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Tarlatamab plus frontline chemoimmunotherapy and PD-L1 maintenance therapy demonstrated both encouraging safety and clinical outcomes in patients with extensive-stage (ES) small cell lung cancer (SCLC), according to cohort results of the phase 1b DeLLphi-303 study (NCT05361395) that were presented during the European Society for Medical Oncology Congress 2025 and simultaneously published in The Lancet Oncology.^1,2

At a median follow-up of 13.8 months (95% CI, 12.5-15.0), the objective response rate (ORR) was 71% (95% CI, 61%-80%), with a complete response rate of 5% and a partial response rate of 66%; 11% of patients had stable disease. Eight percent of patients had progressive disease, and 9% of patients’ responses were not evaluable (NE).

The median duration of response (DOR) was 11.0 months (95% CI, 8.5-NE), the disease control rate was 82% (95% CI, 73%-89%), and the median duration of disease control was 10.7 months (95% CI, 7.7-18.8). Additionally, disease control was sustained for at least 52 weeks in 39% of patients, with ongoing responses in 49% of patients at data cutoff with data continuing to mature, said lead study author Martin Wermke, MD, director of Trial Management/Early Clinical Trial Unit, NCT/UCC Early Clinical Trial Unit, of the German Cancer Research Center, University Hospital Carl Gustav Carus Dresden in Dresden, Germany.

Regarding safety, with a median duration of treatment of 46 weeks (IQR, 14-60), 3 dose limiting toxicities were observed overall, with all patients experiencing treatment-related adverse events (TRAEs) that were grade 3 (43%) or 4 (35%), with 1 patient who died from a TRAE due to sepsis, attributable to the chemotherapy component of the regimen, Wermke said.

Tarlatamab-related AEs that led to treatment discontinuations occurred in 6% of patients, and immune-related adverse events—not including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and associated neurological events—were reported in 2% of patients.

The addition of tarlatamab to chemoimmunotherapy demonstrated a manageable safety profile that was consistent with the profiles of each individual agent, explained Wermke.

“I hope I could convince you that the combination of another frontline chemoimmunotherapy [that is] PD-L1 targeting in the maintenance [setting] is safe and has a manageable toxicity profile,” Wermke said in an oral presentation of the data. “There is no indication of additive or synergistic toxicity.”

Currently, standard treatment for patients with ES-SCLC comprises chemoimmunotherapy followed by PD-1/PD-L1 treatment as maintenance. Tarlatamab is a bispecific T-cell engager that has been assessed in the second-line setting as a single agent³ in the phase 3 DeLLphi-304 trial (NCT05740566) and in the frontline maintenance setting with a PD-L1 inhibitor in this patient population, as seen in parts 5, 6, and 8 of the phase 1b DeLLphi-303 study.

At the 2025 ESMO Congress, Wermke presented on safety and efficacy outcomes from parts 2, 4, and 7 from the phase 1b DeLLphi-303 study, which explored tarlatamab in combination with frontline chemoimmunotherapy, followed by tarlatamab with PD-L1 maintenance therapy in patients with ES-SCLC.

The study enrolled adult patients with ES-SCLC who had received 1 cycle of chemoimmunotherapy, consisting of platinum-etoposide plus an anti-PD-L1 inhibitor, regardless of response to therapy. Patients were also required to have measurable disease via modified RECIST 1.1 criteria, an ECOG performance status of 0 or 1, and no active autoimmune disease or disease that required immunosuppressive therapy. Those with treated and asymptomatic brain metastases were permitted.

In cycles 1 to 3, patients received tarlatamab at 20 mg intravenously (IV) every 3 weeks plus platinum-etoposide (carboplatin to match area under the curve 5 IV on day 1 and etoposide at 100 mg/m² on days 1 to 3) and a PD-L1 inhibitor, which consisted of atezolizumab (Tecentriq) at 1200 mg IV every 3 weeks or durvalumab (Imfinzi) at 1500 mg IV every 3 weeks. In the frontline maintenance setting, which was cycles 4 and beyond, patients received tarlatamab at 20 mg IV every 3 weeks plus either of the PD-L1 inhibitors at the aforementioned doses. Treatment was administered until disease progression.

