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Updated Data From Phase 1 Trials Support Shifts in the Lung Cancer Treatment Paradigm

Martin E. Gutierrez, MD, discusses steps towards a continuous shift in both the NSCLC and SCLC treatment paradigms, based on trials presented at ASCO 2025.

Martin E. Gutierrez, MD

Martin E. Gutierrez, MD

Among the treatments that are slowly moving the needle in the non–small cell lung cancer (NSCLC) and extensive-stage small cell lung cancer (ES-SCLC) treatment landscapes are datopotamab deruxtecan-dlnk (Dato-DXd; Datroway) plus rilvegostomig (formerly AZD2936), and zocilurtatug pelitecan (ZL-1310), respectively, according to Martin E. Gutierrez, MD.

Updated results from the phase 1b TROPION-Lung04 trial (NCT04612751), presented at the 2025 ASCO Annual Meeting, revealed that the safety profile of the antibody-drug conjugate (ADC) Dato-DXd plus rilvegostomig was consistent with the known safety profiles of the respective agents alone for the treatment of patients with advanced or metastatic, squamous or nonsquamous NSCLC without actionable genomic alterations.1 Additionally, the combination demonstrated preliminary efficacy data as a treatment in the first-line setting. Specifically, a confirmed objective response rate (ORR) was shown in 57.5% (95% CI, 40.9%-73.0%) of all patients on the study (n = 40), regardless of histology. Best objective responses included 1 complete response (CR) and 22 partial responses (PR); stable disease (SD) was observed in 15 patients, and 2 patients had progressive disease (PD). Notably, the median duration of response was 5.8 months (95% CI, 4.5-not evaluable), and the disease control rate (DCR) was 95.0% (95% CI, 83.1%-99.4%).

Regarding safety, treatment-emergent adverse effects (TEAEs) were reported in 100% of patients on the study, with 90.0% being treatment-related AEs (TRAEs). Grade 3 or greater TEAEs were reported in 60.0% of patients, and 25.0% were TRAEs. Moreover, serious TEAEs were observed in 50.0% of patients, of which 15.0% were TRAEs. The most common grade 1/2 TEAEs reported in at least 15% of patients included stomatitis (52.5%), fatigue (50.0%), alopecia (45.0%), nausea (42.5%), rash (32.5%), constipation (27.5%), vomiting (25.0%), decreased appetite (22.5%), pneumonia (20.0%), increased amylase (17.5%), dry eye (17.5%), abnormal hepatic function (17.5%), musculoskeletal pain (17.5%), anemia (15.0%), chills (15.0%), dysgeusia (15.0%), pneumonitis (15.0%), and pruritus (15.0%).

Furthermore, updated results from a phase 1 study (NCT06179069) assessing the DLL3-directed ADC zocilurtatug pelitecan demonstrated an ORR of 37% in patients with ES-SCLC regardless of previous lines of therapy (n = 74).2 Of these responses, 1 was a confirmed CR, 1 was an unconfirmed CR, 26 were confirmed PRs, and 10 were unconfirmed PRs. SD was observed in 31 patients, and 5 patients had PD; the DCR was 93%. Among all patients included in the safety analysis (n = 89), any TEAEs were observed in 89%, and TEAEs related to zocilurtatug pelitecan were observed in 73% of patients. Grade 3 or greater TEAEs were observed in 29% of patients, with grade 3 or greater TEAEs related to zocilurtatug pelitecan reported in 23%. Additionally, serious TEAEs were observed in 21% of patients, of which 8% were serious TEAEs associated with zocilurtatug pelitecan. TEAEs leading to dose interruption, reduction, discontinuation, or death were observed in 28%, 7%, 6%, and 2% of patients, respectively. Of note, the most common any-grade TRAEs observed in at least 10% of patients included anemia (40%), neutropenia (30%), nausea (26%), leukopenia (23%), thrombocytopenia (17%), decreased appetite (15%), fatigue (11%), lymphopenia (10%), and pneumonitis/interstitial lung disease (ILD; 10%).

“[DLL3] is an important molecule. [When targeted,] it has [shown improved] activity in central nervous system disease and [among] patients [with ES-SCLC] who had previously [received] a DLL3[-directed] T-cell engager,” Gutierrez explained in an interview with OncLive® at the meeting.

In the interview, Gutierrez discussed the background, efficacy, and safety of Dato-DXd plus rilvegostomig in patients with advanced or metastatic NSCLC from the TROPION-Lung04 trial, and updated outcomes from the phase 1 study evaluating zocilurtatug pelitecan in ES-SCLC.

Gutierrez is the chief of thoracic oncology and director of the Experimental Therapeutics Program at Hackensack Meridian Health in New Jersey.

OncLive: What was the background for evaluating Dato-DXd plus rilvegostomig in advanced or metastatic NSCLC in the TROPION-Lung04 study?

Gutierrez: TROPION-Lung04 is a quite large trial [evaluating the] TROP2 inhibitor [Dato-DXd] with a bispecific antibody [directed] against PD-L1 and TIGIT. We have enrolled a total of 40 patients in this study, with 20 patients continuing the treatment.

What were the efficacy and safety findings from the TROPION-Lung04 study?

We [saw] a response rate of 57% [in patients with advanced or metastatic NSCLC]. The adverse [effects] have been tolerable, specifically looking at ILD and corneal abnormalities, and [have been] encouraging with the results we have seen. [This study represents] one of [many ongoing] efforts to improve on current chemotherapy and checkpoint inhibitors vs standard therapy.

What did the updated outcomes of the phase 1 study evaluating zocilurtatug pelitecan in patients with ES-SCLC demonstrate?

The [phase 1 study evaluated zocilurtatug pelitecan], an ADC [directed] against DLL3, as a single agent in the second- and third-line settings [for patients with] heavily pretreated SCLC with an adequate performance status. We [saw] a response rate of 68% [in dose escalation], which is quite amazing, and a DCR of 97% [in patients who received 1 prior line of therapy]. Some responses were durable, at least for 5 to 6 months, and [more than] half of patients are continuing treatment.

References

  1. Waqar SN, Cuppens K, Campelo RG, et al. First-line (1L) datopotamab deruxtecan (Dato-DXd) + rilvegostomig in advanced or metastatic non-small cell lung cancer (a/mNSCLC): results from TROPION-Lung04 (cohort 5). J Clin Oncol. 2025; 43(suppl 16):8521. doi:10.1200/JCO.2025.43.16_suppl.8521
  2. Patel MR, Wu YL, Wang Z, et al. ZL-1310, a DLL3 ADC, in patients with extensive stage small cell lung cancer: ph1 trial update. J Clin Oncol. 2025;43(suppl 16):3041. doi:10.1200/JCO.2025.43.16_suppl.3041

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