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Adagrasib shows promising response, disease control with KRAS G12C + NSCLC

Adagrasib shows promising response, disease control with KRAS G12C + NSCLC

 


In the Phase 1/2 KRYSTAL-1 trial (NCT03785249), the single agent adagressive provided promising objective response and disease control rate (DCR), and overall survival (OS) in previously treated patients. Shown. KRAS According to the results of Cohort A presented at the 2022 ASCO Annual Meeting, G12C mutant non-small cell lung cancer (NSCLC).1

At the conference, Alexander I. Spira, MD, PhD, FACP, Co-Director of the Virginia Cancer Specialists Research Institute, Director of the Chest and Phase I Program, and Clinical Assistant Professor of the Johns Hopkins School of Medicine presented data as of October. Studies published simultaneously from 15, 2021, Registration Phase 2 Cohort New England Journal of Medicine..

After a median follow-up of 12.9 months, 112 patients with baseline measurable disease had an objective response rate (ORR) of 43% (95% CI, 33.5% -52.6%). It contained one complete response (CR; 1). %) And 47 partial responses (PR; 42%). With a DCR of 80%, 41 patients had stable disease (SD; 37%) and 6 (5%) had progressive disease (n = 89; 95% CI, 70.8% -86.5%). ). In exploratory analysis, there was no difference in ORR between subgroups.

“The response is deep, with 75% of responders appearing to show tumor shrinkage of more than 50%,” Spira said.

In addition, the median time to response with the KRAS G12C inhibitor was 1.4 months (range, 0.9-7.2) and the median duration of response was 8.5 months (95% CI, 6.2-13.8).

At the time of the data cutoff, Spira said treatment was ongoing in half (n = 24) of patients who experienced a response, and 33% (n = 16) maintained the response.

Finally, median progression-free survival (PFS) was 6.5 months (95% CI, 4.7 to 8.4), with 6-month and 12-month PFS rates of 52% and 29%, respectively. Similarly, the median OS is 12.6 months (95% CI, 9.2-19.2), and the 6-month and 12-month OS rates are 71% (95% CI, 61.1-78.3) and 51% (95%). CI, 40.9-60.0). ), Respectively.

The researchers also evaluated the efficacy of 33 patients with stable central nervous system (CNS) metastases treated. The intracranial ORR was 33% (n = 11; 95% CI, 18% -52%), which included 5 CRs (15%) and 6 PRs (18%). There were 17 (52%) SD patients with a DCR of 85% (n = 28; 95% CI, 68% -95%). The median intracranial PFS was 5.4 months (95% CI, 3.3-11.6).

Treatment-related adverse events (TRAEs) of all grades occurred in 113 patients (97%), of whom 50 (43%) were grade 3/4 severity. The most frequent TRAEs of all grades are diarrhea (63%), nausea (62%), vomiting (47%), malaise (41%), increased ALT (28%), and increased blood creatinine (26%). , AST increased (25%), and loss of appetite (24%). Two grade 5 events occurred, heart failure and pulmonary hemorrhage.

TRAE led to dose reduction in 60 patients (52%), discontinuation in 71 (61%), and discontinuation in 8 (7%).

Dr. Suhumani Kaul Pada of the Samuel Oschin Cancer Center at Cedars-Sinai Medical Center said of the presentation: We always talk about this because it is related to targeted therapies … co-mutations KRAS–Mutant non-small cell lung cancer. “

Adagrasib (formerly MRTX849) is a covalent inhibitor that irreversibly and selectively binds to KRASG12C. “We know that KRAS The G12C mutation acts as a carcinogenic driver and occurs in about 14% of patients with non-small cell lung cancer, primarily adenocarcinoma, “Spira explained. “Approximately 27% to 42% of these patients develop CNS metastases at diagnosis. Optimized for the desired properties of Adagrasib… KRAS G12C inhibitors with long half-life, about 23 hours, dose-dependent pharmacokinetics, and CNS penetration. “

In the agent’s first human trial, 15 patients KRAS G12C mutant NSCLC showed a median ORR of 53.3%, a median DOR of 16.4 months, and a median PFS of 11.1 months. “As previously reported, clinical activity with adaptive has been shown in a variety of areas. KRAS Of course, G12C mutant solid tumors, including non-small cell lung cancer, colorectal cancer, pancreatic cancer, ovarian cancer, endometrial cancer, and other gastrointestinal cancers, “Spira said.

Therefore, in the multicohort KRYSTAL-1 trial, researchers found that adaglacib was used as a monotherapy or in combination with other therapies. KRAS G12C mutation.

In the Enrollment Phase 2 Cohort A study, 116 patients with NSCLC who were previously treated with platinum-based chemotherapy and anti-PD-1 / L1 therapy received 600 mg of oral adagressive twice daily. The investigator was intended to assess ORR, DCR, PFS, OS, and safety.

The main eligibility criteria are: KRAS Pretreatment with G12C mutations, unresectable or metastatic disease, and chemotherapy in combination or with continuous PD-1 / L1 inhibitors. Patients with stable CNS metastases treated were admitted to the study.

The median age was 64 years (range, 15-89). Most patients were female (56%), Caucasian (84%), ECOG status 1 (84%), ex-smokers (86%), and had previously received platinum-based treatment and checkpoint inhibitor treatment. (98%).

“Based on these data, [new drug application] for adagrasib has been approved and is under review in the United States for expedited approval. [marketing authorization applications] It was recently submitted to the European Medicines Agency, “said Spira, a Phase 3 KRYSTAL-12 designed to evaluate the comparison between adagressive monotherapy and docetaxel in previously treated patients. The test (NCT04685135) was added. KRAS G12C-mutant NSCLC is ongoing.

References

1. Spira AI, Riely GJ, Gadgeel SM, etc. KRYSTAL-1: Activity and safety of adagressive (MRTX849) in patients with advanced / metastatic non-small cell lung cancer (NSCLC) with KRAS G12C mutations. J Clin Oncol.. 2022; 40 (suppl 16): 9002 doi: 10.1200 / JCO.2022.40.16_suppl.9002

2. Jänne PA, Riely G, Gadgee SM, etc. Adhesive in non-small cell lung cancer with the KRASG12C mutation. N Engl J Med.. 2022; 386: 22. doi: 10.1056 / NEJMoa2204619.

Sources

1/ https://Google.com/

2/ https://www.targetedonc.com/view/adagrasib-displays-encouraging-responses-disease-control-in-kras-g12c-nsclc

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