The Latest in Biomarker-Driven Non–Small Cell Lung Cancer Treatment

Liza C. Villaruz, MD

Through decades of research, key biomarkers for non–small cell lung cancer (NSCLC) have been established and agents have been developed to offer a targeted approach to treating patients with this disease. Such biomarkers include, EGFR, KRAS, ALK, ROS1, and RET, according to Liza C. Villaruz, MD.

As targeted therapies have become more widely used, the next step in research is to better understand mechanisms of resistance to said therapies, and to develop regimens to overcome those mechanisms, like introducing more multi-drug combinations.

“There's a lot out there, and it's encouraging. I think where we go from here is sort of figuring out how best to identify mechanisms of resistance and the best ways to tailor our targeted therapies, which are specific to the acquired resistance mechanism,” Villaruz, medical oncologist/hematologist at UPMC Hillman Cancer Center told Targeted Oncology^TM, in an interview.

In the interview, Villaruz, discussed important new therapies for biomarker-driven NSCLC, and novel biomarkers they may bring new treatments in the near future.

TARGETED ONCOLOGY: Can you talk about the latest therapies to be introduced in non–small cell lung cancer?

Villaruz: I think that the greatest area of growth within the recent past has been within areas of oncogenes driven non–small cell lung cancer, in particular specific subsets. There have been a lot of developments in the last couple of years in the smaller subsets of EGFR mutant disease, such as the EGFR exon 20 insertions, where we now have 2 approved agents, mobocertinib [Exkivity] and amivantamab [Rybrevant], which are promising agents in previously-treated patients with EGFR exon 20 insertion-positive tumors.

In addition to that, there have been a lot of activity, specifically in the KRAS G12C non–small cell lung cancer space. This is particularly important as this has historically been an incredible unmet need. It's a significant proportion of our patients with metastatic non–small cell lung cancer and to have effective targeted therapies, specifically in the KRAS G12C space, is a major advancement.

Which research in the KRAS G12C-mutated NSCLC space appears promising right now?

Adagrasib [Krazati] is an encouraging drug. It's a direct inhibitor of KRAS G12C, and it has activity that is somewhat similar to sotorasib [Lumakras]. What's encouraging is it looks as though it has a fair amount of central nervous system activity, which is quite nice. I think that it's another promising agent, it's good to have another drug within our toolbox to treat KRAS G12C-mutated non­–small cell lung cancer. I think the important thing to look forward to in the future is knowing ways in which tumors can become resistance to adagrasib, and ways in which we can combine that adagrasib with other drugs to lessen that resistance.

For EGFR-positive disease, which research has caught your attention?

In terms of EGFR-mutant disease, I think the greatest area of growth is within acquired resistance to osimertinib therapy and ways of attacking and treating that resistance. I think there are several different agents which have shown activity across numerous different resistance mechanisms, such as the bispecific monoclonal antibody, amivantamab. This has been combined with a third generation EGFR inhibitor, lazertinib [Leclaza], and it looks as though there could potentially be activity across several different resistance mechanisms in patients with acquired TKI resistance. In addition, there are some antibody-drug conjugates, like pertuzumab [Perjeta], which has fairly encouraging activity across a number of different resistance mechanisms.

There's a lot out there, and it's encouraging. I think where we go from here is sort of figuring out how best to identify mechanisms of resistance and the best ways to tailor our targeted therapies, which are specific to the acquired resistance mechanism.

What are some of the novel biomarkers under investigation in NSCLC?

We have our oncogene driven disease, and they are the gold standard in terms of predictive biomarkers of therapeutic benefit regarding EGFR, ALK, ROS1, and RET. We also have PD-L1, which is the gold standard for predicting therapeutic benefits to immunotherapy, either by itself, chemoimmunotherapy combinations, or immunotherapy/immunotherapy combinations just combined PD-1 and CTLA4, therapies.

I think as we go forward, [it will] be interesting to see how TROP is predictive of benefit to TROP2 inhibitors, and also CEACAM5, because there are novel therapies aimed toward that as well. I think it'll be interesting to see how all of these different biomarkers could potentially predict the benefit of their targeted agents. There is also still a fair amount of work with NET, and several different NET antibody-drug conjugates which are also within development.