Four independent studies published in the Journal of Thoracic Oncology demonstrate that rovalpituzumab tesirine (Rova-T), a first-in-class antibody-drug conjugate directed against delta-like protein 3 (DLL3), is not effective against small cell lung cancer (SCLC). An accompanying editorial by Uprety et al explores recent clinical trials of rovalpituzumab and suggests possible reasons why the drug has not been effective.
Background of Rovalpituzumab Tesirine
According to the editorial, SCLC remains a difficult disease to treat, especially at the time of relapse. Currently, topotecan is among the most effective agents, but it is not the most desirable and favored drug in the second-line setting because of its toxicity profile. Still, it has been difficult for new agents to “beat” this drug in the second-line setting. Several phase III clinical trials have failed to reveal improved survival over topotecan.
In 2017, clinicians were cautiously optimistic when Rudin et al published one of the first studies on Rova-T in The Lancet Oncology.
“The first in-human phase I clinical trial with Rova-T elicited significant enthusiasm because of the efficacy results—11 of 60 assessable patients with pretreated SCLC who received an active dose of Rova-T achieved a confirmed response for an objective response rate (ORR) of 18%, tumors with high DLL3 expression (50% expression on tumor cells), the ORR was 38%. In a post hoc analysis, the ORR did not differ between those treated in the second- or third-line setting,” according to the editorial.
Four Recent Studies
However, the four studies published in this month’s the Journal of Thoracic Oncology demonstrate that rovalpituzumab tesirine could not displace topotecan as an effective therapy for SCLC.
In the phase III TAHOE study published by Blackhall et al, the authors concluded that “compared with topotecan, which is the current standard second-line chemotherapy, Rova-T exhibited an inferior overall survival and higher rates of serosal effusions, photosensitivity reaction, and peripheral edema in patients with SCLC.”
In a second study—a phase I/II trial focused on the combination of Rova-T with nivolumab plus or minus ipilimumab—Malhotra et al reported, “Despite encouraging antitumor activity in previously treated extensive-stage SCLC, combination therapy with Rova-T and nivolumab plus or minus ipilimumab was not well tolerated at the dose levels and administration schedules evaluated.”
In a third study—published by Hann et al and focused on using the agent in the frontline setting—the researchers found that there was no clear efficacy benefit of adding Rova-T to chemotherapy and etoposide.
Finally, the last study by Johnson et al—the phase III MERU trial, which was focused on using Rova-T as a maintenance therapy after first-line platinum-based chemotherapy—found that, “Because of the lack of survival benefit in the Rova-T arm, the study did not meet its primary endpoint and was terminated early.”
Speculation on Rova-T’s Inefficacy
The editorial’s authors suggest three reasons why the therapy has not progressed passed stage I:
1) First, the Rova-T development strategy is an example of the dangers of moving directly from positive, small phase I studies to large registrational phase III studies without confirming the safety and efficacy data in phase II studies.
2) Second, Rova-T may not be an ideal antibody-drug conjugate. The safety and efficacy of antibody-drug conjugates depend on a number of factors, including the drug-antibody ratio, which is the average number of cytotoxic molecules attached to each antibody; the cytotoxic “payload,” in which there is invariably some diffusion of cytotoxin into the bloodstream and normal tissues; and the linker, which links the payload to the antibody, that must be stable to avoid significant release of the drug into the circulation.
3) Third, the failure of all the Rova-T trials begs the question of whether DLL3 is a valid target in SCLC.
The authors suggested that future studies should, therefore, focus on better understanding of disease biology and targeting treatment based on the new emerging molecular subtypes.
Disclosure: For full disclosures of the study authors, visit jto.org.
