Room to Grow in the Small Cell Lung Cancer Treatment Landscape

Nitika Sharma, MD

A collection of chemotherapy, targeted therapy, and immunotherapy agents are improving outcomes for patients with small cell lung cancer (SCLC) in the first-line setting.

As more understanding of biomarkers in SCLC is spread in the oncology community, outcomes for patients with SCLC may become more similar to the non–small cell lung cancer population, according to Nitika Sharma, MD.

“Small cell lung cancer is now being looked at with a molecular characterization based on whether it's a cold tumor or a hot tumor. We know, in general, a cold tumor may respond to chemotherapy whereas a hot tumor may have better responses to the immunotherapy. This characterization of the small cell lung cancer is vital in exploring further treatment strategies for this tumor," said Sharma, a medical oncologist, and hematologist at Cancer Treatment Centers of America Atlanta, in an interview with Targeted Oncology™.

Some of the treatments for SCLC include durvalumab (Imfinzi) for the treatment of patients with extensive stage-SCLC and lurbinectedin (Zepzelca) for the treatment of patients with metastatic SCLC. Moreover, agents being investigated in clinical trials are show promising to become the next available strategies for first-line SCLC. These investigational agents include serpulilimab (HLX10), and toripalimab.

In the interview, Sharma discussed frontline treatment options for SCLC and data supporting their use. Sharma also discussed ongoing clinical trials that may bring new therapies in the near future.

TARGETED ONCOLOGY: What advances have been seen in the SCLC space over recent years?

Sharma: Nearly 2-thirds of the patients with small cell lung cancer present with extensive-stage of small cell at diagnosis, and the prognosis is usually poor with a 5-year survival rate of less than 7%. The median survival is limited to approximately 10 months. Small cell lung cancer is a highly proliferative, aggressive form of lung cancer that carries a poor prognosis for close to 40 years, and the preferred decades old treatment is platinum etoposide. In the first-line setting, patients respond well with platinum etoposide. We see responses in more than 60% of the patients. However, that response is usually short-lived. Traditionally, the second-line treatment is with topotecan, and that works in platinum-sensitive patients, has a response rate of about 20%, but has a more modest improvement in survival over best supportive care.

This disease has been called recalcitrant, and for a good reason, because most patients relapse after the generally favorable response in the first-line setting. They respond, and when they relapse, we have limited therapies to offer them with not much promise. The progress in the treatment for this type of cancer has been at a standstill for a number of years, until in about 2018. Then, we started to see the role of immunotherapy for these patients.

Initially, we started with nivolumab [Opdivo] and pembrolizumab [Keytruda], which are anti-PD-1 agents, and gradually we had improved approval of atezolizumab [Tecentriq] in 2019, and then durvalumab in 2020, in the first-line setting. Subsequently, we had an approval of lubenetidin, in the second-line setting and rilaciclib in the first-line setting to avoid myelosuppression related to the chemotherapy. In 2021, there was withdrawal of approval of nivolumab and pembrolizumab, which was in the subsequent-line setting. But still, we use it in the first-line setting in combination with chemotherapy and immune therapies, such atezolizumab and durvalumab.

The premise of immunotherapy in small cell lung cancer is that there tends to be high tumor mutational burden, which may be associated with the use of tobacco in these patients. There is a high tumor mutational burden, with known response to immune checkpoint inhibitors. That may or may not be the case in small cell lung cancer, because we’re still trying to see which biomarkers would suggest a better response to treatment for these patients. Likewise. The small cell lung cancer tends to be associated with autoimmune paraneoplastic syndromes. There is universal loss of tumor suppressor genes such as tp53 and retinal blastoma genes for these tumors, and those may drive immunogenicity through genetic instability.

Can you discuss the efficacy or durvalumab in SCLC and how it fits into the landscape?

Let’s discuss the CASPIAN trial [NCT03043872]. The CASPIAN trial assessed durvalumab, which is an anti-PD-L1 antibody, with or without tremelimumab [Imjudo], which is a CTLA-4 antibody in combination with chemotherapy and platinum and etoposide chemotherapy in extensive-stage small cell lung cancer patients. The patients were randomly assigned 1:1:1 to durvalumab and platinum etoposide chemotherapy, durvalumab and tremelimumab plus chemotherapy, or just the chemotherapy.

The durvalumab plus chemotherapy combination in the first-line setting showed a significant improvement in overall survival. Now, the arm with durvalumab and tremelimumab in combination with chemotherapy did not show a statistically significant improvement in overall survival as compared to chemotherapy alone. This trial, noted some interesting observations.

