Adagrasib Plus Pembrolizumab Shows Best Efficacy in PD-L1–High NSCLC

Targeted KRAS inhibitors are approved as second-line therapy for patients with advanced KRAS G12C-mutated non–small cell lung cancer (NSCLC), and trials are now moving into the first line and investigating combinations of immunotherapy and chemotherapy. 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, looked at recent data from combination KRAS inhibitor trials and discussed the approach to managing adverse events shared by both the KRAS inhibitor and immunotherapy agent.

This article is part 2 of a 2-part series from a Case-Based Roundtable event.

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Targeted Oncology: What trials are investigating KRAS inhibitors in NSCLC in combination with immunotherapy or chemotherapy?

Christine Bestvina, MD: Pembrolizumab [Keytruda] plus adagrasib [Krazati] is currently being moved forward in a few different settings. KRYSTAL-7 [NCT04613596] is investigating a combination of pembrolizumab plus adagrasib. There's also a secondary KRYSTAL-4 trial [NCT06875310] that's looking at an all-comer combination of carboplatin, pemetrexed, pembrolizumab, and adagrasib.

[In CodeBreaK 100/101 (NCT03600883, NCT04185883)], when patients were given sotorasib [Lumakras] plus either pembrolizumab or atezolizumab [Tecentriq], there was a grade 3/4 hepatotoxicity of 45% with a lead-in and 72% grade 3/4 with concurrent administration,¹ so that drug is not moving forward in combination with immunotherapy.²

[In the KANDLELIT-001 trial (NCT05067283)], Merck has a compound called MK1084 that is showing some nice early results in combination with pembrolizumab.³ Then the confirmatory trial for FDA approval for sotorasib is CodeBreaK 101, in patients with PD-L1–negative [disease receiving] carboplatin, pemetrexed, and sotorasib vs carboplatin, pemetrexed, and pembrolizumab.

Could you describe the outcomes of KRYSTAL-7 in more detail?

To me, these were some of the most exciting data we've seen at ASCO, as far as what is going to move over. [It investigated] adagrasib plus pembrolizumab. These are patients who had known PD-L1, but they could be any PD-L1 expression, so they were not selected for PD-L1 high. Treated, neurologically stable brain metastases were allowed, and they were treatment naive.

Progression-free survival [PFS] was a median of 11 months. Again, this is an all-comer PD-L1 population. The median overall survival was 18 months. But I think what's exciting is the PFS according to PD-L1 status. For patients with PD-L1 of 50% or greater, the median PFS is 28 months for the combination of adagrasib/pembrolizumab. The overall response rate here was 36% for the [PD-L1] negative [group], 41% for [PD-L1] 1% to 49%, and 61% for PD-L1 high.⁴

How was the combination of adagrasib and pembrolizumab tolerated?

The combination was tolerable; dose interruptions were frequent at 68% but the large majority of patients were able to go back on the drug either with dose reduction or just dose interruption. Pembrolizumab was discontinued in about 17% of all patients; both were discontinued in only 7%.⁴

I think if this trial were run again now, these numbers would be lower. As somebody who participated in this trial, as well as the combination sotorasib and immunotherapy trials, when we were first seeing the liver function test [LFT] elevations, it was hard to determine if it was from the pembrolizumab vs the KRAS inhibitor. In the early stages of the trial, sometimes we were discontinuing pembrolizumab or giving steroids. I think now we feel a little bit more comfortable holding the KRAS inhibitor, knowing that's likely the causative agent and that things will improve within a few days.

This strategy is moving forward in development. They are looking only for the PD-L1–high patients with this combination, and then in the PD-L1 negative or moderate [population], it will be a quadruplet regimen of carboplatin, pemetrexed, pembrolizumab, and adagrasib.

Would you treat patients with high PD-L1 expression this way now?

We're participating in the trial, but I probably wouldn't use this off protocol unless it was a patient who had comorbidities or was more resistant. I think if that was the case, I would consider it.I have a feeling that you probably could get it approved with the data that were presented here as well as the data that were presented at the European Lung Cancer Congress. I think if the patient is aware of what some of the toxicities are, it would be reasonable.

How do you determine whether an adverse event is caused by pembrolizumab or adagrasib?

Typically, what we're doing with these patients is essentially holding the KRAS inhibitor and checking up with them, depending on the grade of diarrhea—hopefully, they don't need to be admitted.I would expect it to improve within 2 to 5 days. It also depends on how toxic it is. If the LFT is 10 times the upper limit of normal or more, I would give steroids. I wouldn't even wait the 48 hours [to confirm it was not adagrasib-related]. I think gastrointestinal toxicity with adagrasib does occur; while it’s manageable, it occurs at a high enough rate that I probably would first try a dose interruption and see if that resolves it.

Looking at the hepatic events, aspartate aminotransferase and alanine aminotransferase increase of any grade [occurred in] 36% and 40% [respectively] but the large majority were grade 1 or grade 2.⁴ Very rarely was there an associated bilirubin increase [4% any-grade]. I think that’s the other important point. If you're seeing [LFT elevation], and you're considering that this is likely from adagrasib…make sure that the bilirubin is still normal.

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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. Li BT, Falchook GS, Durm GA, et al. OA03.06 CodeBreaK 100/101: First report of safety/efficacy of sotorasib in combination with pembrolizumab or atezolizumab in advanced KRAS p.G12C NSCLC. J Thorac Oncol. 2022;17(suppl 9):S10-S11. doi:10.1016/j.jtho.2022.07.025

2. 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

3. Sacher AG, Şendur MAN, Stathis A, et al. MK-1084 for KRAS G12C-mutated (mut) metastatic non–small-cell lung cancer (mNSCLC): Results from KANDLELIT-001. J Clin Oncol. 2025;43(suppl_16):8605. doi:10.1200/JCO.2025.43.16_suppl.8605

4. 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