Second-line therapy with the KRAS inhibitor adagrasib modestly improved progression-free survival and objective response rate over docetaxel in previously treated patients with advanced KRAS G12C–mutated non–small cell lung cancer (NSCLC), according to the primary analysis of the phase III KRYSTAL-12 trial, presented at the 2024 ASCO Annual Meeting.1 Results also showed more than a doubling of intracranial response among the adagrasib-treated patients compared with those given the standard-of-care docetaxel.
Median progression-free survival was 5.5 months with adagrasib vs 3.8 months with docetaxel, reducing the risk of disease progression by 42% (P < .0001). Objective response rate was 32% vs 9%, respectively (P < .001). Further, intracranial objective response rates were 24% and 11%, respectively.
Tony S.K. Mok, MD, FRCPC, FASCO
“Overall, KRYSTAL-12 confirmed the efficacy of adagrasib as second-line therapy for patients with KRAS G12C mutations, with evidence of higher tumor response rates and longer progression-free survival over current standard care,” stated lead author Tony S.K. Mok, MD, FRCPC, FASCO, of the Chinese University of Hong Kong. KRYSTAL-12 is ongoing and will assess overall survival in the future.
Background
In the past, although KRAS was an identified treatment target for NSCLC, no investigative treatments were successful until the KRAS inhibitor sotorasib, which received accelerated approval from the U.S. Food and Drug Administration in 2021 for patients with previously treated KRAS G12C–mutated NSCLC.2 However, the supplemental new drug application for sotorasib was rejected, based on limitations of the phase III CodeBreaK 200 trial, and a new confirmatory study is being conducted to support full FDA approval. Results are expected in 2028.
Adagrasib has received accelerated approval based on the phase I/II KRYSTAL-1 trial in patients with previously treated KRAS G12C–mutated NSCLC. KRYSTAL-12 is a confirmatory phase III trial in this population. On the heels of the results of KRYSTAL-12, the phase III KRYSTAL-7 trial is designed to compare first-line therapy with adagrasib plus the PD-1 inhibitor pembrolizumab vs pembrolizumab monotherapy; it is currently enrolling patients with advanced KRAS G12C–mutated NSCLC and PD-L1 total positive score of 50 or higher.
Study Details
KRYSTAL-12 included 453 patients with locally advanced or metastatic KRAS G12C–mutated NSCLC previously treated with platinum-based chemotherapy and anti–PD-L1 or anti–PD-1 therapy. Patients were randomly assigned 2:1 to receive adagrasib twice daily or intravenous docetaxel at 75 mg/m2 every 3 weeks. Crossover was allowed.
Baseline characteristics were well balanced between the two treatment arms. Median patient age was about 64, most patients were male, three-quarters of the population were not from the Asia Pacific region, 68% had an Eastern Cooperative Oncology Group performance score of 1, about 95% had metastatic disease, about 95% had adenocarcinoma, about three-quarters were former smokers, and 73% received concurrent chemoimmunotherapy.
Assigned treatment was delivered to 99% of the adagrasib group vs 92% of the docetaxel group. Among those given docetaxel, 44 (29%) crossed over to adagrasib at disease progression.
Key Results
At a median follow-up of 9.4 months, median progression-free survival was 5.5 months with adagrasib vs 3.8 months with docetaxel, reducing the risk of disease progression by 42% (P < .0001). The difference between the two arms in progression-free survival was statistically significant and clinically meaningful, Dr. Mok said. The 6-month progression-free survival rate was 45% vs 30%, respectively. Adagrasib remained superior to docetaxel across all key subgroups for progression-free survival.
Overall response rate was 32% vs 9% respectively (P < .0001). The disease control rate was 78% for adagrasib vs 50% for docetaxel. Median duration of response was 8.3 months vs 5.4 months, respectively. Intracranial overall response rate was doubled with adagrasib (24% vs 11%). Intracranial disease control rates were 82% and 56%, respectively. Also, adagrasib prolonged the time to deterioration vs docetaxel (3 months vs 1.5 months).
