How Will ADCs Influence the Treatment Landscape in SCLC?

How can the treatment of patients who have small cell lung cancer (SCLC) and brain metastases be sequenced? That was the big question during a recent Frontline Forum that took place during the European Society for Medical Oncology Congress (ESMO) 2025. Clinicians in the lung cancer space gathered to discuss recent advances in SCLC, as well as the impact that emerging clinical data have on decision-making.

The panel was led by Ticiana Leal, MD, associate professor in the Department of Hematology and Oncology and director of thoracic medical oncology at Winship Cancer Institute of Emory University in Atlanta, Georgia. She was joined by Sandip P. Patel, MD, professor in the Department of Medicine at the University of California San Diego (UCSD); Christine Bestvina, MD, associate professor of medicine at the University of Chicago Medicine in Illinois; Luis Raez, MD, FACP, FCCP, FASCO, medical director of Memorial Cancer Institute and oncology research director and director of the Thoracic Oncology Program of Memorial Healthcare System, and clinical associate professor of medicine at Florida International University; Julia Rotow, MD, clinical director of the Lowe Center for Thoracic Oncology and director of clinical research at Dana-Farber Cancer Institute, and assistant professor of medicine at Harvard Medical School; Edgardo S. Santos, MD, medical director of The Oncology Institute of Hope and Innovation and clinical affiliate associate professor at Florida Atlantic University; Hatim Husain, MD, professor in the Department of Medicine at UCSD; and Jared Weiss, MD, section chief of thoracic and head/neck oncology, and professor of medicine at the University of North Carolina School of Medicine.

Management of Limited-Stage SCLC

To begin, Leal reviewed results from the phase 3 ADRIATIC trial (NCT03703297), which had a median progression-free survival (PFS) of 16.6 months (95% CI, 10.2-28.2) in the durvalumab (Imfinzi) plus tremelimumab (Imjudo) arm and 9.2 months (95% CI, 7.4-12.9) in the placebo arm (HR, 0.76; 95% CI, 0.61-0.95; P = .0161).¹ The median overall survival was 55.9 months (95% CI, 37.3-not eligible [NE]) vs 33.4 months (95% CI, 25.5-39.9) in the durvalumab and placebo arms, respectively (HR, 0.73; 95% CI, 0.57-0.93; P = .0104).

“These are data that were immediately practice changing, and for all of us, we now use this regularly in clinical care,” Rotow said.

The PFS by percutaneous coronary intervention (PCI) was 28.2 months (95% CI, 16.8-44.2) in the durvalumab arm vs 13.0 months (95% CI, 9.2-17.0) in the placebo arm (HR, 0.73; 95% CI, 0.52-1.00). If patients did not have PCI, the PFS was 9.1 months (95% CI, 7.3-14.3) in the durvalumab arm vs 7.4 months (95% CI, 5.7-9.2) in the placebo arm (HR, 0.80; 95% CI, 0.59-1.09). In the intent-to-treat (ITT) analysis, the PFS was 16.6 months (95% CI, 10.2-28.2) vs 9.2 months (95% CI, 7.4-12.9), respectively (HR, 0.76; 95% CI, 0.61-0.95).

The OS by PCI status was not reached (95% CI, 43.9-NE) in the durvalumab arm vs 42.5 months (95% CI, 33.4-NE) in the placebo arm (HR, 0.75; 95% CI, 0.52-1.07). For those who did not receive PCI, the OS was 37.3 months (95% CI, 24.3-NE) vs 24.1 months (95% CI, 18.8-31.1) in each arm (HR, 0.71; 95% CI, 0.51-0.99). In the ITT analysis, the OS in the durvalumab arm was 55.9 months (95% CI, 37.3-NE) vs 33.4 months (95% CI, 25.5-39.9) in the placebo arm (HR, 0.73; 95% CI, 0.57-0.93).

When looking at these data, Leal wondered if they changed how her colleagues would practice. Raez noted that it would not change his practice. Rotow called the data “informative” but noted it wasn’t a randomized trial.

“The reason we don’t want to do PCI is the toxicity. If we’re curing [patients] with extended durvalumab, then we have left them with lifelong dementia. It’s a catch-22. We want to cure patients. Relapse is the worst possible thing, but I argue the second worst thing we can do is unnecessary PCI for a patient who otherwise would have been cured. Because of what we’re doing,they’re going to spend the rest of their life with dementia when they didn’t need [the PCI],” Patel said.

