Beyond Docetaxel: Adagrasib Shows Promise in KRAS G12C-Mutant NSCLC

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

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.

Patients were randomized to receive adagrasib (n = 301) or docetaxel (n = 152), and all patients were previously treated with chemotherapy and immunotherapy. 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.

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

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

Robert Jotte, MD

Targeted Oncology: Can you provide some background on adagrasib?

Jotte: Adagrasib is a well-targeted molecule that binds to a particular protein product called KRAS, and this is a particular signaling molecule that is involved in cell growth and differentiation. It is well known now that just under 15% of patients with non–small cell lung cancer will harbor a mutation in a portion of that protein at the 12th amino acid position, so a mutation that leads to an amino acid mutation that is termed as G12C. That is 1 of the more common ones that multiple oral therapies are particularly targeting. There, you can see other types of mutations at that particular protein locus, as well as some others.

Adagrasib is an oral molecule that targets and binds to that mutation in G12C, which leads to a shutdown of that protein, if you will, in the sense that with that mutation, that protein is constituent doubly turned on. That leads to overgrowth and cell differentiation and the malignant phenotype that we are familiar with, with tumor cells that grow out of control, so to speak.

Multiple studies have been done already with this molecule, as well as some others, looking at its utility in diseases such as lung cancer, which are known to harbor this mutation. What we found in some of those earlier 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 the sense that this drug is given twice a day, and its pharmacokinetics are such that you have a pretty good steady state of that drug in your system.

What was KRYSTAL-12 evaluating?

KRYSTAL-12 was a large study, just under 500 patients, that evaluated looking at dosing adagrasib in patients that harbored this KRAS G12C mutation and compared it with the standard of care of docetaxel in the second-line setting. These are patients that had already received standard chemotherapy and immunotherapy, either together or sequentially.

Can you summarize the findings that were reported?

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. 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.

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.

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.

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.

Based on these findings, what would you consider to be the biggest implications for physicians?

I think the biggest takeaway is that this phase 3 KRYSTAL-12 study now confirms this standard of care in the second-line setting for patients that have non–small cell lung cancer that harbors this KRAS G12C mutation. Adagrasib has become a standard of care for medical oncologists and providers taking care of patients that have this mutation in the second-line setting.

What do you see as the next steps to this research?

Overall survival will be an important objective that we are evaluating in this trial. You must take into consideration also, because of results such as this, that many patients will now be treated with the adagrasib. In this trial, for those patients that were randomized to receive docetaxel, we will need to evaluate how many of those went on to receive adagrasib after having received the docetaxel. So, interpreting that data so that we can get a feel for how much of a benefit the adagrasib provides even those patients, because 1 of the pieces that we know in this patient population is the difficulty that we have, oftentimes, in getting next lines of therapy into these patients. They tend to be a sicker patient population. While we like to think that we are good at identifying progression at an early date in the patient's care, oftentimes those patients’ performance status drops to a level where providing or administering further therapy in them becomes less likely because of declines in their performance status. All those will be features that we are looking into as we evaluate the data for the overall survival.

As far as where studies like this take us in the future, already, many studies are underway evaluating the utilization of adagrasib, not only in the frontline setting but in combination with chemotherapy, as well as immunotherapy, and looking at the subgroup analysis and in studies as far as PD-1, PD-L1 expression, etc. All of that is 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) harboring a KRAS G12C mutation. J Clin Oncol. 2024;42(suppl 17): abstr LBA8509. doi:10.1200/JCO.2024.42.17_suppl.LBA8509