Toxicity
Treatment discontinuation was reported in 62% of the adagrasib arm and 81% of the docetaxel arm. They were the result of disease progression, adverse events, or “other” causes. Treatment-related adverse events led to treatment discontinuation in 8% and 14%, respectively. Dose reductions were reported in 48% and 24%, respectively; and dose interruption occurred in 59% and 19%, respectively.
The most frequently reported treatment-related adverse events with adagrasib and docetaxel included gastrointestinal toxicity (diarrhea, nausea, and vomiting), increased liver enzymes, decreased appetite, increased serum creatinine, anemia, asthenia, fatigue, decreased neutrophil count, and alopecia.
Expert Point of View
Invited discussant of the study on the use of adagrasib vs docetaxel in patients with previously treated, advanced or metastatic non–small cell lung cancer (NSCLC), Adrian Sacher, MD, of the Princess Margaret Cancer Centre, Toronto, shared these comments: “KRYSTAL-12 demonstrated a modest improvement in overall response rate and progression-free survival with adagrasib compared to docetaxel and supports the use of adagrasib in the later-line setting, where treatment options for KRAS G12C–mutant metastatic NSCLC are limited.” He also noted the magnitude of benefit with adagrasib over docetaxel is similar to that of sotorasib.
“The optimal KRAS inhibitor monotherapy in the second- and third-line settings needs to be defined. Newer, more potent KRAS G12C inhibitors, such as divarasib, olomorasib, opnurasib, and glecirasib, could potentially provide superior response rates and durable responses,” he continued. “The optimal KRAS backbone in combination may differ from the optimal KRAS monotherapy. All eyes are now on ongoing studies of KRAS G12C inhibitor combination strategies, which include PD-L1/PD-1 antibodies, EGFR inhibitors, and chemotherapy. These combinations may soon displace KRAS G12C inhibitor monotherapy approaches,” Dr. Sacher told listeners.
DISCLOSURE: Dr. Mok has stock and other ownership interests in Aurora Tele-Oncology Platform, Hutchison China Meditech, and Sanomics; has received honoraria from ACEA Pharmaceutical Research, Alpha Biopharma, Amgen, Amoy Diagnostics, AstraZeneca, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo/UCB Japan, Fishawack Facilitate, InMed, Lilly, Merck Sharp & Dohme, Novartis, Origimed, Pfizer, Prime Oncology, Roche, Sanofi Aventis GmbH, Taiho Pharmaceutical, and Takeda; has served as a consultant or advisor to AbbVie, ACEA Pharmaceutical Research, Alpha Biopharma, Amgen, Amoy Diagnostics, AstraZeneca, BeiGene, Berry Oncology, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, CStone Pharmaceuticals, Curio Science, Daiichi Sankyo/UCB Japan, Eisai, Fishawack Facilitate, Gritstone Bio, Guardant Health, Hengrui Therapeutic, Ignyta, Incyte, Inivata, IQvia, Lilly, Loxo, Lunit, Merck Serono, Merck Sharp & Dohme, Mirati Therapeutics, Novartis, Pfizer, Puma Biotechnology, Roche, SFJ Pharmaceuticals Group, Takeda, Vertex, and Yuhan; and has received institutional research funding from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, G1 Therapeutics, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer, Roche, SFJ Pharmaceuticals Group, Takeda, and Xcovery. Dr. Sacher has received institutional research funding from Amgen, AstraZeneca, Bristol Myers Squib, Bridgebio, CRISPR Therapeutics, Genentech/Roche, GlaxoSmithKline, Hotspot Therapeutics, Iovance Biotherapeutics, Lilly Loxo, Pfizer, and Spectrum Pharmaceuticals; and has received reimbursement for travel expenses from Amgen and Merck.
REFERENCES
1. Mok TSK, Yao W, Duruisseaux M, et al: KRYSTAL-12: Phase 3 study of adagrasib versus docetaxel in patients with previously treated, advanced/metastatic non-small cell lung cancer harboring a KRAS G12C mutation. 2024 ASCO Annual Meeting. Abstract LBA8509. Presented June 1, 2024.
2. Skoulidis F, Li BT, Dy GK, et al: Sotorasib for lung cancers with KRAS p.G12C mutation. N Engl J Med 384:2371-2381, 2021.