Weiss noted he was in the minority who does use PCI but is left wondering whether he is right to do so. While neurocognitive effects do take time to manifest, once a patient develops brain metastases, the outcome is typically not good.

Leal then turned to the safety results and asked how her colleagues counsel patients considering the risk of pneumonitis.² Overall, radiation pneumonitis occurred in 22.9% of patients in the durvalumab arm vs 23.4% in the placebo arm, decreased appetite in 16.8% vs 12.8%, hypothyroidism in 16.0% vs 3.8%, and pneumonitis in 10.7% vs 6.0%.

For patients with PCI, the grade 3/4 treatment-emergent adverse effects (TEAEs) occurred in 28.4% vs 29.6%, compared with those who did not have a PCI of 19.8% vs 17.9%. Additionally, TEAEs leading to treatment discontinuation occurred in 17.0% vs 15.5% of patients who had PCI and 15.7% vs 4.9% for those who did not.

Santos believes all clinicians need to be educated on how to treat patients who may present to the hospital with pneumonia, chronic obstructive pulmonary disease, or COVID-19. Once it’s made clear they are receiving durvalumab, a diagnosis of interstitial lung disease is given, which may not be the cause of their symptoms.

Rotow and Bestvina would like to see real-world data regarding the safety. These will help them further determine which patients would benefit best from this treatment.

Management of Extensive-Stage SCLC

Real-World Data

When the panelists were looking at key trials in the first-line space, they discussed the phase 3 IMpower133 trial (NCT02763579) with atezolizumab (Tecentriq) plus carboplatin and etoposide.³ The median OS was 12.3 months in the atezolizumab arm (95% CI, 10.8-15.8) vs 10.3 months (95% CI, 9.3-11.3) in the placebo arm (HR, 0.76; 95% CI, 0.60-0.95; P = .0154). The median PFS was 5.2 months (95% CI, 4.4-5.6) vs 4.3 months (95% CI, 4.2-4.5), respectively (HR, 0.77; 95% CI, 0.63-0.95). The overall response rate (ORR) was 60.2% (95% CI, 53.1%-67.0%) in the atezolizumab arm vs 64.4% (95% CI, 57.3%-71.0%) in the placebo arm. Common AEs included neutropenia, anemia, and thrombocytopenia.

The phase 3 CASPIAN trial (NCT03043872) looked at durvalumab plus etoposide and cisplatin or carboplatin.⁴ The median OS was 12.9 months (95% CI, 11.3-14.7) in the durvalumab arm vs 10.5 months (95% CI, 9.3-11.2) in the chemotherapy arm. The median PFS was 5.1 months in the durvalumab arm and 5.4 months in the placebo arm (HR, 0.78; 95% CI, 0.65-0.94).⁵

Retrospective real-world data assessed atezolizumab vs durvalumab at Moffitt Cancer Center and across 3 centers in China.⁶ At Moffitt, the median OS was 11.6 months (95% CI, 8.4-13.6) vs 14.7 months (95% CI, 10.6-17.9) in each arm, respectively (HR, 1.68; 95% CI, 1.09-2.61; P = .0185). The median PFS was 5.9 months (95% CI, 5.7-6.7) in the atezolizumab arm and 6.3 months (95% CI, 5.8-7.0) in the durvalumab arm (HR, 1.22; 95% CI, 0.81-1.84; P = .3440). Across the 3 centers in China, the median OS was 10.0 months (95% CI, 7.0-13.0) in the atezolizumab arm and 22.0 months (95% CI, 18.4-25.6) in the durvalumab arm (HR, 2.03; 95% CI, 1.11-3.73; P = .029). The median PFS was 7.0 months vs 6.0 months, respectively (P = .41).

When looking at these data, Patel highlighted that the data from the retrospective study weren’t consistent. There was also a discordance in hospitalizations, where they were higher with atezolizumab, but durvalumab had higher discontinuation rates. He said the best data they have are from frontline studies. The choice between atezolizumab and durvalumab depends on the clinician’s preferred maintenance: lurbinectedin maintenance or tarlatamab-dlle (Imdelltra) maintenance.

