100 Percent Disease Control Rate with Adagrasib in Gastrointestinal Cancers

The KRAS G12C mutation is the target of the covalent inhibitor adagrasib, a new experimental cancer drug candidate. According to a presentation at the ASCO Gastrointestinal (GI) Cancers Symposium 2022 of the KRYSTAL-1 trial, patients with gastrointestinal (stomach and intestinal) cancers achieved a 100% disease control rate.

NOTE: Disease Control Rate (Disease COntrol Rate= DCR), also known as the clinical benefit rate, is defined in clinical trials involving patients with advanced cancer as the sum of the rates of complete response, partial response and stable disease obtained with the drug being tested. 

KRYSTAL-1 was designed to test adagrasib as a single treatment or in combinations in patients with advanced solid (organ) tumors, as a phase 1/2 clinical trial.

At ASCO GI 2022, Dr Tanios Bekaii-Saab considered cancers other than colorectal cancers and reported data on the activity and safety of adagrasib in patients with advanced GI tumors.

KRAS and Adagrasib

KRAS is known to be among the most frequently mutated oncogenes in human cancer. Mutations in KRAS drive the growth and proliferation of multiple cancer types through the RAS/MAPK signaling cascade.

The most common KRAS G12 mutations are G12D (36%), G12C (14%) and G12V (23%).

KRAS mutations were once considered untargetable and untreatable, but Lumakras, containing sotorasib proved effective against non-small cell lung cancers with a KRAS G12C mutation and received FDA (US Food and Drug Administration) approval. In May 2021, sotorasib thus became the first KRAS-targeted cancer treatment approved for use in the USA.

Dr Bekaii-Saab stated that adagrasib selectively and irreversibly inhibits KRAS G12C, locking cancer cells to guanosine diphosphate and inactivating them. With a 24-hour half-life, extensive tissue distribution and dose-dependent pharmacokinetics, oral tablet administration at 600 mg twice daily exposes cancer cells to adagrasib at blood levels above the threshold for KRAS inhibition.

Small-molecule inhibitors and degraders targeting KRAS G12 mutations may represent an important therapeutic advance in cancers with few effective options, such as pancreatic ductal adenocarcinoma. Dr Bekaii-Saab noted that, unfortunately, although KRAS mutations occur in approximately 90% of pancreatic cancers, only approximately 2% are G12C mutations.

Adagrasib in Gastrointestinal Cancers

Dr Bekaii-Saab presented data from group 1 of the KRYSTAL-1 trial. Group 1 included 30 patients with previously treated GI tumors – 12 with pancreatic adenocarcinoma, 8 with biliary tract cancer, 5 with appendix cancer, 2 with small intestinal cancer, 2 with gastroesophageal junction cancer and 1 with esophageal cancer.

• The median age was 65.5 (range, 40-89), and 60% were male.
• Patients had good overall performance status [ECOG PS 0 (20%) or 1 (80%)].
• Of the patients, 17% had previously received at least 4 lines of systemic therapy.
• Patients received 600 mg adagrasib twice daily.
• The median follow-up was 6.3 months.

Results

• Among 27 patients evaluable for response, the objective response rate (ORR) was 41%. All 11 responses were partial responses.
• The disease control rate (DCR) was 100%.
• In 10 patients with pancreatic cancer, the objective response rate was 50% and the disease control rate was 100%. The median duration of response was 6.97 months, and median progression-free survival (PFS) was 6.6 months. At the data cutoff, 50% of patients remained on treatment.
• For 17 patients with other GI cancers, the objective response rate was 35% and the disease control rate was 100%. Median PFS and median duration of response were both 7.85 months. At the data cutoff, 65% of patients remained on treatment.

Treatment-related adverse effects of any grade occurred in 87% of patients. The most common were nausea (50%), vomiting (40%), diarrhea (37%) and fatigue (33%).

Serious (grade 3) adverse effects occurred in 27% of patients. The most common grade 3 adverse effect was fatigue (10%). There were no grade 4 or 5 adverse effects, and treatment-related adverse effects did not lead to treatment discontinuation.

Implications of the Study

Studies showed that adagrasib was well tolerated and produced responses in multiple tumor types. The current update demonstrates encouraging clinical activity for adagrasib in previously treated patients with conventional pancreatic cancer (ductal adenocarcinoma) and other noncolorectal gastrointestinal tumors.

Dr Bekaii-Saab noted that the phase 2 portion of KRYSTAL-1 was ongoing and that an expanded access program was available for previously treated patients with advanced KRAS G12C-mutant solid tumors who could not participate in the trial.

For patients who develop resistance to KRAS G12C-targeted treatment, knowledge of potential resistance mechanisms is expanding rapidly. Preclinical studies suggest that drug combinations may bypass some of the most common resistance patterns.

The prognosis of patients with KRAS G12C-mutant tumors is debated. Although much remains to be learned about how to use KRAS G12C-targeted therapy most effectively, periodic updates from KRYSTAL-1 suggest substantial potential benefits for patients with a wide variety of clinically challenging tumors.