Efforts Underway to Generate Real-World Evidence for Second-line Strategies in SCLC

Nicolas Girard, MD, PhD

Several studies are underway to gain a better understanding of how patients with small cell lung cancer (SCLC) are selected for and treated with lurbinectedin (Zepzelca) in clinical practice, according to Nicolas Girard, MD, PhD. He added that these efforts also seek to confirm the agent’s efficacy in this population and to compare real-world data with those reported on clinical trials.^1-3

“It will be interesting to analyze the patient characteristics and the outcomes with lurbinectedin, and also to understand the treatment sequences in those patients,” said Girard, who is a professor of respiratory medicine at Versailles Saint Quentin University and a professor and head of the Curie-Montsouris Thorax Institute at Institut Curie in France. “This information is not available from the clinical trials that only focus on 1 specific line [of therapy].”

LURBICLIN (NCT05285033), is a real-world study that is ongoing in France in which investigators are evaluating data from patients with SCLC who received lurbinectedin as part of the French Early Access Program.¹ The key objectives of this study are to understand patient characteristics, analyze outcomes with the agent, and investigate the treatment sequences they received to best leverage the agent in this population. A similar study, CLINATEZO (NCT04920981), is evaluating the outcomes of patients treated with atezolizumab (Tecentriq).²

“It’s important to generate real-world evidence in patients with SCLC, because we have clinical trials, but we also have many real-world patients who are receiving these agents,” Girard added.

In an interview with OncLive^®, Girard highlighted current treatment practices, the value real-world data would provide for future investigative approaches in SCLC, and the observed benefit of administering available treatment options such as lurbinectedin as early as possible.

What limitations may physicians experience when treating SCLC?

Most patients [who receive a diagnosis of] SCLC [have] metastatic disease. In such situations, their treatment is chemotherapy-based, [using agents such as] platinum [and] etoposide. [Historically, we have also] combined chemotherapy with immune checkpoint inhibitors, such as the PD-L1 inhibitors atezolizumab or durvalumab [Imfinzi] for 4 cycles, [with subsequent] maintenance therapy until toxicity or disease progression. [With this approach, we have seen] some long-term efficacy.

[Prior data have shown] progression-free survival and overall survival [OS] benefit with these combinations over chemotherapy alone. [For example,] approximately 17% of patients [were] alive at 3 years with durvalumab [in the phase 3 CASPIAN trial (NCT03043872)].⁴ This is obviously limited, but in SCLC, which is an aggressive disease, it’s interesting to see that we can increase the survival of patients through [the use of] such combinations.

The main issue is what to do in the second-line setting, as many patients develop disease progression after first-line treatment. In such situations, we are differentiating between 2 groups of patients. The first group is patients who are refractory and who have cisplatin-resistant tumors and disease progression early, less than 3 months after the initiation of first-line therapy. We consider patients progressing after 3 months to be sensitive to platinum.

In the [platinum]-sensitive patients, we can rechallenge with chemotherapy, although we do not know how to do that in combination with immunotherapy, and some patients may discontinue immunotherapy and start chemotherapy alone again. My practice is to continue immunotherapy and reintroduce chemotherapy these patients.

Still, at some point, patients may develop disease progression. In those patients, the standard of care has been topotecan, with limited efficacy. Response rates have been less than 10% in the historical studies, so it’s better than placebo. However, its efficacy is limited, and this is because of the aggressiveness of the disease. We need additional options.

Lurbinectedin, an original compound, has broad biological efficacy. We have seen data with lurbinectedin as a single agent with high response rates, over 35%.⁵ [There has been a] significant response rate in the clinic for patients with refractory disease. We have also seen data from the randomized [phase 3 ATLANTIS study (NCT02566993)] investigating lurbinectedin plus the anthracycline doxorubicin vs topotecan, although this was a negative study.⁶

In France, we have access to lurbinectedin in the second-line setting through an expanded access program. [In partnership with] French Intergroup, we are conducting 2 [real-world] studies.^1,2 One study is a real-world evidence study for patients who received the combination of chemotherapy plus atezolizumab in the first-line setting.² This study is ongoing, and we will hopefully get the results soon. Another study is looking at real-world data for patients with SCLC who received lurbinectedin.¹

It’s important to understand the strategy, the treatment sequencing, and how patients are selected and treated in a real-world setting. [We are also aiming to] confirm the efficacy [of these agents], compare [those data] with clinical trials, and understand clinical practices. We are waiting for the results of those real-world evidence cohorts. There will hopefully be an opportunity to present those data at future meetings.

