Adagrasib Demonstrates Superiority in KRAS G12C NSCLC

Adagrasib (Krazati) showed deep, durable responses in patients with previously treated KRAS G12C-mutated non–small cell lung cancer (NSCLC) in the phase 1/2 KRYSTAL-1 trial (NCT03785249). The phase 3 KRYSTAL-12 study (NCT0468513) sought to build on these findings and compared adagrasib with docetaxel in this intent-to-treat population.

Findings were presented at the 2024 ASCO Meeting, with updated data shared at the 2024 ESMO Congress. At ASCO, data showed a significant improvement in the primary end point of progression-free survival (PFS) with adagrasib over docetaxel (HR, 0.58; 95% CI, 0.45-0.76, P <.0001), with a median PFS of 5.49 months vs 3.84 months. Adagrasib also elicited more responses, with an overall response rate of 31.9% (95% CI, 26.7%-37.5%) vs 9.2% (95% CI, 5.1%-15.0%) with docetaxel.

At ESMO, findings demonstrated that among patients with baseline brain metastases, the median intracranial time to progression was 18.6 months (95% CI, 9.6-not evaluable [NE]) in the adagrasib arm and NE (95% CI, 4.2-NE) in the docetaxel arm (HR, 0.60; 95% CI, 0.26-1.40). Additionally, the intracranial PFS hazard ratio for patients with brain metastases was 0.93 (95% CI, 0.50-1.73).

Here, Robert Jotte, MD, PhD, medical oncologist/hematologist at Rocky Mountain Cancer Center, discusses these findings and their implications.

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0:05 | Our key takeaway from this large phase 3 trial was that it initially looked at progression-free survival, and we are currently awaiting the overall survival data. It did demonstrate a statistically significant improvement in progression-free survival of adagrasib over standard of care docetaxel in patients that have previously been treated with this KRAS G12C mutation.

0:38 | That improvement in progression-free survival was 5.5 months in the adagrasib population that were treated with the oral drug vs 3.8 months in those patients that were treated with standard of care [intravenous (IV)] chemotherapy docetaxel. That progression-free survival was witnessed across all of the subgroups that we typically evaluate. For example, male vs female, whether someone has brain metastases at the time of treatment, or bone metastases or liver metastases. These are all different types of characteristics of patient presentation that may predict better worse outcomes based on those clinical scenarios. We saw that benefit across all those different key subgroups.

1:48 | The overall response was also identified as being better in the adagrasib-treated patients vs docetaxel-treated patients. That response rate was about 32% in those that received adagrasib vs just 9% in the docetaxel [arm], which is consistent with prior studies looking at docetaxel as a single agent. Those responses not only were higher, but they were also more durable, a key parameter as far as what we look for in a lot of targeted therapies as far as their duration of response. The duration of response was 8.3 months in the adagrasib group vs 5.4 months and the docetaxel group.

2:31 | Another important and key feature that was identified in this protocol and results in this phase 3 study was that we saw a doubling of the intracranial response. In other words, if someone presents with intracranial metastases and underlying clinical characteristics that we know predicts a poor outcome, we saw a doubling of the response rate of adagrasib in those that were treated with it vs the docetaxel.

3:01 | Another important piece is that we did not see any new toxicity features in this study outside of what we are consistently seeing with both of these drugs. So, no increased toxicity with the adagrasib in this larger phase 3 study vs prior experience in the same with docetaxel.