Lurbinectedin Maintenance Yields Improved Survival in ES-SCLC

Pursuing long-term survival in patients with extensive-stage small cell lung cancer (ES-SCLC) is the top priority for researchers. Immunotherapy has led to durable responses for a small percentage of patients, but more work is being done to expand on this, as was discussed by Tejas Patil, MD, in a Community Case Forum event in Denver, Colorado. Patil, assistant professor of medicine at the University of Colorado School of Medicine and medical oncologist at University of Colorado Anschutz Medical Campus, reviewed the trials that added immune checkpoint inhibitors to frontline chemotherapy regimens and then discussed the IMforte trial (NCT05091567), which recently reported the results of adding lurbinectedin (Zepzelca) as additional maintenance therapy.

Register today to join a Case-Based Roundtable near you.

Targeted Oncology: Could you summarize the findings that led to the use of atezolizumab (Tecentriq) in ES-SCLC?

Tejas Patil, MD: This was the IMpower133 trial [NCT02763579]; a couple of things to highlight about this study were that patients had measurable ES-SCLC with an ECOG performance status [PS] of 0 or 1. I think this is an important characteristic to flag, because how many [oncologists] see patients with SCLC with ECOG PS 0 or 1? I don't routinely see them. I think most of them are showing up ECOG PS of 2, sometimes 3, and I'm very nervous. I [think], should I even treat them? I flagged that because this is a study that—although positive and showed a survival benefit—if we pushed this in the real world, I think we might have not seen that [benefit]. Patients with treated, asymptomatic brain metastases were eligible.

The primary end points were investigator-assessed progression-free survival [PFS] and overall survival [OS], and patients were randomly assigned to either atezolizumab or placebo [in addition to chemotherapy]. There was a PFS and OS difference.^1,2 What I'm struck by is not the difference between the [Kaplan-Meier] curves.

I think there are a couple things to show here. One is that there's a massive drop-off early on, so within 6 months, your patients are either going [experience progression] and die, or they're going to respond. The thing that's very striking is the long-term results. Approximately 15% to 20% of patients are going to have a durable response, and those curves flatten. That means those are the patients [like those] in my clinic; I've seen several who are 4 years out after being treated with atezolizumab. I haven't used durvalumab [Imfinzi] as much; I'm using it more recently.

The adverse event [AE] profile was predictable. There were very few [atezolizumab-associated] grade 3 to 4 AEs; the ones that we did see were neutropenia driven by etoposide and thrombocytopenia driven by chemotherapy.

How did the trial of durvalumab differ from that of atezolizumab?

The CASPIAN study [NCT03043872] had a design that was interesting. It was in treatment-naive patients with very similar baseline characteristics, but instead of 1:1 randomization, there was also a durvalumab/tremelimumab [Imjudo] arm. Tremelimumab is a CTLA-4 inhibitor combined with durvalumab, and that led to durvalumab maintenance. There was no tremelimumab maintenance here, even though they got the CTLA-4. In contrast to the prior study, OS was [the sole] primary end point. Also, in contrast to the prior study, there was no specification for just carboplatin. This study allowed you to use cisplatin.

There were very similar findings. There's a separation of the curves that plateaus out and adverse events [were similar].^3,4

So, we have carboplatin [with atezolizumab], and with durvalumab you can use carboplatin or cisplatin. You can administer atezolizumab every 2 weeks, which I never do. It's very inconvenient for patients, so I don't think anyone does that.

What advances have been made in terms of maintenance for ES-SCLC?

The [phase 3] IMforte study was presented at the American Society of Clinical Oncology Annual Meeting this year. This was looking at lurbinectedin [Zepzelca] maintenance. I want to go through the design of the study carefully. Patients had to have no prior systemic therapy for ES-SCLC. I want to flag a very important exclusion criteria, which is no central nervous system [CNS] metastases. It's not even the same as treated CNS; [they could have] no brain metastases, so keep that in mind. Then patients received the IMpower133 regimen, which was carboplatin, etoposide, and atezolizumab. This was the induction phase. Then there was a second screening, and in this second screening, an imaging assessment needed to be done that showed the patients either achieved a complete response, partial response, or stable disease, and at that time point, had an ECOG PS of 0 or 1.

I want to [emphasize] how many people started and how many people subsequently were eligible in the screening [660 and 483 patients, respectively].^5,6 The stratification factors [included ECOG PS, lactate dehydrogenase level, and liver metastases]. The focus of this study was giving lurbinectedin, which we typically have used in the second-line setting, in combination with atezolizumab vs atezolizumab by itself. It was a 1:1 randomization. There was treatment given until progression or unacceptable toxicity. There was no crossover allowed, and the primary end points were PFS and OS.

What baseline characteristics were most important in this patient population?

