Adagrasib Demonstrates Promising Activity in KRAS G12C–Mutated Solid Tumors

Treatment with adagrasib (Krazati) monotherapy led to clinically meaningful activity and a manageable safety profile in patients with KRAS G12C–mutated solid tumors, according to updated data from the phase 2 KRYSTAL-1 study (NCT03785249) presented at the April 2023 ASCO Plenary Session.

Patients with solid tumors, excluding those with colorectal cancer (CRC) and non–small cell lung cancer (NSCLC; n = 57) who received the covalent KRAS inhibitor in the phase 1/2 study experienced an objective response rate (ORR) of 35.1% per blinded independent central review (BICR). All responses were partial responses. At the data cutoff of October 1, 2022, with a median follow-up 16.8 months, the median progression-free survival (PFS) was 7.4 months (95% CI, 5.3-8.6). the 6- and 12-month PFS rates were 56.5% and 17.7%, respectively. The median overall survival (OS) was 14.0 months (95% CI, 8.5-18.6) and the 6- and 12-month OS rates were 84.0% and 53.5%, respectively.¹

With a median duration of treatment of 5.3 months, the median time to response was 1.4 months and 8.8% of patients had progressive disease. The disease control rate (DCR) was 86.0% with 50.9% of patients experiencing stable disease.

The study authors noted that the “clinical activity of adagrasib in patients with [pancreatic ductal adenocarcinoma] PDAC and [biliary tract cancer] BTC is noteworthy, as chemotherapy has limited clinical activity in these patient populations in the second-line setting.”

Patients with PDAC (n = 21) experienced a confirmed ORR of 33.3% and a DCR of 81.0%, median PFS of 5.4 months (95% CI, 3.9-8.2), and a median OS of 8.0 months (95% CI, 5.2-11.8). The 6-month PFS rate for patients with PDAC was 49.3%. The 6- and 12-month OS rates in this population were 69.7% and 14.0%, respectively.

Comparatively, patients with BTC (n = 12) had a confirmed ORR of 41.7% and a 91.7% DCR. The median PFS was 8.6 months (95% CI, 2.7-11.3), with 6- and 12-month PFS rates of 58.3% and 14.6%, respectively. The median OS was 15.1 months (95% CI, 8.6-not estimable) and the 6-month OS rate was 100% and the 12-month OS rate was 87.5%.

No patients with appendiceal cancer (n = 7) experienced a response; however, these patients had a DCR of 85.7%. Two patients with small bowel cancer had disease control, with 1 patient achieving a partial response. Among patients with gastroesophageal junction (GEJ)/esophageal cancer (n = 3), 1 patient had an ORR. The DCR in this population was 66.7%.

Seven patients had gynecologic tumors and the ORR and DCR were 57.1% and 85.7%, respectively. The 4 responses were observed among 2 patients each with ovarian (n = 4) and endometrial cancer (n = 3). The DCR was 75% for patients with ovarian cancer and 100% for patients with endometrial cancer.

Finally, among a cohort that combined patients with unknown primary (n = 4) or breast cancer (n = 1), the ORR was 40% and the DCR was 100%. The sole patient with breast cancer achieved a partial response in addition to 1 patient with unknown primary tumor.

Adagrasib Is Well Tolerated

Treatment-related adverse events (TRAEs) were evaluable in 63 patients. The with the most common any-grade events included nausea (49.2%), diarrhea (47.6%), fatigue (41.3%), vomiting (39.7%), and blood creatine increase (15.9%). Most TRAEs were grade 1 or 2, with 1 patient experiencing grade 4 febrile neutropenia.

Adagrasib was given orally twice daily at 600 mg to patients and TRAEs led to dose reduction in 39.7% of patients as well as dose interruptions in 44.4%; however, no events led to treatment discontinuation. Grade 3 events included fatigue (6.3%), electrocardiogram QT prolongation (6.3%), aspartate transaminase increase (3.2%), nausea (1.6%), diarrhea (1.6%), vomiting (1.6%), and anemia (1.6%).

Fitting Adagrasib Into the Treatment Paradigm

The study authors noted that adagrasib has a long half-life of 23 hours, dose-dependent pharmacokinetics, and central nervous system penetration, leading to its selection for this trial.

“KRAS G12C–targeted agents may represent a novel, tumor agnostic treatment option for patients with solid tumors harboring a KRAS G12C mutation,” they wrote.

The KRAS G12C variant has prevalence in several solid tumors and serve as oncogenic drivers in approximately 14% in NSCLC, 3% to 4% in CRC, 3% to 4% in appendiceal cancer, 0.4% in ovarian cancer, 1% to 3% in PDAC, 1% to 3% in small bowel cancer, 1% in biliary tract cancers, and 1.5% in endometrial cancers.¹

On December 12, 2022, adagrasib was approved for the treatment of adult patients with KRAS G12C–mutated locally advanced or metastatic NSCLC who received at least 1 prior systemic therapy based on data from the KRYSTAL-1.²

Additionally, data from the CRC cohort of KRYSTAL-1 supported the breakthrough therapy designation of adagrasib plus cetuximab (Erbitux) in patients with KRAS G12C–mutated, advanced CRC whose cancer has progressed following prior treatment with chemotherapy and an anti-VEGF therapy.³

A Closer Look at Patient Characteristics

Tumor types in the study included PDAC (21%), BTC (12%), appendiceal (10%), ovarian (5%), unknown primary (4%), GEJ/esophageal (4%), endometrial (3%), small bowel (3%), breast (1%) and glioblastoma (1%).

The median age of patients was 65 years (range, 21-89), 51.6% were women, 75.0% were White, 9.4% were Black, 4.7% were Asian, and 10.9% were a different ethnicity. ECOG performance scores were 0 (37.5%) and 1 (60.9%), and patients received a median of 2 prior lines of therapy (range, 0-7) with most receiving 2 prior lines (35.9%). To be enrolled in the trial, patients had to have no other available treatment options with curative intent and unresectable or metastatic disease, excluding NSCLC and CRC. Six participants were excluded from the efficacy analysis as they did not have measurable disease at baseline per BICR.

References

1. Pant S, Yaeger R, Spira AI, et al. KRYSTAL-1: activity and safety of adagrasib (MRTX849) in patients with advanced solid tumors harboring a KRASG12C mutation. J Clin Oncol. 2023;41(suppl 36):425082. doi:10.1200/JCO.2023.41.36_suppl.425082
2. FDA grants accelerated approval to adagrasib for KRAS G12C-mutated NSCLC. FDA. December 12, 2022. Accessed April 24, 2023. https://bit.ly/3WdCKPs
3. Mirati announces adagrasib (Krazati) receives breakthrough therapy designation from FDA for Patients with advanced, KRAS-mutated colorectal cancer and NEJM publishes phase 1b/2 data from adagrasib with or without cetuximab in colorectal cancer. News release. Mirati Therapeutics, Inc. December 21, 2022. Accessed May 1, 2023. bit.ly/40RHXyA