Novel Drug Cuts Risk for Death by 44% in Squamous Lung Cancer Trial

Second-line treatment with an investigational anti-CTLA-4 immunotherapy improved survival in squamous non-small cell lung cancer (NSCLC) compared with chemotherapy, according to results of the phase III PRESERVE-003 trial.

Among metastatic patients who progressed on PD-(L)1 inhibitors and platinum-based chemotherapy, median OS was 18.5 months in the gotistobart group versus 10 months in the docetaxel group, a 44% reduction in the risk for death (HR 0.56, 95% CI 0.33-0.95), reported Rama Balaraman, MD, of the Ocala Oncology Center in Florida, at the World Conference on Lung Cancer in Seoul, South Korea.

In an exposure-response analysis, higher gotistobart exposure was associated with improved OS, which supports advancing gotistobart at two loading doses of 10 mg/kg followed by 6 mg/kg once every 3 weeks.

Gotistobart “offers a chemo-free option for patients who had previous exposure to [chemotherapy and immunotherapy] in a squamous cell lung cancer population with a critical unmet need,” Balaraman said.

“It is rare to find targetable mutations in this population,” she explained, adding that multiple trials in heavily pretreated patients have failed to achieve meaningful responses.

Once the disease progresses, treatment options are limited; docetaxel, with or without ramucirumab (Cyramza), is standard of care. However, Balaraman pointed out that docetaxel is associated with modest efficacy, with overall response rates ranging from 10.5% to 12.7%, and OS ranging from around 8 to 9.4 months.

Gotistobart is an investigational anti-CTLA-4 monoclonal antibody designed to selectively deplete regulatory T cells within the tumor microenvironment.

“This microenvironment depletion leads to tumor cell death [and] also minimizes immune-related adverse events,” Balaraman noted. “Importantly, this mechanism has translated to meaningful activity in the PRESERVE-003 study without increasing toxicity.”

It’s unclear when gotistobart might get approved. Developer BioNTech, known for pairing up with Pfizer on the mRNA COVID vaccine, received FDA’s fast track designation in 2022 for the cancer immunotherapy and an orphan drug designation last year for gotistobart as a second-line NSCLC treatment.

Balaraman was presenting updated results from stage 1 of the phase III trial. Initial results suggested a clinically meaningful OS benefit with gotistobart, with a median OS not reached versus 10 months with docetaxel (HR 0.46, 95% CI 0.25-0.84).

While median progression-free survival (PFS) was similar between the gotistobart and docetaxel arms (2.4 vs 2.6 months), a trend of improved PFS was observed in the gotistobart arm (HR 0.69, 95% CI 0.42-1.13). In addition, the confirmed objective response rate was 20% with gotistobart compared with 4.8% with docetaxel.

In PRESERVE-003, 217 patients with metastatic NSCLC were randomized into stage 1 of the study from June 2023 to September 2024 in centers in the U.S., Australia, China, Korea, and the U.K. Of these patients, 91 had squamous NSCLC and 126 had non-squamous NSCLC.

Four of the 91 patients with squamous NSCLC were randomized to receive gotistobart 3 mg/kg before that arm of the trial was terminated following the recommendation of the Data Monitoring Committee. The remaining 87 patients were randomized to receive either gotistobart monotherapy 6 mg/kg with two 10-mg/kg loading doses (n=45) or docetaxel 75 mg/m² (n=42) in the second-line or later treatment setting.

Median age was 64 years in the gotistobart arm and 68.5 years in the docetaxel arm. Most patients were men, Asian, and former smokers, and about one-quarter came from the U.S. All patients had metastatic disease at baseline, and about 70% had received one prior line of systemic therapy, while the remaining 30% had received two or more prior lines of therapy.

Adverse events (AEs) with gotistobart were mainly immune-related or inflammatory, while those with docetaxel were predominantly hematologic.

Grade 3 or higher AEs occurred in 44.4% of patients in the gotistobart arm and 48.8% of those in the docetaxel arm, the most common of which were colitis (8.9%) and decreased neutrophil count (24.4%), respectively. AEs leading to treatment discontinuation occurred in 15.6% and 4.9%.

While stage 1 of PRESERVE-003 was exploratory and not powered for efficacy, stage 2 of the trial is ongoing at 160 global sites and is designed to validate gotistobart in 478 patients with metastatic squamous NSCLC.