KRAS G12C inhibitors show promise in metastatic colorectal and pancreatic cancers

The KRAS^G12C inhibitors, adagrasib and sotorasib, have shown promising antitumour activity in patients with heavily pretreated metastatic colorectal cancer (mCRC) and metastatic pancreatic cancer, respectively.

Adagrasib in KRAS^G12C-mutated mCRC

In the open-label, phase I–II, nonrandomized KRYSTAL-1 trial, 76 patients with heavily pretreated, KRAS^G12C-mutated mCRC received adagrasib (600 mg orally BID) as monotherapy (n=43; median age, 59 years; female, 50 percent) or in combination with cetuximab (intravenously, 400 mg/m² initial loading dose followed by 250 mg/m² QW, or 500 mg/m² Q2W) (n=32; median age, 60 years; female, 53 percent). At baseline, the patients had received a median of three prior lines of therapy. [N Engl J Med 2023;388:44-54]

The primary endpoint of objective response (ie, complete or partial response) was achieved in 19 percent of patients in the adagrasib monotherapy group and 46 percent of those in the adagrasib/cetuximab combination therapy group, after a median follow-up of 20.1 months and 17.5 months, respectively. Median duration of response (DoR) was 4.3 months and 7.6 months, respectively.

Median progression-free survival (PFS) was 5.6 months in the adagrasib monotherapy group and 6.9 months in the adagrasib/cetuximab combination therapy group.

Grade 3/4 treatment-related adverse events (TRAEs) were reported in 34 percent of patients in the monotherapy group and 16 percent of those in the combination therapy group. No grade 5 AEs were observed.

In the monotherapy group, the most common grade 3/4 TRAEs were anaemia (9 percent) and diarrhoea (7 percent). TRAEs led to dose reduction in 39 percent of patients, without resulting in treatment discontinuation.

In the combination therapy group, the most common grade 3/4 TRAEs were diarrhoea, dermatitis acneiform, stomatitis, and infusion-related reactions (3 percent each). TRAEs led to dose reduction of adagrasib in 31 percent of patients and cetuximab in 3 percent of patients, and to cetuximab discontinuation in 16 percent of patients. None of the patients required adagrasib discontinuation due to TRAEs.

“Adagrasib showed promising clinical activity in heavily pretreated patients with KRAS^G12C-mutated mCRC. Its biologic activity appeared to be even greater in combination with cetuximab and supports ongoing clinical investigation,” the investigators concluded. “Both treatments produced reversible toxic effects in the majority of patients and resulted in no new safety concerns.”

Sotorasib in KRAS^p.G12C-mutated metastatic pancreatic cancer

In the single-group, phase I–II CodeBreaK 100 trial, sotorasib’s safety and efficacy were evaluated in 38 patients with KRAS^p.G12C-mutated metastatic pancreatic cancer who had received a median of two prior lines of chemotherapy. The primary objective of phase I was to evaluate safety and identify the recommended dose for phase II. In phase II, patients received sotorasib 960 mg QD, and the primary endpoint was centrally confirmed objective response (ie, complete or partial response). Efficacy endpoints were evaluated in the pooled population from both phases, as was safety. [N Engl J Med 2023;388:33-43]

In the pooled population, the centrally confirmed objective response rate was 21 percent, with a median DoR of 5.7 months. Median PFS was 4.0 months, while median overall survival was 6.9 months.

Grade 3 TRAEs were reported in 16 percent of patients, the most common of which were diarrhoea and fatigue (5 percent each). No grade 4/5 TRAEs were reported. TRAEs led to dose reduction or interruption in 13 percent of patients, without resulting in treatment discontinuation.

“Pancreatic cancer is one of the most difficult cancers to diagnose and treat,” the investigators noted. “The promising clinical activity of sotorasib shown in this trial provides evidence that targeting KRAS is a viable strategy for treatment of advanced pancreatic cancer.”