KRAS Lung Cancer Patient Communication Group(Click)

Lung Cancer | Precision Medicine, New Breakthrough in KRAS Mutation Targeted Therapy

NEJM | Lung Cancer, Amgen's KRAS Inhibitor Phase II Study Results Promising, ORR Reaches 37.1%

Due to the Phase 3 EXCLAIM-2 study not meeting its primary endpoint, on October 2, Takeda announced plans to initiate a voluntary withdrawal of Mobocertinib worldwide. For more details:Lung Cancer EGFR 20ins Mutation: Mobocertinib (TAK-788) to Be Withdrawn from the Market. SubsequentlyAfter Takeda's Mobocertinib, October 5Day,FDA ODAC (Oncologic Drugs Advisory Committee) with2 votes in favor, 10 votes againstThe result suggests that Amgen's KRAS inhibitor Lumakras (sotorasib) IIIThe progression-free survival (PFS) results of the CodeBreaK 200 study cannot be reliably interpreted. However, at the end of the meeting, the FDA indicated that it would not immediately withdraw drugs that failed in confirmatory studies but would make a decision based on the overall outcomes and the current treatment landscape.

In May 2021, sotorasib received FDA accelerated approval based on the Phase I/II CodeBreak100 study for patients with locally advanced or metastatic NSCLC harboring the KRAS G12C mutation who had previously received at least one systemic therapy. As part of the post-marketing requirement to verify the clinical benefit of sotorasib, Amgen initiated the Phase III CodeBreaK 200 study.Next,We reviewedsotorasibThe results of the two studies.

From August 13, 2019, to February 5, 2020, a total of 126 previously treated patients with KRAS p.G12C-mutant NSCLC were enrolled and received at least one dose.sotorasibTreatment. Two patients had no measurable lesions at baseline and thus could not be evaluated for response.

Baseline Characteristics of Patients

2. Among the 46 patients who achieved objective response, the median time to response was 1.4 months (1.2-10.1), and the median duration of response was 11.1 months (95% CI, 6.9-not evaluable). Of the responding patients, 33 (71.7%)Relief was observed at the time of the first tumor assessment (approximately Week 6) in China.

3. All 126 patients,OS was 12.5 months (95% CI, 10.0-not evaluable)(Figure 1D)。

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Phase III Efficacy

CodeBreaK 200 Study:It is a randomized, controlled, multicenter, open-label Phase III study aimed at evaluating the efficacy and safety of Sotorasib versus docetaxel in patients with NSCLC carrying the KRAS G12C mutation who have previously received platinum-based chemotherapy and immune checkpoint inhibitor treatment. The study enrolled 345 patients, with progression-free survival (PFS) as the primary endpoint and key secondary endpoints including overall survival, objective response rate, and patient-reported outcomes.

Study Design

Baseline Characteristics

Research Results:The study met its primary endpoint, showing a significant improvement in progression-free survival (PFS) with sotorasib treatment compared to docetaxel after a median follow-up of 17.7 months.The median PFS was 5.6 vs 4.5 months (HR 0.66; 95% CI: 0.51-0.86; p=0.002); The 1-year PFS rates were 24.8% vs 10.1%, with consistent PFS benefits across all subgroups.

PFS

Subgroup Analysis

The ORR assessed by BICR was 28.1% (sotorasib, not impressive) and 13.2% (docetaxel), respectively.; Tumor shrinkage was observed in 80.4% and 62.8% of patients in the two groups, respectively; the disease control rates (DCR) were 82.5% and 60.3%, respectively.

ORR

DoR

Overall survival (OS) showed no difference, with median OS of 10.6 months and 11.3 months in the sotorasib and chemotherapy groups, respectively (HR=1.01; p=0.53). The reason was that the study protocol allowed crossover, and subsequent treatments impacted OS.

Safety:Sotorasib is superior to docetaxel, with the incidence of treatment-related adverse events (TRAE) of grade ≥3 being 33.1% and 40.4%, respectively, and the incidence of serious TRAE being 10.7% and 22.5%, respectively.

OS

Safety

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Although CodeBreaK 200 reached its primary endpoint, the FDA noted that the median PFS benefit in the sotorasib group (~5 weeks) was less than the interval between imaging follow-ups (6 weeks). Considering the inherent error in PFS assessment at the end of the imaging follow-up interval—given that progression could actually occur at any time point within the interval—the FDA based its evaluation on interval censoring.Interval censoring: For patients assessed as having disease progression during the follow-up interval, it is assumed that the event may occur at any time within the interval.Further analysis showed that the mPFS was 4.47 months in the sotorasib group and 4.3 months in the docetaxel group. Although a statistically significant difference was still observed, the difference between the two groups was only about 5 days. Additionally, no statistically significant difference in OS was found between the two groups, raising concerns from the FDA regarding the actual clinical benefit of the sotorasib group.