Real world evidence of treatment practices and therapeutic outcomes for newly diagnosed NSCLC patients with non-classical EGFR mutations demonstrates high unmet medical need

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Dr. Xiuning Le highlights real-world data on therapeutic outcomes for newly diagnosed NSCLC patients with non-classical EGFR mutations, emphasizing the need for improved treatments, at ESMO Congress 2024.

Real World Evidence of Treatment Practices and Therapeutic Outcomes for Newly Diagnosed NSCLC Patients With Non-Classical EGFR Mutations Demonstrates High Unmet Medical Need

Dr Le on SOHO-01 Data With BAY 2927088 in HER2-Mutated NSCLC

Xiuning Le, MD, PhD, associate professor, Department of Thoracic/Head and Neck Medical Oncology, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, discusses updated findings from the phase 1/2 SOHO-01 trial (NCT05099172).

SOHO-01 examined the oral, reversible TKI BAY 2927088, which has been shown to potently inhibit activating 

 mutations in preclinical models. Data from SOHO-01 presented during the 

2024 IASLC World Conference on Lung Cancer

 showed that patients with advanced non–small cell lung cancer harboring 

 exon 20 insertions who were targeted therapy naive (n = 43) achieved an investigator-assessed objective response rate (ORR) of 72.1% (95% CI, 56.3%-84.7%), including a 2.3% complete response rate. The disease control rate (DCR) was 83.7% (95% CI, 69.3%-93.2%), the median duration of response (DOR) was 8.7 months (95% CI, 4.5-not evaluable [NE]), and the median progression-free survival (PFS) was 7.5 months (95% CI, 4.4-12.2), Le adds.

 YVMA insertions (n = 30) experienced an ORR of 90.0% (95% CI, 73.5%-97.9%) and a DCR of 96.7%, Le highlights. Among these patients, the median DOR was 9.7 months (95% CI, 5.5-NE) and the median PFS was 9.9 months (95% CI, 6.9-NE), Le says. In the safety population (n = 44), patients experienced any-grade treatment-related adverse effects (TRAEs; 95.5%) and grade 3 or higher TRAEs (43.2%). The most common any-grade TRAEs included diarrhea (86.4%), rash (43.2%), paronychia (25.0%), and nausea (25.0%). Three patients experienced TRAEs leading to treatment discontinuation, 31.8% had dose reductions due to TRAEs, and 11.4% experienced serious TRAEs.

Xiuning Le, MD, PhD, discusses updated findings from the phase 1/2 SOHO-01 trial.

Xiuning Le, MD, PhD, assistant professor, Department of Thoracic/Head and Neck Medical Oncology, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, discusses findings from the interim analysis of the phase 2 RAMOSE trial (NCT03909334) in patients with TKI-naïve metastatic non–small cell lung cancer (mNSCLC) harboring 

RAMOSE enrolled patients with advanced NSCLC and classical 

 mutations who had not received prior TKIs or VEGF-directed therapy. Patients needed to have an ECOG performance status of 0 or 1, stable central nervous system metastases, if present, and no recent pulmonary embolism or stroke. Patients were randomly assigned 2:1 to receive either osimertinib (Tagrisso) plus ramucirumab (Cyramza) or osimertinib monotherapy. The primary end point of this trial was investigator-assessed progression-free survival (PFS) per RECIST v1.1. Key secondary end points include overall response rate, disease control rate, overall survival, and safety.

A total of 139 patients in the United States were treated in this study, 93 in the combination arm and 46 in the monotherapy arm. All patients included in the interim analysis had received at least 1 efficacy scan, Le says. In the combination arm, 64.5% of patients were White, 25.8% of patients were Asian, 3.2% of patients were Black, and 6.5% of patients were other races. These percentages in the monotherapy arm were 56.5%, 21.7%, 4.3%, and 17.4%, respectively.

At a median follow-up of 16.6 months, the median PFS by investigator assessment was 24.8 months (95% CI, 17.9-not reached) with the combination vs 15.6 months (95% CI, 11.7-22.8) with osimertinib monotherapy (HR, 0.55; 95% CI, 0.32-0.93; log-rank 

 = .026). The median duration of ramucirumab treatment in the combination arm was 14.2 months, and patients received ramucirumab at 86.6% dose intensity. 

These findings show that the combination of osimertinib and ramucirumab prolongs PFS and provides patients with additional survival benefits vs osimertinib monotherapy, Le concludes.

