Ferdinandos Skoulidis, MD, PhD, MRCP, associate professor, Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, discusses the methods utilized in a retrospective study that investigated molecular determinants of KRAS G12C inhibitor efficacy in patients with advanced non–small cell lung cancer (NSCLC). 

At the 2023 AACR Annual Meeting, Skoulidis and colleagues presented retrospective data of patients with advanced 

 G12C–mutated NSCLC treated with either sotorasib (Lumakras) or adagrasib (Krazati) to assess the effect of co-mutations on clinical outcomes. Investigators found that patients who harbored co-alterations in the tumor suppressor genes 

 had significantly shorter progression-free survival.

Data were gathered from 20 academic institutions across the United States and Europe. Patients included in the study were required to have baseline genomic profiling prior to starting treatment with a KRAS G12C inhibitor therapy. Profiling was allowed to be conducted with commercially available assays or any assay run through a certified laboratory, Skoulidis says.

Based on the findings from this study, future research could include expansion to a larger cohort of patients who have undergone broad, comprehensive genomic profiling, which could increase understanding of less prevalent molecular determinants of KRAS G12C inhibition in patients with NSCLC, Skoulidis expands.

Beyond co-mutational determinants of sensitivity, other determinants at the transcriptional and proteomic level could also play a role on the effect of this treatment, Skoulidis explains. The tumor microenvironment is hypothesized to play an important role in modulating response, sensitivity, and resistance to KRAS G12C inhibitors, and future research could help address this possibility, Skoulidis concludes.

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Ferdinandos Skoulidis, MD, PhD, MRCP, discusses the methods utilized in a retrospective study that investigated molecular determinants of KRAS G12C inhibitor efficacy in patients with advanced non–small cell lung cancer.


Dr Skoulidis on the Methods of Analyzing KRAS G12C Inhibitor Efficacy in NSCLC

Ferdinandos Skoulidis, MD, PhD, MRCP, associate professor, Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, discusses molecular determinants of KRAS G12C inhibitor efficacy in advanced non–small cell lung cancer (NSCLC).

The development of KRAS G12C inhibitors has represented a key milestone in targeted therapy for the treatment of cancer, Skoulidis begins. Although agents such as sotorasib (Lumakras) or adagrasib (Krazati) have been approved by the FDA and have displayed efficacy in the treatment of patients with 

 G12C-mutated NSCLC, there are currently no methods to identify which patients are likely to derive long-term benefit from single-agent treatment with a KRAS G12C inhibitor. By being able to more accurately identify patients who are less likely to benefit from single-agent treatment with a KRAS G12C, it could allow for an intensified approach to therapy, or a different course of treatment entirely, Skoulidis says.

To address the molecular determinants of the efficacy of KRAS G12C inhibitors, Skoulidis and colleagues collected and analyzed retrospective data of patients with advanced 

 G12C–mutated NSCLC treated with either sotorasib or adagrasib to assess the effect of co-mutations on clinical outcomes.

Findings presented at the 2023 AACR Annual Meeting showed that co-alterations in the tumor suppressor genes 

 were individually and independently associated with worse clinical outcomes, Skoulidis expands. Approximately one-third of patients in the study harbored a 

 co-mutation, and more than half of patients who experienced disease progression within 3 months had one of those co-mutations, Skoulidis says.

Findings from the study demonstrated which co-mutations could lead to early disease progression following treatment with KRAS G12C inhibitors, and these results could help inform strategies and potential drug combinations to individualize treatment.

Ferdinandos Skoulidis, MD, PhD, MRCP, discusses molecular determinants of KRAS G12C inhibitor efficacy in advanced non–small cell lung cancer.


Dr Skoulidis on Determinants of KRAS G12C Inhibitor Efficacy in NSCLC

Ferdinandos Skoulidis, MD, PhD, MRCP, associate professor, Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, discusses the clinical implications for data from the combination of tremelimumab-actl (Imjudo) plus durvalumab (Imfinzi) and chemotherapy in metastatic non–small cell lung cancer (NSCLC) without sensitizing 

 tremelimumab plus durvalumab and platinum-based chemotherapy for adult patients with metastatic NSCLC without sensitizing 

 aberrations. The approval was supported by results of the phase 3 POSEIDON trial (NCT03164616), which showed that the combination of tremelimumab, durvalumab, and chemotherapy significantly improved overall survival (OS) vs chemotherapy alone at 14 months (95% CI, 11.7-16.1) vs 11.7 months (95% CI, 10.5-13.1), respectively (HR, 0.77; 95% CI, 0.65-0.92; 2-sided 

POSEIDON generated excitement because it enabled the direct comparison of chemoimmunotherapy regimen encompassing an anti–PD-L1 inhibitor (durvalumab), with or without an anti–CTLA-4 inhibitor (tremelimumab), vs chemotherapy alone, Skoulidis says. This study uniquely addressed the question of whether patients could benefit for the combination of 2 agents with a chemotherapy backbone, or if there were subsets of patients who could benefit different combinations, Skoulidis expands.

One of the most important conclusions drawn from the trial was that patients with co-alterations, such as 

, were associated with primary resistance to immune checkpoint inhibitor monotherapy, or chemoimmunotherapy that includes only an anti–PD-(L)1 agent, Skoulidis notes. However, these patients did derive benefit from the addition of tremelimumab to durvalumab and chemotherapy in the POSEIDON study, Skoulidis emphasizes. Although these data stemmed from a subgroup analysis, the signal observed was strong and supports that the incorporation of tremelimumab plus durvalumab with chemotherapy for this subset of patients.

