Drug Combo’s Response Rates Top 90% in Small Cell Lung Cancer Trial

Up to 90% of patients with advanced small cell lung cancer (SCLC) responded to a PD-L1/VEGF bispecific antibody linked to an antibody-drug conjugate (ADC), a preliminary trial showed.

Response rates ranged from 52.4% in patients who received pumitamig/elfetabart drozuntecan (elfe-D) as third-line therapy to 92.3% in those who received the novel therapy in first line. Other subgroup response rates included 60.4% in patients with prior exposure to immuno-oncology (IO) therapies, and 87.5% in a small group of patients previously treated with a delta-like ligand 3 (DLL3) T-cell engager (such as tarlatamab [Imdelltra]). Response rates remained consistent regardless of smoking status and presence or absence of brain metastases.

The two agents have largely non-overlapping toxicities, and the tolerability was favorable, as expected, reported Adam J. Schoenfeld, MD, of Memorial Sloan Kettering Cancer Center in New York City, at the World Conference on Lung Cancer in Seoul, South Korea.

“This is the first data for a PD-L1/VEGF bispecific antibody in combination with an ADC in lung cancer,” said Schoenfeld. “There were no unexpected safety signals, and the safety profile was as expected given the individual profile of each agent. Most adverse events were grade 1/2, and there was a low rate of ILD [interstitial lung disease]. The combination treatment showed encouraging early efficacy in small cell lung cancer across all lines of therapy and dose levels. … We also saw substantial ct (circulating tumor)DNA reduction achieved in 96% of patients that were evaluable.”

“The results support further clinical development of the combination in small cell lung cancer, and is also ongoing in non-small cell lung cancer [NSCLC]. Data in other tumor types will also be reported at ESMO [European Society for Medical Oncology] later this year,” he added.

The results were robust across a wide range of key subgroups in a rapidly evolving therapeutic landscape, said invited discussant Mariana Brandão, MD, PhD, of Institut Jules Bordet in Brussels. The clinical data, accompanied by the declines in ctDNA provided strong evidence of response.

However, pumitamig/elfe-D is not the only PD-L1/ADC combination competing for a role in SCLC, she continued. Multiple ADCs are being paired with PD(L)-1 inhibitors, some of which have already shown a survival advantage. Additionally, she questioned the need for adding an ADC.

“The question we have to ask is what is pumitamig doing here?” said Brandão. “Should they really add an anti-PD-L1/VEGF to this combination? This is just food for thought.”

“Pumitamig/elfe-D showed high activity, but we have to ask ourselves, what’s the added value of this combination versus an ADC alone,” she concluded.

The rationale for combining pumitamig and elfe-D included preclinical evidence of synergistic activity and xenograft studies showing durable tumor regression and tumor control and significantly lower tumor volumes compared with monotherapy, said Schoenfeld. Additionally, pumitamig (alone or in combination with chemotherapy) and elfe-D showed early efficacy and tolerability in SCLC and NSCLC.

Schoenfeld reported findings from the SCLC component of BNT324-01, a phase Ib/II study of pumitamig plus elfe-D in advanced lung cancer. Patients were enrolled irrespective of PD-L1 status. The second part of the study included dose optimization and signal-seeking in various subgroups.

The primary endpoints were safety and objective response rate (ORR). Key secondary points included disease control rate (DCR), progression-free survival, duration of response, and overall survival.

Investigators in North America, Europe, Asia, and Australia enrolled a total of 279 patients across four dose groups. The safety analysis encompassed all patients and showed that a third developed grade ≥3 treatment-emergent adverse events (TEAEs), and a fourth developed grade ≥3 treatment-related adverse events (TRAEs). The most common TRAEs (all grades) were nausea (40.9%), decreased appetite (22.9%), anemia (21.5%), fatigue (19.4%), decreased white blood cell count (18.6%), decreased neutrophils (17.9%), vomiting (17.6%), decreased platelets (10.8%), and hypertension (10%). Most TRAEs were grade 1/2.

The safety profile in the 78 patients with SCLC was similar to the overall population. Eight patients discontinued because of TRAEs, five related to pumitamig, two to elfe-D, and one related to both drugs.

Baseline demographics in the 78 patients included brain metastases in 44.9% and liver metastases in 42.3%. Two-thirds of the patients were former smokers, and 15.4% were current smokers.

The combination produced an ORR of 70.4% in 71 efficacy-evaluable patients (including one complete response) and a DCR of 93.0%. Subgroup response rates included 73.2% and 60.0% in current/former smokers and never smokers, respectively, and 71.0% and 70.0% in patients with and without brain metastases. Response rates by prior lines of therapy were 92.3% for no prior treatment, 76.2% for second-line therapy, and 52.4% for third line. Responses occurred across the range of doses.

“We observed encouraging objective response rates across lines of therapy, including patients treated with the emerging standard of care,” said Schoenfeld.

In 26 patients with ctDNA assessment, 100% clearance occurred in 12 patients, 90% in 19 patients, and 50% in 25.