Future Directions: Panel Discusses Unanswered Questions in Lung Cancer

At the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting, an expert panel convened to discuss non–small cell lung cancer (NSCLC), with an emphasis on young-onset lung cancer, psychosocial considerations, and the evolution of molecular testing and targeted therapy in NSCLC.

Moderated by Millie Das, MD, of Stanford University and the Palo Alto VA, the roundtable featured perspectives from Martin Dietrich, MD, PhD, of the US Oncology Network; Stephen Liu, MD, of Georgetown University; and Eric Singhi, MD, of the University of Texas MD Anderson Cancer Center.

In the final segment of this roundtable discussion, the panel reflects on the most important unanswered questions in lung cancer and what could be on the horizon.

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Dr. Das: Martin, we’re going to talk a little bit about future directions and unanswered questions. What are the questions that you would most like to see addressed in the targeted therapy space?

Dr. Dietrich: There are many. I do want to say that the targeted therapy space is dividing into 10 or more genetic subtypes that are defining non–small cell lung cancer the way we see it now. Each of them has its own individual set of challenges.

We see some intrinsic resistance that we oftentimes don’t understand, and [we] can’t predict how we see some initial responses with eventual growth of resistance and recurrence. We need to understand the evolution and some of the risk prognostication. We’ll need additional technology to help guide us [in] what to select and how to intensify treatment.

We’ve seen the first-line EGFR space evolving with additional combination options in addition to the third-generation EGFR TKIs [tyrosine kinase inhibitors]. Who needs them? Who needs more than just an EGFR TKI? Who are the patients that benefit long term? Who would do well without it?

We have to get away from thinking about this monogenically and think about the entire set of biology, [the] challenges for treatment. Subsequent lines of therapies have to be developed. We have to think about orthogonal mechanisms of action. We spoke earlier about immunotherapy for our patients with oncogenic drivers, and with the exception of KRAS and maybe BRAF, we don’t have many expectations that they would work. In fact, there’s a concern that they may actually be adding additional amplified toxicity to the targeted therapy.

We really want to be very cautious there, not just to give immunotherapy because it is effective in some subtypes of lung cancer, and then obviously, to see if we can moderate on-target toxicity.

I want to give an example: ALK or the ROS1 inhibitors, where we see closely related kinases that are targeted by the currently approved tyrosine kinase inhibitors and [are] really trying to have drugs that are very specific to the individual target and avoiding these off-target toxicities.

Or in the context of MET, for example, how to reach the therapeutic window between suppression of oncogenic signaling, or normalization of oncogenic signaling, but not necessarily the suppression of physiological signaling, to avoid some of the on-target side effects that we’re seeing.

There’s still a lot that we need to refine for our patients. There’s a lot of progress, a lot of new options that we see for patients. I do feel a lot of optimism about the understanding of a disease translating into additional therapy options. But there’s still a lot to be learned. We’re still in the beginning of precision medicine becoming a next leap towards the cure.

Dr. Das: Eric, what do you see on the horizon for targeted therapies in the next 5 to 10 years? Do you think we’re going to be using ctDNA [circulating tumor DNA], for example, in helping to make treatment decisions for our patients? Are there other things that you’re thinking about?

Dr. Singhi: I hope so. I’m really excited about it. Right now, the sensitivity just isn’t there to guide our treatment decision-making in terms of intensifying, in terms of de-escalating therapy. But I do feel that is on the horizon. It would be very exciting to be able to personalize even further our treatment options and the duration of therapy for a lot of patients.

As you know, we’re continuing to move a lot of these targeted therapies into earlier stages of disease. Just as much as the outcomes of survival matter for these patients, so does the quality of life. We need to think about the toxicity, the tolerability of these drugs that people are signing up for—sometimes for an indefinite amount of duration. I’m very hopeful for it, and I’m excited for it, and we’ll continue to see what happens.