Single-Agent Divarasib (GDC-6036) in Solid Tumors with a KRAS G12C Mutation
Another KRAS G12C inhibitor. Congrats to FCS Director of Drug Development Manish Patel, MD, one of the authors. Durable responses with less adverse events.
Neoadjuvant Pembrolizumab in Localized Microsatellite Instability High/Deficient Mismatch Repair Solid Tumors
Author(s): Kaysia Ludford, MD1,2; Won Jin Ho, MD3; Jane V. Thomas, MD2; Kanwal P.S. Raghav, MBBS2; Mariela Blum Murphy, MD2; Nicole D. Fleming, MD4; Michael S. Lee, MD2; Brandon G. Smaglo, MD2; Y. Nancy You, MD5; Matthew M. Tillman, MD5; Carlos Kamiya-Matsuoka, MD6; Selvi Thirumurthi, MD7; Craig Messick, MD5; Benny Johnson, DO2; Eduardo Vilar, MD, PhD8; Arvind Dasari, MBBS2; Sarah Shin, BS3; Alexei Hernandez, BS3; Xuan Yuan, MD3; Hongqui Yang3; Wai Chin Foo, MD9; Wei Qiao, MS, PhD10; Dipen Maru, MD9; Scott Kopetz, MD, PhD2; and Michael J. Overman, MD2
Source: DOI: 10.1200/JCO.22.01351 Journal of Clinical Oncology 41, no. 12 (April 20, 2023) 2181-2190.
Dr. Maen Hussein's Thoughts
Neoadjuvant immunotherapy is gaining momentum in breast (triple negative) and lung cancer, now showing promise in MSI high tumors.
PURPOSE
Pembrolizumab significantly improves clinical outcomes in advanced/metastatic microsatellite instability high (MSI-H)/deficient mismatch repair (dMMR) solid tumors but is not well studied in the neoadjuvant space.
METHODS
This is a phase II open-label, single-center trial of localized unresectable or high-risk resectable MSI-H/dMMR tumors. Treatment is pembrolizumab 200 mg once every 3 weeks for 6 months followed by surgical resection with an option to continue therapy for 1 year followed by observation. To continue on study, patients are required to have radiographic or clinical benefit. The coprimary end points are safety and pathologic complete response. Key secondary end points are response rate and organ-sparing at one year for patients who declined surgery. Exploratory analyses include interrogation of the tumor immune microenvironment using imaging mass cytometry.
RESULTS
A total of 35 patients were enrolled, including 27 patients with colorectal cancer and eight patients with noncolorectal cancer. Among 33 evaluable patients, best overall response rate was 82%. Among 17 (49%) patients who underwent surgery, the pathologic complete response rate was 65%. Ten patients elected to receive one year of pembrolizumab followed by surveillance without surgical resection (median follow-up of 23 weeks [range, 0-54 weeks]). An additional eight did not undergo surgical resection and received less than 1 year of pembrolizumab. During the study course of the trial and subsequent follow-up, progression events were seen in six patients (four of whom underwent salvage surgery). There were no new safety signals. Spatial immune profiling with imaging mass cytometry noted a significantly closer proximity between granulocytic cells and cytotoxic T cells in patients with progressive events compared with those without progression.
CONCLUSION
Neoadjuvant pembrolizumab in dMMR/MSI-H cancers is safe and resulted in high rates of pathologic, radiographic, and endoscopic response, which has implications for organ-sparing strategies.
Author Affiliations
1Department of General Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX2Department of Gastrointestinal Medical Oncology, The University of Texas. MD Anderson Cancer Center, Houston, TX3Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD4Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX5Department of Colon and Rectal Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX6Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX7Department of Gastroenterology Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX8Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX9Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX10Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TXRelated Articles
First-in-Human Phase I/IB Dose-Finding Study of Adagrasib (MRTX849) in Patients With Advanced KRASG12C Solid Tumors (KRYSTAL-1)
This is an important progress for patients with KRASG12C mutation. Median PFS of 11 months is very encouraging for a previously “undruggable” molecular signature.