Remember, these are the baseline characteristics from the second screening. Highlighted here were some factors that I think we have known to be associated with worse outcomes. Liver metastases are a poor prognostic factor [and were present in approximately 40% of patients]. Time from induction to cycle 1 to randomization is [3.2 months in both arms], with the point that it’s trying to show is that there wasn't a delay in randomization. That could also potentially be a confounding variable, [if] the lurbinectedin arm had received its maintenance sooner or something like that.

What were the efficacy outcomes with the addition of lurbinectedin?

It shows a PFS benefit with an HR of 0.54 favoring lurbinectedin and atezolizumab [95% CI, 0.43-0.67; 2-sided P < .0001]. The response from the OS, which was another primary end point, was also positive, so this trial did meet its primary end point of OS as well [stratified HR, 0.73; 95% CI, 0.57-0.95; 2-sided P = .0174]. It’s important to highlight that IMforte results don't include time on induction treatment, so this is truly the OS from maintenance, from the second screening. This is not including that start on platinum [chemotherapy].

When we look at responses, tumor response in the maintenance phase was assessed against the maintenance baseline. Patients [received] induction platinum chemotherapy, and they got a maintenance scan. That's what led the investigators to decide whether the patient was eligible or not, and based on that scan, these were the responses that were being captured [overall response rate, 19.4% with lurbinectedin vs 10.4% without]. There was a higher rate of partial responses seen in the lurbinectedin and atezolizumab maintenance arm [17.1% vs 9.9%], and then there was a higher rate of progressive disease [with atezolizumab alone]: if you look at that, it's 19.4% vs 47.8%, [respectively].

Subsequent treatments are shown…I think one thing to notice that's very striking is how at clinical cutoff, no patient from the lurbinectedin/atezolizumab arm had follow-up lurbinectedin treatment [vs 9.1% in the atezolizumab arm]. I think it's important to highlight that. There was no crossover allowed, but once they experienced progression, they were not receiving lurbinectedin.

One of the things we want to think about is, remember the intention of maintenance. When we looked at the original IMpower133 data, the goal of maintenance was to use immune therapy to induce a long-term response.

What stood out in terms of tolerability?

AEs leading to discontinuation of any study drug, which was either lurbinectedin or atezolizumab, in the lurbinectedin/atezolizumab group, was 6.2% and then for the atezolizumab arm, it was 3.3%. Patients had complications, but the discontinuation rates were relatively low.

[When using lurbinectedin], I feel like I've seen some outliers who are asymptomatic and doing amazing, [but generally patients] had fatigue and neutropenia, and that comports with what this trial found, which is that neutropenia and hematologic toxicities were more commonly seen in the lurbinectedin arm. It's worth pointing out that the rates of neutropenia in the lurbinectedin arm are lower than in the basket trial [NCT02454972], and that's in part because there was proactive use of granulocyte colony–stimulating factor.

Register today to join a Case-Based Roundtable near you.

DISCLOSURES: Patil previously reported receiving grants from Janssen and Gilead; consulting fees from AstraZeneca, Aadi Bioscience, Boehringer Ingelheim, Bristol Myers Squibb, Bicara, Caris, Daiichi-Sankyo, Foundation Medicine, Gilead, Merus, Janssen, Mirati Therapeutics, Pfizer, Sanofi, Regeneron, Roche/Genentech, and Takeda; others from Elevation Oncology.

REFERENCES:

1. Horn L, Mansfield AS, Szczęsna A, et al; IMpower 133 Study Group. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med. 2018;379(23):2220-2229. doi:10.1056/NEJMoa1809064

2. Liu SV, Reck M, Mansfield AS, et al. Updated overall survival and PD-L1 subgroup analysis of patients with extensive-stage small-cell lung cancer treated with atezolizumab, carboplatin, and etoposide (IMpower133). J Clin Oncol. 2021;39(6):619-630. doi:10.1200/JCO.20.01055

3. Goldman JW, Dvorkin M, Chen Y, et al. Durvalumab, with or without tremelimumab, plus platinum-etoposide versus platinum-etoposide alone in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): updated results from a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2021;22(1):51-65. doi:10.1016/S1470-2045(20)30539-8

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):100408. doi:10.1016/j.esmoop.2022.100408

5. Paz-Ares L, Borghaei H, Liu SV, et al. Efficacy and safety of first-line maintenance therapy with lurbinectedin plus atezolizumab in extensive-stage small-cell lung cancer (IMforte): a randomised, multicentre, open-label, phase 3 trial. Lancet. 2025;405(10495):2129-2143. doi:10.1016/S0140-6736(25)01011-6

6. Paz-Ares L, Borghaei H, Liu SV, et al. Lurbinectedin (lurbi) + atezolizumab (atezo) as first-line (1L) maintenance treatment (tx) in patients (pts) with extensive-stage small cell lung cancer (ES-SCLC): Primary results of the phase 3 IMforte trial. J Clin Oncol. 2025;43(suppl 16):8006. doi:10.1200/JCO.2025.43.16_suppl.8006