Recent Advances in Small-Cell Lung Cancer - Episode 8

Unmet Needs and Challenges in Treating R/R SCLC

August 20, 2020
Vivek Subbiah, MD, MD Anderson Cancer Center

,
Anne Chiang, MD, PhD, Yale School of Medicine Smilow Cancer Hospital

,
Apar Ganti, MD, University of Nebraska Medical Center

Vivek Subbiah, MD: What other unmet needs and challenges are there in treating relapsed/refractory small cell lung cancer? Dr Ganti?

Apar Ganti, MD: We talked about new options like lurbinectedin and immunotherapy, but at the end of the day, overall survival in the relapsed setting, even with the phase 2 data from lurbinectedin, is still less than a year old. Earlier, we talked about immunotherapy being a big advance; again, the median overall survival is only about 13 months, slightly more than a year. We need better drugs, and we have to do better in this disease. There is a big unmet need, the recent advances in the use of immunotherapy notwithstanding. We need to do better by our patients. I think there is a lot of effort that needs to be put into identifying newer drugs and newer pathways, understanding the mechanism of resistance, and looking at biomarkers to see which patients can benefit and which don’t so we don’t expose them to some of these adverse effects. Those things need to be looked into for small cell lung cancer.

Vivek Subbiah, MD: Thank you. Dr Chiang?

Anne Chiang, MD, PhD: Clinically, I think that brain metastases are a difficult challenge for these patients. Many of these patients have metastases to the brain, either at diagnosis or during the course of their disease; once they’ve had prophylactic cranial radiation or whole-brain radiation, you often see situations where you have progression or recurrence in other parts of the brain, and they’ve maxed out on radiation therapy. You certainly can use Gamma Knife [radiosurgery] or local approaches. Then there are some drugs that have penetration through the blood-brain barrier, such as temozolomide and some of our standard drugs like taxanes or topotecan as well. For this population, brain metastases are difficult. Many of the clinical trials will also exclude patients who have a history of brain metastases. Sometimes we have patients with leptomeningeal disease.

I think that, as Dr Ganti mentioned, understanding the biomarkers that can predict response is important. This is a heterogeneous population of patients and, Dr Subbiah, you already referred to a new paradigm in thinking about this disease, that there are ways to categorize molecular subtypes that overexpress certain genes, such as YAP1 or pUAH3, or other ones. Those different subtypes can also have a different natural history of the disease. I think that being able to dissect what kinds of small cell lung cancer they have and then figure out more targeted approaches for those subtypes would be great and will continue to be one avenue of investigation. Biomarkers such as TMB [tumor mutational burden] look at the tumor microenvironment and infiltrate T cells. There may be a blood-based analysis of the circulating tumor DNA or other assays that are not based on obtaining tissue but on the blood that can be very useful in managing this disease. I think tissue is something that’s difficult for these patients. Many of them are still diagnosed via fine-needle aspirates, and I think that the more tissue we can get to study, the more useful it will be to help figure out what’s going on. Ultimately, thinking about the patient as a whole and how they’re resilient and respond to this disease is super important. Many of these patients have a terrific response to chemotherapy, in the 60% to 80% or sometimes even 90% response range, and they’re blindsided. Even though you tell them at the beginning, they’re blindsided when they have recurrent disease and have to shift their paradigm to thinking about different ways of coping and the impact of this disease on their lives. I think there still needs to be a lot of work in that area to investigate how patients can develop approaches to be resilient and cope with an incurable, chronic disease. We hope that the tail of the curve pans out for these patients, that some of those treated with immunotherapy can have an extended survival. I’ve had patients who have done very well. There’s a lot of room for hope.

Vivek Subbiah, MD: I think in small cell lung cancer, especially in relapsed/refractory disease, we have miles to go before we sleep. We are hopeful that, given the enthusiasm with multiple agents being approved in small cell lung cancer and in clinical development, there is more enthusiasm in this field.

Transcript Edited for Clarity