What has been your experience with using lurbinectedin, and in which patients will you typically consider this therapy?

Lurbinectedin is a new line of treatment for patients. Besides first-line treatment with chemotherapy plus immunotherapy and topotecan, we need additional options. Overall, in lung cancer and other solid cancers, offering more lines [of therapy] to a patient, with an early assessment to decide quickly whether they’re working, is a way to improve OS.

Lurbinectedin is not replacing the other options that we have, but it adds a new line of treatment for patients. Close monitoring of the patients is a way to assess whether [the agent is] working. Then, we can continue or switch to another line of treatment.

In my practice, I use lurbinectedin as early as possible, and in most of my patients, as second-line treatment. Again, SCLC is an aggressive disease. The [longer] you wait, the higher the risk that the patient has a poorer general condition and more tumor burden, [and it is] more difficult to get disease control.

What data are being collected on patients who are receiving lurbinectedin through the France Compassionate Care Act (Authorization d’Accès Compassionnel)?

This will be the topic of the real-world evidence study called LURBICLIN. It’s an expanded access program for patients previously treated for SCLC. It will be interesting to see which lines of treatment [these patients received], as well as their general condition, [as follows:]

• Are these patients sensitive or refractory?
• How many courses of chemotherapy have they received?
• What is the efficacy [of these agents] in the real-world setting?
• What are the subsequent therapies?

Those are the objectives of this study. We have nearly 100 patients [enrolled], so it will be a large cohort.

The generated [data] are from routine care, so it’s not an interventional study. It will be interesting to compare [these patient outcomes] with [those from] other real-world studies that have been previously conducted in SCLC.³

In France, we also have another ongoing initiative, the ESME-AMLC study [NCT03848052], [where we’re evaluating] a historical cohort of patients with SCLC.⁷ It will be interesting to see how, from an old cohort to a more recent cohort, integrating new options such as lurbinectedin can incrementally increase the overall survival of patients. This is a way that we will improve the outcomes of patients.

What are some of the anticipated therapeutic alternatives for this patient population?

There are new options coming in SCLC, including many developments regarding the targeting of DLL3, which is one of the antigens expressed on SCLC tumor cells. We have seen data with targeted agents against DLL3, and we also have new compounds such as immunotherapy with antibodies that target DLL3 on 1 side and attract the T cells near the cancer cells. These treatments are currently in phase 2 studies, and they may transform the outcomes of patients with refractory disease.

We also [now have a better understanding of] the biology of SCLC, with 4 groups of patients defined by their RNA sequencing. This is another way to separate groups of patients based on their biology and maybe [implement] different strategies. It’s important to try to correlate these molecular clusters with [treatment] efficacy and individual selection of patients from 1 strategy or another.

References

1. RW effectiveness of lurbinectedin in extensive stage SCLC (LURBICLIN). ClinicalTrials.gov. Updated August 10, 2022. Accessed October 7, 2022. https://clinicaltrials.gov/ct2/show/NCT05285033
2. Atezolizumab combined with chemotherapy in extensive stage SCLC (CLINATEZO). ClinicalTrials.gov. Updated October 5, 2022. Accessed October 7, 2022. https://clinicaltrials.gov/ct2/show/NCT04920981
3. Toublanc AC, Guecamburu M, Veillon R, Rosellini P, Girodet PO, Zysman M. Second-line lurbinectedin as a new treatment option for small-cell lung cancer: preliminary results in real-clinical practice. Thorac Cancer. 2022;13(15)L2248-2252. doi:10.1111/1759-7714.14464
4. Paz-Ares L, Chen Y, Reinmuth N, et al. Durvalumab, with or without tremelimumab, plus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer: 3-year overall survival update from CASPIAN. ESMO Open. 2022;7(2):100409. doi:10.1016/j.esmoop.2022.100408
5. Patel S, Petty WJ, Sands JM. An overview of lurbinectedin as a new second-line treatment option for small cell lung cancer. Ther Adv Med Oncol. 2021;13:17588359211020529. doi:10.1177/17588359211020529
6. Paz-Ares L, Ciuleanu T, Navarro A, et al. Lurbinectedin/doxorubicin versus CAV or topotecan in relapsed SCLC patients: phase III randomized ATLANTIS trial. J Thorac Oncol. 2021;16(suppl 10):S844-S845. doi:10.1016/j.jtho.2021.08.030
7. Evolution of the therapeutic care in advanced or metastatic lung cancer from 2013 (ESME-AMLC). ClinicalTrials.gov. Updated July 6, 2022. Accessed October 7, 2022. https://clinicaltrials.gov/ct2/show/NCT03848052