Adagrasib delays progression of pretreated KRAS-mutant lung cancer
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Key takeaways:
- Significant median PFS improvement with adagrasib over docetaxel for pretreated NSCLC.
- Treatment-related adverse events led to discontinuation in nearly twice as many patients who received docetaxel.
CHICAGO — Individuals with KRAS-mutant lung cancer treated with adagrasib experienced significantly prolonged PFS compared with docetaxel, randomized study results presented at ASCO Annual Meeting showed.
The overall response rate with adagrasib demonstrated a significant improvement over docetaxel among adults with previously untreated KRASG12C-mutated locally advanced or metastatic non-small cell lung cancer, according to researchers.
“These results reinforce [adagrasib] as an efficacious treatment option for patients with KRASG12C-mutated [non-small cell lung cancer] after disease progression on prior chemotherapy and immunotherapy,” Tony S. K. Mok, BBS, chairman of the department of clinical oncology at The Chinese University of Hong Kong, said during a presentation. “[Adagrasib] showed intracranial efficacy among patients with brain metastases at baseline, with a response rate that was more than double that observed with [docetaxel].”
Background and methodology
Adagrasib (Krazati, Bristol Myers Squibb) is a covalent KRASG12C inhibitor that demonstrated deep and durable responses with promising PFS and OS among patients with previously treated KRASG12C-mutated non-small cell lung cancer in the phase 1/phase 2 KRYSTAL-1 trial.
Researchers conducted the open-label phase 3 KRYSTAL-12 trial to assess the efficacy and safety of adagrasib, compared with docetaxel, among patients with KRASG12C-mutated locally advanced or metastatic NSCLC who had previously received platinum-based chemotherapy, either concurrently or sequentially with anti-PD-(L)1 therapy.
Researchers randomly assigned patients in a 2:1 ratio to receive either 600 mg oral adagrasib twice daily (n = 301) or 75 mg/m2 intravenous docetaxel once every 3 weeks (n = 152), with patients in the docetaxel arm able to crossover upon disease progression.
Researchers noted no requirement for a washout period between prior anti-PD-(L)1 therapy and study treatment.
PFS as assessed per blinded independent central review according to RECIST v1.1 served as the study’s primary endpoint, with secondary endpoints including overall response rate, duration of response, OS, 1-year OS rate and safety.
Researchers noted a median follow-up of 9.4 months at data cutoff.
Results
Researchers observed a median PFS of 5.49 months among patients in the adagrasib arm and 3.84 months among patients in the docetaxel arm (HR = 0.58; 95% CI, 0.45-0.76) and an overall response rate of 31.9% (95% CI, 26.7-37.5) among patients in the adagrasib arm and 9.2% (95% CI, 5.1-15) among patients in the docetaxel arm (OR = 4.68; 95% CI, 2.56-8.56).
Researchers also noted a median duration of response benefit among patients in the adagrasib arm (8.31 months; 95% CI, 6.05-10.35) compared with the docetaxel arm (5.36 months; 95% CI, 2.86-8.54).
Treatment-related adverse events occurred in 94% of patients treated with adagrasib and 86.4% of patients treated with docetaxel, with grade 4 or grade 5 treatment-related adverse events occurring in 47% of patients in the adagrasib arm and 45.7% of patients in the docetaxel arm.
Treatment-related adverse events led to the discontinuation of 7.7% of patients in the adagrasib arm and 14.3% in the docetaxel arm.
Next steps
Researchers noted that the administration of adagrasib over docetaxel both improved survival outcomes while showing intracranial efficacy among patients with brain metastases at baseline, with a response rate that doubled that observed docetaxel.
“A phase 3 trial comparing first-line [adagrasib] plus pembrolizumab vs. pembrolizumab alone is currently enrolling patients with advanced KRASG12C-mutated NSCLC and PD-L1 of at least 50%,” Mok added.
Perspective
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Robert Chun-Hao Hsu, MD
The KRYSTAL-12 study is a phase 3 study evaluating the use of adagrasib compared with docetaxel in KRAS G12C-mutated previously treated NSCLC.This study is similar to the CodeBreaK 200 study, in which the FDA's Oncologic Drugs Advisory Committee felt that the PFS data could not be relied on because of the disproportionate dropout rate in the docetaxel arm, that the difference in PFS was small between the sotorasib and docetaxel arms, and there was no difference in OS.
The KRYSTAL-12 trial demonstrated statistically significant PFS improvement with adagrasib (5.6 months vs. 3.8 months). Further, adagrasib was relatively well tolerated.
This study helps confirm the findings from CodeBreaK 200, yet the modest difference in median PFS remains. This data alone may not be convincing for some providers and patients to afford the use of KRAS G12C inhibitor. There probably should be conversation between oncologists and patients about possible financial toxicity versus taking a daily pill. Further strategies, though, ultimately maybe more appealing moving forward, including the implementation of anti-PD-1 therapy as shown in the combination of olomorasib and pembrolizumab, or the use of an anti-EGFR antibody such as cetuximab, as seen in the KROCUS study with fulzerasib and cetuximab.
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