At the 2024 Targeted Therapies of Lung Cancer meeting, which took place February 21-24 in Santa Monica, California, Anne Chiang, MD, PhD, faced off with Stephen Liu, MD, to debate the use of biomarkers in the clinical management of patients with extensive-stage small cell lung cancer (SCLC)

Arguing in favor of biomarkers in this space, Dr. Chiang, Associate Professor and Associate Cancer Center Director at Yale School of Medicine, New Haven, Connecticut, began by addressing what she said are the top myths about treating SCLC.
No. 1: It is difficult to obtain tumor tissue from small cell patients. This, she said, is not necessarily true. Using one of her own patients as an example, Dr. Chiang showed there is a lot of tissue, and the only difference is that there is not a biomarker requirement for a treatment decision.
No. 2: There’s a one-size-fits-all homogeneous approach. “We’ve seen a lot of data in this session alone that shows we have differences,” she said. “That’s really exciting because that means we can target those selective vulnerabilities.”
No. 3: SCLC patients are not ideal clinical trial candidates because they have a poor performance status. Dr. Chiang argued biomarker trials could be designed in ways to better include SCLC patients. She pointed to the Southwest Oncology Group’s (SWOG) 1929 trial (S1929) as an example.
“This is the first biomarker-directed trial of a PARP inhibitor plus atezolizumab versus atezolizumab alone to show a positive benefit. The amazing thing about this is that it accrued well because it allowed patients to consent after that first cycle of therapy.”
Given the recent influx of data showing the heterogenous nature of SCLC and evidence that biomarker-driven trials can be successful, Dr. Chiang said she believed biomarkers use could be effective in this space.
“I think we need to take a page out of the book for from KRAS,” she said. “This was the undruggable target, right? And now we have FDA approved drugs for a single mutation as well as lots of other drugs in development. I think that you have to vote for a positive approach for our patients going forward.”
Dr. Chiang said this is important because of the unmet clinical need in SCLC and the high rate of recurrence. Given the feasibility of biomarker-directed therapy demonstrated by S1929, she said it was time to stop treating all SCLC the same and to start targeting selective vulnerabilities while expanding the knowledge base in the process.

However, Dr. Liu, Associate Professor of Medicine, Director of Thoracic Oncology, and Head of Developmental Therapeutics at Georgetown University Lombardi Comprehensive Cancer Center, Washington, DC, disagreed.
“I’m a biomarker guy,” he began. “l am totally in favor of biomarkers when they are validated; when they predict outcomes; when they direct treatment; and when they help our patients. But the bottom line is biomarkers are just not ready in small cell.”
Dr. Liu said he understands that the current frontline treatment of chemoimmunotherapy (chemo-IO) does not achieve the results clinicians and patients would wish to see. However, he said, survival has improved since the IMpower 133 and CASPIAN trials made chemo-IO standard.
“We know that these responses can last,” he said. “We have long-term survival data in CASPIAN. At 3 years, 18% of patients are alive; at 5 years, 12% of patients are alive. These are better than what we had in the past.”
Unfortunately, he said, when it comes to using biomarkers to identify SCLC patient who may benefit from targeted treatment, the data is just not there to inform those decisions.
“We’ve looked at the usual suspects, PDL1, TMB,” he said. “We’ve looked at every clinical characteristic that makes sense and a bunch that don’t make sense. We’ve looked at the genomic data. We’ve generated dozens of signatures. We just don’t have it. It’s just not there.”
Dr. Liu explained that while many efforts to find actionable targets look promising on paper or in vitro, the promise has faded in practice.
“Look at PARP inhibitors,” he said. “On paper, PARP inhibitors look great. Preclinical data look fantastic. The subset data? There is a clear benefit from PARP inhibition in those that express SLFN11.”
However, he said that while S1929 was notable as a biomarker study in SCLC, he would not call it a positive trial.
“This (SLFN11) is not a biomarker that’s ready for the clinic,” Dr. Liu said. “It is not there yet. We can’t force it.”
He said having recent research that has demonstrated the heterogeneity of SCLC is a huge first step. As is other recent research showing that liquid biopsy can be used to identify subsets of SCLC.
“I think we have two pieces of a 1,000-piece puzzle here,” Dr. Liu said. “The promise here is that these subtypes can reveal therapeutic vulnerabilities… I know some believe we can leverage these unique biologies like we do in non-small cell, but we’re not there yet in the real world. It’s a little different. These aren’t genomically defined clonal driver populations. It’s not like an EGFR permutation or an ALK fusion, where all tumor cells have that same vulnerability. These are very heterogeneous. These states coexist and are not mutually exclusive. They often feed off each other; communicate to each other. We don’t understand that yet.
“I understand the urge to use them because when you have a perfectly controlled environment lots of things seem like they’re going to work. But we’ve seen dozens of phase III studies based on solid science that fall apart in small cell lung cancer.”
The bottom line, he said, is the standard remains chemo-IO for all—for now.