Drug Combo for Lung Cancer Beats Pembrolizumab in First-Line Trial

CHICAGO — Adding an investigational TROP2-targeted antibody-drug conjugate (ADC) to first-line immunotherapy for PD-L1-positive non-small cell lung cancer (NSCLC) reduced the risk of disease progression and may have improved survival as well, interim data from a Chinese phase III study indicated.

Over a median follow-up of 10.5 months, sacituzumab tirumotecan (sac-TMT) plus pembrolizumab (Keytruda) cut the risk for disease progression or death by 65% versus single-agent pembrolizumab (HR 0.35, 95% CI 0.26-0.47, P<0.0001). A median value for progression-free survival (PFS) was not reached in the combination arm as compared with 5.7 months with the PD-1 inhibitor alone, reported Caicun Zhou, MD, PhD, of Shanghai East Hospital.

Including sac-TMT was associated with more toxicity but showed a “clear” early trend for an overall survival (OS) benefit, with an estimated 1-year OS rate of 80% versus 69% with pembrolizumab alone (HR 0.55, 95% CI 0.36-0.85), findings presented here at the American Society of Clinical Oncology (ASCO) annual meeting and published simultaneously in The Lancet showed.

“According to the progression-free survival data, I’m sure we can get an overall survival benefit,” said Zhou, who pointed out that the OS data remain immature.

Sac-TMT, an ADC that links an anti-TROP2 monoclonal antibody with a belotecan-derived topoisomerase I inhibitor, is not approved in the U.S., but the FDA late last year awarded the drug a Commissioner’s National Priority Voucher that aims to speed up the review process to just 1 to 2 months from the time a new drug application is submitted.

“These are very impressive results. This could well be a practice-changing study, though we do need to have global validation,” said ASCO discussant Natalie Vokes, MD, of the University of Texas MD Anderson Cancer Center in Houston.

She drew particular attention to the study’s control arm.

In the U.S., guidelines recommend single-agent pembrolizumab only for patients with non-squamous histology and high PD-L1 expression (≥50%), otherwise the PD-1 inhibitor is used in combination with chemotherapy. But the trial included patients with both non-squamous and squamous histology who had PD-L1 levels of 1% and above.

Sac-TMT is primarily being developed alongside immunotherapy, but it’s “worth highlighting that about 20% of these patients would do very well with immunotherapy alone,” noted Vokes. “Under this development strategy, the proposal would now be to add chemotherapy exposure to all of these patients with all of the associated side effects.”

In addition to cytopenias, she cited other toxicities that could impact quality of life, such as alopecia, stomatitis, decreased appetite, weight loss, fatigue, weakness, nausea, and rash.

“When we’re talking about adding ADCs to patients who would’ve been treated with immunotherapy alone, this feels like a lot of toxicity to give to them,” said Vokes. “The efficacy is going to have to be good enough to make us feel comfortable doing that.”

Findings from the so-called OptiTROP-Lung05 study presented by Zhou at ASCO showed that the PFS benefit with the addition of the ADC was consistent regardless of tumor histology or PD-L1 expression, as measured by tumor proportion score (TPS):

• Non-squamous: HR 0.28 (95% CI 0.18-0.43)
• Squamous: HR 0.44 (95% CI 0.29-0.66)
• TPS 1-49%: HR 0.28 (95% CI 0.19-0.41)
• TPS ≥50%: HR 0.47 (95% CI 0.29-0.77)

Response rates reached 70% in the combination arm versus 42% with pembrolizumab alone, while disease control rates were 94% and 72%, respectively.

TROP2 is expressed in epithelial cancers such as NSCLC and tends to be associated with more aggressive disease. In the study, the PFS benefit was observed both in patients with high and low TROP2 expression.

Zhou said that another phase III trial, to be presented at a future meeting, is testing pembrolizumab with either sac-TMT or chemotherapy in PD-L1-negative NSCLC. Sac-TMT has also demonstrated antitumor activity in pretreated EGFR-mutant NSCLC and other cancers.

Study Details

Zhou presented an interim analysis of OptiTROP-Lung05, an open-label phase III trial that randomized 413 patients with previously untreated locally advanced or metastatic NSCLC at 68 hospitals in China to either pembrolizumab alone or with sac-TMT, with both drugs delivered intravenously. Participants needed to have no targetable genomic alterations and a PD-L1 TPS of 1% or higher.

Baseline characteristics were generally well balanced, said Zhou. The patient population had a median age of about 65 years and over 80% were men. More than 90% had stage IV disease, 40% had squamous histology, 40% had high PD-L1 expression (TPS ≥50%), and more than one-fourth had three or more distant sites of metastatic disease.

PFS was the primary endpoint and OS was the key secondary endpoint.

Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 55% of patients in the combination arm and 31% of those in the single-agent pembrolizumab arm. The most common of these included decreases in neutrophils (17% vs <1%, respectively), anemia (9% vs 1%), decreases in white blood cell counts (9% vs <1%), pneumonia (8% vs 5%), and stomatitis (5% vs none). Patients were given medication to prevent stomatitis, said Zhou.

Serious TEAEs occurred in 39% of the combination arm and 29% of the pembrolizumab-alone arm, with TEAEs resulting in permanent drug discontinuation in 4% of the combination arm (either sac-TMT or pembrolizumab) and in 5% of the pembrolizumab arm.

Low-grade ocular surface toxicity in the combination arm — including dry eye, conjunctivitis, or increased tearing — occurred in 14% of patients. Grade 5 events considered treatment related occurred in 1% or less of patients in each arm.