Four independent studies show rovalpituzumab tesirine ineffective
against small cell lung cancer

Date:
September 7, 2021
Source:
International Association for the Study of Lung Cancer
Summary:
Four independent studies demonstrate that rovalpituzumab tesirine
for small-cell lung cancer (SCLC) is not effective against SCLC,
casting a pall over the future of the therapy and closing a door
that seemed opened four years ago when the first study on the
therapy was published.



FULL STORY ==========================================================================
Four independent studies published in the Journal of Thoracic Oncology
(JTO) demonstrate that rovalpituzumab tesirine for small-cell lung cancer (SCLC) is not effective against SCLC, casting a pall over the future of
the therapy and closing a door that seemed opened four years ago when
the first study on the therapy was published. The JTO is the official
journal of the International Association for the Study of Lung Cancer.


==========================================================================
An accompanying editorial written by Dr. Dipesh Uprety, Dr. Jordi Remon,
and JTO Editor Dr. Alex A. Adjei, discusses the recent history of the
therapy's clinical trials and suggests some possible reasons why the
drug has not been effective.

According to the editorial, SCLC remains a difficult disease to treat, especially at the time of relapse. Currently, topotecan is among the
most effective, 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 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 the editorial.

But the four studies published in this month's JTO demonstrates that rovalpituzumab tesirine could not displace topotecan as an effective
therapy for SCLC.



==========================================================================
In one study published in the JTO -- "Efficacy and Safety of
Rovalpituzumab Tesirine Compared With Topotecan as Second-Line Therapy
in DLL3-High SCLC: Results From the Phase 3 TAHOE Study," lead author
Dr. Fiona Blackhall, The University of Manchester, Manchester, United
Kingdom, 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." A second study published in
JTO, "A Phase 1-2 Study of Rovalpituzumab Tesirine in Combination With Nivolumab Plus or Minus Ipilimumab in Patients With Previously Treated Extensive-Stage SCLC," the researchers, led by Dr. Jyoti Malhotra, Rutgers Cancer Institute of New Jersey, New Brunswick, N.J., 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 study, "A Phase 1 Study Evaluating Rovalpituzumab Tesirine in Frontline Treatment of Patients with Extensive-Stage SCLC," 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 study "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," by
Dr. Melissa Johnson, from Sarah Cannon Research Institute in Nashville,
Tenn., found that "Because of 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 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.

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.

========================================================================== Story Source: Materials provided by International_Association_for_the_Study_of_Lung_Cancer.

Note: Content may be edited for style and length.


========================================================================== Journal References:
1. 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 DOI: 10.1016/j.jtho.2021.07.012
2. Fiona Blackhall, Kevin Jao, Laurent Greillier, Byoung Chul Cho,
Konstantin Penkov, Noemi Reguart, Margarita Majem, Kristiaan
Nackaerts, Konstantinos Syrigos, Karin Hansen, Wolfgang Schuette,
Jeremy Cetnar, Federico Cappuzzo, Isamu Okamoto, Mustafa Erman,
Seppo W. Langer, Terufumi Kato, Harry Groen, Zhaowen Sun, Yan
Luo, Poonam Tanwani, Laura Caffrey, Philip Komarnitsky, Niels
Reinmuth. 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 DOI: 10.1016/j.jtho.2021.02.009
3. 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 DOI: 10.1016/j.jtho.2021.02.022
4. 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 DOI: 10.1016/j.jtho.2021.06.022
5. Melissa L. Johnson, Zanete Zvirbule, Konstantin Laktionov, Aslaug
Helland, Byoung Chul Cho, Vanesa Gutierrez, Benoi^t 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 DOI: 10.1016/j.jtho.2021.03.012 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/09/210907110650.htm

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