Positive Trials Continue to Shape the SCLC Treatment Landscape

Ariel Lopez-Chavez, MD

Recent advancements in small cell lung cancer (SCLC) treatments have introduced transformative therapies and trial results, according to Ariel Lopez-Chavez MD.

Notably, the FDA granted accelerated approved to tarlatamab-dlle (Imdelltra), a bispecific T-cell engager (BiTE) for the treatment of SCLC that has progressed on or after platinum-based chemotherapy, in May 2024, offering a new option for patients with second-line SCLC.1 This approval was based on findings from the phase 2 DeLLphi-301 study (NCT05060016).²

Additionally, positive findings from trials like ADRIATIC (NCT03703297) and IMforte (NCT05091567) are further shaping treatment approaches.

In extensive-stage SCLC, immune checkpoint inhibitors atezolizumab (Tecentriq) and durvalumab (Imfinzi) have improved survival but lack validated biomarkers to predict patient responses. For recurrent cases, the use of newer agents like lurbinectedin (Zepzelca) and tarlatamab provides better tolerability than older drugs, enhancing treatment choices. Surgical options are limited to early-stage cases with specific criteria, such as small tumors without nodal involvement.

In an interview with Targeted Oncology^TM, Ariel Lopez-Chavez, MD, medical oncologist, director of precision medicine and developmental therapeutics at Allegheny Health Network Cancer Institute, discussed recent developments in the SCLC space.

Small cell lung cancer: © Констянтин Батыльчук- stock.adobe.com

Targeted Oncology: What are the most promising advancements in targeted therapies for small cell lung cancer, and how are they changing the standard of care?

Lopez-Chavez: There were 4 major advancements or major news in the world of small cell lung cancer [this year], and the first one came in May of this year with the approval of the first bispecific T-cell engager targeting DLL3. That was the approval of tarlatamab in May of this year, 2024.

Then in June at [The American Society of Clinical Oncology Annual Meeting (ASCO), there was] the presentation of the results of the ADRIATIC trial in small cell lung cancer. Then in August, also, something very interesting [happened] in targeted therapies, [which] is that the FDA granted breakthrough therapy designation to the first B7-H3 targeted antibody-drug conjugate.

And then the IMforte trial testing lurbinectedin in the maintenance setting after induction chemoimmunotherapy read out positive. That is an [important] phase 3 trial.

So, a lot of excitement in the world of small cell lung cancer, and obviously, [this is] shaping the landscape of therapeutics already, right? Because tarlatamab was approved, that is changing how we treat second-line small cell lung cancer, and then with the readout of the IMforte trial, that is changing how we treat small cell lung cancer in the limited-stage setting.

How effective do you think immunotherapy is in the treatment of extensive-stage small cell lung cancers? What factors predict response or resistance to these treatments?

We have the approvals of 2 checkpoint inhibitors in this space. First is atezolizumab, which received approval based on the results of the IMpower133 trial [NCT02763579]. The second is durvalumab, also gaining approval based on the results of the CASPIAN trial [NCT03043872]. Both have demonstrated effectiveness, with hazard ratios ranging from 0.73 to 0.77, indicating their value in this area. Additionally, there is an improvement in median overall survival of 2 to 3 months compared [with] standard chemotherapy.

Unfortunately, we do not have any factors that predict response to therapy. At the beginning of the trial designs, there were discussions and hypotheses about tumor mutational burden possibly being a predictive marker, or PD-L1 expression being another candidate. However, these have not been validated as markers. So far, we lack any validated markers of response to these therapies in the extensive-stage setting.

What is the current approach to managing recurrent small cell lung cancer, especially in patients who have progressed after first-line chemotherapy?

For years, the only things we had were topotecan and irinotecan, but as of May of 2020, we got the approval of lurbinectedin. Then more recently, we got the approval of tarlatamab in the second-line setting. Now, we have 4 agents. The use of these agents has been shifting to the newer agents, lurbinectedin and tarlatamab, because they have a better toxicity profile. It is very exciting to have more agents in this space now. The question [now] will be what to choose, in particular, between lurbinectedin and tarlatamab. How do we choose between these 2 agents, which are very different? They have different toxicity profiles, and they have different mechanisms of actions.

The other interesting facts on how to use them is that there are trials moving them into an earlier space, into the maintenance setting. IMforte is a trial of lurbinectedin in combination with atezolizumab after induction with chemotherapy and atezolizumab. If that is a positive trial, then the question would be, are people going to treat first with lurbinectedin in the maintenance setting and when they progress, use tarlatamab in the second line? We also have the DeLLphi-305 trial in which then tarlatamab is moving into the maintenance setting. If that turns out to be positive, then we will have 2 agents there in the maintenance setting. Then, we are back at how to choose between those 2 agents.

How does comprehensive genomic profiling impact the treatment and clinical management of patients with small cell lung cancer?

In the frontline setting, it does not have such a big role. Mainly it is reserved for patients that have never smoked because small cell lung cancer, being a disease mainly in people that have smoked heavily, whenever we have a patient that has never smoked, comprehensive molecular profiling is important right at diagnosis or when there are questions in regards to the diagnosis of small cell lung cancer. If there is a question of small cell vs large cell carcinoma or the diagnosis is not clear, then definitely it is recommended. The other option would be, once patients relapse, they may be looking for other therapies. Then, comprehensive molecular profiling may offer something there.

Should oncologists integrate novel agents into the small cell lung cancer treatment paradigm?

The first priority is the novel agents entering clinical trials, which I believe should continue to take precedence. Participating in these trials of novel agents should remain a top priority. It will then depend on the readouts from these trials to determine how we will integrate these therapies into practice. I believe the newer agents, especially in the second-line setting and beyond, are particularly favorable compared to other treatments, like topotecan, because they tend to be more tolerable. These newer agents are a welcome addition to our treatment model for small cell lung cancer.

What role does surgery have in the management of patients with limited stage small cell lung cancer? And how do you determine which patients are suitable for resection?

[Surgery] is primarily limited to patients with very early-stage disease, typically stage I or IIa at most. This includes tumors that are less than 5 cm in size and have no nodal involvement. These are essentially the only cases in which surgery is recommended for small cell lung cancer. So, the guidelines focus on cases with no nodal involvement and tumors under 5 cm to determine whether the small cell lung cancer may be operable.

What else are you most looking forward to seeing with future research in this space?

I am excited about the B7-H3 agent that recently received breakthrough therapy designation from the FDA. This designation was based on a small phase 1 trial with a limited number of patients, but it showed a response rate of more than 60%, which is rare to see in the small cell lung cancer space.

I am looking forward to the phase 2 trials of this agent. Additionally, the positive results from the important trial will be presented at an upcoming meeting, which is exciting. The DeLLphi-305 trial is also nearing completion, and once it accrues fully and reads out, it will be interesting to see those results as well. Overall, there are some exciting developments in this field, and I am looking forward to all of it.

REFERENCES:

1. FDA grants accelerated approval to tarlatamab-dlle for extensive stage small cell lung cancer. News release. US FDA. May 16, 2024. Accessed November 6, 2024. https://tinyurl.com/bddwjpk2

2. Paz-Ares L, Ahn M, Felip E, et al. Tarlatamab for patients (pts) with previously treated small cell lung cancer (SCLC): Primary analysis of the phase II DeLLphi-301 study. Presented at: European Society for Medical Oncology Congress 2023; October 20-24, 2023; Madrid, Spain. Abstract LBA92.