乌鸦传媒

A once-hopeful antibody-drug conjugate for small cell lung cancer (SCLC) failed to demonstrate a survival benefit in two large randomized studies, and was mostly too toxic.

In the phase III , patients with extensive-stage SCLC who received rovalpituzumab tesirine (Rova-T) as maintenance therapy after first-line platinum-based chemotherapy had a median overall survival (OS) of 8.8 months, which was numerically worse than the 9.9 months for those receiving placebo, reported Melissa L. Johnson, MD, of the Sarah Cannon Research Institute in Nashville, Tennessee, and colleagues.

And in the , another phase III study, Rova-T as second-line therapy in patients with advanced or metastatic DLL3-high SCLC tumors led to inferior OS versus topotecan (median 6.3 vs 8.6 months, respectively), according to Fiona Blackhall, MD, PhD, of the University of Manchester in England, and colleagues.

Despite recent approvals of PD-1/L1 inhibitors "in the first- and third-line settings, no treatment has substantially improved OS in [extensive-stage]-SCLC since the 1970s," noted Blackhall and co-authors.

Findings from the two negative trials, as well as two early-phase studies of Rova-T, were published in the Journal of Thoracic Oncology.

Good news on Rova-T arrived in 2016, when a first-in-human trial demonstrated a response rate of 18% in SCLC patients whose tumors expressed DLL3, a Notch pathway ligand, and an even higher rate of response for those with DLL3-high tumor expression. But subsequent studies failed to support the early promise and development of the drug has now been terminated.

"The Rova-T development strategy is a perfect example of the dangers of moving directly from promising small phase I studies to large registrational phase III studies without confirming the safety and efficacy data in phase II studies," said Dipesh Uprety, MD, of the Karmanos Cancer Institute in Detroit, and colleagues, writing in an .

They suggested that the responses from the earlier trials may have been in part due to the selection of patients with good prognostic features, rather than a group that represents "real world" patients such as those enrolled in the phase III studies.

Further, the editorialists argued that perhaps Rova-T is simply not a good antibody-drug conjugate.

"The pattern and severity of the toxicity of the payload are important considerations," Uprety and colleagues stressed. "And the 'payload' of Rova-T ... is unacceptably toxic." A substantial proportion of patients could not complete two cycles of Rova-T, which "could have contributed to the poor efficacy results."

Lastly, they said the negative findings with Rova-T raise the question of whether DLL3 remains a valid target in SCLC, but called for more studies with less toxic therapies.

Phase III Trials

The MERU trial involved 748 patients with extensive-stage SCLC who were randomized to maintenance Rova-T (0.3 mg/kg every 6 weeks, with a break every third cycle) or placebo after first-line platinum-based chemotherapy. Over three-quarters of patients had stage IV disease. The median time on the study was 8 months. At study end, 60% of patients randomized to Rova-T had died as had 56% of patients on placebo.

Median progression-free survival (PFS) was 3.7 months in the Rova-T arm compared with 1.4 months in the placebo arm. OS did not differ markedly between patients with DLL3-low tumor expression versus those DLL3-high tumors (9 and 8.5 months, respectively).

Patients treated with Rova-T experienced higher rates of treatment-emergent adverse events (TEAEs), at 93% versus 80% with placebo, and more grade ≥3 events (59% vs 30%, respectively). The most common TEAEs with the study drug included pleural effusion, decreased appetite, peripheral edema, photosensitivity reactions, and fatigue.

The TAHOE study randomized 296 patients with DLL3-high SCLC tumors to Rova-T, while 148 patients received topotecan. Overall response rates were 14.3% and 21%, respectively. After a median follow-up of 8.3 months, 86% of patients had died on the Rova-T arm compared with 78% of patients on the topotecan arm.

Median PFS was 3.0 months with Rova-T compared to 4.3 months with topotecan. Almost all patients in both treatment arms experienced at least one TEAE, the most common with Rova-T again being pleural effusion, decreased appetite, dyspnea, and fatigue. In the topotecan arm, the most common TEAEs were hematologic in nature.

Quality-of-life analyses indicated that declines in both global health and physical functioning were greater in Rova-T recipients.

Early-Phase Trials

In a reported by Christine Hann, MD, PhD, of Johns Hopkins Medical Center in Baltimore, and colleagues, Rova-T alone or with platinum-based chemotherapy showed no clear benefit for the frontline treatment of extensive-stage SCLC.

At the lower doses used in this study of 26 patients, Rova-T was generally tolerable and manageable, Hann and colleagues noted, though TEAEs were common, regardless of the dose used.

In a reported by Jyoti Malhotra, MD, MPH, of Rutgers Cancer Institute of New Jersey, and colleagues, 42 previously treated patients with extensive-stage SCLC received Rova-T in combination with nivolumab (Opdivo) plus or minus ipilimumab (Yervoy).

"All patients experienced one or more TEAEs," the group noted, with almost two-thirds experiencing grade ≥3 TEAEs. The most common high-grade events were pleural effusion, and there were three deaths due to TEAEs, including from pneumonitis and acute kidney injury.

In all, 30% of patients had partial responses, while none had a complete response. Depending on the treatment protocol, the median PFS ranged from 4.1 to 4.8 months, while median OS ranged from 7.4 to 11 months.

The authors felt that the combination of Rova-T plus nivolumab with or without ipilimumab had encouraging antitumor activity, especially in a heavily pretreated group of patients such as those in the study, but whatever the regimen used, treatment was not well tolerated at the doses or schedules evaluated.