Identifying New Treatments and Biomarkers in Small-Cell Lung Cancer

Clinical trials are a key aspect of developing new therapies in any disease, but one area where they are well-known to patients and the public is oncology. Cancer has long proven a difficult disease to treat, but novel therapies and combinations are finally beginning to show significantly improved patient outcomes in several types of cancer. 

One patient population that has certainly benefitted from the plethora of clinical trials in recent years and the subsequent drug approvals are those with lung cancer, who make up roughly 13% of cancer patients in the United States. But the vast majority of newly approved lung cancer treatments are for non–small cell lung cancer. Small-cell lung cancer (SCLC), on the other hand, has not seen all that much progress until recently.

Charles Rudin, MD, chief of Thoracic Oncology Service at Memorial Sloan Kettering Cancer Center and principal investigator of the National Cancer Institute Small Cell Lung Cancer Consortium, gave The American Journal of Managed Care (AJMC^®) his insights into the state of SCLC treatment, clinical trials, and what the future may hold.

The following has been edited lightly for clarity.

AJMC®: SCLC treatment has been relatively slow to adapt as far as the identification of new, effective therapy options. What treatments have shown the most promise in recent trials?

Rudin: Probably the most important recent advance in small-cell has been the advent of immunotherapy for small-cell as part of its first-line therapy, so the introduction of either atezolizumab or durvalumab, both of which are PD-L1 antibodies. When added to first-line chemotherapy, they showed a significant survival advantage. It's really the first time in a very long time we've had a positive trial for first-line metastatic small-cell, so those really serve as benchmarks.

AJMC®: Identifying biomarkers predictive of therapy response has also been a challenge in SCLC. Have any trials in particular shed light on biomarkers for SCLC that can help guide ongoing clinical trials and treatment?

Rudin: Defining biomarkers for small-cell lung cancer has been a real challenge. I think we are beginning to make progress in that domain. One biomarker that we think is of interest is some market called Schlafen-11. When Schlafen-11 is silenced, it causes resistance to both chemotherapy and to PARP inhibitors, and there's been clinical data suggesting that Schlafen-11 may be a predictive biomarker for PARP inhibitor activity. The other biomarker framework that I think is emerging in small-cell lung cancer is the understanding that there are different transcriptional subsets of small-cell lung cancer—we call them subtypes—driven by transcription factors ASCL1, NEUROD1, and POU2F3. We think these may dictate differential sensitivity to a variety of therapies.

AJMC®: Where in the current SCLC treatment algorithm would you say there is the most room for new therapy options/improvements?

Rudin: There's room for new therapy opportunities across the board. In our first line therapy, the advent of immunotherapy has improved outcomes. But if we look at the median, it really only moves it by a couple of months in median survival, from maybe 11 months to 13 months. We need to do better than that. We know that immunotherapy benefits a minority of patients, maybe 10% to 20%. There's 80 to 90% where it doesn't work, so I think even in the very first-line setting, there's real room for improvement.

In limited-stage small-cell lung cancer, about a quarter of patients derive long-term benefit from the combination of chemotherapy and radiation, but unfortunately, 75% do not, so there’s plenty of room for improvement there. And in recurrent small-cell lung cancer, which is common, we don't have good therapies for it. It's hard to define 1 field—I think they're all important.

AJMC®: Based on current trials and real-world data, what do you see in the future of SCLC treatment?

Rudin: I think we can build on the initial benefit that we've seen with immunotherapy. There is a lifting of the tail of the survival curve—a durable benefit in 10% to 20% of patients, probably closer to 10%. But I think that serves as an important guide to a path forward if we can further raise the tail of that curve. I think a number of strategies are being looked at to try to induce immune reactivity in the 80% to 90% of tumors that are not immunoresponsive. Some of those strategies include epigenetically targeted drugs, other immunotherapy drugs that may be complimentary to PD-1, or the use of DNA damage inhibitors that may also induce inflammation within the tumor and lead to greater immune reactivity. All these strategies are being explored now.

AJMC®: The pandemic has brought challenges in both cancer care and clinical trials. How have the trials you are involved in adapted to the new reality? Have there been any helpful changes you think might be here to stay?

Rudin: Certainly, the advent of COVID was a huge blow across the board for cancer care, and for small-cell lung cancer patients as well. What I think was remarkable is the rapidity with which we were able to, as a field, actually implement changes in clinical trials—allowing patients to do more telemedicine visits, allowing patients to have multiple months’ worth of medication at home as opposed to needing to check into the clinic every 3 weeks, more flexibility in terms of active surveillance of patients on clinical trials—without an evident decrease in the safety of those trials, or the ability to monitor those trials. In a way, this has been a learning opportunity for the field in how to do more remote medicine, which is of benefit to patients. It saves them trips, it saves them time, and if we can do this more efficiently with increased use of telemedicine, I think that is a benefit.

AJMC®: What would you say to SCLC patients hesitant to participate in a clinical trial?

Rudin: There's a lot of excitement now in the field of small-cell lung cancer, with a lot of new therapy approaches that are coming to the fore. Historically, this has been a very difficult to treat with very poor outcomes. I think there's reason to be hopeful that that is going to change based on emerging science and new concepts. The way to get access to those new concepts and to that new science is by active participation in clinical trials. These clinical trials are set up, in general, to offer patients the standard of care with the addition of an investigational drug. So oftentimes, it allows patients to receive good care with close monitoring, and get access to what I would consider to be the cutting edge of oncology care.