Updated KRYSTAL-7 Data Show PFS Beyond 27 Months for Adagrasib Plus Pembro in First-Line Treatment of KRAS-Mutated NSCLC

Use of the targeted therapy adagrasib with the immunotherapy pembrolizumab allowed certain patients with newly diagnosed KRAS^G123-mutated non–small cell lung cancer (NSCLC) to live more than 27 months without disease progression, according to data presented Thursday at the European Lung Cancer Conference in Paris, France.¹

Updated results from the phase 2 KRYSTAL-7 trial (NCT04613596) evaluated adagrasib (Krazati; Mirati Therapeutics) and pembrolizumab (Keytruda; Merck) in patients harboring a KRAS^G12C mutation with PD-L1 ≥ 50%. In first-line treatment, the combination showed a median progression-free survival (PFS) of 27.7 months (95% CI, 8.1-NE) with a manageable safety profile, according to the abstract presented by Marina C. Garassino, MD, of the University of Chicago School of Medicine.¹ The phase 3 portion of KRYSTAL-7 is already recruiting,² according to the study authors.

Positive PFS results for first-line treatment with the targeted therapy show the “synergistic effect we expect in combining with immunotherapy to stop the tumor growth,” said Abderrahim Oukessou, MD, vice president and head of Late Clinical Development, Oncology at Bristol Myers Squibb, which acquired Mirati Therapeutics.

Krazati packaging | Image credit: Mirati Therapeutics

Not only do the results show a median PFS of 27 months, he said in an interview, “Amazingly, we have 60% of the subjects who are free of progression at 12 months.”

These new data, Oukessou noted, “compare quite favorably to the historical data with immunotherapy in a similar patient population.”

First-Line Combination Study Follows Monotherapy Approval

In December 2022, the FDA granted accelerated approval to adagrasib for use in patients with KRAS^G12C-mutated, locally advanced or metastatic NSCLC who had received at least 1 prior systemic therapy, including immunotherapy.³ The targeted therapy has since been approved for use with cetuximab to treat patients with KRAS^G12C-mutated locally advanced or metastatic colorectal cancer.⁴

Approval in the first-line setting would potentially reach the estimated 11% of all patients with NSCLC who have a KRAS^G123 mutation, which was once considered “undruggable.” The median PFS reported Thursday is more than twice as long as the 10.3 months reported for first-line use of pembrolizumab alone in tumors expressing PD-L1.

The authors reported that 149 patients received the combination as of August 23, 2024. Results from the 54 patients with PD-L1 ≥ 50% demonstrated that the combination produced an overall response rate of 59.3%, with a median duration of response of 26.3 months. Median follow-up, which was more than 22 months, also showed a promising signal in overall survival (OS), with the 18-month rate at 62%, according to the authors. Details showed 1 patient achieving a complete response (1.9%), 31 achieving a partial response (57.4%), and 12 patients with stable disease (22.2%); 2 patients (3.7%) had progressive disease, and 8 patients were not evaluable (14.7%).

Abderrahim Oukessou, MD | Image credit: Bristol Myers Squibb

All the data related to efficacy “are trending in the same direction,” Oukessou said. “We have higher response rates. We have longer duration of response. We have long PFS…but also, we have an interesting overall survival signal.”

While OS data are not mature, he said, “This we will continue to follow.”

Safety data show the rate of treatment-related adverse events (TRAEs) of grade 3 or greater was higher with the combination than seen in the KEYNOTE-024 trial, which evaluated pembrolizumab monotherapy in this population. Among all 149 patients, TRAEs of any grade were seen in 94.6% of patients, with 68.4% reporting events of grade 3 or 4. Three deaths were reported: 2 from pneumonia and 1 from pneumonitis. The most common events—mostly grades 1 and 2—were nausea (55.7%), diarrhea (47.0%), and increases in alanine transaminase (39.6%), which can indicate effects on the liver. TRAEs led to discontinuation of adagrasib in 13.4% of patients and of pembrolizumab in 23.5%; 6.7% stopped taking both drugs.

Oukessou said while comparisons across trials are difficult, safety data thus far “are consistent with the individual components of the treatment.”

Previously reported results from KRYSTAL-12 (NCT04685135), a phase 3 trial comparing adagrasib with docetaxel in previously treated patients with KRAS^G12C-mutated NSCLC, showed TRAEs in 94.0% of patients receiving adagrasib vs 86.4% receiving chemotherapy; grade 3 or higher TRAEs were seen in 47.0% and 45.7% of patients, respectively. Some of those patients would have received immunotherapy prior to treatment with adagrasib.⁵

“So, obviously we have no data in combination with pembrolizumab in second line,” Oukessou said. “Oftentimes, the patient in first line gets immunotherapy plus or minus chemotherapy; then they become not eligible for immunotherapy.”

He pointed out that prior trials have evaluated adagrasib at 600 mg, while the results reported in Paris involved a dose of 400 mg daily of adagrasib with 200 mg of pembrolizumab given intravenously every 3 weeks.

“That’s something we need to keep in mind when comparing the safety profile,” Oukessou said, noting that results are “quite consistent” with earlier studies at the higher dose. “We have seen some immune adverse events, probably linked to the pembrolizumab, but also we have seen mostly [gastrointestinal] toxicities, which has been consistently observed with monotherapy as well as the combination.”

When asked about results for hospitalizations or quality of life, Oukessou said “extensive data” on these points would be gathered during the phase 3 trial, which will allow comparisons between adagrasib plus pembrolizumab vs pembrolizumab alone.²

References

1. Garassino MC, Theelen W, Jänne PA, et al. First-line adagrasib (ADA) with pembrolizumab (PEMBRO) in patients (pts) with advanced/metastatic KRASG12C-mutated non-small cell lung cancer (NSCLC) and PD-L1 ≥50% from the phase II portion of KRYSTAL-7. Presented at: European Lung Cancer Congress 2025, Paris, France; March 26-29, 2025. Abstract 5MO.
2. Garassino MC, Janne PA, Barlesi F, et al. KRYSTAL-7: A phase III study of first-line adagrasib plus pembrolizumab versus pembrolizumab alone in patients with advanced NSCLC with KRAS^G12C mutation. Ann Oncol. 2024;35(suppl 2):S872-S873. doi:10.1016/j.annonc.2024.08.1449
3. FDA grants accelerated approval to adagrasib for KRAS ^G12C-mutated NSCLC. FDA. Updated December 12, 2022. Accessed March 28, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-adagrasib-kras-g12c-mutated-nsclc
4. Bonavitacola J. FDA approves adagrasib for use in previously treated CRC. FDA. June 21, 2024. Accessed March 28, 2025. https://www.ajmc.com/view/fda-approves-adagrasib-for-use-in-previously-treated-crc
5. Mok TSK, Yao W, Duruisseaux 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): Abstract LBA8509. doi:10.1200/JCO.2024.42.17_suppl.LBA8509