Adagrasib, a covalent inhibitor of the KRASG12C mutation, produced a 100% disease control rate in patients with gastrointestinal (GI) cancers, according to an update from the KRYSTAL-1 study presented at the ASCO Gastrointestinal Cancers Symposium 2022.1

KRYSTAL-1 (ClinicalTrials.gov Identifier: NCT03785249) is a phase 1/2 study designed to test adagrasib, as monotherapy or in combinations, in patients with advanced solid tumors.

At ASCO GI 2022, Tanios Bekaii-Saab, MD, of the Mayo Cancer Center in Scottsdale, Arizona, reported preliminary data on adagrasib’s activity and safety in patients with advanced GI tumors, excluding colorectal cancer.

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KRAS and Adagrasib

KRAS is said to be one of the most highly mutated oncogenes in human cancer.2 Mutations in KRAS drive the growth and proliferation of multiple cancer types via the RAS/MAPK signaling cascade. The most common KRAS-G12 mutations are G12D (36%), G12C (14%), and G12V (23%).3

KRAS was once considered undruggable, but sotorasib has proven effective against KRASG12C–mutated tumors.2 In May 2021, sotorasib became the first KRAS-targeting therapy to be approved for use in the United States.4

Adagrasib inhibits KRASG12C selectively and irreversibly, locking malignant cells to guanosine diphosphate and making the cells inactive, Dr Bekaii-Saab noted. With a half-life of 24 hours, extensive tissue distribution, and dose-dependent pharmacokinetics, oral administration at a dose of 600 mg twice daily exposes malignant cells to adagrasib at blood levels that are above the threshold for KRAS inhibition.5

Small molecule inhibitors and degraders that target KRAS-G12 mutations could represent a significant therapeutic advance in malignancies like pancreatic ductal adenocarcinoma, for which there are few effective treatment options. Unfortunately, although KRAS mutations occur in approximately 90% of pancreatic cancers,6 only about 2% of these are G12C mutations, Dr Bekaii-Saab noted.

Adagrasib in GI Cancers

Dr Bekaii-Saab presented data from 1 cohort of the KRYSTAL-1 trial.1 The cohort included 30 patients with previously treated GI tumors — 12 with pancreatic adenocarcinoma, 8 with biliary tract cancer, 5 with appendiceal cancer, 2 with small bowel cancer, 2 with gastro-esophageal junction cancer, and 1 with esophageal cancer.

The median age of these patients was 65.5 years (range, 40-89 years), and 60% were men. The patients had a performance status of 0 (20%) or 1 (80%). They had received a median of 2 prior lines of therapy (range, 1-5), with 17% of patients having received at least 4 prior lines of systemic therapy.

The patients received adagrasib at 600 mg twice a day. The median follow-up was 6.3 months.

Among the 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 the 10 evaluable patients with pancreatic cancer, the ORR was 50%, and the DCR was 100%. The median duration of response was 6.97 months, and the median progression-free survival (PFS) was 6.6 months. At the data cutoff, treatment was ongoing in 50% of patients.

For the 17 patients with other GI cancers, the ORR was 35%, and the DCR was 100%. The median PFS and median duration of response were both 7.85 months. Treatment was ongoing in 65% of patients at the data cutoff.

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

Grade 3 AEs occurred in 27% of patients. The most common grade 3 AE was fatigue (10%). There were no grade 4 or 5 AEs, and no treatment-related AEs led to treatment discontinuation.

Implications

Research has shown that adagrasib is well-tolerated and produces responses in multiple tumor types.7,8 The current update shows encouraging clinical activity for adagrasib in pretreated patients with pancreatic ductal adenocarcinoma and other non-colorectal GI tumors.

Dr Bekaii-Saab noted that the phase 2 portion of the KRYSTAL-1 trial is ongoing, and there is an expanded access program for patients with previously treated, KRASG12C-mutated advanced solid tumors who cannot participate in the trial.

For patients who develop resistance to KRASG12C-directed therapy, information regarding potential mechanisms of resistance is expanding rapidly. Preclinical studies suggest that drug combinations could circumvent some of the most common resistance patterns.2

The prognostic significance and clinical presentation of KRASG12C-mutated tumors are controversial.9 Although there is much to be learned about how KRASG12C-targeted treatment can be deployed most effectively, the periodic updates of the KRYSTAL-1 trial suggest great potential benefits for patients with a broad range of clinically challenging tumors.

Disclosures: The KRYSTAL-1 trial is sponsored by Mirati Therapeutics Inc. Dr Bekaii-Saab declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.

References

  1. Bekaii-Saab TS, Spira AI, Yaeger R, et al. KRYSTAL-1: Updated activity and safety of adagrasib (MRTX849) in patients (pts) with unresectable or metastatic pancreatic cancer (PDAC) and other gastrointestinal (GI) tumors harboring a KRASG12C mutation. Presented at ASCO GI 2022; January 20-22, 2022. Abstract 519.
  2. Rosen N. Finally, effective inhibitors of mutant KRAS. N Engl J Med. 2021; 384:2447 2449. doi:10.1056/NEJMe2107884
  3. Lu S, Jang H, Nussinov R, Zhang J. The structural basis of oncogenic mutations G12, G13 and Q61 in small GTPase K-Ras4B. Sci Rep. 2016;6:21949. doi:10.1038/srep21949
  4. FDA approves first targeted therapy for lung cancer mutation previously considered resistant to drug therapy. News Release. US Food and Drug Administration. Published May 28, 2021. Accessed February 2, 2022.
  5. Hallin J, Engstrom LD, Hargis L, et al. The KRASG12C inhibitor MRTX849 provides insight toward therapeutic susceptibility of KRAS-mutant cancers in mouse models and patients. Cancer Discov. 2020;10(1):54-71. doi:10.1158/2159-8290.CD-19-1167 
  6. Nollman FI, Ruess DA. Targeting mutant KRAS in pancreatic cancer: Futile or promising? Biomedicines. 2020;8(8):281. doi:10.3390/biomedicines8080281
  7. Janne PA, Rybkin II, Spira A, et al. KRYSTAL-1: Updated safety and efficacy data with adagrasib (MRTX849) in NSCLC with KRASG12C mutation from a phase 1/2 study. Eur J Cancer. 2020;138(supp 2)S1-S2. doi:https://doi.org/10.1016/S0959-8049(20)31076-5
  8. Johnson ML, Ou SHI, Barve M, et al. KRYSTAL-1: Activity and safety of adagrasib (MRTX849) in patients with colorectal cancer (CRC) and other solid tumors harboring a KRAS G12C mutation. Eur J Cancer. 2020;138(supp 2)S1-S2. doi:https://doi.org/10.1016/S0959-8049(20)31077-7
  9. Lyss A. KRAS G12C mutations in metastatic colorectal cancer: Questions remain. Cancer Therapy Advisor. Published July 30, 2021. Accessed February 2, 2022.

Topics:

ASCO GI 2022 Gastrointestinal Cancer Pancreatic Cancer