KRYSTAL-12 boosts adagrasib as 2L Tx alternative for KRASG12C-mutated NSCLC
28 Jun 2024
byAudrey Abella
Findings from the phase III KRYSTAL-12 trial underpin the treatment potential of adagrasib for previously treated metastatic non-small cell lung cancer (NSCLC) harbouring a KRASG12C mutation.
“KRYSTAL-12 confirmed the efficacy of adagrasib as second-line therapy for patients with KRASG12C mutations, with evidence of higher tumour response rates and longer progression-free survival [PFS] over current standard of care,” said Dr Tony Mok from the Chinese University of Hong Kong, Hong Kong SAR, China, at ASCO 2024.
After a median follow-up of 7.2 months, PFS by BICR* was significantly improved with adagrasib vs docetaxel (median, 5.5 vs 3.8 months; hazard ratio [HR], 0.58; p<0.0001). PFS per investigator assessment showed a similar pattern (median, 5.4 vs 2.9 months; HR, 0.57). [ASCO 2024, abstract LBA8509]
“The two treatment curves separated early on and stayed separated,” said Mok, adding that the PFS benefit was consistent across key subgroups.
Objective response rate by BICR was also markedly higher with adagrasib vs docetaxel (32 vs 9 percent; odds ratio, 4.68; p<0.0001), as was median duration of response (8.3 vs 5.4 months). Sixty-four percent of adagrasib recipients were able to sustain their responses for ≥6 months, as opposed to only 39 percent in the docetaxel arm.
Of those with CNS** metastases at baseline, a quarter of adagrasib recipients had intracranial responses. With docetaxel, only 11 percent were able to achieve this outcome.
Treatment-related adverse events (TRAEs) were more frequent with adagrasib vs docetaxel (94 vs 86 percent). About 50 percent of these events were grade ≥3.
The rate of TRAEs leading to discontinuation was twice as high with docetaxel vs adagrasib (14 vs 8 percent), but the opposite was true for TRAEs that led to dose reduction (24 vs 48 percent) and interruption (19 vs 59 percent).
Gastrointestinal toxicities were higher with adagrasib vs docetaxel, but most events were grade 1/2. The most common were diarrhoea (48 vs 26 percent), vomiting (33 vs 6 percent), and nausea (31 vs 19 percent). Adagrasib was also tied to higher rates of AST*** (24 vs 0 percent) and ALT*** elevations (22 vs 3 percent).
Of note was the incidence of blood creatinine increase with adagrasib, which was higher than that seen with docetaxel (20 vs 1 percent). According to Mok, “[this is] one toxicity we cannot explain … [While] most cases were reversible, [and] 13 percent were grade 1 … we do not have a clear explanation as to why this phenomenon occurred.”
Most common driver oncogene
KRASG12C is one of the most common driver oncogenes in lung cancer, accounting for roughly 15 percent of lung cancers. “[The KRASG12C mutation] is a potential targetable molecular driven oncogene that we have been trying to go after for years, but it was only in recent years that we were able to capture this small pocket at G12,” Mok shared in a news release. [https://dailynews.ascopubs.org/do/krystal-12-shows-pfs-benefit-adagrasib-over-docetaxel-previously-treated-advanced-kras]
In the phase I/II KRYSTAL-1 study, adagrasib – a potent covalent KRASG12C inhibitor – showed deep and durable responses, with promising PFS and overall survival in patients with previously treated KRASG12C-mutated NSCLC. [N Engl J Med 2022;387:120-131] These improvements led to the drug’s approval in the US, EU and UK. [https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-adagrasib-kras-g12c-mutated-nsclc; https://www.ema.europa.eu/en/medicines/human/EPAR/krazati#; https://www.gov.uk/government/news/mhra-authorises-krazati-as-a-treatment-for-non-small-cell-lung-cancer-in-adults#]
KRYSTAL-12 evaluated 453 patients (median age, 64 years; men, 68 percent) with KRASG12C-mutated locally advanced or metastatic NSCLC who had previously received platinum-based chemo concurrently or sequentially with anti-PD-(L)1 therapy. They were randomized 2:1 to oral adagrasib 600 mg BID or IV docetaxel 75 mg/m2 Q3W. Docetaxel recipients may cross over to adagrasib upon disease progression.
Combination therapy may have more potential
Discussant Dr Adrian Sacher from Princess Margaret Cancer Centre, Toronto, Ontario, Canada, noted that the improvements with adagrasib were “modest … and support [its] use in the later-line setting where treatment options for KRASG12C-mutant metastatic NSCLC are limited.”
He also underlined the potential of newer and more potent KRASG12C inhibitors to provide superior and durable responses. [N Engl J Med 2023;389:710-721] “All eyes are now on ongoing studies of KRASG12C inhibitor combination strategies, which may soon displace KRASG12C inhibitor monotherapy approaches.”
The phase III KRYSTAL-7 trial shall explore the potential of adagrasib plus pembrolizumab as first-line treatment for advanced KRASG12C-mutated NSCLC patients with PD-L1 TPS# ≥50 percent.