Adagrasib shows promising results in KRAS G12C-mutant NSCLC

KRAS G12C mutation in non-small cell lung cancer: © Aiden – stock.adobe.com

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

Patients were randomized to receive adagrasib (n = 301) or docetaxel (n = 152), and all patients had previously been treated with chemotherapy and immunotherapy. Data showed a significant improvement in the primary endpoint of progression-free survival (PFS) with adagrasib compared with docetaxel (HR, 0.58; 95% CI, 0.45-0.76, P <.0001), with a median PFS of 5.49 months versus 3.84 months. Adagrasib also induced more responses, with an overall response rate of 31.9% (95% CI, 26.7%-37.5%) versus 9.2% (95% CI, 5.1%-15.0%) with docetaxel.

These findings continue to support the use of adagrasib in this patient population, especially given the relatively tolerable safety profile.

In an interview with Targeted Oncology^TMRobert Jotte, MD, PhD, medical oncologist/hematologist at Rocky Mountain Cancer Centers, discussed the study findings and their implications for physicians.

Targeted Oncology: Can you provide some background on adagrasib?

Note: Adagrasib is a targeted molecule that binds to a particular protein product called KRAS, and this is a specific signaling molecule that is involved in cell growth and differentiation. It is now known that just under 15% of patients with non-small cell lung cancer have a mutation in a part of that protein at the 12th amino acid position, so a mutation that leads to an amino acid mutation called G12C. That is one of the most common mutations that multiple oral therapies specifically target. There you can see other types of mutations at that particular protein locus, as well as some other ones.

Adagrasib is an oral molecule that targets and binds to that mutation in G12C, which results in a knockout of that protein, if you will, in the sense that with that mutation, that constituent protein is turned on twice. And that results in overgrowth and cell differentiation and the malignant phenotype that we have, with tumor cells growing out of control, so to speak.

There have been a number of studies done with this molecule, and a number of others, looking at its usefulness in diseases like lung cancer, which are known to harbor this mutation. What we found in some of those early studies is the activity of this drug. This drug is a little bit different than some of the other molecules that are on the market, in that this drug is given twice a day and the pharmacokinetics are such that you have a pretty good steady state of that drug in your system.

What did KRYSTAL-12 evaluate?

KRYSTAL-12 was a large study, involving just under 500 patients, that evaluated the dosing of adagrasib in patients with this condition. SCRATCH G12C mutation and compared it to the standard treatment of docetaxel in the second-line setting. These are patients who had already received standard chemotherapy and immunotherapy, either together or sequentially.

Can you summarize the reported findings?

Our main conclusion from this large phase 3 study was that it initially looked at progression-free survival, and we are currently waiting for the overall survival data. It showed a statistically significant improvement in progression-free survival of adagrasib compared to standard of care docetaxel in patients who had previously been treated in this study. SCRATCH G12C mutation. That improvement in progression-free survival was 5.5 months in the adagrasib population treated with the oral drug versus 3.8 months in those patients treated with standard of care (intravenous (IV)) chemotherapy docetaxel.

That progression-free survival was seen across all of the subgroups that we typically evaluate. For example, male versus female, whether someone has brain metastases at the time of treatment, or bone metastases, or liver metastases. These are all different kinds of characteristics of the patient’s presentation that can predict better or worse outcomes based on those clinical scenarios. We saw that benefit across all of those different important subgroups.

The overall response was also noted to be better in the adagrasib-treated patients versus the docetaxel-treated patients. That response rate was about 32% in those who got adagrasib versus only 9% in the docetaxel arm, which is consistent with previous studies that looked at docetaxel as a single agent. Not only were those responses higher, but they were also more durable, which is an important parameter in terms of what we look for in a lot of targeted therapies in terms of their duration of response. The duration of response was 8.3 months in the adagrasib group versus 5.4 months and the docetaxel group.

Another important and significant feature that was identified in this protocol and the 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 features that we know are predictive of poor outcome, we saw a doubling of the response rate with adagrasib in those who were treated with it versus docetaxel.

Another important point is that we did not see any new toxicity features in this study beyond what we consistently see with both drugs. So no increased toxicity with adagrasib in this larger phase 3 study versus previous experience with docetaxel.

What do you think are the biggest implications for physicians based on these findings?

I think the biggest lesson is that this Phase 3 KRYSTAL-12 trial now validates this standard of care in the second-line setting for patients with non-small cell lung cancer who are SCRATCH G12C mutation. Adagrasib has become a standard of care for medical oncologists and healthcare providers treating patients with this mutation in secondary care.

What do you think are the next steps in this research?

Overall survival is going to be an important goal that we evaluate in this study. You also have to consider the fact that many patients are now being treated with adagrasib because of results like this. In this study, for the patients who were randomized to receive docetaxel, we have to evaluate how many of them received adagrasib after they received docetaxel. So, by interpreting that data, we can get a sense of how much benefit adagrasib provides even for those patients, because one of the things we know in this patient population is the difficulty that we often have in getting subsequent lines of therapy to these patients. They tend to be a sicker patient population. While we like to think that we are good at identifying progression early in the patient’s care, often the performance status of those patients declines to a level where it becomes less likely to provide or administer further therapy to them because of the decline in their performance status. These are all characteristics that we look at as we evaluate the overall survival data.

In terms of where these types of studies are going to take us in the future, there are already a lot of studies underway that are evaluating the use of adagrasib, not just in the frontline setting, but also in combination with chemotherapy and immunotherapy. And they’re also looking at subgroup analysis and looking at PD-1, PD-L1 expression, etc. That’s all where this field is migrating to.

REFERENCE:

Mok T, Yao W, Duruisseuax M, et al. KRYSTAL-12: Phase 3 study of adagrasib versus docetaxel in patients with previously treated advanced/metastatic non-small cell lung cancer (NSCLC) with a KRAS G12C mutation. J Clin Oncol. 2024;42(suppl 17): abstract LBA8509. doi:10.1200/JCO.2024.42.17_suppl.LBA8509