Next-Generation Sequencing Data Inform IO Treatment Sequencing in NSCLC

Somatic mutations in KEAP1 and STK11, identified via next-generation sequencing (NGS), could serve as biomarkers to guide treatment sequencing decisions in the front line for patients with non–small cell lung cancer (NSCLC), with both prognostic and predictive value, according to a presentation given by Ferdinandos Skoulidis, MD, PhD, MRCP, during the 22nd Annual Winter Lung Cancer Conference, an event held by Physicians’ Education Resource, LCC.1

“We have multiple available [treatment] options [in NSCLC], so how do we choose the best therapy for individual patients?” Skoulidis, an associate professor in the Department of Thoracic/Head and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center, in Houston, said. “We normally do not use checkpoint blockade in patients with EGFR mutations or ALK rearrangements. I would argue that we should be also taking into consideration the whole NGS panel, especially in patients [with mutations] in 2 genes: STK11 and KEAP1.”

STK11 alterations are significantly associated with a lack of PD-L1 expression in the tumor cells of immunogenic tumors, Skoulidis explained; a high PD-L1 tumor proportion score (TPS) has been shown to prognosticate favorable outcomes with PD-(L)1 inhibitor monotherapy in frontline NSCLC. In the phase 3 EMPOWER-01 study (NCT03088540), patients who received cemiplimab (Libtayo) with a TPS of at least 90% (n = 99) achieved a median overall survival (OS) of 36.6 months (95% CI, 22.9-not reached [NR]) compared with 23.0 months (95% CI, 18.6-24.7) among those with a PD-L1 TPS of 50% to 89% (n = 185; HR, 0.61; 95% CI, 0.42-0.88; P = .007).2 The objective response rate (ORR) was 60.6% vs 38.9%, respectively (P = .005).

KEAP1 loss of function alterations occur in approximately 10% to 15% of patients with NSCLC. KEAP1 is a negative regulator of Nrf2 which is involved in cytoprotective and detoxifying pathways. STK11 and KEAP1 loss–mediated immune escape contribute to the recruitment of myeloid-derived suppressor cells, repression of STING signaling, and impaired antigen presentation, all of which contribute to a metabolically adverse tumor microenvironment (TME).1

“The key conclusion is that both genes are associated with the TME, [with] unique mechanisms of action,” Skoulidis noted.

Data Demonstrate Prognostic Value of STK11 and KEAP1 Mutation Status

In a retrospective study, investigators analyzed the outcomes of treatment with PD-(L)1 inhibition according to KRAS, STK11, and KEAP1 mutation status in patients with advanced lung adenocarcinoma treated at Dana-Farber Cancer Institute/Massachusetts General Hospital and Memorial Sloan Kettering Cancer Center/MD Anderson Cancer Center from 2013 to 2020.3 Findings from the study showed that patients with KRAS-mutated/STK11 wild-type disease (n = 398) experienced a median progression-free survival (PFS) of 4.8 months (95% CI, 3.7-6.2) compared with 2.0 months (95% CI, 1.7-2.3) among patients with KRAS-mutated/STK11-mutated disease (n = 138; HR, 2.04; 95% CI, 1.66-2.51; P < .0001). The median OS values were 17.3 months (95% CI, 15.1-22.8) vs 6.2 months (95% CI, 4.4-9.2), respectively (HR, 2.09; 95% CI, 1.68-2.61; P < .0001). Similarly, patients with KRAS-mutated/KEAP1 wild-type disease (n = 376) experienced a median PFS of 4.6 months (95% CI, 3.7-5.9) vs 1.8 months (95% CI, 1.7-2.2) among those with KRAS-mutated/KEAP1-mutated disease (n = 101; HR, 2.05; 95% CI, 1.63-2.59; P < .0001). The median OS was 18.4 months (95% CI, 14.9-21.7) vs 4.8 months (95% CI, 4.0-8.0), respectively (HR, 2.24; 95% CI, 1.74-2.88; P < .0001).

In the phase 3 KEYNOTE-189 trial (NCT02578680), a reduced benefit was observed with the addition of pembrolizumab (Keytruda) to platinum doublet chemotherapy in patients with STK11- as well as KEAP1-mutated NSCLC.4 Patients with STK11-mutated disease who received pembrolizumab plus chemotherapy (n = 36) had a median PFS of 6.1 months (95% CI, 3.6-9.2) compared with 10.4 months (95% CI, 8.2-14.0) among those with STK11 wild-type disease (n = 168). The median OS was 17.4 months (95% CI, 4.7-NR) vs 22.5 months (95% CI, 20.1-NR), respectively. Patients with KEAP1-mutated disease who received the combination (n = 45) achieved a median PFS of 5.1 months (95% CI, 3.7-11.1) compared with 10.4 months (95% CI, 8.2-14.0) among those with KEAP1 wild-type disease (n = 159). The median OS was 13.3 months (95% CI, 7.5-NR) vs 23.5 months (95% CI, 20.4-NR), respectively.

The phase 3 POSEIDON trial (NCT03164616) examined durvalumab (Imfinzi) with or without tremelimumab (Imjudo) in combination with chemotherapy for the frontline treatment of patients with EGFR/ALK wild-type NSCLC.5Findings from POSEIDON showed that patients with STK11- and/or KEAP1-mutated disease who received the triplet (n = 42) achieved a median PFS of 6.2 months (95% CI, 4.5-12.0) vs 2.8 months (95% CI, 1.5-4.7) in the doublet arm (n = 43) and 5.1 months (95% CI, 4.1-6.4) in the chemotherapy arm (n = 25). The respective ORRs were 42.9% (95% CI, 27.7%-59.0%), 30.2% (95% CI, 17.2%-46.1%), and 28.0% (95% CI, 12.1%-49.4%). Notably, there were no major differences in median PFS between the 3 arms among patients who were STK11 and KEA1 wild type.