Dr Le reports consulting or advisory fees from Eli Lilly, EMD Serono (Merck, KGaA), AstraZeneca, Spectrum Pharmaceuticals, Novartis, Regeneron, Boehringer Ingelheim, Hengrui Therapeutics, Bayer, Teligene, Taiho, Daiichi Sankyo, Janssen, Blueprint Medicines, Sensei Biotherapeutics, SystImmune, ArriVent, Abion, and AbbVie; institutional research funding from Eli Lilly, EMD Serono, Arrivent, Dizal, Teligene, Regeneron, Janssen, ThermoFisher, Takeda, and Boehringer Ingelheim; travel support from EMD Serono, Janssen, and Spectrum Pharmaceuticals; and stock options from BlossomHill.

Xiuning Le, MD, PhD, discusses findings from the interim analysis of the phase 2 RAMOSE trial in patients with TKI-naïve metastatic non–small cell lung cancer harboring EGFR mutations.

Dr Le on the Efficacy of Osimertinib Plus Ramucirumab in EGFR-Mutant mNSCLC

Xiuning Le, MD, PhD, assistant professor, Department of Thoracic/Head and Neck Medical Oncology, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, discusses ongoing and future investigations with osimertinib (Tagrisso) and chemotherapy in patients with metastatic lung cancer.

Most patients with lung cancer are diagnosed with metastatic disease, Le begins. For patients with locally advanced, 

-mutant non–small cell lung cancer (NSCLC), osimertinib is currently the global standard of care, Le explains. However, investigators continue to discuss new ideas for how to improve upon the current data seen with osimertinib in this population, she adds. For example, investigators want to improve upon the progression-free survival (PFS) advantages associated with osimertinib in patients with 

One such idea to improve upon these data is to add chemotherapy to upfront osimertinib, Le expands. This strategy delivers a toxic regimen to the tumor to decrease the amount of tumor cells upfront, andinvestigators hypothesize that this approach will prolong the benefits of osimertinib, Le explains. Findings from the phase 3 FLAURA2 trial (NCT04035486) have shown that combining chemotherapy with osimertinib upfront is superior to offering osimertinib alone, Le says. These highly anticipated data will be discussed in detail at the International Association for the Study of Lung Cancer 2023 World Conference on Lung Cancer, according to Le.

Another area of consideration when evaluating treatment approaches for patients with metastatic lung cancer is the magnitude of potential benefit that patients can derive from these therapies, Le continues. Additional data from FLAURA2 will indicate whether the addition of chemotherapy to osimertinib provides a long-term PFS benefit in patients with EGFR-mutant NSCLC, Le notes. Another area of interest is the toxicity profile associated with this approach, she says. Overall, these exciting data, once released, will spur further scientific questions, Le concludes.

Xiuning Le, MD, PhD, discusses ongoing and future investigations with osimertinib and chemotherapy in patients with metastatic lung cancer.


Dr Le on the Investigation of Osimertinib and Chemotherapy in Metastatic Lung Cancer

Xiuning Le, MD, PhD, assistant professor, Department of Thoracic/Head and Neck Medical Oncology, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, discusses the emergence of antibody-drug conjugates (ADCs) in non–small cell lung cancer (NSCLC).

In the past 15 years, targeted therapy has revolutionized the treatment of patients with NSCLC who harbor actionable alterations, Le explains. Historically, targeted therapy has consisted of oral small molecule inhibitors that inhibit specific driver oncogenes, such as 

However, novel approaches such as ADCs directed toward targets expressed on the surface of cancer cells are in clinical development, Le says. ADCs offer a promising strategy to target overexpressed proteins with a chemotherapeutic payload. Although ADCs still fall under the umbrella of precision oncology, they could offer a different targeted option to small molecular inhibitors. Moreover, patients who progress on small molecule inhibitors, such as EGFR inhibitors, could be eligible to receive ADCs, Le concludes. 

Xiuning Le, MD, PhD, discusses the emergence of antibody-drug conjugates in non–small cell lung cancer. 



Dr. Le on the Emergence of Antibody-Drug Conjugates in NSCLC 

Xiuning Le, MD, PhD, an assistant professor of thoracic/head and neck medical oncology, Division of Internal Medicine, at The University of Texas MD Anderson Cancer Center, discusses next steps with poziotinib (NOV120101, HM781-36B) in patients with 

- or HER2-positive exon 20–mutant non–small cell lung cancer (NSCLC).

