Jia Luo, MD, is a physician at Dana-Farber Cancer Institute and an instructor in Medicine at Harvard Medical School, both in Boston, Massachusetts. 

Jia Luo, MD, discusses ctDNA outcomes following treatment of daraxonrasib in ctDNA-evaluable patients with RAS G12X–mutant advanced NSCLC.

Dr Luo on the Association Between ctDNA and Response to Daraxonrasib in RAS G12X–Mutant Advanced NSCLC

“The most interesting finding was that individuals who had more of a steep change from baseline to on-treatment circulating tumor DNA [ctDNA] had a better future result, and the change in the ctDNA actually predicted future outcomes in those patients.”

Jia Luo, MD, a physician at Dana-Farber Cancer Institute and an instructor in Medicine at Harvard Medical School, discussed the results from a 

circulating tumor DNA (ctDNA) analysis following the treatment of daraxonrasib

 (RMC-6236) in patients with advanced non–small cell lung cancer (NSCLC) harboring 

The ctDNA analysis from a phase 1 trial (NCT05379985) showed that among ctDNA-evaluable patients (n = 35), 66% experienced complete ctDNA clearance, which was defined as a 100% reduction in 

 variant allele frequency (VAF). Of note, patients who received pretreatment and treatment early on had plasma collected for ctDNA analysis, Luo explained. In the analysis, mutations were distributed based on type, which included 

Moreover, 11 ctDNA-evaluable patients achieved a partial response, and 82% of these patients experienced complete ctDNA clearance. Notably, patients who had a steeper change from baseline to on-treatment ctDNA also had better outcomes, Luo said. Therefore, the change in ctDNA helped predict future outcomes in respective patients, she emphasized.

Early efficacy findings from the phase 1 study revealed that patients with 

G12X–mutant NSCLC treated with daraxonrasib in the second- or third-line setting at 120 mg to 220 mg once daily (n = 40) achieved a confirmed overall response rate of 38%, all of which were partial responses. The median duration of response was 15.1 months (95% CI, 11.1-not evaluable [NE]), with a median time to response of 1.5 months (range, 1.2-6.2). Additionally, the median progression-free survival was 9.8 months (95% CI, 6.0-12.3) and the median overall survival was 17.7 months (95% CI, 13.7-NE).

Any-grade and grade 3 treatment-related adverse effects (TRAEs) occurred in 97% and 16% of patients, respectively; however, there were no reported grade 4 or 5 TRAEs. Dose interruptions due to TRAEs occurred in 34% of patients, with dose reductions and treatment discontinuations reported in 21% and 4%, respectively. Between the findings from the ctDNA analysis and the early efficacy and safety data of daraxonrasib, the next steps are moving towards launching a phase 3, randomized study.

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Jia Luo, MD, medical oncologist, Lowe Center for Thoracic Oncology, cancer researcher, Dana-Farber Cancer Institute, instructor in medicine, Harvard Medical School, discusses a retrospective analysis of initial chemotherapy regimens for the treatment of patients with locally advanced and metastatic NUT carcinoma, which was presented at the 2023 IASLC World Conference on Lung Cancer.

Prior research has determined that select patients with NUT carcinoma are sensitive to chemotherapy. Although limited case reports suggest that platinum- and ifosfamide-based regimens are the most effective treatment options, the chemotherapy most optimal for this subset is not definitively known. Therefore, a retrospective study was conducted to assess which initial chemotherapy regimen was associated with superior survival outcomes.

In the study that was conducted, investigators analyzed primary medical records from 118 patients with non-metastatic or metastatic NUT carcinoma who received chemotherapy treatment and consented to participate in a worldwide registry.

Findings revealed that patients with non-metastatic disease experienced a progression-free survival (PFS) benefit with ifosfamide-based treatment vs a platinum-based regimen, Luo reports, noting that this approach enhanced the depth of responses. However, these positive signals did not extend to overall survival, and were not seen in the metastatic cohort, Luo notes. Consequently, the study's primary recommendation is that ifosfamide-based treatment should not become standard practice for individuals with NUT carcinoma, Luo states.

The second part of the study focused on those who achieved long-term responses, Luo explains. All of these patients had non-metastatic disease and received multimodal therapy, which included surgical resection and often involved radiation therapy, Luo details. This emphasizes the importance of comprehensive and personalized approaches in managing patients with NUT carcinoma, particularly in cases where the disease is resectable at diagnosis, Luo emphasizes.

Overall, these findings underscore the critical need for more effective combination therapies in this population, Luo says. Clinical trials at institutions such as Dana-Farber Cancer Institute are actively addressing this challenge, she adds. The study authors encourage both healthcare providers and patients to consider participating in clinical trials in this disease space, Luo concludes.

Jia Luo, MD, discusses a retrospective analysis of initial chemotherapy regimens for the treatment of patients with locally advanced and metastatic NUT carcinoma, which was presented at the 2023 IASLC World Conference on Lung Cancer.

Dr Luo on Optimal Initial Chemotherapy Regimens in NUT Carcinoma

Jia Luo, MD, medical oncologist, Lowe Center for Thoracic Oncology, cancer researcher, Dana-Farber Cancer Institute, instructor in medicine, Harvard Medical School, discusses the potential use of KB-0742 to target specific MYC-driven tumor types, as well as challenges in the detection of 

 amplification or overexpression in clinical practice.

The novel, highly selective CDK9 inhibitor KB-0742 was specifically designed for the treatment of patients with 

-amplified relapsed/refractory solid tumors or non-Hodgkin lymphoma (NHL), Luo begins. The oral agent is currently under investigation in a phase 1/2 dose-escalation/expansion trial (NCT04718675) of patients with 

-amplified or -overexpressed relapsed/refractory solid tumors, or tumors with transcription factor dysregulation. Preclinical data have demonstrated the agent’s ability to reduce off-target effects and have longer target interaction when compared with other oral CDK-targeted agents. This can be attributed to the agent’s longer half-life and increased selectivity.

Unlike other CDKs that regulate the cell cycle, CDK9 promotes the activation of target genes that control RNA polymerase II transcription, she says. As increased 

 levels are known to upregulate the transcription of RNA polymerases I to III, this is an ideal target for patients with transcriptionally-addicted tumors, Luo explains. Amplification or overexpression of the 

oncogene has been implicated as a driver of several tumor types, including subsets of non–small cell lung cancer, triple-negative breast cancer, and epithelial ovarian cancer. Other cancers with dysregulated transcription due to 

 are soft tissue sarcomas, small cell lung cancer, and NUT carcinoma, Luo adds. 

 amplification or overexpression in these tumors requires broad panel, next-generation sequencing, fluorescent in situ hybridization, or an immunohistochemistry assay, Luo continues. However, these tests are not routinely performed for many patients with advanced solid tumors, she notes. Therefore, it is necessary to increase the use of broad molecular diagnostics for patients with these tumor types, Luo concludes.

Jia Luo, MD, discusses the potential use of KB-0742 to target specific MYC-driven tumor types, as well as challenges in the detection of MYC amplification or overexpression in clinical practice.
 

Jia Luo, MD

Articles

Dr Luo on the Association Between ctDNA and Response to Daraxonrasib in RAS G12X–Mutant Advanced NSCLC

Dr Luo on Optimal Initial Chemotherapy Regimens in NUT Carcinoma

Dr Luo on the Potential Use of KB-0742 In MYC-Amplified Tumors