Rovalpituzumab tesirine (Rova-T) is not effective against small-cell lung cancer (SCLC), four independent studies show. SCLC remains a difficult disease to treat, especially at the time of relapse.
Currently, topotecan is among the most effective treatments, 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.
Early Rova-T Optimism
In 2017, clinicians were cautiously optimistic when Dr. Charles Rudin and colleagues published one of the first studies on rovalpituzumab tesirine in Lancet Oncology.
The first in-human phase 1 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 an editorial1 published in the Journal of Thoracic Oncology (JTO) accompanying the studies.
However, the four studies published in the JTO demonstrate that rovalpituzumab tesirine could not displace topotecan as an effective therapy for SCLC.
Inferior Overall Survival
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 the second study3 published in JTO, the researchers, led by Dr. Jyoti Malhotra, Rutgers Cancer Institute of New Jersey, found that
Despite encouraging antitumor activity in previously treated ES SCLC, combination therapy with Rova-T and nivolumab plus or minus ipilimumab was not well tolerated at the dose levels and administration schedules evaluated,
The third study4, led by Dr. Christine Hamm, Johns Hopkins Medical Center, Baltimore, Md., the researchers found that there was no clear efficacy benefit of adding Rova-T to chemotherapy and etoposide.
Finally, the fourth study5, by Dr. Melissa Johnson, from Sarah Cannon Research Institute in Nashville, Tenn., found that due to the lack of survival benefit in the Rova-T arm, the study did not meet its primary end point and was terminated early.
The editorial’s authors suggest three reasons why the therapy has not progressed passed stage I.
First, the Rova-T development strategy is an 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.
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, must be stable to avoid significant release of the drug into the circulation.
Third, the failure of all the Rova-T trials begs the question of whether DLL3 is a valid target in SCLC.
The authors suggest that future studies should, therefore, focus on better understanding of disease biology and targeting treatment based on the new emerging molecular subtypes.
Dipesh Uprety, Jordi Remon, Alex A. Adjei. All That Glitters Is Not Gold: The Story of Rovalpituzumab Tesirine in SCLC. Journal of Thoracic Oncology, 2021; 16 (9): 1429 ↩︎
Fiona Blackhall, et al. Efficacy and Safety of Rovalpituzumab Tesirine Compared With Topotecan as Second-Line Therapy in DLL3-High SCLC: Results From the Phase 3 TAHOE Study. Journal of Thoracic Oncology, 2021; 16 (9): 1547 ↩︎
Jyoti Malhotra, Petros Nikolinakos, Ticiana Leal, Jonathan Lehman, Daniel Morgensztern, Jyoti D. Patel, John M. Wrangle, Giuseppe Curigliano, Laurent Greillier, Melissa L. Johnson, Neal Ready, Gilles Robinet, Satwant Lally, David Maag, Ricardo Valenzuela, Vincent Blot, Benjamin Besse. A Phase 1–2 Study of Rovalpituzumab Tesirine in Combination With Nivolumab Plus or Minus Ipilimumab in Patients With Previously Treated Extensive-Stage SCLC. Journal of Thoracic Oncology, 2021; 16 (9): 1559 ↩︎
Christine L. Hann, Timothy F. Burns, Afshin Dowlati, Daniel Morgensztern, Patrick J. Ward, Martina M. Koch, Chris Chen, Carrianne Ludwig, Maulik Patel, Halla Nimeiri, Philip Komarnitsky, D. Ross Camidge. A Phase 1 Study Evaluating Rovalpituzumab Tesirine in Frontline Treatment of Patients With Extensive-Stage SCLC. Journal of Thoracic Oncology, 2021; 16 (9): 1582 ↩︎
Melissa L. Johnson, Zanete Zvirbule, Konstantin Laktionov, Aslaug Helland, Byoung Chul Cho, Vanesa Gutierrez, Benoît Colinet, Herve Lena, Martin Wolf, Maya Gottfried, Isamu Okamoto, Cor van der Leest, Patricia Rich, Jen-Yu Hung, Christina Appenzeller, Zhaowen Sun, David Maag, Yan Luo, Caroline Nickner, Alena Vajikova, Philip Komarnitsky, Jair Bar. Rovalpituzumab Tesirine as a Maintenance Therapy After First-Line Platinum-Based Chemotherapy in Patients With Extensive-Stage–SCLC: Results From the Phase 3 MERU Study. Journal of Thoracic Oncology, 2021; 16 (9): 1570 ↩︎