Radiation Plus Immune Checkpoint Blockade May Be an Alternative Option in SCLC

Ashish Saxena, MD

Modest survival benefit has been shown with the addition of immune checkpoint blockade therapy to standard chemotherapy in patients with metastatic small cell lung cancer (SCLC), according to Ashish Saxena, MD. An unmet need for newer therapeutic approaches exists as researchers are looking to better the efficacy of immunotherapy in patients with early and late-stage SCLC.

A current standard of care for patients with SCLC is ionizing radiation. By triggering immunogenic cell death in tumor cells, ionizing radiation is an attractive option to pair with immune checkpoint blockade therapy. However, the optimal radiation dose is still unclear.

In addition, investigators are unsure of the fractionation scheme, target sites for radiation, and sequencing of radiation in relation to immune checkpoint blockade with ionizing radiation in this patient population.

“This is an active area of research for small cell lung cancer. The standard of care at present is still to use immunotherapy in the metastatic or stage IV setting. Hopefully, we'll soon be getting information about using it in the earlier stage setting and limited-stage settings, either after chemo and radiation or with chemo and radiation,” said Ashish Saxena, MD, in an interview with Targeted Oncology^TM.

In the interview, Saxena, assistant professor of medicine at Weill Cornell Medicine, discussed the benefit of radiation for the treatment of SCLC, combining radiation with immune checkpoint blockade treatments, and the next steps for the SCLC space.

Targeted Oncology: Can you discuss the addition of radiation therapy to immune checkpoint blockade therapy for the treatment of small cell lung cancer?

Saxena: The addition of radiation to immune checkpoint therapy in small cell lung cancer is an area that's in active investigation. It is not currently the standard of care, but there are a number of studies going on to see if adding radiation to immunotherapy or in certain situations, adding immunotherapy to radiation and chemotherapy, will improve outcomes in small cell lung cancer. For the limited-stage setting, the standard of care now is chemotherapy and radiation as definitive therapy. There are studies looking to see if adding immune checkpoint blockade therapy to that, either with radiation at the same time as radiation and

chemotherapy or after radiation and chemotherapy, will enhance outcomes like survival. In the metastatic setting or extensive-stage small cell lung cancer setting where the standard of care is chemotherapy and immunotherapy, [we are looking at] whether adding radiation either during or at some point in that treatment would improve outcomes.

Can you explain the benefit of the addition of immune checkpoint blockade to standard chemotherapy for patients with metastatic small cell lung cancer?

In the metastatic setting, there have been studies that have shown that adding immune checkpoint blockade, specifically, the PD-L1 inhibitors, atezolizumab or durvalumab, have improved overall survival and progression-free survival. These are given together with chemotherapy starting with the first cycle. Some patients have very good disease control with these, but the benefits overall are modest. Adding something more to that would hopefully further improve on the benefits of immunotherapy.

Since the benefit is modest, what needs to be further examined in the space?

I'm adding other treatments that are being looked at. Some of these are other drugs targeting different immune checkpoints or other mechanisms that might be sensitive in small cell lung cancer, but the addition of radiation is attractive because we do use radiation a lot in small cell lung cancer. Small cell lung cancer has felt to be very radio sensitive. In addition, adding radiation in other tumor types has shown to enhance the immunogenicity of the tumor and induce immune mediated cell killing. The idea of combining that with immunotherapy is something that's very attractive.

What can you discuss about the optimal radiation dosage in this space?

We don't know the optimal radiation dosage. Different studies are looking at different radiation doses, fractionation scheme, and different techniques of delivering the radiation. One that's commonly used in studies is stereotactic body radiotherapy or SBRT and combining that with immunotherapy. In the limited-stage setting where the standard is sort of definitive radiation, we're using those, since that's already the standard of care in that setting, and combining those with immunotherapy.

In addition, the amount of radiation or how much radiation to use is also sort of an open question about how beneficial it is and whether it will have the most appropriate response, as well as when to give the radiation, is it better to give it together with the immunotherapy, after, or before? Finally, where do you want to radiate? How many sites are going to be more beneficial than just reading in 1 area, and which areas are more important? Those are all questions that are being looked at in studies.

What unmet needs still exist in the SCLC space?

The overall survival is still relatively poor and not a lot has changed over many years of treatment with chemotherapy and radiation. The benefits have been seen with optimization of radiation and with immunotherapy, but I think other treatments that can provide higher cure rates in the sort of limited safe setting and prolong survivals, like with what we see with some of the other cancers in the metastatic setting. That would also be an unmet need. Also, those with limited sort of toxicities.

What are the future directions for SCLC research?

In combining radiation, there are a lot of studies being done, some large trials, looking at adding immunotherapy after radiation and chemotherapy in the limited-stage setting or together with it. We have a trial at Weill Cornell, which I'm involved in, [that is] adding SBRT together with radiation and chemotherapy. It is sort of a limited amount of radiation to

patients that have metastatic disease. Then, the different dosages and targets are intriguing. Finally, using the trials to find either biomarkers or learn more about how small cell lung cancer behaves in response to these therapies are important and exciting.

What are the key takeaways to know about the evolving SCLC space for a community oncologist?

This is an active area of research for small cell lung cancer. The standard of care at present is still to use immunotherapy in the metastatic or stage IV setting. Hopefully, we'll soon be getting information about using it in the earlier stage setting and limited-stage settings, either after chemo and radiation or with chemo and radiation. Hopefully, the addition of radiation will add to another way that we can treat this type of lung cancer, small cell lung cancer.

With small cell lung cancer, getting involved or having patients enter clinical trials is important because we have kind of a long way to go. The only way we'll move the needle forward is by having patients enrolled in studies.

REFERENCE:

Saxena A. Combining radiation therapy with immune checkpoint blockade for the treatment of small cell lung cancer. Semin Cancer Biol. 2023;90:45-56. doi:10.1016/j.semcancer.2023.02.004