to summarize emerging targeted therapy that have been conducted or initiated through first-in-human clinical trials in the past year.

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Section: Krasmentioning

confidence: 87%

“…The data were encouraging and still immature given the high censor rate (68%). Grade 3 or above TRAEs occurred in 35.4% patients, mainly liver enzyme elevation [69]. A phase II trial is currently recruiting (NCT05383898).…”

Section: Krasmentioning

confidence: 99%

Emerging Targeted Therapies in Advanced Non-Small-Cell Lung Cancer

Correia

Wang

et al. 2023

Cancers

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“…Recently, a multicenter phase III trial (KRYSTAL-12, NCT04685135) designed to compare the efficiency and safety of adagrasib versus docetaxel is ongoing in 452 previously treated NSCLC patients. Similarly inhibiting KRAS G12C directly, GDC-6036 and D1553 also showed promising clinical activity in phase I clinical trials [ 128 , 129 ]. Besides, a variety of additional drugs are also being developed to inhibit KRAS indirectly.…”

Section: Kras G12c Mutationsmentioning

confidence: 99%

Molecular pathways, resistance mechanisms and targeted interventions in non-small-cell lung cancer

Wang

Xing

et al. 2022

Mol Biomed

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Lung cancer is the leading cause of cancer-related mortality worldwide. The discovery of tyrosine kinase inhibitors effectively targeting EGFR mutations in lung cancer patients in 2004 represented the beginning of the precision medicine era for this refractory disease. This great progress benefits from the identification of driver gene mutations, and after that, conventional and new technologies such as NGS further illustrated part of the complex molecular pathways of NSCLC. More targetable driver gene mutation identification in NSCLC patients greatly promoted the development of targeted therapy and provided great help for patient outcomes including significantly improved survival time and quality of life. Herein, we review the literature and ongoing clinical trials of NSCLC targeted therapy to address the molecular pathways and targeted intervention progress in NSCLC. In addition, the mutations in EGFR gene, ALK rearrangements, and KRAS mutations in the main sections, and the less common molecular alterations in MET, HER2, BRAF, ROS1, RET, and NTRK are discussed. The main resistance mechanisms of each targeted oncogene are highlighted to demonstrate the current dilemma of targeted therapy in NSCLC. Moreover, we discuss potential therapies to overcome the challenges of drug resistance. In this review, we manage to display the current landscape of targetable therapeutic patterns in NSCLC in this era of precision medicine.

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“…77 In another phase I/II study based in China, ORR reached 37.8% (28/74) and DCR 91.9% (68/74) in a 100% Asian and 11.4% (9/79) female population. 78 …”

Section: Introductionmentioning

confidence: 99%

Direct GDP-KRAS^G12C inhibitors and mechanisms of resistance: the tip of the iceberg

2023

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Kirsten rat sarcoma viral oncogene homolog mutations are observed in 25% of lung adenocarcinoma and 40% of these are G12C mutations. Historically, no approved targeted agents were available for patients with any KRAS mutation, and response rates to standard-of-care therapies were suboptimal. Newly developed inhibitors directed toward KRASG12C have been successful in clinical trials with overall response rates ranging between 32% and 46%, and two FDA approvals were granted in May 2021 and December 2022 as second-line or later monotherapies. However, rapid tumor resistance complicates their use as a monotherapy. With the rapid development of this novel class of inhibitors, it is important to discern the different types of tumor resistance that may arise and how each can differently contribute to tumor growth and survival. G12C inhibitor resistance is under investigation and combinations of therapies with G12C inhibitors have been proposed. Much of this insight is gleaned from preclinical investigations, as our knowledge of clinical resistance is in its infancy. In this review, we summarize the preclinical development of KRASG12C inhibitors, their clinical evaluations, different types of resistance mechanisms to these compounds, and ways of overcoming them. Finally, we underscore the importance of basic and translational investigations of these molecules in a landscape where their clinical evaluations garner the most attention, and we set the stage for what is to come.

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OA03.07 Safety and Efficacy of D-1553 in Patients with KRAS G12C Mutated Non-Small Cell Lung Cancer: A Phase 1 Trial

Cited by 5 publications

References 0 publications

Emerging Targeted Therapies in Advanced Non-Small-Cell Lung Cancer

Emerging Targeted Therapies in Advanced Non-Small-Cell Lung Cancer

Molecular pathways, resistance mechanisms and targeted interventions in non-small-cell lung cancer

Direct GDP-KRAS^G12C inhibitors and mechanisms of resistance: the tip of the iceberg

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OA03.07 Safety and Efficacy of D-1553 in Patients with KRAS G12C Mutated Non-Small Cell Lung Cancer: A Phase 1 Trial

Cited by 5 publications

References 0 publications

Emerging Targeted Therapies in Advanced Non-Small-Cell Lung Cancer

Emerging Targeted Therapies in Advanced Non-Small-Cell Lung Cancer

Molecular pathways, resistance mechanisms and targeted interventions in non-small-cell lung cancer

Direct GDP-KRASG12C inhibitors and mechanisms of resistance: the tip of the iceberg

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Direct GDP-KRAS^G12C inhibitors and mechanisms of resistance: the tip of the iceberg