In terms of OS, the median value among patients with STK11- and/or KEAP1-mutated disease in the triplet arm was 15.8 months (95% CI, 9.5-23.8) compared with 7.3 months (95% CI, 4.2-12.9) in the doublet arm and 10.5 months (95% CI, 6.0-14.7) in the chemotherapy alone arm. Among patients who were STK11 and KEA1 wild type in the triplet (n = 166), doublet (n = 160), and chemotherapy only (n = 176) arms, the median OS was 17.2 months (95% CI, 14.2-24.1), 17.1 months (95% CI, 13.3-22.6), and 13.7 months (95% CI, 12.0-17.8), respectively.

Data from POSEIDON are the most robust in patients with STK11- and/or KEAP1-mutated NSCLC and the incorporation of anti–CTLA-4 with anti–PD(L)1 therapy may represent a preferred approach for these patients, Skoulidis noted in his conclusion slide.

TRITON Study Set to Compare KEYNOTE-189 and POSEIDON Regimens

In the ongoing phase 3b TRITON study (NCT06008093), investigators are aiming to confirm the findings seen in POSEIDON by examining tremelimumab in combination with durvalumab vs pembrolizumab, both in combination with chemotherapy, in adult patients with treatment-naive nonsquamous metastatic NSCLC.6 Eligible patients must have mutations in STK11, KEAP1, or KRAS; have EGFR/ALK wild-type disease; and have an ECOG performance status of 0 or 1.

The coprimary end points are OS in the intention-to-treat population and OS among patients with STK11- and KEAP1-mutated disease. Secondary end points include 12- and 24-month OS rates, PFS, ORR, duration of response, time to first subsequent therapy or death, and safety.

Enrollment in TRITON was initiated in April 2024. The study will include up to 75 sites in the US and the estimated primary completion date is in August 2027.

“STK11 and KEAP1 may represent emerging biomarkers for the selection of first-line regimens, and the current data suggest the selective benefit for the addition of doubling checkpoint blockade,” Skoulidis said in conclusion.

Disclosures: Skouldis reports the following disclosures: consulting fees from Amgen Inc., Revolution Medicines, Novartis, BridgeBio, Beigene, BergenBio, Astra Zeneca, Guardant Health Inc., Calithera Biosciences, Tango Therapeutics, Merck Sharp & Dohme, Roche, Novocure, Hookipa Pharma, Regeneron, Turning Point Therapeutics, BMS; honoraria/lecture fees from Astra Zeneca, Amgen, ESMO, AACR, IASLC, Japanese Lung Cancer Society, Medscape LLC, Intellisphere LLC, VSPO McGill Université de Montreal, MJH Life Sciences, IDEOlogy Health, MI&T, PER LLC, CURIO LLC, DAVA Oncology, BMS and RV Mais Promocao Eventos LTDS; fees for travel, food and beverage from DAVA Oncology, Tango Therapeutics, AstraZeneca Pharmaceuticals, and Amgen Inc., BMS, Revolution Medicines,AACR, IASLC, MJH Life Sciences, IDEOlogy Health, MI&T, PER LLC, CURIO LLC; stock or stock options in BioNTech SE and Moderna Inc; research grants (to institution) from Amgen, Revolution Medicines, Mirati Therapeutics, Merck & Co, and Novartis.; study chair funds (to institution) from Pfizer; consulting fees (spouse) from Roche, Novartis, AImmune

References

1. Skoulidis F. Using the NGS report to tailor IO therapy. Presented at: 22nd Annual Winter Lung Cancer Conference; January 31-February 2, 2025; Hollywood, FL. Accessed February 1, 2025.
2. Ricciuti B, Garassino MC. Precision immunotherapy for STK11/KEAP1-mutant NSCLC. J Thorac Oncol. 2024;19(6):877-882. doi:10.1016/j.jtho.2024.03.002
3. Skoulidis F, Goldberg ME, Greenawalt DM, et al. STK11/LKB1 Mutations and PD-1 Inhibitor Resistance in KRAS-Mutant Lung Adenocarcinoma. Cancer Discov. 2018;8(7):822-835. doi:10.1158/2159-8290.CD-18-0099
4. Garassino MC, Gadgeel S, Novello S, et al. Associations of tissue tumor mutational burden and mutational status with clinical outcomes with pembrolizumab plus chemotherapy versus chemotherapy for metastatic NSCLC. JTO Clin Res Rep. 2022;4(1):100431. doi:10.1016/j.jtocrr.2022.100431
5. Skoulidis F, Araujo HA, Do MT, et al. CTLA4 blockade abrogates KEAP1/STK11-related resistance to PD-(L)1 inhibitors. Nature. 2024;635(8038):462-471. doi:10.1038/s41586-024-07943-7
6. Skoulidis F, Borghaei H, Garon EB, et al. TRITON: phase 3b study of tremelimumab (T) + durvalumab (D) vs pembrolizumab (P), in combination with chemotherapy (CT), in non-squamous (NSQ) metastatic NSCLC (mNSCLC) with STK11 and/or KEAP1 and/or KRAS mutations. J Clin Oncol. 2024;42(suppl 16):TPS8655. doi:10.1200/JCO.2024.42.16_suppl.TPS8655