“As we see more of this data for the brain, it’s increasing my awareness of the brain as an end point, but it is good to note that from the CASPIAN as well as from the earlier studies, how the CNS [central nervous system] was approached. This comes into some early discussionsabout PCI. As a whole, it’s nice. This may come up in the discussion, but how [antibody-drug conjugates (ADCs)] have an influence on the brain could also be an important component of how we think about sequence and kind of where the strategy is,” Husain said.

IMforte

Moving on to the phase 3 IMforte study (NCT05091567) of lurbinectedin plus atezolizumab vs atezolizumab alone, the median PFS was 5.4 months (95% CI, 4.2-5.8) vs 2.1 months (95% CI, 1.6-2.7), between the respective arms (HR, 0.54; 95% CI, 0.43-0.67; P <.0001).⁷ The median OS was 13.2 months (95% CI, 11.9-16.4) in the combination arm and 10.6 months (95% CI, 9.5-12.2) in the atezolizumab arm (HR, 0.73; 95% CI, 0.57-0.95; P = .0174).

“ The median time from induction to randomization was
3.2 months. This is the best OS that we’ve seen in a randomized maintenance phase that has reached the end point of OS. Why aren’t people on team lurbinectedin plus atezolizumab?” Leal asked.

Bestvina pointed out that people are 50/50; however, once tarlatamab becomes a contender, that will be the go-to treatment vs the combination. Patel highlighted that the standard of care for atezolizumab gives you the most options on how to move forward with maintenance therapy.

In the maintenance setting, grade 3/4 AEs occurred in 38.0% of patients in the combination arm and 22.1% in the monotherapy arm, with grade 5 AEs in 5.0% vs 2.5%, respectively. The most common AEs included nausea (36.4% vs 4.2%), anemia (31.8% vs 6.7%), fatigue (20.2% vs 7.9%), and decreased appetite (16.9% vs 6.7%).

As Leal went through the safety data, she noted the rates of discontinuation were lower in the lurbinectedin arm (6.2%) vs the atezolizumab arm (3.3%). Most observed toxicities were manageable.

DeLLphi-301 Trial

The phase 2 DeLLphi-301 trial (NCT05060016) assessed tarlatamab at varying dose levels. In part 1, patients were given either 10 mg or 100 mg. Dose selection occurred, followed by part 2 with treatment at 10 mg, and part 3 at 10 mg.⁸

For parts 1 and 2, the ORR was 40% (95% CI, 30.3%-50.3%), with 3% of patients having a complete response (CR), 37% having a partial response (PR), and 30% having stable disease. The median PFS was 4.3 months (95% CI, 2.9-5.6). The OS rate at 6 months was 73.4%, 57.0% at 12 months, and 46.0% at 18 months.

Cytokine release syndrome (CRS) occurred in 53% of patients within less than 3 months, and 1% of patients between 3 and 12 months.⁹ Overall, 32% of patients had grade 1 CRS, 20% had grade 2, and 1% had grade 3. Additionally, 21% had grade 1 recurrence, and 4% had grade 2. Immune effector cell–associated neurotoxicity syndrome (ICANS) occurred in 10% of patients as grade 1, and 5% had grade 2. Additionally, 5% of patients experienced grade 1 ICANS at less than 3 months, and 3% had grade 2.

Rotow noted that if a patient doesn’t experience ICANS and can get through CRS, then the treatment is well tolerated. Bestvina highlighted how dysgeusia was a bigger issue than anticipated in the trial. Overall, 24% of patients experienced dysgeusia at less than 3 months, 10% at 3 to 12 months, and 4% at 12 months or more.

Leal likened dysgeusia to a quality-of-life issue rather than a nutrition one. Per Bestvina, if patients live alone, they tend to lose weight. However, if they have someone caring for them, the dysgeusia stays as a lifestyle issue.

“While tarlatamab can have activity in the brain, I still worry that we don’t have definitive data to say somebody with 50 brain metastases [should] receive tarlatamab, especially if there’s edema or they’re at risk for something in the posterior fossa,” Leal said.

