This is an important progress for patients with KRASG12C mutation. Median PFS of 11 months is very encouraging for a previously “undruggable” molecular signature.
Adagrasib (MRTX849) is an oral, highly selective, small-molecule, covalent inhibitor of KRASG12C. We report results from a phase I/IB study of adagrasib in non–small-cell lung cancer, colorectal cancer, and other solid tumors harboring the KRASG12C mutation.
Patients with advanced KRASG12C-mutant solid tumors were treated with adagrasib 150 mg orally once daily, 300 mg once daily, 600 mg once daily, 1,200 mg once daily, or 600 mg orally twice a day using an accelerated titration design, which transitioned to a modified toxicity probability interval design when a predefined degree of toxicity was observed or target adagrasib exposure was achieved. Safety, pharmacokinetics, and clinical activity were evaluated.
Twenty-five patients were enrolled and received at least one dose of adagrasib. The recommended phase II dose (RP2D) was 600 mg twice a day on the basis of safety, tolerability, and observed pharmacokinetics properties. No maximum tolerated dose was formally defined. After a median follow-up of 19.6 months, eight of 15 patients (53.3%; 95% CI, 26.6 to 78.7) with RECIST-evaluable KRASG12C-mutant non–small-cell lung cancer treated at 600 mg twice a day achieved a confirmed partial response. The median duration of response was 16.4 months (95% CI, 3.1 to not estimable). The median progression-free survival was 11.1 months (95% CI, 2.6 to not estimable). One of two patients with KRASG12C-mutant colorectal cancer treated at 600 mg twice a day achieved a partial response (duration of response, 4.2 months). At the RP2D, the most common treatment-related adverse events (any grade) were nausea (80.0%), diarrhea (70.0%), vomiting (50.0%), and fatigue (45.0%). The most common grade 3-4 treatment-related adverse event was fatigue (15.0%).
Adagrasib 600 mg twice a day was well tolerated and exhibited antitumor activity in patients with advanced solid tumors harboring the KRASG12C mutation.
This PLK1-inhibitor seems extremely promising. This phase II trial studied pre-treated KRAS-mut patients with FOLFIRI + bev + study drug and the response rates and PFS were quite remarkable. Given the compelling results, they went from this study to a phase III 1L study.
Interesting study where intermittent FOLFIRI + pan was seemingly just as effective as continuous therapy. The ongoing Phase III IMPROVE-2 is the confirmatory trial and if positive could change standard practice. Of note, intermittent meant eight (8) cycles followed by a holiday until progression when it was reinitiated.
Patients were treated with thoracic and extrathoracic radiation to oligometastatic sites and it seems to help with improving survival, something to consider especially with SBRT now. Do our radiation oncologists have additional input?
Improved progression-free survival (PFS), now we have osimertinib and ramucirumab, amivantamab and Lazertinib (PFS 24.8 vs 23 months but NOT head to head).
Combination beat monotherapy is another option for MSI patients. Is combo better then pembro?
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