The agent was examined in the phase 2 ZENITH20 trial (NCT03318939), which administered poziotinib twice daily in patients with 

- or HER2-positive exon 20–mutant NSCLC, according to Le. This trial had numerous arms, with cohort 2 focused on patients with HER2-positive exon 20 disease who had received prior therapies. Patients in this cohort experienced an objective response rate of 27.8%.

The next steps for poziotinib involve going through the FDA fast-track process, Le says. By optimizing the treatment regimen, it is possible to provide patients with a better quality of life, as well as keep them on the drug longer, which may potentially improve efficacy. Through this, it is possible that more patients, including those who are 

positive, may benefit from treatment with poziotinib, Le concludes.

Xiuning Le, MD, PhD, discusses next steps with poziotinib (NOV120101, HM781-36B) in patients with EGFR-positive or HER2-positive exon 20–mutant non–small cell lung cancer.

Dr. Le on Next Steps With Poziotinib in EGFR+ or HER2+ Exon 20 NSCLC

Xiuning Le, MD, PhD, an assistant professor of thoracic/head and neck medical oncology, Division of Internal Medicine, at The University of Texas MD Anderson Cancer Center, discusses the safety findings of the phase 2 ZENITH20-5 study (NCT03318939) with poziotinib in patients with 

- or HER2 exon 20–positive non–small cell lung cancer (NSCLC).

When comparing a 16 mg daily dose of poziotinib with an 8 mg twice daily dose, a significant reduction in adverse effects (AEs), such as diarrhea and rash, were observed, according to Le. This reduction in AEs can significantly improve patient quality of life, Le adds. Additionally, significant reductions or delays to first dose interruption were noted with the twice-daily regimen.

By splitting the daily 16-mg dose into an 8-mg dose given twice daily, the full dose of poziotinib was still received with significantly improved safety, Le says. Currently, investigators are examining whether the total dose intensity of this regimen will be improved, which is likely, Le concludes.

Xiuning Le, MD, PhD, discusses the safety findings of the phase 2 ZENITH20-5 study with poziotinib in patients with EGFR- or HER2 exon 20–positive non–small cell lung cancer.

Dr. Le on the Safety of Twice-Daily Poziotinib in EGFR- or HER2 Exon 20–Positive NSCLC

Xiuning Le, MD, PhD, assistant professor, Department of Thoracic/Head and Neck Medical Oncology, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, discusses the design of the phase 2 VISION trial in 

ex14)—mutant non–small cell lung cancer (NSCLC).

Given the rationale to support the use of the tepotinib (Tepmetko) in this patient population, investigators launched a single-arm design rather than a randomized trial with chemotherapy, Le explains.

The ongoing ​VISION trial ​is a global trial that will determine whether tepotinib has utility as a targeted therapy in patients with this rare alteration, Le concludes.

Xiuning Le, MD, PhD, discusses the design of the phase 2 VISION trial in MET exon 14 skipping—mutant non–small cell lung cancer. 

Dr. Le on the Design of the VISION Trial in METex14-Mutant NSCLC 

Xiuning Le, MD, PhD, assistant professor, Department of Thoracic/Head and Neck Medical Oncology, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, discusses the rationale for tepotinib (Tepmetko) in 

While the role of targeted therapy has grown significantly in lung cancer treatment over the past 2 decades, 

ex14 mutations are a relatively new oncogenic driver, says Le. If the exon 14 is “skipped out” because of the mutation, the 

 signaling keeps going, which drives the cancer cells to grow, explains Le; that cancer cell growth results in the development of lung cancer.

Tepotinib is a small molecule inhibitor that targets intracellular part of 

 alterations, says Le. The agent has been optimized to target 

 amplification, and it has proved to be very potent in cell cultures. In patients, tepotinib has been shown to elicit 99% target engagement, adds Le.

Based on this promise, investigators set out to examine the oral, highly selective 

 inhibitor in patients with locally advanced or metastatic NSCLC who harbor

ex14 skipping mutations identified through liquid or tissue biopsy in the phase 2 VISION trial. Findings from the trial that were recently presented at the 

 demonstrated durable clinical activity and manageable toxicity with tepotinib in this patient population.

Xiuning Le, MD, PhD, discusses the rationale for tepotinib in MET exon 14 skipping

Xiuning Le, MD, PhD

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