Lurbinectedin Contributes to Maintenance of Response in ES-SCLC

Adding immunotherapy to frontline platinum-based chemotherapy was the most recent major shift in extensive-stage small cell lung cancer (ES-SCLC) treatment. Maintaining longer responses in patients receiving chemoimmunotherapy while maintaining quality of life is another advancement in this disease setting. During a live Community Case Forum event in Saddle Brook, New Jersey, Joshua K. Sabari, MD, assistant professor at NYU Grossman School of Medicine in New York, discussed the phase 3 IMforte trial (NCT05091567) of maintenance lurbinectedin (Zepzelca) and atezolizumab (Tecentriq).He discussed theestablished efficacy of this regimen and what it suggests about the durability of response gained from both chemotherapy and immunotherapy components.

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Targeted Oncology: What is important to understand about the design of the IMforte trial?

Joshua K. Sabari, MD: Six hundred and sixty patients with ES-SCLC with no prior systemic therapy, no CNS metastases, and good performance status were enrolled. The patients all got atezolizumab plus carboplatin and etoposide for 4 cycles and that was called the induction phase of the treatment. At the second screening, we assessed [patients] after finishing 4 cycles of chemotherapy and immunotherapy and made a decision on these patients.

Now, 483 of the 660 patients had a complete response, partial response, or stable disease.^1,2 If you had progression of disease or you had a decompensation in your performance status to 2 or 3, those patients were not then randomly assigned into the maintenance phase. It’s very important to understand that concept: 660 enrolled, all get chemotherapy and immunotherapy, in the second screening they had to have response or stability, and then they then got randomly assigned to lurbinectedin at 3.2 mg/m2 plus atezolizumab vs atezolizumab which is the standard of care. They received this until progression and there was no crossover allowed. The trial's primary end point here was the progression-free survival [PFS] and the overall survival [OS].

What stood out from the baseline characteristics after randomization?

When you look at the balance between age, if you look at age less than 65, it was about 50% of patients in the lurbinectedin/atezolizumab vs 37% in the atezolizumab alone. There's a minor discrepancy there. Sex was similar. But [looking at] liver metastases at induction baseline, you could see these are really sick patients. Forty-two percent of the patients receiving lurbinectedin/atezolizumab had liver metastases and 39% receiving atezolizumab had liver metastases. Their ECOG performance status was very well balanced. We looked at their lactate dehydrogenase, which is a marker of disease burden, and it's well balanced. When you look at time to induction from cycle 1, those who have longer time to induction may have had breaks, had neutropenic fever, hospitalization, etc, [but it was] the same 3.2 months median for lurbinectedin/atezolizumab vs atezolizumab alone. If you look at the response rate [before maintenance], [including] complete responses and partial responses, it was 87% for lurbinectedin/atezolizumab, 88% for atezolizumab alone. It was balanced in both arms.

What were the PFS and OS outcomes in this trial?

This is the PFS since randomization—remember, take those 3 months that the patient was on carboplatin, etoposide, and atezolizumab—we then randomly assigned the patients, and the median improvement in PFS is 5.4 months for lurbinectedin/atezolizumab vs 2.1 months for atezolizumab alone with an HR of 0.54, so a 46% reduction in the rate of progression and death with the addition of lurbinectedin maintenance in this population [95% CI, 0.43-0.67; P < .0001]. A lot of people say, 5.4 months PFS doesn't look any different than what we saw in IMpower 133 [NCT02763579] or CASPIAN [NCT03043872], but remember, we add the 3 months to that. That takes us to…8.4 months median PFS. That's very impressive. You see a very clear separation in the curves, starting very early at about 2 months and sustained separation 12 months and beyond. If you look at the 12-month PFS, you see 20.5% of patients are progression free vs 12% who received atezolizumab alone, and then clearly at 6 months, there's a dramatic improvement, 40% vs about 18%.

The take-home from the OS is that if you were to get maintenance lurbinectedin and atezolizumab vs those patients who got atezolizumab alone, the median OS is 13.2 months vs atezolizumab alone at 10.6 months with an HR of 0.73, a 27% reduction in the rate of mortality by receiving atezolizumab and lurbinectedin maintenance vs atezolizumab maintenance therapy alone [95% CI, 0.57-0.95; 2-sided P = .0174]. Remember, when we think about that 13.2 months, a lot of people say that’s not that different from what we saw in IMpower 133 or in CASPIAN, but we’re adding the 3.2 months that they achieved with the first 4 cycles of therapy. Here, we're at 16.4 months, and that's quite impressive for median OS in this patient population. We see very nice separation in the curves at 12 months landmark; 56% of patients alive receiving lurbinectedin/atezolizumab vs 44% receiving atezolizumab maintenance alone.

There does look to be a sustained tail to the curve there. It's a question of, does chemotherapy give you durability? Does immunotherapy give you durability? Clearly, there's some population who has a durable response to immunotherapy. I do think it deepens that response and that duration of response in this patient population.

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_{DISCLOSURES: Sabari previously reported consulting or Advisory role with AstraZeneca, Pfizer, Regeneron, Medscape, Takeda, Janssen, Genentech/Roche, Mirati Therapeutics, AbbVie, Loxo/Lilly, and Sanofi, and institutional support from Janssen, Loxo/Lilly, Mirati Therapeutics, and Regeneron.}

_REFERENCES

_{1. 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}

_{2. 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}