Adagrasib active, safe among patients with KRAS G12C-mutated pancreatic, GI tumors
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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.
“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
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.
Perspective
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Deirdre Cohen, MD
Although not a frequent KRAS subtype in gastrointestinal malignancies, KRAS G12C is important to recognize given that its inhibition has shown impressive efficacy. In this small study of 10 patients with refractory pancreatic cancer and 17 patients with other GI tumors, researchers reported better response rates than we see with front-line chemotherapy and significantly better rates than we observe in second and later lines. To see a 35% to 50% response rate among these heavily pretreated patients is quite impressive. Not only did patients respond to this single-agent oral drug, the responses lasted for about a median of about 7 months. Furthermore, all patients treated with adagrasib seemed to derive some benefit given the 100% disease control rate. Side effects were generally mild and GI in nature. No adverse events led to treatment discontinuation.
This study truly exemplifies precision medicine: targeting an actionable alteration with a very effective and well-tolerated drug. I think adagrasib is a very promising agent for KRAS G12C-mutated GI tumors. I am interested in seeing how it performs in earlier lines of therapy for this rare subset of patients and as a potential strategy to downstage patients for potential curative surgical resection. As with other small-molecule inhibitors, we will need to understand mechanisms of resistance and devise combination strategies to overcome or circumvent them.
Although this is a small subset of KRAS-mutated GI cancers, adagrasib appears poised to be a mighty tool in our armamentarium.
Perspective
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Vincent Chung, MD
Sotorasib (Lumakras, Amgen), the first inhibitor of KRAS G12C, received FDA accelerated approval for adults with NSCLC in May 2021. The FDA based the approval on results of the CodeBreak100 trial, which also accrued 10 patients with pancreatic cancer with KRAS G12C mutations. Sotorasib was given at escalating doses and expanded at the 960 mg dose by study design. Six patients with pancreatic cancer had stable disease with study treatment.
Adagrasib covalently binds to KRAS G12C, keeping it in the inactive state. The drug had a favorable pharmacokinetic profile with a 24-hour half-life and researchers observed central nervous system penetration.
Bekaii-Saab presented preliminary efficacy data on 42 patients accrued to the expansion cohort of the KRYSTAL-1 trial who received adagrasib at 600 mg twice a day. Among 10 evaluable patients with pancreatic cancer, five had partial responses and the other five had stable disease, which is very encouraging in this heavily pretreated population. Additional studies will need to be done to confirm the activity, and ongoing trials are looking at combination therapies.
The future is looking brighter for patients with pancreatic cancer as targeted therapies are developed for specific molecular alterations.
Reference:
Hong DS, et al. N Engl J Med. 2020;doi: 10.1056/NEJMoa1917239.
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Bekaii-Saab TS, et al. Abstract 519. Presented at: ASCO Gastrointestinal Cancers Symposium; Jan 20-22, 2022; San Francisco.
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