Novel KRAS Drug Shows ‘Excellent’ Efficacy in Tough-to-Treat Lung Cancer

SAN DIEGO — Investigational zoldonrasib was well tolerated and showed encouraging clinical activity in previously treated KRAS G12D-mutated non-small cell lung cancer (NSCLC), according to a phase I study.

Among patients previously treated with an immune checkpoint inhibitor and platinum-based chemotherapy (but not docetaxel), the objective response rate was 52%, with a disease control rate of 93%, reported Jonathan Riess, MD, of the University of California Davis Comprehensive Cancer Center, at the American Association for Cancer Research annual meeting.

Median progression-free survival (PFS) was 11.1 months, with a 12-month PFS rate of 48%. Median overall survival (OS) was not reached, with a 12-month OS rate of 73%.

Treatment-related adverse events (TRAEs) at the recommended phase II dose of 1,200 mg were mostly mild grade 1 gastrointestinal events. Grade 3 TRAEs were reported in 13% of patients and included diarrhea and anemia, and no grade ≥4 TRAEs were observed.

Dose interruptions occurred in 15% of patients, dose reductions occurred in 3%, and dose discontinuations occurred in 5%, “highlighting the tolerability of this particular drug,” said invited discussant Daniel S.W. Tan, MBBS, PhD, of the University of Singapore, adding that zoldonrasib also demonstrated “excellent clinical efficacy.”

“Zoldonrasib is ideal for further evaluation of combinations specific to KRAS G12D in non-small cell lung cancer, but also other tumor types,” Tan said.

An Unmet Need

Two KRAS inhibitors — sotorasib (Lumakras) and adagrasib (Krazati) — have been approved by the FDA for the treatment of KRAS G12C-mutated NSCLC. However, no RAS-targeted therapies are currently available for patients whose tumors harbor KRAS G12D mutations, which are found in about 4% to 5% of patients with NSCLC (and are also present in a substantial proportion of patients with pancreatic cancer and other gastrointestinal cancers).

KRAS G12D mutations are often associated with never or light smokers, low tumor mutational burden, and low PD-L1 expression compared with KRAS-mutant tumors that are not G12D.

“Treatment options for patients with KRAS G12D non-small cell lung cancer that has progressed after platinum-based chemotherapy and immune checkpoint inhibitors are limited,” Riess said. The standard of care in this setting is docetaxel, often with ramucirumab (Cyramza), which Riess pointed out can be toxic. Furthermore, patients treated with this combination have low response rates, a median PFS of 3 to 4.5 months, and limited overall survival.

“This illustrates a large unmet need for targeted therapies in KRAS G12D-mutated non-small cell lung cancer,” Riess noted.

Mutations lock KRAS in its active state, which is bound to the GTP molecule, resulting in uncontrolled oncogenic signaling, he explained. Zoldonrasib — an oral, G12D-selective covalent inhibitor — targets the active, GTP-bound state of RAS G12D.

In initial findings from this ongoing phase I study, presented last year at the AACR annual meeting, the objective response and disease control rates were 61% and 89% among 18 patients with NSCLC who received zoldonrasib 1,200 mg daily.

These results led the FDA to grant a breakthrough therapy designation to the drug for the treatment of adults with KRAS G12D-mutated locally advanced or metastatic NSCLC who had been previously treated with anti-PD-1/PD-L1 therapy and platinum-based chemotherapy.

In the current analysis, 40 patients treated at the recommended phase II dose level of 1,200 mg daily were included in the safety cohort. These patients had a median age of 66 years, the majority were women, and 45% were never smokers. They had received a median of two prior lines of therapy.

The efficacy population included 27 patients who had received an immune checkpoint inhibitor and platinum-based chemotherapy, but no docetaxel, which Riess said gave the investigators “an appropriate comparison between that second-line patient population that has progressed on [chemotherapy and immunotherapy], but has not received standard-of-care docetaxel.” Median age was 65 years, 63% were women, and 56% were never smokers.

Median time to response was 1.4 months, and median duration of response was not reached.

Noting that about half of the patients in the study were never smokers, Tan said that an important question going forward is whether there is any difference in response or outcomes in patients who are never smokers and those with past or current tobacco use.

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