Timothy Burns, MD, PhD, associate professor of medicine, associate program director, Research, associate program director, Hematology/Oncology Fellowship Program, Department of Medicine, Division of Hematology-Oncology, UPMC Hillman Cancer Center, discusses the evolution of antibody-drug conjugates (ADCs) in 

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

Although ADCs have been employed as an effective treatment option in the breast cancer space for several years, these agents have only recently been evaluated and approved for lung cancer, Burns begins.

Fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) received a breakthrough therapy designationfrom the FDA in 2020 for patients with metastatic NSCLC whose tumors express 

 mutations and who have disease progression on or after platinum-based therapy. This designation was based on the results of the phase 2 DESTINY-Lung01 trial (NCT03505710), which evaluated the efficacy and safety of T-DXd in patients with HER2-overexpressing tumors (2+ or 3+ via immunohistochemistry) and 

 mutations. In the latter population, the regimen elicited an objective response rate (ORR) of 54.9%, Burns says.

On August 11, 2022, T-DXd became the first ADC to gain FDA approval for this specific patient population, Burns continues. Notably, it is also the first non-TKI targeted therapy to show activity in 

-mutant NSCLC, which is a smaller subgroup within lung cancer, Burns adds. The regimen’s approval was based on efficacy findings from the phase 2 DESTINY-Lung02 trial (NCT04644237), in which T-DXd elicited a confirmed ORR of 57.7% and a median duration of response of 8.7 months.

There’s also increased interest in expanding the use of ADCs for other HER2-expressing tumors, Burns says. Moreover, ADCs are being investigated for other molecular targets beyond HER2, Burns details. These mutations could function as oncogenic drivers and others may help define select populations within small cell lung cancer or mesothelioma that could benefit from ADCs, he states.

Although these agents are not new, novel methods of linking drugs to antibodies could be explored to improve their efficacy in other disease spaces, Burns explains. For example, ado-trastuzumab emtansine (Kadcyla) showed success in the treatment of HER2-positive breast cancer, but was less effective in HER2-overexpressing lung cancers, he expands. Therefore, it is important to find the optimal drug to utilize in NSCLC, Burns concludes.

 Dr Burns is on advisory boards for Amgen, AstraZeneca, Blueprint Medicines Corporation, EMD Serono Inc, Janssen, Mirati Therapeutics, and Takeda; is on the data and safety monitoring board for Advarra, Inc; and has received research funding for an investigator-initiated trial from Novartis (Inst.).

Videos

Timothy Burns, MD, PhD, discusses the evolving use of antibody-drug conjugates  in HER2-mutant non–small cell lung cancer.

Dr. Burns on the Evolving Use of ADCs in HER2-mutant NSCLC

Timothy F. Burns, MD, PhD, medical oncologist, UPMC Hillman Cancer Center, associate professor of medicine, associate program director, Research, Hematology/Oncology Fellowship Program, University of Pittsburgh, discusses key developments in the frontline treatment of patients with 

-positive non–small cell lung cancer (NSCLC).

Recent considerations for first-line therapy have focused on 

 fusions. Although these targets are well known, specific drugs to address these markers were not available until recently, and previous agents utilized in this setting elicited only modest response rates of approximately 30%, Burns says. Additionally, patients with 

positive NSCLC can be difficult to treat as they often do not respond to immunotherapy, chemotherapy, or a combination of both modalities, Burns explains.

Agents such as selpercatinib (Retevmo) and pralsetinib (Gavreto) have received regulatory approval, and both specifically target 

 alterations, Burns adds. The agents have demonstrated high response rates of approximately 60%. In those who are treatment naïve, response rates are as high as 85%, Burns says. For many of these patients, the median overall survival has not yet been reached, but could range from 18 months to 2 years. As such, these agents represent a major advance for this patient population, Burns concludes.

Timothy F. Burns, MD, PhD, discusses key developments in the frontline treatment of patients with RET-positive non–small cell lung cancer.

Dr. Burns on Key Advances Made in RET+ NSCLC 

Timothy F. Burns, MD, PhD, medical oncologist, UPMC Hillman Cancer Center, associate professor of medicine, associate program director, Research, Hematology/Oncology Fellowship Program, University of Pittsburgh, discusses the promise of combination regimens for patients with 

 G12C–mutated non–small cell lung cancer (NSCLC).

Although the approvals of targeted agents for patients with 

 G12C–mutated NSCLC advanced the lung cancer paradigm, most patients will progress on these agents. This underscores the need for improved options in these patient subtypes, Burns explains.

As such, it will be important to understand mechanisms of resistance to targeted agents and tease out the optimal way to treat patients who develop resistance. Combining targeted therapy with chemotherapy or immunotherapy could offer improved strategies vs single-agent targeted therapy, Burns says. Additionally, targeting pathways, such as VEGF, as well as developing novel monoclonal antibodies could be beneficial in this patient population. 

Finally, although challenges with toxicity could arise, combining targeted therapies with other agents could improve upon response rates and avoid acquired resistance, Burns concludes. 

Timothy F. Burns, MD, PhD, discusses the promise of combination regimens for patients with EGFR exon 20 insertion– and KRAS G12C–mutated non–small cell lung cancer. 



Dr. Burns on the Promise of Combination Regimens in EGFR Exon 20 Insertion+ and KRAS+ NSCLC 

Timothy F. Burns, MD, PhD, assistant professor of medicine, Department of Medicine, Division of Hematology/Oncology, at the University of Pittsburgh Cancer Institute, and medical oncologist at University of Pittsburgh Medical Center Hillman Cancer Center, discusses methods of identifying genetic alterations in lung cancer.

There are several ways to identify a translocation, but a tumor biopsy is the gold standard. For 

, approaches include immunohistochemistry, fluorescence in situ hybridization (FISH), and next-generation sequencing (NGS). For 

, there is FISH and NGS, says Burns. If adequate tissue can’t be collected, blood-based testing is recommended. Standard blood-based testing with Guardant360 or FoundationOne sequences the DNA in the blood, but it also does fusion capture. However, fusion capture can be inaccurate, says Burns, and although a blood-based test can identify an 

 translocation that is missed on a blood-based assay, it is simply a failure of the fusion capture, says Burns. Therefore, blood-based assays have to be interpreted with caution. When it comes to sequencing the 

 gene for second-site mutations, both tissue-based and blood-based assays can be used to identify the right treatment for patients, concludes Burns.

Timothy F. Burns, MD, PhD, discusses methods of identifying genetic alterations in lung cancer.

Timothy F. Burns, MD, PhD

Articles

Dr. Burns on the Evolving Use of ADCs in HER2-mutant NSCLC

Dr. Burns on Key Advances Made in RET+ NSCLC

Dr. Burns on the Promise of Combination Regimens in EGFR Exon 20 Insertion+ and KRAS+ NSCLC

Dr. Burns on Identifying Genetic Alterations in Lung Cancer