The coprimary end points were dose-limiting toxicities, treatment-emergent AEs, and TRAEs; secondary end points were ORR, DOR, disease control, progression-free survival (PFS), and overall survival (OS).

Regarding baseline characteristics, the median age across both arms was 63.0 years (range, 37-86), and 67% of patients were male. Patients were mostly White (74%), followed by Asian (16%), Other (9%), and Black (1%). At diagnosis, 77% had ES disease and 55% had an ECOG performance status of 1. Three-fourths of patients were former smokers, and 67% had prior receipt of a PD-L1 inhibitor in the first standard-of-care cycle; 16% and 45% of patients had treated asymptomatic brain metastases and liver metastases, respectively. The median sum of diameters of target lesions was 82.3 mm (range, 10.0-358.2).

Wermke noted that the trial was not designed to compare the PD-L1 inhibitors and there were no randomizations between the treatment arms, adding that there were imbalances in baseline characteristics between the atezolizumab and durvalumab groups.

Further efficacy data showed that the median PFS was 10.3 months (95% CI, 7.2-13.6), starting from the first dose of tarlatamab treatment; the Kaplan-Meier estimate of the 12-month PFS rate was 43.1% (95% CI, 32.0%-53.7%). The median OS is not yet estimable; however, the Kaplan-Meier estimate of the 12-month OS rate with the tarlatamab regimen was 80.6%.

Investigators also assessed treatment-emergent CRS and ICANS by cycle, which primarily occurred during cycle 1 of tarlatamab (59%) and were mostly of grades 1/2; all CRS/ICANS events resolved. CRS and ICANS events led to both dose interruptions and discontinuations in 1% of patients each, with no fatalities reported. The median time to CRS onset from the last prior tarlatamab dose was 13.3 hours (IQR, 8.0-19.3), and the median time to ICANS onset from the same time point was 5 days (IQR, 3.0-50).

Wermke concluded that these data support further investigation of this regimen, which will be explored in the phase 3 DeLLphi-312 study (NCT07005128).⁴

Disclosures: Wermke cited honoraria from Amgen, BMS GmbH & Co. KG, Boehringer Ingelheim, GWT, Janssen, Lilly, Merck Serono, MJH/PER, Novartis, Pfizer, Regeneron, SYNLAB, and Takeda; consulting or advisory roles for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo Europe GmbH, Genentech, ImCheck Therapeutics, Immatics, Iovance Biotherapeutics, ISA Pharmaceuticals, Lilly, Novartis, PharmaMar, Regeneron, Tacalyx, T-knife, and Zymeworks; receipt of research funding from Roche (paid to the institution); and travel and accommodation expenses from Amgen, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo Europe GmbH, GEMoaB, Iovance Biotherapeutics, Immatics, Janssen Oncology, Merck Serono, Pfizer, and Sanofi/Aventis.

References

1. Wermke M, Lau SCM, Moskovitz M, et al. Tarlatamab with first-line chemoimmunotherapy for extensive stage small cell lung cancer (ES-SCLC): DeLLphi-303 study. Ann Oncol. Abstract 2757O
2. Mountzios G, Sun L, Cho BC, et al. Tarlatamab in small-cell lung cancer after platinum-based chemotherapy. N Eng J Med. 2025;393:349-361. doi:10.1056/NEJMoa2502099
3. Paulson KG, Lau SCM, Ahn MJ, et al. Safety and activity of tarlatamab in combination with a PD-L1 inhibitor as first-line maintenance therapy after chemo-immunotherapy in patients with extensive-stage small-cell lung cancer (DeLLphi-303): a multicentre, non-randomised, phase 1b study. Lancet Oncol. 2025;26(10):1300-1311. doi:10.1016/s1470-2045(25)00480-2
4. A Study Comparing Tarlatamab, Durvalumab, Carboplatin, and Etoposide Versus Durvalumab, Carboplatin, and Etoposide in First-line Extensive Stage Small-Cell Lung Cancer (ES-SCLC) (DeLLphi-312). ClinicalTrials.gov. Last Updated October 14, 2025. https://tinyurl.com/56ss66yd