TROPiCS-03

The phase 2 TROPiCS-03 trial (NCT03964727) aimed to assess the ADC sacituzumab govitecan in patients with locally advanced solid tumors.¹⁰ A preliminary analysis showed that sacituzumab govitecan had promising efficacy/safety data among patients with extensive-stage SCLC.

The ORR was 41.9% (95% CI, 27.0%-57.9%), the disease control rate was 83.7% (95% CI, 69.3%-93.2%), and the clinical benefit rate was 48.8% (95% CI, 33.3%-64.5%). The median duration of response was 4.7 months (95% CI, 3.5-6.7). The median PFS was 4.40 months (95% CI, 3.81-6.11), and the median OS was 13.60 months (95% CI, 6.57-14.78).

Regarding safety, the most common grade 1/2 AEs were diarrhea (67%), fatigue (58%), neutropenia (12%), constipation (42%), and nausea (40%).

“I’ve been super impressed by this target. It’s part of my enthusiasm. SCLC probably had the greatest transformation in the past 2 years—the idea of potentially doing something such as the DeLLphi [regimen] with consolidation tarlatamab up front and then the second line being able to use drugs like this or ifinatamab deruxtecan [I-DXd],” Patel said.

IDeate-Lung01

The phase 2 IDeate-Lung01 trial (NCT05280470) assessed I-DXd at 12 mg/kg every 3 weeks.¹¹ The confirmed ORR was 48.2% (95% CI, 39.6%-56.9%), with 2.2% having a CR and 46.0% having a PR. The disease control rate was 87.6% (95% CI, 80.9%-92.6%). The median PFS was 4.9 months (95% CI, 4.2-5.5), and the median OS was 10.3 months (95% CI, 9.1-13.3).

Treatment-related AEs occurred in 89.8% of patients. Grade 3 or higher occurred in 36.5%. The most common any-grade AEs included nausea (43.1%), neutropenia (34.3%), anemia (34.3%), decreased appetite (32.8%), and leukopenia (23.4%).

Patel was impressed with those data, and when looking at the ADC space as a whole, he wondered howthey would look in the frontline setting. Raez chimed in that ADC plus immunotherapy might be the way to go.

“The efficacy of an ADC may depend more on the disease state than on what it targets. I conceptualize them as having 3 mechanisms of action…The most important thing isn’t what you target so much as the linker and having the topoisomerase payload,” Weiss said.

Rotow believes the SCLC landscape is heading toward a space where I-DXd or ABV-706 will be approved in the previously treated setting. She emphasized the need for more information about their toxicity profiles and how to sequence the drugs.

In all patients, the CNS ORR was 46% (95% CI, 34%-59%).¹² The CNS disease control rate was 91%, the duration of response was 6.2 months, and the median time to response was 1.4 months.

Leal asked her colleagues how they felt about the concordance between the systemic and CNS response rates. The CNS best ORR showed a CR of 31%, a PR of 15%, and stable disease of 45%.

“It’s very compelling that you’re going to have a systemic therapy that is going to be working as well as the CNS in the brain system. Especially in those who don’t have brain metastases, we move to give the patient I-DXd. We are going to feel comfortable that there is a protective effect in the brain, especially in those patients whom we are keeping on surveillance,” Santos said. “Ifinatamab has continued holding the original response rate that I saw 2 years ago when [these data were presented]. Through the years and several [American Society of Clinical Oncology] and ESMOs, patients on this ADC continue holding that great clinical response.”

Rotow asked if the results from the IDeate-Lung01 trial were expected to be better than those with platinum etoposide. She noted that response rates with etoposide were high, and the PFS between the 2 treatments was similar. Overall, she wondered if I-DXd would be more effective than etoposide in a patient who is untreated.

Patel believes platinum therapy plus I-DXd will be better than platinum plus etoposide but says toxicity should be monitored in these combinations. Patel also noted that giving etoposide is logistically complicated.

“I wonder if it could be better than carboplatin/etoposide. The reasoning is that the PFS we’re seeing here in late line is on par with what we’re used to seeing with platinum etoposide in the front line. When you move pretty much any agent, particularly cytotoxics, but any agent into the front line, the numbers always get better. It would be perfectly valid to do a study with platinum [therapy] and ADC. I’d like to argue it would also be valid to do a study of ADC without the platinum [therapy],” Weiss said.

References

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