Gastrointestinal Cancers Symposium

Gastrointestinal Cancers Symposium

Perspective from Deirdre Cohen, MD
Perspective from Vincent Chung, MD
Source:

Bekaii-Saab TS, et al. Abstract 519. Presented at: ASCO Gastrointestinal Cancers Symposium; Jan 20-22, 2022; San Francisco.

Disclosures: Bekaii-Saab reports consultant/advisory roles with AbbVie, Amgen, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Celularity, Daiichi Sankyo/UCB Japan, Eisai, Eli Lilly and Company, Exact Sciences, Foundation Medicine, Immuneering, Incyte, Ipsen, Janssen, Natera, Pfizer, Roche/Genentech, SeaGen, Sobi and Treos Bio; patents WO/2018/183488 and WO/2019/055687; and other relationships with AstraZeneca, Eli Lilly, Exelixis, Merck and Pancreatic Cancer Action Network. Please see the abstract for all other researchers’ relevant financial disclosures.
January 21, 2022
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Adagrasib active, safe among patients with KRAS G12C-mutated pancreatic, GI tumors

Perspective from Deirdre Cohen, MD
Perspective from Vincent Chung, MD
Source:

Bekaii-Saab TS, et al. Abstract 519. Presented at: ASCO Gastrointestinal Cancers Symposium; Jan 20-22, 2022; San Francisco.

Disclosures: Bekaii-Saab reports consultant/advisory roles with AbbVie, Amgen, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Celularity, Daiichi Sankyo/UCB Japan, Eisai, Eli Lilly and Company, Exact Sciences, Foundation Medicine, Immuneering, Incyte, Ipsen, Janssen, Natera, Pfizer, Roche/Genentech, SeaGen, Sobi and Treos Bio; patents WO/2018/183488 and WO/2019/055687; and other relationships with AstraZeneca, Eli Lilly, Exelixis, Merck and Pancreatic Cancer Action Network. Please see the abstract for all other researchers’ relevant financial disclosures.
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Adagrasib induced promising clinical activity as monotherapy among pretreated patients with unresectable or metastatic pancreatic cancer and other gastrointestinal tumors that harbor a KRAS G12C mutation, according to study results.

The agent also had a manageable safety profile, research presented at ASCO Gastrointestinal Cancers Symposium showed.

Response rates from phase 2 study.
Data derived from Bekaii-Saab TS, et al. Abstract 519. Presented at: ASCO Gastrointestinal Cancers Symposium; Jan 20-22, 2022; San Francisco.

Adagrasib is a KRAS G12C selective covalent inhibitor with a long half-life that enables exposure above a target threshold throughout the dosing interval,” Tanios S. Bekaii-Saab, MD, FACP, leader of the gastrointestinal cancer program at Mayo Clinic Cancer Center, said during a presentation.

Rationale

KRAS, an important mediator of RAS/MAPK signaling that promotes cellular proliferation and growth, is the most frequently mutated oncogene in cancer. KRAS mutations have been identified in about 90% of pancreatic cancers, and about 2% are KRAS G12C mutations.

Adagrasib (MRTX849, Mirati Therapeutics Inc.) irreversibly and selectively binds to KRAS G12C and locks it in its inactive state.

Methodology

Tanios S. Bekaii-Saab, MD, FACP
Tanios S. Bekaii-Saab

Bekaii-Saab presented preliminary data of patients enrolled in a phase 2 cohort of the KRYSTAL-1 trial, which is investigating adagrasib as monotherapy or with other treatments among patients with advanced KRAS G12C-mutated solid tumors. The cohort included 42 patients (median age, 63.5 years; range 21-89; 52% women; 71% white) with previously treated unresectable or metastatic solid tumors, excluding colorectal and non-small cell lung cancers. Among the patients, 30 had KRAS G12C-mutated GI tumors (12 pancreatic, eight biliary tract, five appendiceal, two gastroesophageal junction, two small bowel and one esophageal) and had received at least two previous lines of systemic anticancer therapy.

Patients received 600 mg adagrasib orally twice a day.

Clinical activity, safety and pharmacokinetics served as study endpoints.

Key findings

Results among 27 evaluable patients showed an objective response rate of 41% and a disease control rate of 100%.

Among 10 evaluable patients with pancreatic cancer (median follow-up, 8.1 months), half had partial responses, including one unconfirmed partial response. Median duration of response was 7 months. Researchers reported median PFS of 6.6 months among these patients, and half remained on treatment.

Among the 17 evaluable patients with other GI tumors (median follow-up, 6.3 months), 35% had partial responses, including two unconfirmed partial responses. Bekaii-Saab noted that half of patients with biliary tract cancer responded to treatment.

“Small numbers, but these are solid responses,” he said.

Median duration of response and median PFS among these patients was 7.9 months, and 65% remained on treatment.

Among all 42 patients in the cohort, 91% experienced treatment-related adverse events, including 21% with grade 3 events. The most common grade 3 events included fatigue (7%) and QT prolongation (5%). No treatment-related adverse events led to discontinuation of therapy.

Implications

Bekaii-Saab said adagrasib has shown responses in several other tumor types, including NSCLC and colorectal, gastroesophageal junction, small bowel, ovarian and endometrial cancers.

“Further exploration of adagrasib is ongoing in the KRYSTAL-1 trial and a newly initiated early access program is available to this patient population,” he said.