The combination of datopotamab deruxtecan-dlnk (Dato-DXd; Datroway) and rilvegostomig demonstrated potent antitumor activity as first-line therapy in cisplatin-ineligible and second-line therapy in platinum-pretreated patients with locally advanced or metastatic urothelial cancer, according to data from cohort 6B of the phase 2 TROPION-PanTumor03 trial (NCT05489211) presented at the 2025 ESMO Congress.¹

In the first-line cohort (n = 22), the confirmed objective response rate (ORR) was 68.2% (95% CI, 45.1%-86.1%), and the 12-week disease control rate (DCR) was 95.5% (95% CI, 83.4%-99.5%). The median time to response was 1.4 months (range, 1.2-3.9), and the median duration of response (DOR) was not calculable ([NC] 95% CI, 9.4 months to NC). In the second-line cohort (n = 18), the confirmed ORR was 38.9% (95% CI, 17.3%-64.3%), and the 12-week DCR was 83.3% (95% CI, 66.6%-93.7%). The median time to response was 1.3 months (range, 1.2-8.4), and the median DOR was NC (95% CI, 6.9 months to NC).

“The combination of Dato-DXd plus rilvegostomig demonstrated promising efficacy in patients with locally advanced or metastatic urothelial cancer who were cisplatin-ineligible and patients who had progressed on prior platinum-based chemotherapy,” lead study author Sun Young Rha, MD, PhD, professor of medical oncology in the Department of Internal Medicine and the director of Songdang Institute for Cancer Research, Yonsei University College of Medicine, Yonsei University Health System in Seoul, Korea, stated in the presentation.

What Was TROPION-PanTumor03 Designed to Answer?

Despite the evolution in first- and second-line treatments for patients with locally advanced or metastatic urothelial cancer, a clinical need remains for effective therapy. Dato-DXd is a TROP2-directed antibody-drug conjugate (ADC) and rilvegostomig is an Fc-reduced, monovalent, bispecific IgG1 antibody directed against PD-1 and TIGIT receptors.

TROPION-PanTumor03 is an open-label trial evaluating dato-DXd as monotherapy or in combination with anticancer agents in patients with advanced or metastatic solid tumors.²

Investigators enrolled patients with histologically confirmed, unresectable, locally advanced or metastatic urothelial cancer who had not received prior PD-(L)1, CTLA-4, or TIGIT inhibitors, enfortumab vedotin-ejfv (Padcev), or TROP2-directed or deruxtecan-based ADCs.¹ Patients had to be cisplatin-ineligible in the first-line setting or platinum-treated in the second line. Patients in the former cohort also had to have either an ECOG performance status between 0 and 2, creatinine clearance of at least 30 mL/min but less than 60 mL/min, NCI CTCAE 5.0 grade 2 or greater hearing loss, or NCI CTCAE 5.0 grade 2 or greater peripheral neuropathy. Patients in the latter cohort had to also have an ECOG performance status of 0 or 1.

Forty patients received 6 mg/kg of intravenous dato-DXd every 3 weeks plus 750 mg of rilvegostomig every 3 weeks in the first- and second-line cohorts. In the first-line cohort, the median age was 71 years (range, 53-85). Most patients were male (77.3%), had an ECOG performance status of 0 (77.3%), and had AJCC stage IV disease (86.4%). Most patients were untreated (86.4%), although some had received neo(adjuvant) cisplatin therapy (13.6%). In the second-line cohort, the median age was 66 years (range, 56-78). Most patients were male (83.3%), had an ECOG performance status of 0 (72.2%), and had AJCC stage IV disease (88.9%). Most patients had received 1 prior line of therapy (61.1%), with cisplatin (88.9%) being the most common.

The primary end points were investigator assessed ORR per RECIST 1.1 criteria, safety, and tolerability. Secondary end points were DCR, DOR, and investigator assessed progression-free survival (PFS) per RECIST 1.1 criteria.

How Durable Were the Responses?

In the first-line cohort, the median PFS was NC (95% CI, 10.8 months to NC) at median follow-up of 10.8 months (range, 2.6-19.4); the 6- and 12-month PFS rates were 85.9% (95% CI, 62.4%-95.2%) and 73.5% (95% CI, 46.5%-88.4%), respectively. In the second-line cohort, the median PFS was 12.5 months (95% CI, 4.2-NC) at median follow-up of 9.7 months (range, 8.1-17.8); the 6- and 12-month PFS rates were 72.2% (95% CI, 45.6%-87.4%) and 60.0% (95% CI, 33.7%-78.7%), respectively.

