KRAS Inhibitors Show Efficacy in Randomized NSCLC Trials

In patients with advanced KRAS G12C-mutated non–small cell lung cancer, research is shedding light on how to effectively target the driver mutation. The targeted therapies adagrasib (Krazati) and sotorasib (Lumakras) received accelerated approval and now data from randomized trials have supported the continued use of these therapies in the second line. In a live Case-Based Roundtable event in Chicago, Illinois, Christine Bestvina, MD, associate professor of medicine in the section of hematology/oncology at the University of Chicago Department of Medicine, discussed the recent data from the randomized trials of these therapies and observed the differences between the trial designs and the reported toxicity profiles of the 2 agents.

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Targeted Oncology: What data confirmed the efficacy and safety of adagrasib for patients with KRAS-mutated NSCLC?

Christine Bestvina, MD: KRYSTAL-12 [NCT04685135] was the randomized study of adagrasib vs docetaxel. Patients were randomly assigned in a 2:1 fashion. All patients had prior treatment with platinum chemotherapy as well as an anti–PD-1/PD-L1, and an [ECOG] performance status of 0 to 2. The trial did allow for stable, treated brain metastasis, so that's one thing to note, and 17% of patients had brain metastases at baseline.¹

There was a 32% overall response rate for adagrasib vs 9% for docetaxel. Duration of response was 8.3 months for adagrasib vs 5.4 months for docetaxel. The primary end point of this trial was progression-free survival [PFS], and the median PFS was 5.5 months for adagrasib vs 3.8 months with docetaxel, and it did meet statistical significance [HR 0.58; 95% CI, 0.45-0.76; P < .0001]. This trial did look at patients who had baseline central nervous system [CNS] metastasis and looked at the intracranial response rate. Interpret this with a grain of salt, because these [metastases] were all treated, but the intracranial response was 24% with adagrasib vs 11% with docetaxel, indicating that there likely was deeper CNS responses. In the overall CNS-evaluable patient population that includes only patients who had at least 1 [measurable target lesion], the intracranial response rate was 40%.

What were the safety outcomes with adagrasib in this trial?

As far as safety, approximately 47% in both arms had some grade 3 toxicity. However, it was decently well tolerated in both arms. Very rarely did adagrasib need to be discontinued, in only 8% of patients [vs 14% with docetaxel]. I think that number is really important.

The majority of the toxicity is gastrointestinal [GI] toxicity, [most commonly] diarrhea; 37% have grade 1, 11% have grade 2, 5% have grade 3. Nausea, vomiting, and also aspartate aminotransferase and alanine aminotransferase elevations [were reported]…but my experience has been that [adagrasib] was quite well tolerated. I think GI toxicities are the biggest thing to be aware of.

What randomized trial data supported the use of sotorasib in this population?

In the CodeBreak 200 trial [NCT04303780], patients were randomly assigned 1:1 to sotorasib vs docetaxel in a similar patient population, [but] they could not have had active brain metastasis in this trial. It was a little bit more restrictive on the brain metastases. Patients did need to be treated both with prior chemotherapy as well as an immune checkpoint inhibitor [ICI].

PFS was the primary end point here, [with a median of] 5.6 months with sotorasib vs 4.5 months with docetaxel, and the HR was 0.66 [95% CI, 0.51-0.86; P = .0017], which did meet statistical significance, so this was a positive trial.²

What adverse events were of most concern with sotorasib?

We do see a bit less diarrhea than we did with adagrasib, but the LFT [liver function test] elevation is a bit higher in this trial.² This is one of the trials that triggered Project Optimus, which is the FDA mandating more dose optimization cohorts. There was a study that looked at 240 mg vs 960 mg and showed almost exactly equivalent results.³ The FDA recommended dose is still technically 960 mg but I often will start at 480 mg.

There is some information on hepatotoxicity for patients who received prior ICI.⁴ These are very small numbers; [4] patients who received the sotorasib within 30 days of an ICI, 11 patients received sotorasib within 31 to 90 days, and [13] patients had a longer window of more than 90 days. It just shows that there's a much higher risk of LFT elevation if sotorasib is given in close proximity to [ICI]. When this combination was studied in a phase 1 trial of immunotherapy plus sotorasib, it was found to not be tolerable due to the LFT elevation, so this is not a combination that is moving forward in development, and is something to be aware of if you're switching your patients right from immunotherapy to sotorasib. Both the CodeBreak 100 [NCT03600883] and CodeBreak 200 clinical trials mandated a washout period of 28 days or more after prior ICI.

Adagrasib does combine safely with immunotherapy…so adagrasib does not have the same mandated washout period.⁵

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DISCLOSURES: Bestvina previously reported personal consulting fees/advisory board from: AbbVie, Amgen, AstraZeneca, BMS, Daiichi, EMD Serono, Genentech, Gilead, Guardant, Johnson and Johnson, Mirati, Novocure, Pfizer, Sanofi, Tempus, Turning Point Therapeutics.

REFERENCES:

1. Mok TSK, Yao W, Duruisseaux I, 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):LBA8509. doi:10.1200/JCO.2024.42.17_suppl.LBA8509

2. de Langen AJ, Johnson ML, Mazieres J, et al. Sotorasib versus docetaxel for previously treated non-small-cell lung cancer with KRAS^G12C mutation: a randomised, open-label, phase 3 trial. Lancet. 2023;401(10378):733-746. doi:10.1016/S0140-6736(23)00221-0

3. Hochmair MJ, Vermaelen K, Mountzios G, et al. Sotorasib (960 mg or 240 mg) once daily in patients with previously treated KRAS G12C-mutated advanced NSCLC. Eur J Cancer. 2024;208:114204. doi:10.1016/j.ejca.2024.114204

4. Desai A, Rakshit S, Bansal R, et al. Time from immune checkpoint inhibitor to sotorasib use correlates with risk of hepatotoxicity in non-small cell lung cancer: A brief report. Cancer Treat Res Commun. 2023;36:100743. doi:10.1016/j.ctarc.2023.100743

5. Jänne P, Theelen W, Garassino M, et al. First-line adagrasib (ADA) with pembrolizumab (PEMBRO) in patients (pts) with advanced/metastatic KRAS^G12C-mutated non-small cell lung cancer (NSCLC) from the phase 2 portion of the KRYSTAL-7 study. J Clin Oncol. 2025;43(suppl 16):8500. doi:10.1200/JCO.2025.43.16_suppl.8500