First-in-Class KRAS-Degrader Promising in Pancreatic, Lung Cancers

Setidegrasib showed promising efficacy in patients with previously treated advanced KRAS G12D-mutated pancreatic ductal adenocarcinoma (PDAC) or non-small cell lung cancer (NSCLC), results from a phase I trial suggested.

Among 21 patients with metastatic PDAC who received 600 mg of the drug as second- or third-line treatment, five had an objective response, and median progression-free survival (PFS) and overall survival (OS) were 3 months and 10.3 months, respectively, reported Wungki Park, MD, of Memorial Sloan Kettering Cancer Center in New York City, and colleagues in the New England Journal of Medicine.

Among the 31 patients with PDAC who received 600-mg setidegrasib as second-line, third-line, or later-line treatment, an objective response was seen in six patients (19%).

While a number of therapies — such as sotorasib (Lumakras) and adagrasib (Krazati) — are approved for use against KRAS G12C mutations, including NSCLC, no targeted therapies directed against KRAS G12D have FDA approval. In the case of PDAC, the KRAS G12C variant is particularly rare, while KRAS G12D is the most common oncogenic driver, occurring in 40% of patients.

“Despite this, it has historically been a difficult target to treat and patients with advanced pancreatic cancer currently have no standard chemotherapy options after two prior lines of treatments in the metastatic setting,” Park told MedPage Today. “There is a clear unmet need for therapies that can more directly and effectively target this biology.”

Setidegrasib represents a different approach compared with other investigational drugs currently being evaluated, he added. “As a KRAS G12D-targeted protein degrader, it degrades and lowers the actual level of the KRAS protein itself rather than chemically inhibiting to stop the growth signaling. This is the first time we are seeing this novel strategy translate into clinical activity against this major oncogene.”

Park pointed out that the PDAC patients were heavily pretreated, with 14 of 21 patients having received the drug as third-line therapy in the metastatic setting.

“In that context, an objective response rate of approximately 24% and a median overall survival of about 10 months are very encouraging and compare favorably with what we typically expect from available standard therapies in this setting,” he said.

Setidegrasib in NSCLC

About 5% of patients with NSCLC harbor the KRAS G12D variant.

This study evaluated setidegrasib (formerly ASP3082) in 45 patients with advanced NSCLC who received the drug as second-line treatment or later. An objective response occurred in 36% of patients, with a median PFS of 8.3 months, and estimated 6- and 12-month OS rates of 77% and 59%.

Among the 32 patients who received setidegrasib as a second- or third-line treatment, the objective response rate was 38%, and median PFS was 11.2 months.

“In non-small cell lung cancer, the activity was also notable,” Park said. “While cross-trial comparisons should be made cautiously, these results suggest that targeting KRAS G12D with a degrader can lead to meaningful clinical responses in multiple tumor types.”

The trial involved a total of 203 patients (59 with NSCLC, 124 with PDAC, and 20 with other solid tumors) who were enrolled across 28 centers in five countries. The recommended phase II dose of 600-mg setidegrasib was administered intravenously once weekly, and was delivered to 76 patients (45 with NSCLC and 31 with PDAC).

The median age was 68 among patients with NSCLC (62% women, 70% white, 30% Asian) and 65 among patients with PDAC (42% women, 38% white, 57% Asian). The median number of previous lines of anticancer therapy was two in both groups.

Among the patients with NSCLC, 93% had previously received platinum-based chemotherapy plus an immune checkpoint inhibitor, while 84% of patients with PDAC had previously received gemcitabine plus paclitaxel or nab-paclitaxel (Abraxane), and 52% had previously received a modified FOLFIRINOX regimen (folinic acid, fluorouracil, irinotecan, and oxaliplatin).

Park said the treatment was well tolerated, with most adverse events limited to transient infusion-related reactions and mild nausea or vomiting.

All 76 patients who received setidegrasib at a dose of 600 mg experienced a treatment-emergent adverse event (TEAE) of any grade, with 42% experiencing a grade ≥3 adverse event. Treatment-related adverse events (TRAEs) of any grade occurred in 93% of patients, with grade ≥3 TRAEs reported in 9%. Infusion-related reactions (80%) and nausea (30%) were the most common TRAEs.

Serious TRAEs and TRAEs that led to dose reduction were observed in 5% each, while TEAEs leading to permanent treatment discontinuation occurred in 3% of patients. No TRAEs led to treatment discontinuation.

“This favorable tolerability is important because it provides an opportunity to explore combination strategies and move this approach earlier in treatment settings,” Park observed. “Overall, these findings represent an important step forward in novel targeting of KRAS G12D and provide a foundation for ongoing studies evaluating combination approaches and earlier-line therapy.”

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