Was the Regimen Well Tolerated?

In the first- and second-line cohorts, respectively, treatment-related adverse effects (TRAEs) led to dose reduction (63.6% vs 22.2%), interruption (45.5% vs 33.3%), and discontinuation (9.1% vs 16.7%).

“The safety profile of Data-DXd plus rilvegostomig was consistent with previous reports of this combination. No new safety signals were identified,” Rha stated.

Adverse effects of special interest (AESIs) for Dato-DXd in the first-line cohort included oral mucositis/stomatitis (any grade, 40.9%; grade ≥3, 0%), ocular surface events (any grade, 18.2%; grade ≥3, 0%), and adjudicated drug-related interstitial lung disease (ILD)/pneumonitis (any grade, 4.5%; grade ≥3, 0%). AESIs for rilvegostomig included hepatic events (any grade, 13.6%; grade ≥3, 0%), diarrhea/colitis (any grade, 4.5%; grade ≥3, 0%), dermatitis/rash (any grade, 50.0%; grade ≥3, 0%), and infusion-related reaction/hypersensitivity reaction (any grade, 9.1%; grade ≥3, 0%).

AESIs for Dato-DXd in the second-line cohort included oral mucositis/stomatitis (any grade, 61.1%; grade ≥3, 5.6%), ocular surface events (any grade, 22.2%; grade ≥3, 0%), and adjudicated drug-related ILD/pneumonitis (any grade, 11.1%; grade ≥3, 0%). AESIs for rilvegostomig included hepatic events (any grade, 5.6%; grade ≥3, 5.6%), diarrhea/colitis (any grade, 5.6%; grade ≥3, 0%), and dermatitis/rash (any grade, 44.4%; grade ≥3, 0%).

The most common TRAEs that occurred in at least 10% of patients in the first- and second-line cohorts, respectively, were stomatitis (40.9% vs 50.0%), nausea (18.2% vs 44.4%), asthenia (40.9% vs 5.6%), fatigue (13.6% vs 33.3%), rash (31.8% vs 0%), amylase increase (22.7% vs 56.7%), decreased appetite (22.7% vs 16.7%), constipation (22.7% vs 11.1%), pruritus (13.6% vs 22.2%), decreased neutrophil count/neutropenia (4.5% vs 22.2%), alopecia (18.2% vs 16.7%), anemia (9.1% vs 16.7%), dry eye (13.6% vs 5.6%), aspartate aminotransferase increase (13.6% vs 0%), and dry mouth (0% vs 11.1%).

“These results warrant further exploration of Dato-DXd plus rilvegostomig in the first-line locally advanced or metastatic setting,” Rha concluded.

Disclosures: Rha reported being a consultant or advisor for Amgen, Arcus Biosciences, Astellas Pharma, AstraZeneca, Eisai, Jazz, Daiichi Sankyo, Gilead, Indivumed, LG Chem, MSD Oncology, Ono Pharmaceutical, and Toray Inc; speaker for Amgen, Arcus Biosciences, Astellas Pharma, AstraZeneca, Bristol-Myers Squibb/Ono, Daiichi Sankyo, Eisai, BeOne, and MSD Oncology; and research funding from Amgen (inst), ASLAN Pharmaceuticals, Astellas Pharma, AstraZeneca, Bayer, BeOne, Bristol-Myers Squibb, Daiichi Sankyo, Eisai, Indivumed, Eli Lilly, Gilead, MSD Oncology, Roche/Genentech, Sillajen, and Jazz.

References

1. Young Rha S, Lim SH, Zhou F, et al. Datopotamab deruxtecan (Dato-DXd) + rilvegostomig (rilve) in patients (pts) with locally advanced or metastatic urothelial cancer (a/mUC): results from the phase 2 TROPION-PanTumor03 study. Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract 3072MO.
2. Study of dato-DXd as monotherapy and in combination with anti-cancer agents in patients with advanced solid tumors (TROPION-PanTumor03). ClinicalTrials.gov. Updated July 11, 2025. Accessed October 18, 2025. https://www.clinicaltrials.gov/study/NCT05489211