Additionally, these outcomes were in line with other studies in NSCLC that have also suggested some genomic subsets of patients may benefit from the incorporation of an anti–CTLA-4 agent to a chemoimmunotherapy backbone, Skoulidis notes. He says he currently uses tremelimumab plus durvalumab and chemotherapy in clinical practice specifically for patients with difficult-to-treat disease and baseline 

Ferdinandos Skoulidis, MD, PhD, MRCP, discusses the clinical implications for data from the combination of tremelimumab plus durvalumab and chemotherapy in metastatic non–small cell lung cancer without sensitizing EGFR mutation or ALK aberrations.

Dr Skoulidis on the Implications of the POSEIDON Trial of Tremelimumab Plus Durvalumab in NSCLC

Ferdinandos Skoulidis, MD, PhD, MRCP, assistant professor, Department of Thoracic/Head and Neck Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discusses the rationale to target TROP-2 in lung cancer.

TROP2 is a transmembrane glycoprotein that is involved in intracellular calcium signaling transduction and facets of tumorigenesis, including proliferation and metastasis, Skoulidis explains. Notably, TROP2 is overexpressed across a range of cancer types, including lung adenocarcinoma and squamous cell lung carcinoma, Skoulidis adds. As such, TROP2-directed treatments could offer a new generation of precision medicine–based lung cancer treatment. 

Findings from the ongoing phase 1 TROPION-PanTumor01 trial (NCT03401385), which were presented during the 

, demonstrated encouraging clinical efficacy with the TROP2-directed antibody-drug conjugate datopotamab deruxtecan (dato-DXd; DS-1062a) in patients with relapsed/refractory advanced or metastatic non–small cell lung cancer. At the dosing regimen of 6 mg/kg every 3 weeks, dato-DXd elicited an overall response rate of 26% and a median duration of response of 10.5 months in these patients, many of whom received prior immunotherapy and chemotherapy, Skoulidis concludes.

Ferdinandos Skoulidis, MD, PhD, MRCP, discusses the rationale to target TROP-2 in lung cancer.   



Dr. Skoulidis on the Rationale to Target TROP2 in Lung Cancer 

Ferdinandos Skoulidis, MD, PhD, MRCP, assistant professor, Department of Thoracic/Head and Neck Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discusses the results of a subgroup analysis from the phase 2 CodeBreaK 100 trial (NCT03600883) in patients with 

 G12C-mutant non–small cell lung cancer (NSCLC). 

Findings from the registrational CodeBreaK 100 study demonstrated a 37.1% objective response rate (ORR) with sotorasib (Lumakras) in patients with pretreated 

 G12C-mutant NSCLC. The median progression-free survival was 6.8 months. Notably, based on these findings, sotorasib was approved by the FDA on May 28, 2021, for the treatment of patients with 

 G12C-mutated NSCLC who have received at least 1 prior systemic therapy. 

During the 2021 ASCO Annual Meeting, overall survival (OS) data and exploratory subgroup analyses from the CodeBreaK 100 trial were presented virtually. The results revealed a median overall survival of 12.5 months with sotorasib. Additionally, sotorasib demonstrated efficacy across various prespecified patient and molecular subgroups. Notably, sotorasib was effective in patients whose tumors harbored 

 mutations, which is a population that has inferior outcomes with standard therapies, concludes Skoulidis. 

Ferdinandos Skoulidis, MD, PhD, MRCP, discusses the results of subgroup analysis from the phase 2 CodeBreaK 100 trial in patients with KRAS G12C-mutant non–small cell lung cancer. 










Dr. Skoulidis on the Results of Subgroup Analyses of the CodeBreaK 100 Trial in KRAS G12C-Mutant NSCLC 

Ferdinandos Skoulidis, MD, PhD, MRCP, assistant professor, Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, discusses combining chemotherapy and immunotherapy in non—small cell lung cancer (NSCLC).

The KEYNOTE-021 data suggested a combination of pembrolizumab (Keytruda) with carboplatin/pemetrexed was associated with a 55% objective response rate, almost more than a chemotherapy doublet alone.

Combining chemotherapy with immunotherapy benefited PD-L1—negative tumors and has an additive effect, so it would be a valid treatment option for patients who express low levels of PD-L1, explains Skoulidis.

Ferdinandos Skoulidis, MD, PhD, MRCP, assistant professor, Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, discusses combining chemotherapy and immunotherapy in non-small cell lung cancer (NSCLC).

Ferdinandos Skoulidis, MD, PhD, MRCP

Articles

Dr Skoulidis on the Methods of Analyzing KRAS G12C Inhibitor Efficacy in NSCLC

Dr Skoulidis on Determinants of KRAS G12C Inhibitor Efficacy in NSCLC

Dr Skoulidis on the Implications of the POSEIDON Trial of Tremelimumab Plus Durvalumab in NSCLC

Dr. Skoulidis on the Rationale to Target TROP2 in Lung Cancer

Dr. Skoulidis on the Results of Subgroup Analyses of the CodeBreaK 100 Trial in KRAS G12C-Mutant NSCLC

Dr. Skoulidis on Combining Chemotherapy and Immunotherapy in NSCLC