Adagrasib Strengthens Its Position in KRASG12C-Mutated Lung Cancer: ASCO24

KRYSTAL-12 showed that adagrasib provided a significant efficacy benefit over docetaxel in previously treated advanced KRASG12C-mutated non-small cell lung cancer (NSCLC), improving progression-free survival (PFS) and objective response rate (ORR). ASCO 2024 featured these results in its most notable presentation on the second day. The findings support adagrasib in advanced NSCLC, where treatment options are limited.

What Is KRAS?

KRAS is among the most frequently mutated  oncogenes  in human cancer. KRAS mutations drive the growth and proliferation of several cancer types through the RAS/MAPK signaling cascade.

KRAS mutations were once considered untargetable and untreatable. However,  Lumakras, whose active ingredient is sotorasib , proved effective against KRAS G12C-mutated NSCLC and received FDA approval in May 2021. Sotorasib thus became the first approved KRAS-targeted cancer treatment.

The most common KRAS G12 mutations are G12D (36%), G12C (14%) and G12V (23%). Currently, G12C is the only KRAS mutation with an approved targeted treatment.

Results Reinforcing Accelerated FDA Approval

After sotorasib, adagrasib (Krazati, Mirati Therapeutics, Inc.) received approval based on KRYSTAL-1 for adults with advanced KRAS G12C-mutated NSCLC who had received at least one systemic treatment. It received accelerated FDA approval in December 2022 .

The Standout Study on Day 2 of ASCO 2024: KRYSTAL-12

Adagrasib significantly improved progression-free survival (PFS) and objective response rate (ORR) compared with docetaxel in previously treated, locally advanced or metastatic KRASG12C-mutated NSCLC. These results came from the phase 3 KRYSTAL-12 study presented at the 2024 ASCO Annual Meeting.

Responses to adagrasib appear durable, and intracranial responses were also observed in patients with brain metastases. Safety findings were consistent with previous reports.

KRYSTAL-12 confirms adagrasib's efficacy as second-line treatment for patients with KRASG12C mutations, showing higher tumor response rates and longer PFS than the current standard treatment.

The rationale for KRYSTAL-12 is that KRASG12C is a targetable molecular driver oncogene. Attempts to target this mutation have continued for years, but only recently has targeting a small pocket at G12 made it possible to develop targeted treatments.

In May 2021, the US Food and Drug Administration (FDA) granted accelerated approval to the KRASG12C inhibitor sotorasib after an ORR of 37% in the phase 2 CodeBreaK-100 study. Although the phase 3 CodeBreaK-200 study showed a significant PFS benefit over docetaxel, the FDA's Oncologic Drugs Advisory Committee rejected the supplemental new drug application for full approval because of study limitations. The committee concluded that PFS could not be reliably interpreted because of several problems in the study and its conduct, including a higher dropout rate in the docetaxel arm. The FDA is requesting completion of a new confirmatory study by February 2028 for full approval.

Adagrasib received accelerated approval in December 2022 after an ORR of 43% in the phase 1/2 KRYSTAL-1 study. KRYSTAL-12 is the confirmatory phase 3 study comparing adagrasib with docetaxel for efficacy and safety in this population.

A total of 453 patients with locally advanced or metastatic KRASG12C-mutated NSCLC, previously treated with platinum-based chemotherapy and anti–PD-L1/PD-1 therapy, were randomized to adagrasib 600 mg orally twice daily (301 patients) or docetaxel 75 mg/m2 intravenously every 3 weeks (152 patients).

The study was designed to maximize the likelihood of obtaining data that could reliably detect differences between the arms. First, it used 2:1 randomization to increase the chance of receiving targeted treatment, encouraging enrollment. Second, crossover after confirmed progression was permitted, reducing dropout rates.

Key findings included that 99% of patients assigned to adagrasib and 92% assigned to docetaxel received their randomized treatment. In the docetaxel arm, 44 patients (29%) crossed over to adagrasib after confirmed disease progression.

After a median follow-up of 7.2 months, the study met its primary endpoint: adagrasib significantly improved PFS by blinded independent central review (BICR) compared with docetaxel (median PFS 5.5 months versus 3.8 months; HR 0.58, 95% CI [0.45, 0.76]; P < 0.0001). Adagrasib's superiority was maintained across key subgroups.

BICR-assessed ORR was 32% with adagrasib and 9% with docetaxel (odds ratio 4.68, 95% CI [2.56, 8.56]; P < 0.0001). Median response duration was 8.3 and 5.4 months, respectively, with responses lasting at least 6 months in 64% and 39% of patients, respectively.

Among patients with central nervous system metastases at baseline, intracranial responses occurred in 24% of those receiving adagrasib (19 of 78 patients) and 11% receiving docetaxel (4 of 36 patients). Patient-reported outcomes on the Lung Cancer Symptom Scale also showed a significant benefit in median time for docetaxel compared with adagrasib (3.0 months versus 1.5 months; HR 0.57, 95% CI [0.45, 0.74]).

Regarding safety, adagrasib was associated with certain gastrointestinal toxicities. Grade 1/2 diarrhea was more common with adagrasib than docetaxel (48% versus 26%), as were grade 1/2 vomiting (33% versus 6%) and nausea (31% versus 19%). Adagrasib was also associated with increased aspartate aminotransferase (24% versus 0%) and alanine aminotransferase (22% versus 3%).

Creatinine elevations were also more frequent with adagrasib than docetaxel (19% versus 1%), but it is not yet known whether these reflect true renal impairment or other causes.

As a next step, the phase 3 KRYSTAL-7 study (NCT04613596) will compare adagrasib plus pembrolizumab with pembrolizumab alone in advanced KRASG12C-mutated NSCLC with a PD-L1 tumor proportion score ≥ 50%.

Newer, more potent KRASG12C inhibitors, such as divarasib, may potentially provide better response rates and longer treatment duration. Attention is focused on ongoing studies of KRASG12C inhibitor combination strategies, which may soon replace KRASG12C inhibitor monotherapy.

In summary, KRYSTAL-12 shows that adagrasib provides important benefits over docetaxel in progression-free survival (PFS) and objective response rate (ORR) in advanced KRASG12C-mutated non-small cell lung cancer (NSCLC). These findings identify adagrasib as a promising option in advanced treatment settings with limited alternatives.