First, the benefit that was seen was irrespective of PD-L1. There still is a need to recognize the biomarkers for which patients would benefit more from immunotherapy. At present, the treatment of extensive-stage lung cancer still is as if one-size-fits-all. There is a need to recognize the biomarkers that would suggest response to a certain treatment, maybe less toxicity and a more durable response.

The other thing is 40% to 50% of patients with small cell lung cancer develop brain metastasis, and we are still not clear if there is an effective role of immunotherapy in controlling the disease in the brain compartment. Also, what is the best way to manage the brain metastasis? We have done prophylactic brain radiation for these patients in the past. Does that still carry a role or not? It's still unclear.

What research has illustrated the role of atezolizumab in SCLC treatment?

The use of atezolizumab for SCLC is based on the IMpower133 trial [NCT02763579], which demonstrated that adding atezolizumab to chemotherapy with platinum and etoposide in the first-line setting for extensive-stage small cell lung cancer resulted in significant improvement in overall survival and progression-free survival vs placebo plus chemotherapy. This study showed an improvement of median overall survival to 12.3 months with the combination of chemotherapy and immunotherapy compared with 10.3 months with chemotherapy alone, with a 24% reduction in the risk of death, and a hazard ratio of 0.76. At 18 months, 34% of the patients were alive in the chemoimmunotherapy arm compared with 21% with the chemotherapy alone. Even in this trial, patients derive benefit from immunotherapy, irrespective of the PD-L1 and tumor mutational burden.

Can you discuss the newer studies that are exploring anti-PD-1 therapy in the first-line setting?

There was a presentation on serplulimab at the American Society of Clinical Oncology [ASCO] 2022, which a first dual monoclonal antibody combination therapy with target PD-1 and VEGF-expressing tumors. We know that small cell lung cancer with its innate nature tends to be highly vascular and rich in VEGF receptors. This randomized, double-blind, phase 3 study used this agent with chemotherapy in the previously untreated patients with extensive-stage small cell lung cancer. That demonstrated an improvement in overall survival compared with chemotherapy alone. In this trial, the median follow-up duration was 12 months, and the median overall survival was significantly prolonged with the use of this agent to 15.4 months compared with 10.9 months with chemotherapy alone.

We also have another agent called toripalimab. This agent has been granted an orphan drug designation. It is an anti-PD-1 inhibitor for patients with small cell lung cancer that is being studied in the JUPITER-08 trial [NCT04012606]. We do not yet have results of that, but we will look for the results to see the efficacy of this agent in the first-line setting.

What challenges are oncologists facing when treating SCLC?

A lot of the small cell lung cancer so far is treated with one-size-fits-all approach. But more importantly, especially after the results from the IMpower 133 trial, we now know that the small cell lung cancer can be stratified based on certain biomarkers and transcription factors. There are certain transcription factors that would yield a better response to either platinum chemotherapy, PARP inhibitors, or immunotherapy. Small cell lung cancer is now being looked at with a molecular characterization, based on whether it's a cold tumor or a hot tumor. We know in general, a cold tumor may respond to chemotherapy whereas a hot tumor may have better responses to the immunotherapy. This characterization of the small cell lung cancer is vital in exploring further treatment strategies for this tumor.

The major cause of a knowledge gap in this setting is that small cell lung cancer tends to be relatively less frequently found as compared with non–small cell lung cancer. About 15% to 20% of lung cancer cases are small cell as compared with non­–small cell. It comprises a small sample size, in general. There is also paucity of adequate tumor specimens to guide the drug design. Because surgery is rarely used to treat such a small cell cancer, a small cell cancer is considered to be metastatic upon the initial diagnosis, and as such surgery is not always a consideration in the event in a limited-stage setting. We don't have enough tumor specimens to work with in the lab to know about the genetic makeup and what the cancers may be sensitive to.

Also, biopsy in the setting of a disease relapse is a major challenge, but liquid biopsies may add useful information when a tissue biopsy is challenging. Then, unlike non–small cell lung cancer where multiple driver mutations have been identified, there are only few driver mutations that exist in small cell lung cancer.

Lastly, there is a lot of heterogeneity in these types of tumors, and we do not see the response we would expect from the treatment. Now, there is a lot of promise because as we discussed, we are starting to see activity in this tumor type, where now the industry is more in in interested in exploring and coming up with treatment options. The subtypes are being looked at the genomic proteomic and epigenetic landscape of small cell lung cancer is being studied. There is hope that we can target the biology of the cancer with more precise and personalized treatment to get better responses.

What advice to you have for oncologists in the community setting?

I would encourage that we enroll these patients in clinical trials because that is how we get the best evidence and the safety of the treatment modality in this hard-to-treat tumor biology. Looking forward, these are exciting times for small cell lung cancer, clinical research, and I hope that we build upon and improve the outcomes of this type of cancer.